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Medicographia
Vol 31, No. 1, 2009
ISSN 0243-3397
ACE I nhibition as a C ornerstone of
H ypertension T reatment
S. LAURENT, FRANCE
A journal of
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and international
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EDITORIAL
ACE INHIBITION AS A CORNERSTONE OF HYPERTENSION TREATMENT. L’INHIBITION DE L’ENZYME DE
CONVERSION DE L’ANGIOTENSINE, PIERRE ANGULAIRE
DU TRAITEMENT DE L’HYPERTENSION
3
9
C. J. PEPINE, USA
PLEIOTROPIC EFFECTS OF ACE INHIBITORS
B. I. LÉVY, FRANCE
ARE THERE DIFFERENCES BETWEEN THE
RAAS INHIBITORS?
16
R. FERRARI, ITALY
DO ACE INHIBITORS DIFFER, AND IN WHICH WAY?
24
G. M. LONDON, FRANCE
ARTERIAL COMPLIANCE, CENTRAL AORTIC BLOOD
PRESSURE, AND ACE INHIBITION
32
P. ROSSIGNOL AND
F. ZANNAD, FRANCE
COMBINATION STRATEGY BASED ON PERINDOPRIL
FOR THE TREATMENT OF HYPERTENSION: WHAT ARE
THE OPTIONS?
38
P. SEVER,
UNITED KINGDOM
ANGLO-SCANDINAVIAN CARDIAC OUTCOMES
TRIAL–BLOOD PRESSURE LOWERING ARM (ASCOTBPLA): EVIDENCE FOR THE USE OF AN AMLODIPINE-
43
PERINDOPRIL COMBINATION
G. GRASSI AND
G. MANCIA, ITALY
TREATING DIABETIC HYPERTENSIVE PATIENTS: NEW
INSIGHTS FROM THE ADVANCE TRIAL
51
Contents continued overleaf...
Medicographia
Vol 31, No. 1, 2009
I S S U E
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...Contents continued from cover page
ACE I nhibition as a C ornerstone of
H ypertension T reatment
A. DE LA SIERRA, SPAIN / CONTROVERSIAL QUESTION
M. ROSAS PERALTA,
WHAT DETERMINES YOUR CHOICE BETWEEN FREE
MEXICO /
AND FIXED COMBINATIONS IN THE MANAGEMENT OF
R. R. AZAR, LEBANON /
YOUR HYPERTENSIVE PATIENTS?
J. CHIN TAY, SINGAPORE /
T. ECDER, TURKEY /
A. TYKARSKI, POLAND /
J. CHALMERS, AUSTRALIA /
Z. D. KOBALAVA, RUSSIA /
B. TRIMARCO, ITALY /
P. RAMACHANDRAN, INDIA
O. A. ASEEVA, FRANCE
COVERSYL
COVERSYL: AT THE CORE OF CARDIOVASCULAR
57
69
DISEASE PREVENTION AND TREATMENT
J. C. TARDIF AND
K. NAJEM, CANADA
INTERVIEW
ACE INHIBITION AND ATRIAL FIBRILLATION
F. M. TURNBULL,
AUSTRALIA
FOCUS
INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM —
INSIGHTS FROM THE BLOOD PRESSURE LOWERING
TREATMENT TRIALISTS’ COLLABORATION
A. S. HALL,
UNITED KINGDOM
UPDATE
WHAT IS NEW IN THE GENETICS OF THE RENINANGIOTENSIN-ALDOSTERONE SYSTEM?
C. RÉGNIER, FRANCE
D. CAMUS, FRANCE
A TOUCH OF FRANCE
SPICES, DIAMONDS, AND AYURVEDIC MEDICINE:
FRENCH PHYSICIANS IN 17TH-CENTURY MUGHAL
INDIA
A TOUCH OF FRANCE
WEST MEETS EAST: PONDICHERRY AND THE FRENCH
EAST INDIA COMPANY
77
81
87
92
100
E
D I T O R I A L
ACE inhibition as a cornerstone
of hypertension treatment
by S. Laurent, France
A
Stéphane LAURENT, MD, PhD
Department of Pharmacology
and INSERM UMRS 872
Hôpital Européen
Georges Pompidou
Université René Descartes
Paris, FRANCE
Address for correspondence:
Professor Stéphane Laurent, MD,
PhD, Service de Pharmacologie
et INSERM UMRS 872, Hôpital
Européen Georges Pompidou,
20 rue Leblanc,
75015 Paris, France
(e-mail: stephane.laurent@
egp.ap-hop-paris.fr)
Medicographia. 2009;31:3-8.
NGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS WERE
introduced in clinical practice in the 1980s for the treatment of hypertension as the first agents able to block the renin-angiotensin aldosterone system (RAAS). Their effectiveness in reducing elevated
blood pressure (BP) and preventing cardiovascular complications in hypertensive patients is
solidly documented. The first morbidity-mortality trials of ACE inhibitors in hypertension, such
as the Swedish Trial in Old Patients with Hypertension–2 (STOP-HT2) and CAPtopril Prevention
Project (CAPPP) evidenced similar benefits with first-generation ACE inhibitors in comparison
with earlier established antihypertensive agents like the β-blockers and diuretics.1,2 Subsequently, the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT)
reported similar effects with an ACE inhibitor and a thiazide diuretic, despite a greater BP reduction with the later.3 The Blood Pressure Lowering Treatment Trialists’ Collaboration metaanalysis, which included 18 229 patients from six trials of ACE-inhibitor–based therapy, showed
significant reductions in risk of total major cardiovascular events in patients assigned to ACEinhibitor treatment, with risk reductions of 28% in stroke, 20% in coronary heart disease, 22%
in major cardiovascular events, 18% in heart failure, 20% in cardiovascular death, and 12% in
total mortality, in comparison with placebo.4
Pharmacodynamic studies in hypertensive patients have shown that ACE inhibitors are able
to reduce target-organ damage. In particular, ACE inhibitors reduce left ventricular hypertrophy, albuminuria, and arterial damage, which are established intermediate end points for cardiovascular events. Because structural and functional changes in large and small arteries in hypertension, even at the early stages, may affect one or several end organs like the brain, heart,
and kidney, contributing to cardiovascular morbidity and mortality, modern treatment strategies
should not only target BP reduction, but also seek to normalize vascular structure and function.
Several randomized, double-blind, parallel studies, conducted in accordance with Good Clinical
Practice guidelines, have established the efficacy of ACE inhibition with perindopril in reducing
BP, reversing vascular structure and function abnormalities in patients with essential hypertension, and ultimately preventing cardiovascular events. A positive relationship between arterial wall hypertrophy reduction and BP reduction in small resistance arteries has been evidenced
following long-term treatment with perindopril, but not atenolol. Of particular interest is how
the improvement in small artery function in response to structural changes impacts on the coronary circulation. Indeed, in the coronary arterioles, perindopril achieves an increase in coronary
blood flow and coronary reserve, in parallel with a regression of periarteriolar and interstitial
collagen. In large arteries, long-term treatment with perindopril reduces carotid and radial artery
wall hypertrophy, as well as carotid artery internal diameter. These structural changes result in
an improvement in large artery function, with an increase in carotid and brachial arterial distensibility, and normalization of coronary arterial dilation in response to the cold-pressor test or an
increase in blood flow.5,6
In addition to their antihypertensive effect, ACE inhibitors exert direct vascular and cardioprotective effects, which appear to be independent of hemodynamic changes. ACE inhibitors act
by improving the balance between the production of angiotensin II, a potent vasoconstrictor,
and the prevention of bradykinin degradation, a potent stimulator of nitric oxide release.7 Nitric
ACE inhibition as a cornerstone of hypertension treatment – Laurent
MEDICOGRAPHIA, VOL 31, No. 1, 2009
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EDITORIAL
oxide plays a crucial role in attenuating endothelial dysfunction, an early manifestation of atherosclerosis. The effects of ACE inhibitors on smooth muscle cell growth and proliferation, fibrinolysis and thrombogenesis, and endothelial apoptosis may result in antiatherogenic benefits. The
currently available ACE inhibitors exhibit important differences regarding chemical structure,
potency, bioavailability, plasma half-life, distribution, and elimination. Their BP-independent
effects vary depending on their activity on tissue RAAS and their affinity for bradykinin binding
sites versus angiotensin I binding sites.8 This could explain that ACE inhibitors differ in their
effects on nitric oxide production and endothelial apoptosis rate reduction, for a same BP reduction.9 ACE inhibitors are also known to reduce insulin resistance and improve insulin sensitivity, thereby contributing to prevent new-onset diabetes, and thus reduce the risk of micro- and
macroangiopathy.
Several long-term follow-up trials have shown that ACE inhibition exerted BP-independent
effects on large and small arteries. For instance, the Diabetes Artery Perindopril Hypertension
Normalization Excess sTiffness (DAPHNET) study in hypertensive patients with type 2 diabetes
showed that a 6-month treatment with perindopril 8 mg increased carotid distensibility to a
greater extent than perindopril 4 mg, for a similar reduction in ambulatory BP.5 In hypertensives,
a 1-year treatment with perindopril normalized the media-to-lumen ratio of small arteries, whereas atenolol did not.10 These BP-independent effects of ACE inhibitors could confer additional efficacy in terms of prevention of cardiac, cerebrovascular, and renal outcomes.
According to the latest European Society of Hypertension–European Society of Cardiology
(ESH-ESC) Guidelines for the management of arterial hypertension (2007), ACE inhibitors are
recommended as first-line treatment in a vast range of hypertensive patients, especially those with
subclinical organ damage (left ventricular hypertrophy, asymptomatic atherosclerosis, microalbuminuria, or renal dysfunction); cardiovascular events (previous myocardial infarction (MI), heart
failure, recurrent atrial fibrillation, end-stage renal disease or proteinuria); and various clinical
conditions (metabolic syndrome, diabetes mellitus).11 ACE inhibitors display the highest range
of proven benefits in terms of long-term total risk of cardiovascular morbidity and mortality,
which, according to the ESH/ESC guidelines is the primary goal of antihypertensive treatment.
Whether ACE inhibitors provide better cardiovascular protection than angiotensin-receptor blockers (ARBs) has been intensely debated. Four years ago, Verma and Strauss challenged
the protective effects of ARBs against coronary events in general and myocardial infarction (MI)
in particular, and suggested that ARBs may increase MI.12 These authors reviewed various data
suggesting that the deleterious effect of ARBs could occur through AT2 receptor stimulation,
which, under certain circumstances, could mediate growth promotion, fibrosis, and hypertrophy, as well as proatherogenic and proinflammatory effects.12 The first direct, head-to-head comparison between an ACE inhibitor and an ARB was the recent ONgoing Telmisartan Alone and
in combination with Ramipril Global Endpoint Trial (ONTARGET). This study showed that despite a more specific blockade of RAAS, ARBs are not superior to ACE inhibitors in reducing fatal and nonfatal cardiovascular events.13 The most recent meta-analysis, performed on 6 large
clinical trials including the ONTARGET trial, and gathering 49 924 patients, showed that ARBs
were as effective as ACE inhibitors regarding the risk of MI.14
ACE inhibitors with a long duration of action and an improved tolerability profile, such as
ramipril, perindopril, and trandolapril, ensure effective and well-tolerated long-term treatment
both in monotherapy and in combination. The resulting long-term BP lowering is a major factor
in the reduction in cardiovascular events in several major morbidity-mortality trials, such as the
Heart Outcomes Prevention Evaluation (HOPE) study, the EUropean trial on Reduction Of coronary events with Perindopril in stable coronary Artery disease (EUROPA), and the Prevention of
Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial.15-17 An indirect demonstration of the major role played by the improvement in large artery function in the reduction in
cardiovascular events has been reported in patients with end-stage renal disease. In these patients, perindopril decreased pulse wave velocity independently of BP changes, resulting in a
highly significant relative risk reduction in all-cause and cardiovascular mortality.18 In addition,
the multifactorial antiatherosclerotic profile of perindopril suggests a beneficial effect not only
in hypertensive patients, but also in patients with established coronary heart disease or previous
stroke as has been demonstrated in the EUROPA and the Perindopril pROtection aGainst Recurrent Stroke Study (PROGRESS) trials.16,19
In the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOTBPLA), modern combination treatment, based on amlodipine/perindopril, was shown to be significantly more effective in reducing all-cause and cardiovascular mortality, stroke, total cardio4
MEDICOGRAPHIA, VOL 31, No. 1, 2009
ACE inhibition as a cornerstone of hypertension treatment – Laurent
EDITORIAL
vascular events and procedures, and in the prevention of new-onset diabetes, in comparison with
conventional treatment based on a β-blocker and a thiazide diuretic.20 The Conduit Artery Function Evaluation (CAFE) substudy of ASCOT-BPLA sheds light on the pathophysiological mechanisms that underlie the differences in clinical outcomes.21 In CAFE, treatment with amlodipine/
perindopril resulted in a significantly greater reduction in central aortic pressures in comparison with β-blocker/thiazide diuretic treatment, despite a similar reduction in brachial pressure.
In turn, central aortic pressures appears to better correlate with cardiovascular outcomes than
peripheral, including brachial, pressures. This finding underscores the importance of not only
targeting brachial BP reduction, but also normalizing vascular structure and function, which,
when impaired, affect end organs (brain, heart, kidneys) and contribute to cardiovascular morbidity and mortality.
More recently, in the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation (ADVANCE) trial in patients with diabetes mellitus, perindopril in combination with a metabolically neutral diuretic indapamide showed a reduction in total and cardiovascular mortality, a composite end point of macro- and microvascular events, as well as in
coronary and renal outcomes.22 These effects of the perindopril/indapamide combination were
not confounded by initial BP levels or concomitant use of other treatments.
As most hypertensive patients need more than one drug to achieve their BP target, ACE inhibitors, which are effective antihypertensive drugs with pleiotropic effects, should be considered as a cornerstone of combination treatment. As such, perindopril both in monotherapy and
in combination with indapamide or amlodipine, can claim the largest number of large clinical
trials showing a significant reduction in cardiovascular events in a vast range of hypertensive
patients.16,19-22 REFERENCES
1. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised
trial. Lancet. 1999;353:611-616.
2. Hansson L, Lindholm LH, Ekbom T. Randomised trial of old
and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish trial in old patients
with hypertension-2 study. Lancet. 1999;354:1751-1756.
3. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme
inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack
Trial (ALLHAT). JAMA. 2002;288:2981-2997.
4. Blood Pressure Lowering Treatment Trialists’ Collaboration.
Effects of different blood-pressure-lowering regimens on major
cardiovascular events: results of prospectively-designed overviews
of randomised trials. Lancet. 2003;362:1527-1535.
5. Tropeano AI, Boutouyrie P, Pannier B, Joannides R, Balkestein
E, Katsahian S, Laloux B, Thuillez C, Struijker-Boudier H, Laurent S. Brachial pressure-independent reduction in carotid stiffness after long-term angiotensin-converting enzyme inhibition
in diabetic hypertensives. Hypertension. 2006;48:1-7
6. Antony I, Lerebours G, Nitenberg A. Angiotensin-converting
enzyme inhibition restores flow-dependent and cold pressor testinduced dilations in coronary arteries of hypertensive patients.
Circulation. 1996;94:3115-3122.
7. Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998;97:1411-1420.
8. Ceconi C, Francolini G, Olivares A, Comini L, Bachetti T, Ferrari R. Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic
ACE. Eur J Pharmacol. 2007;577:1-6.
9. Ceconi C, Francolini G, Bastianon D, Gitti G.L, Comini L, Ferrari R. Differences in the effect of angiotensin-converting enzyme
inhibitors on the rate of endothelial cell apoptosis: in vitro an in
vivo studies. Cardiovasc Drugs Ther. 2007;21:423-429.
10. Thybo NK, Stephens N, Cooper A, et al. Effects of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. Hypertension. 1995;25:474-481.
11. The Task Force for the Management of Arterial Hypertension
of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2007 Guidelines for the management of arterial hypertension. Eur Heart J. 2007;28:1462-1536.
12. Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ. 2004;329:1248–1249.
13. The ONTARGET Investigators. Telmisartan, ramipril, or both
in patients at high risk for vascular events. N Engl J Med. 2008;
358:1547-1559.
14. Reboldi G, Angeli F, Cavallini C, Gentile G, Mancia G, Verdecchia P. Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis. J Hypertens.
2008;26:1282-1289.
15. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor,
ramipril, on cardiovascular events in high-risk patients. N Engl J
Med. 2000;342:145-153.
16. The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of
perindopril in reduction of cardiovascular events among patients
with stable coronary artery disease: randomised, double-blind,
placebo-controlled, multicentre trial (the EUROPA study). Lancet.
2003;362:782-788.
17. The PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med.
2004;351:2058-2068.
18. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation. 2001;103:987-922.
19. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-perssure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack.
Lancet. 2001;358:1033-1041.
20. Dahlöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes
Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-906.
21. Williams B, Lacy PS, Thom SM, et al. Differential impact of
blood pressure-lowering drugs on central aortic pressure and clinical outcomes. Principal Results of the Conduit Artery Function
Evaluation (CAFÉ) study. Circulation. 2006;113:1213-1225.
22. ADVANCE Collaborative Group. Effects of a fixed combination
of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the
ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:
829-840.
Keywords: renin-angiotensin-aldosterone system; angiotensin-converting enzyme inhibitor; perindopril;
pleiotropic effects; guidelines; evidence-based medicine
ACE inhibition as a cornerstone of hypertension treatment – Laurent
MEDICOGRAPHIA, VOL 31, No. 1, 2009
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ÉDITORIAL
L’inhibition de l’enzyme de conversion
de l’angiotensine, pierre angulaire
du traitement de l’hypertension
par S. Laurent, France
L
ES INHIBITEURS DE L’ENZYME DE CONVERSION DE L’ANGIOtensine (IEC), qui sont apparus en pratique clinique dans les années 1980 pour le traitement de l’hypertension, ont constitué les
premiers médicaments permettant de bloquer le système rénineangiotensine-aldostérone. Leur efficacité dans la réduction de l’hypertension et la prévention des
complications cardio-vasculaires est abondamment documentée. Les premiers essais de morbidité et de mortalité menés sur les IEC dans l’hypertension, par exemple l’étude STOP-HT2
(Swedish Trial in Old Patients with Hypertension–2) et l’étude CAPPP (CAPtopril Prevention Project), ont montré que les IEC de première génération induisaient des bénéfices similaires à ceux
obtenus par les agents antihypertenseurs précédemment établis, tels les bêtabloquants et les
diurétiques.1,2 Par la suite, l’étude ALLHAT (Antihypertensive and Lipid-Lowering treatment to
prevent Heart Attack Trial) a mis en évidence la comparabilité des effets entre un IEC et un diurétique thiazidique, malgré la réduction plus importante de la pression artérielle (PA) obtenue
avec ce dernier.3 La méta-analyse Blood Pressure Lowering Treatment Trialists’ Collaboration,
qui a porté sur 18 229 patients ayant participé à 6 études effectuées sur des traitements à base
d’IEC, a montré des réductions significatives des risques d’événements cardio-vasculaires majeurs chez les patients recevant un traitement à base d’IEC. Les réductions des risques par rapport au placebo ont été de 28 % pour les accidents vasculaires cérébraux, 20 % pour les coronaropathies, 22 % pour les événements cardio-vasculaires majeurs, 18 % pour l’insuffisance
cardiaque, 20 % pour les décès cardio-vasculaires et 12 % pour la mortalité totale.4
Les études pharmacodynamiques menées chez des patients hypertendus ont montré que
les IEC permettaient de réduire les lésions des organes cibles. Plus particulièrement, les IEC ont
réduit l’hypertrophie ventriculaire gauche, l’albuminurie, et les lésions artérielles, qui sont des
critères intermédiaires établis pour les événements cardio-vasculaires. Dans la mesure où les
altérations structurelles et fonctionnelles des artères de grand et de petit calibre dans l’hypertension, même dès les stades précoces, risquent d’affecter un ou plusieurs organes cibles comme
le cerveau, le cœur et le rein, aggravant la morbidité et la mortalité cardio-vasculaires, les stratégies thérapeutiques modernes doivent non seulement cibler une réduction de la PA, mais également viser à normaliser la structure et de la fonction vasculaires. Plusieurs études parallèles
randomisées et en double aveugle effectuées conformément aux directives des Bonnes Pratiques
Cliniques ont établi l’efficacité de l’inhibition de l’enzyme de conversion par le perindopril pour
la réduction de la PA, la correction des anomalies structurelles et fonctionnelles vasculaires chez
les patients atteints d’hypertension essentielle et, finalement, la prévention des événements cardio-vasculaires. Une relation positive entre la réduction de l’hypertrophie des parois artérielles
et la réduction de la PA dans les artères à faible résistance a été mise en évidence après un traitement à long terme par le perindopril, mais n’a pas été retrouvée avec l’aténolol. Il est particulièrement intéressant de considérer l’impact sur la circulation coronaire de l’amélioration de
la fonction des petites artères en réponse aux changements structurels. Ainsi, il apparaît que,
dans les artérioles coronaires, le perindopril entraîne une augmentation du débit sanguin coronaire et de la réserve coronaire, parallèlement à une régression du collagène périartériolaire
et interstitiel. Dans les artères de grand diamètre, un traitement à long terme par le perindopril réduit l’hypertrophie de la paroi des artères carotides et radiales, ainsi que le diamètre in6
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Les IEC, pierres angulaires du traitement de l’hypertension – Laurent
ÉDITORIAL
terne des artères carotides. Ces changements structurels entraînent une amélioration de la fonction des grandes artères, qui s’accompagne d’une augmentation de la distensibilité des artères
carotides et brachiales et d’une normalisation de la dilatation des artères coronaires en réponse
à l’épreuve du froid ou à une augmentation du débit artériel.5,6
Outre leur effet antihypertenseur, les IEC exercent des effets vasculaires directs et cardioprotecteurs, qui semblent être indépendants des changements hémodynamiques. Les IEC agissent en améliorant l’équilibre entre la production d’angiotensine II, un vasoconstricteur puissant,
et la prévention de la dégradation de la bradykinine, un stimulateur puissant de la libération
de monoxyde d’azote.7 Le monoxyde d’azote joue un rôle essentiel dans l’atténuation du dysfonctionnement endothélial, une manifestation précoce de l’athérosclérose. Les effets des IEC
sur la croissance et la prolifération des cellules musculaires lisses, la fibrinolyse et la thrombogenèse, ainsi que sur l’apoptose endothéliale pourraient entraîner des bénéfices anti-athérogènes. Les IEC actuellement disponibles présentent d’importantes différences quant à leur structure chimique, leur puissance, leur biodisponibilité, leur demi-vie plasmatique, leur distribution
et leur élimination. Leurs effets indépendants de la PA varient en fonction de leur activité sur le
système rénine-angiotensine-aldostérone tissulaire et leur affinité pour les sites de liaison de la
bradykinine par rapport aux sites de liaison de l’angiotensine I.8 Ces mécanismes pourraient
expliquer pourquoi les IEC présentent ces différences dans leurs effets sur la production de monoxyde d’azote et la réduction du taux d’apoptose endothéliale, pour une même réduction de
la PA.9 Il a également été établi que les IEC réduisaient l’insulinorésistance et amélioraient la
sensibilité à l’insuline, contribuant ainsi à prévenir les nouveaux cas de diabète, et réduisant
le risque de micro- et macroangiopathie.
Plusieurs études de suivi à long terme ont montré que l’inhibition de l’enzyme de conversion
exerçait des effets indépendants de la PA sur les artères de faible et de grand calibre. Ainsi,
l’étude DAPHNET (Diabetes Artery Perindopril Hypertension Normalization Excess sTiffness)
effectuée chez des patients hypertendus atteints de diabète de type 2 a montré qu’un traitement
de 6 mois par le perindopril à la posologie de 8 mg augmentait de façon plus importante la
distensibilité des carotides qu’à la posologie de 4 mg, pour une réduction similaire de la PA
ambulatoire.5 Chez les sujets hypertendus, un traitement d’un an par le perindopril a permis de
normaliser le rapport média/lumière des petites artères, ce qui n’a pas été le cas de l’aténolol.10
Ces effets indépendants de la PA exercés par les IEC pourraient conférer une efficacité supplémentaire quant à la prévention des événements cardiaques, vasculaires cérébraux et rénaux.
Les dernières directives de la Société européenne d’hypertension et de la Société européenne
de cardiologie (European Society of Hypertension – European Society of Cardiology, ESH-ESC)
concernant la prise en charge de l’hypertension artérielle (2007) recommandent d’utiliser les
IEC comme traitement de première intention chez une large variété de patients hypertendus,
en particulier lorsqu’ils présentent des lésions organiques subcliniques (hypertrophie ventriculaire gauche, athérosclérose asymptomatique, microalbuminurie ou dysfonctionnement rénal) ; des événements cardio-vasculaires (antécédents d’infarctus du myocarde (IDM), insuffisance cardiaque, fibrillation auriculaire récurrente, insuffisance rénale de stade terminal ou
protéinurie) ; ou différentes affections cliniques (syndrome métabolique, diabète sucré).11 Les IEC
apportent la gamme la plus importante de bénéfices démontrés en ce qui concerne le risque total de morbidité et de mortalité cardio-vasculaires à long terme, qui constitue, selon les directives de l’ESH/ESC, l’objectif principal d’un traitement antihypertenseur.
Il a été longuement débattu pour déterminer si les IEC apportaient une meilleure protection cardio-vasculaire que les antagonistes des récepteurs de l’angiotensine II (ARA). Il y a 4 ans,
Verma et Strauss, examinant les effets protecteurs des ARA sur les événements coronaires en
général et l’infarctus du myocarde (IDM) en particulier, ont suggéré que les ARA pouvaient augmenter l’IDM.12 Ces auteurs ont analysé un certain nombre de données suggérant que les effets
délétères des ARA pourraient résulter de la stimulation des récepteurs AT2 , qui, dans certaines
circonstances, assureraient la médiation de la promotion de la croissance, de la fibrose et de l’hypertrophie, ainsi que d’effets pro-athérogènes et pro-inflammatoires.12 La première comparaison bilatérale directe effectuée entre un IEC et un ARA a été la récente étude ONTARGET
(ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). Cette
étude a montré que, malgré un blocage plus spécifique du système rénine-angiotensine-aldostérone, les ARA n’étaient pas supérieurs par rapport aux IEC pour la réduction des événements
cardio-vasculaires fatals et non fatals.13 La méta-analyse la plus récente, effectuée sur 6 études
cliniques à grande échelle (y compris l’étude ONTARGET), qui a porté sur 49 924 patients, a
montré que les ARA étaient aussi efficaces que les IEC en ce qui concerne le risque d’IDM.14
Les IEC, pierres angulaires du traitement de l’hypertension – Laurent
MEDICOGRAPHIA, VOL 31, No. 1, 2009
7
ÉDITORIAL
Les IEC présentant une longue durée d’action et un profil de tolérance amélioré, comme le
ramipril, le perindopril et le trandolapril, permettent d’assurer un traitement à long terme efficace et bien toléré à la fois en monothérapie et en association. La réduction à long terme de
la PA obtenue est un facteur majeur de réduction des événements cardio-vasculaires, comme
cela a été démontré dans plusieurs études majeures de morbidité et de mortalité, notamment
l’étude HOPE (Heart Outcomes Prevention Evaluation), l’étude EUROPA (EUropean trial on Reduction Of coronary events with Perindopril in stable coronary Artery disease), et l’étude PEACE
(Prevention of Events with Angiotensin Converting Enzyme Inhibition).15-17 Une démonstration
indirecte du rôle majeur joué par l’amélioration de la fonction des grandes artères dans la réduction des événements cardio-vasculaires a été fournie chez des patients atteints d’insuffisance
rénale au stade terminal. Chez ces patients, le perindopril a diminué la vitesse de l’onde du pouls
aortique indépendamment des modifications de la PA, entraînant une réduction du risque relatif hautement significative de la mortalité cardio-vasculaire et de toute cause.18 En outre, le
profil anti-athéroscléreux multifactoriel du perindopril suggère l’existence d’un effet bénéfique
non seulement chez les patients hypertendus, mais également chez les patients atteints de coronaropathies établies ou présentant des antécédents d’accidents vasculaires cérébraux,
comme cela a été démontré dans les études EUROPA et PROGRESS (Perindopril pROtection
aGainst Recurrent Stroke Study).16,19
Dans l’étude ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm), une association thérapeutique moderne, regroupant l’amlodipine et le perindopril,
s’est avérée être significativement plus efficace pour réduire la mortalité cardio-vasculaire et la
mortalité de toute cause, les accidents vasculaires cérébraux, les événements cardio-vasculaires
totaux et les procédures, ainsi que dans la prévention des nouveaux cas de diabète, par rapport
à un traitement conventionnel utilisant un bêtabloquant et un diurétique thiazidique.20 La sousétude CAFE (Conduit Artery Function Evaluation) de l’étude ASCOT-BPLA a mis en lumière les
mécanismes physiopathologiques sous-jacents permettant d’expliquer les différences des résultats cliniques.21 Dans la sous-étude CAFE, le traitement par l’association amlodipine/perindopril a entraîné une réduction significativement supérieure des pressions aortiques centrales
par rapport au traitement par le bêtabloquant et le diurétique thiazidique, malgré une réduction similaire de la pression de l’artère brachiale. En outre, les pressions aortiques centrales
semblent montrer une meilleure corrélation avec les résultats cardio-vasculaires que les pressions périphériques, notamment de l’artère brachiale. Ce résultat souligne l’importance non
seulement de cibler une réduction de la PA brachiale, mais également de normaliser la structure et la fonction vasculaires, qui, lorsqu’elles sont altérées, affectent les organes cibles (cerveau, cœur, reins) et contribuent à la morbidité et à la mortalité cardio-vasculaires.
Plus récemment, dans l’étude ADVANCE (Action in Diabetes and Vascular disease: PreterAx
and DiamicroN MR Controlled Evaluation) réalisée chez des patients atteints de diabète, le perindopril en association avec un diurétique métaboliquement neutre, l’indapamide, a entraîné une
réduction de la mortalité cardio-vasculaire et totale (un paramètre composite des événements
macro- et microvasculaires), ainsi que des événements coronaires et rénaux.22 Ces effets de l’association perindopril/indapamide n’ont pas été modifiés par les facteurs de confusion représentés par les valeurs initiales de la PA ou utilisation concomitante d’autres traitements.
Dans la mesure où la plupart des patients hypertendus nécessitent plusieurs médicaments
pour atteindre leurs valeurs cibles de PA, les IEC, en raison de leur efficacité antihypertensive
et des effets pléiotropes dont ils sont doués, doivent être considérés comme la pierre angulaire
des associations thérapeutiques. À cet égard, le perindopril, tant en monothérapie qu’en association avec l’indapamide ou l’amlodipine, peut revendiquer le nombre le plus important d’études
cliniques à grande échelle ayant démontré une réduction significative des événements cardiovasculaires chez une large variété de patients hypertendus.16,19-22 8
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Les IEC, pierres angulaires du traitement de l’hypertension – Laurent
ACE INHIBITION
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
ngiotensin-converting enzyme (ACE) inhibitors were introduced over two decades
ago for the management of hypertension,
but since then they have been increasingly recognized to have important accessory or pleiotropic effects that extend well beyond those expected from
blood pressure (BP) reduction. These pleiotropic effects include: decreased heart failure symptoms and
hospitalizations associated with important effects
on remodeling, neuroprotection, improved glycemic
control, reduction in renal dysfunction (microvascular), reduction in atherothrombotic events, and
more recently reduced frequency of atrial fibrillation (AF) and possibly aortic aneurysm formation.
The purpose of this themed paper is to review the
clinical evidence supporting these pleiotropic effects
of ACE inhibition and review the possible mechanisms responsible for these beneficial effects. Since
this is one area where the clinical findings lead the
basic science, it is appropriate to begin with the clinical trial results that initiated this very important
area of investigation.
A
Carl J. PEPINE, MD, MACC, FAHA
Eminent Scholar Emeritus
Professor of Medicine
Division of Cardiovascular Medicine
University of Florida College of Medicine
Gainesville, Fla, USA
Pleiotropic effects of
ACE inhibitors
by C. J. Pepine, USA
Trials examining effects
of ACE inhibition
Studies in patients with left ventricular
linical trials document that angiotensin-converting enzyme (ACE) inhibitors improve cardiovascular morbidity and mortality in patients with
hypertension, heart failure, left ventricular dysfunction, acute myocardial infarction, and more recently in patients with stable coronary artery disease without left ventricular dysfunction, as well as those with dysglycemia and
atrial fibrillation. Recent data also suggest improved arterial stiffness and reduced aortic aneurysm in Marfan syndrome. Pleiotropic effects of ACE inhibitors might be responsible for prevention of coronary disease–related adverse
outcomes seen in meta-analyses in comparison with angiotensin receptor blockers. Also, reduced insulin resistance and improved insulin sensitivity have been
associated with prevention of new-onset diabetes in patients treated by ACE
inhibitors in comparison with diuretics and -blockers. Accumulating evidence
indicates that ACE inhibitors have direct vascular and myocardial protective
effects that may explain their benefits. These effects, beyond those expected from
blood pressure lowering, might also vary between individual ACE inhibitors,
being dependent on tissue penetration and potency for tissue ACE and other
characteristics. ACE inhibitors improve the balance between production of angiotensin II, a potent vasoconstrictor, and prevention of degradation of bradykinin, the latter being a potent stimulator of nitric oxide release. Angiotensin II
has detrimental effects on vascular function and structure, while nitric oxide
plays a crucial role in attenuation of endothelial dysfunction, an early manifestation of atherosclerosis. The effects of ACE inhibitors on smooth muscle cell
growth and proliferation, fibrinolysis, and thrombogenesis, as well as endothelial apoptosis, may result in antiatherothrombotic benefits in excess of those
expected from blood pressure lowering alone.
C
Medicographia. 2009;31:9-15.
(see French abstract on page 15)
Keywords: angiotensin-converting enzyme inhibitor; pleiotropic effect;
cardiovascular morbidity and mortality; hypertension; coronary artery
disease; heart failure; diabetes; atherosclerosis; angiotensin II; bradykinin;
nitric oxide
www.medicographia.com
Address for correspondence: Carl J. Pepine, MD, Eminent Scholar, AHA – Suncoast Chapter Chair,
Professor of Medicine, Division of Cardiovascular Medicine, 1600 SW Archer Road/Box 100277,
Gainesville, FL 32610-0277 (e-mail: [email protected]; Web site: www.medicine.ufl.edu)
Pleiotropic effects of ACE inhibitors – Pepine
dysfunction
The ACE inhibitors were introduced for hypertension and shortly thereafter for symptomatic relief
in heart failure. But then in Studies Of Left Ventricular Dysfunction (SOLVD) combined trials1 we observed an unanticipated reduction in acute myocardial infarction (MI). It is important to understand
that the SOLVD project participants were mostly
chronic coronary artery disease (CAD) patients with
asymptomatic left ventricular (LV) dysfunction. We
were attempting to prevent progression of LV dysfunction to symptomatic heart failure, hospitalization, and death. Data on acute MI were captured
because of concern that ACE-inhibition–related BP
lowering may have the potential to provoke MI. Instead, we observed a highly significant reduction in
the occurrence of MI with enalapril. Shortly thereafter in the Survival And Ventricular Enlargement
(SAVE) trial,2 captopril use was associated with reduction in nonfatal MI by about a quarter in highrisk post MI patients.
Then a series of four trials in almost 100 000 patients showed that ACE inhibition started in the
acute phase (0 to 36 h) of MI and continued for 4 to
6 weeks reduced early mortality.3 These observations
led to studies of vascular biology of the renin-angiotensin-aldosterone system (RAAS) in CAD patients specifically attempting to explain these protective findings of ACE inhibition. Because systemic
evidence that the RAAS was activated in patients
with LV dysfunction, it was reasoned that ACE inhibition would not be effective without LV dysfunction. Yet, we had observed that coronary artery endothelial dysfunction that underlies atherosclerosis
could be modified by ACE inhibition in the Trial on
Reversing ENdothelial Dysfunction (TREND) in patients without LV dysfunction.4 These effects were
confirmed by others and it was also observed that
MEDICOGRAPHIA, VOL 31, No. 1, 2009
9
ACE I
NHIBITION
SELECTED
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
ABBREVIATIONS AND ACRONYMS
ACE
AF
Ang II
ARB
AT1 , AT2
BP
CAD
CV
EC
EUROPA
angiotensin-converting enzyme
atrial fibrillation
angiotensin II
angiotensin receptor blocker
angiotensin II type 1 and type 2 receptors
blood pressure
coronary artery disease
cardiovascular
endothelial cell
EURopean trial On reduction of cardiac events with
Perindopril in stable coronary Artery disease
HOPE
Heart Outcomes Prevention Evaluation
INVEST
INternational VErapamil SR–trandolapril STudy
MI
myocardial infarction
PC
progenitor cell
PCI
percutaneous coronary intervention
PEACE
Prevention of Events with Angiotensin-Converting
Enzyme inhibition
PERTINENT PERindopril-Thrombosis, InflammatioN, Endothelial
dysfunction and Neurohormonal activation Trial
QUIET
QUinapril Ischemic Event Trial
RAAS
renin-angiotensin-aldosterone system
SAVE
Survival And Ventricular Enlargement
SMC
smooth muscle cell
SOLVD
Studies Of Left Ventricular Dysfunction
TREND
Trial on Reversing ENdothelial Dysfunction
ACE expression was upregulated in atherosclerotic
plaque and colocalized with low-density lipoprotein
(LDL) cholesterol.5-7 This evidence supported the
notion that ACE expression and angiotensin II
(Ang II) were involved in plaque instability, which
was responsible for progression and acute atherothrombotic events.
Studies in patients without LV dysfunction
or acute MI
The forgoing findings provided the background for
a series of trials attempting to modify acute coronary events with ACE inhibition. The QUinapril Ischemic Event Trial (QUIET) was the first attempt to
test the hypothesis that prolonged ACE inhibition
would reduce the morbidity and mortality associated with CAD.8 Unfortunately, this trial suffered
from numerous design issues, being the initial
trial to address this important question. Very important was clinical revascularization as a component of the primary outcome. During the course of
the trial it became evident that percutaneous coronary intervention (PCI) was evolving as a practice
option rather than a reliable indicator of disease
progression. Coronary revascularization was highly prevalent in both treatment groups (38.6%). This
resulted in a lack of power to detect differences in
the more objective events (cardiovascular [CV]
death, 1.5% and MI, 4.6%), which comprised the
other components of the primary outcome cluster
of events. The secondary outcome, death, MI, and
resuscitated cardiac arrest, showed an interesting
trend suggesting an approximately 13% relative
risk reduction for ACE inhibition (Figure 1). The
10
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Heart Outcomes Prevention Evaluation (HOPE)
used a higher-risk population (placebo CV mortality 8.1% vs 1.5% in QUIET), more extended followup (5 vs 2.25 years), a more appropriate cluster
of events as the primary outcome (death, MI, or
stroke), and a much more appropriate sample size
(9297 vs 1750).9 In HOPE, ACE inhibition with
ramipril 10 mg daily reduced MI risk by about 20%,
stroke by 33%, and CV mortality by 25% in highrisk patients without clinical heart failure or a reduced ejection fraction (Figure 1). Subsequently,
the EURopean trial On reduction of cardiac events
with Perindopril in stable coronary Artery disease
(EUROPA) confirmed that perindopril 8 mg daily
in CAD patients without heart failure reduced CV
mortality, nonfatal MI, and resuscitated cardiac arrest by 20% (Figure 1).10 Nonfatal MI alone was reduced 22%. In contrast, the Prevention of Events
with Angiotensin-Converting Enzyme inhibition
(PEACE) trial failed to show benefit with trandolapril 4 mg daily in CAD patients without heart failure or LV dysfunction (Figure 1).11 However, as in
QUIET, the PEACE population was at lower risk for
CV death and MI (than either HOPE or EUROPA)
and had a relative low compliance rate with study
medication. But perhaps also important, coronary
revascularization was the major contributor (19.1%)
to the cluster of events chosen for the primary outcome. This revascularization outcome issue was
similar in QUIET,8 and again since revascularization
was used frequently in both treatment groups (19%)
PEACE was underpowered.
An overview analysis of these 4 trials in a total of
31 555 patients (136 882 patient-years follow-up)
with stable vascular disease without LV systolic dysfunction or heart failure has confirmed that ACE
inhibition significantly reduces risk for all-cause
mortality, CV mortality, nonfatal MI, stroke, need
for PCI or coronary artery bypass surgery, and hospitalization for congestive heart failure, but not for
hospitalization for angina.12 Occurrence of new-onset diabetes was also significantly reduced. They
estimated that treating about 100 patients for about
4.5 years would prevent 1 death, 1 nonfatal MI, 1
CV death, or 1 coronary revascularization. Treating
about 50 patients for this duration would prevent
1 MI (fatal and nonfatal) or 1 new case of diabetes.
The exact magnitude of the contribution of BP
reduction from ACE inhibition to these improved
outcomes remains controversial. In HOPE, mean
systolic BP/diastolic BP reductions were 3/2 mm Hg
and in EUROPA, 5/2 mm Hg, respectively. Clearly,
BP reduction plays a role, but detailed analyses indicate that the improvement in outcomes exceeded
that predicted from BP lowering alone.13 Furthermore, metaregression analyses, that include hypertension trials, confirm that outcomes in patients
receiving ACE inhibitors are better than would be
expected from BP lowering alone.14 A recent metaregression analysis of 140 000 subjects comparing
ACE inhibitor and Ang II receptor blocker (ARB)
trials concluded that ACE inhibition had a 9%
greater effect on the reduction of MI and CV death,
and benefits independent of BP reduction.15 Interestingly, with the ARBs, similar BP-independent ef-
Pleiotropic effects of ACE inhibitors – Pepine
ACE I
NHIBITION
fects were not observed and a suggestion of increased
MI was noted. As a consequence of the above studies, guidelines for the management of MI, heart failure hypertension, and diabetes recommend that
ACE inhibition be considered in patients at a very
high risk for recurrent vascular events.
Other areas
Insulin resistance (dysglycemia) and diabetes
development
Hypertension, heart failure, CAD, and CV risk factors like obesity, inactivity, etc, are major risk conditions for insulin resistance and development of
type 2 diabetes, which is becoming epidemic. This
knowledge has led to the concept of a continuum
for hyperglycemia ranging from prediabetes to the
development of new-onset diabetes. Furthermore,
8
A
CORNERSTONE
QUIET
HOPE
CV death/MI/stroke
20
13% RRR
HR=0.87 (0.59- 1.29)
Placebo
Quinalapril
20 mg
1
0
Figure 1. Summary of outcomes for trials with ACE
inhibition in patients with
or at high risk for CAD and
no evidence for LV dysfunction or heart failure. Note
that secondary outcome is
shown for QUIET since this
more closely resembled the
primary outcomes for HOPE
and EUROPA. The primary
out come for QUIET closely
resembles the primary outcome for PEACE. Based on
data from references 8-11.
10
Ramipril
10 mg
5
0
0
1
2
3
0
1
2
EUROPA
CV death/MI/CABG/PCI
30
20% RRR
HR=0.80 (0.71- 0.91)
P=0.0003
Patients (%)
Perindopril
8 mg
0
Placebo
4% RRR
HR=0.96 (0.88 -1.06)
P=0.43
Placebo
10
5
4
PEACE
CV death/MI/cardiac arrest
15
3
Time (years)
Time (years)
Patients (%)
HYPERTENSION TREATMENT
Placebo
22% RRR
HR=0.78 (0.70- 0.86)
P<0.001
15
Patients (%)
3
OF
based vs atenolol-based strategy (P<0.01). Characteristics associated with diabetes risk included place
of residence (in the USA), LV hypertrophy, previous
stroke/transient ischemic attack, Hispanic ethnicity, prior coronary revascularization, hypercholesterolemia, increased body mass index, and higher
follow-up systolic BP (Figure 2, page 12). Addition
of trandolapril to verapamil SR decreased diabetes
risk and addition of hydrochlorothiazide to atenolol
was associated with a dose-dependent increase in
diabetes risk. We concluded that clinical findings
associated with more severe vascular disease and
Hispanic ethnicity identify a subgroup of patients
at high risk for developing diabetes, whereas lower
on-treatment BP and treatment with a calcium antagonist–ACE inhibition strategy attenuated this
risk. Thus, the latter strategy should be preferred
among patients at high risk for diabetes.
CV death/MI/cardiac arrest
5
Patients (%)
AS
20
Trandolapril
4 mg
10
0
0
1
2
3
4
5
Time (years)
we found in the INternational VErapamil SR-trandolapril STudy (INVEST) that the presence of diabetes in patients with CAD is associated with approximately a doubling in risk for death, MI, or
stroke.16 Interest in prevention of diabetes among
patients with CV disease has been stimulated by the
understanding that certain drugs contribute to diabetes risk. In INVEST,17 a calcium antagonist–based
(verapamil-SR) and a β-blocker–based (atenolol)
strategy were compared with control BP in over
16 000 CAD patients without diabetes who were
followed for adverse outcomes.18 During follow up,
we observed approximately 400/year cases of new
diabetes, and overall risk for newly diagnosed diabetes was reduced by 15% in the verapamil SR–
Pleiotropic effects of ACE inhibitors – Pepine
0
1
2
3
4
5
6
Time (years)
Abbreviations: see box page 10.
Modified after references 8-11:
Pitt B, O'Neill B, Feldman R, et
al. Am J Cardiol. 2001;87:10581063. © Elsevier, Inc; Yusuf S,
Sleight P, Pogue J, Bosch J,
Davies R, Dagenais G; Heart Outcomes Prevention Evaluation
Study Investigators. N Engl J Med.
2000;342:145-153. © Massachusetts
Medical Society; Fox KM; EURopean trial On reduction of cardiac
events with Perindopril in stable
coronary Artery disease Investigators. Lancet. 2003;362:782-788.
© Elsevier, Ltd;Braunwald E,
Domanski MJ, Fowler SE, et al.
N Engl J Med. 2004;351:2058-2068.
© Massachusetts Medical Society.
Recently, Elliott and Meyer,19 using a networkbased meta-analysis of 22 BP-lowering trials that
included 143 153 nondiabetic participants, confirmed that ACE-inhibitor use was associated with
a 30% reduction in risk (P=0.0001) for new diabetes compared with diuretic use. The risk for developing diabetes was very similar comparing a diuretic and a β-blocker. The odds ratios for reduction
in new diabetes did not differ significantly between
an ACE inhibitor and an ARB. These findings have
very important adverse outcome implications considering the long-term duration of hypertension
treatment, as emphasized by others.20-23 Recently,
glucose levels have also been associated with risk
for developing AF.24
MEDICOGRAPHIA, VOL 31, No. 1, 2009
11
NHIBITION
Incidence (%) of
patients developing diabetes
12
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
1.8
Incidence (%)
Hazard ratio (P<0.001)
10
1.6
1.4
8
1.2
1.0
6
0.8
4
0.6
0.4
2
0
Estimated hazard ratio
ACE I
0.2
<120
Patients who developed
diabetes (n)
79
Total patients
1270
120 to
<130
285
4842
130 to 140 to
<140
<150
SBP (mm Hg)
372
5313
276
2728
150
0.0
222
2023
Figure 2. Relation between follow-up systolic blood pressure (SBP) and diabetes development shows relative hazard for follow-up SBP (mean of measurements before
diabetes development or censoring) with reference (hazard ratio=1.0) for 120 mm Hg.
An SBP <120 mm Hg is associated with a 6.2% incidence of new diabetes, whereas
an SBP 150 mm Hg is associated with an 11.0% incidence of new diabetes. From
the stepwise model, an SBP=150 mm Hg is associated with 53% excess risk for diabetes compared with SBP=120 mm Hg.
Modified after reference 18: Cooper-Dehoff R, Cohen JD, Bakris GL, et al. Predictors of development of
diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (findings
from the INternational VErapamil SR-Trandolapril STudy [INVEST]). Am J Cardiol. 2006;98:890-894.
© 2006, Elsevier Inc.
Atrial fibrillation
AF is another CV epidemic, affecting 5% of individuals aged >65 years, and is associated with increased
risk of stroke and a doubling of mortality. Evidence
in experimental models and patients suggests that
RAAS inhibition may reduce the incidence of newonset AF and also AF recurrence. A recent metaanalysis of 11 studies concluded that RAAS inhibition (ACE inhibition or ARB) was associated with
reduced AF risk by 28% (Figure 3).25 Another study
suggests that combination of perindopril and lowdose amiodarone is more effective than amiodarone
alone for prevention of AF recurrence in lone paroxysmal AF.26 Adding perindopril to amiodarone also
inhibited left atrial enlargement in this group of
patients. In these studies, the incidence of new AF
was low, so a more definitive answer to the question
whether patients without LV dysfunction benefit
with reduced episodes of AF will require completion of several ongoing trials (second Canadian Trial on Atrial Fibrillation [CTAF-2],27 Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention
of Vascular Events [ACTIVE-I],28 etc). At present it
appears that ACE inhibitors and ARBs clearly prevent AF.
Large artery stiffness, aortic aneurysm,
and Marfan syndrome
Weakening of the aorta wall leads to progressive
dilation (eg, aneurysm formation), which is often
not diagnosed, but as the diameter exceeds 5.5 cm,
risk for rupture increases markedly. Treatment for
aneurysms >5.5 cm is surgical, with or without endovascular repair, and better therapies are needed
to prevent enlargement of aneurysms <5 cm. In rat
12
MEDICOGRAPHIA, VOL 31, No. 1, 2009
models, ACE inhibition suppressed development
of aortic aneurysms,29,30 and in aneurysm patients,
ACE inhibition was associated with decreased stiffness and greater collagen turnover, both of which
are favorable as increased stiffness is a risk factor
for adverse events.31 In a recent case-control study,
ACE inhibition, but not β-blockers, calcium antagonists, thiazides, or ARBs, was associated with reduced risk of abdominal aortic aneurysm rupture.32
Although the number of patients using ARBs was
small, their surprising lack of effect in reducing
aneurysm formation has also been reported in animal studies. 29,30 This finding suggests that ACEinhibition–related protective effects on aneurysm
formation and enlargement may be mediated by
other angiotensin receptor subtypes, or production
of other RAAS peptides, and/or reduced bradykinin
degradation.33 Perindopril reduced both aortic stiffness and diameter in Marfan syndrome patients
taking β-blockers, possibly through attenuation of
transforming growth factor (TGF)-β signaling.34
These are clearly very important findings, and large
clinical trials are needed to assess the benefit of ACE
inhibition in Marfan syndrome and other aortic
aneurysm patients.
What is the mechanism responsible
for these pleiotropic effects
of ACE inhibition?
Endothelial function
In the clinical circumstances reviewed above, there
is evidence that tissue ACE expression is increased,
local Ang II is increased, and that signaling through
both the angiotensin type-1 (AT1) and type-2 (AT2)
receptor pathways contributes to the vascular disease processes. A unifying theme is that prolonged
periods of oxidative stress result in dysfunction at
the endothelial (EC) and smooth muscle cell (SMC)
level, and also within the monocular cells residing
in the vessel wall and bone marrow–derived vascular progenitor cells (PCs). Oxidative stress arises
from a number of conditions (oxidized LDL cholesterol, increased BP, smoking, hyperglycemia, etc),
which produce reactive oxygen species that cannot be adequately quenched by our antioxidant systems. Excess oxidative stress shifts the balance in
physiologic state that exists to maintain processes
involved in vascular tone, cell growth, and proliferation, coagulation, platelet aggregation, inflammation, etc. These processes are, in part, mediated
via local Ang II production acting via AT1 receptors to activate NADH/NADPH oxidase, producing
superoxide anion. At the EC and SMC level, superoxide anion reduces bioavailability of nitric oxide
(NO) and also produces peroxynitrite, which is a
potent oxidant. Ang II also releases endothelin and
norepinephrine. These actions result in cellular
dysfunction. Ang II stimulates SMC migration and
replication and cardiomyocyte hypertrophy as well
as plasminogen activator (PA) inhibitor (PAI)-1 synthesis to alter fibrinolytic balance (tissue [t]-PA/
PAI-1 ratio). The overall vascular effect is to enhance
tone (activate SMC contraction), promote inflammation (induce expression of monocyte chemotac-
Pleiotropic effects of ACE inhibitors – Pepine
ACE I
NHIBITION
tic protein [MCP]-1, vascular cell adhesion molecule
[VCAM], tissue necrosis factor [TNF]-α, interleukin
[IL]-6 and activate monocytes/macrophages, stimulate remodeling [induce platelet-derived growth
factor (PDGF)], basic fibroblast growth factor
[bFGF] insulin-like growth factor [IGF]-1, TGF-β
expression to stimulate matrix glycoprotein/metalloproteinase production) and trigger thrombosis
(activate platelets/increase aggregation/adhesion).35
ACE plays a key role in the above, via production
of circulating and tissue Ang II acting at several
specific receptors. Inhibition of ACE (eg, ACE inhibitors) decreases local Ang II production and blocks
bradykinin degradation. The importance of this
mechanism has been documented in studies showing that it permits ACE inhibition to lower BP in
patients with low-renin hypertension. Others have
directly confirmed that bradykinin contributes to
short-term effects of ACE inhibitors on BP in both
normotensive and hypertensive persons.36 Improved
endothelial function in response to ACE inhibition
is muted when a bradykinin B2 receptor blocker is
coadministered.37,38 ACE inhibition results in a shift
in the PAI/tPA ratio to favor local fibrinolysis.39,40
In the PERindopril-Thrombosis, InflammatioN,
Endothelial dysfunction and Neurohormonal activation Trial (PERTINENT) substudy of EUROPA,
abnormal endothelial function was documented by
elevated von Willebrand factor (vWf) measurements
in a subgroup of 1200 patients, and the level correlated with CV events.41 The occurrence of CV events
was related to vWf level at entry. Furthermore, vWF
levels significantly decreased after 1 year of perindopril treatment. Multivariable analysis confirmed
that changes in vWf levels were related to this ACEinhibition treatment effect. Additionally, perindopril increased protein expression/activity of EC NO
synthase and reduced apoptosis coincident with
significant reduction in Ang II, an increase in bradykinin and reduction in TNF-α, and an increase nitrite/nitrate. All of these effects likely contributed
to the clinical benefit documented in EUROPA.
Vascular progenitor cells and vascular repair
New data suggest the regenerative potential of endothelial PCs and modulation of RAAS for remodeling/repairing defects of the vasculature. The concentration of PCs in the blood has an inverse
relationship to the risk factor profile,42 and the presence and severity of CAD.43,44 Reduced levels of circulating endothelial PCs independently predict adverse cardiac events.45-47 The ability of bone marrow
to generate enough numbers of functional PCs to
provide adequate vascular repair of injury that is
mediated by risk conditions is likely critical to the
expression of CAD.48 Data linking endothelial dysfunction with low PC levels49 suggest that ongoing
endothelial damage may lead to bone marrow depletion, resulting in insufficient repair or adverse
remodeling of injured arteries, while a competent
response may stabilize or fully repair the injury.
This EC-mediated function is lost early in the
course of vascular injury due to a variety of inciting
factors (risk conditions). ECs play an important regulatory role in the coronary microcirculation and
Pleiotropic effects of ACE inhibitors – Pepine
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
where tissue-based components of the RAAS are
synthesized29,50 NO and other EC-derived vasodilators (prostaglandin I2 [PGI2], endothelial-derived
hyperpolarizing factor [EDHF], bradykinin, etc)
offset constrictive effects of Ang II generated by tissue-based ACE and other endothelium-derived constrictive factors (endothelin, etc). When ECs are
damaged, the microvessels and macrovessels rapid-
Favors treatment
ACE inhibitors
CAPP
GISSI
HOPE
SOLVD
STOP-H2
TRACE
Ueng
Van Den Berg
Subtotal
Captopril
Lisinopril
Ramipril
Enalapril
Enalapril
Trandolapril
Enalapril
Lisinopril
ARBs
CHARM
LIFE
Madrid
ValHeFT
Subtotal
Candesartan
Losartan
Irbesartan
Valsartan
Favors control
Total
0.1
0.2
1
2
0.5
RR (random)
95% CI
5
Figure 3. Summary of meta-analysis for renin-angiotensin-aldosterone system (RAAS)
inhibition with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in suppressing atrial fibrillation. Both approaches to modulation
of the RAAS are associated with reduction in atrial fibrillation of similar magnitude.
Acronyms of studies: CAPP, CAptopril Prevention Project; CHARM, Candesartan in Heart failure Assessment in Reduction of Mortality; GISSI; Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico; HOPE, Heart Outcomes Prevention Evaluation; LIFE, Losartan Intervention For Endpoint reduction in hypertension; SOLVD, Studies Of Left Ventricular Dysfunction; STOP-H2, Swedish
Trial in Old Patients with Hypertension–2; TRACE, TRANdolapril Cardiac Evaluation; Val-HeFT, Valsartan–Heart Failure Trial.
Modified after reference 26: Yin Y, Dalal D, Liu Z, et al. Prospective randomized study comparing amiodarone vs. amiodarone plus losartan vs. amiodarone plus perindopril for the prevention of atrial fibrillation recurrence in patients with lone paroxysmal atrial fibrillation. Eur Heart J. 2006;27:1841-1846.
© 2007, Oxford University Press.
ly lose their ability to dilate appropriately via endothelium-dependent pathways.51 Hence, even metabolic-induced arteriolar dilation may not provide
sufficient increase in coronary flow when dysfunctional ECs do not provide mediators for shear-related vasodilation.52
Treating CAD patients with ACE inhibition (ramipril, 5 mg/day) for only 4 weeks resulted in a 3fold increase in circulating endothelial PC number
and improved function (eg, migration, proliferation,
adhesion, and in vitro vasculogenesis capacity).53
Type 2 diabetics treated with Ang II type 1 (AT1) receptor blockade (olmesartan, 40 mg/day or placebo) for 12 weeks increased circulating CD34+ progenitor cells.54 These results were verified in a second
trial treating type 2 diabetic patients with another
AT1 blocker (irbesartan, 300 mg/day) for 12 weeks.
With AT1 receptor blockade (irbesartan) endothelial
PC number increased significantly after 4 weeks
and continued at 12 weeks. In contrast, in patients
treated with other antihypertensive agents to reduce BP to similar levels, similar effects on endothelial PCs were not observed. Exposure of cultured
endothelial PC to Ang II significantly accelerates
MEDICOGRAPHIA, VOL 31, No. 1, 2009
13
ACE I
NHIBITION
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
rates of senescence and leads to impairment of proliferative activity.55 Ang II-induced endothelial PC
senescence is inhibited by pretreatment with either
AT1 receptor blockade (valsartan) or adding superoxide dismutase. Ang II significantly diminishes
telomerase activity, which critically influences cellular senescence, although the effect was significantly reduced by pretreatment with either AT1 receptor blockade or superoxide dismutase.
All of these studies suggest that Ang II accelerates endothelial PC dysfunction through induction
of oxidative stress, and that attenuation of the RAAS
provides vascular benefit through improvement in
vascular repair via PCs.
Glucose metabolism
The specific mechanisms responsible for ACE-inhibitor–related improvement in insulin resistance
(dysglycemia) and reduced diabetes development
are incompletely understood. Hyperglycemia decreases bioavailability of NO and PGI2 while increasing synthesis of vasoconstrictor prostanoids and
endothelin. ACE inhibition acts to counter many
of these effects in hyperglycemia to improve vascular function. Clearly improved vascular function,
mostly at the microvascular level, is important, involving skeletal muscle, the kidney, and probably
even the pancreas. Also, maintenance of intracellular potassium, particularly the ATP-sensitive potassium channel, is important, but is unlikely to be
the only mechanism.
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Atrial fibrillation
Potential mechanisms for ACE-inhibition and ARB
prevention of AF include: (i) direct modulation of
ionic channels; (ii) hemodynamic improvement;
(iii) reduction of atrial stretching; and (iv) suppression of atrial fibrosis.56 Similarly, improved atrial
endocardial function has been proposed by the
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Summary
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and possibly ARBs alters pathological processes contributing to atherosclerosis and atherothrombosis.
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Blood-pressure reduction and cardiovascular risk in HOPE study.
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386-392.
15. Turnbull F, Neal B, Algert C, et al. Effects of different blood
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16. Bakris GL, Gaxiola E, Messerli FH, et al. Clinical outcomes
in the diabetes cohort of the INternational VErapamil SR-Trandolapril study. Hypertension. 2004;44:637-642.
17. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a noncalcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized
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18. Cooper-Dehoff R, Cohen JD, Bakris GL, et al. Predictors of development of diabetes mellitus in patients with coronary artery
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19. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:
201-207.
20. Verdecchia P, Reboldi G, Angeli F, et al. Adverse prognostic
significance of new diabetes in treated hypertensive subjects. Hypertension. 2004;43:963-969.
21. Verdecchia P, Angeli F, Reboldi G. New-onset diabetes, anti-
Pleiotropic effects of ACE inhibitors – Pepine
ACE I
NHIBITION
hypertensive treatment, and outcome. Hypertension. 2007;50:
459-460.
22. Aksnes TA, Kjeldsen SE, Rostrup M, Omvik P, Hua TA, Julius S.
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trial population. Hypertension. 2007;50:467-473.
23. Held C, Gerstein HC, Yusuf S, et al. Glucose levels predict
hospitalization for congestive heart failure in patients at high
cardiovascular risk. Circulation. 2007;115:1371-1375.
24. Varughese GI, Tahrani AA, Scarpello JH. The putative link between glycemic control and cardiac arrhythmias. Arch Intern
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25. Salehian O, Healey J, Stambler B, et al. Impact of ramipril on
the incidence of atrial fibrillation: results of the Heart Outcomes
Prevention Evaluation study. Am Heart J. 2007;154:448-453.
26. Yin Y, Dalal D, Liu Z, et al. Prospective randomized study comparing amiodarone vs. amiodarone plus losartan vs. amiodarone
plus perindopril for the prevention of atrial fibrillation recurrence
in patients with lone paroxysmal atrial fibrillation. Eur Heart J.
2006;27:1841-1846.
27. Tardif JC, Talajic M. Perindopril and prevention of atrial fibrillation. European Heart Journal. 2007;9:E25-E29.
28. Connolly S, Yusuf S, Budaj A, et al. Rationale and design of
ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for
prevention of vascular events. Am Heart J. 2006;151:1187-1193.
29. Liao S, Miralles M, Kelley BJ, Curci JA, Borhani M, Thompson
RW. Suppression of experimental abdominal aortic aneurysms
in the rat by treatment with angiotensin-converting enzyme inhibitors. J Vasc Surg. 2001;33:1057-1064.
30. Nagashima H, Uto K, Sakomura Y, et al. An angiotensin-converting enzyme inhibitor, not an angiotensin II type-1 receptor
blocker, prevents beta-aminopropionitrile monofumarate-induced aortic dissection in rats. J Vasc Surg. 2002;36:818-823.
31. Wilmink AB, Vardulaki KA, Hubbard CS, et al. Are antihypertensive drugs associated with abdominal aortic aneurysms?
J Vasc Surg. 2002;36:751-757.
32. Hackam DG, Thiruchelvam D, Redelmeier DA. Angiotensinconverting enzyme inhibitors and aortic rupture: a populationbased case-control study. Lancet. 2006;368:659-665.
33. Heeneman S, Sluimer JC, Daemen MJ. Angiotensin-converting enzyme and vascular remodeling. Circ Res. 2007;101:441-454.
34. Ahimastos AA, Aggarwal A, D’Orsa KM, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients
with Marfan syndrome: a randomized controlled trial. JAMA.
2007;298:1539-1547.
35. Dzau VJ. Theodore Cooper Lecture: Tissue angiotensin and
pathobiology of vascular disease: a unifying hypothesis. Hypertension. 2001;37:1047-1052.
36. Azizi M, Chatellier G, Guyene TT, Murieta-Geoffroy D,
Menard J. Additive effects of combined angiotensin-converting
enzyme inhibition and angiotensin II antagonism on blood
pressure and renin release in sodium-depleted normotensives.
Circulation. 1995;92:825-834.
37. Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect
of bradykinin-receptor blockade on the response to angiotensinconverting-enzyme inhibitor in normotensive and hypertensive
subjects. N Engl J Med. 1998;339:1285-1292.
38. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation. 1997;95:1115-1118.
39. Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace
FJ, Pfeffer MA. Effects of ramipril on plasma fibrinolytic balance
in patients with acute anterior myocardial infarction. HEART
Study Investigators. Circulation. 1997;96:442-447.
40. Vaughan DE, Brown NJ. Effects of acute angiotensin II type 1
receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation. 2000;102:E43.
41. Ceconi C, Fox KM, Remme WJ, et al. ACE inhibition with
perindopril and endothelial function. Results of a substudy of the
EUROPA study: PERTINENT. Cardiovasc Res. 2007;73:237-246.
42. Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely
correlate with risk factors for coronary artery disease. Circ Res.
2001;89:E1-E7.
43. Kunz GA, Liang G, Cuculi F, et al. Circulating endothelial progenitor cells predict coronary artery disease severity. Am Heart J.
2006;152:190-195.
44. Guven H, Shepherd RM, Bach RG, Capoccia BJ, Link DC. The
number of endothelial progenitor cell colonies in the blood is increased in patients with angiographically significant coronary
artery disease. J Am Coll Cardiol. 2006;48:1579-1587.
45. Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial
progenitor cells and cardiovascular outcomes. N Engl J Med.
Pleiotropic effects of ACE inhibitors – Pepine
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A
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2005;353:999-1007.
46. Schmidt-Lucke C, Rossig L, Fichtlscherer S, et al. Reduced
number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation. 2005;111:
2981-2987.
47. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl
J Med. 2003;348:593-600.
48. Zengin E, Chalajour F, Gehling UM, et al. Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development. 2006;133:1543-1551.
49. Werner N, Wassmann S, Ahlers P, et al. Endothelial progenitor cells correlate with endothelial function in patients with
coronary artery disease. Basic Res Cardiol. 2007;102:565-571.
50. Rubanyi GM. The role of endothelium in cardiovascular
homeostasis and diseases. J Cardiovasc Pharmacol.1993;22(suppl 4):S1-S14.
51. Lüscher TF, Richard V, Tschudi M, Yang ZH, Boulanger C.
Endothelial control of vascular tone in large and small coronary
arteries. J Am Coll Cardiol. 1990;15:519-527.
52. Liao JC, Kuo L. Interaction between adenosine and flow-induced dilation in coronary microvascular network. Am J Physiol.
1997;272:H1571-H1581.
53. Min TQ, Zhu CJ, Xiang WX, Hui ZJ, Peng SY. Improvement
in endothelial progenitor cells from peripheral blood by ramipril
therapy in patients with stable coronary artery disease. Cardiovasc Drugs Ther. 2004;18:203-209.
54. Bahlmann FH, de Groot K, Mueller O, Hertel B, Haller H,
Fliser D. Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension. 2005;45:526-529.
55. Imanishi T, Hano T, Nishio I. Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress. J Hypertens. 2005;23:97-104.
56. Serra JL, Bendersky M. Atrial fibrillation and renin-angiotensin system. Ther Adv Cardiovasc Dis. 2008;2:215-223.
57. Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysm: pathogenesis and implications for management.
Arterioscler Thromb Vasc Biol. 2006;26:2605-2613.
EFFETS
PLÉIOTROPES DES
IEC
es études cliniques ont démontré que les inhibiteurs de l’enzyme de
conversion (IEC) amélioraient la morbi-mortalité cardio-vasculaire chez
les patients atteints d’hypertension, d’insuffisance cardiaque, de dysfonction du ventricule gauche, d’infarctus aigu du myocarde et plus récemment,
chez les patients coronariens stables sans dysfonction ventriculaire gauche ou
ceux présentant des troubles de la régulation glycémique ou une fibrillation
auriculaire. Des résultats récents sont aussi en faveur d’une amélioration de la
rigidité artérielle et d’une diminution de l’anévrysme aortique dans le syndrome
de Marfan. Les métaanalyses comparant les inhibiteurs des récepteurs de l’angiotensine et les IEC montrent que les effets pléiotropes de ces derniers pourraient être à l’origine de la prévention des événements indésirables de la maladie coronaire. De même, les IEC, comparés aux diurétiques et aux bêtabloquants,
préviendraient l’apparition d’un diabète en réduisant la résistance à l’insuline
et en améliorant la sensibilité à l’insuline. De plus en plus de données montrent
que les IEC ont un effet protecteur direct vasculaire et myocardique qui pourrait expliquer leurs avantages. Ces effets au-delà de ceux attendus d’une baisse
de la pression artérielle peuvent varier d’un IEC à l’autre, selon leur potentiel
de pénétration tissulaire et d’affinité pour l’enzyme de conversion tissulaire ou
d’autres caractéristiques. Les IEC améliorent l’équilibre entre la production
d’angiotensine II, vasoconstricteur puissant, et la dégradation de la bradykinine, puissant stimulant de la libération de monoxyde d’azote. L’angiotensine II
altère la structure et la fonction vasculaires alors que le monoxyde d’azote joue
un rôle fondamental dans l’atténuation de la dysfonction endothéliale, manifestation précoce de l’athérosclérose. L’effet des IEC sur la croissance et la prolifération des cellules musculaires lisses et sur la fibrinolyse et la thrombogenèse
comme sur l’apoptose endothéliale, peuvent entraîner des bénéfices anti-athérothrombotiques supérieurs à ceux attendus d’une simple baisse de pression
artérielle.
L
MEDICOGRAPHIA, VOL 31, No. 1, 2009
15
ACE INHIBITION
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
Bernard I. LÉVY, MD, PhD
Cardiovascular Research Center INSERM U689
Department of Noninvasive Investigations
Hôpital Lariboisière
Paris, FRANCE
Are there differences
between the RAAS inhibitors?
by B. I. Lévy, France
he renin-angiotensin-aldosterone system
(RAAS) plays a major role in the systemic regulation of cardiovascular and renal homeostasis. Furthermore, there is now increasing evidence
that RAAS may affect the normal and pathological
vascular system through its action on fibrosis, angiogenesis, cellular proliferation, apoptosis, and in-
T
he role of the tissue renin-angiotensin-aldosterone system (RAAS) is complex because renin is synthesized in the kidney, but also in other tissues,
including brain, adrenal gland, ovary, visceral adipose tissue, heart, and
blood vessels. Similarly, the primary source of systemic circulating angiotensinogen is the liver, but angiotensinogen mRNA expression has also been detected in the kidney, brain, heart, blood vessels, adrenal gland, ovary, placenta, and
adipose tissue. Two main angiotensin II (Ang II) receptors have been identified.
AT1 (Ang II type 1 receptor) transactivates growth pathways and mediates major Ang II effects such as vasoconstriction, increased cardiac contractility, renal sodium reabsorption, cell proliferation, vascular and cardiac hypertrophy,
inflammatory response, oxidative stress, angiogenesis, as well as being antiapoptotic. AT2 (Ang II type 2 receptor) is believed to induce opposite effects, including vasodilation and antigrowth and antihypertrophic effects. There is evidence, however, that signaling via AT2 can be proangiogenic in the retinal vessels
and result in cardiovascular proliferation. The RAAS can be blocked at different
levels by angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor
blockers (ARBs), and direct renin inhibitors, all of which exhibit experimental
and clinical differences. Most antihypertensive drugs improve cardiovascular
risk in relation with the degree of blood pressure reduction. However, inhibition
of the RAAS achieves additional beneficial effects beyond the lowering of blood
pressure. ACE inhibitors and ARBs have different biological and therapeutic
effects in hypertensive patients, as well as in diabetic (hypertensive or normotensive) patients and patients with heart failure. The available evidence suggests that ACE inhibitors are more effective in this respect than ARBs. In practice, as a clinical guideline, it is proposed that ACE inhibitors be used first line
to block the RAAS, while ARBs should be considered as an alternative in patients
who cannot tolerate ACE inhibitors.
T
Medicographia. 2009;31:16-23.
(see French abstract on page 23)
Keywords: angiotensin; bradykinin; vasomotion; renin-angiotensin-aldosterone
system; AT1 and AT2 receptors
www.medicographia.com
Address for correspondence: Prof Bernard Lévy, INSERM U689, 41, Bd de la Chapelle,
75010 Paris, France (e-mail: [email protected])
16
MEDICOGRAPHIA, VOL 31, No. 1, 2009
flammation. Recently, a significant role has been
shown for endothelial cell apoptosis resulting from
oxidative stress, the latter possibly related to the
abnormal activation of membrane-bound reduced
nicotinamide dinucleotide phosphate (NADPH) oxidase by angiotensin II (Ang II).1 Ang II–derived O2
is an important signaling component of the classic effects of Ang II.2 There has been substantial
progress in the understanding of the relationship
between Ang II, activation of the AT1 subtype receptor of angiotensin II (AT1 ), and NADPH oxidase
production of O2.
It is now possible to block the RAAS at several levels, resulting in different biological and therapeutic
effects. Three classes of drugs inhibiting the RAAS
are currently available for the treatment of hypertension. This review discusses: (i) recent insights
into the biology of the RAAS; (ii) the main therapeutic classes of RAAS inhibitors, as well as their
biological and clinical effects; and (iii) the differences in clinical results obtained with these RAAS
inhibitors.
The renin-angiotensin-aldosterone system
The renin-angiotensin aldosterone system (RAAS)
hormonal cascade starts with the synthesis of renin
by the juxtaglomerular cells that line the afferent
arteriole of the renal glomerulus (Figure 1). Renin
is synthesized as a preprohormone, and mature (active) renin is formed by a proteolytic process. MaSELECTED
ACE
Ang II
ARB
AT1,
AT2, etc
CHF
MI
NO
RAAS
ABBREVIATIONS
angiotensin-converting enzyme
angiotensin II
angiotensin receptor blocker
angiotensin II type 1, 2, etc, receptors
congestive heart failure
myocardial infarction
nitric oxide
renin-angiotensin-aldosterone system
Are there differences between the RAAS inhibitors? – Lévy
ACE I
NHIBITION
AS
CORNERSTONE
A
Figure 1. The renin-angiotensin-aldosterone
system (RAAS) hormonal cascade.
Abbreviations: ACE, angiotensin-converting enzyme;
Ang, angiotensin; AT1 R, AT2 R, etc, angiotensin II type 1, 2, etc,
receptor; MAS, MAS oncogene; NEP neutral endopeptidase;
PEP, prolyl-endopeptidase; tPA, tissue plasminogen activator.
ture renin is stored in granules of the juxtaglomerular cells and is released in the systemic circulation
by an exocytic process. Active renin secretion is regulated principally by 4 interdependent factors: (i) a
baroreceptor mechanism in the afferent glomerular
arteriole reacting to changes in renal arterial perfusion pressure; (ii) changes in the urinary outflow
of NaCl sensed by the macula densa cells of the distal tubule, close to the juxtaglomerular cells; (iii)
sympathetic nerve stimulation via β1-adrenergic
receptors; and (iv) negative feedback by a direct
action of Ang II on the juxtaglomerular cells.3 Thus,
renin secretion is stimulated by a fall in perfusion
pressure or in NaCl delivery, and/or by an increase
in sympathetic activity. Renin is also synthesized in
other tissues, including brain, adrenal gland, ovary,
and visceral adipose tissue, and perhaps heart and
vascular tissue. The factors regulating the synthesis and possible actions of renin in these other tissues are poorly understood.
Renin regulates the initial, rate-limiting step of
the RAAS by cleaving the N-terminal portion of a
large-molecular-weight globulin, angiotensinogen,
to form the biologically inert decapeptide Ang I or
Ang-(1-10). The primary source of systemic circulating angiotensinogen is the liver, but angiotensinogen mRNA expression has also been detected in
many other tissues, including kidney, brain, heart,
vascular, adrenal gland, ovary, placenta, and adipose
tissue.4 Angiotensinogen is secreted constitutively
by the liver, so that plasma levels are generally stable and do not undergo acute changes; however,
both hepatic and extrahepatic synthesis have been
shown to rise in response to glucocorticoids, estrogens and other sex steroids, thyroid hormone, inflammatory cytokines (eg, interleukin-1 and tumor
necrosis factor), and Ang II.
The inactive decapeptide Ang I is hydrolyzed by
angiotensin-converting enzyme (ACE) to form the
biologically active octapeptide Ang II [Ang-(1-8)].
ACE is a membrane-bound exopeptidase, which is
localized on the plasma membranes of various cell
types, including vascular endothelial cells, microvillar brush border epithelial cells (renal proximal
tubule cells), and neuroepithelial cells. It is this
membrane-bound ACE that is thought to be physiologically important. ACE (first known as kininase II) metabolizes a number of other peptides,
including the vasodilator peptides bradykinin and
kallidin, to inactive metabolites (Figure 2, page 18).5
Thus, functionally, the enzymatic actions of ACE
potentially result in increased Ang II and decreased
bradykinin concentrations and thus in increased
vasoconstriction and decreased vasodilation.
The majority of Ang II effects are mediated by the
AT1 receptor. The AT1 receptor is expressed in many
adult tissues, including blood vessels, adrenal cortex,
liver, kidney, and brain.6,7 A second receptor encoded by a different gene, the AT2 receptor, is predom-
Are there differences between the RAAS inhibitors? – Lévy
OF
HYPERTENSION TREATMENT
Angiotensinogen (1-12)
Elastase
Kallikrenin
tPA
Cathepsin G
Renin
Ang I (1-10)
ACE2
Chymase
Carboxypeptidase ACE
Cathepsin
AT1 R
Ang II (1-8)
ACE2
Proinflammatory
Proangiogenic
Trophic
Na retention
AT2 R
Vasodilation
Antangiogenic
Trophic?
Antitrophic?
AT3 R
Angiotensin-(1-9)
PEP
NEP
ACE, NEP
Ang- (1-7)
MAS-receptor
Ang III (2-8)
Ang IV (3-8)
Vasodilation
Antitrophic
Antiangiogenic
Natriuresis
ACE
Ang- (1-5)
Unknown
Function?
AT4 R
Proinflammatory
Proangiogenic
Proliferative
inantly expressed during fetal life, but is present
at a lower level in a few adult tissues such as the
adrenal medulla, uterus, and ovarian follicle.8 The
two Ang II receptors, both of which belong to the
superfamily of G-protein–coupled receptors, have
different signaling pathways and different functions.9 The AT1 receptor transactivates growth pathways and mediates major Ang II effects such as vasoconstriction, increased cardiac contractility, renal
tubular sodium reabsorption, cell proliferation, vasSTUDY
ACRONYMS
AIRE
CAPPP
CHARM
Acute Infarction Ramipril Efficacy
CAPtopril Prevention Project
Candesartan in Heart failure Assessment in Reduction of
Mortality
CONSENSUS COoperative North Scandinavian ENalapril SUrvival Study
HOPE
Heart Outcomes Prevention Evaluation
IDNT
Irbesartan in Diabetic Nephropathy Trial
LIFE
Losartan Intervention For Endpoint reduction in
hypertension
ONTARGET ONgoing Telmisartan Alone and in combination with
Ramipril Global Endpoint Trial
OPTIMAAL OPtimal Trial In Myocardial infarction with Angiotensin II
Antagonist Losartan
PEACE
Prevention of Events with Angiotensin-Converting
Enzyme inhibition
RENAAL
Reduction of Endpoints in Noninsulin-dependent diabetes
mellitus with Angiotensin II Antagonist Losartan
SAVE
Survival And left Ventricular Enlargement
SOLVD
Studies Of Left Ventricular Dysfunction
TRACE
TRAndolapril Cardiac Evaluation
Val-HeFT
Valsartan–Heart Failure Trial
VALIANT
VALsartan In Acute myocardial iNfarcTion
VALUE
VAlsartan antihypertensive Long-term Use Evaluation
V-HeFT-II
Vasodilator-Heart Failure Trial II
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cular and cardiac hypertrophy, inflammatory responses, and oxidative stress angiogenesis, as well
as being antiapoptotic.10 The AT2 receptor is believed
to induce essentially opposite effects, including vasodilation and antigrowth and antihypertrophic effects,11 and to play a significant role in blood pressure (BP) regulation. There is evidence, however,
that signaling via the AT2 receptor induces proangiogenic effects in the retinal vessels12 and antiangiogenic effects in the skeletal muscle.13 The MAS
oncogene is another RAAS receptor, which binds
the Ang-(1-7) peptide.14 Ang-(1-7) may be generated directly from Ang II by the enzymatic activity of
ACE2 (an exopeptidase that catalyses the conversion
of angiotensin I to the nonapeptide angiotensin[19]), or from Ang I, via Ang-(1-9), a pathway that involves both ACE2 and ACE.15 ACE2 is present in a
many tissues with high concentrations in the heart,
kidney, and gastrointestinal track. Ang-(1-7) appears to have an inhibitory influence on many of
BK1 R
Inactive protein
ACE
Proinflammatory
Proangiogenic
Bradykinin
BK2 R
Vasodilator
Anti-inflammatory
Proangiogenic
Figure 2. Metabolization of bradykinin to inactive protein by angiotensinconverting enzyme.
Abbreviations: ACE, angiotensin-converting enzyme; BK1, 2 R, bradykinin 1 and 2 receptors.
the events induced by Ang II. Ang-(1-7) has depressor, vasodilator, apoptotic, and antiproliferative actions.16 Ang-(1-7) is suggested to inhibit angiogenesis, although further investigations are needed to
confirm these effects in a wider range of patho/
physiological conditions. In contrast, Ang-(1-7) may
mimic some actions of Ang II such as the release
of prostanoids, and also increase proliferation of
some cells, such as epidermal stem cells after injury17 and hematopoietic progenitors in the bone
marrow of myelosuppressed mice.18 The variety of
physiological responses to the RAAS reflects that of
the peptides and receptors and the different signaling pathways they induce.
It is generally thought that the physiologic role
of tissue RAAS is complementary to the classic circulating RAAS and serves as a mechanism for the
longer-term maintenance of balance or homeostasis at the tissue level between opposing effects mediated by this system (eg, growth promotion and
inhibition in the heart and vasculature). Pathophysiological processes might hypothetically occur when
components of the RAAS are overexpressed or inhibited, thus disturbing the intricate balance of this
regulatory system.
Ang II, via the AT1 receptor, also stimulates the
production of aldosterone by the zona glomerulosa
of the adrenal cortex. Aldosterone is a major regulator of sodium and potassium balance and thus
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plays a major role in regulating extracellular volume. It enhances the reabsorption of sodium and
water in the distal tubules and collecting ducts and
thus promotes potassium excretion. Ang II and the
extracellular potassium levels are the major regulators of aldosterone.
Inhibitors of the RAAS
Angiotensin-converting enzyme inhibitors
Early studies performed in the 1960s showed that
peptides from the venom of a Brazilian viper inhibited kinase II, an enzyme that facilitates degradation of bradykinin, and which was later shown to
be identical to ACE.19
The first of the orally active ACE inhibitors, captopril, included a sulfhydryl-containing amino acid
to serve as ligand for the zinc moiety. Numerous
side effects of captopril, such as proteinuria, skin
rashes, and altered taste, were attributed to the sulfhydryl group, subsequent work led to the development of ACE inhibitors that replaced this group
with a carboxyl group (eg, lisinopril, benazepril,
quinapril, ramipril, perindopril, cilazapril, trandolapril) or phosphoryl group (fosinopril).20 The presence of the carboxyl group conferred greater lipophilicity, which actually improved binding to ACE
as well as tissue penetration.21 ACE inhibitors competitively block the action of ACE and thus the conversion of Ang I to Ang II, thereby reducing circulating and local levels of Ang II. ACE inhibitors also
decrease aldosterone secretion and sympathetic
nerve activity. Short-term ACE-inhibitor therapy is
associated with a decrease in Ang II and aldosterone
and an increase in renin release and Ang I. There
is evidence, however, that over the long term ACE
inhibition may be associated with a return of Ang II
and aldosterone to baseline levels (“ACE escape”)—
perhaps, it is proposed, through activation of the
so-called alternate pathways (Figure 1).22,23 Because
ACE inhibitors all are competitive inhibitors of the
enzyme, it is possible that increased levels of Ang I
(provoked by the compensatory increase in plasma
renin activity due to loss of negative feedback inhibition) can tend to partially overcome the blockade.24 In general, short-term pharmacodynamic
responses to decreases in Ang II through inhibition
of ACE include dose-dependent reductions in cardiac preload and afterload, with lowering of systolic
and diastolic blood pressure, but, in normotensive
and hypertensive patients without cardiac dysfunction, little or no change in cardiac output or capillary wedge pressure. Interestingly, unlike direct-acting arterial vasodilators, ACE inhibitor–induced
reductions in total peripheral vascular resistance
occur without significant change in heart rate. ACE
inhibitors also decrease renal vascular resistance,
increase renal blood flow, and promote sodium and
water excretion. ACE inhibitors may also prevent
the progression of microalbuminuria to proteinuria, reduce proteinuria in patients with established
glomerular disease, and prevent or delay the progression of renal insufficiency to end-stage renal
disease. Efficacy in long-term trials has been demonstrated particularly in patients with nondiabetic
Are there differences between the RAAS inhibitors? – Lévy
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nephropathies or in patients with insulin-dependent
(type 1) diabetes.25,26 Because ACE is identical to
kininase II, ACE inhibitors may also lead to elevation of bradykinin levels in some tissues; this effect
is potentially associated with increased bradykinindependent release of NO and vasoactive prostaglandins, including prostacyclin and prostaglandin E2.27
These actions may potentially contribute to the vasodilatory, antithrombotic, antiatherogenic, and antiproliferative effects of ACE inhibitors, although
the importance of this pathway is debated. In 40%
to 60% of patients with mild-to-moderate hypertension, ACE-inhibitor monotherapy produces a
satisfactory reduction in blood pressure.28 In this
population, ACE inhibitors contribute to the reversal of cardiac hypertrophy, and do so with significantly greater efficacy than β-blockers.29 In patients
with congestive heart failure (CHF), ACE inhibitors
relieve pulmonary congestion by a balanced reduction in cardiac preload and afterload. They appear
to induce venous vasodilation, which increases peripheral venous capacitance and reduces right atrial pressure, pulmonary arterial pressure, capillary
wedge pressure, and left ventricular filling volumes
and pressures. ACE inhibitors also induce arterial
vasodilation, which reduces peripheral vascular resistance (afterload) and increases cardiac output in
this patient population. ACE inhibitors have also
been shown to improve endothelial dysfunction in
patients with heart failure, as well as in patients
with coronary artery disease and type 2 diabetes. In
early landmark trials in patients with CHF (such
as CONSENSUS, SOLVD, and V-HeFT-II [COoperative North Scandinavian ENalapril SUrvival Study;
Studies Of Left Ventricular Dysfunction; Vasodilator-Heart Failure Trial II]), ACE inhibitors were
shown not only to markedly improve symptoms and
functional status, but also to dramatically reduce
mortality. In subsequent studies in patients who
have suffered a myocardial infarction (MI), such as
SAVE, AIRE, and TRACE (Survival And left Ventricular Enlargement; Acute Infarction Ramipril Efficacy; TRAndolapril Cardiac Evaluation), ACE-inhibitor therapy has been shown to prevent or retard
ventricular remodeling and progression to CHF,
and thereby to reduce overall mortality and prolong
survival.30-37 Furthermore, the results of HOPE
(Heart Outcomes Prevention Evaluation) and other smaller studies have reported broad cardiovascular benefits of ACE-inhibitor therapy in “high-risk”
patients (including both hypertensive and normotensive individuals), and it is possible that these
benefits occur in part independently of their blood
pressure-lowering effect.37 Several large-scale studies of various ACE inhibitors have shown a reduction in incidence of new-onset diabetes in association with ACE-inhibitor therapy. For example, this
has been shown with captopril in hypertensive patients (CAPPP [CAPtopril Prevention Project]),38
with ramipril in patients at high risk for cardiovascular disease (HOPE), with enalapril in patients
with left ventricular dysfunction (SOLVD),39 and
with trandolapril in patients with stable coronary
disease (PEACE [Prevention of Events with Angiotensin-Converting Enzyme inhibition]).40 The
Are there differences between the RAAS inhibitors? – Lévy
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mechanism of this benefit has not been determined.
ACE-inhibitor therapy is generally well tolerated by
most patients, but is nonetheless associated with
some significant side effects. Most frequent among
these is a dry cough, which has been attributed to
accumulation of substance P (which is normally
degraded by kininase II). More serious side effects
common to all ACE inhibitors include angioedema
(which is potentiated by decreased catabolism of
kinins) and fetal abnormalities and mortality.
Angiotensin receptor blockers
As mentioned earlier, the AT1 receptor mediates
most of the known actions of Ang II that contribute
to hypertension and volume dysregulation (vascular smooth muscle contraction, aldosterone secretion, renal sodium reabsorption, and pressor and
tachycardiac responses) as well as to cardiovascular
damage (cellular hypertrophy or proliferation, prothrombotic and proinflammatory effects, and superoxide formation). Thus, specific Ang II antagonism action at the AT1 receptor became a logical
therapeutic target, one considered likely to be more
specific than ACE inhibition. Development of orally active, nonpeptide, selective AT1 receptor blockers
began in the 1990s with the synthesis of losartan.19
Since that time, several ARBs have been synthesized, including valsartan, irbesartan, candesartan,
eprosartan, telmisartan, and olmesartan. In contrast
to the ACE inhibitors, ARB therapy actually results
in an increase in Ang II levels. As with ACE inhibition, AT1 receptor blockade inhibits the negative
feedback loop, leading to increased renin secretion
and thus increased Ang I synthesis. In the case of
ARBs, the increase in Ang I leads to an increase in
Ang II, which is able to bind freely to AT2 or other
receptor subtypes. Earlier preclinical studies have
suggested that, beyond AT1 receptor blockade, activation of the AT2 receptor may mediate additional
beneficial actions on the vasculature, heart, and
kidneys, in part via a bradykinin/NO/ cGMP pathway, an effect that would further distinguish ARBs
from ACE inhibitors. But as attractive as this hypothesis is, there are no clinical data to indicate
that this pathway is a major mechanism of ARB action in humans. Furthermore, accumulating evidence now suggests that long-term AT2 stimulation
may also exert a hypertrophic and antiangiogenic
influence on cardiovascular tissues. Thus, the longterm consequences of ARB therapy may be less beneficial than previously supposed and could even be
harmful in some circumstances. The potential consequences of such effects, if found to be clinically
important, could include cardiac hypertrophy, vascular fibrosis, and decreased neovascularization in
hypoxic tissues such as the myocardium.41 Like ACE
inhibitors, ARBs reduce blood pressure by decreasing systemic vascular resistance; they do not affect heart rate and have minimal effect on cardiac
output in the nonfailing heart. Reduced systemic
vascular resistance results from a combination of
inhibition of Ang II-mediated vasoconstriction, reduced sympathetic nervous system activity, and reduced extracellular volume (ie, by direct inhibition
of proximal sodium reabsorption and by inhibition
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of aldosterone release). ARB monotherapy produces
a satisfactory reduction in blood pressure in 40%
to 60% of patients with mild-to-moderate hypertension.28 ARB therapy has also been shown to reduce inflammation markers in patients with atherosclerosis,42,43 suggesting an anti-inflammatory effect,
and to reverse endothelial dysfunction in patients
with hypertension, indicating the possibility of significant antiatherogenic effects.
In patients with hypertension and left ventricular
hypertrophy, ARB-based therapy, compared with
β-blocker (atenolol)–based therapy with identical
blood pressure control, has been shown to significantly reduce the composite risk of cardiovascular
death, stroke, and MI and to decrease the rate of
new-onset diabetes (LIFE [Losartan Intervention
For Endpoint reduction in hypertension study]).44
Similarly, ARB-based therapeutic regimens, compared with conventional therapy, have been shown
to reduce the progression of nephropathy in patients with diabetic nephropathy (IDNT, RENAAL
[Irbesartan in Diabetic Nephropathy Trial; Reduction of Endpoints in Noninsulin-dependent diabetes
mellitus with Angiotensin II Antagonist Losartan]).26,45 In patients with chronic heart failure,
addition of an ARB, compared with placebo, to conventional treatment has been shown to significantly reduce the risk of cardiovascular mortality and
hospitalization (CHARM, Val-HeFT [Candesartan in
Heart failure Assessment in Reduction of Mortality; Valsartan–Heart Failure Trial]).46,47 In high-risk
post-MI patients, ARB therapy has been shown to
reduce the risks of all-cause mortality, recurrent
MI, sudden cardiac death, revascularization, coronary artery bypass grafting, or all-cause hospital
admission to a degree similar to that of ACE-inhibitor therapy (OPTIMAAL [OPtimal Trial In Myocardial infarction with Angiotensin II Antagonist
Losartan]).48
Most adverse events reported with ARB therapy
are related to expected potential effects of RAAS
blockade — for example, hypotension, hyperkalemia, and worsening renal function—and are similar to those encountered in patients taking ACE
inhibitors.
Direct renin inhibitors
Because renin is the initial and rate-limiting step
in the RAAS cascade, it has long been considered
the logical therapeutic target for blocking the system. Preclinical studies with antirenin antibodies
and early synthetic renin inhibitors established the
potential utility of RAAS inhibition. However, pharmacologic activity of the early renin inhibitors
could only be achieved with intravenous infusion,
and the development of an orally active direct renin
inhibitor was fraught with numerous difficulties
arising from issues of potency, low bioavailability,
duration of action, and costs of synthesis. As a result, further development of these agents was halted in the mid-1990s. Concurrently, other strategies
for inhibiting the RAAS progressed to clinical use.
At present, the first nonpeptide orally active renin
inhibitor has been developed and approved, with
indications for the treatment of hypertension and
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cardiovascular and renal disorders. Renin inhibition
induces a decrease in plasma renin activity, Ang I,
Ang II, and aldosterone, alongside that in blood
pressure.49 However blood-pressure–lowering activity has been found to be small. Because normal
feedback inhibition is interrupted by angiotensin II,
renin inhibition consistently elicits a rise in circulating active renin.
This escape process, which also occurs, at a lower degree, during treatment with ACE inhibitors
and ARBs, explains why these three drug classes
behave as incomplete blockers of the renin system.
Whether renin inhibitors also improve insulin sensitivity, as ACE inhibitors and ARBs do, needs to be
clarified. Sealey and Laragh recently published a
review of 6 clinical trials of aliskiren involving more
than 5000 patients.50 Because many antihypertensive drugs are already available in extended release
form or in combination with other agents, these
authors asked if there was anything unique about
aliskiren that could justify its use. Although aliskiren suppresses plasma renin activity, it causes a
much greater reactive rise in plasma renin concentration than any other antihypertensive class tested.
Because aliskiren only blocks 90% to 95% of plasma renin, the pressor consequences of its greater
reactive increase in plasma renin concentration appear to offset its net ability to lower blood pressure,
especially at higher doses. We believe that this new
therapeutic class will find its right place in combination with one or several other antihypertensive
drugs. We are still lacking clinical data on these
combinations; thus, we will not discuss here the use
of renin inhibitors in the treatment of hypertension, but rather focus on the comparison between
ACE inhibitors and ARBs.
Differences in clinical results
obtained with the different
therapeutic classes
Over the past 15 years, accumulating data have confirmed that ARBs indeed possess many of the same
clinical benefits as ACE inhibitors, including blood
pressure lowering, improvement in CHF symptoms,
prevention of diabetic renal disease, reduction in
stroke rates, and likely prevention of new-onset diabetes mellitus and atrial fibrillation. However, until 2008, we lacked clear, final, and definitive information to compare the clinical results obtained
following treatment with ACE inhibitors and ARNs.
However, despite these obvious similarities, it is
now clear that ARBs and ACE inhibitors have significant differences, and experimental findings suggest that ACE inhibitors may provide better longterm benefits 41,42 for at least two reasons:
The increased stimulation of AT2 receptors that
occurs in the presence of AT1 receptor blockade is
believed to contribute to the benefits of ARBs, not
just through control of BP, but also through antihypertrophic and antifibrotic effects. However, it is
now clear that the effects of AT2 receptor stimulation are context-dependent. There are vessel type–
dependent differences in the vascular responses to
AT2 stimulation, and it is therefore difficult to pre-
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dict the effects in human beings of long-term overstimulation of AT2 receptors by ARBs. This information needs to be obtained by clinical trials in patients.
Another factor, the effect on bradykinin, is likely
to favor ACE inhibition over ARB therapy. ACE inhibition prevents the breakdown of bradykinin, a
peptide that has vasodilator and other favorable effects. Interestingly, a recent study using knockout
mice lacking the B1 receptor for bradykinin suggests that these receptors play an essential role in
the host defense response to ischemic injury.51
Since 2006, several meta-analyses and one major
clinical trial directly comparing the effects of ARBs
and ACE inhibitors have been published, which provide more arguments in favor of ACE inhibitors:
The Blood Pressure Lowering Treatment Trialist’s
Collaboration (BPLTT) published a meta-analysis of
26 large-scale trials totaling more than 146 000 individuals, comparing an ACE inhibitor or an ARB
with placebo or another drug class.52 In this metaanalysis, treatment-relative risks for major causespecific outcomes (stroke, major coronary heart
diseases events and heart failure) were regressed
against follow-up blood pressure differences. The
findings showed comparable blood pressure–dependent reductions in risk with ACE inhibitors and
ARBs. They also showed that ACE inhibitors elicited a blood pressure–independent reduction in relative risk of coronary disease events of 9%, while no
such effect was detected with the ARBs. This difference between ACE inhibitors and ARBs was statistically significant (P=0.002). For both stroke and
heart failure, there was no evidence of any blood
pressure–independent effects with either the ACE
inhibitors or the ARBs. This publication provided
the first statistical evidence of an effect “beyond
blood pressure reduction” for ACE inhibitors and
not for ARBs.
Actually, despite their clear theoretical and intellectual interest, meta-analyses cannot provide
definitive evidence; some systematic reviews of major ARB trials have concluded that ARBs do not prevent MI or prolong survival, even when compared
with placebo, whereas others conclude that their
effects are “either neutral or may actually increase
the rate of MI despite similar levels of blood pressure
reduction.”21 The discordant results of meta-analyses reflect their high degree of dependence on the
trials that have been included or excluded in them.
In an extensive review of the literature, Strauss and
Hall53 defended that ARBs could increase the risk of
MI. A careful analysis of the available major trials
indicates that whereas ACE inhibitors produce a
marked and consistent reduction in myocardial MI
and cardiovascular death, the same cannot be said of
ARBs. The major ARB trials in high-risk patients
have so far demonstrated an almost complete lack
of reduction in MI and mortality despite significant
reduction in blood pressure. Nine of 11 key clinical
ARB trials have even reported and excess of MI that
achieved statistical significance in two cases: VALUE
(VAlsartan antihypertensive Long-term Use Evaluation) and CHARM-Alternative. The marked benefits of ACE inhibitors in terms of MI and mortality
in patients with heart failure seem disproportion-
Are there differences between the RAAS inhibitors? – Lévy
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ate to the drop in systolic pressure. The difference
in favor of ACE inhibitors has been attributed, by
Strauss and Hall, to overstimulation of the AT2 , and/
or the AT4 receptors occurring during treatments
with ARBs. This latter receptor (AT4) could be responsible for higher release of plasminogen activator inhibitor (PAI-1), a major inhibitor of fibrinolysis. Finally, as already discussed above, the effect
on bradykinin is likely to favor ACE inhibitor over
ARB therapy.51
Last year, Patel and coworkers54 published the
findings of a large clinical trial, in which a total of
11 140 patients with type 2 diabetes were randomized to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary end points
were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, nonfatal stroke, or nonfatal MI,
and new or worsening renal or diabetic eye disease.
After a mean of 4.3 years of follow-up, compared
with patients assigned placebo, those assigned active therapy had a mean reduction of 5.6 mm Hg in
systolic blood pressure and 2.2 mm Hg in diastolic
blood pressure. The relative risk of major macrovascular or microvascular event was reduced by
9% (P=0·04). The relative risk of death from cardiovascular disease was reduced by 18% (P=0·03),
and death from any cause was reduced by 14%
(P=0·03). There was no evidence that the effects of
the study treatment differed by initial blood pressure level or concomitant use of other treatments
at baseline. The authors concluded that: “Routine
administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes
was well tolerated and reduced the risks of major
vascular events, including death.” This study underlines the importance of treating diabetic patients
whatever the level of blood pressure.
Finally, as discussed above, the only definitive
clinical comparison between ACE inhibitors and
ARBs can be provided only by a large trial designed
to compare these two therapeutic classes. The results of ONTARGET (Ongoing Telmisartan Alone
and in Combination with Ramipril Global Endpoint Trial) have been recently published by Yusuf
et al.55 This large study (more than 25 000 patients)
confirmed beyond doubt that ARBs are no better
than ACE inhibitors at reducing fatal and nonfatal
cardiovascular events in patients who had vascular
disease or high-risk diabetes without failure. In this
trial, the authors showed that telmisartan (80 mg
once daily) preserved 94% of the benefit of 10 mg
of ramipril daily, as reported in the HOPE trial; in
a previous study with an almost identical design
(VALIANT [VALsartan In Acute myocardial iNfarcTion]), valsartan (160 mg twice daily) preserved
100% of the benefit of 50 mg of captopril three
times daily in patients with acute MI. There are of
course many methodological difficulties associated
with designing and interpreting large trials aiming to evidence noninferiority of two treatments.
I conclude by citing the title used by John McMurray 56 in his editorial on the ONTARGET trial: “ACE
inhibitors in cardiovascular disease—unbeatable?”
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At present, there is strong evidence from experimental and clinical findings to suggest that:
Most antihypertensive drugs improve cardiovascular risk in relation with the degree of reduction
in blood pressure they achieve. However, inhibition
of the RAAS has additional beneficial effects beyond
the lowering of blood pressure.
ACE inhibitors and ARBs have different biologi-
cal and therapeutic effects in hypertensive patients,
but also in diabetic (hypertensive or normotensive)
patients and in patients with heart failure. The
available evidence suggests that ACE inhibitors
could provide better results than ARBs.
Finally, following John McMurray,56 we might
propose that “Because ARBs are more costly than
ACE inhibitors, their primary value is an alternative
for patients who cannot tolerate ACE inhibitors because of cough.” REFERENCES
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31. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302.
32. Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto
Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl
trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet.1994;343:
1115-1122.
33. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing
early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669-685.
34. Pfeffer MA, Braunwald E, Moye LA, et al; SAVE Investigators.
Effect of captopril on mortality and morbidity in patients with left
ventricular dysfunction after myocardial infarction. Results of
the survival and ventricular enlargement trial. N Engl J Med.
1992;327:669-677.
35. Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of
acute myocardial infarction with clinical evidence of heart failure.
Lancet. 1993;342:821-828.
36. EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease [EUROPA] Investigators. Efficacy of perindopril in reduction of cardiovascular events among
patients with stable coronary artery disease: randomised, doubleblind, placebo-controlled, multicentre trial (the EUROPA study).
Lancet. 2003;362:782-788.
37. Yusuf S, Sleight P, Pogue J, et al; Heart Outcomes Prevention
Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in
high-risk patients. N Engl J Med. 2000;342:145-153.
38. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised
trial. Lancet. 1999;353:611-616.
39. Vermes E, Ducharme A, Bourassa MG, Lessard M, White M,
Tardif JC. Enalapril reduces the incidence of diabetes in patients
with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation. 2003;107:1291-1296.
40. PEACE Trial Investigators. Angiotensin-converting-enzyme
Conclusion
22
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Are there differences between the RAAS inhibitors? – Lévy
ACE I
NHIBITION
inhibition in stable coronary artery disease. N Engl J Med. 2004;
351:2058-2068.
41. Lévy BI. Can angiotensin II type 2 receptors have deleterious
effects in cardiovascular disease? Implications for therapeutic
blockade of the renin-angiotensin system. Circulation. 2004;109:
8-13.
42. Navalkar S, Parthasarathy S, Santanam N, Khan BV. Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers
of inflammation in patients with premature atherosclerosis. J Am
Coll Cardiol. 2001;37:440-444.
43. Koh KK, Ahn JY, Han SH, et al. Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. J Am Coll
Cardiol. 2003;42:905-910.
44. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular
morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003.
45. Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2
diabetes and nephropathy. N Engl J Med. 2001;345:861-869.
46. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic
heart failure: the CHARM-Overall programme. Lancet. 2003;362:
759-766.
47. Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan
on morbidity and mortality in patients with heart failure not
receiving angiotensin-converting enzyme inhibitors. J Am Coll
Cardiol. 2002;40:1414-1421.
48. Dickstein K, Kjekshus J. Effects of losartan and captopril on
LES
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial
in Myocardial Infarction with Angiotensin II Antagonist Losartan.
Lancet. 2002;360:752-760.
49. Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet.
2006;368:1449-1456.
50. Sealey JE, Laragh JH. Aliskiren, the first renin inhibitor for
treating hypertension: reactice renin secretion may limit its effectiveness. Am J Hypertens. 2007;20:587-597.
51. Emanueli C, Salis MB, Stacca T, et al. Targeting kinin B1 receptor for therapeutic neovascularization. Circulation. 2002;105:
360-366.
52. Turnbull F, Neal B, Pfeffer M, et al; Blood Pressure Lowering
Treatment Trialists’ Collaboration. Blood pressure-dependent and
independent effects of agents that inhibit the renin-angiotensin
system. J Hypertens. 2007;25:951-958.
53. Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation. 2006;114:838-854.
54. Patel A MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and
indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
55. Yusuf S, Teo KK, Pogue J, Dyal L, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for
vascular events. N Engl J Med. 2008;358:1547-1559.
56. McMurray JJ. ACE inhibitors in cardiovascular disease-unbeatable? N Engl J Med. 2008;358:1615-1616.
INHIBITEURS DU SYSTÈME RÉNINE-ANGIOTENSINEALDOSTÉRONE DIFFÈRENT-ILS ENTRE EUX ?
L
e rôle du système tissulaire rénine-angiotensine-aldostérone (SRAA)
est complexe car la rénine est synthétisée non seulement par et dans le
rein mais aussi dans d’autres tissus comme le cerveau, les surrénales, les
ovaires, le tissu adipeux viscéral, le cœur et les vaisseaux sanguins. De la même
façon, si le foie est la première source d’angiotensinogène systémique circulant,
l’expression de l’ARNm de l’angiotensinogène a été détectée également dans le
rein, le cerveau, le cœur, les vaisseaux sanguins, les surrénales, les ovaires, le
placenta et le tissu adipeux. Deux récepteurs principaux de l’angiotensine II
(Ang II) ont été identifiés : le récepteur de type 1 de l’Ang II (AT1 ) [trans]active les voies de la croissance et assure la médiation des effets principaux de
l’Ang II tels la vasoconstriction, l’augmentation de la contractilité cardiaque,
la réabsorption rénale du sodium, la prolifération cellulaire, l’hypertrophie cardiaque et vasculaire, la réponse inflammatoire, le stress oxydatif, l’angiogenèse ; le récepteur AT1 a également des effets anti-apoptotiques ; le récepteur de
type AT2 de l’Ang II a des effets vasomoteurs opposés (vasodilatation) et des possibles effets anticroissance et antihypertrophique. Cependant, l’activation des
récepteurs AT2 est pro-angiogénique au niveau de la rétine et entraîne une prolifération cardio-vasculaire. Les IEC (inhibiteurs de l’enzyme de conversion de
l’angiotensine), les antagonistes des récepteurs de l’angiotensine (ARA) et les
inhibiteurs directs de la rénine peuvent bloquer le SRAA à différents niveaux,
avec des différences sur les plans clinique et expérimental. La plupart des antihypertenseurs améliorent le risque cardio-vasculaire proportionnellement au
degré de réduction de la pression artérielle. Cependant, l’inhibition du SRAA
se traduit par effets bénéfiques supplémentaires indépendants de la baisse de la
pression artérielle. Les IEC et les ARA ont des effets thérapeutiques et biologiques différents chez les hypertendus, les diabétiques (hypertendus ou non) et
les insuffisants cardiaques, les IEC s’étant montrés plus efficaces que les ARA.
En pratique clinique, les recommandations actuelles préconisent le recours en
première intention aux IEC pour bloquer le SRAA, les ARA restant une alternative pour les patients qui ne tolèrent pas les IEC.
Are there differences between the RAAS inhibitors? – Lévy
MEDICOGRAPHIA, VOL 31, No. 1, 2009
23
ACE INHIBITION
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
ngiotensin-converting enzyme (ACE) inhibitors have an established role in the treatment of patients across the cardiovascular
disease continuum, from uncomplicated hypertension and other risk factors to established cardiovascular disease. The term “cardiovascular continuum”
was used first in 1991 by Dzau and Braunwald to
describe cardiovascular disease as a sequence of related pathological events.1 In this model, the progression of cardiovascular disease starts from risk
factors such as hypertension and diabetes leading
through coronary artery disease (CAD), myocardial
ischemia, to congestive heart failure (HF) and endstage heart disease (Figure 1).1,2 Thus, a hypertensive patient, if left unmanaged, can be predicted to
progress down the cardiovascular continuum and
develop CAD. Similarly, a CAD patient has a greater
risk of more serious cardiovascular outcomes, such
as myocardial infarction (MI), stroke, or HF. The intimate mechanism underlying the cardiovascular
continuum is not known. It is likely that it is multifactorial, but clearly endothelial dysfunction and
consequent atherosclerosis are the key starting
points. The most effective management strategies
to break this concatenation of events and to stop
progression through the cardiovascular continuum
is inhibition of the renin-angiotensin-aldosterone
(RAAS) system by means of angiotensin-converting
enzyme (ACE) inhibition, and today these drugs are
widely used for the treatment of hypertension as
well as myocardial infarction, diabetes, HF, and secondary prevention of CAD. Among the ACE inhibitor class, perindopril has marked restorative effects
on endothelial function,3 thus inhibiting the pathophysiological continuum from the start. This is not
the case for all ACE inhibitors. In this article, I will
firstly review the role of perindopril at all stages of
the cardiovascular continuum, and, secondly, consider the possibility that perindopril is different from
other ACE inhibitors.
A
Roberto FERRARI, MD, PHD
Chair of Cardiology
University of Ferrara
and Cardiovascular Research Center
Salvatore Maugeri Foundation
Ferrara, ITALY
Do ACE inhibitors differ,
and in which way?
by R. Ferrari, Italy
he cardiovascular continuum is a sequence of related pathological predispositions and events running inexorably (if untreated) from risk factors to end-stage heart disease. Although its intimate mechanism is unknown and presumably multifactorial, key starting points include endothelial
dysfunction and atherosclerosis, making inhibition of the renin-angiotensinaldosterone system (RAAS) the prime treatment target. As a class, angiotensinconverting enzyme (ACE) inhibitors have an established preventive and therapeutic role across the continuum, enjoying the highest levels of evidence for
efficacy and tolerability. But ACE-inhibitor profiles differ in critical pharmacological and clinical respects. Perindopril and ramipril markedly reduce cardiovascular risk in stable coronary artery disease (CAD), unlike quinapril or
trandolapril. Major differences exist in tissue ACE affinity, bradykinin selectivity and potentiation, and effects on endothelial apoptosis. Perindopril (active form: perindoprilat) has a relative tissue affinity much greater than that of
other ACE inhibitors, correlating with its antiatherosclerotic activity. Its effect
on bradykinin potentiation is particularly marked: the bradykinin/angiotensin I
selectivity ratio is much greater in vitro than with other ACE inhibitors, accounting for its greater efficacy in reducing cardiovascular events. In vivo, perindopril increases endothelial nitric oxide synthase expression and activity more
than trandolapril, quinapril, ramipril, and enalapril at equihypotensive doses.
Perindopril, and to a lesser degree ramipril, are the only ACE inhibitors to significantly reduce apoptotic rate. The burden of the experimental and clinical
evidence supports that an ACE inhibitor such as perindopril or ramipril is a superior therapeutic option, in particular in low-dose combination therapies, than
certain other ACE inhibitors in stable CAD.
T
Medicographia. 2009;31:24-31.
(see French abstract on page 31)
Keywords: cardiovascular disease; coronary artery disease; cardiovascular
continuum; risk factor; endothelial dysfunction; atherosclerosis; renin-angiotensin-aldsosterone system; bradykinin; endothelial nitric oxide synthase;
apoptosis rate; ACE inhibitor; perindopril;
www.medicographia.com
Address for correspondence: Prof Roberto Ferrari, Chair of Cardiology, University of Ferrara and
Cardiovascular Institute, Arcispedale S. Anna, Corso Giovecca 203, 44100 Ferrara, Italy
(e-mail: [email protected])
24
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Benefits of ACE inhibition throughout
the cardiovascular continuum
ACE inhibitors are recommended as first-line therapy in the management of hypertension in patients
aged <55 years and in patients with compelling indications such as HF, left ventricular (LV) dysfunction, MI, diabetes, or recurrent stroke.4
Patients with prolonged and uncontrolled hypertension have an increased risk of chronic renal disease due to the development of nephrosclerosis.
SELECTED
ACE
ACS
BP
eNOS
FMD
HF
MI
RAAS
vWF
ABBREVIATIONS
angiotensin-converting enzyme
acute coronary syndromes
blood pressure
endothelial nitric oxide synthase
flow-mediated dilation
heart failure
myocardial infarction
renin-angiotensin-aldosterone system
von Willebrand factor
Do ACE inhibitors differ, and in which way? – Ferrari
ACE I
NHIBITION
These structural changes within the kidney cause
further increases in blood pressure (BP), forming a
vicious cycle, and accelerating the pathophysiological continuum. The first sign of renal impairment
in hypertensive patients is a reduced glomerular filtration rate. If poorly managed, this stage can rapidly progress to increasing levels of albuminuria and
end-stage renal failure. Aggressive and sustained
BP lowering in itself provides renal protection, and
target BP goals are <130/80 mm Hg in hypertensive
patients with renal disease. In type 2 diabetics who
are either normotensive or well controlled with other antihypertensive agents, ACE inhibition with
perindopril significantly reduces the progression
of renal disease compared with placebo or a calcium channel blocker.5,6 This shows a direct renoprotective action of ACE inhibition, which is independent of its antihypertensive efficacy.
Type 2 diabetes mellitus is a major risk factor for
the onset of cardiovascular disease. Moreover, over
70% of diabetics also suffer from hypertension, and
the primary cause of death in diabetics is cardiovascular disease. For this reason, patients with both
hypertension and diabetes need to be aggressively managed with BP targets <130/80 mm Hg. In
the Anglo-Scandinavian Cardiac Outcomes Trial
(ASCOT), 27% of the study population (n=5137)
had diabetes at baseline, but no history of cardiovascular disease.7 In this subpopulation, amlodipine/perindopril reduced total cardiovascular events
and procedures by 23% compared with β-blocker/
diuretic (P<0.05). More recently, the Action in Diabetes and Vascular disease: PreterAx and DiamicronN-MR Controlled Evaluation (ADVANCE) study
evaluated the clinical benefits of background BP
lowering with a fixed combination of perindopril
and indapamide on top of standard management in
a cohort of 11 140 diabetic patients.8 Perindopril/
indapamide fixed combination reduced the incidence of the composite primary end point of macrovascular (nonfatal stroke, nonfatal MI, and cardiovascular death) and microvascular (new or worsening nephropathy and retinopathy) events by 9%
versus placebo (P<0.05). Similar results were not
reported from the INternational VErapamil SR Trandolapril study (INVEST), which tested a combination of trandolapril and verapamil in a similar population.9
Although BP lowering in hypertensive patients is
an effective primary prevention, the risks of stroke
and major cardiovascular events are greater in patients with established cerebrovascular disease and
there have been few clinical studies investigating
the effects of BP lowering in this high-risk group.
Perindopril is a useful treatment in this scenario as
it maintains cerebral blood flow, even in normotensive patients.10,11 The Perindopril pROtection aGainst
REcurrent Stroke Study (PROGRESS) was the first
large-scale study to show that a perindopril-based
regimen achieved a relative risk reduction (RRR) of
stroke by 28%, major cardiovascular events by 27%,
and nonfatal MI by 38%.12
Coronary artery disease (CAD) is a consequence
of endothelial dysfunction and atherosclerosis, ie,
the effects of the pathophysiological continuum on
Do ACE inhibitors differ, and in which way? – Ferrari
AS
CORNERSTONE
A
OF
Coronary
thrombosis
HYPERTENSION TREATMENT
Myocardial
infarction
Arrhythmia
loss of muscle
Myocardial
ischemia
Cardiac
remodeling
Coronary
artery disease
CARDIOVASCULAR
CONTINUUM
Ventricular
dilation
Atherosclerosis
Endothelial
dysfunction
Risk factors
Hypertension
Dyslipidemia
Diabetes
Insulin resistance
Smoking
Congestive
heart failure
End-stage
heart disease
Figure 1. The cardiovascular continuum in cardiovascular disease.
Adapted from reference 2: Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part I: Pathophysiology and clinical trial
evidence (risk factors through stable coronary artery disease). Circulation. 2006;114:2850-2870. Copyright © 2006, American Heart Association.
the cardiovascular continuum. The prevalence of
CAD is higher in men than women, and rises sharply
with age after the fourth decade.13,14 CAD may first
manifest as myocardial ischemia and angina pectoris, and can ultimately progress to MI.
The management of CAD targets both symptomatic management and secondary prevention.13 The
first proof of the efficacy of ACE inhibitors for the
prophylaxis of cardiovascular events came from the
STUDY
ACRONYMS
ACTION
A Coronary disease Trial Investigating Outcome with
Nifedipine GITS
ADVANCE
Action in Diabetes and Vascular disease: PreterAx and
DiamicronN-MR Controlled Evaluation
AIRE
Acute Infarction Ramipril Efficacy
ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes Trial–Blood
Pressure Lowering Arm
EUROPA
EUropean trial on Reduction Of cardiac events with
Perindopril among patients with stable coronary Artery
disease
HOPE
Heart Outcomes Prevention Evaluation
INVEST
INternational VErapamil SR Trandolapril study
PEACE
Prevention of Events with Angiotensin Converting
Enzyme inhibition
PERFECT
PERindopril–Function of the Endothelium in Coronary
artery disease Trial
PERTINENT PERindopril–Thrombosis, InflammatioN, Endothelial
dysfunction, and Neurohormonal activation Trial
PROGRESS Perindopril pROtection aGainst REcurrent Stroke Study
QUIET
QUinapril Ischemic Event Trial
TRACE
TRAndolapril Cardiac Evaluation
MEDICOGRAPHIA, VOL 31, No. 1, 2009
25
ACE I
NHIBITION
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
results of the Heart Outcomes Prevention Evaluation (HOPE) trial, which demonstrated that the
ACE inhibitor ramipril significantly reduced the incidence of cardiovascular events in a wide range of
high-risk patients, including those with CAD.15 The
EUropean trial on Reduction Of cardiac events with
Perindopril among patients with stable coronary
Artery disease (EUROPA)16 evaluated patients with
a generally lower level of cardiovascular risk than in
difference in the incidence of the primary combined
end point (death from cardiovascular causes, MI, and
coronary revascularization) versus placebo. There
has been much debate surrounding the differences
in the results of EUROPA, HOPE, and PEACE.19 One
hypothesis was that the negative result in PEACE
was associated with the lower overall risk of the
population. However, further analysis of EUROPA
showed heterogeneous populations in terms of car-
HOPE
QUIET
Primary end point
CV death, MI, cardiac arrest,
revascularization, hospitalization
for unstable angina
CV death, MI, stroke
Patients (%)
40
Quinalapril
20 mg/day
30
Placebo
20
4% increase in risk
RR=1.04 (CI, 0.89 -1.22)
P=0.6
10
20
Ramipril
10 mg/day
10
5
0
0
0
1
2
0
3
1
2
Primary end point
Primary end point
CV death, MI, cardiac arrest
CV death, MI, revascularization
20% reduction in risk
RR=0.80 (CI, 0.71- 0.91)
P=0.0003
30
8
4
Perindopril
8 mg/day
0
1
2
3
4
5
Time (years)
MEDICOGRAPHIA, VOL 31, No. 1, 2009
20
Trandolapril
4 mg/day
10
0
0
the HOPE study. Nevertheless, EUROPA corroborated and extended HOPE study findings: that is, in
the EUROPA trial in >12 000 randomized patients,
perindopril (added to standard background therapy
with antiplatelet agents [92% of patients], β-blockers [62%], and/or lipid-lowering agents [58%]) significantly reduced relative risk of the composite
primary end point of cardiovascular death, myocardial infarction (MI), or cardiac arrest by 20% versus
placebo (P=0.0003).16
Before HOPE and EUROPA, another trial, the
QUinapril Ischemic Event Trial (QUIET) tested the
hypothesis that quinapril could be beneficial to patients subjected to elective angioplasty. Unfortunately, however, no benefits were shown (Figure 2).15-18
Subsequent to the HOPE and EUROPA trials, the
findings of the Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) trial questioned the efficacy of ACE inhibition in certain types of patients with stable CAD.18 The PEACE
trial examined the effects of trandolapril in patients
aged >50 years with stable CAD and preserved LV
function. After a median of 4.8 years, there was no
26
Placebo
4% reduction in risk
RR=0.96 (CI, 0.88 -1.06)
P=0.43
Placebo
Patients (%)
Patients (%)
Abbreviations: CI, confidence
interval; CV, cardiovascular;
EUROPA, EUropean trial on
Reduction Of cardiac events with
Perindopril in stable coronary
Artery disease; HOPE, Heart Outcomes Prevention Evaluation;
MI, myocardial infarction; PEACE,
Prevention of Events with Angiotensin-Converting Enzyme inhibition; QUIET, QUinapril Ischemic
Event Trial; RR, risk reduction.
4
PEACE
EUROPA
12
3
Time (years)
Time (years)
Figure 2. Primary
outcomes of the four major
angiotensin-converting
enzyme (ACE) inhibitor
trials in stable coronary
artery disease. Based on
data from references 15-18.
Placebo
22% reduction in risk
RR=0.78 (CI, 0.70 - 0.86)
P=0.001
15
Patients (%)
50
Primary end point
0
1
2
3
4
5
6
Time (years)
diovascular risk. Deckers et al investigated this point
by classifying EUROPA patients according to baseline cardiovascular risk, ie, high (>3%), medium
(1%-3%), or low (<1%) risk of reaching the primary end point at the end of the trial.20 Within each
subgroup, perindopril treatment significantly reduced the risk of the primary end point by 17%,
32%, and 12%, respectively, compared with placebo.
Importantly, the cardiovascular risk of the lowest
tertile of EUROPA (n=3976) was lower than the average cardiovascular risk in the PEACE population.21
Moreover, the primary end point was also reduced
by perindopril in EUROPA subgroups with preserved
LV function (n=6878; RRR 16%, P<0.05)22 and with
previous coronary revascularization (n=6709; RRR
17%, P<0.05).23 Notably, patients with previous
coronary revascularization in HOPE had a similar
15% reduction in the primary end point, though
this failed to reach statistical significance.24 Considering these results, we can be confident that the
differences between the three studies are not linked
to baseline risk of the populations.19 The other hypothesis is that ACE inhibitors are not equal with
Do ACE inhibitors differ, and in which way? – Ferrari
ACE I
NHIBITION
respect to efficacy against cardiovascular disease
and the positive results of HOPE and EUROPA are
therefore due to the ACE inhibitors used in the
trials.
The benefits of ACE inhibitors in the postinfarct
setting are unequivocal.25,26 For instance, a metaanalysis of data from almost 100 000 patients with
acute MI revealed that early ACE inhibition (ie, administered within 36 hours of MI) significantly
reduced mortality during the first week and first
month post infarct.25 Longer-term studies in postAMI patients with left ventricular (LV) dysfunction
(EF <40%), such as the Acute Infarction Ramipril
Efficacy (AIRE) trial,27 the TRAndolapril Cardiac
Evaluation (TRACE),28 and the Survival And Ventricular Enlargement (SAVE) study,29 confirmed that
these benefits are maintained over several years.
Nearly two thirds of EUROPA patients (n=7190)
had a history of MI. In these patients, perindopril
significantly reduced the primary end point versus placebo (RRR 22.4%, P<0.001).30 The main
long-term complications following MI are further
progression down the cardiovascular continuum
starting with changes in ventricle size, shape, and
function, a process referred to as cardiac remodeling, which can result in HF. Numerous studies have
shown that ACE inhibition reduces morbidity and
mortality in patients with residual LV dysfunction
following MI through prevention of remodeling,
and ACE inhibitors are therefore administered as
prophylactic treatment 24 hours following MI.31
However up to 40% of MI patients admitted to hospital are elderly and have preserved LV function.
Until recently, the benefits of ACE inhibitors for this
patient subset were unclear. The Perindopril and
Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) trial has shown that LV remodeling occurs in elderly post-MI patients with preserved LV function and that these changes can be
prevented by perindopril.26 Patients aged >65 years
with recent MI and LV ejection fraction >40%
(n=1252) were randomized to treatment with either
perindopril or placebo on top of standard management. After 12 months, the composite primary end
point of death, hospitalization for HF, and LV remodeling showed a RRR of 38% in favor of perindopril (P<0.001). The marked effects of perindopril
on remodeling were the most beneficial component
of the combined end point. Although HF represents
one of the final stages of the cardiovascular continuum, successful management of patients here can
still improve prognosis. ACE inhibitors are indicated in HF, and have beneficial effects on mortality,
hospital admission rates, symptoms, and cardiac
performance in patients with systolic HF.32
Mechanisms of action of ACE inhibition
on the cardiovascular continuum
One mechanism of the beneficial effects of ACE inhibition in the cardiovascular continuum is BP reduction, though this may not be the only one. For
example, the degree of BP reduction was very similar in all trials on secondary prevention of CAD with
quinapril, ramipril, perindopril, and trandolapril,
Do ACE inhibitors differ, and in which way? – Ferrari
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
and, ironically, was slightly less in EUROPA and
HOPE than in QUIET and PEACE, which do not
show any benefit! Indeed, BP reduction alone could
not be the sole explanation for the results of EUROPA, since the effect of perindopril was independent of BP at entry and was even recorded in patients in whom there was no reduction in BP upon
perindopril treatment.33 Further evidence for the
absence of an exclusive direct link between BP lowering and cardiac outcomes in CAD patients comes
from ACTION (A Coronary disease Trial Investigating
Outcome with Nifedipine GITS), which tested the
effect of a calcium channel blocker on clinical outcomes in the same type of population as in EUROPA.34 Nifedipine produced greater reductions in
BP in ACTION (– 6/3 mm Hg) than perindopril in
EUROPA (– 5/2 mm Hg),16 and yet it was not associated with a prognostic benefit. These observations
imply that BP reduction is not the only explanation
for the clinical efficacy of ACE inhibition in stable
CAD. Another possible mechanism for the action of
ACE inhibition on coronary atherosclerosis is a beneficial effect on the endothelium. In this context,
we should note that the primary end point of the
EUROPA trial (ie, cardiovascular death, nonfatal
MI, or resuscitated cardiac arrest) is a composite of
acute coronary syndromes (ACSs). The most common cause of ACS is progression and subsequent
disruption of atherosclerotic plaque, which is directly related to damage of the endothelium. This
implies that, if the endothelium was somehow protected by ACE inhibition, atherosclerosis would not
progress or would progress to a lesser extent, and
thus ACS would be prevented. The endothelium is
the lining of the vessel, which is made up of a continuous layer of cells, rather like tiles on a floor. The
average human endothelium weighs around 1.5 kg,
with a surface area of more than 800 m 2! It is capable of producing more than 250 biologically active substances that help regulate vascular structure and function. ACE is primarily a tissue enzyme
(80% to 90%) and indeed it is present, among many
other tissues, in the endothelium and smooth muscle. ACE promotes the formation of angiotensin II
from angiotensin I in the RAAS, as well as the degradation of bradykinin, leading to the regulation of
BP.35 Chronic overexpression of tissue ACE results
in the overproduction of angiotensin II, a potent
constrictor and growth factor, which among several other actions causes vasoconstriction, inflammation, vascular remodeling, thrombosis, apoptosis,
and eventually plaque rupture. The concomitant
decrease in bradykinin reduces the vasodilatory, antioxidant, profibrinolytic, and antiapoptotic effects
of this kinin, ie, protective effects against angiotensin II. Experiments in genetically modified mice
with no tissue ACE found that they developed hypotension as a result of inactivation of the RAAS.36
This shows just how vital tissue ACE is to BP regulation, even in the presence of plasma ACE. Another important, and often forgotten, feature of the endothelium is that, like almost every cell of the body
it undergoes a life/death cycle, which includes the
process of programmed cell suicide or apoptosis,21,37
matched by a consequent regeneration.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
27
ACE I
NHIBITION
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
If there is an imbalance between the endothelial
life/death cycle, and apoptosis outweighs regeneration, then there is a loss of continuity of the layer
of the vessel, thus favoring the occurrence and progression of atherosclerosis. Furthermore, if the imbalance occurs at the level of endothelium already
covering an existing atherosclerotic plaque, then
thrombus formation is likely to occur, leading to
an ACS.
Tissue ACE is known to be upregulated in ACS patients,38 which implies an alteration in the balance
between angiotensin II and bradykinin. The increase
Reduced angiotensin II
leads to reduced
Increased bradykinin leads
to increased
Endothelial dysfunction
Extracellular matrix degradation
Monocyte adhesion
Oxygen free radical production
PAI-1 and thrombogenesis
SMC growth, proliferation,
Antioxidant activity
Antiremodeling activity
eNOS expression
Monocyte antiadhesion
Preservation of endothelial
and migration
Vasoconstriction
function
t-PA and fibrinolysis
Vasodilation
Table I. Angiotensin-converting enzyme (ACE) inhibitors reduce tissue and
circulating levels of angiotensin II, and increase levels of bradykinin correspondingly.
Abbreviations: eNOS, endothelial nitric oxide synthase; PAI-1, plasminogen activator inhibitor–1; SMC, smooth muscle cell; t-PA, tissue plasminogen activator.
Based on data from reference 32: Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;
348:2007-2018. Copyright © 2003, Massachusetts Medical Society.
in angiotensin II and reduction in bradykinin has a
net negative effect on endothelial function, including the rate of its life/death cycle, which is another
central feature of atherosclerosis. All this points
toward the endothelium as another possible target, in addition to hypertension, for the prevention
of ACS via ACE inhibition.
ACE inhibition and endothelial function
The beneficial effect of ACE inhibition on endothelial function can be assessed via biological end points
of endothelial function, the most widely used being the activity and expression of endothelial nitric
oxide synthase (eNOS) and the rate of endothelial
apoptosis. These parameters, however, are difficult
to measure in humans. Instead, in the clinical setting, endothelial function can be evaluated by measurement of levels of the procoagulant von Willebrand factor (vWf), which is a marker of endothelial
damage, or by evaluation of endothelium-dependent
dilations or of ischemia-induced flow-mediated dilatation (FMD). In order to assess the effect of perindopril on patients with stable CAD, an attempt was
made to determine endothelial function via all of
these routes in EUROPA.3,16,39
The PERTINENT substudy (PERindopril–Thrombosis, InflammatioN, Endothelial dysfunction, and
Neurohormonal activation Trial)3 assessed both clinical and biological markers of endothelial function.
Blood samples were collected from EUROPA patients (n=1200) at baseline and after 1 year of perindopril or placebo for evaluation of vWf. Elevated
28
MEDICOGRAPHIA, VOL 31, No. 1, 2009
vWf at baseline (ie, higher than the median level
of 142%/unit) was significantly related to the occurrence of cardiovascular events over the 4 years of
the EUROPA study (P<0.01).3 This constitutes direct
evidence of endothelial damage in the EUROPA population, and of the serious implications of its presence. ACE inhibition with perindopril improved
endothelial function after just 1 year in the PERTINENT population, as shown by the significant
reduction in vWf versus placebo (P<0.001).3
In a smaller subgroup of PERTINENT, isolated
human endothelial cells were incubated with serum
from EUROPA patients with stable CAD (n=43 perindopril; n=44 placebo) and with serum from healthy
age-matched controls (n=45).3 These experiments
were designed to mimic the effects of circulating
blood on endothelial function by measuring eNOS
protein expression and activity and the rate of apoptosis. Incubation with serum from the stable CAD
patients at baseline caused significantly greater
downregulation of eNOS protein expression and activity, by 26% and 30%, respectively, than incubation with serum from the healthy controls (P<0.01).3
This is most likely directly related to the upregulation of ACE in stable CAD, which increases the
degradation of bradykinin, leading to reduced eNOS
expression and activity in stable CAD. When these
patients are treated with perindopril for 1 year,
which increases bradykinin levels, eNOS protein expression and activity were upregulated by 19% and
27% versus placebo (P<0.05).3 In addition, there
was a significant difference between the rates of
apoptosis upon incubation with serum from CAD
patients at baseline versus serum from healthy controls (1.3%±0.6% for controls versus 7.8%±2.9%
for CAD patients, P<0.01).3 In agreement with the
increased rate of apoptosis, incubation with the
serum of CAD patients also resulted in an increase
in the Bax/Bcl-2 ratio (from 0.3±0.2 for controls
versus 0.9±0.9 for CAD patients, P<0.01).3
In parallel to PERTINENT, another EUROPA substudy, PERFECT (PERindopril-Function of the Endothelium in Coronary artery disease Trial),39 assessed change in ischemia-induced FMD over 3
years in patients (n=333) receiving perindopril or
placebo. Perindopril produced a greater reduction
in FMD (2.6% to 3.3% over 3 years) than placebo
(2.8% to 3.0%), and the 6-monthly change in FMD
was significant for perindopril (0.14%, P<0.05), but
not for placebo (0.02%, P=0.74).39 Thus, it is possible to postulate a series of events, which could be
summarized in simple terms as follows:
CAD itself causes an upregulation of tissue ACE,
particularly that in the vascular tissue.
As a consequence, these autocrine changes alter
the balance of angiotensin II/bradykinin with an increase in angiotensin II, which is proapoptotic, and
a decrease in bradykinin, which is antiapoptotic.
The cycle between endothelial life and death is
altered, with an excess of apoptosis, leading to a
Loss of endothelial continuity,
Which facilitates the origin and progression of
the atherosclerotic process.
Effective ACE inhibition with perindopril slows
down and/or prevents this series of events.
Do ACE inhibitors differ, and in which way? – Ferrari
ACE I
NHIBITION
AS
CORNERSTONE
A
HYPERTENSION TREATMENT
OF
All ACE inhibitors are not the same
Do ACE inhibitors differ, and in which way? – Ferrari
8
Tissue potency
DD5010–11
6
4
2
0
t
rila
op
nd
eri
t
rila
ap
in
Qu
P
lat
pri
mi
Ra
t
rila
lap
a
En
t
rila
op
n
osi
F
l
pri
pto
Ca
Figure 3. Relative tissue affinity of various ACE inhibitors. DD50, ACE inhibitor concentration required for 50% displacement of bound radioligand.
Adapted from reference 45: Ferrari R. Preserving bradykinin or blocking angiotensin II:
the cardiovascular dilemma. Dialogues Cardiovasc Med. 2004;9:71-89. Copyright ©
2004, LLS.
**
8
Bradykinin/angiotensin I
selectivity ratio
The properties and effects of ACE inhibitors are often attributed solely to a class effect. However, and
particularly in CAD, all ACE inhibitors are not necessarily the same: several key pharmacological, efficacy, and tolerability differences exist between
compounds in this class.40 Regarding basic pharmacology, some ACE inhibitors are prodrugs that require initial metabolism for activation, whereas others are not. Substantial differences exist between
ACE inhibitors in terms of absorption, plasma levels, intermediary metabolism, half-lives, elimination
characteristics, durations of action, and trough/peak
plasma concentration relationships.
Major differences have been reported among ACE
inhibitors in terms of affinity for tissue ACE, bradykinin selectivity and potentiation, and effects on endothelial cell apoptosis.41-43 For example, perindopril is a prodrug ester that is converted, in the liver
and plasma, to perindoprilat, a potent, lipophilic
ACE inhibitor with high tissue ACE affinity and a
long duration of action.44 Perindoprilat has wideranging pharmacodynamic properties that include
the following: vasodilation; restriction of cardiovascular remodeling; antiatherogenic, anti-ischemic,
and antithrombotic activity; enhanced endothelial function; and improved fibrinolytic balance
(Table I).32,41,44
Perindoprilat in vitro has demonstrated greater
relative tissue affinity than other ACE inhibitors
(Figure 3),45 and this affinity is correlated with antiatherosclerotic activity.41,44,45 Moreover, perindoprilat has a particularly marked effect on bradykinin
potentiation.41 In in vitro double-displacement binding experiments, various ACE inhibitors displayed
different affinity for bradykinin than angiotensin I
binding sites on ACE, thus suggesting that ACE
inhibitors are, primarily, inhibitors of bradykinin
degradation and, secondarily, inhibitors of angiotensin II formation.42 Importantly, in vitro, perindoprilat demonstrated a markedly greater bradykinin/
angiotensin I selectivity ratio than other ACE inhibitors (Figure 4),42 and in a different experimental model, restoration of bradykinin levels has been
reported at perindopril dosages much lower than
those needed to decrease angiotensin II levels.43
These findings of bradykinin potentiation with
perindoprilat are supported by clinical data from
the PERTINENT trial46; showing that marked bradykinin/angiotensin I binding-site selectivity may, to
some extent, explain the substantial efficacy of perindopril in reducing cardiovascular events, which has
been widely observed in clinical trials.42
In an in vivo model, perindopril increased eNOS
protein expression and activity in rat aortic endothelial cells to a greater extent than trandolapril,
quinapril, ramipril, and enalapril administered at
equihypotensive dosages.47 Regarding eNOS protein
expression, perindopril was significantly more effective than enalapril (P<0.001), ramipril (P<0.05)
and quinapril (P<0.01); and regarding eNOS activity, perindopril was significantly more effective than
enalapril (P<0.01), ramipril (P<0.05) and trandolapril (P<0.05). The favorable effects of perindopril
6
*
4
2
0
P
t
rila
op
nd
eri
t
ila
ipr
m
Ra
ap
in
Qu
t
rila
Tra
t
rila
lap
o
nd
lat
pri
la
na
E
Figure 4. Relative selectivity of perindoprilat and other angiotensin-converting enzyme (ACE) inhibitors for bradykinin versus angiotensin I
binding sites on ACE: results from double-displacement binding studies.
Statistical significance: P<0.001 by ANOVA for repeated measures; **P<0.001 versus
the other 4 ACE inhibitors; *P<0.01 versus enalaprilat.
Adapted from reference 42: Ceconi C, Francolini G, Olivares A, Comini L, Bachetti T,
Ferrari R. Angiotensin-converting enzyme (ACE) inhibitors have different selectivity
for bradykinin binding sites of human somatic ACE. Eur J Pharmacol. 2007;577:1-6.
Copyright © 2007, Elsevier Ltd.
on eNOS were attributed to increased bradykinin
bioavailability.47 In a similar in vivo rat model, in
which endotoxic shock induced by bacterial lipopolysaccharide was shown to significantly increase
the rate of apoptosis in aortic endothelial cells, perindopril and ramipril were the only ACE inhibitors
tested to significantly reduce the apoptotic rate
(Figure 5, page 30),48 with the effects of perindopril being superior to those of ramipril. A cautious
explanation for this favorable perindopril effect was
greater bradykinin/angiotensin I binding-site selectivity for perindopril relative to the other ACE inhibitors.48 This is important because bradykinin has
a strong antiapoptotic action, whereas angiotensin
is proapoptotic.
Regarding clinical differences among ACE inhibitors, the disparate results from EUROPA and
HOPE on the one hand, and PEACE and QUIET on
the other, highlight the fact that an ACE inhibitor
such as perindopril or ramipril is likely to be a better therapeutic option than certain other ACE inhibitors in the setting of stable CAD.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
29
ACE I
NHIBITION
AS
A
CORNERSTONE
12
OF
HYPERTENSION TREATMENT
P<0.001
P<0.001
Rate of apoptosis (%)
10
Figure 5 Effects of 7 days’ angiotensin-converting enzyme
(ACE)–inhibitor administration
on the rate of lipopolysaccharide
(LPS)–induced endothelial apoptosis in rat aorta. *P<0.001 versus
vehicle plus LPS-treated animals.
Adapted from reference 48:
Ceconi C, Francolini G, Bastianon D,
Gitti GL, Comini L, Ferrari R. Differences
in the effect of angiotensin-converting enzyme inhibitors on the rate of endothelial
cell apoptosis: in vitro and in vivo studies.
Cardiovasc Drugs Ther. 2007;21:423-429.
Copyright © 2007, Springer Verlag.
NS
P<0.001
8
6
*
4
2
0
Vehicle
only
Vehicle +
LPS-treated
Enalapril
(20 mg/
kg/day)
Perindopril
(3 mg/
kg/day)
Quinapril
(10 mg/
kg/day)
Ramipril
(1 mg/
kg/day)
Trandolapril
(1 mg/
kg/day)
Among cardiovascular medications, ACE inhibitors
have the greatest level of evidence for cardiovascular prevention across the entire spectrum of cardiovascular disease (Figure 1).2 Compared with other
agents targeting the RAAS, ACE inhibitors remain
the drug of choice. It is important to emphasize
that not all ACE inhibitors are the same in terms
of their pharmacological efficacy and tolerability
profiles. Perindopril and ramipril, for example, have
demonstrated markedly reduced cardiovascular risk
in patients with stable CAD, whereas quinapril and
trandolapril have had no such effects.
Importantly, a current major trend in cardiovascular disease and other areas of medicine is a move
toward increased use of combination therapies.
Such therapies are associated with simplification of
treatment regimens, greater convenience for patients, improved patient adherence to medication
schedules and, potentially, with improved clinical
efficacy and tolerability. The data presented in this
manuscript underline that, in the arena of cardiovascular therapeutics, any combination therapy designed to provide secondary prevention should contain an ACE inhibitor as one of the constituents.
Perindopril has the largest body of evidence of any
ACE inhibitor, with data from the ASCOT-BPLA
(Blood Pressure Lowering Arm), ADVANCE, and
PROGRESS studies confirming the major cardiovascular risk-reducing benefits obtained with perindopril-containing combination schedules. REFERENCES
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3. Ceconi C, Fox KM, Remme WJ, et al. ACE inhibition with
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4. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines
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11. Nazir FS, Overell JR, Bolster A, Hilditch TE, Lees KR. Effect
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13. Fox K, Garcia MA, Ardissino D, et al; Task Force on the Management of Stable Angina Pectoris of the European Society of
Cardiology; ESC Committee for Practice Guidelines (CPG).
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14. Rosamond W, Flegal K, Furie K, et al. Heart Disease and
Stroke Statistics 2008 Update. A Report From the American Heart
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15. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.
Effects of an angiotensin-converting-enzyme inhibitor, ramipril,
on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation study investigators. N Engl J Med.
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16. Fox KM; EUropean trial on Reduction Of cardiac events with
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Conclusions
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Do ACE inhibitors differ, and in which way? – Ferrari
ACE I
NHIBITION
patients with stable coronary artery disease: randomised, doubleblind, placebo-controlled, multicentre trial (the EUROPA study).
Lancet. 2003;362:782-788.
17. Pitt B, O’Neill B, Feldman R, et al. The QUinapril Ischemic
Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:1058-1063.
18. Braunwald E, Domanski MJ, Fowler SE, et al; PEACE Trial
Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058-2068.
19. Remme WJ. Secondary prevention of coronary artery disease and the choice of the ACE inhibitor: why EUROPA and not
PEACE? Cardiovasc Drugs Ther. 2007;21:405-407.
20. Deckers JW, Goedhart DM, Boersma E, et al. Treatment benefit by perindopril in patients with stable coronary artery disease
at different levels of risk. Eur Heart J. 2006;27:796-801.
21. Buemi M, Corica F, Marino D, et al. Cardiovascular remodeling, apoptosis, and drugs. Am J Hypertens. 2000;13:450-454.
22. Bertrand ME, Remme WJ, Fox KM, Ferrari R, Simoons ML.
Effects of perindopril on long-term clinical outcome of patients
with coronary artery disease and preserved left ventricular function. Int J Cardiol. 2007;121:57-61.
23. Fox KM, Bertrand ME, Remme WJ, Ferrari R, Simoons ML,
Deckers JW. Efficacy of perindopril in reducing risk of cardiac
events in patients with revascularized coronary artery disease.
Am Heart J. 2007;153:629-635.
24. Yusuf S, Pogue J, Myers MG, et al. ACE inhibition in stable
coronary artery disease. N Engl J Med. 2005;352:937-939.
25. ACE Inhibitor Myocardial Infarction Collaborative Group.
Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from
100,000 patients in randomized trials. Circulation.1998;97:22022212.
26. Ferrari R. Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical
outcome: results of the randomized Perindopril and Remodeling
in Elderly with Acute Myocardial Infarction (PREAMI) Study.
Arch Intern Med. 2006;166:659-666.
27. Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of
acute myocardial infarction with clinical evidence of heart failure.
Lancet. 1993;342:821-828.
28. Kober L, Torp-Pedersen C, Carlsen JE, et al; TRAndolapril
Cardiac Evaluation (TRACE) Study Group. A clinical trial of the
angiotensin-converting-enzyme inhibitor trandolapril in patients
with left ventricular dysfunction after myocardial infarction.
N Engl J Med. 1995;333:1670-1676.
29. Pfeffer MA, Braunwald E, Moye LA, et al; SAVE investigators.
Effect of captopril on mortality and morbidity in patients with left
ventricular dysfunction after myocardial infarction. Results of the
Survival And Ventricular Enlargement trial. N Engl J Med.1992;
327:669-677.
30. Fox KM. Management of coronary artery disease: Implications of the EUROPA trial. Br J Cardiol. 2004;11:195-204.
31. Van de WF, Ardissino D, Betriu A, et al. Management of acute
myocardial infarction in patients presenting with ST-segment
elevation. Eur Heart J. 2003;24:28-66.
32. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:
2007-2018.
33. Remme WJ. Prevention of cardiovascular events by perindopril in patients with stable coronary disease does not depend on
blood pressure and its reduction — results from the EUROPA
study. Circulation. 2004;110:III628.
34. Poole Wilson PA, Lubsen J, Kirwan BA, et al. Effect of longacting nifedipine on mortality and cardiovascular morbidity in
patients with stable angina requiring treatment (ACTION trial):
randomised controlled trial. Lancet. 2004;364:849-857.
35. Dzau VJ, Bernstein K, Celermajer D, et al. The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data. Am J Cardiol. 2001;88:1L-20L.
36. Esther CR, Marino EM, Howard TE, et al. The critical role of
tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J Clin Invest. 1997;99:2375-2385.
37. Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol.
2006;47:C7-C12.
38. Hoshida S, Kato J, Nishino M, et al. Increased angiotensinconverting enzyme activity in coronary artery specimens from
patients with acute coronary syndrome. Circulation. 2001;103:
630-633.
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AS
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CORNERSTONE
OF
HYPERTENSION TREATMENT
39. Bots ML, Remme WJ, Lüscher TF, et al. ACE Inhibition and
endothelial function: main findings of PERFECT, a sub-study of
the EUROPA Trial. Cardiovasc Drugs Ther. 2007;21:269-279.
40. Borer JS. Angiotensin-converting enzyme inhibition: a landmark advance in treatment for cardiovascular diseases. Eur Heart
J Suppl. 2007;9(suppl E):2-9.
41. Ferrari R, Pasanisi G, Notarstefano P, Campo G, Gardini E,
Ceconi C. Specific properties and effect of perindopril in controlling the renin-angiotensin system. Am J Hypertens. 2005;18:
142S-154S.
42. Ceconi C, Francolini G, Olivares A, Comini L, Bachetti T, Ferrari R. Angiotensin-converting enzyme (ACE) inhibitors have
different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol. 2007;577:1-6.
43. Ferrari R, Guardigli G, Mele D, Valgimigli M, Ceconi C. Myocardia1 ischaemia: new evidence for angiotensin-converting enzyme inhibition. Eur Heart J Suppl. 2003;5(suppl E):11-17.
44. Ferrari R. Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril. Expert Rev Cardiovasc Ther. 2005;3:15-29.
45. Ferrari R. Preserving bradykinin or blocking angiotensin II:
the cardiovascular dilemma. Dialogues Cardiovasc Med. 2004;9:
71-89.
46. Ferrari R, Bertrand ME, Remme WJ, Simoons WL, Deckers
JW, Fox KM; EUROPA Investigators. Insight into ACE inhibition
in the prevention of cardiac events in stable coronary artery disease: the EUROPA trial. Expert Rev Cardiovasc Ther. 2007;5:10371046.
47. Comini L, Bachetti T, Cargnoni A, et al. Therapeutic modulation of nitric oxide: all ace inhibitors are not equivalent. Pharmacol Res. 2007;56:42-48.
48. Ceconi C, Francolini G, Bastianon D, Gitti GL, Comini L, Ferrari R. Differences in the effect of angiotensin-converting enzyme
inhibitors on the rate of endothelial cell apoptosis: in vitro and
in vivo studies. Cardiovasc Drugs Ther. 2007;21:423-429.
LES IEC
DIFFÈRENT-ILS ENTRE EUX ET COMMENT
?
L
e continuum cardio-vasculaire désigne une suite d’événements et de prédispositions pathologiques intriqués, progressant inexorablement (en
l’absence de traitement) du stade de facteurs de risque au stade terminal de la maladie cardiaque. Bien que le mécanisme intime de ce continuum soit
inconnu et sans doute multifactoriel, les principales circonstances déclenchantes
sont représentées par la dysfonction endothéliale et l’athérosclérose. De ce fait,
l’inhibition du système rénine-angiotensine-aldostérone (SRAA) est la cible
principale dans l’abord thérapeutique du continuum cardio-vasculaire. Dans
ce contexte, la classe des inhibiteurs de l’enzyme de conversion de l’angiotensine (IEC) joue un rôle préventif et thérapeutique démontré, satisfaisant aux
critères les plus élevés de preuve d’efficacité et de tolérance. Toutefois, les IEC
diffèrent par l’importance de leurs caractéristiques cliniques et pharmacologiques. Le perindopril et le ramipril réduisent nettement le risque cardio-vasculaire dans la maladie coronaire (MC) stable, contrairement au quinapril ou au
trandolapril. Il existe en outre des différences considérables parmi les IEC en
ce qui concerne l’affinité pour l’enzyme de conversion tissulaire, la sélectivité
pour la bradykinine et sa potentialisation et les effets sur l’apoptose endothéliale. L’affinité tissulaire relative du perindopril (forme active : le perindoprilate) est beaucoup plus importante que celle des autres IEC, en relation avec
son activité antiathéroscléreuse. Son effet sur la potentialisation de la bradykinine est particulièrement marqué : le taux de sélectivité bradykinine/angiotensine I in vitro est beaucoup plus important qu’avec les autres IEC, expliquant
sa plus grande efficacité à réduire l’incidence des événements cardio-vasculaires.
Le perindopril, in vivo, augmente l’activité et l’expression de la NO (monoxyde
d’azote) synthase endothéliale de façon plus importante que le trandolapril,
le quinapril, le ramipril et l’énalapril à doses hypotensives équivalentes. Enfin,
le perindopril, et à un degré moindre le ramipril, sont les seuls IEC réduisant
significativement le taux d’apoptose. Les données cliniques et expérimentales
permettent donc largement d’affirmer la supériorité pour le traitement de la
MC stable des IEC comme le perindopril ou le ramipril par rapport aux autres
IEC, et ce tout particulièrement dans le cadre d’associations thérapeutiques à
faibles doses.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
31
ACE INHIBITION
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
ypertension is a well-established risk factor
for cardiovascular disease.1 Traditionally, the
severity of hypertension was evaluated by
blood pressure (BP) measurements recorded in peripheral arteries, usually the brachial artery. As the
first randomized trials were focused on middle-aged
populations in whom diastolic blood pressure (DBP)
was more strongly associated with the clinical impact,2 the severity of hypertension was classified on
the basis of DBP. Nevertheless, many cross-sectional studies have shown that end-organ damage in hypertensive people was more strongly associated with
systolic blood pressure (SBP, and recent prospective
epidemiological studies have focused the attention
on SBP as a better guide than DBP to evaluate cardiovascular mortality.3,4
Blood pressure measured conventionally over the
brachial artery was assumed to adequately reflect
pressures in all parts of arterial system. However,
this neglected an essential fact, namely, that peripheral (brachial) blood pressure differs from blood
pressure recorded in the aorta and central arteries
such as common the carotid artery (Figure 1).5-7
While mean BP and diastolic pressure are almost
constant along the arterial tree, due to the stiffness
of large arteries and the timing and magnitude of
wave reflections, SBP and pulse pressure are amplified from the aorta to peripheral arteries, so that
brachial artery SBP only indirectly reflects SBP in
the aorta and central arteries.5,6 Several recent studies have shown that the effects of antihypertensive
drugs are not the same in peripheral and central
arteries, a fact that could account for the differing
effects of various drugs in terms of improvement in
end-organ damage, such as regression of left ventricular hypertrophy.8-12 Moreover, it has been shown
that aortic and central artery pressure (or their determinants) are stronger predictors of end-organ
damage and cardiovascular outcome than conventionally measured brachial pressure.13-15
H
Gérard M. LONDON, MD
Manhès Hospital
Fleury-Mérogis, FRANCE
Arterial compliance,
central aortic
blood pressure,
and ACE inhibition
by G. M. London, France
ecent prospective epidemiological studies suggest that systolic blood
pressure (SBP) may be a better predictor of cardiovascular mortality
and end-organ damage than diastolic blood pressure (DBP). SBP is the
resultant of: (i) left ventricular ejection parameters (left ventricular ejection
time and stroke volume); (ii) aortic stiffness; and (iii) wave reflection intensity
and the timing of incident and reflected pressure waves. Under physiological
conditions, the interaction of arterial stiffness and wave reflection determines
the magnitude of SBP and of the amplification of pulse pressure from the aorta
toward the peripheral arteries. Left ventricular function is mainly influenced by
the pressure in the aorta. However, a preferential decrease in aortic pressure does
not always translate into measurable changes in peripheral (brachial) BP. Recently published interventional studies (pREterax in regression of Arterial Stiffness in a cOntrolled double-bliNd study [REASON] and Conduit Artery Functional Endpoint/Anglo-Scandinavian Cardiac Outcomes Trial [CAFE/ASCOT])
have documented that antihypertensive treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril in combination with a diuretic (indapamide) or a calcium blocker (amlodipine) was associated with a greater decrease in SBP and pulse pressure in the aorta and central arteries than in the
brachial artery. These findings have focused attention on the role of drug treatments able to selectively reduce arterial stiffness and wave reflections, which,
by preferentially reducing central and aortic pressures, have a more pronounced
beneficial effect on end-organ protection and patient outcomes.
R
Medicographia. 2009;31:32-37.
(see French abstract on page 37)
Keywords: arterial stiffness; wave reflection; aortic pressure; ACE inhibition;
perindopril
www.medicographia.com
Address for correspondence: Gérard M. London, MD, Centre Hospitalier Manhès,
8 rue Roger Clavier, 91712 Fleury-Mérogis, France.
(e-mail: [email protected])
32
MEDICOGRAPHIA, VOL 31, No. 1, 2009
General principles and
determinants of arterial pressure
BP is the resultant of the mechanical energy imparted to the blood by ventricular ejection and of
the resistance of the systemic arterial system. Because ventricular contraction is intermittent, BP is
recorded as a pressure oscillation around a mean
value during cardiac cycles, ie, in the form of an arterial pulse pressure curve. Using Fourier analysis
of oscillatory phenomena, the pulse pressure curve
can be decomposed into two distinct components:
a steady component, namely, mean blood pressure
(MBP), determined exclusively by cardiac output
(CO) and total peripheral resistance (TPR), and an
oscillation around this mean—the pulse pressure,
whose boundaries during a cardiac cycle are the
SBP and DBP.16,17
Mean blood pressure
The driving force of systemic blood flow from the
aorta through tissues back to the right atrium is
the difference between the MBP and right atrial
pressure (RAP). By analogy with Ohm’s law, system-
Arterial compliance, central aortic blood pressure, and ACE inhibition – London
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Central aortic pressure vs conventional
After reference 7: Nichols WW, Avolio AP, Kelly RP, O’Rourke MF. Effects of age and of hypertension on
wave travel and reflections. In: O’Rourke M, Safar M, and Dzau V, eds. Arterial Vasodilatation: Mechanisms and Therapy. London, UK: Edward Arnold; 1993:23-40. Copyright © 1993, Edward Arnold.
brachial artery pressure: role of arterial stiffness
and wave reflection
SBP results from the interaction of three main factors: left ventricular ejection parameters (left ventricular ejection time and stroke volume); the dampening function of large arteries, ie, arterial stiffness
(compliance or distensibility); the propagative and
reflective properties of the arterial tree (intensity
of wave reflections and timing of incident and reflected pressure waves).20 Besides their role as conduits, arteries dampen the pressure oscillations resulting from intermittent left ventricular ejection
and transform the arterial pulsatile flow and pressure into an almost steady flow in peripheral tissues
and organs. During systole, roughly 40% to 50% of
stroke volume is forwarded directly to peripheral
tissues, while the remainder is stored in the aorta
and central arteries, distending their walls. Approximately 10% of the energy produced by the heart
is diverted for the distension of arteries and “accumulated” in the walls. During diastole, most of the
“accumulated” energy is released (recoil) by the
aorta, squeezing the stored blood forward into the
peripheral tissues. For this function to be efficient,
the energy necessary for arterial distension and recoil should be as low as possible, ie, the artery should
SELECTED
ACE
ASCOT
ABBREVIATIONS AND ACRONYMS
angiotensin-converting enzyme
Anglo-Scandinavian Cardiac Outcomes
Trial
BP
blood pressure
CAFE
Conduit Artery Functional Endpoint
(trial)
CO
cardiac output
DBP
diastolic blood pressure
MBP
mean blood pressure
PWV
pulse wave velocity
RAP
right atrial pressure
REASON pREterax in regression of Arterial
Stiffness in a cOntrolled double-bliNd
study
SBP
systolic blood pressure
TPR
total peripheral resistance
Maximum
amplification
(mm Hg)
Figure 1. Pressure waves recorded along the arterial tree and relationship to age.
Maximum
early wave
reflection
150
(mm Hg)
ic blood flow can be calculated as MBP-RAP/TPR,
where TPR is total peripheral resistance. Systemic
blood flow is equal to cardiac output (CO), and since
RAP is small, the usual expression of the formula
becomes: MBP= CO TPR. Essential and chronic
hypertension is most frequently characterized by
normal CO and increased TPR, whose magnitude
depends on the number of arterioles and on their
radius. Reduced number of arterioles (rarefaction)
as well as reduced arteriolar radius are classically
observed in essential hypertension and secondary
hypertension.18 MBP is maintained by a hierarchy
of control systems. The keystone of long-term BP
control is the kidney–blood volume–pressure regulatory system19 known as the pressure–natriuresis
relationship.
150
Early return of reflected
wave, high pulse wave
velocity
100
50
Late return of reflected
wave, low pulse wave
velocity
100
50
Femoral artery
Iliac artery
Ascending aorta
P forward
P backward (reflected)
Recorded aortic
pressure wave
Tsh
Time delay of pressure wave to
and back from reflection sites
Recorded peripheral
pressure wave
Forward and backward pressures
are in phase, no time delay
Figure 2. Schematic representation of peripheral and aortic interactions between forward- (dotted line) and backward-reflected (solid line) pressure waves.
be distensible and have low stiffness. Stiffness relates the change in transmural pressure (dP) for a
given change in volume (dV) of the vasculature and
is expressed as dP/dV (ie, elastance; the reciprocal
value dV/dP is called compliance). Due to the nonuniformity of arterial wall elasticity, the pressure–
volume relation is nonlinear and stiffness is dependent on the position on the pressure–volume curve
(Figure 2). The dampening function is altered when
arterial walls become stiff, with increased SBP and
decreased DBP (resulting in high pulse pressure)
as the principal consequence.16,17,20,21
Arterial stiffening influences SBP by two mechanisms (Figure 3, page 34). The first is a direct
mechanism that involves generation of a higher
pressure wave (incident or forward pressure wave)
by the left ventricle, ejecting into a stiff arterial system. The second is an indirect mechanism that acts
via the influence of arterial stiffening on pulse wave
velocity (PWV increases with increased stiffness)
and the timing of incident and reflected pressure
waves.17,20,22,23 The incident wave propagates along
the arterial tree at a PWV of 5 to 15 m/s, and as the
wave moves away from the heart, part of the energy is reflected back at various sites of the arterial
Arterial compliance, central aortic blood pressure, and ACE inhibition – London
MEDICOGRAPHIA, VOL 31, No. 1, 2009
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tree in the form of a reflected or backward wave.
Under normal circumstances the major sites of wave
reflections are in small peripheral conduit highresistance arterioles.17 The high PWV ensures that
the reflected waves return toward the aorta during
the same heart contraction in which they were generated, merging with the incident wave. As the pressure wave travels at a finite velocity, the timing
and the final characteristics of the pressure wave
depend on the arterial site where the pressure wave
is recorded. Peripheral arteries generate local reflections and are closer to peripheral reflecting sites and
Normal conditions
PRESSURE
Stiffening = increased slope
of pressure-volume relationship
dP/dV
VOLUME
Figure 3. Diagrammatic representation of pressure-volume relationships.
incident and reflected waves merge almost instantaneously, with a resulting pressure wave amplitude that is the summation of the two waves.22,23
The aorta is distant from peripheral reflecting sites
and, due to the finite PWV, it takes a certain time for
the reflected wave to return from these sites. When
the PWV is high, the reflected wave returns to the
aorta during systole, merging with the incident wave
and increasing aortic systolic and pulse pressures
to the same extent as in peripheral arteries. When
the PWV is low, the reflected wave returns to the
aorta later, during early diastole. The incident and
reflected waves are not in phase and the reflected
wave does not influence the aortic systolic and pulse
pressures, which are lower than in the peripheral
arteries. The timing of incident and reflected pressure waves depends on the PWV and traveling distance (body height) and duration of left ventricular
ejection (depending on heart rate).19,22-24
Arterial stiffness also plays a determinant role in
the control of diastolic BP. In stiff arteries, the slope
of the volume–pressure relationship is very steep.
This means that during left ventricular ejection
systolic pressure (incident wave) sharply increases,
but during diastolic runoff the pressure drop is also
accentuated and diastolic pressure lower (and pulse
pressure increased). By favoring high incident pressure waves and early wave reflections, arterial stiffening contributes to the development of left ventricular hypertrophy and decreased subendocardial
blood flow.7,25-28 Recent studies have demonstrated
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MEDICOGRAPHIA, VOL 31, No. 1, 2009
that arterial stiffening and increased wave reflections are per se independent predictors of all-cause
and cardiovascular mortality in patients with essential hypertension, in elderly subjects, diabetics,
and end-stage renal disease patients.13-15,29-35 In all
these populations, aortic PWV was an independent
and significant predictor of all-cause and cardiovascular mortality. Arterial stiffening is primarily
observed with aging, and arterial stiffness is increased in isolated systolic hypertension in the elderly, in sustained systolic-diastolic hypertension
in middle age, in type 2 diabetes, and in patients
with chronic kidney disease and end-stage renal
disease.2,13,21,34
Central vs brachial arterial pressure to
assess cardiovascular structural damage:
lessons from clinical trials
Evidence from clinical and epidemiological studies
based on conventional brachial artery pressure
measurements has shown that this measurement
remains an invaluable tool in epidemiology and
clinical practice. Why then measure aortic and central blood pressure and/or the different factors influencing pressure wave amplitude and shape?
During systole, the left ventricle directly faces the
aorta and central arteries whose geometrical and
structural properties determine the actual resistance to ventricular ejection (characteristic impedance). Brachial pressure is measured at a site distant from the heart and only reflects the left ventricular pressure load. Because central artery BP—
and not brachial BP— is directly “facing” the left
ventricle, it more realistically reflects cardiac load.
Aortic systolic pressure is more strongly associated
with left ventricular mass and function, and aortic
systolic and pulse pressure are much stronger predictors of clinical outcomes than conventional brachial pressure.12,14 Moreover, analysis of aortic pulse
wave morphology in parallel with the study of aortic stiffness (PWV) permits a detailed analysis of the
mechanisms responsible for abnormal systolic or
pulse pressure amplitude. Indeed, high aortic systolic pressure could be the resultant of different alterations: (i) stiffening and higher incident/forward
pressure wave; (ii) high wave reflection coefficient;
(iii) different timing between duration of ventricular ejection (left ventricular ejection time/heart rate)
and transit time of wave reflections (depending on
the proximity of reflecting sites/arterial length and
PWV), or combination of all of the above.
The understanding of these mechanisms also allows a better approach to drug effects and drug
indications. Short-term and longitudinal studies
have shown that different antihypertensive classes
have more important BP-lowering effects on aortic
or central artery systolic and pulse pressures, despite similar effects on brachial pressure.9,10,12,36-38
These pressure differences could account for differences in observed clinical outcomes and regression of end-organ damage. Indeed, experimental
and human studies have documented that despite
similar reduction in peripheral (brachial) blood pressure, several antihypertensive drugs are more ef-
Arterial compliance, central aortic blood pressure, and ACE inhibition – London
ACE I
A
0
P<0.001
P<0.001
–12
–22.5
–16
A
CORNERSTONE
–5.3
–3
–6
–11.3
–9
–20
–24
P<0.001
Perindopril/
Indapamide
–12
Atenolol
Perindopril/
Indapamide
P<0.001
fective at regressing left ventricular hypertrophy,
carotid intima thickness, and remodeling of resistive arteries. These observations are at the origin of
a debate about how much of these beneficial effects
are due to blood pressure reduction or to drug-specific effects “beyond blood pressure reduction.” But
the problem of all these debates is that they consider only brachial blood pressure and not the fact that
brachial and aortic pressures can be different and
differently affected by drugs.
While almost all drugs that reduce BP improve
arterial stiffness, not all drugs have a similar effect
on the intensity and timing of wave reflections. Reduction of wave reflections can be achieved by arterial- and arteriolar-dilating agents. Nitrates are
particularly effective and can virtually abolish wave
reflections in the ascending aorta, with a reduction
in aortic peak systolic pressure, without this leading to any apparent change in peripheral brachial
blood pressure. This left ventricular afterload–reducing effect (which, again, goes undetected by the
measurement of brachial pressure) is in great part
responsible for the high efficacy of nitrates in the
treatment of acute pulmonary edema and angina
pectoris.39
Angiotensin-converting enzyme (ACE) inhibitors
have a beneficial effect on aortic stiffness and can
reduce the intensity of wave reflections,9 resulting
in a greater fall in aortic pressure than expected
from brachial pressure changes. This was demonstrated by the recently published REASON trial
(pREterax in regression of Arterial Stiffness in a
cOntrolled double-bliNd study),36 which showed
that the fixed perindopril/indapamide combination
induced a more pronounced reduction in systolic
and pulse pressure in the central (carotid) artery
than in the peripheral brachial artery, in comparison with atenolol (Figure 4a).10 While PWV decreased in parallel with BP to the same extent with
perindopril/indapamide and atenolol, the more pronounced effect of perindopril/indapamide on central
BP was related to a significant attenuation of wave
reflections with perindopril/indapamide. This more
pronounced effect of perindopril/indapamide on central BP was associated with a significantly greater
reduction in left ventricular hypertrophy than with
atenolol despite similar changes in brachial BP (Fig-
OF
HYPERTENSION TREATMENT
P=0.031
0
–8.0
–8
AS
B
ΔLVMI (g/m2)
ΔAoSBP (mm Hg)
–4
NHIBITION
Atenolol
P=0.012
Figure 4. Panel A shows the
different effect of two treatments
(combination of perindopril/
indapamide versus atenolol) on
aortic systolic pressure (ΔAoSBP).
Panel B shows the different
effect on left ventricular mass
index (ΔLVMI).
After reference 10: Asmar RG, London
GM, O’Rourke MF, Safar ME. Improvement in blood pressure, arterial stiffness
and wave reflections with a very-low-dose
perindopril/indapamide combination in
hypertensive patients. A comparison with
atenolol. Hypertension. 2001;38:922-926.
ure 4b).10,36,37 Moreover, the differences in left ventricular mass were linked to changes in central and
not peripheral pulse pressure. Therapeutic regimens that preferentially decrease aortic and central
artery BP should be associated with better organ
protection and better cardiovascular outcomes. This
was recently demonstrated by a large-scale clinical
trial, CAFE (Conduit Artery Functional Endpoint),
a large ASCOT substudy (Anglo-Scandinavian Cardiac Outcomes Trial).12 CAFE compared the central
aortic versus brachial blood pressure–lowering effects of two drug combinations, amlodipine ± perindopril and atenolol ± thiazide. Despite a similar reduction in brachial systolic BP between treatment
groups, there was a more efficient reduction in central aortic pressure with the amlodipine regimen.
By means of Cox proportional hazards models, it
was shown that central pulse pressure was significantly associated with a post-hoc-defined composite
outcome of cardiovascular events. This strongly suggested that central aortic pulse pressure may be a determinant of clinical outcome, and that differences
in central pressure with different drug regimens
may explain the differences in clinical outcomes
with different drug regimens. Moreover, understanding the different factors influencing the amplitude
and shape of pressure waves permits a more subtle analysis of the different drug effects. In the
REASON and CAFE trials, it was shown that the differences in effect could not be attributed to changes
in aortic stiffness, since pulse wave velocity was similar with both treatments. The difference was due
to the higher percentage of systolic pressure attributable to wave reflection (augmentation index)
in the atenolol group. The principal mechanisms
for this effect was the different timing between incident and reflected waves, with a longer duration of
ventricular ejection time with atenolol, responsible
for a higher overlap with reflected waves. The possibility that the drug treatments had a different impact on the systemic reflection coefficient was not
investigated in the CAFE substudy, and cannot be
ruled out. Results of the above trials, and especially of the CAFE trial, support those of recent metaanalyses that suggest that some β-blockers may not
be the optimal recommendation for treatment of
essential uncomplicated hypertension.
Arterial compliance, central aortic blood pressure, and ACE inhibition – London
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35
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Conclusion
The European Society of Hypertension guidelines
state that central (aortic) blood pressure, which is
usually lower than pressure measured in the arm,
may be more predictive of outcome in certain populations and differently affected by antihypertensive drugs.
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COMPLIANCE ARTÉRIELLE, PRESSION AORTIQUE CENTRALE
ET INHIBITION DE L’ENZYME DE CONVERSION DE L’ANGIOTENSINE
D
es études épidémiologiques prospectives récentes indiquent que la pression artérielle systolique (PAS) serait un meilleur facteur prédictif de
mortalité cardio-vasculaire et des lésions des organes cibles que la pression diastolique (PAD). La PAS résulte : 1) des paramètres d’éjection ventriculaire gauche (temps d’éjection ventriculaire gauche et volume systolique) ;
2) de la rigidité aortique ; et 3) de l’intensité de l’onde réfléchie et de la chronologie des ondes de pression réfléchies et incidentes. Dans les conditions physiologiques, l’interaction de la rigidité artérielle et de la réflexion de l’onde détermine l’amplitude de la PAS et de l’amplification de la pression pulsée de
l’aorte jusqu’aux artères périphériques. La fonction ventriculaire gauche est
influencée principalement par la pression aortique. Cependant, une diminution
préférentielle de la pression aortique ne se traduit pas toujours par des modifications mesurables de la PA périphérique (brachiale). Des études interventionnelles récemment publiées, l’étude REASON (pREterax in regression of
Arterial Stiffness in a cOntrolled double-bliNd study) et l’étude CAFE/ASCOT
(Conduit Artery Functional Endpoint/Anglo-Scandinavian Cardiac Outcomes
Trial) ont démontré qu’un traitement antihypertenseur avec un inhibiteur de
l’enzyme de conversion de l’angiotensine (le perindopril) associé à un diurétique (l’indapamide) ou à un inhibiteur calcique (l’amlodipine) conduisait à une
diminution plus importante de la PAS et de la pression pulsée dans l’aorte et les
artères centrales que dans l’artère brachiale. Ces résultats soulignent le rôle des
traitements capables de réduire de façon sélective la rigidité artérielle et la réflexion de l’onde. En réduisant préférentiellement les pressions centrale et aortique, ces médicaments présentent un effet bénéfique plus prononcé sur la protection des organes cibles et sur l’évolution clinique des patients.
Arterial compliance, central aortic blood pressure, and ACE inhibition – London
MEDICOGRAPHIA, VOL 31, No. 1, 2009
37
ACE INHIBITION
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
Patrick ROSSIGNOL,1-4 MD, PhD
Faiez ZANNAD,1-5 MD, PhD
1INSERM,
Centre d’Investigation
Clinique 9501, Dommartin-lès-Toul,
F-54201, FRANCE; 2CHU de Nancy,
Hôpital Jeanne d’Arc, Nancy;
3Université Henri Poincaré, Nancy;
4INSERM 684, Nancy; 5CHU de Nancy,
Hôpital Brabois, Hypertension and
Heart Failure Unit, Department of
Cardiology, Nancy, F-54000, FRANCE
Combination strategy
based on perindopril
for the treatment
of hypertension:
what are the options?
b y P. R o s s i g n o l a n d
F. Z a n n a d , F r a n c e
ngiotensin-converting enzyme (ACE) inhibitors are recommended for
the treatment of hypertension, both uncomplicated (as one of the firstline antihypertensive agents) and in the presence of subclinical organ
damage and concomitant cardiovascular diseases. Among the ACE inhibitors,
robust evidence concerning perindopril has been provided by several large, welldesigned and conducted trials (PROGRESS*, EUROPA, PREAMI, ASCOTBPLA, ADVANCE). Perindopril is a true once-daily ACE inhibitor with demonstrated effectiveness in monotherapy in the control of blood pressure. However,
taking into consideration the fact that any monotherapy achieves normalization in only a fraction of patients, combination therapy is required in order to
achieve optimal blood pressure control. Thus, combination of perindopril with
indapamide, a thiazide-like diuretic, or amlodipine, a long-acting calcium channel blocker, should be considered on the basis of their additive mechanisms of
action, complementary pharmacological effects in hypertension (REASON,
CAFE), safety profile, and data from large outcome trials (PROGRESS, HYVET,
ADVANCE, ASCOT).
A
Medicographia. 2009;31:38-42.
* For full names of studies, see Trials Acronyms Box page 39.
www.medicographia.com
Address for correspondence: Prof Faiez Zannad, Centre d’Investigation Clinique (CIC)
INSERM-CHU, Hôpital Jeanne d’Arc, BP 90303, F-54201 Dommartin-lès-Toul, France
(e-mail: [email protected])
MEDICOGRAPHIA, VOL 31, No. 1, 2009
A
Blood pressure studies
The combination of a renin-angiotensin system
(RAS) inhibitor with a diuretic is potentially advantageous: the RAS inhibitor offsets the diuretic-induced increase in plasma renin activity, whereas the
diuretic-induced salt loss potentiates the effect of
the RAS inhibitor. This latter effect may be further
magnified if the dietary salt intake is reduced. The
benefits and the tolerance of the perindopril/indapamide combination compared with other treatments have been investigated in several clinical
settings.
The pREterax in regression of Arterial Stiffness
in a contrOlled double-bliNd (REASON) study was
a 12-month, multicenter, controlled, randomized,
double-blind, two-parallel-group trial,1 which enrolled 562 patients with essential hypertension,
without cardiovascular complications or diabetes.
This study aimed at determining whether a perindopril (2 mg/day)/indapamide (0.625 mg/day) combination was able to decrease systolic blood pressure (SBP) and pulse pressure (PP) more than the
β-blocker atenolol (50 mg/day), for the same diastolic blood pressure (DBP) reduction. The study
drug dosage could be doubled if deemed necessary
depending on blood pressure levels. The study further aimed to elucidate whether the perindopril/indapamide combination’s blood pressure–lowering
effect was mediated by a decrease in large artery
stiffness and attenuation of wave reflections. After
1-year follow-up, office measurements of brachial
SBP, DBP, and PP decreased significantly in the two
(see French abstract on page 42)
Keywords: hypertension; perindopril; indapamide; amlodipine; combination
therapy
38
ngiotensin-converting enzymes (ACE) inhibitors are recommended for the treatment
of hypertension, both uncomplicated (as one
of the first-line antihypertensive agents) and in the
presence of subclinical organ damage and concomitant cardiovascular diseases. Perindopril is a true
once-daily ACE inhibitor with demonstrated effectiveness in monotherapy in the control of blood
pressure. However, taking into consideration the
fact that any monotherapy achieves normalization
in only a fraction of patients, a combination therapy
is needed in order to achieve optimal blood pressure control. Combinations of perindopril with indapamide, a thiazide-like diuretic, or amlodipine, a
long-acting calcium channel blocker, are of particular interest due to their additive mechanisms of
action, complementary pharmacological effects in
hypertension, safety profile, and data from large
outcome trials, which are discussed in the following review.
SELECTED
ACE
AER
LVH
PP
RAS
RRR
ABBREVIATIONS
angiotensin-converting enzyme
albumin excretion rate
left ventricular hypertrophy
pulse pressure
renin-angiotensin system
relative risk reduction
Combination therapy based on perindopril for the treatment of hypertension – Rossignol and Zannad
ACE I
NHIBITION
treatment groups. The magnitude of the decrease
in DBP was the same in each treatment group, but
the perindopril/indapamide combination achieved
a significantly greater reduction in office brachial
SBP and PP than atenolol (SBP --6.02 [95% confidence interval (CI), --8.9 to --3.14]; PP --5.57 [--7.7 to
--3.44, P<0.001]). A subsequent ambulatory blood
pressure measurement ancillary study confirmed
these results.2 Of note, the safety pattern was comparable (96 emergent adverse events in 60 patients
given atenolol and 94 events in 66 patients receiving the perindopril/indapamide combination, leading to 20 and 19 dropouts, respectively). The most
frequently reported adverse events (5%) were
headache, dizziness, asthenia, and cough. Interestingly, in the REASON study, pulse wave velocity decreased significantly in both treatment groups, and
almost identically, whereas decreases in carotid and
aortic SBP and PP were substantially higher with
perindopril/indapamide as compared with atenolol
(P<0.001).1 This hemodynamic profile reflected
changes of wave reflections originating from distal
arterial and arteriolar territory, where perindopril/
indapamide, but not atenolol, is known to improve
vessel wall structure.3 This greater reduction in arterial stiffening with the perindopril/indapamide
combination, compared with atenolol, may have
major implications, since arterial stiffness is an independent predictor of cardiovascular events in several clinical settings, including hypertension.4 Interestingly, a REASON substudy revealed that left
ventricular mass decreased significantly more with
the perindopril/indapamide combination than with
atenolol, the effects being more pronounced on central than on brachial measurements.5
The STRAtegies of Treatment in Hypertension:
Evaluation (STRATHE) study was assessed to compare the efficacy and tolerability of 3 different therapeutic approaches in the treatment of hypertension.6
Hypertensive patients (n=533) were randomized
to a 9-month treatment aimed at lowering blood
pressure below 140/90 mm Hg. The study was discontinued in patients with normal blood pressure
at month 6. In the combination group (n=180),
perindopril (2 mg) and indapamide (0.625 mg)
were administered first, with the possibility of increasing the dosage in two steps up to 4 mg and
1.25 mg, respectively. In the “sequential monotherapy” group (n=176), the treatment was initiated
with atenolol (50 mg), and replaced if necessary by
losartan (50 mg), and then by amlodipine (5 mg).
In the “stepped-care” group (n=177), valsartan was
given first at a 40-mg dose, then at a 80-mg dose,
and finally, if needed, to be coadministered with
hydrochlorothiazide 12.5 mg. The percentage of patients having achieved the target blood pressure
was significantly greater in the combination group
(62%) than in the sequential monotherapy (49%,
P=0.02) and stepped-care group (47%, P=0.005).
The percentage of patients having normalized their
blood pressure without experiencing drug-related
adverse events was also significantly higher in the
combination group (56%) than in the sequential
monotherapy (42%, P=0.002) and the stepped-care
group (42%, P=0.004).6
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
Outcome studies
Perindopril/amlodipine combination and
prevention of cardiovascular events
The Anglo-Scandinavian Cardiac Outcomes Trial–
Blood Pressure Lowering Arm (ASCOT-BPLA) study
sought to compare the effect of the amlodipine/perindopril combination versus atenolol/thiazide on
nonfatal myocardial infarction and fatal coronary
heart disease.7 This was a multicenter, prospective,
randomized controlled trial in 19 257 patients aged
40 to 79 years, with hypertension and at least three
other cardiovascular risk factors. Patients were assigned either to amlodipine 5 to 10 mg, adding
perindopril 4 to 8 mg as needed, or atenolol 50 to
100 mg, adding bendroflumethiazide 1.25 to 2.5 mg
and potassium as needed, depending on the blood
pressure levels. At every follow-up visit, the antihypertensive therapy was titrated to achieve target
blood pressures (<140/90 mm Hg for patients without diabetes and <130/80 mm Hg for patients with
diabetes). After a median follow-up of 5.5 years, the
study was prematurely stopped because of a significantly higher mortality in the atenolol-based group.
By the end of the trial, most patients (78 %) were
taking at least two antihypertensive agents. Compared with patients allocated the β-blocker-diureticbased regimen, blood pressure values were lower
throughout the trial in those allocated the amlodipine/perindopril-based regimen, with an average
difference of 2.7/1.9 mm Hg. Fewer patients on the
amlodipine/perindopril regimen experienced a primary end point compared with the atenolol/bendroflumethiazide-based regimen, although this
did not reach statistical significance (429 vs 474;
hazard ratio 0.9 [0.79-1.02]; P=0.1), presumably
because the study was underpowered for this end
point, in the early discontinuation setting. However, all other prespecified secondary end points
(except fatal and nonfatal heart failure, with a nonsignificant 16% reduction) were significantly reduced in patients allocated the amlodipine/perinTRIAL
ACRONYMS
ADVANCE
Action in Diabetes and Vascular disease: PreterAx and
DiamicronN-MR Controlled Evaluation
ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes Trial–
Blood Pressure Lowering Arm
CAFE
Conduit Artery Functional Endpoint
EUROPA
EURopean trial On reduction of cardiac events with
Perindopril in stable coronary Artery disease
HOPE
Heart Outcomes Prevention Evaluation
HYVET
HYpertension in the Very Elderly Trial
PICXEL
Perindopril/Indapamide in a double blind Controlled study
versus Enalapril in Left ventricular hypertrophy
PREAMI
Perindopril and Remodeling in Elderly with Acute
Myocardial Infarction
PREMIER
PREterax in albuMInuria rEgRession
PROGRESS Perindopril pROtection aGainst REcurrent Stroke Study
REASON
pREterax in regression of Arterial Stiffness in a cOntrolled
double-bliNd study
STRATHE
STRAtegies of Treatment in Hypertension: Evaluation
Combination therapy based on perindopril for the treatment of hypertension – Rossignol and Zannad
MEDICOGRAPHIA, VOL 31, No. 1, 2009
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ACE I
NHIBITION
AS
A
CORNERSTONE
OF
HYPERTENSION TREATMENT
dopril treatment: nonfatal myocardial infarction
and fatal coronary heart disease were reduced by
13%; total coronary events by 13%; fatal and nonfatal stroke by 23%; total cardiovascular events and
procedures by 16%, and all-cause mortality by 11%.
The incidence of new-onset diabetes was also less
frequent in the amlodipine/perindopril group (30%).
As treatment with amlodipine was initiated first, it
is unclear to which extent each drug contributed
to the beneficial outcome, although divergence of
the primary outcome curves at 1 year suggest that
later addition of perindopril was of value. Interestingly, the CAFE (Conduit Artery Function Evaluation) study, an ASCOT-BPLA substudy conducted in
2199 patients from five ASCOT centers, evidenced
substantial reductions in central aortic pressure
(central aortic SBPΔ 4.3 mm Hg; 95% CI, 3.3 to 5.4;
P<0.0001; central aortic PP Δ 3.0 mm Hg; 95% CI,
2.1 to 3.9; P<0.0001) only in the amlodipine/perindopril group, while brachial SBP was similar in both
treatment groups. In addition, central PP was significantly associated with a post-hoc defined composite outcome of total cardiovascular events/procedures and development of renal impairment in
this substudy cohort,8 suggesting that this differential impact of the amlodipine/perindopril combination on arterial stiffness may be of paramount
importance in terms of cardiovascular outcomes.
Perindopril/indapamide combination and
prevention of stroke
The Perindopril Protection Against Recurrent
Stroke Study (PROGRESS) was a double-blind placebo-controlled study designed to determine the
effects of a BP-lowering regimen.9 This regimen
involved administration of perindopril (4 mg daily)
either alone or in combination with indapamide
(2.5 mg daily) to hypertensive and nonhypertensive patients with a history of stroke or transient ischemic attack during the previous 5 years. The rationale for using combination therapy rather than
single-drug therapy was to maximize the differences
in BP between the treatment groups. Among the
6105 participants, 727 experienced a total of 886
new strokes over a mean follow-up of 3.9 years (307
in the active group and 420 in the placebo group;
relative risk reduction [RRR], 28%; 95% CI, 17%38%). The cumulative stroke incidence curves diverged early and continued to diverge throughout
follow-up. Active treatment also reduced the risk of
total major vascular events (RRR, 26%; 95% CI, 1634), including nonfatal myocardial infarction (RRR,
38%; 95% CI, 14-15). BP (systolic/diastolic) was reduced by an average of 9.0/4.0 mm Hg (SE 0.3/0.2)
among patients assigned active treatment compared
with those assigned placebo. There were only small
differences between the BP reductions seen among
participants classified as hypertensive and those
classified as nonhypertensive at entry. The RRR for
stroke was similar for both hypertensive (RRR, 32%;
95% CI, 17-44) and nonhypertensive (RRR, 27%;
95% CI, 8-42) patients. BP in patients treated with
combination therapy (12.3/5.0 mm Hg, SE 0.5/
0.3) was reduced by about twice as much as for participants treated with single-drug therapy (4.9/2.8
40
MEDICOGRAPHIA, VOL 31, No. 1, 2009
mm Hg, SE 0.6/0.3). Combination therapy reduced
stroke risk by about two fifths, with similar benefits
seen in both hypertensive and nonhypertensive participants. By contrast, reduction in recurrent stroke
with single-drug therapy was not statistically significant. Subgroup analysis showed that BP-lowering treatment was associated with beneficial effects
for most stroke subtypes at baseline, including ischemic stroke, intracerebral hemorrhage, and transient ischemic attacks.10 The nonsignificant effect
of single-drug therapy in preventing stroke recurrence in PROGRESS was associated with a limited
decrease in BP. Similar results were seen in the
Heart Outcomes Prevention Evaluation [HOPE] trial.11 Reductions in SBP and DBP were modest (3.8/
2.8 mm Hg in the ramipril group, 0.7/1.1 mm Hg
in the placebo group). Furthermore, ramipril administration did not achieve significant secondary
cerebrovascular protection in the 1013 patients
with previous stroke or transient ischemic attacks.12
PROGRESS results suggest that 5 years of treatment
with the perindopril/indapamide combination would
have resulted in the avoidance of 1 case of stroke
for every 14 patients assigned to active treatment.
Thus, BP should be lowered, even in normotensive
patients, to achieve efficient secondary prevention
after stroke.
The Hypertension in the Very Elderly Trial
(HYVET) sought to determine whether treatment
of hypertensive patients aged 80 years or older is
beneficial. It has been suggested that antihypertensive therapy may reduce the risk of stroke, while
possibly increasing the risk of death. HYVET was a
placebo-controlled, double-blind trial with indapamide (sustained release, 1.5 mg) adding perindopril (2 mg or 4 mg) if needed to reach the target
blood pressure (SBP<150 mm Hg and DBP<80
mm Hg).13 The primary end point was any stroke
(fatal and nonfatal). 3845 patients, mean age 83.6
years, were randomized. The study was discontinued early for ethical reasons, since an interim analysis showed evidence of a significant reduction in
all-cause death rate in the active treatment group.
After a median duration of follow-up of 1.8 years,
mean sitting blood pressure was 15.0/6.1 mm Hg
lower in the active treatment group than in the
placebo group. This was mostly achieved by means
of an indapamide/perindopril combination, since
25.8% of patients received indapamide alone, 23.9%
indapamide and perindopril 2 mg, and 49.5 % indapamide and perindopril 4 mg. The active treatment was associated with a 30% reduction in rate
of fatal or nonfatal stroke [--1 to 51; P=0.06], a
39% reduction in rate of death from stroke [1 to 62;
P=0.05], a 21% reduction in rate of all-cause death
[4 to 35; P=0.02], a 23% reduction in rate of death
from cardiovascular causes [--1 to 40; P=0.06], and
a major reduction in heart failure rate (64% [42 to
78; P<0.001]). The benefits of treatment began to
be apparent within the first year. The active treatment was well tolerated, since fewer serious adverse
events were reported in the active-treatment group
(358) than in the placebo group (448) (P=0.001).
Despite some limitations mainly due to the fact
that HYVET patients were generally healthier than
Combination therapy based on perindopril for the treatment of hypertension – Rossignol and Zannad
ACE I
NHIBITION
those in the general population, HYVET provides
unique evidence that hypertension treatment based
on indapamide, (mostly) with or without perindopril, in the very elderly, with a target blood pressure of 150/80 mm Hg, is beneficial, with a numberneeded-to-treat of 40 to prevent 1 death during a
2-year period.13
Clinical efficacy in diabetes
The Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation
(ADVANCE) study was a large-scale trial designed
to investigate the benefits of blood pressure lowering and intensive glucose control in patients with
type 2 diabetes.14 It was a 22 factorial, randomized,
controlled trial evaluating the effects on macrovascular and microvascular disease achieved by decreasing the blood pressure using a fixed combination of perindopril (2 to 4 mg) and indapamide
(0.625 to 1.25 mg) versus placebo, and by an intensive gliclazide MR–based glucose control regimen,
targeting an HbA1c of 6.5% or less vs standard guidelines–based therapy for glucose control. The primary end points were composites of major cardiovascular and microvascular events, defined as death
from cardiovascular disease, nonfatal stroke or nonfatal myocardial infarction, and new or worsening
renal or diabetic eye disease. A total of 11 140 patients with type 2 diabetes were randomized. The
results of ADVANCE15 are discussed in detail elsewhere in this issue. Importantly, they show that after a mean of 4.3 years of follow-up, the relative risk
of a major macrovascular or microvascular event
in the active treatment group was reduced by 9%
(P=0.04), suggesting that for every 66 patients
commencing long-term treatment with perindopril and indapamide, 1 patient would avoid at least
1 major vascular event in 5 years as a direct consequence of this treatment.15
The PREterax in albuMInuria rEgRession (PREMIER) study was conducted to compare the efficacy of a perindopril 2 mg/indapamide 0.625 mg
combination (uptitrated to 8 mg/2.5 mg if needed
to achieve a BP target of below 140/90 mm Hg) versus 10 mg enalapril (uptitrated to 40 mg if needed)
for 52 weeks, on urinary albumin excretion rate
(AER) in patients aged between 40 and 75 years with
type 2 diabetes with hypertension and albuminuria.16 This was a 12-month, randomized, controlled,
double-blind, 2-parallel-group study. Results from
REFERENCES
1. Asmar RG, London GM, O’Rourke ME, Safar ME. Improvement in blood pressure, arterial stiffness and wave reflections
with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension.
2001;38(4):922-926.
2. Mallion JM, Chamontin B, Asmar R, et al. Twenty-four-hour
ambulatory blood pressure monitoring efficacy of perindopril/
indapamide first-line combination in hypertensive patients: the
REASON study. Am J Hypertens. 2004;17(3):245-251.
3. London GM, Asmar RG, O'Rourke MF, Safar ME. Mechanism(s)
of selective systolic blood pressure reduction after a low-dose
combination of perindopril/indapamide in hypertensive subjects:
comparison with atenolol. J Am Coll Cardiol. 2004;43(1):92-99.
4. Laurent S, Boutouyrie P, Asmar R, et al. Aortic stiffness is an
independent predictor of all-cause and cardiovascular mortality
in hypertensive patients. Hypertension. 2001;37(5):1236-1241.
5. de Luca N, Asmar RG, London GM, O’Rourke MF, Safar ME.
AS
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CORNERSTONE
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HYPERTENSION TREATMENT
457 patients (intention-to-treat analysis) were available. The main outcome measures were overnight
AER and supine BP. Although both treatments reduced BP, perindopril/indapamide treatment resulted in a statistically significantly higher fall in both
BP (--3 mm Hg [--5.6; --0.4], P=0.012 for SBP; --1.5
[--3; --0.1], P=0.019 for DBP) and AER (--42% versus
--27% with enalapril). Importantly, the greater AER
reduction remained significant even after adjustment for mean BP. Adverse events were similar in
both groups.16
Effects on cardiac structure and function
The Perindopril/Indapamide in a double blind Controlled study versus Enalapril in Left ventricular
hypertrophy (PICXEL) was a 1-year multicenter,
randomized, double-blind study aimed at comparing the efficacy of a first-line combination with
perindopril/indapamide (n=284) versus monotherapy with enalapril (n=272) (both uptitrated from
2 mg/0.625 mg to 8 mg/ 2.5 mg, and 10 to 40 mg,
respectively) to achieve predefined BP targets depending on BP levels at baseline) in reducing left
ventricular hypertrophy (LVH) in hypertensive patients. The perindopril/indapamide combination
achieved a significantly greater degree of LVH reduction than enalapril monotherapy, with a between-group difference of 9.3 g/m2 [5.7; 13],
P<0.0001, and a higher blood pressure decrease (between-group difference of 4.9 [2.7; 7.1], P<0.0001,
and 2 [0.6; 3, 4], P= 0.003 for SBP and DBP, respectively. Adverse events related to treatment occurred
in 17.3% of patients in the perindopril/indapamide
group vs 15.7 % in the enalapril group (P=0.57),
the most common side effect being cough (4.1 % vs
4.4 %, P=0.83).17
Conclusion
In conclusion, the aforementioned data support the
widespread use, both in primary and secondary prevention setting, of a combination therapy based on
perindopril with either indapamide or amlodipine.
Such combinations have been found to be effective
and safe.
For patients requiring three-drug therapy to
achieve blood pressure control, a combination of
perindopril, indapamide, and amlodipine could be
considered, although, to date, no specific comparative study has addressed this question. Selective reduction of cardiac mass and central blood pressure
on low-dose combination perindopril/indapamide in hypertensive
subjects. J Hypertens. 2004;22(8):1623-1630.
6. Mourad JJ, Waeber B, Zannad F, Laville M, Duru G, Andrejak
M. Comparison of different therapeutic strategies in hypertension:
a low-dose combination of perindopril/indapamide versus a sequential monotherapy or a stepped-care approach. J Hypertens.
2004;22(12):2379-2386.
7. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine
adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac
Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a
multicentre randomised controlled trial. Lancet. 2005;366(9489):
895-906.
8. Williams B, Lacy PS, Thom SM, et al. Differential impact of
blood pressure-lowering drugs on central aortic pressure and clin-
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ical outcomes: principal results of the Conduit Artery Function
Evaluation (CAFE) study. Circulation. 2006;113(9):1213-1225.
9. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or
transient ischaemic attack. Lancet. 2001;358(9287):1033-1041.
10. Chapman N, Huxley R, Anderson C, et al. Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the
PROGRESS Trial. Stroke. 2004;35(1):116-121.
11. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events
in high-risk patients. The Heart Outcomes Prevention Evaluation
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12. Bosch J, Yusuf S, Pogue J, et al. Use of ramipril in preventing stroke: double blind randomised trial. BMJ. 2002;324(7339):
699-702.
13. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;
358(18):1887-1898.
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14. Rationale and design of the ADVANCE study: a randomised
trial of blood pressure lowering and intensive glucose control
in high-risk individuals with type 2 diabetes mellitus. Action in
Diabetes and Vascular Disease: PreterAx and DiamicroN ModifiedRelease Controlled Evaluation. J Hypertens Suppl. 2001;19(4):
S21-S28.
15. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and
microvascular outcomes in patients with type 2 diabetes mellitus
(the ADVANCE trial): a randomised controlled trial. Lancet.2007;
370(9590):829-840.
16. Mogensen CE, Viberti G, Halimi S, et al. Effect of low-dose
perindopril/indapamide on albuminuria in diabetes: preterax in
albuminuria regression: PREMIER. Hypertension. 2003;41(5):
1063-1071.
17. Dahlof B, Gosse P, Gueret P, et al. Perindopril/indapamide
combination more effective than enalapril in reducing blood
pressure and left ventricular mass: the PICXEL study. J Hypertens. 2005;23(11):2063-2070.
QUELLE ASSOCIATION THÉRAPEUTIQUE COMPORTANT
LE PERINDOPRIL FAUT-IL ENVISAGER DANS LE TRAITEMENT
DE L’HYPERTENSION ARTÉRIELLE ?
L
es inhibiteurs de l’enzyme de conversion de l’angiotensine (IEC) sont
recommandés dans le traitement de l’hypertension artérielle, tant en
première intention, en l’absence de complications, qu’en présence d’atteintes subcliniques des organes cibles ou de maladies cardio-vasculaires associées. Parmi les IEC, des résultats solidement étayés et concordants provenant
d’études bien conçues et menées, telles les études PROGRESS*, EUROPA,
PREAMI, ASCOT-BPLA, et ADVANCE, sont venus confirmer l’intérêt du perindopril. Le perindopril est un IEC dont l’efficacité en monothérapie sur le
contrôle de l’hypertension sur 24 heures est démontrée. Cependant, quel que
soit le traitement, la normalisation de la pression artérielle n’est obtenue que
chez une partie des patients. Il est donc nécessaire de recourir à une association thérapeutique pour assurer un contrôle optimal de la pression artérielle.
C’est dans ce contexte qu’il convient de prendre en compte l’association du perindopril avec l’indapamide – un diurétique dont l’action s’apparente à celle
des thiazidiques (= thiazide-like) – ou avec l’amlodipine – un inhibiteur calcique à longue durée d’action. En effet, ces associations sont caractérisées par
leurs mécanismes d’action additifs, leurs effets pharmacologiques complémentaires dans l’hypertension artérielle (REASON, CAFE), leur sécurité d’emploi
et des résultats concordants provenant d’essais thérapeutiques à grand échelle
(PROGRESS, HYVET, ADVA NCE, ASCOT).
* Les noms complets des études sont indiqués dans l’encadré au bas de la page 39.
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Combination therapy based on perindopril for the treatment of hypertension – Rossignol and Zannad
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Peter SEVER, PhD, FRCP
International Centre for Circulatory Health
Imperial College London
UNITED KINGDOM
Anglo-Scandinavian
Cardiac Outcomes Trial–Blood Pressure
Lowering Arm (ASCOT-BPLA):
Evidence for the use of an
amlodipine-perindopril combination
b y P. S e v e r , U n i t e d K i n g d o m
he Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering
Arm (ASCOT-BPLA) trial in 19 257 hypertensive patients at moderate
risk of developing cardiovascular events was terminated prematurely because of significant reductions in several end points, including all-cause mortality (11%; P=0.025) and cardiovascular mortality (24%; P=0.001) in the amlodipine±perindopril group compared with the atenolol±thiazide group. Due to
the early termination of the trial, together with increasing statin use throughout the trial, the relative risk reduction of 10% in primary end point (nonfatal
myocardial infarction and fatal coronary heart disease [CHD]) in the amlodipine ± perindopril arm did not reach statistical significance because of insufficient numbers of events (903 end points reached versus 1150 planned). Nevertheless, the newer therapy was associated with a 13% decrease in coronary
events (P=0.007), a 23% decrease in total stroke (P=0.003), a 16% reduction in
all cardiovascular events and procedures (P<0.0001), and a 30% reduction in
new-onset diabetes (P<0.0001). The average blood pressure difference throughout the trial was 2.7/1.9 mm Hg in favor of amlodipine±perindopril. In multiple adjustment analyses, adjustment for blood pressure difference explained
about 30% of the difference in stroke outcome between the two treatment groups
and had virtually no impact on the differences in CHD outcome. The ASCOTBPLA results form the rationale for the use of combinations of amlodipine and
perindopril in the management of hypertension.
T
Medicographia. 2009;31:43-50.
(see French abstract on page 50)
Keywords: hypertension; risk factor; coronary heart disease; new-onset
diabetes; combined regimen; perindopril; amlodipine
www.medicographia.com
Address for correspondence: Professor Peter Sever, PhD, FRCP, International Centre for Circulatory
Health, Imperial College London, 59 Wharf Road, London W2 1LA, UK
(e-mail: [email protected])
ASCOT-BPLA: evidence for an amlodipine-perindopril combination – Sever
nitial discussions on a trial that eventually became the Anglo-Scandinavian Cardiac Outcomes
Trial (ASCOT) study took place almost 20 years
ago.1 In the late 1980s, despite the advent of the angiotensin-converting enzyme (ACE) inhibitors and
the calcium channel blockers (CCB), there were no
plans to conduct outcome trials with these drugs in
hypertensive populations. Many expressed concern
that their increasing use as part of treatment strategies for hypertension lacked a firm evidence base
from morbidity/mortality trials. Outcome trials with
older drugs, particularly diuretics and β-blockers
and their combination, had provided good evidence
for the prevention of stroke, but less convincing
evidence for protection against coronary heart disease (CHD) events.2
Several hypotheses had been put forward to explain the latter, which included adverse metabolic
effects associated with both diuretics and β-blockers. It thus seemed reasonable that, with newer
classes of drugs apparently immune from adverse
metabolic sequelae, the shortfall in CHD prevention seen in the earlier trials could be overcome
with trials based on ACE inhibitors and CCBs. However, at the time, prospects for such outcome studies were bleak.
Simultaneously in Europe and in the USA, discussions were taking place on the design of studies
addressing the question of “was new better than
old?” and several trial designs were considered.1 In
the USA, support from the National Heart, Lung,
and Blood Institute (NHLBI) led to the design and
launch of the Antihypertensive and Lipid-Lowering
Treatment to prevent Heart Attack Trial (ALLHAT)
study.3 In Europe, despite substantial enthusiasm
for such a study, funding sources were not appar-
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ent. However, by the mid 1990s, reports began to
emerge from Curt Furberg and his colleagues about
potential hazards of CCBs4 and a possible increase
in CHD events in studies particularly with shortacting dihydropyridines. Although most of these
studies had significant design flaws, the damage had
been done and many clinicians were anxious about
possible harm associated with CCBs. It was this issue that is likely to have persuaded Pfizer (who was
already contributing to the ALLHAT study) to offer
funding for a major European outcome trial incorporating amlodipine as the CCB, in a strategy of a
new antihypertensive regimen compared with an
older diuretic/β-blocker–based regimen on cardiovascular (CV) outcomes.
The ASCOT Working Group, and subsequently
the Steering Committee, considered several possible designs1 and ultimately came up with a simple
comparison of a regimen of amlodipine combined
with an ACE inhibitor and a β-blocker combined
with a diuretic. Discussions then took place on
which ACE inhibitor, which β-blocker, and which
diuretic?
The angiotensin-converting
enzyme inhibitor
The more widely used ACE inhibitors at the time
were captopril, enalapril, and lisinopril, but several
other drugs including ramipril, perindopril, quinapril, and trandolapril were occupying an increasing share of the market. Along with many others,
the Working Group was concerned about the relatively short action of many ACE inhibitors and the
necessity to provide more than one daily dose. Based
on a review of pharmacokinetic and pharmacodynamic modeling studies, we confined our selection
to two long-acting ACE inhibitors — perindopril5
and trandolapril.6
Following discussions with Servier in Paris, we
reached an agreement that they would provide
perindopril for use in ASCOT.
SELECTED
ABBREVIATIONS AND ACRONYMS
ACE
ACS
ALLHAT
angiotensin-converting enzyme
acute coronary syndromes
Antihypertensive and Lipid-Lowering
Treatment to prevent Heart
Attack Trial
ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure
Lowering Arm
ASCOT-LLA Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm
BPLTTC
Blood Pressure Lowering Treatment
Trialists Collaboration
CCB
calcium channel blocker
CHD
coronary heart disease
CVD
cardiovascular disease
MI
myocardial infarction
VALUE
Valsartan Antihypertensive Longterm Use Evaluation [trial]
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The β-blocker and diuretic
Atenolol was by far the most widely used β-blocker
in Europe and many other countries. In retrospect,
it was probably the β-blocker with the least impressive record in outcome studies, as has subsequently been reported.7,8 In much of Europe, particularly
in Scandinavia, atenolol along with other β-blockers were used preferentially as first-line treatment,
no doubt influenced by the massive marketing campaign for “cardioprotection” afforded by β-blockers
(never ultimately to be proven in hypertension).
In the UK, physicians were divided by their choices
of either a diuretic or β-blocker as first-line treatment.
The Working Group selected the β-blocker atenolol as first-line treatment, to which a thiazide diuretic would be added. Several authorities had advocated the use of low-dose thiazides, based on very
limited data suggesting most of the antihypertensive effect of thiazides was apparent at low dose,
with little or no benefits from higher doses, but with
the latter associated with increasing side effects.9,10
Interestingly, it has taken more than a decade to establish that these early reports advocating the benefits from low- and very-low-dose thiazides were
almost certainly wrong.
The Working Group was, however, in 1996, offered bendroflumethiazide-K at doses of 1.25 mg
or 2.5 mg by Leo Laboratories and these doses were
used in the trial.
Other trial design issues
Blood pressure (BP) targets were derived from contemporary guidelines, and were set at <140/90 mm
Hg in those without diabetes and <130/80 mm Hg
in those with diabetes. Obviously, in order to achieve
BP targets in a large hypertensive population, additional drugs would be required. The α-blocker
doxazosin was widely used in combination therapy11
and selected as a common add-on to each limb of
the trial. Other drugs included moxonidine and
spironolactone, but were left to the choice of the
trial physician. The design recommended avoiding
an ACE inhibitor or CCB as add-on drugs in the
β-blocker/diuretic limb, and vice versa.
Because pooled analyses of the earlier placebocontrolled trials of drug intervention in hypertensive patients had suggested a shortfall in prevention of CHD events,2 the Working Group proposed
that the primary end point in ASCOT should be
CHD events. Initial power calculations indicated that
to observe a reasonable benefit (circa 15%) on CHD
outcome in favor of the newer regimen of the CCB
and ACE inhibitor, we would require 1150 CHD
events. We predicted that following 18000 patients
for 5 years would achieve this objective.
From the outset we were impressed by the emerging benefits of statins in the prevention of CHD
events,12,13 and because of the relative lack of benefit on CHD in the early hypertension trials, we
planned in ASCOT to test an additional hypothesis,
by way of a factorial designed trial of lipid-lowering,
that lowering cholesterol with a statin, atorvastatin,
ASCOT-BPLA: evidence for an amlodipine-perindopril combination – Sever
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would confer additional benefits compared with
placebo on CHD events in this hypertensive population (Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm [ASCOT-LLA]).
number of additional composite CV end points. Prespecified tertiary objectives included an evaluation
of any synergy between the BP-lowering and lipidlowering regimens.
Trial design and methods
Statistical methods
The detailed ASCOT protocol has been published
previously14 and further information is available at
www.ascotstudy.org. In summary, patients were
recruited between February 1998 and May 2000,
largely from family practices in the UK, Ireland, and
the Nordic countries. Hypertensive patients, on or
off antihypertensive treatment, with no prior history of myocardial infarction (MI) or clinical CHD, but
with three or more risk factors for cardiovascular
disease (CVD), were eligible for the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure
Lowering Arm (ASCOT-BPLA). These risk factors included male sex, age >55 years, a history of smoking, left ventricular hypertrophy or other specified
ECG abnormalities, a history of early CHD in a firstdegree relative, microalbuminuria or proteinuria,
non–insulin-dependent diabetes, peripheral vascular disease, previous stroke or transient ischemic attack, or ratio of plasma total cholesterol–to–highdensity lipoprotein (HDL) cholesterol of 6 or higher.
Exclusion criteria included prior MI, currently treated angina, cerebrovascular event within the previous 3 months, fasting serum triglycerides greater
than 4.5 mmol/L, heart failure, uncontrolled arrhythmias, or any clinically important hematological or biochemical abnormalities.
Following a 4-week run-in period, during which
eligibility and consent were confirmed, patients
were randomized to one of the two BP strategies in
ASCOT-BPLA, either amlodipine ± perindopril or
atenolol ± bendroflumethiazide, and those with a
fasting total cholesterol of 6.5 mmol/L (250 mg/dL)
who were currently untreated with a statin or fibrate were randomized, using a factorial design, to
either 10 mg atorvastatin daily or matching placebo in ASCOT-LLA. Overall 19 342 patients were assigned either amlodipine±perindopril treatment or
atenolol ± thiazide treatment and, of these, 10 305
were assigned atorvastatin or placebo. The management of those randomized to ASCOT-BPLA is
detailed elsewhere.14 In summary, at each follow-up
visit, antihypertensive drug therapy was titrated
and additional drugs added (perindopril to amlodipine and bendroflumethiazide-K to atenolol) to
achieve target BP levels of <140/90 mm Hg for nondiabetic patients and <130/80 mm Hg for diabetic
patients.
Following randomization, information was recorded about adverse events and any new CV event
or procedure including the cause for any hospital
admission. Central review of end points by the End
point Committee was carried out blinded to treatment allocation using the criteria for classifying
diagnoses that have been reported at www.ascotstudy.org. The primary end point of both ASCOTLLA and ASCOT-BPLA was the composite of nonfatal (including silent) MI and fatal CHD. Secondary
end points included nonfatal or fatal stroke and a
Time to first events in the atorvastatin and placebo
groups were compared on an intention-to-treat basis until closeout of ASCOT-LLA (median follow-up
time 3.3 years) and subsequently at the end of the
ASCOT-BPLA (median follow-up time 5.5 years)
using the log-rank and Cox proportional hazard
models. In order to check the proportional hazard
assumption, we assessed the proportionality by considering the interaction of the treatment indicators
and time. The P-values for time-intervention were
for all end points larger than 0.30. Wald’s test for
interaction between atorvastatin and the two BP
treatment strategies was performed using the full
Cox model. All significance tests were two-tailed and
conducted at the 0.05 level.
Results
Baseline population characteristics
ASCOT recruited 19 342 patients between February
1998 and May 2000. They were randomized to one
of the two antihypertensive treatment regimens.
The characteristics of the hypertensive patients at
baseline in the two randomized groups were well
matched.15 Subjects were mainly white (95%) and
male (77%) with a mean age of 63 years. The most
common risk factors were age 55 years (in 84%
of patients) and male sex (in 77%). At baseline, approximately 80% of subjects were receiving treatment with prior antihypertensive drugs; however,
BPs were poorly controlled and were similar in the
two treatment groups (164 mm Hg systolic and
95 mm Hg diastolic pressure).
Blood pressure reduction
BPs were substantially reduced in both treatment
arms, although notably in the first 6 months of the
trial, BP lowering was more effective on the amlodipine±perindopril strategy compared with the
atenolol±thiazide strategy (Figure 1, page 46).15 By
the end of the trial, BPs had fallen to 137.7/79.2
mm Hg in the atenolol ± thiazide strategy treatment group, and to 136.1/77.4 mm Hg in the amlodipine ± perindopril treatment group. The majority of patients (77.8%) by the end of the trial
were taking at least two antihypertensive drugs,
and for 50% and 55% of the total patient-years of
follow-up, the prespecified combinations, with or
without other drugs, were taken in the atenolol ±
thiazide and amlodipine ± perindopril treatment
groups respectively (Table I, page 46).15
Premature termination of ASCOT-BPLA
The study was stopped prematurely after 5.5 years
median follow-up and accumulated a total of 106153
patient-years of observation. The Data Safety Monitoring Board (DSMB) recommended to the Steering Committee that the trial be stopped early on the
ASCOT-BPLA: evidence for an amlodipine-perindopril combination – Sever
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grounds that there were significant reductions in
all-cause mortality and stroke events in those assigned amlodipine±perindopril and it was deemed
unethical to continue the trial, despite the fact that
a significant reduction in the primary CHD end
point had not been achieved. A major consequence
of the early stopping of the trial was that this occurred when only 903 primary events had been reported, whereas the trial was appropriately powered
on the basis of attaining 1150 primary end points.
At the final BPLA visits, complete information was
obtained on more than 98% of the subjects randomized.
In the amlodipine±perindopril treatment group,
there was a nonsignificant 10% reduction in the
primary end point of nonfatal MI and fatal CHD
when compared with the atenolol thiazide treatment group, and there were significant reductions
in several of the secondary end points in the trial
among those allocated to the amlodipine±perindopril treatment group, including all-cause mortality, total coronary events, total CV events and procedures, CV mortality, and fatal and nonfatal stroke
Atenolol ± thiazide
Amlodipine ± perindopril
180
160
164.1 SBP
163.9
Mean difference 2.7
137.7
mm Hg
140
136.1
120
100
80
94.8
DBP
Mean difference 1.9
94.5
79.2
77. 4
60
Baseline
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Time (years)
5.5
Last
visit
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure.
Modified after reference 15: Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of
cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required
versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes
Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet.
2005;366:895-906. Copyright © 2005, Elsevier Ltd.
All study
Randomized to amlodipine ± perindopril
Amlodipine
(+/- others)
Perindopril
(+/- others)
Amlodipine + perindopril
(+/- others)
82.5
58.5
49.5
Randomized to atenolol ± thiazide
Atenolol
Bendroflumethiazide
Atenolol + bendroflumethiazide
79.4
65.7
54.9
(+/- others)
(+/- others)
(+/- others)
Table I. Mean proportion of time on antihypertensive treatment by
treatment
Modified after reference 15: Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of
amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
Lancet. 2005;366:895-906. Copyright © 2005, Elsevier Ltd.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Post-hoc analysis
Two factors dictated the conduct of a post-hoc analysis, which included the primary end point to which
the number of coronary revascularization procedures was added. As ASCOT progressed, the management of acute coronary syndromes (ACS) in clinical practice changed and increasing numbers of
revascularization procedures were being undertaken for patients presenting with ACS, thereby reducing the potential number of primary end points.
In addition, because the trial was stopped early and
there was an associated loss of power in detecting a
significant difference in the primary end point, it
was deemed reasonable to repeat the coronary end
point analysis using a combined primary end point
plus coronary vascularization procedures. This analysis included observations on 1284 coronary events
and confirmed a significant 14% risk reduction in
favor of amlodipine±perindopril. In subgroup analyses, there was no evidence for heterogeneity, inasmuch as the risk reductions in all predefined subgroups did not differ significantly from that of the
whole trial population. Approximately 25% of the
subjects stopped therapy due to adverse events, but
there were no significant differences overall between the two groups. Stopping therapy due to serious adverse events occurred in 1.7% in those assigned amlodipine ± perindopril and 2.6% in those
assigned atenolol ± thiazide.
Discussion
Figure 1. Systolic and diastolic blood pressure responses to atenolol ± thiazide and
amlodipine ± perindopril.
46
(Figure 2).15 One of the most striking findings
among the predefined tertiary end points was a
>30% lower incidence of the development of new
onset-diabetes mellitus in those assigned amlodipine ± perindopril (Figure 3).15 Assignment to amlodipine ± perindopril compared with atenolol ±
thiazide was also associated with a highly significant reduction in the onset of renal impairment.
Premature termination and study power:
the post-hoc analysis
The early stopping of outcome trials invariably causes problems,16 not least because failure to reach the
anticipated number of primary end points reduces
the power of the study. In ASCOT, the Steering
Committee was persuaded by the Drug Safety Monitoring Board (DSMB) that the trial should be
stopped when all-cause mortality and stroke outcome were significantly reduced in those assigned
amlodipine±perindopril. By the time the trial was
stopped, there had been almost 750 strokes and over
1550 deaths. It was felt that in continuing the trial,
there would be a persistent excess of strokes and
deaths in those assigned atenolol±thiazide and that
this was both unacceptable and unethical.
The trial was stopped at a time when 903 primary events had been recorded — a number significantly lower than the 1150 planned, thereby reducing the power to detect potential differences between
the two treatment groups in their impact on CHD
outcome. As mentioned earlier, the failure to reach
the anticipated number of primary events was compounded by the fact that as the trial continued ac-
ASCOT-BPLA: evidence for an amlodipine-perindopril combination – Sever
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Unadjusted
hazard ratio (95% CI)
Primary
Nonfatal MI (including silent) + fatal CHD
0.90 (0.79-1.02)
Secondary
Nonfatal MI (excluding silent) + fatal CHD
Total coronary end points
Total CV events and procedures
All-cause mortality
Cardiovascular mortality
Fatal and nonfatal stroke
Fatal and nonfatal heart failure
0.87 (0.76-1.00)
0.87 (0.79-0.96)
0.84 (0.78-0.90)
0.89 (0.81-0.99)
0.76 (0.65-0.90)
0.77 (0.66-0.89)
0.84 (0.66-1.05)
Tertiary
Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Life-threatening arrhythmias
New-onset diabetes mellitus
New-onset renal impairment
1.27 (0.80-2.00)
0.68 (0.51-0.92)
0.98 (0.81-1.19)
0.65 (0.52-0.81)
1.07 (0.62-1.85)
0.70 (0.63-.078)
0.85 (0.75-0.97)
Post-hoc
Primary end point + coronary revasc.
procedures
CV death + MI + stroke
0.86 (0.77-0.96)
0.84 (0.76-0.92)
1.00
1.45
2.00
0.50
0.70
Amlodipine ± perindopril better
Atenolol ± thiazide better
The area of the blue square is proportional to the amount of statistical information
How much of the BP reduction in ASCOT
was due to a true drug effect?
Hypertensive patients recruited into ASCOT were
poorly controlled at baseline. While selection of patients for the trial does not necessarily indicate that
they are typical of those hypertensives routinely
followed in clinical practice, their BP levels, reflecting inadequate treatment, are commonplace in the
“real” world. After randomization and following the
instigation of a defined algorithm, irrespective of
treatment arm, there were substantial falls in BP, by
on average 27/17 mm Hg. In the absence of a placebo control, it is not possible to ascertain how much
of the BP fall was attributable to a true drug effect,
but by extrapolation from earlier placebo-controlled
trials of BP reduction where the placebo response
averaged out about 10-15 mm Hg systolic and 510 mm Hg diastolic, a genuine treatment effect in
ASCOT would be of the order of 15 mm Hg systolic
and 10 mm Hg diastolic pressures.
From observational data18,19 and the pooled analyses of the intervention trials2,20 on outcome in relation to the magnitude of the BP reduction, we
Figure 2 – Effect of amlodipine ±
perindopril and atenolol ± thiazide
on primary, secondary, tertiary,
and post-hoc end points.
Abbreviations: CHD, coronary heart disease;
CV, cardiovascular; MI, myocardial infarction.
Modified after reference 15: Dahlöf B, Sever
PS, Poulter NR, et al; ASCOT Investigators.
Prevention of cardiovascular events with an
antihypertensive regimen of amlodipine adding
perindopril as required versus atenolol adding
bendroflumethiazide as required, in the AngloScandinavian Cardiac Outcomes Trial-Blood
Pressure Lowering Arm (ASCOT-BPLA):
a multicentre randomised controlled trial.
Lancet. 2005;366:895-906. Copyright © 2005,
Elsevier Ltd.
10
Cumulative events (%)
tual event rates for CHD were declining, partly due
to changing cardiological practice and an increasing tendency for early intervention to prevent MI
in those presenting with ACS, and increasing use
of statins following the earlier closure of LLA.17
Our post-hoc analysis, in which the primary CHD
events and the number of coronary revascularization procedures were combined, restored the power of the study and clearly demonstrated a significant benefit in favor of amlodipine ± perindopril.
The robustness of this conclusion is also supported
by the fact that a secondary composite coronary end
point was also significantly reduced by amlodipine
± perindopril.
HYPERTENSION TREATMENT
Atenolol ± thiazide
(No. of events = 799)
8
30%*
6
4
Amlodipine ± perindopril
(No. of events = 567)
2
HR=0.70 (0.63- 0.78)
P<0.0001
0
0
Number at risk
Amlodipine ± perindopril 9639
Atenolol ± thiazide
9618
Years
1
2
3
4
5
9383
9295
9165
9014
8966
8735
8726
8455
7618
7319
* 34% after correction for baseline variables
Figure 3. Effect of amlodipine ± perindopril and atenolol ± thiazide on the incidence
of new-onset diabetes. (HR = hazard ratio).
Modified after reference 15: Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of
cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required
versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes
Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet.
2005;366:895-906. Copyright © 2005, Elsevier Ltd.
predicted that this would be associated with a reduction in CHD incidence of about 30% and a stroke
incidence of about 45%. These risk reductions are
broadly similar to those observed in the trial in subjects not randomized to atorvastatin.21 Of particular note is the rapidity with which benefit is conferred both for CHD and for stroke outcome21 and
adds support for the urgency for BP control in the
hypertensive population.
In order to achieve BP targets, the majority of patients needed to take two or more drugs (77.8%)
and for 55% and 50% of the total patient-years of
follow-up, the prespecified combinations (with or
without other drugs) were taken in the amlodipine
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±perindopril and atenolol±thiazide groups, respectively. Third- and fourth-line drug use occurred
more frequently in the atenolol ± thiazide group.
Separating out the blood pressure–lowering
benefits in ASCOT
One of the crucial questions is to what extent the
differences in CV outcome in ASCOT could be attributed to the differences in BP between the two
treatment groups, as the average difference throughout the trial was 2.7/1.9 mm Hg in favor of amlodipine±perindopril treatment. This issue was discussed
at length in a second manuscript accompanying the
original report of the BPLA findings.22
Various statistical models have been used in an
attempt to separate out BP-lowering benefits, but all
are potentially flawed. Serial mean (median) matching and multiple regression analyses all have their
problems as they involve breaking the randomization of comparator groups and thus the true robustness of randomized-controlled comparison is
lost.23 Not withstanding these cautions, post-hoc
analyses demonstrated no temporal relationship between BP differences (maximal in the first year of
the trial) and CV outcomes (no differences in the first
year of the trial).22 These observations contrast with
the reported finding from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial.24
In multiple regression analyses, adjustments for
BP had virtually no impact on the differences in
CHD outcome, but explained about 30% of the difference in stroke outcome between the two treatment groups. Including other variables in the regression analysis demonstrated that differences in
HDL cholesterol (largely due to atenolol) explained
about 30% of the differences in CHD outcome. While
this type of analysis may underestimate the contribution of changes in in-trial variables, such as BP
and cholesterol, there is a strong indication that an
alternative explanation is required to fully account
for the observed benefits of the amlodipine ± perindopril strategy on CV outcome in ASCOT-BPLA.
Further insight into these differences is provided
by the Conduit Artery Functional Endpoint (CAFE)
substudy of ASCOT.25 CAFE clearly differentiated the
hemodynamic response to atenolol±thiazide from
that of amlodipine ± perindopril regimen. In the
former, despite equivalent brachial artery pressures,
when compared with the amlodipine ± perindopril,
central pressures remained higher by, on average,
4 mm Hg systolic pressure. Together with reports
from other studies showing reductions in cerebral
blood flow with β-blockers compared with vasodilator drugs,26 on occasions when peripheral artery
pressures were equivalent, these studies highlight
the hemodynamic disadvantages of β-blocker-based
regimens, which could contribute to their adverse
effects (compared with other drugs) particularly on
stroke outcome.
ACE-inhibitor therapy: CHD benefits beyond
those attributable to BP reduction
Despite opinions that outcome differences in ASCOTBPLA could be all attributed to BP,27 (an opinion the
ASCOT authors reject!),28 apart from the analyses
48
MEDICOGRAPHIA, VOL 31, No. 1, 2009
reported above, two other issues are important. The
first is that, in recently reported pooled analyses
from the Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC)20 and from Staessen
and colleagues,29 trial regimens based on ACE inhibitors confer benefits on CHD outcome that are
greater than those predicted from the magnitude
of the BP lowering—an observation influenced by
outcome trials with ACE inhibitors in high CV risk
patients. Moreover, in outcome trials based on CCBs,
there is an excess benefit on stroke compared with
that predicted from the magnitude of BP lowering.
It is therefore, perhaps, not altogether surprising
that in ASCOT we have observed and reported on
excess benefit on both CHD and stroke outcome
with both the CCB and ACE inhibitor, that appears
to go beyond the lowering of BP.
ASCOT-BPLA: benefits associated with amlodipine ± perindopril enhanced by atorvastatin
The second important issue is the potential influence of atorvastatin on the CV benefits of the amlodipine±perindopril regimen. We had prespecified
that we would investigate any potential interaction
between blood pressure and lipid-lowering regimens in ASCOT.14 LLA was also stopped prematurely, after 3.3 years follow-up, on account of major CV
benefits of atorvastatin, including a highly significant reduction in the primary end point of nonfatal myocardial infarction and fatal CHD.17 Overall,
the primary end point was reduced by 36% compared with placebo. However, when the LLA population was divided by blood pressure treatment
groups, atorvastatin reduced CHD events by 53% in
those assigned amlodipine ± perindopril (P<0.001)
but nonsignificantly by 16%, in those assigned
atenolol ± thiazide.30 Tests for heterogeneity, indicative of possible synergy, were of borderline significance (P=0.02). It thus seems that atorvastatin
enhances the benefits associated with the amlodipine ± perindopril regimen on CHD end points. If
these observations were confirmed in other trials,
the implications for future therapeutics strategies
in hypertension would be profound.
Dramatic decrease in new-onset diabetes
A recent overview of treatment in patients with diabetes concluded that proportional benefits of BP
lowering on CV outcomes were similar in those with
and without diabetes and were not influenced by assignment to any particular drug group.31 In those
with diabetes, there is more substantial evidence for
the benefits devised by achieving lower target pressures. ASCOT randomized over 5000 patients with
type 2 diabetes and the risk reductions associated
with the amlodipine±perindopril arm for the composite CV end point were similar to those observed
in the nondiabetic.15
One of the more dramatic observations in the trial was the development, over the course of the 5.5
years follow-up, of new-onset diabetes in 1366 cases with more than 30% fewer cases (34% after correction for baseline variables) in those assigned amlodipine ± perindopril (P<0.001 versus atenolol±
thiazide).32 The differential effect of the two antihy-
ASCOT-BPLA: evidence for an amlodipine-perindopril combination – Sever
ACE I
NHIBITION
pertensive regimens is likely to be a composite of adverse effects produced by atenolol ± thiazide plus
the protective effect of perindopril, with amlodipine probably playing a neutral role.
ASCOT rewrites the guidelines
Clearly, the longer-term risks associated with newonset diabetes give cause for concern, and the weight
of evidence implicating both β-blockers and diuretics in its causation is now substantial.33 Of all the
hypertension trials reported over the last decade,
the results of ASCOT have probably had the greatest impact on guidelines for the prevention of CV
disease. ASCOT-LLA was stopped early because of
substantial benefits of atorvastatin in the primary
prevention of CHD in a hypertensive population at
modest risk, but with normal or only modestly raised
cholesterol levels. The more recent recommendations, including reductions in the thresholds for intervention with lipid-lowering therapy, have been
strongly influenced by the ASCOT results.34,35 The
ASCOT-BPLA results have also resulted in changes
to the latest UK guidelines reported by the National Institute for Clinical Excellence (NICE) and the
British Hypertension Society (BHS).34
These guidelines advocate selection of first-line
drugs based on the age of the hypertensive patient,
advocating, in younger subjects (<55 years), treatment with a drug that blocks the renin system (ACE
inhibitor or angiotensin receptor blocker [ARB] in
case of ACE-inhibitor intolerance), whereas in older subjects (and blacks), low renin status is more
common, and a CCB or a thiazide-like diuretic is
recommended. These recommendations have been
confirmed following analyses of the ASCOT database which show highly significant effects of age on
the BP-lowering efficacy of antihypertensive drugs
REFERENCES
1. Poulter NR, Sever P. The history of ASCOT. In: Poulter NR,
Sever P, eds. Anglo-Scandinavian Cardiac Outcomes Trial: History, Results and Implications for Clinical Practice. Birmingham,
UK: Sherborne Gibbs Ltd Publications; 2005:5-18.
2. Collins R, Peto R. Antihypertensive drug therapy: effects on
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3. ALLHAT Research Group. Rationale and design for the antihypertensive and lipid lowering treatment to prevent design heart
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6. Peters DC, Noble S, Plosker GL. Trandolapril: an update of its
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8. Lindholm LH. Carlberg B, Samuelsson O. Should beta-blockers remain first choice in the treatment of primary hypertension?
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9. Wiggam MI, Bell PM, Sheridan B, Walmsley A, Atkinson AB.
Low dose bendroflumethiazide (1.25 mg) effectively lowers blood
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10. Harper R, Ennis CN, Sheridan B, Atkinson AB, Johnston GD,
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(to be published). Moreover, the removal of β-blockers as an alternative first-line option in younger
hypertensives from the AB-CD rule, to create a new
A-CD rule, resulted from the observations of an
excess of new-onset diabetes in those receiving βblocker/diuretic based treatment, confirming similar observations from several other trials.33
Several health economic analyses are currently
under way based on the ASCOT resource. Interestingly, in the NICE/BHS report, regimens based on
CCBs and ACE inhibitors were found to be the most
cost-effective when compared with β-blockers and
diuretics.34
Conclusions
In summary, ASCOT, which was one of the largest
trials to be conducted in a hypertensive population,
was designed to evaluate optimal treatment strategies in hypertension to prevent CHD, stroke, and
other outcomes.
Lowering BP with defined algorithms was associated with dramatic and early reductions in CV
events. There were clear advantages of the amlodipine±perindopril strategy on many CV end points
and this combination was far less likely to cause
diabetes compared with atenolol ± thiazide. The
ASCOT-BPLA results form the rationale for the use
of combinations of amlodipine and perindopril in
the management of hypertension. ASCOT was conceived, designed, and coordinated by an
investigator-led independent Steering Committee, members of which represented all the countries where the trial was undertaken. The principal funding source (Pfizer)
had two-nonvoting members on the steering committee.
Data analyses and the preparation of this report were
done independently of the principal funding source.
uretic on insulin action in essential hypertension. BMJ.1994:306:
226-230.
11. Zusman RM. The role of alpha 1-blockers in combination
therapy for hypertension. Int J Clin Pract. 2000;54:36-40.
12. Scandinavian Simvastatin Survival Study Group. Randomised
trial of cholesterol lowering in 4444 patients with coronary heart
disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.
1994;344:1383-1389.
13. Shepherd J, Cobbe SM, Ford I, et al; West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men and women with hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.
14. Sever PS, Dahlöf B, Poulter NR, et al; ASCOT Investigators.
Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. J Hypertens. 2001;6:1139-1147.
15. Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators.
Prevention of cardiovascular events with an antihypertensive
regimen of amlodipine adding perindopril as required versus
atenolol adding bendroflumethiazide as required, in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering
Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
Lancet. 2005;366:895-906.
16. Montori VM, Devereaux PJ, Adhikari NK, et al. Randomized
trials stopped early for benefit: a systematic review. JAMA. 2005;
294:2203-2209.
17. Sever PS, Dahlöf B, Poulter NR, et al; ASCOT Investigators.
Prevention of coronary and stroke events with atorvastatin in
hypertensive patients who have average or lower-than-average
cholesterol concentrations, in the Anglo-Scandinavian Cardiac
Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003:361;1149-1158.
18. MacMahon S. Blood pressure and the risks of cardiovascular
disease. In: Swales JD, ed. Textbook of Hypertension. Oxford, UK:
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Blackwell Scientific Publications; 1994:46-57.
19. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual
blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet.
2002;360:1903-1913.
20. Blood Pressure Lowering Treatment Trialists’ Collaboration.
Effects of different blood-pressure-lowering regimens on major
cardiovascular events: results of prospectively designed overviews
of randomised trials. Lancet. 2003;362:1527-1535.
21. Sever P, Poulter N, Dahlöf B, Wedel H; ASCOT Investigators.
Different time course for prevention of coronary and stroke events
by atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA). Am J Cardiol. 2005;(suppl
96):39F-44F.
22. Poulter NR, Wedel H, Dahlöf B, et al; ASCOT Investigators.
Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac
Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA).
Lancet. 2005;366:907-913.
23. Staessen JA, Birkenhager WH. Cognitive impairment and
blood pressure: quo usque tandem abutere patientia nostra? Hypertension. 2004;44:612-613.
24. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment
on clinical events in the VALUE Trial. Lancet.2004;363:2049-2051.
25. Williams B, Lacy PS, Thom SM, et al; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE
Steering Committee and Writing Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure
and clinical outcomes: principal results of the Conduit Artery
Function Evaluation (CAFE) study. Circulation. 2006;113:12131225.
26. Ariff B, Zambanini A, Vamadeva S, et al. Candesartan- and
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atenolol-based treatments induce different patterns of carotid
artery and left ventricular remodelling in hypertension. Stroke.
2006;37:2381-2384.
27. Staessen JA, Birkenhäger WH. Evidence that new antihypertensives are superior to older drugs. Lancet. 2005;366:869-871.
28. Sever PS, Poulter NR. Blood pressure reduction is not the
only determinant of outcome. Circulation. 2006;113:2754-2774.
29. Verdecchia P, Reboldi G, Angeli F, et al. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertens. 2005;46;
386-392.
30. Sever P, Dahlöf B, Poulter N, et al; ASCOT Steering Committee Members. Potential synergy between lipid-lowering and bloodpressure-lowering in the Anglo-Scandinavian Cardiac Outcomes
Trial. Eur Heart J. 2006;27:2982-2888.
31. Blood Pressure Lowering Treatment Trialists Collaboration.
Effects of different blood pressure-lowering regimens on major
cardiovascular events in individuals with and without major diabetes mellitus. Results of Prospectively Designed Overviews of
Randomised Trials. Arch Intern Med. 2005;165:1410-1419.
32. Gupta AK, Dahlof B, Dobson J, Sever PS, Wedel H, Poulter
NR; ASCOT Investigators. Determinants of new-onset diabetes
among 19,257 hypertensive patients randomised in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering
Arm and the relative influence of antihypertensive medication.
Diab Care. 2008;31:982-988.
33. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:
201-207.
34. CG34 Hypertension. Full guidelines. www.nice.org.uk. Accessed September 19; 2008.
35. JBS 2. Joint British Societies’ Guidelines on Prevention of
Cardiovascular Disease in Clinical Practice. Heart. 2005;9(supp
V): v1-v52.
ASCOT-BPLA (ANGLO-SCANDINAVIAN CARDIAC
OUTCOMES TRIAL–BLOOD PRESSURE LOWERING ARM) :
ARGUMENTS EN FAVEUR DE L’UTILISATION DE
L’ASSOCIATION PERINDOPRIL-AMLODIPINE
L’
étude ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial–Blood
Pressure Lowering Arm), réalisée chez 19 257 patients hypertendus à
risque modéré de développer des événements cardio-vasculaires, a été
arrêtée prématurément à cause de la réduction du nombre de critères atteints,
comme la mortalité toutes causes (11 % ; p = 0,025) et la mortalité cardio-vasculaire (24 % ; p = 0,001) dans le groupe amlodipine ± perindopril comparé au
groupe aténolol ± thiazide. Étant donné l’arrêt précoce de l’étude et la prescription croissante des statines tout au long de l’étude, la réduction du risque
relatif de 10 % du critère primaire (infarctus du myocarde non fatal et maladie coronaire [MC] fatale) dans le bras amlodipine ± perindopril n’a pas atteint
la significativité statistique en raison du nombre insuffisant d’événements (903
critères atteints contre 1 150 prévus). Néanmoins, ce traitement était associé
à une diminution de 13 % des événements coronaires (p = 0,007), de 23 % des
AVC totaux (p = 0,003), de 16 % de tous les événements et interventions cardiovasculaires (p < 0,0001) et de 30 % d’apparition de nouveaux diabètes (p <
0,0001). La différence moyenne de pression artérielle en cours d’étude était de
2,7/1,9 mmHg en faveur de l’association amlodipine ± perindopril. Les analyses après ajustements multiples ont montré que l’ajustement pour la pression artérielle expliquait environ 30 % de la différence de survenue des AVC
entre les deux groupes de traitement alors qu’il n’a eu quasiment aucun impact sur la MC. Les résultats de l’essai ASCOT-BPLA fournissent ainsi l’argumentaire pour la prescription de l’association amlodipine-perindopril dans le
traitement de l’hypertension artérielle.
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ASCOT-BPLA: evidence for an amlodipine-perindopril combination – Sever
AS
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ACE INHIBITION
Guido GRASSI,* MD
Giuseppe MANCIA,* MD, PhD
*Full Professor of Medicine
Department of Clinical Medicine
and Cardiovascular Prevention
San Gerardo Hospital
and Milano-Bicocca University
and Centro Auxologico Italiano
Milan, ITALY
Treating diabetic
hypertensive patients:
new insights from
the ADVANCE trial
by G. Grassi and G. Mancia, Italy
herapeutic interventions aimed at reducing elevated blood pressure in
diabetic hypertensive patients encompass a number of limitations and
are frequently faced with at least partial clinical lack of success. Several
reasons may explain this discouraging scenario, among which two stand out:
first, the difficulties to achieve optimal blood pressure control; and second, no
more than 10% to 15% treated hypertensive diabetics in current clinical practice display blood pressure values less than 130/80 mm Hg, as recommended by
current guidelines. Another reason that may explain the abovementioned findings is that the drugs used to lower elevated blood pressure in diabetic patients
are not always capable of exerting cardioprotective and nephroprotective effects and thus of improving the elevated risk profile of these subjects. A challenging strategy in the therapeutic approach to diabetic hypertension is that
adopted by the Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation (ADVANCE) trial. In this trial, the largest ever
performed in diabetes, use of the perindopril/indapamide combination allowed
effective blood pressure control and significantly reduced the risk of the major
macrovascular and microvascular complications that these high-risk patients
frequently display. The favorable effects of this angiotensin-converting enzyme
inhibitor/diuretic combination, together with its excellent tolerability profile,
make it the first-choice treatment in the management of the diabetic patient.
T
Medicographia. 2009;31:51-56.
(see French abstract on page 56)
Keywords: hypertension; diabetes; antihypertensive treatment; cardiovascular
risk; clinical trial; ACE inhibitor; diuretic; perindopril; combination
treatment
www.medicographia.com
Address for correspondence: Prof Guido Grassi, Clinica Medica, Ospedale San Gerardo,
Università Milano-Bicocca, Via Pergolesi 33, 20052 Monza (Milano), Italy
(e-mail: [email protected])
Treating diabetic hypertensive patients: new insights from ADVANCE – Grassi and Mancia
OF
HYPERTENSION TREATMENT
ypertension is common in patients with diabetes mellitus and represents an important
risk factor for cardiovascular events, including macro- and microvascular complications, such
as nephropathy.1,2 Evidence provided by large-scale
clinical trials has shown, however, that the risk is
not irreversible and that blood pressure reduction
by antihypertensive treatment can provide effective
cardiovascular protection in patients classified, according to the 2007 European Society of Hypertension/European Society of Cardiology (ESH/ESC)
Guidelines on Hypertension, as being at “very highrisk.”3
This paper focuses on three major issues. First, it
examines the benefits of blood pressure reduction
in providing cardiovascular protection in hypertensive patients with diabetes mellitus. Second, it examines the differences in obtaining optimal blood pressure control in these patients and the therapeutic
strategies to achieve this goal. Finally, we discuss
the main features and the results obtained so far
in the Action in Diabetes and Vascular disease:
PreterAx and DiamicroN-MR Controlled Evaluation
(ADVANCE) trial,4 the largest trial ever performed
in a population of diabetic hypertensives.
H
Benefits of blood pressure reduction
in diabetic hypertensives
Evidence from several studies has clearly demonstrated that the risk associated with elevated blood
pressure in patients with diabetes is reversible if
blood pressure is reduced, regardless of the therapeutic strategy employed. The Systolic Hypertension in the Elderly Program (SHEP) enrolled patients, aged 60 years and older, with isolated systolic
hypertension, including 4149 patients without diaSELECTED
ABBREVIATIONS AND ACRONYMS
ABCD
Appropriate Blood pressure Control in
Diabetes
ADVANCE Action in Diabetes and Vascular disease:
PreterAx and DiamicroN-MR Controlled Evaluation
ASCOT
Anglo-Scandinavian Cardiac Outcomes
Trial
HOT
Hypertension Optimal Treatment
IDNT
Irbesartan Diabetic Nephropathy Trial
INSIGHT International Nifedipine GITS Study
Intervention as a Goal in Hypertension Treatment
LIFE
Losartan Intervention For Endpoint
reduction in hypertension
PAMELA Pressioni Arteriose Monitorate E Loro
Associazioni
RENAAL Reduction of Endpoints in Non-insulin
dependent diabetes mellitus with the
Angiotensin II Antagonist Losartan
SHEP
Systolic Hypertension in the Elderly
Program
STRATHE STRAtegies of Treatment in Hypertension Evaluation
UKPDS
United Kingdom Prospective Diabetic
Study
MEDICOGRAPHIA, VOL 31, No. 1, 2009
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betes and 583 with type 2 diabetes.5 After treatment
with either chlorthalidone 12 to 25 mg/day, with
step-up therapy with reserpine or atenolol if required, or placebo (in addition to any preexisting
antihypertensive medication), the 5-year cumulative rate of major cardiovascular events among patients with diabetes was significantly lower for those
receiving the diuretic, with a reported relative risk
reduction amounting to 34%.
Although recent studies have shown the antihypertensive drug regimens based on β-blockers6 have
dyslipidemic effects and increase the incidence of
new-onset diabetes, data from a number of placebocontrolled studies have indicated that β-blockers
can reduce the risk of recurrent myocardial infarction in patients with existing diabetes, with a relative risk ranging from 0.31 to 0.76.7-11 Newer an-
2.0
1.5
In (RR)
1.0
0.5
0.0
–0.5
–1.0
–1.5
<120
121130
131140
141150
151160
161170
171180
>180
Average follow-up SBP (mm Hg)
Figure 1. Impact of systolic blood pressure (SBP) reduction on risk of renal
end point. RR: relative risk.
Modified after reference 14: Pohl MA, Blumenthal S, Cordonnier DJ, et al. Independent and
additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial: clinical implications and limitations. J Am
Soc Nephrol. 2005;16:3027-3037. Copyright © 2005, American Society of Nephrology.
tihypertensive drugs are also associated, with a
reduced risk of adverse cardiovascular events.12
Although recent data have indicated that there is
a degree of protection associated with blood pressure levels less than 140/90 mm Hg, even greater
protection is associated with levels less than 130/
80 mm Hg. In the Hypertension Optimal Treatment
(HOT) study,13 patients were randomly assigned to
target diastolic blood pressure values of 90 mm Hg
or less, 85 mm Hg or less, and 80 mm Hg or less,
and were followed for 3.3 to 4.9 years. In a subanalysis of 1501 patients with diabetes randomized to
two blood pressure reduction target groups, the
group with the target reduction of 80 mm Hg or less
showed a 51% reduction in the risk of major cardiovascular events (including myocardial infarction,
stroke, and cardiovascular-related death) compared
with those with a target of 90 mm Hg or less. A retrospective analysis of the data collected in patients
with diabetic nephropathy in the Irbesartan Diabetic Nephropathy Trial (IDNT) demonstrated that
reductions in systolic blood pressure (SBP) to 130
mm Hg or less were associated with a lower relative
risk of congestive heart failure than those whose
SBP remained higher than 130 mm Hg14,15 The IDNT
also highlighted the fact that aggressive blood pres52
MEDICOGRAPHIA, VOL 31, No. 1, 2009
sure reduction is also associated with additional
nephroprotection. SBP amounting to 130 mm Hg
or less was associated with improved renal and patient survival compared with systolic values of more
than 130 mm Hg, including patients achieving a
blood pressure level of less than 140 mm Hg (Figure 1.)14 Furthermore, a 20-mm Hg reduction in
SBP was associated with a 47% reduction in the
risk of developing a renal end point.
Optimal blood pressure control
in patients with diabetes
Evidence suggests that it is advantageous to initiate
antihypertensive therapy in patients with diabetes
who have blood pressure levels in the high–normal
range with the goal of reducing SBP to less than
130 mm Hg. The Appropriate Blood pressure Control in Diabetes (ABCD) trial evaluated the effect of
moderate or intensive antihypertensive therapy on
diabetic vascular complications in normotensive patients with type 2 diabetes.16 A total of 480 patients
were randomly assigned to receive 5 years’ treatment with “intensive therapy” with either enalapril
or nisoldipine, or moderate therapy,” with placebo
and then either enalapril or nisoldipine in those
who subsequently became hypertensive during the
study. Respective mean blood pressure for the past
4 years of the study was 128/75 and 137/81 mm Hg,
in the intensive and moderate therapy groups. Cerebrovascular events occurred in a significantly smaller proportion of patients in the intensive therapy
group than the moderate therapy group. As a result
of the ABCD trial, and in the face of similar evidence
from other studies, guidelines for the management
of hypertension and diabetes currently recommend
a target blood pressure of less than 130/80 mm Hg
in patients with diabetes, renal disease, or high cardiovascular risk.3 In addition, antihypertensive therapy should be initiated in high-risk patients with
blood pressure in the high–normal range of less
than 140/90 mm Hg.3,17-18
Evidence from the United Kingdom Prospective
Diabetic Study (UKPDS)19 trial indicated that blood
pressure reduction contributed to the relative reduction in cardiovascular events to a greater extent
than glycemic control.20 A comparison of “tight”
blood pressure control and “tight” glucose control
in patients with type 2 diabetes has shown that
blood pressure control was associated with significantly greater risk reductions in stroke, diabetic end
points, diabetes-related mortality, and microvascular complications. Two possible mechanisms may
explain the advantages of rigorous blood pressure
control in patients with diabetes. First, patients with
diabetes lose the ability to autoregulate blood pressure early on, and so there is a passive increase in
blood pressure at the level of microcirculation,
transmitting the traumatic effect of pressure from
the arterial compartment into arterioles and capillaries of the target organs.21,22 A second possible
mechanism suggests that even in the “uncomplicated phase,” patients with diabetes may lose the
ability to lower blood pressure during sleep, even
in the early stages of the disease. Data from a study
Treating diabetic hypertensive patients: new insights from ADVANCE – Grassi and Mancia
NHIBITION
using 24-hour intra-arterial blood pressure monitoring demonstrated that mean arterial pressure
and heart rate both decrease significantly at night,
compared with daytime values, in normotensive and
hypertensive patients with and without diabetes.23
The results of another study,24 however, suggested
that the nighttime decrease in arterial pressure and
heart rate in hypertensive patients with diabetes
may be only approximately 50% of the reduction
observed in hypertensive patients without diabetes.
In the absence of a decrease in blood pressure during sleep, patients with diabetes would therefore
have a 24-hour blood pressure load that is greater
than patients without diabetes for any given daytime blood pressure.
Blood pressure control in diabetes:
current evidence and future strategies
It is becoming increasingly clear that it is difficult
to control blood pressure to the degree that scientific evidence and guidelines indicate is necessary
to provide adequate protection. An analysis performed few years ago by our group on 22 sets of
blood pressure values from 13 hypertension trials
showed that whereas diastolic blood pressure was often reduced to less than 85 mm Hg, SBP remained
greater than 130 mm Hg, and even greater than 140
mm Hg in several studies.25 Moreover, in the AngloScandinavian Cardiac Outcomes Trial (ASCOT),26
only approximately 30% of patients with diabetes
achieved blood pressure targets (defined as a blood
pressure level of <130/80 mm Hg), compared with
60% of patients without diabetes (defined as a blood
pressure level of <140/90 mm Hg).
In clinical practice, it appears that even fewer patients are being treated to target. A cross-sectional
survey of diabetic patients determined that only
17.4% of respondents with concomitant hypertension had blood pressure controlled to less than 140/
90 mm Hg, and this rate was not significantly different between the subgroups of patients with
macroalbuminuria or microalbuminuria.27 In the
ForLife study,28 only 3% of 2491 patients with diabetes and hypertension achieved blood pressure
control to less than 130/80 mm Hg, in agreement
with the ESH/ESC Guidelines.3 Whereas a further
14.9% achieved a blood pressure level between 130/
80 and 140/90 mm Hg, 85.1% of the study population had blood pressure greater than 140/90 mm
Hg.28 These data suggest that the rate of optimal
blood pressure control is very low and that the target of 130/80 mm Hg is ambitious.
AS
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CORNERSTONE
It is widely acknowledged that combination therapy
is necessary to achieve adequate blood pressure control in patients with diabetes and hypertension. On
average more than two antihypertensive agents
were required to achieve adequate blood pressure
control in the UKPDS study, and more than three
were required in the Reduction of Endpoints in NonInsulin dependent diabetes mellitus with the Angio-
HYPERTENSION TREATMENT
P=0.005
70
P=0.01
60
62%
50
40
49%
47%
Sequential
monotherapy
(n=176)
Stepped-care
(n=177)
30
20
10
0
Improving blood pressure control
in diabetic hypertensives
OF
tensin II Antagonist Losartan (RENAAL) and IDNT
studies.20,29-30 In the HOT, Losartan Intervention For
Endpoint reduction in hypertension (LIFE), and International Nifedipine GITS Study Intervention
as a Goal in Hypertension Treatment (INSIGHT)
studies, a greater proportion of hypertensive patients with diabetes required combination therapy
compared with those without diabetes.13,31-32 Furthermore, despite the greater use of combination
treatment, SBP values during treatment remained
higher in patients with diabetes compared with
those without. Current guidelines recommend that
high-risk patients start with combination treatment.3,17-18 Three different 9-month treatment strategies were compared in the STRAtegies of Treatment in Hypertension Evaluation (STRATHE)
study.33 These included: (i) combination treatment
(perindopril 2 mg plus indapamide 0.625 mg) with
an increase in dosage according to patient response;
(ii) sequential monotherapy strategy with atenolol
initially, changing to losartan (if no response), then
to amlodipine; and (iii) the classic step-by-step
strategy with valsartan monotherapy, with an increase in the dose (if no response), and then combining valsartan plus hydrochlorothiazide.The combination treatment strategy was accompanied by a
significantly greater rate of blood pressure reduction to less than140/90 mm Hg (Figure 2).22 This difference was clear from the beginning of treatment
and was mainly the result of a better decrease in SBP
in the group treated by perindopril/indapamide.
Finally, evidence has been provided that not only
office (or sphygmomanometric), but also 24-hour
blood pressure have a major impact on cardiovascular morbidity and mortality. The Pressioni Arteriose
Monitorate e Loro Associazioni (PAMELA) study34
investigated home, office, and 24-hour ambulatory
blood pressure measurements, and fatal events and
their causality in a cohort of over 2000 patients followed for more than 12 years. Patients in whom
blood pressure was normal when recorded by each
of the three methods had a favorable outcome, but
Patients with BP
<140/90 mm Hg (%)
ACE I
Low-dose
combination
(n=189)
Figure 2. Percentage of patients achieving a blood pressure of less than
140/90 mm Hg after 6 or 9 months of treatment with antihypertensive
drugs and various treatment schedules. Patients who reached the target
blood pressure at 6 months were discontinued form the study at that
time; otherwise, treatment continued for 9 months.
Modified after reference 33: Mourad JJ, Waeber B, Zannad F, Laville M, Duru G, Andrejak
M; Investigators of the STRATHE Trial. Comparison of different therapeutic strategies
in hypertension: a low-dose combination of perindopril/indapamide versus a sequential
monotherapy or a stepped-care approach. J Hypertens. 2004;22:2379-2386. Copyright ©
2004, Lippincott Williams & Wilkins.
Treating diabetic hypertensive patients: new insights from ADVANCE – Grassi and Mancia
MEDICOGRAPHIA, VOL 31, No. 1, 2009
53
ACE I
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AS
A
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HYPERTENSION TREATMENT
OF
Modified after reference 4: ADVANCE Collaborative Group. Effects of a fixed combination of
perindopril and indapamide on macrovascular
and microvascular outcomes in patients with
type 2 diabetes mellitus (the ADVANCE trial);
a randomized controlled trial. Lancet. 2007;
370:829-840. Copyright © 2007, Elsevier Ltd.
20
Placebo
Perindopril-Indapamide
15
HR=0.91 (95% CI 0.81- 1.00)
P=0.041
Macro
+ micro
All
deaths
CV
deaths
5
0
6 12
18 24 30 36 42 48 54 60
Follow-up (months)
CHD
Stroke
Renal
New
MA
–21
–21
*
*
–6
–9
--15%
--20%
*
–14
*
–14
–18
*
--25%
*
Figure 4. Percent reduction in micro- and macrovascular events, coronary
heart disease (CHD), stroke, renal disease and new microalbuminuria (MA)
in the Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR
Controlled Evaluation (ADVANCE) trial.
Modified after reference 4: ADVANCE Collaborative Group. Effects of a fixed combination of
perindopril and indapamide on macrovascular and microvascular outcomes in patients with
type 2 diabetes mellitus (the ADVANCE trial); a randomized controlled trial. Lancet. 2007;
370:829-840. Copyright © 2007, Elsevier Ltd.
epidemiology precedes treatment, it does provide
information that can be used for treatment. Therefore, ideally, blood pressure control should be assessed not only by measuring office blood pressure,
but also home and 24-hour ambulatory blood pressure. The practicality of implementing this in clinical practice (particularly in diabetic hypertensives),
however, warrants further discussion.
ADVANCE trial: objectives and design
The difficulties in achieving blood pressure control
in diabetic hypertensives as well the lack of information related to the benefits of blood pressure and
blood pressure–lowering interventions on major
vascular disease represent the background for
ADVANCE, the largest multicenter, multinational,
randomized prospective trial ever carried out in
patients with type 2 diabetes.4 This trial had three
54
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Placebo
Perindopril-Indapamide
HR=0.86 (95% CI 0.75- 0.98)
P=0.025
15
10
5
0
0
--5%
--10%
20
10
outcome, including both cardiovascular-related
deaths and all-cause fatalities, worsened progressively as the number of methods that recorded an
elevated blood pressure increased. This increased
mortality occurred regardless of whether blood pressure elevations were detected on the basis of office
versus ambulatory or office versus home blood pressure methods. Although it is acknowledged that
0
All-cause mortality
Cumulative incidence (%)
Figure 3. Combined primary
outcome and mortality curves
in patients of the Action in Diabetes
and Vascular disease: PreterAx and
DiamicroN-MR Controlled Evaluation
(ADVANCE) trial randomized to
placebo or perindopril/indapamide
combination treatment.
Cumulative incidence (%)
Combined primary outcome
0
6 12
18 24 30 36 42 48 54 60
Follow-up (months)
major goals, which included a blood pressure– as
well as a blood glucose–lowering arm.35-37 First,
ADVANCE was planned with the aim of determining
the effects of blood pressure reduction on macrovascular and microvascular disease. Specifically,
the trial evaluated the effects of a fixed combination
of an ACE inhibitor (perindopril) and a diuretic (indapamide) given on top of all other cardiovascular
therapy on vascular events. Finally, ADVANCE was
also aimed, in its blood glucose-lowering arm, at
assessing whether more intensive blood glucose
control (glycated hemoglobin levels <6.5%) could
prevent microvascular as well as macrovascular disease and death.
The study population included patients aged 55
years or more and with type 2 diabetes. More than
70% of the enrolled patients were hypertensives and
already under antihypertensive drug. Following a
6-week run-in phase, during which patients were
assessed for their eligibility and likely compliance
with treatment, patients were assigned to a randomized treatment. For the blood pressure–lowering
arm of ADVANCE, participants were randomly assigned, on a double-blind basis, to perindopril–indapamide fixed-dose combination (initially 2.0/0.625
mg, increasing to 4.0/1.25 mg a day after 3 months)
or matching placebo in addition to standard antihypertensive therapy, as required. For the glucose control arm of the study, participants were randomly
assigned to an open comparison of a gliclazide-MR–
based intensive glucose control regimen, targeting
on HbA1c levels of 6.5% or less, compared with a
standard guidelines–based glucose regimen.35-36 Results of this glucose-lowering arm have been recently published, providing evidence on the benefits (--10% of the primary end point represented by
combined macrovascular and microvascular events)
of an intensive glucose-lowering intervention.38
The primary outcome of ADVANCE, which was
the same for the two arms of the study, was a composite macrovascular end point (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular
death) and a composite microvascular end point
(new or worsening nephropathy or microvascular
eye disease), analyzed together or separately.35-36
All suspected primary outcomes and all deaths
were reviewed by an End Point Adjudication Committee that was blind to randomized treatments
for both the blood pressure and the glucose control
Treating diabetic hypertensive patients: new insights from ADVANCE – Grassi and Mancia
ACE I
NHIBITION
arms. The trial was an independent, investigatorled study, which was carried out in more than 200
clinical centers located in Europe, North America,
Asia, and Australia. Coordination was performed at
the University of Sidney, with participation of five
coordinating centers located in the five aforementioned geographic areas of the world.
ADVANCE trial: main results
The results of the blood pressure–lowering treatment arm have been published in 2007 in Lancet.4
A total of 11 140 diabetic patients were randomized
to active treatment or placebo. More than 2/3 of
them, as already mentioned, were hypertensives
and their entry mean blood pressure values were,
despite treatment, well above the target recommended by current guidelines (145/81 mm Hg).3
The results of the trial can be summarized ad follows. First, administration of a fixed combination
of indapamide and perindopril was associated with
a greater reduction in systolic and diastolic blood
pressure (5.6/2.2 mm Hg) than was placebo. This
blood pressure difference was accompanied by a
significant reduction in the combined incidence of
macrovascular and microvascular complications
(Figure 3).4 It was further accompanied by reductions of 14% in coronary events, 21% in renal events,
and 14% in all-cause death (Figure 4).4 Thisleaves no
doubt as to the protective effects of blood pressure–
lowering strategies in diabetics. It also illustrates
the value of strategies than can lower blood pressure
more effectively than is commonly achieved in clinical practice. This because in ADVANCE the blood
pressure values achieved were 140/73 mm Hg in
the placebo group and 136/73 mm Hg in the actively treated group, indicating that the beneficial
effects are evident at blood pressure values below
140/90 mm Hg. This is also because the benefits are
apparent not only in the hypertensive patients, but
also in those who did not have a history of hypertension and/or who displayed initial blood pressure
values below 140/90 mm Hg.
Three other aspects of the study are also worthy
of mention. First, the patients recruited were well
treated for the diabetic condition and for the frequent coexistence of cardiovascular risk factors,
and more so during treatment than at baseline.
As a result, average values were as follows: glycated
hemoglobin 6.9%, total serum cholesterol 176
mg/dL, low-density lipoprotein (LDL) cholesterol
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Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Insulin
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2. Pieske B, Wachter R. Impact of diabetes and hypertension on
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3. Mancia G, De Backer G, Dominiczak A, et al. Management of
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4. ADVANCE Collaborative Group. Effects of a fixed combination
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AS
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CORNERSTONE
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HYPERTENSION TREATMENT
100 mg/dL, and triglycerides 66 mg/dL. This indicates that the benefit of the fixed combination of
perindopril-indapamide administration occurred
on top of what was an optimal cardiovascular preventive treatment. Second, reduction in renal events
in the perindopril-indapamide group includes a
21% lower incidence of new-onset microalbuminuria. This suggests that the treatment employed in
the study had a primary preventive effect on the
appearance of diabetic nephropathy, a benefit presumably shown for ACE-inhibitor administration
at blood pressure values higher than those explored
in ADVANCE.39 Microalbuminuria and nephropathy considerably increase the already elevated cardiovascular risk of diabetes,40 in addition to shortening the life of the kidneys. Finally, the results of
the ADVANCE are likely to considerably modify the
idea that antihypertensive treatment of diabetes is
difficult, frequently unsuccessful, and subject to
great caution because of the high incidence of hypertension and other side effects.3
Conclusions
The ADVANCE results provide evidence that the
fixed combination treatment used in the trial and
administered on top of all other drugs (antihypertensive drugs, statins, aspirin, and blood glucose–
lowering agents) had a favorable impact on the
elevated cardiovascular risk profile of the diabetic
patient. This makes this therapeutic strategy mandatory in diabetic patients because, according to the
ADVANCE trial results it is: (i) practical and affordable in clinical practice around the world; (ii) safe,
well tolerated, and requires little monitoring; and
(iii) effective in the majority of patients, independently of age, gender, baseline blood pressure, and
level of cardiovascular risk.
In commenting on the ADVANCE trial results,
an obvious question should be addressed, namely
whether the study data imply that the fixed combination of perindopril/indapamide should become
a routine therapeutic approach for patients with diabetes mellitus, even when blood pressure is not
elevated. An analysis of the ADVANCE data suggest
that this is the case, also considering the fact that
the recent European Guidelines for the management of hypertension speak in favor of initiating antihypertensive treatment in diabetic patients even
when blood pressure is still in the high-normal
range. cular outcomes in patients with type 2 diabetes mellitus (the
ADVANCE trial); a randomized controlled trial. Lancet. 2007;370:
829-840.
5. Curb JD, Pressel SL, Cutler JA, et al; Systolic Hypertension in
the Elderly Program Cooperative Research Group. Effect of diuretic-based antihypertensive treatment on cardiovascular disease
risk in older diabetic patients with isolated systolic hypertension.
JAMA. 1996;276:1886-1892.
6. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens. 2006;24:3-10.
7. Beta-blocker Heart Attack Trial Research Group (BHAT).
A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA. 1982;247:17071714.
8. First International Study of Infarct Survival Collaborative
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9. Herlitz J, Elmfeldt D, Holmberg S, et al. Goteborg Metoprolol
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10. MIAMI Trial Research Group. Long-term prognosis after early intervention with metoprolol in suspected acute myocardial
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230:233-237.
11. Pedersen TR. The Norwegian Multicenter Study of Timolol
after Myocardial Infarction. Circulation. 1983;67:I49-I53.
12. Turnbull F, Neal B, Algert C, et al; Blood Pressure Lowering
Treatment Trialists’ Collaboration. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med.
2005;165:1410-1419.
13. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients
with hypertension: principal results of the Hypertension Optimal
Treatment (HOT) randomised trial. Lancet.1998;351:1755-1762.
14. Pohl MA, Blumenthal S, Cordonnier DJ, et al. Independent
and additive impact of blood pressure control and angiotensin II
receptor blockade on renal outcomes in the irbesartan diabetic
nephropathy trial: clinical implications and limitations. J Am Soc
Nephrol. 2005;16:3027-3037.
15. Berl T, Hunsicker LG, Lewis JB, et al; Collaborative Study
Group. Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial. J Am Soc
Nephrol. 2005;16:2170-2179.
16. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002;
6:1086-1097.
17. Chobanian AV, Bakris GL, Black HR, et al; National High
Blood Pressure Education Program Coordinating Committee.
The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Complete report. Bethesda, Md: National Institutes of
Health; 2004. Available at: http://www.nhlbi.nih.gov/guidelines/
hypertension/jnc7full.pdf.
18. WHO; International Society of Hypertension Writing Group.
2003 World Health Organization (WHO)/International Society
of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21:1983-1992.
19. Adler AI, Stratton IM, Neil HA, et al. Association of systolic
blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419.
20. Bakris GL, Williams M, Dworkin L, et al; National Kidney
Foundation Hypertension and Diabetes Executive Committees
Working Group. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis.
2000;36:646-661.
21. Fegan PG, Tooke JE, Gooding KM, Tullett JM, MacLeod KM,
Shore AC. Capillary pressure in subjects with type 2 diabetes and
hypertension and the effect of antihypertensive therapy. Hypertension. 2003;41:1111-1117.
22. Schofield I, Malik R, Izzard A, Austin C, Heagerty A. Vascular structural and functional changes in type 2 diabetes mellitus:
evidence for the roles of abnormal myogenic responsiveness and
dyslipidemia. Circulation. 2002;106:3037-3043.
23. Mancia G, Ferrari A, Gregorini L, et al. Blood pressure and
heart rate variabilities in normotensive and hypertensive human
beings. Circ Res. 1983;53:96-104.
24. Frattola A, Parati G, Castiglioni P, et al. Lacidipine and blood
pressure variability in diabetic hypertensive patients. Hypertension. 2000;36:622-628.
25. Mancia G, Grassi G. Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens. 2002;20:14611464.
26. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine
adding perindopril as required plus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005; 366:895-906.
27. Collado-Mesa F, Colhoun HM, Stevens LK, et al. Prevalence
and management of hypertension in type 1 diabetes mellitus in
Europe: the EURODIAB IDDM Complications Study. Diabet Med.
1999;16:41-48.
28. Mancia G, Ambrosioni E, Rosei EA, Leonetti G, Trimarco B,
Volpe M; ForLife Study Group. Blood pressure control and risk of
stroke in untreated and treated hypertensive patients screened
from clinical practice: results of the ForLife study. J Hypertens.
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2005;23:1575-1581.
29. Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study
Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl
J Med. 2001;345:861-869.
30. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study
Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.
31. Kjeldsen SE, Dahlof B, Devereux RB, et al. Lowering of blood
pressure and predictors of response in patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint. Am J Hypertens. 2000;13:899-906.
32. Brown MJ, Castaigne A, de Leeuw PW, et al. Influence of diabetes and type of hypertension on response to antihypertensive
treatment. Hypertension. 2000;35:1038-1042.
33. Mourad JJ, Waeber B, Zannad F, Laville M, Duru G, Andrejak
M; Investigators of the STRATHE Trial. Comparison of different
therapeutic strategies in hypertension: a low-dose combination
of perindopril/indapamide versus a sequential monotherapy or a
stepped-care approach. J Hypertens. 2004;22:2379-2386.
34. Mancia G, Facchetti R, Bombelli M, Grassi G, Sega R. Longterm risk of mortality associated with selective and combined
elevation in office, home, and ambulatory blood pressure. Hypertension. 2006;47:846-853.
35. ADVANCE Management Committee. Study rationale and design of ADVANCE: action in diabetes and vascular disease – Preterax and Diamicron MR controlled evaluation. Diabetologia.
2001;44:1118-1120.
36. ADVANCE Collaborative Group. Rationale and design of the
ADVANCE study: a randomised trial of blood pressure lowering
and intensive glucose control in high risk individuals with type 2
diabetes mellitus. J Hypertens. 2001;19(suppl 4):S21-S28.
37. ADVANCE Collaborative Group. ADVANCE action in diabetes
and vascular disease: patient recruitment and characteristics of
the study population at baseline. Diabet Med. 2005;22:882-888.
38. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl
J Med. 2008;358:2560-2572.
39. Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V,
et al. for the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in
type 2 diabetes. N Engl J Med. 2004;351:1941-1951.
40. Miettinen H, Haffner SM, Lehto S, Rönnemaa T, Pyörälä K,
Laakso M. Proteinuria predicts stroke and other atherosclerotic
vascular disease events in nondiabetic and non-insulin-dependent
diabetic subjects. Stroke. 1996;27:2033-2039.
LE
TRAITEMENT DU PATIENT DIABÉTIQUE HYPERTENDU
RÉFLEXIONS SUR L’ÉTUDE ADVANCE
:
L
es traitements visant à abaisser la pression artérielle des patients diabétiques hypertendus sont confrontés à un certain nombre de limites et et
ne rencontrent souvent qu’un succès clinique partiel. Ce scénario décourageant peut s’expliquer de plusieurs façons, deux d’entre elles se distinguant : tout d’abord, la difficulté d’obtention d’un contrôle optimal de la pression artérielle ; et d’autre part, le fait que pas plus de 10 % à 15 % des diabétiques
hypertendus traités en pratique clinique actuelle ne présentent des valeurs de
pression artérielle inférieures à 130/80 mmHg, comme les directives le préconisent. Une autre raison pouvant expliquer cet état de fait est que les médicaments utilisés pour abaisser la pression artérielle élevée des diabétiques ne sont
pas toujours capables d’exercer des effets cardioprotecteurs et néphroprotecteurs
et donc d’améliorer le risque élevé de ces patients. L’étude ADVANCE (Action in
Diabetes and Vascular disease : PreterAx and DiamicroN-MR Controlled Evaluation) a adopté une stratégie novatrice dans son approche thérapeutique de l’hypertension chez les diabétiques. Dans cette étude, la plus grande jamais réalisée sur le diabète, l’utilisation de l’association perindopril/indapamide a permis
un contrôle efficace de la pression artérielle et a réduit de façon significative le
risque des complications macrovasculaires et microvasculaires majeures présentées fréquemment par ces patients à haut risque. Les effets positifs de cette
association d’un inhibiteur de l’enzyme de conversion de l’angiotensine et d’un
diurétique, assortis d’une excellente tolérance, en font le traitement de premier
choix dans la prise en charge du patient diabétique.
Treating diabetic hypertensive patients: new insights from ADVANCE – Grassi and Mancia
C
O N T R O V E R S I A L
Q
U E S T I O N
What determines your choice
between free and fixed combinations
in the management of
your hypertensive patients?
1
A. de la Sierra, Spain
T
Alejandro DE LA SIERRA,
MD, PhD
Hypertension Unit
Department of Internal
Medicine, Hospital Clinic
Universtiy of 170-Villarroel
08036 Barcelona
SPAIN
(e-mail: [email protected])
www.medicographia.com
he established view on antihypertensive
therapy (and also the treatment plan used
in most published clinical trials) is that
treatment should commence with a single drug,
with the possibility of combining two drugs being
reserved for patients who do not achieve target
blood pressure. However, recent guidelines 1,2 suggest antihypertensive treatment may be initiated
with a combination of two drugs at low doses.
Also, when considering combination therapy,
whether at the beginning of treatment or as addon therapy, doctors frequently ask themselves
if it’s better to use two agents separately (a free
combination) or as a single tablet (fixed-dose
combination). What are the advantages and disadvantages of fixed-dose combinations? There are
obviously some disadvantages but, fortunately,
most remain theoretical. Firstly, a combination
of two agents may increase the number of adverse
reactions. If this occurs when using a fixed-dose
combination, it may be more difficult to identify
the causal agent of the adverse effect. Moreover,
if this usually implies downtitration or interruption of the drug responsible, it is usually difficult
to proceed without modifying the entire treatment. However, recently developed antihypertensive drugs are almost free of side effects and the
sum of two drugs with side effects does not usually result in an increase. In fact, some reports
suggest that combining low-dose diuretics or calcium channel blockers (CCBs) with angiotensinconverting enzyme (ACE) inhibitors or angiotensin
receptor blockers (ARBs) reduces the deleterious
metabolic effects of diuretics and the pedal edema
associated with CCBs, in comparison with when
these agents are used in monotherapy.3 Secondly, most fixed-dose combinations are not available
at low doses and doctors are concerned about
an excessive blood pressure drop if a fixed-dose
combination is used as initial therapy. Therefore,
combinations containing low doses of both antihypertensives, such as the perindopril/indapamide
combination, are preferable when used as initial
therapy. In contrast, the greatest advantages associated with antihypertensive treatment based
on fixed-dose combinations are the improvement
Free or fixed antihypertensive drug combinations?
in compliance and the achievement of earlier
blood pressure control in a higher proportion of
patients with a single tablet. The latter is extremely important in high-risk hypertensives, as was
clearly demonstrated in the VAlsartan antihypertensive Long-term Use Evaluation (VALUE) 4 trial,
where the benefits observed in the group receiving amlodipine were associated with a greater
and more rapid blood pressure reduction. Two
recent trials have clearly shown the benefits of
antihypertensive treatment based on fixed-dose
combinations, either as add-on antihypertensive
treatment or as initial treatment. The Action in
Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation (ADVANCE) 5
trial used the fixed-dose combination of perindopril and indapamide in more than 11 000 type 2
diabetic patients, hypertensives, or normotensives.
Even when used on top of other drugs blocking
the renin-angiotensin system, such as an ACE
inhibitor or an ARB, treatment with perindopril
and indapamide significantly reduced the rate
of combined microvascular and macrovascular
events (9%) and total (14%) and cardiovascular
(18%) mortality. The other trial in favor of fixeddose combination, whose findings are not yet
published, is the Avoiding Cardiovascular events
through COMbination therapy in Patients LIving
with Systolic Hypertension (ACCOMPLISH) trial.6
This trial used two fixed combinations of an ACE
inhibitor with either a CCB or a thiazide diuretic
in high-risk hypertensives (60% diabetics). Beginning treatment with such fixed-dose combinations was associated with a high percentage of
patients whose blood pressure was controlled
(80%) and with an unexpectedly low proportion
of add-on antihypertensive treatments required.
As mentioned above, fixed-dose combinations are
also associated with better compliance than free
combinations.7 This is essentially related to the
simpler therapeutic scheme and the lower number of pills. This better compliance is important
for all types of patients, including younger patients, because they will need antihypertensive
therapy for a longer period of time in order to
adequately prevent lifelong complications, as well
MEDICOGRAPHIA, VOL 31, No. 1, 2009
57
CONTROVERSIAL QUESTION
as for high-risk patients with multiple comorbidities and on polypharmacy, who usually require
several treatments for these comorbidities. All
efforts to simplify the therapeutic scheme are
therefore welcome. In conclusion, a greater proportion of hypertensive patients are candidates
for treatment with a combination of two antihypertensives to achieve better blood pressure con-
trol and more efficacious cardiovascular protection. Fixed-dose combinations represent an alternative to free combinations. They are associated with documented better protection in
high-risk patients and their use also improves
treatment adherence. Based on these arguments
they are the treatment of choice for most hypertensive patients. REFERENCES
1. Chobanian AV, Bakris GL, Black HR, et al; National High
Blood Pressure Educations Program Coordinating Committee.
Seventh report of the Joint National Committee on Prevention,
Detection, Evaluation and Treatment of High Blood Pressure.
JNC 7—Complete version. Hypertension. 2003;42:1206-1252.
2. Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for the management of arterial hypertension. J Hypertens.
2007;25:1105-1187.
3. De la Sierra A. Combinations as a first-step therapy in hypertension. Curr Hypertens Rep. 2007;9:251-252.
4. Julius S, Kjeldsen SE, Weber M, et al; VALUE Trial Group.
Outcomes in hypertensive patients at high cardiovascular risk
treated with regimens based on valsartan or amlodipine: the
VALUE randomised trial. Lancet. 2004;363:2022-2031.
5. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and
microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.
Lancet. 2007;370:829-840.
6. ACCOMPLISH trial. www.cardiosource.com/clinicaltrials/
trial.asp?trialID=1666. Accessed on September, 7th, 2008.
7. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH.
Fixed-dose combinations improve medication compliance: a
meta-analysis. Am J Med. 2007;120:713-719.
2
M. Rosas Peralta, Mexico
ne of the most fascinating moments in the
history of medicine was the discovery of
substances in the human blood able to induce major changes in function in multiple tissues when Robert Adolph Armand Tigerstedt, a
physician from the Karolinska Institute, and his
young collaborator Ron Bergman discovered
renin in 1898.1 They were far from imagining that
their extraordinary contribution to the understanding of a new system would continue to this
day to yield surprising insights. Pharmacotherapy
targeting the renin-angiotensin system (RAS)
is one of the most successful strategies for the
treatment and control of a number of diseases
such as: hypertension, stroke, heart failure, proteinuria, and ischemic heart disease, particularly
in type 2 diabetic patients.2 Renin was discovered
in 1898 by Tigerstedt.3 The first ACE inhibitor to
be developed, in 1975, was captopril, which was
shown to increase survival in patients with heart
failure thanks to its antihypertensive efficacy.
This was followed by a spate of basic science and
clinical studies that evidenced new effects of angiotensin-converting enzyme inhibition relative
to the kinin-kallikrein system, mitotic activation, and its role as indirect modulator of the
thrombotic system, principally via angiotensin
(Ang) IV.4 Nevertheless, despite the success of
drugs that block RAS activity, the prevalence of
cardiovascular disease (CVD) has been increasing steadily over the past several decades. This
has led many researchers to conclude that new
approaches and drug targets must be discovered
in order to develop more effective therapeutics
for both better control and eventual cure of CVD.
In this regard, the discovery of ACE2 and the
O
Martin ROSAS PERALTA
MD, PhD
Chief, Adult Cardiology
Department III, National
Institute of Cardiology of
Mexico, “Ignacio Chávez”
and Chief of Advanced
Research Unit of
Hypertension and
Cardiovascular Risk Factors
Juan Badiano 1, secc.XVI,
Tlalpan, Mexico City 14080
MEXICO
(e-mail:
[email protected])
58
MEDICOGRAPHIA, VOL 31, No. 1, 2009
prorenin receptor (PRR) are extremely relevant
because they provide novel targets for CVD therapeutics.5 Robust evidence has confirmed that
the ACE inhibitors have a major role in the treatment of CVD. Their therapeutic efficacy and safety is so far superior to that of other drug classes,
and for the first time it was possible to demonstrate that a drug was able to increase both quality and quantity of life in patients with heart failure.6 Paradoxically, their principal side effect,
cough, which occurs in around 10% to 20% of
patients, and which is related to the capability
of ACE inhibitors to block the breakdown of
bradykinin, may be useful as bradykinin is a
powerful vasodilator. The discovery of specific angiotensin II type 1 (AT1 ) receptors showed that
this receptor played a crucial in vascular injury
and mitotic effects via Ang II.7 However, despite
the numerous large trials that have attempted to
prove the superiority of other treatment strategies, the ACE inhibitors remain unparalleled to
date, and their use in combination to elicit double
renin-angiotensin-aldosterone system blockade
has now also been approved.8 ACE inhibition increases the levels of Ang (1-7). Over the last 5
years, several studies have demonstrated the crucial role of Ang (1-7) as a vasodilator and antitrophic peptide in cardiovascular drug therapy.
In addition, new pathophysiological mechanisms
have been discovered in connection with the currently available RAS blocking agents (ACE inhibitors and angiotensin receptor blockers [ARBs]),
which heighten the potential therapeutic impact
of Ang (1-7) in clinical practice.9 Another relevant point to keep in mind is the role of sodium
in hypertension. More than 50% of hypertensive
Free or fixed antihypertensive drug combinations?
CONTROVERSIAL QUESTION
patients are salt-sensitive, and this disorder increases with the patients’ age. Indapamide is a
diuretic that possesses all the properties of hydrochlorothiazide and the same potency, but is
free of effects on carbohydrate metabolism. Based
on findings from the most recent large clinical
trial (PROGRESS,10 ADVANCE,2 HYVET,11 ASCOTBPLA,12 CAFE13) and the outcomes of ONTARGET,
STITCH, and others, there is now strong evidence
that a fixed-dose combination of ACE inhibitor
and indapamide is beneficial in the treatment
of hypertension. Finally, although there is class
effect of ACE inhibitors, important differences
have been evidenced that may be relevant for
combined therapy, Perindopril elicits a rapid increase in bradykinin levels, and yet the rate of
cough was found to be lower in the PERTINENT
study, which suggests that other mediators of
cough exist apart from bradykinin. Further studies are needed to clarify this point. The benefits
of fixed-dose combination therapy, based primarily on RAS blockade and ACE inhibition plus indapamide, amlodipine, and others at appropriate
dose are now well established.14-19 Compliance
and adherence to treatment are paramount to
achieve vascular and target-organ protection. In
addition, the individual pathological and comorbidity profile of each hypertensive patient should
also be taken into consideration, including genetic and sociocultural aspects, when selecting a
first-line antihypertensive drug therapy. REFERENCES
1. Agency for Healthcare Research and Quality (AHRQ),
Rockville, MD (Contract No. 290-02-0025, Nov. 2007). Comparative Effectiveness of Angiotensin-Converting Enzyme
Inhibitors (ACEIs) and Angiotensin II Receptor Antagonists
(ARBs) for Treating Essential Hypertension. http://effective
healthcare.ahrq.gov/repFiles/ACEI_ARBFullReport.pdf?
Accessed September 19, 2008.
2. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril
and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE
trial): a randomised controlled trial. Lancet. 2007;370:829-840.
3. Marks LS, Maxwell MH. Tigerstedt and the discovery of
renin. An historical note. Hypertension. 1979;1:384-388.
4. Matchar DB, McCrory DC, Orlando LA, et al. Systematic
review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008;148:16-29.
5. Raizada MK, Paton JF. Recent advances in the renin-angiotensin system: angiotensin-converting enzyme 2 and
(pro)renin receptor. Exp Physiol. 2008;93:517-518.
6. CONSENSUS Trial Study Group. Effects of enalapril on
mortality in severe congestive heart failure. Results of the
Cooperative North Scandinavian Enalapril Survival Study
(CONSENSUS). N Engl J Med. 1987;316:1429-1435.
7. Werner C, Baumhäkel M, Teo KK, et al. RAS blockade with
ARB and ACE inhibitors: current perspective on rationale and
patient selection. Clin Res Cardiol. 2008;97:418-431.
8. Unger T, Stoppelhaar M. Rationale for double renin-angiotensin-aldosterone system blockade. Am J Cardiol. 2007;100
(3A):25J-31J.
9. Trask AJ, Ferrario CM. Angiotensin-(1-7): pharmacology
and new perspectives in cardiovascular treatments. Cardiovasc
Drug Rev. 2007;25:162-174.
10. PROGRESS Collaborative Group. Randomised trial of a
perindopril-based blood pressure lowering regimen among
6105 individuals with previous stroke or transient ischaemic
attack. Lancet. 2001;358:1033-1041.
11. Beckett NS, Peters R, Fletcher AE, et al; HYVET Study
Group. Treatment of hypertension in patients 80 years of age
or older. N Engl J Med. 2008;358:1887-1898.
12. Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators.
Prevention of cardiovascular events with an antihypertensive
regimen of amlodipine adding perindopril as required versus
atenolol adding bendroflumethiazide as required, in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomized controlled
trial. Lancet. 2005;366:895-906.
13. Williams B, Lacy PS, Thom SM, et al; CAFE Investigators;
Anglo-Scandinavian Cardiac Outcomes Trial Investigators;
CAFE Steering Committee and Writing Committee. Differential
impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit
Artery Function Evaluation (CAFE) study. Circulation. 2006;
113:1213-1225.
14. Unger T, Jakobsen A, Heroys J, Ralph A, Rees T, Shaw M.
Targeting cardiovascular protection: the concept of dual reninangiotensin system control. Medscape J Med. 2008;10(suppl):S4.
15. Ceconi C, Fox KM, Remme WJ, et al. ACE inhibition with
perindopril and markers of atherosclerosis and thrombosis:
results of the PERTINENT study. J Mol Cell Cardiol. 2007;42
(suppl 1):S237.
16. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis:
effect of monotherapy and combination therapy with inhibitors
of the renin–angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:30-48.
17. Chobanian AV, Bakris GL, Black HR, et al.; National Heart,
Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure. The Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
18. Matchar DB, McCrory DC, Orlando LA, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors
(ACEIs) and Angiotensin II Receptor Antagonists (ARBs) for
Treating Essential Hypertension. Comparative Effectiveness
Review No. 10. (Prepared by Duke Evidence-based Practice
Center under Contract No. 290-02-0025.) Rockville, MD:
Agency for Healthcare Research and Quality. November 2007.
Available at: www.effectivehealthcare.ahrq.gov/reports/final.
cfm. Accessed September 19, 2008.
19. Hiremath S et al. Systematic review of ARB and ACE inhibitor use in kidney transplant recipients. Nat Clin Pract
Nephrol. 2008;4:9.
Free or fixed antihypertensive drug combinations?
TRIAL
ACRONYMS
ADVANCE
Action in Diabetes and Vascular disease: PreterAx
and DiamicroN-MR Controlled Evaluation
ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes Trial–
Blood Pressure Lowering Arm
CAFE
Conduit Artery Function Evaluation trial
HYVET
HYpertension in the Very Elderly Trial
ONTARGET ONgoing Telmisartan Alone and in combination
with Ramipril Global Endpoint Trial
PERTINENT PERindopril-Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal
activation Trial
PROGRESS
Perindopril pROtection aGainst REcurrent Stroke
Study
STITCH
Simplified Treatment Intervention to Control
Hypertension
MEDICOGRAPHIA, VOL 31, No. 1, 2009
59
CONTROVERSIAL QUESTION
3
R. R. Azar, Lebanon
R
Rabih R. AZAR
MD, MSc, FACC
Associate Professor of
Medicine, Saint Joseph
University School of
Medicine, Director of
Cardiovascular Research
Division of Cardiology
Hotel-Dieu de France
Hospital, Beirut
LEBANON
(e-mail: [email protected])
60
ecent hypertension guidelines recommend
starting a combination of two antihypertensive agents in the treatment of patients
with blood pressure 20/10 mm Hg above of its
target.1 This is based on the knowledge that
monotherapy alone is not sufficient to control
blood pressure in this category of patients. In addition, even in patients with mild hypertension,
combination therapy with two agents at low dose
allows a superior reduction in blood pressure and
a lower rate of side effects when compared with
a single agent at high dose.2 This has led the
pharmaceutical industry to develop multiple fixed
combinations of antihypertensive agents that can
be used in the treatment of mild-to-moderate
hypertension. Fixed antihypertensive combinations have many advantages over free combinations. The compliance rate is higher in patients
receiving fixed-dose combinations. This is an important issue because antihypertensive drugs are
a lifelong treatment. The National Council on
Patient Information and Education estimated
that the compliance rate is just over 30% for
chronic conditions like hypertension.3 Polypharmacy is among the most important causes of noncompliance. Persistence on therapy decreases
as the number of pills taken per day increases.4
Sturkenboom et al 5 compared compliance rates
between fixed-dose and free combination therapies of angiotensin-converting enzyme (ACE) inhibitors and diuretics in 755 hypertensive patients.
Persistence with treatment was 12% lower (at 1
and 2 years) in patients on two pills versus patients on a one pill combination. Similarly, Bangalore et al 6 performed a meta-analysis of nine
studies of 20 242 patients with various chronic
conditions who were on fixed versus free drug
combinations. Fixed-dose combinations resulted
in a 24% greater patient compliance compared
with free drug combinations. Another advantage
of fixed combinations is the overall reduction in
cost of treatment because the patient is buying a
single medication rather than two separate drugs.7
Finally, fixed combinations contain two drugs
that work well together. The combination is usually “ideal,” allowing enhancement of each drug’s
antihypertensive effect and attenuation of each
other’s side effects (ie, the hypokalemia caused
by thiazide diuretics can be prevented by concurrent use of an ACE inhibitor). Fixed combinations, however, may have disadvantages over
free combinations. The physician does not have
the freedom of choosing and titrating the dose of
an individual component because they usually
come with fixed doses. For example, the dose
of one of the two components may not be high
enough to obtain a specific effect (ie, more potent diuresis or an effect beyond blood pressure
lowering). In addition, most of the fixed combinations available contain a diuretic and/or a
-blocker. Recent studies comparing “new” drugs
(calcium channel blockers + ACE inhibitors or
angiotensin receptor blockers (ARBs) versus “old”
drugs (diuretics+ -blockers) have shown the
superiority of “new” antihypertensive combinations in reducing the morbidity of hypertension.8,9
Fixed combinations containing an ACE inhibitor
(or ARB) and a calcium channel blocker are less
available in some parts of the world, and may
be more expensive than a free combination of
generic drugs. Finally, if a side effect occurs,
substitution of the responsible drug is easier in
free compared to fixed combinations. In conclusion, to the question “What determines your
choice between free and fixed combinations in
the management of your hypertensive patients?”
my answer is the availability of the two drugs
I want to use in a single pill at the appropriate
dosage (the dose proven in clinical trials to reduce morbidity and mortality of hypertension).
Compliance with treatment is the most important issue in a lifelong therapy. I have no doubt
that compliance is much better with fixed combination, especially in patients on polypharmacy
who have multiple risk factors or multiple comorbidities. REFERENCES
1. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection,
evaluation, and treatment of high blood pressure: the JNC 7
report. JAMA. 2003;289:2560-2572.
2. Mourad JJ, Waeber B, Zannad F, Laville M, Duru G, Andrejak M. Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril/indapamide
versus a sequential monotherapy or a stepped-care approach.
J Hypertens. 2004;22:2379-2386.
3. Dezii CM. Medication noncompliance: what is the problem.
Manag Care. 2000;9:7-12.
4. Greenberg RN. Overview of patient compliance with
medication dosing: a literature review. Clin Ther. 1984;6:
592-599.
5. Sturkenboom MC Picelli G, Dieleman JP; Mozaffari E,
Pompen M, van der Lei J. Patient adherence and persistence
with 1- and 2-pill combinations of antihypertensive drugs:
P212. Circulation. 2005;111:e351-e352.
6. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH.
Fixed dose combination improves medication compliance:
a meta-analysis. Am J Med. 2007;120:713-19.
7. Taylor AA, Shoheiber O. Adherence to antihypertensive therapy with fixed-dose amlodipine besylate/benazepril HCl versus
comparable component-based therapy. Congest Heart Fail.
2003;9:324-332.
8. Dahlöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding
bendroflumethiazide as required, in the Anglo-Scandinavian
Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOTBPLA): a multicentre randomised controlled trial. Lancet.
2005;366:895-906.
9. Jamerson KA; ACCOMPLISH Investigators. Avoiding cardiovascular events in combination therapy in patients living
with systolic hypertension. American College of Cardiology
Scientific Sessions. March 31, 2008; Chicago, IL.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Free or fixed antihypertensive drug combinations?
CONTROVERSIAL QUESTION
4
J. Chin Tay, Singapore
I
Jam CHIN TAY, MBBS,
MRCP, FAMS, FRCP(Edin)
Acting Head of Department
& Senior Consultant
General Medicine II
Tan Tock Seng Hospital
11 Jalan Tan Tock Seng
308433 SINGAPORE
(e-mail:
[email protected])
n the management of hypertension, low-dose
monotherapy is recommended as initial therapy. If blood pressure is not controlled, the
initial drug may be given at full dose or a new
drug of a different class may be substituted especially if there is no response to the first agent.
Although this “sequential monotherapy” approach
may allow individualized therapy, it is not a
popular choice for the practicing clinicians and
patients. It is time-consuming and laborious, and
many patients are frustrated that their blood
pressures remain uncontrolled with this empirical
trial-and-error approach. Furthermore, achievement of target blood pressure goals usually does
not exceed 20% to 30% of all hypertensive patients with monotherapy. Major clinical trials
have shown that target blood pressures can be
achieved with a combination of two or more
drugs. The concept of combination therapy is not
new. Antihypertensive drugs of different classes
can be combined if they have different and complementary mechanisms of action. Often the
combined antihypertensive effect is greater than
that of either component alone. Recent guidelines
now recommend the use of combination therapy
as an alternative to monotherapy in the initial
therapy for hypertension. The advantages of using this approach are:
Blood pressure goals and targets can be
achieved more effectively and earlier and in more
patients, which is of critical importance especially in high-risk patients.
Adverse reactions or side effects may be fewer
because of the smaller doses of individual medications than with single agents at higher dose.
Combination therapy can be given either as a free
or fixed combination. The advantages of free
combination are flexibility in dosing and timing.
Each drug can be titrated and adjusted according to the patients’ blood pressure responses.
However, multiple drugs have the potential of
becoming very complex and expensive for the
patients. In practice, most drugs used in combination therapy are often given together at standard doses. Fixed combination is therefore much
preferred. It is convenient and easy to prescribe
by busy clinicians and convenient for the patients.
The cost of fixed-dose combinations is usually
less than that of the constituents prescribed separately. In my practice, I usually start low-dose
monotherapy in patients with mild hypertension,
especially in the elderly, many of whom respond
well to monotherapy. However, most of my patients often require two or more antihypertensive
medications especially the diabetic, renal, and
high-risk patients. However, many patients are
not keen to start with more than one drug as
they are wary of the side effects associated with
multiple-drug therapy, especially diabetic and
high-risk patients who are already taking many
other medications. One approach is to titrate each
individual component and once the appropriate
Free or fixed antihypertensive drug combinations?
dose of each is reached, an appropriate fixeddose combination that contains the same doses
of each component can then be given. Another
approach is to substitute the initial monotherapy
with a fixed-dose combination when the former
fails to control the blood pressures to target. The
latter approach often achieves blood pressure
control earlier and causes less frustration to patients, with minimal changes in medications
and pills. Reducing the number of pills necessary
to control hypertension is an important factor
in improving blood pressure control and compliance. When patients see fewer pills to control
their blood pressure, psychologically, they perceive their hypertension as less severe and well
under control. They will be happy with the treatment and less likely to try another complementary approach, which often results in noncompliance with the antihypertensive therapy. It is
also not uncommon that patients do not take
all the medications as prescribed. They may
intentionally reduce the dosage or omit some
tablets, often claiming side effects as a reason,
while in fact, for cultural reasons, they feel that
too many “Western” medicines are harmful to
one’s body. Fixed-dose combination therapy with
fewer pills will thus contribute to a better rate of
patient adherence to therapy and a better outcome. Only a small number of my patients are
not on fixed-dose combination, in the following
cases:
When fixed-combination dosages are not
appropriate.
When fixed combination of the two drugs are
not available at our hospital, and
When patients cannot tolerate combined
dosages taken at the same time.
There are many fixed-dose combinations available on the market. The -blocker atenolol and
dihydropyridine calcium antagonist nifedipine
fixed-dose combination is popular among many
general practitioners in Singapore as it is relatively inexpensive, effective, and relatively free of
side effects. The concern with this combination
is whether it is effective with once-a-day dosing.
The combination of a thiazide diuretic and a
-blocker is also a time-honored combination,
which has been used successfully in many trials.
But this combination is not very commonly used
in practice as most clinicians are concerned about
the dysmetabolic side effects when they are administered together, especially to diabetic and
dyslipidemic patients. Angiotensin-converting
enzyme (ACE) inhibitor and thiazide-like diuretic
(perindopril/indapamide), and thiazide diuretic
and angiotensin receptor antagonist (ARB) fixed
combinations (hydrochlorothiazide and lorsartan/valsartan/candesartan/ telmisartan) are the
most commonly used fixed combinations. The
combination of a diuretic and ACE inhibitor or
ARB is well tolerated and highly effective. Both
classes of drugs have reduced morbidity and morMEDICOGRAPHIA, VOL 31, No. 1, 2009
61
CONTROVERSIAL QUESTION
tality in long-term outcome trials in hypertensive
patients. More recently, the Action in Diabetes
and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation (ADVANCE) trial showed
that the combination of perindopril/indapamide
reduces mortality in type 2 diabetic patients, irrespective of their blood pressure. The combination is useful in elderly and blacks with low-renin
hypertension, and in patients with heart failure,
5
T. Ecder, Turkey
T
Tevfik ECDER, MD
Professor of Medicine
Istanbul School of Medicine
Department of Internal
Medicine, Division of
Nephrology, Istanbul
TURKEY
(e-mail:
[email protected])
62
left ventricular dysfunction, diabetic nephropathy, and left ventricular hypertrophy. In conclusion, fixed-dose combinations often contain the
appropriate drugs at the effective dosage, with
minimal side effects. They are easy and convenient to use and simplify the treatment regimen.
They improve cost-effectiveness and compliance.
For all these reasons, they preferred by many
clinicians and patients. he primary goal of treatment of hypertensive patients is to achieve maximum reduction in the long-term total risk of cardiovascular morbidity and mortality. This starts with
the lifestyle modifications and with the addition
of different antihypertensive agents. According
to current guidelines, blood pressure should be
reduced to at least below 140/90 mm Hg and to
lower values, if tolerated, in all hypertensive patients. Target blood pressure should be less than
130/80 mm Hg in diabetics and in high- or veryhigh-risk patients, such as those with associated
stroke, myocardial infarction, renal dysfunction,
or proteinuria. Many hypertensive patients need
the combination of two or more drugs to reach
blood pressure goals. In patients with stage 2 hypertension, therapy should be started with a combination. Moreover, combination treatment should
be considered as first choice particularly when
there is a high cardiovascular risk, such as subclinical organ damage, diabetes, or renal or cardiac disease. Starting treatment with a two-drug
combination allows blood pressure targets to be
reached earlier than with monotherapy, which is
of critical importance in high-risk patients. The
2007 European Society of Hypertension and European Society of Cardiology (ESH/ESC) Guidelines for the Management of Arterial Hypertension
recommend starting therapy with a two-drug
combination at low doses in patients with marked
blood pressure elevation, in patients with high/
very high cardiovascular risk, and in conditions
with a lower blood pressure target. If the target
blood pressure level is not reached, increasing the
previous combination to full dose or adding a
third drug at low dose is recommended. The advantages of combination therapy are that the antihypertensive efficacy can be maximized by the
additive effects. Moreover, the two drugs can be
given at low doses, which are more likely to be free
of side effects compared will full-dose monotherapy. The combination therapy can be given either
as a free or fixed combination. Free combination
MEDICOGRAPHIA, VOL 31, No. 1, 2009
of different drugs allows upward and downward
dose titration of each agent. However, it has the
disadvantage of using a higher number of pills.
This is an important drawback, especially in highrisk patients who need to use several other medications, such as statins, antiplatelet agents, and
additional antihypertensive agents. Combinations
of two drugs in a single tablet, usually at low
doses, are now widely available, particularly those
of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)
with a diuretic or with a calcium channel blocker.
Although the fixed combination limits the flexibility of upward and downward dose titration, it
has several advantages. Fixed combinations reduce the number of tablets to be taken by the
patients, which increases compliance with treatment and improves the rate of hypertension control. The results of the ADVANCE (Action in
Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation) trial suggest
that the use of a fixed combination has the advantage of reducing the risks of major vascular
events and death in patients with type 2 diabetes
mellitus. The ADVANCE trial was designed to
assess the effects on vascular disease of a fixed
combination of the ACE inhibitor perindopril, and
the diuretic indapamide, in a diverse population
of patients with type 2 diabetes and a broad range
of blood pressure values. This study showed that
the addition of a fixed combination of perindopril
and indapamide on the background therapy of
patients with type 2 diabetes significantly reduced
the risks of death and major macrovascular or
microvascular complications, irrespective of initial blood pressure level. The fixed combination
regimen used in ADVANCE was also well tolerated.
In conclusion, fixed combinations have the advantage of ensuring early and effective blood pressure control in hypertensive patients with cardiovascular disease. These are generally well
tolerated and can be given once daily, providing
better compliance with treatment. Free or fixed antihypertensive drug combinations?
CONTROVERSIAL QUESTION
6
A. Tykarski, Poland
T
Andrzej TYKARSKI, MD, PhD
Department and Clinic of
Hypertension, Angiology
and Internal Medicine
Poznan University of
Medical Science
1/2 Dluga Str.
PL 61-848 Poznan
POLAND
(e-mail: [email protected])
reatment of hypertension may be initiated
either with monotherapy or combination
therapy. According to the European Society
of Hypertension /European Society of Cardiology
(ESH/ESC) 2007 Guidelines,1 treatment with
combination therapy is recommended in patients
at higher cardiovascular risk: particularly those
with high blood pressure values or multiple risk
factors, subclinical organ damage, diabetes mellitus, or renal or cardiovascular disease. Both
forms of combination therapy—free and fixed
drugs combinations—have their advantages and
disadvantages. Simplification of therapy using
fixed-dose combination preparations significantly
increases patient motivation to comply with the
therapy, as well as their satisfaction.2 Usage of
fixed doses of two antihypertensive drugs increases
the probability of achieving target blood pressure
in more patients and earlier, thus decreasing the
number of follow-up visits, titrations of doses, and
modifications of preparations used. Furthermore,
it is also cost-effective.3 However, fixed-dose combinations have their disadvantages as well. It is
more difficult to find the most appropriate dose,
although some of the combinations are available
in a wide range of dosages now. If patients present
with side effects, it is more difficult to determine
which substance is the one responsible for them.
In my opinion, fixed-drug combinations should
be preferred in patients suspected to be poor compliers, as reduction in the daily number of pills
increases compliance. It should also be the therapeutic approach of choice when the patient does
not require any particular proportions of doses
of the drugs used. An example of such a situation
may be moderate hypertension (stage 2) when
only one pill per day may help achieve normal
blood pressure values. The STRAtegies of Treatment in Hypertension: Evaluation (STRATHE)
study,4 which compared the antihypertensive
effectiveness of three approaches to treatment
initiation: (i) fixed-dose combination (perindopril/indapamide); (ii) sequential monotherapy
(atenolol switched to losartan and further to amlodipine); and (iii) stepped-care approach (valsartan uptitrated, and hydrochlorothiazide added) in
533 patients with hypertension of at least mod-
erate severity. Initiation of treatment with fixeddose combination was found to be the most effective. Another example of a situation in which
I prefer fixed-dose combinations is mild-to-moderate hypertension with concomitant diabetes.
The goal for blood pressure values is lower than
standard and often more than one drug is needed
to achieve it. Therefore, fixed-dose combination
treatment, adding one pill only to the number
already taken by the patient may help maintain
compliance high and allows for early target blood
pressure achievement. The Action in Diabetes and
Vascular disease: PreterAx and DiamicroN-MR
Controlled Evaluation (ADVANCE) study has also
shown that the fixed-drug combination of an
angiotensin-converting enzyme (ACE) inhibitor
and a diuretic could reduce the risk of macroand microvascular complications in diabetic patients, irrespective of initial blood pressure values.5 This study included 11 140 type 2 diabetic
patients with cardiovascular disease or at least
one risk factor, and the observation lasted for
4.3 years. In my clinical practice free-drug combinations are a preferable option for antihypertensive treatment when maximal doses of drugs
are required, for example as with the ACE inhibitors in hypertension concomitant with heart
failure. Also, patients with a history of multiple
side effects are more likely to develop side effects
during a future treatment, and should be preferably given free combination, which allows easy
withdrawal of the drug responsible for the unwanted effect. I would also recommend this approach in the event that high dosages of drugs
(exceeding doses used in fixed-dose combinations)
are expected to be necessary to reach target blood
pressure values. In summary, clinical situations
when free combinations are to be preferred include: severe hypertension; when high doses or
three-drug combination treatment are needed;
patients with a history of multiple side effects;
heart failure concomitant with hypertension; left
ventricular hypertrophy in a patient with hypertension (higher dose of ACE inhibitor preferred);
or hypertension in a post–myocardial infarction
patient when a -blocker not used in fixed drug
combinations is required. REFERENCES
1. Task Force for the Management of Arterial Hypertension
of the European Society of Hypertension (ESH) and of the
European Society of Cardiology (ESC). 2007 Guidelines for the
Management of Arterial Hypertension. J Hypertens. 2007;25;
1105-1187.
2. Waeber B, Burnier M, Brunner HR. Compliance with antihypertensive therapy. Clin Exp Hypertens. 1999;21:973-985.
3. Ambrosioni E. Pharmacoeconomics of hypertension
management: the place of combination therapy. Pharmacoeconomics. 2001;19: 337-347.
4. Mourad JJ, Waeber B, Zannad F, Laville M, Duru G, Andrejak M. Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril/indapamide
versus a sequential monotherapy or a stepped-care approach.
J Hypertens. 2004;22:2379-2386.
5. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and
indapamide on macrovascular and microvascular outcomes
in patients with type 2 diabetes mellitus (the ADVANCE trial):
a randomised controlled trial. Lancet. 2007;370:829-840.
Free or fixed antihypertensive drug combinations?
MEDICOGRAPHIA, VOL 31, No. 1, 2009
63
CONTROVERSIAL QUESTION
7
J. Chalmers, Australia
T
John CHALMERS, MD, PhD
The George Institute for
International Health
Kind George V Building
Royal Prince Alfred Hospital
Missenden Road
Camperdown
Sydney NSW 2050
AUSTRALIA
(e-mail: jchalmers@
thegeorgeinsitute.org)
here is now universal agreement among
authoritative guidelines, that the great majority of patients with hypertension will need
combination treatment to achieve recommended targets.1-6 Indeed, the most recent European
guidelines state that concentration on choice of
initial drug is outdated due to the need for combination treatment in most cases.7 This is because
the combination of drugs with different primary
actions increases efficacy, while permitting the
use of lower doses that decrease side effects and
improve tolerability.7,8 These guidelines also stress
the advantage of fixed combinations in improving adherence and thus, contributing to improving the efficacy of treatment.9-12 The increasing
complexity of chronic illness in an aging population, and increasing awareness of the need to
address total cardiovascular risk, have multiplied
the number of drugs the patient has to take everyday and sometimes 2 or 3 times a day. It is not
uncommon for a patient with previous myocardial infarction to have hypertension, and diabetes
requiring 2 blood pressure–lowering drugs, 2 oral
hypoglycemic agents and a -blocker, an angiotensin-converting enzyme (ACE) inhibitor, a
statin, and aspirin for the coronary disease—a
total of 8 drugs. Elderly patients may be taking
10, 12, or more drugs each day. Any measures
that simplify the therapeutic regimen will be welcomed by patients and it makes great sense to
reduce the number of tablets a patient has to
swallow, by combining some of the drugs into a
fixed-dose combination. Many physicians have
an ingrained resistance to the use of fixed combinations, preferring to titrate each individual
drug to optimal dose, before introducing the next
drug. However, the weight of opinion, exemplified
by the guidelines quoted earlier, is slowly moving toward the use of fixed combinations.
Factors that will influence the choice of free or
fixed combinations of blood pressure–lowering
drugs
Two of the main factors will be the number and
complexity of comorbidities and risk factors that
accompany the patient’s hypertension, and the
number of drugs the patient is already taking
(see Box below). The patient’s total cardiovascular
risk will plainly be a major influence. Factors
relating to the blood pressure will include the
FACTORS INFLUENCING THE CHOICE
OF FIXED OR FREE COMBINATIONS
Number of comorbidities present
Number of risk factors needing drug therapy
Total cardiovascular risk
Level of blood pressure—especially systolic blood
pressure
Target blood pressure
Availability of suitable fixed-dose formulations
64
MEDICOGRAPHIA, VOL 31, No. 1, 2009
current level of the pressure, the target blood
pressure the physician is aiming to achieve, and
the magnitude of the gap between these two pressures. Yet another factor will be the blood pressure–lowering drugs that the patient may already
be taking and the doses of these drugs, since if
there is a fixed dose combination available for
these same drugs, at the same doses, the switch
to a fixed dose combination becomes simple.
Finally, of course, the availability of a fixed-dose
combination that combines the two drugs that
the physician wishes to prescribe in a dosage
that suits the purpose. Another consideration may
well be the availability of this fixed-dose combination in multiple strengths, so that the physician
can start with a low dose form and increase the
dose progressively.
Factors favoring the choice of fixed
combinations
Most physicians will be tempted to use a fixeddose combination (see Box below) for patients at
high cardiovascular risk, who have multiple risk
factors and comorbidities and a relatively high
FACTORS FAVORING THE USE
OF FIXED-DOSE COMBINATIONS
High total cardiovascular risk
Presence of comorbidities (especially diabetes,
coronary, cerebrovascular, and renal disease)
Multiple cardiovascular risk factors
High levels of blood pressure—especially systolic
Low target blood pressure
Availability of suitable fixed-dose formulation
Patient already stabilized on separate components
of a fixed-dose combination
Evidence of efficacy from randomized clinical
trials
blood pressure. Some may only use the fixeddose combination if the patient has already been
stabilized on the component entities in the free
combination. But increasingly, where a patient
is at high risk and is facing complex multidrug
therapy, many physicians will now use a fixeddose combination de novo. Many physicians will
now use a fixed-dose combination to initiate blood
pressure lowering in the high-risk patient with
a low target blood pressure, and a history of previous vascular disease or diabetes.1-8 Where a patient has hypertension alone, the use of fixed-dose
combinations might focus on individuals with relatively high pressures already on multiple blood
pressure–lowering agents.
Factors favoring the use of free combinations
Many physicians, particularly those who graduated some years ago, will have been trained to
titrate the dose of each individual drug they prescribe for a patient until they observe the desired
Free or fixed antihypertensive drug combinations?
CONTROVERSIAL QUESTION
effect— in this case achieving the target blood
pressure— or until a side effect intervenes. For
these physicians, prescription of a fixed-dose combination before they have stabilized the patient
on both of the separate components requires a
change in mindset. That change is gradually
happening with increasing evidence that starting
treatment with a low-dose combination is both
safe and effective, as recommended by the 2007
European Guidelines.7 Apart from the conservative mindset of many physicians, other factors
that may militate against use of a fixed-dose
combination (see right Box) include lack of a
formulation combining the two drugs that the
physician wishes to prescribe, or lack of a formulation combining these two agents in the dosages
that the physician might wish to use for a particular patient. In these situations the physician
will clearly choose to use a free combination of
the desired drugs at the appropriate dosage.
ter 3 months. This treatment, given on top of all
other drugs, including other blood pressure–lowering drugs, statins, aspirin, and glucose-lowering agents, reduced the blood pressure to below
135/75 mm Hg, and was remarkably well tolerated, with adherence in the 11 140 patients at
the end of follow up being virtually the same as
FACTORS FAVORING THE USE
OF FREE COMBINATIONS
Traditional preference for dose titration of indi-
vidual drugs
Lack of formulation combining the two preferred
drugs
Lack of formulation combining the desired drugs
in the preferred dosage
The tipping point: positive results from the
blood pressure arm of ADVANCE
ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled
Evaluation) is the largest ever trial in type 2 diabetes. The blood pressure–lowering arm of this
trial, reported in the Lancet in September 2007 13
provides definitive evidence in favor of fixed-dose
combinations. This trial used the fixed combination of the ACE inhibitor perindopril and the diuretic indapamide, compared with matching placebo, starting with 2 mg perindopril and 0.625 mg
indapamide and increasing to 4 mg/1.25 mg af-
adherence to placebo (74% vs 73%). The benefits
were handsome, with reduction of 14% in allcause mortality, 18% in cardiovascular death,
14% in coronary events, and 21% in renal events.
This is the first major cardiovascular mortality
trial to demonstrate the safety and efficacy of a
fixed-dose combination. It did this in a simple
pragmatic manner that should readily be translated into clinical practice. Further, since it combines
2 drugs—perindopril and indapamide—each of
which has a long and distinguished history of
safety and efficacy, physicians will be reassured
to prescribe it for their patients, either de novo
for the new hypertensive patient or on top of all
other treatments for those already receiving other
blood pressure–lowering agents. REFERENCES
1. European Society of Hypertension-European Society of
Cardiology Guidelines Committee. 2003 European Society of
Hypertension-European Society of Cardiology guidelines for
the management of arterial hypertension. J Hypertens. 2003;
21:1011-1053.
2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh
Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the
JNC 7 report. JAMA. 2003;289:2560-2572.
3. World Health Organization/International Society of Hypertension Writing Group. 2003 World Health Organization
(WHO)/International Society of Hypertension (ISH) statement
on management of hypertension. J Hypertens. 2003;17:
1983-1992.
4. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT,
Potter JF, et al. British Hypertension Society guidelines for
hypertension management 2004 (BHS-IV): summary. BMJ.
2004;328:634-640.
5. National Institute for Health and Clinical Excellence. Hypertension: management of hypertension in adults in primary
care (partial update of NICE clinical guideline 18). Clinical
Guideline 34. 2006; June 2006.
6. Khan NA, McAlister FA, Rabkin SW, Padwal R, Feldman RD,
Campbell NR, et al. The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part II - Therapy. Can J Cardiol. 2006;22:583-593.
7. Mancia G, De Backer G, Dominiczak A, et al. 2007
Guidelines for the Management of Arterial Hypertension:
The Task Force for the Management of Arterial Hypertension
of the European Society of Hypertension (ESH) and of the
European Society of Cardiology (ESC). J Hypertens. 2007;25:
1105-1187.
8. Chalmers J. The importance of drug combinations for effective control of hypertension. Clin Exp Hypertens. 1999;21:
875-884.
9. Taylor AA, Shoheiber O. Adherence to antihypertensive
therapy with fixed-dose amlodipine besylate/benazepril HCl
versus comparable component-based therapy. Congest Heart
Fail. 2003: 9:324-332.
10. Connor J, Rafter N, Rodgers A. Do fixed-dose combination
pills or unit-of-use packaging improve adherence? A systematic review. Bull WHO. 2004:82:935-939.
11. Waeber B, Burnier M, Brunner HR. Compliance with antihypertensive therapy. Clin Exp Hypertens. 1999;21:973-985.
12. Bangalore S, Kamalakkannan G, Panjrath G, et al. Fixeddose combination improves medication compliance: a metaanalysis. J Clin Hypertens. 2006;suppl A:A72.
13. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed
combination of perindopril and indapamide on macrovascular
and microvascular outcomes in patients with type 2 diabetes
mellitus (the ADVANCE trial): a randomised control trial.
Lancet. 2007;370:829-840.
Free or fixed antihypertensive drug combinations?
MEDICOGRAPHIA, VOL 31, No. 1, 2009
65
CONTROVERSIAL QUESTION
8
Z. D. Kobalava, Russia
F
Zhanna D. KOBALAVA, MD
Head, Professor, Chair of
Cardiology and Clinical
Pharmacology
Chair of Propedeutics of
Internal Diseases
People’s Friendship
University of Russia
61 Vavilova str, Moscow
RUSSIA
(e-mail: [email protected])
or years, hypertension experts have argued that monotherapy seldom gets blood
pressure (BP) down to target and that
combination therapy is a better treatment option.
Numerous regular and low-dose fixed combinations are available nowadays. We can choose between thiazide- or nonthiazide-based preparations.
But many clinicians are still reluctant to start off
with a combination therapy, keeping this approach as a preferential option for severe and/or
resistant hypertension. With recent consensus
reports1,2 endorsing the need for more intensive
BP control below traditionally accepted levels in
much larger patient populations, there is a far
greater need for initial combination therapy. According to the European Society of Hypertension/
European Society of Cardiology (ESH/ESC) recommendations, such a therapeutic strategy may
be valuable in all patients, regardless of the severity of hypertension, but preference should be
given to fixed low-dose combinations as initial
therapy.1 According to US experts, the use of firstline combination therapy should be considered
in patients with systolic blood pressure (SBP)
160 mm Hg and/or diastolic blood pressure
(DBP) 100 mm Hg.2 Until recently, advocates
of initial fixed-dose combination therapy had no
data to make their case. The results from recent
Advantages
Disavantages
Simple to use
Improved patient compliance
Increased antihypertensive efficacy
Lower doses of components
Probability of exposing patients to an
Preserved tolerability
Early and sustained BP control
Decrease in fluctuations associated
with adjustments in antihypertensive therapy
Reduced costs
Table I.
66
unnecessary agent
Loss of dosing flexibility
Limited value in upward and down-
ward treatment strategies
Difficulties in identifying the agent
responsible for nonspecific adverse
reactions.
Potential risk of administration of a
contraindicated agent
clinical trials have changed the situation. The Anglo-Scandinavian Cardiac Outcomes Trial–Blood
Pressure Lowering Arm (ASCOT-BPLA) 3 and
Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic
Hypertension (ACCOMPLISH) 4 trial provided
very important data through comparison of efficacy and tolerability of different combinations of
antihypertensive agents. As a consequence, the
traditionally popular combination of a thiazide
diuretic and a -blocker is under revision at least
in patients with the metabolic syndrome or at high
risk of incident diabetes. The ACCOMPLISH 4 data
strongly supported combination antihypertensive
therapy as a comprehensive strategy and confirmed the high value of the angiotensin-converting enzyme (ACE) inhibitor/calcium channel
blocker (CCB) combination. After the VAlsartan
antihypertensive Long-term Use Evaluation
MEDICOGRAPHIA, VOL 31, No. 1, 2009
(VALUE) 5 trial, we know that if BP in high-risk
hypertensives is not controlled well within the
first 6 months, we get higher morbidity and mortality. So time to target BP is probably an important consideration in high-risk hypertensive
patients. The data from the Action in Diabetes and
Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation (ADVANCE) 6 trial significantly broadened our experience with fixed-dose
antihypertensive therapy by demonstrating its
efficacy, safety, and good tolerability in type 2 diabetic patients irrespective of initial BP level or
the use of other antihypertensive drugs. The
STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) 7 trial clearly demonstrated
that a therapeutic strategy based on fixed low-dose
perindopril/indapamide combination was more
effective in achieving target BP than “step-by-step”
or sequential monotherapy approaches. Thus, in
view of all currently available data, it is time to
put the old “start low, go slow” strategy to rest.
What determines the choice between free and
fixed combinations in the management of hypertensive patients? First of all, the advantages and
disadvantages of both regimens. For fixed-dose
combinations these are summarized in Table I.
The advantages presented in Table I are in favor
of the used of fixed-dose combinations, while the
situations listed as disadvantages support the use
of free combinations. The choice of free or fixed
combinations should take into account both the
individual patient’s clinical profile (eg, other cardiovascular risk factors, coexisting disorders limiting the use of particular classes of antihypertensive drugs or requiring a special titration
regimen), and the potential of the combination
to prevent or reverse target-organ disease. Lowdose fixed combination could be the initial treatment for mild BP elevation with a low or moderate total cardiovascular risk. It is a good initial
choice in uncomplicated hypertensives and in the
elderly, where antihypertensive therapy should
normally be initiated gradually. Switching from
ineffective monotherapy is another option for lowdose fixed combinations. But low-dose combinations, even if more effective in lowering BP than
monotherapies, do not allow BP normalization
in every patient at the initial dose and it is occasionally necessary to use a combination containing the same components, but at higher doses.
A combination of two drugs at regular doses
should be preferred as first-step treatment in the
presence of grade 2 or 3 initial BP or when total
cardiovascular risk is high or very high. In highrisk hypertensives, target BP should be achieved
more promptly, which favors initial regular-dose
combination therapy and quicker adjustment of
doses. If we are looking to achieve SBP/DBP reduction of more than 30 mm Hg, we should start
in most cases with a free full-dose combination.
But the fixed combination of a regular-dose combination (eg, ACE inhibitor/diuretic) with an addi-
Free or fixed antihypertensive drug combinations?
CONTROVERSIAL QUESTION
tional drug (eg, CCB) is also an option. We can
also start with a free combination of two agents
and then substitute it with a fixed-dose preparation. This approach is usually tried in inpatients
or outpatients with exacerbated arterial hypertension. Treatments with lower and higher doses of
the same agents are becoming more and more
popular. This means that we can resort to “stepby-step” strategy with regard to combination
therapy. Moreover a “step-down” scheme in patients with well controlled BP may also be used.
The treatment of hypertension is growing increas-
ingly complex, but in everyday practice, a simpler,
easier approach is generally sufficient. The Simplified Treatment Intervention to Control Hypertension (STITCH) 8 trial has clearly demonstrated
the advantages of a simplified approach to antihypertensive treatment with fixed-dose combinations. Initial combination therapy is very effective, and there is now substantial evidence to
broaden the use of combination therapy as initial treatment. At this point, continued hesitation about the use of combinations, whether free
or fixed-dose, does more harm than good. REFERENCES
1. Mancia G, de Backer G, Dominiczak Ä, et al. 2007 Guidelines for the Management of Arterial Hypertension The Task
Force for the Management of Arterial Hypertension of the
European Society of Hypertension (ESH) and of the European
Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.
2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report
of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.
3. Dahlöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine
adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac
Outcomes Trial–Blood Pressure Lowering Arm (ASCOT–BPLA):
a multicentre randomised controlled trial. Lancet. 2005;366:
895-906.
4. Kjeldsen SE, Jamerson KA, Bakris GL, et al; Avoiding Cardiovascular events through COMbination therapy in Patients
LIving with Systolic Hypertension Investigators. Predictors of
blood pressure response to intensified and fixed combination
treatment of hypertension: the ACCOMPLISH study. Blood
Press. 2008;17:7-17.
5. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure
dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet. 2004;
363:2049-2051.
6. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus
(the ADVANCE trial): a randomised controlled trial. Lancet.
2007;370:829-840.
7. Mourad JJ, Waeber B, Zannad F, et al. Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril/indapamide versus a sequential monotherapy or a stepped-care approach. J Hypertens. 2004;22:
2379-2386.
8. Feldman RD, Zou G, Feagen BG, et al; STITCH Investigators.
The Simplified treatment Intervention to Control Hypertension
(STITCH) trial: a cluster randomized controlled trial of a stepcare algorithm using initial fixed dose combination therapy
for the management of hypertension. Presented at Scientific
Sessions 2007 of the American Heart Association, November
4-7, 2007; Orlando, Florida. http://www.medscape.com/view
article/568786_print. Accessed September 19, 2008.
9
B. Trimarco, Italy
L
Bruno TRIMARCO, MD
Professor, Dipartimento
di Medicina Clinica e
Scienze Cardiovascolari
ed Immunologiche,
Università degli Studi
Federico II
Via S. Pansini 5
80131 Naples
ITALY
(e-mail: [email protected])
arge intervention trials have clearly demonstrated that monotherapy is able to adequately control blood pressure levels only
in about 30% of hypertensive patients, thus suggesting that combination therapy is needed in the
majority of patients. Accordingly, the European
Society of Hypertension/European Society of Cardiology (ESH/ESC) Guidelines for the Management of Arterial Hypertension, published in 2007,
stated that initial treatment can make use of
monotherapy or combination of two drugs at low
doses with a subsequent increase in drug doses
or number, if needed. The availability of fixed
combinations of antihypertensive drugs has certainly improved antihypertensive therapy by
reducing the daily number of pills, which is inversely correlated with the patient’s adherence to
the treatment. This influence on compliance is
further corroborated by the observation that despite the limitations in terms of flexibility of upward and downward titration attached to the
fixed doses of the combination components, the
use of fixed combinations in the treatment of hypertension is larger than in any other therapeutic
Free or fixed antihypertensive drug combinations?
field. This being said, if fixed combinations represent the first choice, why are many physicians
still using free combinations? In my opinion, the
main determinant of this choice is the clinical
characteristics of the patients. First of all, we have
to consider the severity of hypertension. In a patient with grade I hypertension, the probability
that one drug alone will achieve satisfactory blood
pressure control is quite high, and it is therefore
justified to start with one drug and, subsequently,
if the blood pressure response is not satisfactory,
to add a new drug as a free combination, so that
the initial prescription can be maintained. The
obvious disadvantage of initiating treatment with
two drugs is that of potentially exposing some
patients to an unnecessary agent. On the contrary, in a patient with stage 2 or 3 hypertension,
it makes sense to start with a fixed combination,
since it has been demonstrated that early control of blood pressure is associated with better
improvement in cardiovascular prognosis. Furthermore, use of combination therapy has been
found to be even more frequently needed in diabetic, renal, and high-risk patients, and in genMEDICOGRAPHIA, VOL 31, No. 1, 2009
67
CONTROVERSIAL QUESTION
eral whenever lower blood pressure targets are
pursued. All fixed combinations of angiotensinconverting enzyme (ACE) inhibitors or angiotensin
receptor antagonists (ARBs) and diuretics utilize
thiazides, and it is well known that the latter are
contraindicated in patients with severe renal
impairment. This explains why it is necessary to
prescribe free combinations with loop diuretics
in those patients. Similarly, combinations of thiazide diuretics and a -blocker are also largely
used, but evidence is now available that these
drugs have unfavorable metabolic effects, which
may be even more pronounced when they are
administered together. On the contrary, -blockers
with vasodilating properties, such as carvedilol
10
and nebivolol, which have less or no dysmetabolic action as well as a lower incidence of new-onset diabetes compared with classic -blockers,
are not available in fixed combinations. Furthermore, the combination of a thiazide and a potassium-sparing diuretic has been widely used for
years in order to prevent the loss of potassium
associated with thiazide administration, possibly
preventing glucose intolerance and decreasing
the incidence of diabetes associated with thiazideinduced hypokalemia. Thus, in patients with
metabolic syndrome and when there is a high
risk of incident diabetes, it is mandatory to use
a free combination of vasodilating -blockers
and diuretics. P. Ramachandran, India
T
Panchapakesan
RAMACHANDRAN, MD, DM
Senior Interventional
Cardiologist, Apollo Hospitals
21 Greams Lane, Off Greams
Road, Chennai 600 006
INDIA
(e-mail: [email protected])
68
he benefit and safety of an aggressive strategy to reduce blood pressure to a target of
below 140 mm Hg systolic and 90 mm Hg
diastolic has been clearly demonstrated.1 Hypertension-induced stroke appears to be largely
preventable, and a significant reduction is seen
in hypertension-attributable coronary artery disease.2 However, reaching and maintaining this
target is a challenge in the majority of patients.
Clinical practice has been to begin monotherapy
with an antihypertensive agent and follow a
stepped up, sequential drug strategy till the blood
pressure target is reached. However, in many
cases, stepping up the dose leads to only modest
increases in blood pressure response at the cost
of more frequent or severe side effects,3 and most
patients need more than one drug either as multiple “free” individual drugs, or as a fixed-dose
combination (FDC). Compliance with treatment
is a sine qua non for the successful long-term
management of hypertension. FDCs have a major
advantage because they simplify the medication
regimen and improve compliance. In a recent
meta-analysis involving 20 242 patients, FDCs
significantly decreased the risk of noncompliance
by 24% compared with free-drug combination
regimens.4 Although there is no randomized trial
evidence to guide in the selection of a specific
formulation, the FDC of amlodipine 5 mg and
perindopril 4 mg mirrors the application of these
agents in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study. This study, the only
one to date comparing treatment regimens,
demonstrated substantial and significant cardiovascular risk reduction, and long-term acceptability with the free combination of amlodipine
and perindopril compared with atenolol and diuretic.5 Consistent with present guidelines, and
provided there is no contraindication or compelling need to use other agents, the FDC of amlodipine and perindopril can be used for the initial
treatment of patients with stage 2 hypertension.
In uncontrolled patients, it can replace monotherapy with a calcium channel blocker or an
angiotensin-converting enzyme inhibitor, or a
2-drug combination regimen. In patients under
blood pressure control, it can substitute another
2-drug combination if there are serious side effects, or if compliance is poor with a free 2-drug
regimen. REFERENCES
1. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients
with hypertension; principal results of the Hypertension Optimal
Treatment (HOT) randomised trial. Lancet. 1998;351:1755-1762.
2. Beevers DG. Introduction: control of blood pressure by
combination therapies. J Hum Hypertens. 1991;5:1-2.
3. Fagan TC. Remembering the lessons of basic pharmacology.
Arch Int Med. 1994;154:1430-1431.
4. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH.
Fixed-dose combinations improve medication compliance:
a meta-analysis. Am J Med. 2007;120:713-719.
5. Dahlöf B, Sever PS, Poulter NR; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive
regimen of amlodipine adding perindopril as required versus
atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure
Lowering Arm (ASCOT-BPLA): a multicentre randomised
controlled trial. Lancet. 2005;366:895-906.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Free or fixed antihypertensive drug combinations?
C
O V E R S Y L
COVERSYL: AT THE CORE OF
CARDIOVASCULAR DISEASE PREVENTION
AND TREATMENT
b y O. A . A s e e v a , F r a n c e
ngiotensin-converting enzyme (ACE) inhibitors were initially developed for the treatment of hypertension, for which they remain a cornerstone of therapy. According to recent
guidelines, among the available classes of antihypertensive agents, ACE inhibitors have the broadest
spectrum of use, and are particularly recommended in hypertensive patients with concomitant subclinical organ damage (left ventricular hypertrophy
[LVH], microalbuminuria), clinical events (previous
myocardial infarction, stroke, heart failure, atrial
fibrillation), or conditions (diabetes mellitus, metabolic syndrome).1 Meta-regression findings published in 2003 by the Blood Pressure Lowering
Treatment Trialists’ Collaboration (BPLTTC) have
A
SELECTED
ACE
ARB
CCB
RAAS
Olga A. ASEEVA, MD
Cardiovascular Division
Servier, FRANCE
ABBREVIATIONS
angiotensin-converting enzyme
angiotensin receptor blocker
calcium channel blocker
renin-angiotensin-aldosterone system
A
ngiotensin-converting enzyme (ACE) inhibitors are widely recognized for their ability to reduce mortality, myocardial infarction, stroke, and heart failure in patients at
risk of cardiovascular events. In contrast, results from recent studies in a broad population of patients with vascular disease indicate that the effects of the angiotensin receptor blockers in prevention of cardiovascular outcomes are less robust. ACE inhibitors
should thus remain the gold standard in cardiovascular prevention and treatment. Among these, Coversyl stands out because of
its proven benefits on arterial structure and function, including
its marked restorative effects on endothelial dysfunction. These
properties translate into clinical benefits for patients at all stages
of the cardiovascular disease continuum. Large-scale clinical trials have shown that Coversyl-based therapy reduces cardiovascular morbidity and mortality in patients with risk factors for
cardiovascular disease. In hypertensive patients, the addition
of Coversyl to amlodipine results in a significantly superior reduction in risk of stroke, coronary events, and procedures, as well
as in risk of new-onset renal impairment and diabetes, compared
with a -blocker/thiazide combination. In patients with type 2
diabetes mellitus, the Coversyl/indapamide combination reduces
Coversyl: at the core of cardiovascular disease prevention and treatment – Aseeva
shown a 28% reduction in stroke, 20% reduction in
coronary heart disease, and 22% reduction in major cardiovascular events with ACE inhibitors in
comparison with placebo.2 More recently, ACE inhibitors were shown to be associated with a blood
pressure (BP)-independent reduction in risk of coronary heart disease, an effect not necessarily shared
by other newer antihypertensive classes such as
angiotensin receptor blockers (ARBs) or calcium
channel blockers (CCBs).3,4
Finally, the ASCOT-BPLA (Anglo-Scandinavian
Cardiac Outcomes Trial–Blood Pressure Lowering
Arm) was the first trial to show a superior effect
of more recently introduced antihypertensive
therapies such as ACE inhibition with perindopril
(Coversyl)* , in terms of reduction of total and cardiovascular mortality, in comparison with the traditional approach based on a β-blocker and a thiazide diuretic.5 In ASCOT-BPLA, the amlodipine/
*Coversyl®(perindopril) is also available under the trade names:
Aceon, Acertil, Armix, Bioprexanil, Coverene, Coverex, Coversum,
Prestarium, Prexum, Vectoryl.
the risk of death and coronary and renal events. In patients at a
more advanced stage of the cardiovascular disease continuum,
such as those with coronary artery disease or cerebrovascular
disease, use of Coversyl in high-dose monotherapy or in combination with indapamide significantly reduces the risk of subsequent cardiovascular events. Coversyl also reduces cardiac remodeling following myocardial infarction and improves patient
symptoms and prognosis in diastolic heart failure. Current trial
evidence confirms the clinical benefits of Coversyl, all along the
cardiovascular disease continuum, both as monotherapy, and in
combination with the long-acting calcium channel blocker amlodipine or with indapamide.
Medicographia. 2009;31:69-76.
(see French abstract on page 76)
Keywords: Coversyl (perindopril); ACE inhibition; cardiovascular disease continuum; hypertension; diabetes; coronary
artery disease
www.medicographia.com
Address for correspondence: Olga A. Aseeva, Cardiovascular Division, Servier,
192 avenue Charles de Gaulle, 92758 Neuilly-sur-Seine Cedex, France
(e-mail: [email protected])
MEDICOGRAPHIA, VOL 31, No. 1, 2009
69
COVERSYL
Year
Table I. Summary of
evidence with Coversyl
from the morbiditymortality trials.
Abbreviations: TIA, transient
ischemic attack; CAD, coronary
artery disease; HT, hypertension; CV, cardiovascular;
MI, myocardial infarction;
HF, heart failure.
Trial acronyms:
see box on same page.
Based on data from
references 5-9.
Trial
6
Patients (number)
Intervention
Main results
Post stroke/TIA
(6105)
Stable CAD
(12 218)
HT at risk of CV
events (19 257)
Perindopril±indapamide
vs placebo
Perindopril high dose
vs placebo
Amlodipine±perindopril
vs atenolol±thiazide
diuretic
Perindopril high dose
vs placebo
Perindopril vs placebo
Perindopril+indapamide
vs placebo
Recurrent stroke: --28%
2001
PROGRESS
2003
EUROPA7
2005
ASCOT-BPLA5
2006
PREAMI 8
Post-MI (1 252)
2006
2007
PEP-CHF 9
ADVANCE 10
Diastolic HF (850)
Type 2 diabetes
(11140)
perindopril regimen showed a significantly greater
reduction in total mortality by 11%, major cardiovascular events and procedures by 16%, and newonset diabetes by 31%, in comparison with the
atenolol/thiazide regimen. The ASCOT-BPLA investigators based their choice of Coversyl on its long
duration of antihypertensive action.
Today, Coversyl, which is the focus of this review,
is one of the best studied antihypertensive agents,
with evidence ranging from experimental research
to large morbidity/mortality trials involving the entire extent of the cardiovascular disease continuum,
from treatment of patients with risk factors for cardiovascular disease, such as hypertension and diabetes mellitus, to established coronary artery disease and heart failure (Table I).5-10
STUDY
ACRONYMS
Action in Diabetes and Vascular disease: PreterAx and
DiamicroN MR Controlled Evaluation
ASCOT-BPLA
Anglo-Scandinavian Cardiac Outcomes Trial—Blood
Pressure–Lowering Arm
BPLTTC
Blood Pressure Lowering Treatment Trialists’ Collaboration
CAFE
Conduit Artery Function Evaluation
DAPHNET
Diabetes Artery Perindopril Hypertension Normalization
Excess sTiffness
EUROPA
EUropean trial on Reduction Of cardiac events with
Perindopril in stable coronary Artery disease
PEP-CHF
Perindopril in Elderly People in Chronic Heart Failure
PERSPECTIVE PERindopril’S Prospective Effect on Coronary aTherosclerosis by IntraVascular ultrasound Evaluation
PERTINENT
PERindopril—Thrombosis, InflammatioN, Endothelial
dysfunction and Neurohormonal activation Trial
PICXEL
Perindopril/Indapamide in a double blind Controlled
study versus Enalapril in Left ventricular hypertrophy
PREAMI
Perindopril and Remodeling in Elderly with Acute Myocardial Infarction
PREMIER
PREterax in albuMInuria rEgRession
PROGRESS
Perindopril pROtection aGainst REcurrent Stroke Study
REASON
pREterax in regression of Arterial Stiffness in a contrOlled
double-bliNd study
ONTARGET
ONgoing Telmisartan Alone and in combination with
Ramipril Global Endpoint Trial
PRoFESS
PRevention Regimen For Effectively avoiding Second
Stroke
MEDICOGRAPHIA, VOL 31, No. 1, 2009
CV mortality: --24%
CV events and procedures: --16%
Death/HF/cardiac remodeling: --22%
Death/HF hospitalization: --31%
Macro and microvascular events: --9%
Total mortality: --14%
Coversyl in patients with risk factors
for cardiovascular disease
ADVANCE
70
CV death/MI/cardiac arrest: --20%
Hypertensive patients
The antihypertensive efficacy of Coversyl has been
demonstrated in monotherapy in a large population of 10 425 hypertensive patients, including the
elderly, blacks, and patients nonresponsive to previous antihypertensive therapy.11-14 In the subgroup
of 970 patients who were not responding to previous therapy with ACE inhibitors, Coversyl achieved
a clinically and statistically significant decrease in
BP with a mean decrease in BP from baseline to
week 12 of 13.3 mm Hg for systolic blood pressure
(SBP) and 6.9 mm Hg for diastolic blood pressure
(DBP).11 Overall, 34.7% of patients nonresponsive
to previous therapy with ACE inhibitors other than
Coversyl achieved BP control on Coversyl at the end
of the 12-week study.14 This remarkable efficacy of
Coversyl in comparison with other antihypertensives, including other ACE inhibitors, appears to
result, at least in part, from its long duration of action and specific effects on arterial function and
structure. Coversyl compares favorably with other
ACE inhibitors owing to its true 24-hour BP control with once-daily dosage, the trough-to-peak ratio of Coversyl being 75% to 100%.15 In contrast to
other antihypertensive agents, including vasodilating β-blockers and ARBs, Coversyl has been shown
to improve endothelial function to a larger extent
than expected from BP reduction alone.16 The effects of long-term treatment with Coversyl on arterial structure and function have been extensively
studied both in monotherapy and in combination
with the diuretic indapamide (perindopril/indapamide=Preterax†). In a 12-month comparative study
versus atenolol, despite similar BP reduction in
both treatment groups, only Coversyl restored impaired media-to-lumen ratio of subcutaneous arteries to normal values.17 In comparison with a thiazide diuretic, only Coversyl significantly increased
common carotid artery distensibility after 6 months,
whereas both treatments produced similar BP-lowering effects.18 REASON (pREreterax in regression
of Arterial Stiffness in a contrOlled double-bliNd
† Preterax (perindopril/indapamide) is also available under
the trade names: Bionoliprel, Biprel, Bipreterax, Coversyl Plus,
Predonium, Prelectal, Noliprel, Noriplex.
Coversyl: at the core of cardiovascular disease prevention and treatment – Aseeva
COVERSYL
study) was a multicenter, multinational, controlled,
randomized, double-blind study conducted in 406
patients to compare effects of Coversyl/indapamide
combination versus atenolol on brachial and central BP parameters.19 At 12 months, for the same diastolic BP reduction, the Coversyl/indapamide combination produced a greater reduction in systolic BP
and pulse pressure in comparison with atenolol.
This difference was significantly more pronounced
at the carotid artery level than at the brachial artery
level. In hypertensive heart disease, Coversyl decreases LVH and induces structural repair of coronary arteries.20 In the PICXEL study (Perindopril/
Indapamide in a double blind Controlled study versus Enalapril in Left ventricular hypertrophy), 556
hypertensive patients with LVH were treated for 1
year either with the Coversyl/indapamide combination or with enalapril, at equihypotensive dosages.
At the end of follow-up, reduction in left ventricular [LV] mass index was significantly greater with
the Coversyl/indapamide combination than with
enalapril (P<0.001).21 Furthermore, treatment of
hypertensive patients with the Coversy/indapamide
combination has been shown to restore coronary
reserve to normal values and thus, to increase myocardial perfusion.22
Coversyl was chosen among the available ACE
inhibitors for the landmark ASCOT-BPLA trial because of its true 24-hour antihypertensive efficacy
with once-daily dosage. ASCOT-BPLA was the first
trial to study the comparative effects of the amlodipine/Coversyl combination and a conventional combination of atenolol/thiazide diuretic.5 Nine out of
10 patients in ASCOT-BPLA were receiving two or
more antihypertensive drugs, and in the amlodipine/Coversyl arm most patients received Coversyl.
ASCOT-BPLA was stopped earlier than scheduled
due to the significantly lower mortality observed on
amlodipine/Coversyl therapy, thus decreasing the
statistical power of the study with respect to its primary end point. However, risk for all prespecified
secondary and tertiary end points was lower on amlodipine/Coversyl therapy, including a significant
24% reduction in cardiovascular death (P=0.001),
13% reduction in total coronary events (P=0.007),
23% reduction in stroke (P=0.0003), and 15% reduction in new-onset renal impairment (P<0.002).
The benefits on amlodipine/Coversyl were consistent among all prespecified subgroups of hypertensive patients and remained significant after adjustment for SBP.23 The effects on central aortic BP—
considered to accurately reflect target-organ damage in hypertension — have been assessed in the
CAFE (Conduit Artery Function Evaluation) substudy of ASCOT-BPLA, which included 2199 patients. In this substudy, amlodipine/Coversyl therapy was more effective in reducing central systolic
and pulse pressures than atenolol/thiazide despite
a similar reduction in brachial pressures on both
treatments. Central aortic pressure reduction in
CAFE was associated with a reduction in a composite end point of major cardiovascular and renal outcomes and death (P<0.01).24
Finally, in ASCOT, analysis of 14120 hypertensive
patients who did not have diabetes at the time of
Coversyl: at the core of cardiovascular disease prevention and treatment – Aseeva
inclusion showed that there were significantly fewer new cases of diabetes on amlodipine/Coversyl in
comparison with atenolol/thiazide (relative risk reduction 34%; P<0.001). This was attributed by the
investigators to a composite of the adverse effects
on risk produced by atenolol and thiazide, with the
protective effects of Coversyl and amlodipine probably playing a neutral role.25
Patients with type 2 diabetes mellitus
It has been clearly established that the coexistence
of hypertension and diabetes substantially increases
the risk of developing renal and other organ damage, leading to a much higher incidence of stroke,
coronary heart disease, congestive heart failure,
peripheral artery disease and cardiovascular mortality. Although BP lowering per se provides a remarkable cardiac protective effect in type 2 diabetic
patients with hypertension, the renin-angiotensinaldosterone system (RAAS) inhibitors should be the
preferred antihypertensive monotherapy and a regular component of combination treatment, because
of their specific renal protective properties.1
In diabetic patients with hypertension, Coversyl
provides dose-dependent improvement in structure
and function of conduit arteries.26 Coversyl appears
to be more effective than ARBs with respect to improvement of insulin sensitivity and fibrinolytic balance.27,28 Coversyl has been shown to prevent progression of diabetic renal disease through its direct
renal protective effects such as prevention of interstitial collagen expansion and reduction in transforming growth factor–β (TGF-β) activation.29-31
In view of the currently recommended tighter BP
goals (below 130/80 mm Hg), early use of combination treatment is perfectly adapted to the needs of
diabetic hypertensive patients. Robust data confirm
that Coversyl, in combination with the only glucose-friendly thiazide-like diuretic indapamide, ensures antihypertensive efficacy, reduction in renal
and other target-organ damage, and prevention of
cardiovascular outcomes in patients with type 2 diabetes mellitus. In the PREMIER study (PREterax
in albuMInuria rEgRession), 482 type 2 diabetic patients were treated with Coversyl/indapamide or
enalapril for 1 year. Coversyl/indapamide reduced
albumin excretion rate to a significantly greater extent than enalapril (--42% vs --27%, respectively,
P=0.002).32 This effect was maintained after adjustment for the decrease in mean BP, suggesting a
specific renal protective effect of the Coversyl/indapamide combination. At 1 year, significantly fewer patients experienced clinical cardiovascular adverse events (myocardial infarction, stroke, heart
failure, cardiovascular death) in the Coversyl/indapamide group than in the enalapril group (2.5%
vs 6.3%, respectively, P=0.036).
Recently, the ADVANCE trial (Action in Diabetes
and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation) confirmed morbidity-mortality benefits with the Coversyl/indapamide combination in type 2 diabetic patients.29 ADVANCE,
which included 11 140 diabetic patients, both with
and without hypertension, is the largest morbiditymortality trial ever performed in type 2 diabetes.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
71
COVERSYL
A
Patients with stable CAD
EUROPA
Post-stroke/TIA patients
PROGRESS
Recurrent stroke
0
--5
--10
--5
--10
--20
--20
--30
--20%
--19%
CV death, MI, cardiac arrest
Recurrent stroke
Macro- and microvascular events
--15
--20%
--18%
--20%
0
--10
RRR (%)
RRR (%)
RRR (%)
--10
--20
--30
Overall study population
--28%
--27%
Coversyl in patients with
established cardiovascular disease
Patients with cerebrovascular disease
PROGRESS (the Perindopril pROtection aGainst
Recurrent Stroke Study) was the first study to assess the effects of ACE-inhibitor–based treatment
on recurrent stroke in patients with cerebrovascular
disease. Coversyl was chosen because of its true 24hour BP-lowering efficacy,15 its safety, attributable
to the maintenance of cerebral blood flow in poststroke patients,35 and its well-documented improve-
--5
--10
--32%
Subpopulation with hypertension
The BP arm of ADVANCE assessed the effects of
the Coversyl/indapamide combination vs placebo on
top of other therapies, including antihypertensive
agents, aspirin, and lipid-lowering drugs. Over 4.3
years of follow-up, Coversyl/indapamide significantly reduced risk of macrovascular and microvascular
events in comparison with placebo (relative risk reduction 9%, P=0.04). This was accompanied by a
14% reduction in all-cause mortality (P=0.005), 18%
reduction in cardiovascular mortality (P=0.03), 14%
reduction in the risk of coronary events (P= 0.02),
and 21% reduction in total renal events (P<0.01).10
Benefits obtained in other large morbidity-mortality trials with Coversyl either in monotherapy,
or in combination with indapamide or amlodipine,
were consistent in diabetic patients with hypertension, as well as in diabetic patients with cerebrovascular or coronary artery disease.5,33,34
It should be pointed out that the consistent benefit of Coversyl regarding cardiovascular outcomes
are not confounded by the presence or absence of
risk factors such as hypertension or diabetes mellitus (Figures 1A and 1B).5-7,10,33
MEDICOGRAPHIA, VOL 31, No. 1, 2009
--18%
Diabetic patients
ADVANCE
0
--5
--13%
--16%
Subpopulation without diabetes
Post-stroke/TIA patients
PROGRESS
0
--20
--20
--38%
Subpopulation with diabetes
Patients with stable CAD
EUROPA
--10
--15
--28%
--28%
--40
--19%
Overall study population
B
RRR (%)
0
--15
72
Total CV events and procedures
0
RRR (%)
RRR (%)
CV death, MI, cardiac arrest
Hypertensive patients
ASCOT-BPLA
--9%
--9%
--10%
Subpopulation without hypertension
Figure 1A. Consistent
effect of Coversyl in
patients with and
without diabetes
mellitus.
Figure 1B. Consistent
effect of Coversyl in
patients with and
without hypertension.
Abbreviations:
CAD, coronary artery
disease; TIA, transient ischemic attack; CV, cardiovascular; MI, myocardial
infarction; RRR, relative
risk reduction.
Trial acronyms:
see box on page 70.
Figure 1A: based on data
from references 5, 10,
and 33. Figure 1B: based
on data from references
6, 7, and 10.
ment in endothelial function and correction of vascular remodeling.17,18 PROGRESS randomized 6105
patients with previous stroke or transient ischemic
attack, either with or without hypertension, to Coversyl±indapamide or placebo. At 4 years, risk reduction of recurrent stroke was 28% (P<0.0001)
with Coversyl-based treatment.6 Benefits were observed for all stroke types and were consistent across
all patient subpopulations, including diabetics.33,36
Coversyl-based treatment also reduced the risk of
dementia and cognitive decline associated with recurrent stroke.37 The PROGRESS Magnetic Resonance Imaging substudy revealed that Coversylbased treatment stopped or delayed the progression
of white matter hyperintensities, ie, of the brain abnormalities associated with cognitive decline or dementia.38 A substantial reduction in the risk of cardiac outcomes was also reported, irrespectively of
the presence or absence of history of hypertension
or coronary heart disease.39 Coversyl-based therapy
significantly reduced the risk of major coronary
events by 26% and of nonfatal myocardial infarction by 38%. In a subgroup of patients with atrial
fibrillation, Coversyl-based treatment offered protection against major vascular events irrespective
of the use of anticoagulant therapy or of the presence of hypertension.4 To conclude, PROGRESS
showed Coversyl-based treatment to be effective,
safe, and well tolerated across all the study’s subgroups defined by age, sex, and region.41
Patients with coronary artery disease
EUROPA (EUropean trial on Reduction Of cardiac
events with Perindopril in stable coronary Artery
disease) was the first trial specifically aimed at a
population with established stable coronary artery
Coversyl: at the core of cardiovascular disease prevention and treatment – Aseeva
COVERSYL
disease and without clinically apparent heart failure.7 Coversyl was chosen for this study in view of
its documented anti-ischemic, antithrombotic, and
antiarteriosclerotic properties and beneficial effects
on vascular remodeling and endothelial function.42-45
In EUROPA, 12 218 patients with stable CAD were
randomized to high-dose monotherapy with Coversyl or placebo on top of their current preventive
treatments, which were considered standard at that
time (antiplatelets, lipid-lowering agents, β-blockers after myocardial infarction). After 4.2 years of
treatment with Coversyl, the incidence of the primary outcome (a composite of cardiovascular death,
nonfatal MI, or resuscitated cardiac arrest) was significantly decreased by 20%, fatal and nonfatal MI
by 24%, and hospitalization for heart failure by
39%.7 These cardioprotective effects of Coversyl
were consistent whatever the BP levels before randomization or BP changes during the course of the
study and were independent of renal function at
baseline.46,47 The treatment benefits of Coversyl in
patients with stable CAD were thus observed across
all levels of cardiovascular risk at baseline and were
of the same magnitude whether patients had prior
myocardial infarction or had undergone revascularization.48,49 In patients with preserved LV function
(mean LV ejection fraction 57%), which made up
most of EUROPA’s population, the reduction in major cardiac events with Coversyl was similar to that
in the overall EUROPA population.50
The EUROPA substudies provide further insights
into the mechanism of vascular protective action of
Coversyl. In PERTINENT (PERindopril-Thrombosis, InflammatioN, Endothelial dysfunction and
Neurohormonal activation Trial), as early as by the
1st year, Coversyl restored the balance between angiotensin II and bradykinin in favor of bradykinin,
improved endothelial function, and decreased the
endothelial cell apoptosis rate.51 Intracoronary ultrasound findings from the PERSPECTIVE (PERindopril’S Prospective Effect on Coronary aTherosclerosis by IntraVascular ultrasound Evaluation)
substudy showed that treatment with Coversyl was
associated with a more stable pattern of coronary
remodeling and a reduction in size of noncalcified
coronary plaques.52,53 Together with data from the
DAPHNET (Diabetes Artery Perindopril Hypertension Normalization Excess sTiffness) and CAFE
studies in hypertensive patients, PERTINENT and
PERSPECTIVE provide consistent evidence of Coversyl’s action at multiple pathophysiological levels
underlying the clinical cardiovascular disease continuum (Figure 2).24,26,51,53
It is doubtful that the aforementioned cardioprotective benefits obtained in EUROPA with Coversyl are attributable to the class of ACE inhibitors
as a whole. This is because of the potential longterm consequences of pharmacokinetic differences
between these agents, such as duration of action
and affinity for tissue versus circulating ACE. A recent comparative study of ACE inhibitors (perindopril, enalapril, ramipril, trandolapril, quinapril)
indicated that when these agents were used at equihypotensive dosages, only Coversyl significantly reduced endothelial cell apoptosis, one of the initi-
ating events in the atherosclerosis process.54 Further evidence of Coversyl’s benefits in coronary disease comes from PREAMI (Perindopril and Remodeling in Elderly with Acute Myocardial Infarction),
the first morbidity-mortality study of ACE inhibition in elderly patients with acute myocardial infarction and preserved LV function. Early after acute
myocardial infarction (mean 11 days), 1252 elderly patients (mean age 72 years) with preserved LV
function (mean LV ejection fraction 59%) were randomized to the high dosage of Coversyl or to placebo on top of other therapies, including β-blockers
(in 71% of patients) and followed for 12 months.
Coversyl resulted in a significant reduction in the
composite primary end point by 22% vs placebo,
mainly attributable to the prevention of cardiac
remodeling. LV end-diastolic volume increased
by 0.7 mL on Coversyl versus 4.0 mL on placebo
(P<0.001 for between-group difference ).8 Analysis
of the “PREAMI-like” population of EUROPA (elderly patients with prior myocardial infarction and LV
ejection fraction >40%) showed a significant 36%
Endothelial damage
CAFE/ASCOT-BPLA
Central aortic pressures
PERTINENT/EUROPA
Endothelial cell apoptosis
Central aortic pressures
Pathophysiological
continuum
Atherosclerosis
DAPHNET
Large artery stiffness
PERSPECTIVE/EUROPA
Noncalcified plaque size
Stiffening of large arteries
Figure 2. Coversyl’s action
at multiple pathophysiological levels underlying
the clinical cardiovascular
disease continuum.
Trial acronyms:
see box on page 70.
Based on data from references
24, 26, 51, and 53.
Coversyl: at the core of cardiovascular disease prevention and treatment – Aseeva
reduction in major cardiac events with Coversyl.
The high dosage of Coversyl is well tolerated, as
shown by the fact that in EUROPA and PREAMI, at
the end of follow up, 93% and 94% of patients assigned to Coversyl, respectively, were still on the
high dosage.7,8
Patients with heart failure
Coversyl’s improved pharmacological profile (prolonged duration of action, higher affinity for tissue
ACE, better tolerability), has a special impact in
heart failure where, compared with conventional
ACE inhibitors, Coversyl was not associated with
systemic hypotension at the initiation of treatment,
even in elderly patients.55 Coversyl improves systemic and regional hemodynamics in heart failure
patients.56 The switch from enalapril to Coversyl results in significant improvement in New York Heart
Association [NYHA] class.57 In a population-based
study of 43 316 patients with chronic heart failure,
in which ramipril was used as reference category
for comparison, 1-year mortality was significantly
higher in patients treated with enalapril or with captopril (+10% and +13%, respectively), while it was
10% lower on Coversyl.58
Although the effects of ACE inhibition in patients
with heart failure with systolic dysfunction were
well established, until the Perindopril in Elderly
People in Chronic Heart Failure (PEP-CHF) study it
remained unclear how heart failure with diastolic
MEDICOGRAPHIA, VOL 31, No. 1, 2009
73
COVERSYL
dysfunction responded.9 PEP-CHF, despite statistical limitations due to the loss of randomization
power after 1 year, showed a reduction in unplanned
heart failure–related hospitalization and an improvement in functional capacity and symptoms in
patients treated with Coversyl. There was also a
strong tendency for improvement in the primary
end point (all-cause mortality and unplanned heart
failure–related hospitalization) of similar magni-
Stable CAD
Diastolic HF
Post-AMI
Post-stroke
0
--5
--10
RRR (%)
--15
--20
--25
--30
--35
--40
--26%
--28%
P = 0.02
NS
--39%
P = 0.002
--37%
P = 0.033
--45
Figure 3. Coversyl prevents occurrence of heart failure and/or hospitalizations for heart failure in different populations of patients with cardiovascular disease.
Abbreviations: AMI, acute myocardial infarction; CAD, coronary artery disease; HF, heart
failure; RRR, relative risk reduction.
Based on data from references 7-9, and 39
Ramipril Global Endpoint Trial), there was no significant difference between telmisartan alone or the
telmisartan/ramipril combination versus ramipril
on the primary outcome in high-risk patients with
vascular disease or diabetes despite differences in
BP reduction in favor of telmisartan.60 In a population of patients intolerant to ACE inhibitors similar
to that of ONTARGET, TRANSCEND (Telmisartan
Randomized AssessmeNt Study in ACE iNtolerant
trial subjects with cardiovascular Disease), telmisartan did not reduce the risk of cardiovascular death,
myocardial infarction, stroke, or hospitalization for
heart failure in comparison with placebo, despite a
significant reduction in BP.61 Surprisingly, both in
the TRANSCEND and PRoFESS trials, there was no
effect of angiotensin receptor blockade on hospitalization for heart failure. In contrast with these
findings, treatment with Coversyl systematically
leads to reduction in hospitalization for heart failure or occurrence of heart failure in patients with
cardiovascular disease (Figure 3).7-9,39
Recent trials have confirmed previous findings of
a lesser protection against coronary heart disease
with ARBs in comparison with ACE inhibitors.3
Overall, data supporting the use of ARBs to prevent
vascular events in various groups of cardiovascular
patients, other than those with heart failure, are
incomplete.62
Conclusion
tude to that in SOLVD (Studies Of Left Ventricular
Dysfunction) in patients with heart failure with LV
systolic dysfunction. Coversyl significantly reduced
the end point of cardiovascular mortality and unplanned heart failure–related hospitalization by
18% at 1 year.9 Taking into account the scarcity of
morbidity-mortality data in heart failure with preserved LV function, Coversyl appears to be a valuable therapy in this particular population.
Evidence for RAAS inhibition along the
cardiovascular disease continuum
Usefulness of ACE inhibitors in prevention and
treatment of cardiovascular disease is supported by
the bulk of evidence from large randomized clinical trials. Findings from recent studies with ARBs
lead to the conclusion that they are not as effective
as the ACE inhibitors in preventing cardiovascular
events in patients with vascular disease. In the PRoFESS (PRevention Regimen For Effectively avoiding Second Stroke) trial in patients after an ischemic
stroke, telmisartan did not reduce the risk of subsequent stroke, major cardiovascular events, or,
new-onset diabetes, despite greater BP reduction in
comparison with placebo.59 In ONTARGET (ONgoing Telmisartan Alone and in combination with
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MEDICOGRAPHIA, VOL 31, No. 1, 2009
Recent trials have shown that the clinical effects of
ARBs are less robust than those of ACE inhibitors.
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51. Ceconi C, Fox KM, Remme WJ et al; EUROPA Investigators; PERTINENT Investigators and the Statistical Committee. ACE inhibition with perindopril
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54. Ceconi C, Francolini G, Bastianon D, et al. Differences in the effect of angiotensin-converting enzyme inhibitors on the rate of endothelial cell apoptosis: in vitro and in vivo studies. Cardiovasc Drugs
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55. MacFadyen RJ, Lees KR, Reid JL. Differences in
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COVERSYL
58. Pilote L, Abrahamowicz M, Eisenberg M, Humphries K, Behlouli H. Effects of different angiotensinconverting-enzyme inhibitors on mortality among
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COVERSYL :
N Engl J Med. 2008;359:1225-1237.
60. Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients
at high risk for vascular events. N Engl J Med. 2008;
358:1547-1559.
61. Telmisartan Randomised AssessmeNt Study in
ACE iNtolerant subjects with cardiovascular Disease
AU CŒUR DE LA PRÉVENTION ET DU TRAITEMENT DE LA MALADIE CARDIO-VASCULAIRE
es IEC (inhibiteurs de l’enzyme de conversion de l’angiotensine) sont largement reconnus pour leur capacité à
réduire la mortalité, l’infarctus du myocarde, l’accident
vasculaire cérébral (AVC) et l’insuffisance cardiaque chez les personnes à risque d’événements cardio-vasculaires. À l’inverse, les
résultats d’études récentes menées dans d’importantes populations de patients atteints de maladie vasculaire montrent que les
effets des antagonistes des récepteurs de l’angiotensine sont moins
établis dans la prévention des problèmes cardio-vasculaires. Les
IEC gardent donc toute leur place comme médicaments de référence dans la prévention et le traitement des maladies cardiovasculaires. Parmi ceux-ci, Coversyl (perindopril) se distingue
grâce à ses avantages démontrés sur la structure et la fonction
artérielle, ainsi qu’à ses effets marqués sur la restauration de la
dysfonction endothéliale. Ces propriétés se traduisent en termes
de bénéfices cliniques pour les patients à tous les stades du continuum de la maladie cardio-vasculaire. Des études cliniques à
grande échelle ont démontré que le traitement par Coversyl réduit la morbidité et la mortalité cardio-vasculaire chez les patients ayant des facteurs de risque. Chez les patients hypertendus,
L
76
(TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular
events in high-risk patients intolerant to angiotensinconverting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372:1174-1183.
62. Ripley TL, Harrison D. The power to TRANSCEND.
Lancet. 2008;372:1128-1130.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
l’addition de Coversyl à l’amlodipine permet une réduction significativement plus importante du risque d’AVC, d’événements
coronaires, et d’interventions, ainsi que du risque de survenue
d’une insuffisance rénale et d’un diabète, qu’avec l’association
-bloquants/thiazide. Chez les patients diabétiques de type 2, l’association Coversyl/indapamide réduit le risque de décès et d’événements coronaires et rénaux. L’utilisation de Coversyl en monothérapie à forte dose ou en association avec l’indapamide chez les
patients à un stade plus avancé du continuum cardio-vasculaire,
comme ceux atteints de maladie coronaire ou cérébrovasculaire,
réduit de façon significative le risque d’événements cardio-vasculaires ultérieurs. Coversyl réduit également le remodelage cardiaque faisant suite à un infarctus du myocarde et améliore le
pronostic et les symptômes du patient dans l’insuffisance cardiaque diastolique. Les résultats des études en cours confirment
les bénéfices cliniques de Coversyl, d’un bout à l’autre du continuum cardio-vasculaire, que ce soit en monothérapie ou en association avec l’amlodipine (un inhibiteur calcique de longue durée
d’action) ou avec l’indapamide.
Coversyl: at the core of cardiovascular disease prevention and treatment – Aseeva
I
N T E R V I E W
ACE INHIBITION
AND ATRIAL FIBRILLATION
I n t e r v i e w w i t h J . C . Ta r d i f
and K. Najem, Canada
Jean-Claude TARDIF
MD, FRCPC, FACC
Kinda NAJEM
Montreal Heart Institute
Université de Montréal
CANADA
What is the relationship between atrial
fibrillation and hypertension?
trial fibrillation (AF) and hypertension are frequently linked
to each other. In fact, hypertension is the
most prevalent, independent, and potentially modifiable risk factor for AF.1
Chronically elevated blood pressure leads
to left ventricular (LV) hypertrophy, diastolic dysfunction, and increased left
atrial pressure and enlargement. The
latter events increase the probability of
AF, but also of thrombosis and systemic
embolism. In addition, LV mass is an independent predictor of AF in hypertensive patients.1 In the Framingham Study,
a 4-mm increase in LV wall thickness
resulted in a 28% increase in the risk of
developing AF. In that study, left atrial
enlargement was also recognized as a
predisposing factor for AF, with a 5-mm
A
A
increase in left atrial size increasing by
39% the risk of developing AF.2 Other
studies have demonstrated that the degree of left atrial enlargement correlates
with the severity of hypertension.3,4 Moreover, atrial stretching and electrophysiological remodeling comprising changes
in atrial refractoriness and conduction
are thought to contribute to AF maintenance.5 Atrial stretching is involved in
the pathophysiology of AF by shortening
the effective refractory period and lengthening intra-atrial conduction time.1
Angiotensin II increases left atrial pressure and stretch and can promote fibrosis,
which renders the atrium structurally
susceptible to reentry loops that are characteristic of AF. Those intra-atrial conducSELECTED
ABBREVIATIONS AND ACRONYMS
AF
atrial fibrillation
AFFIRM Atrial Fibrillation Follow-up
Investigation of Rhythm
Management [Trial]
AV
atrioventricular
CCB
calcium channel blocker
CTAF-2 Second Canadian Trial on Atrial
Fibrillation
RACE
RAte Control versus Electrical
cardioversion [Trial]
trial fibrillation (AF) is the most prevalent cardiac arrhythmia and is a major health problem in our society. It
is associated with increased rates of hospitalization and
ischemic stroke and doubles the risk of mortality. Hypertension
is the most prevalent independent risk factor for AF and has an
enormous impact on the health system, affecting more than 1 billion individuals worldwide. Presently, the treatment of patients
with AF is inappropriate: more than 50% of patients have recurrences of their arrhythmia within 12 months despite therapy with
standard antiarrhythmic drugs. Experimental data have shown
that angiotensin-converting enzyme (ACE) inhibitors possess antiarrhythmic effects and can potentially decrease the incidence
of AF by reduction of atrial stretch and fibrosis and regulation of
ion channel function. A cohort study of 11 000 patients demonstrated that ACE inhibitors helped to reduce the incidence of AF
ACE inhibition and atrial fibrillation – Tardif and Najem
tion abnormalities arising from fibrosis
of the atrial walls are due to the action
of angiotensin II through cardiac myoblast proliferation, reduced collagenase
activity, and activation of extracellular
signal-regulated and mitogen-activated
protein kinases (MAPK). Finally, increased
angiotensin-converting enzyme (ACE)
expression has been found in the atria of
patients with AF.1 Thus, angiotensin II
is a key hormone linking AF and hypertension.
What are the major difficulties in the
management of patients with atrial
fibrillation and hypertension in clinical
practice?
t present, the treatment of patients with AF is inappropriate: more than 50% of patients have recurrences of their arrhythmia within 12
months despite therapy with standard
antiarrhythmic drugs. In the Atrial Fibrillation Follow-up Investigation of
Rhythm Management (AFFIRM) trial,
rhythm control and rate control strategies of treatment were compared. The
former was aimed at maintaining sinus
rhythm through cardioversion, antiarrhythmic drugs, or atrial catheter abla-
A
and the risk of related hospitalization in hypertensive patients
in a usual care setting. However, sufficient clinical data do not
exist to justify their use as a standard approach to prevent AF.
The ongoing Canadian Trial on Atrial Fibrillation–2 (CTAF-2)
is prospectively testing the hypothesis that the ACE inhibitor
perindopril will prevent recurrences of AF in patients with hypertension.
Medicographia. 2009;31:77-80.
(see French abstract on page 80)
Keywords: atrial fibrillation; arrhythmia; stroke; mortality;
antiarrhythmic drug; ACE inhibitor; clinical trial
www.medicographia.com
Address for correspondence: Jean-Claude Tardif, MD, Montreal Heart Institute,
5000 Belanger Street, Montreal PQ, Canada H1T 1C88
(e-mail: [email protected])
MEDICOGRAPHIA, VOL 31, No. 1, 2009
77
INTERVIEW
tion, whereas the latter was aimed at controlling the ventricular response rate
of AF by means of atrioventricular (AV)
node blocking agents or ablation of the
AV junction and pacemaker implantation.6
The study showed that rate control was
as effective as a rhythm control strategy
that incorporated currently used standard antiarrhythmic drugs. This comparison could not take into account the use
of drugs that may prevent AF without the
side effects or potentially proarrhythmic
effects of standard antiarrhythmic agents.
In addition, a rate-control strategy is often inadequate for patients who experience severe palpitations or who remain
dyspneic despite a controlled ventricular
response.7,8 Rhythm control has been
shown to reduce symptoms related to AF
and improve exercise tolerance and overall quality of life. The best rhythm control strategy is one that would prevent
development of the substrate for AF or
induce its regression.9 Limitations of the
different therapeutic approaches for AF
are summarized in Table I.7,10
Patients with AF and hypertension are
at greater risk of thromboembolic complications than normotensive patients
with AF, in spite of oral anticoagulant us,
as was demonstrated in the AFFIRM and
RAte Control versus Electrical cardioversion (RACE) trials. Another difficult issue is related to the asymptomatic recurrences of AF that may occur and result
in thromboembolic complications. Finally, there is an increased risk of thromboembolic complications following cardioversion in hypertensive patients.11
What is the pathophysiological evidence
to suggest that ACE inhibition may
reduce the incidence of new-onset atrial
fibrillation as well as its recurrence?
CE inhibitors elicit antiarrhythmic effects in AF by at
least three mechanisms: (i) reduction in
atrial stretch; (ii) reduction in atrial fibrosis; and (iii) regulation of ion channel
function.
Reduction in atrial stretch
ACE inhibitors induce systemic arteriolar
dilatation, increase large artery compliance (hemodynamic effects), and decrease
systolic blood pressure and left atrial
pressure. In acute hypertension, atrial
stretch contributes to AF maintenance
by shortening the effective refractory
period through the presumed opening
of stretch-activated channels.
Reduction in atrial fibrosis
Transforming growth factor–β1 (TGF-β1)
appears to play a significant role in the
pathophysiology of atrial fibrosis. Angio-
A
78
MEDICOGRAPHIA, VOL 31, No. 1, 2009
RHYTHM
RATE
CONTROL
CONTROL
Antiarrhythmic drugs
AV-node blocking agents
Class I
Risk of proarrhythmia
Aggravation of heart failure (HF)
Class III
Amiodarone
Bradyarrhythmia
Increased plasma level of warfarin
Side effects and potential toxicity
(lung, thyroid, etc) with chronic use
Digoxin
Efficacy reduced in states of increased
sympathetic tone (acute AF,
exercise)
-Blockers
Nondihydropyridine calcium antagonists
Both classes are associated with different side effects
Cardioversion
Ablation of AV node
High
Necessity
risk of AF recurrence
of pacemaker implantation
Permanent loss of AV node conduction
Atrial catheter ablation
Recurrence
of AF
but clinically significant complications (tamponade, pulmonary
vein stenosis)
Effective for patients without significant
structural heart disease
Rare,
Table I. Limitations of different treatment modalities for atrial fibrillation.7,10
Abbreviatons: AF, atrial fibrillation; AV, atrioventricular; HF, heart failure.
tensin II stimulates TGF-β1 production
and thus can lead to accumulation of fibrous tissue. Several studies have shown
that there is increased expression of angiotensin II and TGF-β1 in the atria (but
not the ventricles) of dogs with heart
failure and transgenic mice, rendering
them more susceptible to atrial fibrosis
and ultimately AF. Similarly, overexpression of ACE has been demonstrated in
the atria of patients with AF.12 Angiotensin II also reduces collagenase activity
therefore limiting collagen degradation.
In an experimental model of AF-induced atrial remodeling, the ACE inhibitor enalapril was found to exert its
actions through the reduction of angiotensin II13 and extracellular signal-regulated kinase (ERK) and not through its
hemodynamic effects. Overall, ACE inhibition reduces atrial fibrosis, intra-atrial conduction abnormalities, and susceptibility to AF.14
Regulation of ion channel function
The angiotensin II type 1 (AT1) receptor
forms a complex with a pore-forming
ion-channel (Kv4.3), which is responsible for the transient outward potassium
current (Ito ) and regulates the receptor
expression at the cell surface. When angiotensin II binds to AT1 , the complex is
internalized, therefore decreasing Ito
and promoting depolarization of the cell
membrane. In AF-induced remodeling,
the transcription of Ito is downregulated
due to the action of angiotensin II. ACE
inhibition favorably impacts on electrophysiological remodeling in AF.
Do we have sufficient clinical data to
support the usefulness of ACE inhibition
in hypertensive patients with AF?
CE inhibitors are an excellent
treatment for hypertension.
Experimental and initial clinical studies
suggested that ACE inhibition may also
prevent the development of AF. Based
on this knowledge, we carried out a retrospective, longitudinal cohort study to
evaluate the impact of ACE inhibitors
on the occurrence of AF in hypertensive
patients.1
The study compared the outcomes in
patients with hypertension treated with
ACE inhibitors versus long-acting calcium-channel blockers (CCB). A total of
10 926 eligible participants were taken
from an integrated medical and pharmacy claims database of over 8 million
subjects in the USA and were equally
matched in each group of medication
(5463 patients in each group). Eligibility
required a diagnosis of hypertension during the 6 months prior to the study and
a filled prescription for either class of
medication. The patients had a mean age
of 65 years and were followed for an average of 4.6 years for the ACE inhibitor
group and 4.2 years for the CCB group.1
Our results showed a significantly
lower incidence of new-onset AF in the
ACE-inhibitor group compared with the
CCB group. The onset of AF occurred at
an average of 29.5 months in the ACEinhibitor group versus 26.1 months in
the CCB group. The incidence rate of AF-
A
ACE inhibition and atrial fibrillation – Tardif and Najem
INTERVIEW
tension, with a systolic blood pressure
160 mm Hg and a diastolic blood pressure 100 mm Hg at the time of screening. The exclusion criteria include the
presence of LV systolic dysfunction with
an ejection fraction 45%; cardiac or
thoracic surgery within the past 3 months
or expected to be performed during the
trial; occurrence of myocardial infarction within the month prior to the selection visit; chronic AF constantly present
for more than 6 months; or use of standard antiarrhythmic drugs.
Eligible patients are first randomized
to perindopril 4 mg per day or placebo
for 2 weeks. Patients are then uptitrated
to 8 mg per day of perindopril or placebo
until the end of the study. Patients who
suffer from symptomatic orthostatic hypotension or for whom there is a risk in
increasing the dosage of the medication
are kept on the initial dose (4 mg per
day). Patients in whom nontolerable side
effects appear have their medication
stopped, but are nonetheless permitted
to remain in the study for intention-totreat analysis.
Patients will be treated for 7 to 13
months (Figure 1). During the first 30
days after inclusion and randomization,
related hospitalizations was also lower
with ACE inhibitors than with CCBs (8.5
vs 11.9 per 1000 patient-years, respectively). Furthermore, a greater benefit of
ACE inhibitors compared with CCBs was
observed in patients with previous history of AF.1 Thus, this cohort study demonstrated that ACE inhibitors reduced the
incidence of AF and the risks of related
hospitalizations in hypertensive patients
in a usual care setting. However, data
definitively demonstrating the beneficial
effects of ACE inhibition for the prevention of AF in a randomized controlled
trial are currently lacking. These data
are necessary before we can recommend
the widespread use of ACE inhibition for
the prevention of AF.
Could you explain the rationale and
design of the CTAF-2, trial, which you
are chairing, and what its status is?
he lack of data from randomized clinical trials demonstrating the benefits of ACE inhibitors as a potential treatment for AF in hypertensive
patients has led us to launch the second
Canadian Trial on Atrial Fibrillation
(CTAF-2). CTAF-2 is testing the hypoth-
T
Double-blind period
End point follow-up period
(D31 to end of study)
Perindopril
4 mg/day
Perindopril 8 mg/day
Placebo
Placebo
D0
D15
Inclusion/randomization
D30
M4
M7
M13
End of study or
premature termination
Figure 1. Study design of the second Canadian Trial of Atrial Fibrillation (CTAF-2).
esis that the ACE inhibitor perindopril
8 mg per day will prevent recurrences of
AF in patients with systemic hypertension.
CTAF-2 is a prospective, multicenter,
parallel-arm, placebo-controlled, doubleblind trial. A total of 320 eligible participants from approximately 30 different
sites will be recruited in the trial. The
main inclusion criterion is the occurrence of at least one episode of symptomatic paroxysmal or persistent AF (with
an indication for cardioversion in the
latter) having lasted 10 minutes or more
within the last 6 months. The patients
also need to have a diagnosis of hyper-
ACE inhibition and atrial fibrillation – Tardif and Najem
cardioversion is carried out in patients
with persistent AF. The patients are then
assessed clinically and the follow-up for
the assessment of the primary end point
starts on day 31 after randomization.
Recurrences of AF occurring on day 1 of
follow-up or later therefore constitute
the study primary end point. Patients suffering from persistent AF during the first
30 days after randomization are considered to have reached the primary end
point on day 1 of follow-up. Patients are
then assessed clinically on the third,
sixth, and up to the twelfth month of the
follow-up phase. The primary efficacy
end point is the time from day 1 of follow-up to the first sustained recurrence
of AF, defined as any electrocardiographically observed AF by 12-lead ECG, transtelephonic ECG monitoring, or 24-hour
Holter monitoring. Secondary efficacy
end points are the proportion of patients
without AF during the first 6 months
of follow-up, the number of relapses of
AF and health care resource utilization.
CTAF-2 is presently in the phase of patient recruitment.
What is the rationale for the choice of
perindopril among other ACE inhibitors
for CTAF-2?
everal ACE inhibitors have been
shown to reduce morbidity and
mortality in patients with heart failure.15
Perindopril has been shown to improve
cardiovascular outcomes in patients with
stable coronary artery disease. Perindopril
has also been shown to be well tolerated
and associated with a low incidence of
either symptomatic or asymptomatic hypotension.16-18 Perindopril was better tolerated in the early stages of treatment
than captopril by patients with recent
myocardial infarction, with a lower incidence of persistent hypotension and a
higher percentage of target dose attainment.19 In addition, perindopril is an effective agent to reach blood pressure
targets.20
Perindopril was also shown to improve cardiac sympathetic nerve activity
and decrease plasma brain natriuretic
peptide levels to a greater extent than
enalapril.21 Furthermore, prospective
studies found that the combination of
perindopril (2 mg) and indapamide (0.625
mg) decreased ambulatory systolic blood
pressure, pulse pressure, and LV mass
more efficiently than enalapril.22,23
Given the incidence of AF and the
limitations of standard antiarrhythmic
drugs, there is a clear need for a novel
effective approach to prevent the onset
of and reduce the recurrence of this
common arrhythmia, which is not associated with the risk of proarrhythmia.
Several lines of evidence implicate the
renin-angiotensin system in the pathophysiology of AF and suggest that ACE
inhibition may prevent or treat AF. Because hypertension is the factor most
frequently associated with AF, prospective confirmation in a randomized trial
that ACE inhibition has a favorable effect
against AF would be of major clinical
importance. CTAF-2 is presently testing
the hypothesis that the ACE inhibitor
perindopril will prevent AF recurrences
in patients with hypertension. S
MEDICOGRAPHIA, VOL 31, No. 1, 2009
79
INTERVIEW
REFERENCES
1. L’Allier PL, Ducharme A, Keller PF, Yu H, Guertin
MC, Tardif JC. Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a
reduction in the occurrence of atrial fibrillation. J Am
Coll Cardiol. 2004;44:159-164.
2. Kannel WB, Wolf PA, Benjamin EJ, Levy D, et al.
Prevalence, incidence, prognosis, and predisposing
conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82:2N-9N.
3. Vaziri SM, Larson MG, Lauer MS, Benjamin EJ,
Levy D. Influence of blood pressure on left atrial size.
The Framingham Heart Study. Hypertension. 1995;
25:1155-1160.
4. Gerdts E, Oikarinin L, Palmieri V, et al; Losartan Intervention For Endpoint Reduction in Hypertension
(LIFE) Study. Correlates of left atrial size in hypertensive patients with left ventricular hypertrophy: the
Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Hypertension. 2002;39:739743.
5. Shi Y, Ducharme A, Li D, Gaspo R, Tardif JC. Remodeling of atrial dimensions and emptying function
in canine models of atrial fibrillation. Cardiovasc Res.
2001;2:217-225.
6. Wyse DG, Waldo AL, DiMarco JP, et al; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate
control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-1833.
7. Savelieva I, Camm J. Update on atrial fibrillation:
part II. Clin Cardiol. 2008;31:102-128.
8. Rienstra M, Van Gelder IC. Who, when and how to
rate control for atrial fibrillation. Curr Opin Cardiol.
INHIBITION
2008;23:23-27.
9. Cohen M, Naccarelli GV. Pathophysiology and
disease progression of atrial fibrillation: importance
of achieving and maintaining sinus rhythm. J Cardiovasc Electrophysiol. 2008;19:885-890.
10. Efremidis M, Pappas L, Sideris A, Fikippatos G.
Management of atrial fibrillation in patients with heart
failure. J Card Fail. 2008;14:232-237.
11. Rienstra M, Van Veldhuisen DJ, Crijns HJ, Van
Gelder IC; RACE Investigators. Enhanced cardiovascular morbidity and mortality during rhythm control
treatment in persistent atrial fibrillation in hypertensives: data of the RACE study. Eur Heart J. 2007;28:
741-751.
12. Ehrlich JR, Hohnloser SH, Nattel S. Role of angiotensin system and effects of its inhibition in atrial
fibrillation: clinical and experimental evidence. Eur
Heart J. 2006;27:512-518.
13. Li D, Shinagawa K, Pang L, et al. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with
ventricular tachypacing-induced congestive heart
failure. Circulation. 2001;104:2608-2614.
14. Shi Y, Li D, Tardif JC, Nattel S. Enalapril effects
on atrial remodeling and atrial fibrillation in experimental congestive heart failure. Cardiovasc Res. 2002;
54:456-461.
15. Masuell M, Brusca G, Pardo A, Piñero D, Checkerdhemian S, Forcada P. ACE inhibitors in heart failure — switching from enalapril to perindopril. Curr
Med Res Opin. 2002;18:296-302.
16. Portuguese Community Hospital Study Group on
Heart Failure. A comparative study of the first dose
DE L’ENZYME DE CONVERSION ET FIBRILLATION AURICULAIRE
a fibrillation auriculaire (FA), arythmie cardiaque la plus
répandue, constitue un problème de santé majeur dans
notre société. Elle est associée à une augmentation des
taux d’hospitalisations et d’accidents vasculaires cérébraux ischémiques et double le risque de mortalité. L’hypertension, facteur
de risque indépendant le plus fréquent pour la FA, a des conséquences énormes sur les systèmes de santé en touchant plus d’1
milliard d’individus à travers le monde. À l’heure actuelle, le traitement de la FA n’est pas satisfaisant : l’arythmie récidive chez
plus de 50 % des patients dans les 12 mois malgré un traitement
antiarythmique standard. Les données expérimentales ont montré que les IEC (inhibiteurs de l’enzyme de conversion) ont des
L
80
hypotensive effects of captopril and perindopril in patients with heart failure. Cardiovasc Drugs Ther. 2001;
15:501-506.
17. Anthopoulos L, Apostolou T, Bonoris P, Foussas S,
Lefkos N, Zombolos S. Comparative haemodynamic
responses to the first dose of short- and long-acting
ACE inhibitors in patients with congestive heart failure. Curr Med Res Opin. 2001;17:290-297.
18. Navookarasu NT, Rahman AR, Abdullah I. Firstdose response to angiotensin-converting enzyme inhibition in congestive cardiac failure: a Malaysian experience. Int J Clin Pract. 1999;53:25-30.
19. Lau CP, Tse HF, Ng W, et al. Comparison of perindopril versus captopril for treatment of acute myocardial infarction. Am J Cardiol. 2002;89:150-154.
20. Lees KR, Reid JL, Scott MG, Hosie J, Herpin D,
Santoni JP. Captopril versus perindopril: a double
blind study in essential hypertension. J Hum Hypertens. 1989;3:17-22.
21. Tsutamoto T, Tanaka T, Sakai H, et al. Beneficial
effect of perindopril on cardiac sympathetic nerve activity and brain natriuretic peptide in patients with
chronic heart failure. Circ J. 2008;72:740-746.
22. Gosse P, Dubourg O, Guéret P, et al. Efficacy of
very low dose perindopril 2 mg/indapamide 0.625 mg
combination on left ventricular hypertrophy in hypertensive patients: the P.I.C.X.E.L. study rationale and
design. J Hum Hypertens. 2002;16:653-659.
23. Asmar R, Garcia-Puig J, Gosse P, et al. Ambulatory blood pressure in hypertensive patients with left
ventricular hypertrophy: efficacy of first-line combination perindopril/ indapamide therapy. Vasc Health
Risk Manag. 2007;3:371-380.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
effets antiarythmiques et pourraient diminuer l’incidence de la
FA en diminuant l’élargissement et la fibrose auriculaires et en
régulant les canaux ioniques. Une étude de cohorte de 11 000 patients a montré que les IEC permettaient de diminuer l’incidence
de la FA et le risque d’hospitalisation chez des patients hypertendus dans un cadre de soins courants. Nous ne disposons cependant pas de données cliniques suffisantes pour justifier leur utilisation en prévention standard de la FA. L’étude en cours CTAF-2
(Canadian Trial on Atrial Fibrillation-2) vérifie de façon prospective l’hypothèse selon laquelle l’IEC perindopril préviendrait les
récidives de FA chez les hypertendus.
ACE inhibition and atrial fibrillation – Tardif and Najem
F
O C U S
INHIBITION OF THE RENIN-ANGIOTENSIN
SYSTEM — INSIGHTS FROM THE BLOOD
PRESSURE LOWERING TREATMENT
TRIALISTS’ COLLABORATION
b y F. M . T u r n b u l l , A u s t r a l i a
The Blood Pressure Lowering Treatment
Trialists’ Collaboration: background
and overview findings
ince the mid 1990s, there has been increasing
recognition of the need for more reliable evidence about the effects of different blood pressure–lowering regimens in a diverse group of patients at risk of cardiovascular disease. Given the
global prevalence of suboptimal blood pressure and
extensive use of treatment, even moderate differences in treatment effects could potentially lead to
the prevention of many thousands or tens of thousands of premature deaths each year.
In 1995, principal investigators of ongoing and
planned major trials of blood pressure–lowering
regimens established the Blood Pressure Lowering
Treatment Trialists Collaboration (BPLTTC). The
Collaboration was formed in response to the lack
of strong evidence about the effects of specific drug
classes and of blood pressure lowering in high-risk
patients without “hypertension.” Although the evidence that blood pressure lowering reduced the
S
T
Fiona M. TURNBULL
MBChB, PhD, FAFPHM
Head, Population Health
Research, Cardiovascular
Division, The George Institute
for International Health and
Senior Lecturer, Faculty of
Medicine, University of Sydney
Sydney, AUSTRALIA
he broad goal of the Blood Pressure Lowering Treatment
Trialists’ Collaboration (BPLTTC) is to provide reliable information about the effects of commonly used blood pressure–lowering regimens on mortality and major morbidity in a
range of patients at risk for cardiovascular disease, using prospective overviews of large randomized trials. The results from the
BPLTTC’s second main cycle of overviews were instrumental in
clarifying the effects of different regimens (including newer agents
such as angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]) on cause-specific cardiovascular outcomes and on defining the major role of blood pressure
reduction in reducing the risk of major cardiovascular events.
While blood pressure reduction per se appeared to be a major
component of the benefit conferred by different regimens, additional analyses were subsequently done to quantify the relative
contributions of blood pressure–dependent and –independent
effects for ACE inhibitors and ARBs. These analyses showed that
ACE inhibitors afforded a small amount (9%) of additional pro-
risk of major cardiovascular disease was beyond
question, there remained considerable uncertainty
about the relative benefits of older drug classes (diuretics and β-blockers) compared with newer drug
classes (ACE inhibitors and calcium antagonists)
and of the effects of blood pressure lowering among
patients with other high-risk conditions such as
cerebrovascular disease, renal disease, and diabetes.
The broad goal of the BPLTTC was therefore to
provide reliable information about the effects of
commonly used blood pressure–lowering regimens
on mortality and major morbidity in a range of patients at risk of cardiovascular disease using prospective overviews of large randomized trials. The
SELECTED
ABBREVIATIONS
ACE
ARB
BPLTTC
CHD
angiotensin-converting enzyme
angiotensin receptor blocker
Blood Pressure Lowering Treatment
Trialists’ Collaboration
coronary heart disease
tection against coronary heart disease by virtue of a blood pressure–independent effect. This drug-specific effect was equivalent
to the estimated effect of an additional 3-mm Hg reduction in systolic blood pressure. The effect was not seen for the outcomes of
stroke or heart failure, nor was it seen in the analyses of ARBs.
These findings suggest that maximization of the benefit may
therefore be achieved with a regimen that includes an ACE inhibitor together with other drugs in an effort to optimize the size of
the blood pressure achieved.
Medicographia. 2009;31:81-86.
(see French abstract on page 86)
Keywords: ACE inhibitor; angiotensin receptor blocker; metaanalysis; blood pressure; major cardiovascular event; blood
pressure–independent effect
www.medicographia.com
Address for correspondence: Fiona M. Turnbull, MBChB, PhD, Head, Population
Health Research, Cardiovascular Division, The George Institute for International
Health, Po Box M201, Missenden Rd, Camperdownn NSW 2050, Australia
(e-mail: [email protected])
Insights from the Blood Pressure Lowering Treatment Trialists’ Collaboration – Turnbull
MEDICOGRAPHIA, VOL 31, No. 1, 2009
81
FOCUS
Trials
Events/Participants
1 st listed
2 nd listed
Mean ΔBP
(mm Hg)1
Favors
1 st listed
Favors
2 nd listed
Relative risk
(95% CI)
P
Stroke
ACEI vs D/BB
5
984/20 195
1178/26 358
+2/0
1.09 (1.00–1.18)
0.13
CA vs D/BB
9
999/31 031
1358/37 418
+1/0
0.93 (0.86–1.00)
0.67
ACEI vs CA
5
701/12 562
622/12 541
+1/+1
1.12 (1.01–1.25)
0.20
Coronary heart disease
ACEI vs D/BB
5
1172/20 195 1658/26 358
+2/0
0.98 (0.91–1.05)
0.21
CA vs D/BB
9
1394/31 031 1840/37 418
+1/0
1.01 (0.94–1.08)
0.48
ACEI vs CA
5
+1/+1
0.96 (0.88–1.04)
0.01
907/12 562
948/12 541
Heart failure
ACEI vs D/BB
3
547/12 498
809/18 652
+2/0
1.07 (0.96–1.19)
0.43
CA vs D/BB
7
732/23 425
850/29 734
+1/0
1.33 (1.21–1.47)
0.92
ACEI vs CA
4
502/10 357
609/10 345
+1/+1
0.82 (0.73–0.92)
0.75
Major cardiovascular events
ACEI vs D/BB
6
2581/20 631 3450/26 799
+2/0
1.02 (0.98–1.07)
0.31
CA vs D/BB
9
2998/31 031 3839/37 418
+1/0
1.04 (1.00–1.09)
0.92
ACEI vs CA
5
1953/12 562 2011/12541
+1/+1
0.97 (0.92–1.03)
0.22
Cardiovascular death
ACEI vs D/BB
6
1061/20 631 1440/26 799
+2/0
1.03 (0.95–1.11)
CA vs D/BB
9
1237/31 031 1584/37 418
+1/0
1.05 (0.97–1.13)
0.33
ACEI vs CA
5
+1/+1
1.03 (0.94–1.13)
0.56)
870/12 562
840/12 541
0.36
Total mortality
ACEI vs D/BB
6
2176/20 631 3067/26 799
+2/0
1.00 (0.95–1.05)
0.76
CA vs D/BB
9
2527/31 031 3437/37 418
+1/0
0.99 (0.95–1.04)
0.71
ACEI vs CA
6
1763/12 998 1683/12 758
+1/+1
1.04 (0.98–1.10)
0.68
0.5
1.0
Relative risk
collaborative group defined the plans for these
overviews and the resultant protocol was published
in 1998.1 At the time the protocol was finalized no
results had been reported from included trials. The
prospective nature of the overviews therefore allowed the specification a priori of a number of important aspects of the research including the principal hypotheses and the criteria for inclusion of
trials. In this way, retrospective outcome-dependent
biases in study questions and trial inclusion could
be avoided.
The first main cycle of overviews
The first main cycle of overviews from the Collaboration was published in the Lancet in 2000 and was
based on information from 15 trials and 74696 patients. This first cycle showed conclusively that the
benefits of blood pressure–lowering regimens were
not limited to those based on diuretics and β-blockers, but extended to newer agents, including ACE
inhibitors, and that these benefits were observed in
a heterogeneous population of patients at high risk
for cardiovascular disease.
In the overviews of placebo-controlled trials of
ACE inhibitors where the weighted mean difference
82
MEDICOGRAPHIA, VOL 31, No. 1, 2009
2.0
Figure 1. Comparisons
of active blood pressure–
lowering regimens
based on different drug
classes.
Abbreviations: ACEI, angiotensin-converting enzyme
inhibitor; BB, β-blocker;
CA, calcium antagonist;
D, diuretic. Copyright ©
2003, Elsevier Ltd.
Modified after reference 2:
Turnbull F. Effects of different blood-pressure-lowering
regimens on major cardiovascular events: results of
prospectively designed
overviews of randomised
trials. Lancet. 2003;362:
1527-1535. Copyright ©
2003, Elsevier Ltd.
between randomized groups was 3/1 mm Hg, there
was 20% to 30% reduction in the risk of stroke,
coronary heart disease (CHD), major cardiovascular events, cardiovascular death, and total mortality
with active treatment. While there was no significant reduction in the risk of heart failure, the 95%
confidence intervals could not exclude a possible
moderate advantage for patients receiving ACE-inhibitor therapy. The first cycle overviews of trials
comparing regimens based on different active agents
showed that where blood pressure differences between randomized groups were small (0-3 mm Hg),
there was no evidence of a difference in the risk of
composite events; major cardiovascular events, cardiovascular death, and total mortality. However,
there was some evidence of moderate, but potentially important, differences between regimens for
the cause-specific outcomes of stroke, CHD, and
heart failure. In the comparisons of ACE inhibitor–
and calcium antagonist–based regimens, there was
a 20% reduction in the risk of both CHD and heart
failure with ACE inhibitor–based regimens. However, for the outcome of CHD, there was significant
(P=0.01) heterogeneity among contributing trials,
and for the outcome of heart failure, the risk reduc-
Insights from the Blood Pressure Lowering Treatment Trialists’ Collaboration – Turnbull
FOCUS
vascular death or total mortality despite a 2-mm Hg
systolic blood pressure reduction.
For all treatment comparisons, including those
of ACE inhibitors and ARBs, there was a direct association between the blood pressure reduction and
the risk of all outcomes, with the exception of heart
failure, suggesting that the blood pressure–lowering effect of these regimens was a major component of their treatment effect. For heart failure, the
lack of direct association appeared to be attributable
to the adverse effects of calcium antagonists. Regimens based on ACE inhibitors and conventional
therapy (diuretics and β-blockers) were both superior to regimens based on calcium antagonists for
this outcome (Figure 1).2
Conversely, for the outcome of stroke, there was
a trend toward greater protection from regimens
based on both calcium antagonists and conventional therapy compared with ACE-inhibitor–based regimens. However, this benefit was in the context of
small differences in blood pressure between treatment groups, which favored both calcium antagonists and diuretics/β-blockers. For the outcome of
CHD, there was no evidence of a difference in the
effects of ACE inhibitors, calcium antagonists, and
diuretics/β-blockers.
tion was of borderline significance. Although the
first cycle of overviews provided many answers to
questions they were designed to address, there remained some uncertainty about others. In particular, while the overviews were able to determine
important differences between active regimens in
their protection against total major cardiovascular
events, the effects on cause-specific events were less
clear. Furthermore, this cycle did not examine the
treatment effects of angiotensin receptor blockers
(ARBs), which were receiving increasing attention
as a new class of renin-angiotensin inhibitor.
The second main cycle of overviews
In the 3 years following the first cycle of overviews,
a number of ongoing trials participating in the Collaboration presented or published their main findings. This resulted not only in substantial new information about the protective effects of different
blood pressure–lowering regimens, including ARBs,
but also a significant increase in data available to the
Collaboration. So, while the first cycle of overviews
had been based on data from 15 trials and 74696
participants, by the middle of 2003, a further 14 trials collectively including 87 645 participants were
added to the BPLTTC dataset, essentially doubling
the number of events available for analyses.
The second cycle overviews confirmed many of
the earlier findings of placebo-controlled comparisons of ACE inhibitors. For the composite outcomes of major cardiovascular events, cardiovascular death, and total mortality, ACE inhibitors
conferred 22%, 20%, and 18% reductions in the risk
of these events, respectively, compared with placebo. However, there were no significant differences
in the protective effects of ACE inhibitors compared
with other active regimens. The estimates of these
treatment effects were based on tens of thousands
of events and are therefore likely to be very reliable. While based on a smaller volume of data and
thus less reliable, ARBs also conferred a 10% reduction in the risk of major cardiovascular events
compared with “other” regimens. However, no significant reductions were seen for the risk of cardio-
Outcome
Defining the blood pressure–dependent
and –independent effects of
ACE inhibitors and ARBs
While the second main cycle of overviews showed
that the risk of major cardiovascular events could be
reduced by a broad range of blood pressure–lowering drugs, including ACE inhibitors and ARBs, and
that blood pressure was a major component of the
benefit, those analyses were unable to detect or refute any plausibly modest independent effects of particular classes of blood pressure–lowering drug on
any cause-specific cardiovascular outcome. Thus,
new analyses to determine the relative contribution of blood pressure–dependent and –independent
mechanisms to the reductions in risk of stroke,
CHD, and heart failure were proposed.
ACE-inhibitor–
based regimens
vs other regimen(a)
ARB based
regimen vs
other regimen(b)
P value for no difference in effect between
ACE inhibitor– and
ARB-based regimens(c)
Blood pressure effect (odds ratio
reduction and 95% CIs for
5 mm Hg lower blood pressure)
Stroke
CHD
Heart failure*
19 (2,33)
16 (7,25)
27 (13,39)
26 (--12,51)
17 (--29,47)
12 (--41,45)
0.6
0.7
0.3
Blood pressure-independent effect
(odds ratio reduction and 95% CIs
at 0 blood pressure reduction)
Stroke
CHD
Heart failure*
--2 (--13,8)
9 (3,14)
5 (--5,15)
1 (--20,18)
--8 (--39,17)
17 (--12,38)
0.6
0.002
0.6
The effect estimates and confidence intervals are (a)odds ratios (and 95% confidence interval) for each 5-mm Hg lower blood pressure and (b)the relative
risk (and 95% confidence interval) at 0 blood pressure reduction. The null hypothesis of no difference between the two drug classes in either their blood
pressure effect or their effect independent of blood pressure is the P-value reported in (c).
*ACE inhibitor and ARB trials in which calcium antagonists were a comparator arm were excluded from the primary analyses of the heart failure outcome.
Table I. Estimates of effect attributable to blood pressure and blood pressure-independent effects of ACE-inhibitors and angiotensin
receptor blockers.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CHD, coronary heart disease.
Modified after reference 29: Turnbull F, Neal B, Pfeffer, et al; Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25:951-958. Copyright © 2007, Lippincott Williams & Wilkins.
Insights from the Blood Pressure Lowering Treatment Trialists’ Collaboration – Turnbull
MEDICOGRAPHIA, VOL 31, No. 1, 2009
83
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Stroke
Odds ratio
The analyses used data from the 26 trials3-28 participating in the Collaboration, which compared an
ACE inhibitor or ARB with placebo or other drug
class. The association between the difference in follow-up systolic blood pressure levels and the log
odds ratio for each of the three outcomes was investigated using random effects meta-regression
analysis. For each outcome, the slopes of the lines
for ACE inhibitors and ARBs were compared, so as
to test for a differential effect of blood pressure reduction on risk in trials of ACE inhibitors compared
with ARBs.
Blood pressure effects
Coronary heart disease
Odds ratio
For trials of both ACE inhibitors and ARBs, the
magnitude of the risk reduction achieved for stroke,
CHD, and heart failure was positively associated with
the size of the blood pressure reduction (Table I,
page 83).29 Treatment with ACE-inhibitor–based
regimens achieved a 19% reduction in the risk of
stroke, 16% reduction in the risk of CHD, and 27%
reduction in the risk of heart failure for each 5-mm
Hg reduction in blood pressure. The corresponding
reductions in risk for ARBs were 26%, 17%, and
12%, respectively, although the confidence limits
around these estimates were wider than for ACE
inhibitors due to the smaller number of patients
studied.
Blood pressure–independent effects
For CHD, there was evidence that ACE inhibitors
provided protection that was greater than that which
could be attributed to the blood pressure differences
observed. At zero blood pressure reduction, the estimated relative risk reduction for CHD was 9% (3%
to 14%, P=0.004) (Table I).29 There was no such
effect apparent for stroke (P=0.8) or heart failure
(P=0.3). For no outcome was there evidence that
ARBs conferred any additional protection beyond
that conferred by blood pressure reduction alone,
although confidence intervals about these estimates
were again wider than for the analyses of ACE inhibitors.
For the outcomes of stroke and CHD, the sensitivity analyses did not provide any evidence to indicate
that the observed blood pressure–dependent and
–independent effects were in any way determined
by the composition of the comparator treatment
regimen. For the outcome of heart failure, however, the inclusion of trials with a calcium antagonist comparator arm indicated, that with zero blood
pressure reduction, there was a borderline 10% (0%
to 19%; P=0.06) reduction in heart failure risk with
ACE-inhibitor treatment and an 18% (9% to 27%;
P=0.001) reduction with ARBs. These effects were
not apparent in the trials that involved other comparator regimens.
Given the known limitations of calcium antagonists in preventing heart failure, this finding suggests a blood pressure–independent adverse effect
of calcium antagonists rather than a blood pressure–independent protective effect of ACE inhibitors or ARBs.
84
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Odds ratio
Sensitivity analyses
Heart failure
Within-trial systolic blood pressure difference between
randomized groups (mm Hg)
Figure 2. Associations of blood pressure reduction with risk reduction for
stroke, coronary heart disease, and heart failure in trials of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Black circles
represent trials of ACE inhibitors and blue circles represent trials of ARB with
the area of each circle inversely proportional to the variance of the log odds
ratio. Fitted lines represent the summary meta-regressions for each outcome.
Modified after reference 29: Turnbull F, Neal B, Pfeffer, et al; Blood Pressure Lowering
Treatment Trialists’ Collaboration. Blood pressure-dependent and independent effects of
agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25:951-958. Copyright
© 2007, Lippincott Williams & Wilkins.
Insights from the Blood Pressure Lowering Treatment Trialists’ Collaboration – Turnbull
FOCUS
Comparisons of ACE inhibitors and ARBs
Indirect comparison
The blood pressure–dependent and –independent effects of ACE inhibitors and ARBs on each outcome
were compared to examine whether there was evidence of a difference between the two drug classes.
The association between magnitude of reduction in
blood pressure and size of relative risk reduction for
stroke, CHD and heart failure were similar for ACE
inhibitors and ARBs (all P>0.2) (Table I).29 There
was also no evidence that ACE inhibitors and ARBs
were different to each other in terms of their likelihood of providing protection independent of blood
pressure lowering for stroke or heart failure (both
P=0.6). A single combined regression of ACE and
ARB trials was therefore calculated for stroke and
heart failure (Figure 2).29 There was, however, evidence (P=0.002) of a difference between ACE inhibitors and ARBs for CHD, suggesting greater protection independent of blood pressure lowering with
ACE inhibitors than ARBs (Table I, Figure 2).29
Direct comparison
The effects of ACE inhibitors and ARBs were directly compared in the supplementary meta-analysis of
three head-to-head trials,30-32 collectively including
18 447 individuals with acute myocardial infarction
and/or heart failure (Figure 3).29 In these studies,
the mean age of participants was 67 years and 70%
were male. A total of 6181 major cardiovascular
events contributed to the analyses. There was an estimated mean 0.7-mm Hg lower follow-up systolic
blood pressure in the ARB group compared to the
ACE-inhibitor group. The meta-analyses identified
no differences between these two drug classes for
any of the three outcomes P, but confidence limits
were wide and could not exclude true difference of
moderate magnitude.
These analyses provide the most reliable information about blood pressure–dependent and –independent effects of ACE inhibitors and ARBs to
date for two main reasons: first, the analyses includes nine new ACE-inhibitor and ARB trials with
data from an additional 48 745 patients; and second, they involve more sophisticated statistical
methods specifically aimed at the identification of
blood pressure–dependent and –independent components of the treatment effects. While the size of
blood pressure reduction achieved with either drug
class was directly associated with the size of the reductions in risks of stroke, CHD, and heart failure,
the analyses also showed that for CHD, treatment
with an ACE inhibitor provides an additional 9%
relative risk reduction beyond that explained by
the observed blood pressure differences. There was
no such effect observed for ARBs, although the confidence limits were too wide to exclude a modest
effect.
While the supplementary meta-analysis involving data from three trials that directly compared an
ACE inhibitor and an ARB in patients with acute
myocardial infarction or heart failure did not detect
a difference between these regimens for any outcome, the confidence limits for CHD were consistent with as much as a 19% lower risk, as well as a
6% greater risk, among those assigned the ACE inhibitor. Furthermore, patients with heart failure or
acute myocardial infarction may respond differently to ACE inhibitors and ARBs compared with patients selected on the basis of high blood pressure
and an elevated cardiovascular risk (who made up
the majority of the population in the trials contributing to the meta-regressions).
Conclusion
In summary, the BPLTTC overview analyses provide
strong evidence to suggest that the size of the reduction in blood pressure achieved with either ACE
inhibitors or ARBs is a major determinant of the
size of the reductions in risk of CHD, stroke, and
heart failure. Additionally, the analyses have identified a potentially important blood pressure inde-
Events/n
ARB
ACE-I
Favours
ARB
Favours
ACE-I
Relative risk
(95% CI)
Stroke
ELITE II
18/1578
OPTIMAAL 140/2744
157/4909
VALIANT
Overall
11/1574
1.63 (0.77, 3.44)
132/2733
1.06 (0.84, 1.33)
166/4909
0.95 (0.76, 1.17)
1.02 (0.87, 1.19)
Major CHD
161/1578
ELITE II
OPTIMAAL 576/2744
868/4909
VALIANT
Overall
129/1574
1.24 (1.00, 1.55)
533/2733
1.08 (0.97, 1.20)
896/4909
0.97 (0.89, 1.05)
1.06 (0.94, 1.19)
Heart failure
46/1578
ELITE II
OPTIMAAL 363/2744
813/4909
VALIANT
Overall
53/1574
0.87 (059, 1.28)
318/2733
1.14 (0.99, 1.31)
801/4909
1.01 (0.93, 1.11)
1.05 (0.95, 1.15)
0.5
1.0
2.0
Relative risk
Figure 3. Meta-analysis of trials directly comparing angiotensin-converting enzyme
inhibitor (ACE-I)- with angiotensin receptor blocker (ARB)-based regimens for the
outcomes of stroke, coronary heart disease (CHD), and heart failure.
Study acronyms: ELITE II, Evaluation of Losartan In The Elderly–II; OPTIMAAL, OPtimal Trial In Myocardial infarction with Angiotensin II Antagonist Losartan; VALIANT, VALsartan In Acute myocardial
iNfarcTion.
Modified after reference 29: Turnbull F, Neal B, Pfeffer, et al; Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the reninangiotensin system. J Hypertens. 2007;25:951-958. Copyright © 2007, Lippincott Williams & Wilkins.
Insights from the Blood Pressure Lowering Treatment Trialists’ Collaboration – Turnbull
pendent protective effect of ACE inhibitors on the
risk of CHD. This blood pressure–independent effect was equivalent to the estimated effect of an additional 3-mm Hg reduction in systolic blood pressure. These findings, therefore, suggest that the
CHD prevention afforded by a blood pressure–lowering regimen may be determined by the choice of
agent as well as the size of the blood pressure reduction achieved. Maximization of the benefit may
therefore be achieved with a regimen that includes
an ACE inhibitor together with other drugs in an
effort to optimize the size of the blood pressure
achieved. MEDICOGRAPHIA, VOL 31, No. 1, 2009
85
FOCUS
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13. Wing L, Reid C, Ryan P, et al; Second Australian
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14. Hansson L, Lindholm L, Niskanen L, et al; Captopril Prevention Project (CAPPP) Study Group. Effect
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morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.
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15. Hansson L, Lindholm L, Ekbom T, et al; STOPHypertension-2 Study Group. Randomised trial of old
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16. UK Prospective Diabetes Study Group. Efficacy of
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17. Estacio R, Jeffers B, Hiatt W, Biggerstaff S, Gifford
N, Schrier R. The effect of nisoldipine as compared
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18. Schrier R, Estacio R, Esler A, Mehler P. Effects of
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20. Lewis E, Hunsicker L, Clarke W, et al. Renoprotective effect of the angiotensin-receptor antagonist
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21. Brenner B, Cooper M, De Zeeuw D, et al. Effects of
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22. Lithell H, Hansson L, Skogg I, Elmfeldt D, Hofman A, Olofsson B; SCOPE Study Group. The Study
on Cognition and Prognosis in the Elderly (SCOPE).
Principal results of a randomised double-blind intervention trial. J Hypertens. 2003;21:875-886.
23. Dahlof B, Devereux R, Kjeldsen S, et al; LIFE
study group. Cardiovascular morbidity and mortality
in the Losartan Intervention For Endpoint reduction
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24. Julius S, Kjeldsen S, Weber M, et al. Outcomes in
hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine:
the VALUE randomised trial. Lancet. 2004;363:20222031.
25. McMurray J, Ostergren J, Swedberg J, et al. Effects
of candesartan in patients with chronic heart failure
and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the
CHARM-Added trial. Lancet. 2003;362:767-771.
26. Granger C, McMurray J, Yusuf S, et al. Effects of
candesartan in patients with chronic heart failure and
reduced left-ventricular systolic function intolerant
to angiotensin-converting-enzyme inhibitors: the
CHARM-Alternative trial. Lancet. 2003;362:772-776.
27. Yusuf S, Pfeffer M, Swedberg K, et al. Effects of
candesartan in patients with chronic heart failure
and preserved left-ventricular ejection fraction: the
CHARM-Preserved Trial. Lancet. 2003;362:777-781.
28. Cohn J, Tognoni G; Valsartan Heart Failure Trial
Investigators. A randomised trial of the angiotensinreceptor blocker valsartan in chronic heart failure.
N Engl J Med. 2001;345:1667-1675.
29. Turnbull F, Neal B, Pfeffer, et al; Blood Pressure
Lowering Treatment Trialists’ Collaboration. Blood
pressure-dependent and independent effects of agents
that inhibit the renin-angiotensin system. J Hypertens. 2007;25:951-958.
30. Dickstein K, Kjekshus J; OPTIMAAL Steering
Committee for the OPTIMAAL Study Group. Effects
of losartan and captopril on mortality and morbidity
in high-risk patients after acute myocardial infarction:
the OPTIMAAL randomised trial. Lancet. 2002;360:
752-760.
31. Pfeffer M, McMurray J, Velazquez E, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction,
or both. N Engl J Med. 2003;349:1893-1906.
32. Miller M, Byington R, Hunninghake D, Pitt B,
Furberg C; Prospective Randomized Evaluation of the
Vascular Effects of Norvasc Trial (PREVENT) Investigators. Sex bias and underutilization of lipid-lowering therapy in patients with coronary artery disease at
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Canada. Arch Intern Med. 2000;160:343-347.
INHIBITION DU SYSTÈME RÉNINE-ANGIOTENSINE : PERSPECTIVES OUVERTES PAR L’ÉTUDE
BLOOD PRESSURE LOWERING TREATMENT TRIALISTS’ COLLABORATION
e BPLTTC (Blood Pressure Lowering Treatment Trialists’
Collaboration) a comme objectif global d’informer de façon fiable des effets des antihypertenseurs courants sur la
morbi-mortalité des patients à risque de maladie cardio-vasculaire, grâce à une analyse prospective d’études randomisées à
grande échelle. Les résultats du second cycle principal d’analyse
par le BPLTTC ont permis de clarifier les effets de différentes
classes thérapeutiques (dont les plus récentes comme les inhibiteurs de l’enzyme de conversion de l’angiotensine [IEC] et les antagonistes des récepteurs de l’angiotensine [ARA]) vis-à-vis des
événements cardio-vasculaires de cause spécifique et de la définition du rôle essentiel de l’abaissement de la pression artérielle sur
la réduction du risque d’événements cardio-vasculaires majeurs.
Bien que l’abaissement de la pression artérielle en elle-même
L
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MEDICOGRAPHIA, VOL 31, No. 1, 2009
semble participer majoritairement aux effets bénéfiques des traitements, des analyses supplémentaires ont été faites pour évaluer
les effets des IEC et des ARA dépendants ou non de la pression artérielle. Ces analyses ont montré que les IEC, en vertu d’un effet
indépendant sur la pression artérielle, procuraient une légère
(9 %) protection supplémentaire contre la maladie coronaire. Cet
effet spécifique était équivalent à celui d’une baisse supplémentaire de 3 mmHg de la pression artérielle systolique, et n’a pas été
observé pour les AVC ou l’insuffisance cardiaque, ni avec les ARA.
Ces résultats suggèrent que l’obtention d’un bénéfice maximal
passe par l’adjonction d’un IEC au traitement antihypertenseur,
dans le but d’atteindre un niveau optimal de baisse de la pression
artérielle.
Insights from the Blood Pressure Lowering Treatment Trialists’ Collaboration – Turnbull
U
P D A T E
WHAT IS NEW IN THE GENETICS OF THE
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM?
by A. S. Hall, United Kingdom
he science of genetics is said to have begun in
1866 with the work of a monk called Gregor
Mendel who liked to spend time in the garden.
However, as with many types of knowledge through
history—an awareness of heredity and the factors
influencing it had been present for much longer.
For example, 2000 years earlier Aristotle and Hippocrates both wrote about the inherited nature of
physical characteristics that depended upon the alternate characteristics of mother and father. However, the exponential growth of knowledge in our
understanding of the human genome has been truly remarkable and has even surprised the enthusiast. Within the last 2 years the use of a new set of
methodologies and laboratory techniques has allowed very large studies to be performed in patients
with common diseases such as diabetes, hypertension, and coronary artery disease (CAD).1,2 These
have used an approach called genome-wide association, which compares the frequency of single
DNA base changes called single nucleotide polymorphisms (SNPs). The first wave of studies studied
gene chips with 100 000 SNPs, while the most recent projects commonly evaluate 1000 000 SNPs on
a single chip.3 Importantly, the study of single SNPs
that have been selected as worthy biological candidates has been largely eclipsed, as have also family-based methodologies that are predicated on the
strict rules of Mendelian inheritance. This is the exciting and rapidly developing context that human
genetics now finds itself in, a context within which
I will seek to review current evidence for clinical
significance for gene variants that code for the elements of the renin-angiotensin-aldosterone system.
T
T
The renin-angiotensin-aldosterone
system (RAAS)
Alistair S. HALL
MB ChB, PhD, FRCP
Institute for Cardiovascular
Research, Yorkshire Heart
Centre, Leeds General Infirmary
Leeds, UNITED KINGDOM
he father of medicine, Hippocrates, wrote that “Where you
find the love of mankind, there you will also find the love
of the art of medicine.” He was well aware how this underpins the physicians’ oath to endeavor to choose treatments for the
good of each patient according to the best of their ability and
judgment—and above all to do no harm. Genetic profiling of patients holds the promise of improved diagnosis, risk prediction,
and therefore also patient selection for treatment, as well as the
ability to select treatments most likely to benefit and least likely
to cause harm. However, this remains an unfulfilled dream at this
point in time, with the many studies of candidate genes having
had little impact on routine clinical care. Nevertheless, the last
year has seen a quantum leap in understanding of the genetics
What is new in the genetics of the RAAS? – Hall
During the evolution of man and other life forms
there has been a key physiological need to retain
sodium and water within the circulation while at
the same time producing urine to excrete waste
products from the body. The extracellular and circulatory fluids of land-dwelling mammals contain
sodium chloride as a principal component. Indeed
so essential to health and well-being are the electrolytes of sodium and chloride, that a very developed homeostasis system is also present in all mammals. A properly functioning renin-angiotensinaldosterone system (RAAS) is essential to healthy
life as is also an adequate intake of salt (Figure 1,
page 88).4 Indeed in ancient times the value of salt
was at some stages higher than that of gold, which
is not essential for healthy life. Troops in the Roman army were paid in salt such that the practice
gave rise to the word “salary”—a strong indicator
SELECTED
ABBREVIATIONS AND ACRONYMS
ACE
ARB
AT1, 2, etc
CAD
CHARM
MMP
RAAS
SNP
angiotensin-converting enzyme
angiotensin receptor blocker
angiotensin II type 1, 2, etc, receptor
coronary artery disease
Candesartan in Heart failure Assessment
in Reduction of Mortality
matrix metalloproteinase
renin-angiotensin-aldosterone system
single nucleotide polymorphism
of common diseases, helped by new research methods and technologies. The stage is therefore set for big advances over the next
decade.
Medicographia. 2009;31:87-91.
(see French abstract on page 91)
Keywords: cardiovascular disease; coronary artery disease;
hypertension; genetics; renin-angiotensin-aldosterone system;
angiotensin-converting enzyme inhibitor; angiotensin receptor
blocker; angiotensin receptor
www.medicographia.com
Address for correspondence: Alistair S. Hall, MB CHB, PhD, FRCP, Institute for
Cardiovascular Research, Yorkshire Heart Centre, G Floor Jubilee Wing, Leeds General
Infirmary, Great George Street, Leeds LS1 3EX, UK (e-mail: [email protected])
MEDICOGRAPHIA, VOL 31, No. 1, 2009
87
UPDATE
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
Legend
Secretion from
an organ
Sympathetic
activity
Lungs
Liver
Angiotensin I
Na +
Tubular Na + CI –
reabsorption and K +
excretion. H2O retention
Surface of pulmonary
and renal endothelium:
ACE
Angiotensinogen
Decrease in
renal perfusion
(juxtaglomerular
apparatus)
Kidney
Stimulatory
signal
Inhibitory signal
K+
Reaction
CI –
Active transport
H2O
Passive transport
Adrenal gland;
cortex
Aldosterone
secretion
Angiotensin II
Water and salt
retention. Effective
circulating volume
increases. Perfusion
of the juxtaglomerular
apparatus increases
Renin
Arteriolar
vasoconstriction
Increase in
blood pressure
Arteriole
Kidney
ADH secretion
Pituitary gland;
posterior lobe
Collecting duct:
H2O absorption
of the value placed on salt. The basic skeleton of the
physiological system for salt retention begins with
a detector mechanism and ends with an effector
mechanism. The detector mechanism includes the
monitoring of sodium status by the macula densa
cells of the juxtaglomerular apparatus located within close proximity to both blood and urine within
the kidney. Sited adjacent to the vascular pole of
each nephron (the glomerulus) and also adjacent to
the distal tubule, the content and rate of flow of
both blood and urine can be monitored and regulated. When the sodium content of the urine is
detected as being high, the bloodborne hormone
renin is released, and the RAAS pathway initiated
(Figure 1).4
Drugs and the RAAS
Dissection and hence understanding of this system
and it’s relevance to clinical medicine has been aided by the development of a series of drugs that block
the system at various levels. These now comprise
the following: (i) renin enzyme inhibitors; (ii) angiotensin-converting enzyme (ACE) inhibitors; (iii)
angiotensin II type 1 (AT1) receptor antagonists
(ARBs); and (iv) aldosterone receptor antagonists.
All four classes have the intended and actual effect
of increasing salt and water excretion through the
kidney. The primary clinical benefits of this are in
the treatment of hypertension and heart failure,
acting much in the same way as more classic diuretics. However, while this aspect of shared efficacy is of clinical value in lowering elevated systemic
blood pressure and reducing fluid retention with
associated ankle swelling and breathlessness, a primary objective of all cardiovascular care is the pre88
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Figure 1. An overview
of the renin-angiotensinaldosterone system.
Abbreviations: ACE, angiotensin-converting enzyme;
ADH, antidiuretic hormone.
Modified after reference 4:
Wikimedia Commons freely
licensed media file repository.
http://en.wikipedia.org/wiki/
Renin-angiotensin_system.
Accessed September 19, 2008.
H2O
vention of major clinical events such as myocardial
infarction, stroke, and death. In this regard these
four drug classes have demonstrated important differences that appear to relate to the “off-target” effects. By their very nature, these important distinctions and differences are not easily studied and
defined, with greater emphasis being placed on the
effects that are judged to be similar.
The genetic “scalpel”
In the laboratory it is possible to genetically modify cells living in culture, whole animals or selected
organs/tissues in an animal at a selected time. Protein encoding genes can be removed (knocked-out),
changed into a variant form (transgene), or made
to be expressed in large amounts (knock-in). This
can result in the loss, the gain, or the selective alteration of function of a selected molecule/enzyme/
receptor/hormone/ligand. These and other techniques have permitted a much greater understanding of the complexity of the RAAS both with regard
the primary axis and also a range of other parallel
effects on other molecular systems. However, it is
both difficult and potentially dangerous to generalize from observations from in vitro cell systems and
in vivo transgenic animal systems to human disease states. A very good example of this relates to
“off-target” events mediated via the angiotensin II
AT2 receptor.5
Function of the AT2 receptor
Angiotensin II mediates its effects through a number of receptors subtypes other than the mainly recognized AT1 receptor, activation of which aggravates
What is new in the genetics of the RAAS? – Hall
UPDATE
the clinical conditions of hypertension and heart
failure through the release of aldosterone. These include the AT2 , AT3 , and AT4 receptor subtypes.5 Of
these, the best known and understood is the AT2
receptor. For years after the existence of this subtype was first described the role and function of
the AT2 was poorly understood, having presumed
significance in new vessel formation both during
embryonic development and also during later tissue repair. Other comparable effects that have been
attributed to this receptor subtype include the modulation of extracellular matrix, neuronal regeneration, cellular differentiation, and apoptosis. Of particular interest is the fact that in arteries damaged
by atherosclerosis the expression of the AT2 receptor increases 8-fold, implicating it as having a role
in the plaque biology.6,7
In humans, the AT2 receptor is located on the X
chromosome,8 suggesting that these receptors may
be involved in diseases (such as CAD) present to a
greater extent in males as compared with females.
The gene is composed of three exons that span a distance of more than 5 kb. Exons-1 & 2 code for a section of untranslated mRNA regions, while exon-3
codes for mRNA that is translated into the AT2 receptor. The promoter region of the gene includes
a possible embryonic long terminal repeat binding
protein site9 In vitro study of Intron-1 using artificially induced mutations indicates that this section
of the gene is necessary for efficient transcription of
the gene.10 In particular, effect relates to a common
human mutation found within intron-1 and annotated by Nishimura as --1332G/A11 and later by Erdmann et al as +1675 G/A.12 Standardization of this
nomenclature has renamed this SNP as rs1403543
and placed it’s location on the X chromosome as
being bp 115,216,220. There is good evidence for an
association between a common AT2 receptor gene
polymorphism (rs1403543) and elevated left ventricular mass in patients with hypertension that
supports the functional significance of this variant.13
It has also been suggested from in vitro studies that
stimulation of the AT2 receptor attenuates atherosclerosis and reduces inflammatory vascular injury.14,15 Furthermore, the AT2 receptor also plays a
role in the regulation of collagen production and
deposition, and to induce the release of matrix metalloproteinases (MMP) 1, 2, and 9, which may be
important for the structural integrity of atheromatous plaques.16-20 These represent potential mechanisms by which a functional AT2 receptor gene polymorphism may contribute to the development and
complications of cardiovascular disease.
ther research into this hypothesis by a number of
clinical investigators. Alfakih et al initially described
an association between rs1403543 and premature
CAD in 509 families with at least on member affected by early CAD.23 However, that study was not
sufficiently large to examine important details of
this primary observation such as the relationship
with other conventional nongenetic risk factors, differential effects based on gender and associations
with coronary atheroma subphenotypes. All of these
aspects have potential relevance to better understanding the differential effects of ACE inhibitors
and ARBs with regard to the prevention of myocardial infarction and cardiovascular death.24
Later, Alfakih et al studied 885 families (2662 individuals) that had been demonstrated to have appropriate Mendelian relationships and successful
genotyped.25 The distribution of polymorphic alleles
of the AT2 receptor gene Intron-1 SNP rs1403543
(G/A) was established. For siblings unaffected by
CAD the A/AA genotype was most frequent (53.7%)
and the G/GG least frequent (46.3%) while to the
contrary for the siblings affected by early contrary
artery disease the A/AA genotype was least frequent
(47.6%) and the G/GG was most frequent (52.4%).
Consequently, the G allele occurred significantly
more frequently with premature CAD than would be
expected if the disease susceptible locus and typed
marker were unlinked (P=0.028). This difference
was driven by a highly statistically significant result
in males in contrast to a negative result for females.
Alfakih et al next subcategorized patients into two
groups based on the occurrence of myocardial infarction and also the extent of stenotic atherosclerosis. Group 1 consisted of patients who had had
myocardial infarction with or without a coronary
revascularization procedure for occlusive disease.
Group 2 was made up of patients with stenotic
atherosclerosis that was of sufficient severity to require revascularization by either coronary artery
bypass surgery of percutaneous coronary intervention. There was a sequential increase in the prevalence of the rs1403543 G/GG genotype in Group 1
siblings as compared to the unaffected sibling and
in Group 2 as compared to Group 1, both in the cohort as a whole and also separately for males and in
females (Figure 2, page 90).25 These data help to
support the hypothesis that the AT2 receptor, and it’s
variable expression, play a role in coronary atheroma. However, to better understand what this role
might be, it is necessary to reconsider the evidence
derived from randomized clinical trials of: (i) ARBs,
which preferentially increase AT2 receptor expression and stimulation; and (ii) ACE inhibitors, which
reduce angiotensin II concentrations and thereby
also AT2 receptor stimulation.
AT2 receptor gene
and cardiovascular disease
AT2 receptor activation
and cardiovascular disease
Two separate genome-wide searches for regions that
may be implicated in the causation of early CAD
have demonstrated a statistical link (linkage) to a
region (Xq23-26) on the X-chromosome where the
AT2 receptor gene is located.21,22 This stimulated fur-
The introduction of a new class of drug capable of
selectively blocking the effects of angiotensin II mediated by the AT1 receptor offered the hope of more
effective treatment than had been possible with the
use of an ACE inhibitor.
The AT2 receptor gene
What is new in the genetics of the RAAS? – Hall
MEDICOGRAPHIA, VOL 31, No. 1, 2009
89
UPDATE
CONTROL
Unaffected by CAD
GROUP-1
Myocardial infarction
GROUP-2
Revascularization
400
Number of siblings
350
300
G/GG
*
A/AA
250
200
**
150
100
†
50
0
Males
Females
Males
Females
††
Males
Females
Figure 2. Bar chart illustrating the sequential increase in frequency of the G/GG
genotype in Group 1 siblings as compared to the unaffected sibling and in Group 2 as
compared with Group 1, in males and in females. *P exact = 0.067; **P exact = 0.023;
†P exact = 0.23; ††P exact = 0.336. CAD, coronary artery disease.
Modified after reference 25: Alfakih K, Brown B, Lawrance R, et al. Effect of a common X-linked angiotensin II type 2-receptor gene polymorphism (--1332 G/A) on the occurrence of premature myocardial
infarction and stenotic atherosclerosis requiring revascularization. Atherosclerosis. 2007;195:e32-e38.
Copyright © 2007, Elsevier Ltd.
Both agents reduce the production of aldosterone
and hence also attenuate hypertension and heart
failure by reduced salt and water retention. However, a large literature suggests that ARBs have
distinct beneficial “off-target” effects as a result of
upregulation of AT2 receptor expression and stimulation. Nevertheless, an overview of the major randomized clinical trials of ARBs suggests that any
such benefits do not extend to the reduction of major cardiovascular events.24
Meta-analysis designed to assess the benefits or
risks of AT2 receptor activation in patients at high
risk of cardiovascular events has demonstrated the
absence of any net statistically significant benefit on
all-cause mortality, stroke, or myocardial infarction
(Table I).24 This observation was true irrespective of
whether ARB treatment was compared with placebo or with all other randomized comparators. Importantly, these analyses excluded trials in which
the alternate strategy of using ARB treatment on
top of ACE-inhibitor therapy was assessed. Under
such circumstances, the attenuating effects of ACE
inhibitors are likely to have diminished ARB-associated AT2 effects. This assumption was based on the
observations from the Candesartan in Heart failure
Assessment in Reduction of Mortality (CHARM)
program of trials in which the ability of ARB candesartan to prevent myocardial infarction was apparent only in the presence of concomitant ACEinhibitor treatment.26-29
Figure 3. Representation of the exonic
structure of a number of RAAS genes indicating
the location of SNPs that have been cited as being
of potential functional interest. These include
(i) beta-hydroxylase (rs1799998);
(ii) angiotensinogen (rs4762; rs699; rs5050;
rs5051); (iii) angiotensin-converting enzyme
(rs4316; rs4317; rs4318; rs4331; rs4341; rs4342;
rs4343); (iv) angiotensin AT1 receptor (rs5183;
rs5186, rs275651, rs275652, rs1492078);
and (v) angiotensin AT2 receptor AGTR2
(rs1403543; rs5193; rs5194; rs5192).
90
MEDICOGRAPHIA, VOL 31, No. 1, 2009
End
points
Number
at risk
RAAS gene variants,
hypertension and drug response
A recent study looked at the blood pressure response
to ACE inhibitors relative to genetic profiles for
RAAS gene variants.30 Specifically, these related to
the angiotensinogen (AGT), angiotensin receptor 1
(AGTR1), and angiotensin receptor 2 (AGTR2) genes
in 1447 Chinese patients with established systemic
hypertension (Figure 3). The AGT SNP rs7079 and
an AGTR1 haplotype were shown to be associated
with blood pressure reduction in response to ACEinhibitor therapy, appearing to explain about 13%
of the drug response. A second group looked at an
even larger selection of SNPs form the RAAS and
other pathways, and demonstrated a significant association between an angiotensinogen SNP and the
prevention of left ventricular hypertrophy induced
by the ARB irbesartan.31 Both of these studies illustrate the potential promise of pharmacogenetic profiling of patients prior to drug selection, though
much larger prospectively designed studies are required in this area.
Number
of events
Control event
rate (%)
Odds ratio
(95% CI)
P value
overall effect
ARBs vs placebo/non-ACEi comparator/ACEi
MI
54 050
3 537
6.3
Stroke
53 318
2 285
4.4
Global death 55 050
7 601
14.0
1.08 (1.01 to 1.16)
0.92 (0.79 to 1.08)
1.01 (0.96 to 1.06)
ACEi vs placebo/non-ARB comparator/ARBs
MI
144 790
8 377
5.8
Stroke
135 803
5 485
4.2
Global death 150 943
1 643
13.0
0.86 (0.82 to 10.90) <0.003***
0.94 (0.83 to 1.06) 0.31
0.91 (0.86 to 0.95) <0.001***
0.03*
0.32
0.80
Table I. Meta-analysis results for angiotensin-converting enzyme inhibitors and ARBs
assessing a range of “hard” cardiovascular end points.
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor inhibitor;
MI, myocardial infarction.
Modified after reference 24: Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk of
myocardial infarction: unraveling the ARB-MI paradox. Circulation. 2006;22:838-854. Copyright ©
American Heart Association.
Angiotensinogen
1
2
rs5051
3
4
5
rs4762 rs6999
rs7079
Angiotensinconverting
enzyme
rs4459609 rs4291
rs1800764
Angiotensin II
AT1 receptor
rs4309
I/D rs4343
2
1
rs4363
rs9896208
3
4
rs1492078 rs2638362 rs2640543 rs389566 rs275649
Angiotensin II
AT2 receptor
1
2
3
rs1403543
Beta-hydroxylase
(Aldosterone synthesis)
1
2
3
4
5
6
7
8
9
rs1799998
What is new in the genetics of the RAAS? – Hall
UPDATE
RAAS gene variants — the future
The advent of gene chip technologies has already
changed the face of human genetic research, though
it has yet to have it’s full impact. Genome-wide studies performed with assays such as the Affymetrix
500K chip1 have covered the human genome with
genetic markers and yet left significant gaps with
regard to candidate genes of biological interest,
such as those relating to the RAAS. For this reason,
a specific cardiovascular chip has been designed and
REFERENCES
1. Samani NJ, Erdmann J, Hall AS, et al. Genome-wide
association analysis of coronary artery disease. N Engl
J Med. 2007;357;443-453.
2. Wellcome Trust Case Control Consortium. Genomewide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature.2007;
447;661-678.
3. Grisham J. Genomics company formed from Framingham heart study. Nat Biotechnol. 2000;18:818-819.
4. Wikimedia Commons freely licensed media file
repository. http://en.wikipedia.org/wiki/Renin-angiotensin_system. Accessed September 19, 2008.
5. Gallinat S, Busche S, Raizada MK, Sumners C. The
angiotensin II type 2 receptor: an enigma with multiple variations. Am J Physiol Endocrinol Metab. 2000;
278:357-374.
6. Sales VJ, Sukhova GK, Lopez-Ilasaca MA, Libby P,
Dzau VJ, Pratt RE. Angiotensin type 2 receptor is expressed in murine atherosclerotic lesions and modulates lesion evolution. Circulation.2005;112:3328-3336.
7. Iwai M, Chen R, and Li Z, et al. Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis
in apolipoprotein E-null mice. Circulation. 2005;112:
1636-1643.
8. Lazard D, Briend-Sutren MM, Villageois P, Mattei
MG, Strosberg AD, Nahmias C. Molecular characterization and chromosome localization of a human angiotensin II AT2 receptor gene highly expressed in
fetal tissues. Receptors Channels. 1994;2:271-280.
9. Martin MM, Elton TS. The sequence and genomic
organization of the human type 2 angiotensin II receptor. Biochem Biophys Res Commun. 1995;209:
554-562.
10. Warnecke C, Willich T, Holzmeister J, Bottari SP,
Fleck E, Regitz-Zagrosek V. Efficient transcription of
the human angiotensin II type 2 receptor gene requires intronic sequence elements. Biochem J. 1999;
340:17-24.
11. Nishimura H, Yerkes E, Hohenfellner K, et al. Role
of the angiotensin type 2 receptor gene in congenital
anomalies of the kidney and urinary tract, CAKUT, of
mice and men. Mol Cell. 1999;3:1-10.
12. Erdmann J, Guse M, Kallisch H, Fleck E, RegitzZagrosek V. Novel intronic polymorphism (+1675G/A)
in the human angiotensin II subtype 2 receptor gene.
Hum Mutat. 2000;15:487.
13. Alfakih K, Maqbool A. Sivananthan M, et al. LV
mass index and the common, functional, X-linked
QUOI
developed.32 Data from the use of this tool are still
awaited later in 2008, which should go a very long
way toward clarifying the clinical significance of
both common and rarer RAAS gene variants. Importantly, rarer, yet biologically important, variants
may also be shown to have significance, in planned
large-scale meta-analyses of more than 120 000 individuals.
Furthermore, important insights into gene-gene,
gene-environment, and gene-drug interactions are
expected. angiotensin II type 2-receptor gene polymorphism
(--1332 G/A) in patients with systemic hypertension.
Hypertension. 2004;43:1189-1194.
14. Stoll M, Steckelings UM, Paul M, et al. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Investig
1995;95:651-657.
15. Wu L, Iwai M, Nakagami H, et al. Roles of angiotensin II type 2 receptor stimulation associated with
selective angiotensin II type 1 receptor blockade with
valsartan in the improvement of inflammation-induced vascular injury. Circulation. 2001;104:27162721.
16. Brassard P, Amiri F, Schiffrin EL. Combined angiotensin II type 1 and type 2 receptor blockade on
vascular remodeling and matrix metalloproteinases in
resistance arteries. Hypertension. 2005;46:598-606.
17. Ma J, Nishimura H, Fogo A, et al. Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant
mice during ureteral obstruction. Kidney Int.1998:
53:937-944.
18. Ferroni P, Basili S, Martini F, et al. Serum metalloproteinase 9 levels in patients with coronary artery
disease: a novel marker of inflammation. J Investig
Med. 2003;51:295-300.
19. Schieffer B, Bunte C, Witte J, et al. Comparative
effects of AT1-antagonism and angiotensin-converting
enzyme inhibition on markers of inflammation and
platelet aggregation in patients with coronary artery
disease. J Am Coll Cardiol. 2004;44:362-368.
20. Kim MP, Zhou M, Wahl LM. Angiotensin II increases human monocyte matrix metalloproteinase-1
through the AT2 receptor and prostaglandin E2: implications for atherosclerotic plaque rupture. J Leukoc
Biol. 2005;78:195-201.
21. Pajukanta P, Cargill M, Viitanen L, et al. Two loci
on chromosomes 2 and X for premature coronary
heart disease identified in early- and late-settlement
populations of Finland. Am J Hum Genet. 2000;67:
1481-1493.
22. Samani NJ, Burton P, Mangino M, et al. BHF
Family Heart Study Research Group. A genomewide
linkage study of 1933 families affected by premature
coronary artery disease: The British Heart Foundation
(BHF) Family Heart Study. Am J Hum Genet.2005;77:
1011-1020.
23. Alfakih K, Lawrance RA, Maqbool A, et al. The
clinical significance of a common, functional, X-linked
angiotensin II type 2-receptor gene polymorphism
(--1332 G/A) in a cohort of 509 families with premature coronary artery disease. Eur Heart J. 2005;26:
584-589.
24. Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation. 2006;22:838854.
25. Alfakih K, Brown B, Lawrance R, et al. Effect of a
common X-linked angiotensin II type 2-receptor gene
polymorphism (--1332 G/A) on the occurrence of premature myocardial infarction and stenotic atherosclerosis requiring revascularization. Atherosclerosis.
2007;195:e32-e38.
26. Pfeffer MA, Swedberg K, Granger CB, et al; CHARM
Investigators and Committees. Effects of candesartan
on mortality and morbidity in patients with chronic
heart failure: the CHARM-Overall Programme. Lancet.
2003;362:759-766.
27. Granger CB, McMurray JJV, Yusuf S, et al; CHARM
Investigators and Committees. Effects of candesartan
in patients with chronic heart failure and reduced leftventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative Trial. Lancet. 2003;362:772-776.
28. McMurray JJV, Östergren J, Swedberg K, et al;
CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and
reduced left-ventricular systolic function taking angiotensin converting-enzyme inhibitors: the CHARMAdded Trial. Lancet. 2003;362:767-771.
29. Yusuf S, Pfeffer MA, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in
patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARM Preserved
Trial. Lancet. 2003;362:777-781.
30. Su X, Lee L, Li X, et al. Association between angiotensinogen, angiotensin II receptor genes, and blood
pressure response to an angiotensin-converting enzyme. Circulation. 2007;115:725-732.
31. Liljedahla U, Kahanb T, Malmqvistb K,et al. Single nucleotide polymorphisms predict the change in
left ventricular mass in response to antihypertensive
treatment. J Hypertens. 2004;22:2321-2328.
32. ITMAT/Broad/CARE (IBC CHIP) Vascular Disease
50k SNP Array Consortia. http://bioinf.itmat.upenn.
edu/cvdsnp/index.php. Accessed September 19, 2008.
DE NEUF DANS LA GÉNÉTIQUE DU SYSTÈME RÉNINE-ANGIOTENSINE-ALDOSTÉRONE
L
e père de la médecine, Hippocrate, a écrit : « Là où est
l’amour des humains, là est aussi l’amour de l’art médical ». Il savait mieux que quiconque combien ceci représentait le fondement du serment des médecins de s’efforcer à
choisir un traitement, au mieux de leur connaissance et de leur
jugement, pour le bien de chaque patient et surtout de ne pas leur
nuire. Le profilage génétique laisse espérer une amélioration du
diagnostic, de la prédiction des risques et donc aussi de l’adéquation du traitement au patient ainsi que de la faculté de choisir
What is new in the genetics of the RAAS? – Hall
?
le traitement le plus susceptible d’améliorer le malade, et le moins
susceptible de lui nuire. Cependant, tout ceci reste à ce jour un
rêve, les nombreuses études sur les gènes candidats ayant eu très
peu d’impact sur la pratique clinique de routine. Néanmoins,
l’année écoulée a fait un bond en avant prodigieux dans la compréhension de la génétique des pathologies courantes, grâce à
des technologies et à des méthodes de recherche nouvelles. La prochaine décennie s’annonce donc comme le théâtre de grandes
avancées.
MEDICOGRAPHIA, VOL 31, No. 1, 2009
91
A
T
O U C H
O F
F
R A N C E
Christian RÉGNIER, MD
Praticien Attaché des Hôpitaux de Paris
Société Internationale d’Histoire de la Médecine
9 rue Bachaumont, 75002 Paris, FRANCE
(e-mail: [email protected])
Spices, diamonds, and
Ayurvedic medicine
French physicians in
17th-century Mughal India
b y C . R é g n i e r, F r a n c e
U
ntil the Suez Canal opened in 1869, the only sea route to India was round the Cape of Good
Hope, pioneered in 1498 by the Portuguese navigator Vasco de Gama. His expedition led to the
establishment of European outposts along the Indian coast, especially by the Portuguese who
secured substantial commercial privileges. Their use of light two-masted caravels allied to their
familiarity with the winds and currents of the Atlantic Ocean enabled them to seize many staging
posts on the voyage to India and play havoc with Arab shipping routes. In a letter to the Portuguese
king Manuel I, the viceroy of India Francisco de Almeida emphasized the importance of maintaining Portuguese supremacy over the high seas: “If you are strong in ships, trade with India is yours; and if you are
not strong in this domain, no fortress you may have on dry land will be of help.”1,2
The birth of the East India Companies
Vasco de Gama brought cinnamon, cloves, ginger, nutmeg, and pepper back with him to Lisbon. For the
first time, his voyage gave Portugal direct access to the spice producers, breaking the Venetian stranglehold on this lucrative trade (a popular expression of the time being “dear as pepper”) and justifying the
primary motivation behind the expedition. From the early 16th century, Lisbon became the crossroads
of the spice market.
E
uropean fascination with the East Indies increased dramatically in the 16th century with
the opening of the sea route. India was not only a theater of contrasting civilizations and religions, it was above all an awesome reservoir of spices and diamonds. Economic and commercial imperatives dictated the initial contacts between Europeans and the Indian rulers.
This inspired the trading post strategy in which bridgeheads were established without the need
for military occupation. The European adventurers who journeyed to India mainly by sea,
but sometimes overland, included merchants, mercenaries, missionaries, diplomatic agents, East India
Company staff, and several physicians and barber-surgeons. European medicine was still highly doctrinal and undoubtedly inferior to its Ayurvedic counterpart in terms of therapeutic efficacy. Only surgeons
enjoyed any professional respect from the Mughal emperors. Yet medicine provided a number of adventurers with a calling card to the courts of the subcontinent, and the subsequent exercise of diplomatic or
commercial influence. The French arrived shortly after the Portuguese, British, and Dutch. Several French
physicians, notably Bernier, Destremeau, Saint-Jacques de Lapalisse, and Dellon, recorded their Indian
experiences in memoirs, manuscripts, letters, reports, logbooks, and drawings, which appealed to European readers’ taste for the exotic.
www.medicographia.com
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MEDICOGRAPHIA, VOL 31, No. 1, 2009
(see French abstract on page 99)
French physicians in 17th-century Mughal India – Régnier
A TOUCH
OF
FRANCE
Map of India from the
Miller Atlas ca. 1519.
© The Gallery
Collection/Corbis.
Merchants flocked from the four corners of Europe. As well as being used to preserve meat, spices appealed to Europe’s gustatory roots that reached back to the Roman Empire. The spice frenzy only faded
somewhat with the arrival of new vegetables in the late 17th century and the marked fall in meat consumption. But spices continued to be prized for their medicinal and perfumery uses.3,4
As Vasco de Gama learned to his cost on his first voyage, what the Indian king on the Malabar coast
wanted in return for spices was not the honey, olive oil, bronze bowls, and hats that Gama had brought,
but gold and silver. Europeans used both these precious metals, mined in the Americas, to secure and maintain their economic domination.1
In the wake of the Portuguese came the British (1599), Dutch (1602), French (1604), and Danes (1616).
In order to operate and organize trade with India, and make it pay, these countries set up dedicated financial structures, East India Companies, which were novel in early European capitalism. The most powerful
Company belonged to the Dutch. These authentic “multinationals” maintained fleets, ports, and fortresses;
they were also beholden to their shareholders who expected dividends. Their archives in Amsterdam,
London, and Paris remain an extraordinary documentary source for
the history of the relationships between European merchants and
Indian rulers from the 17th century onwards.2,5,6
Spices in today’s
Goa market, India.
© Peter Adams/
zefa/Corbis.
Culture shock, medicine shock
For 17th-century European adventurers, India was a land where they
felt they could make a fortune. The French physicians and surgeons
who went to India in the 17th century did so for a variety of motives:
some wanted to see how their own practice would fare in a totally
different world, while others were out to make their fortune (not
necessarily by practicing medicine). Many left with no clear idea in
mind other than that medicine would provide a ready income and/or
open doors to local authorities. Some adventurers even lacked formal qualifications and practiced medicine
or surgery with scant knowledge of either. Although Indians—Hindu and Muslim alike—distrusted European medicine, they often considered Europeans as being naturally versed in the healing arts. “They took
us for physicians, which is very common in India,” wrote Louis Laurent de Féderbe, Count of Modave.2,8
Missionaries also practiced medicine, in particular the Jesuits who applied the rule laid down by Saint
Francis Xavier in 1537. The practice of medicine and surgery, especially with children and the dying,
brought many conversions. Father Pierre Martin testified as much: “Besides, it must not be thought that
zeal and piety alone ensure that one’s labors bear fruit in the land of India (…) Knowledge (…) of mathematics, physics, and even medicine is also needed.” Jean Chardin, a jeweler’s son who arrived in India in
1667 and left a detailed and scrupulous study of local therapeutic practice, confirmed this view:
In those parts, all missionaries are taken for physicians because they dabble in prescribing treatments (…)
As there are no physicians or surgeons, they have made themselves indispensable to the practice of medicine
and surgery, with some being remarkably knowledgeable and practicing with great success.2,9
French physicians in 17th-century Mughal India – Régnier
MEDICOGRAPHIA, VOL 31, No. 1, 2009
93
A T
OUCH
OF
FRANCE
Stone relief carving representing the death
of Saint Francis Xavier (1506-1552),
Jesuit missionary to India. © Brooklyn
Museum/Corbis.
However, modesty was obligatory given
that the therapeutic achievements of the
Europeans were open to comparison with
those of Indian practitioners. European
physicians found it hard to gain the confidence of the Mughal courts. “Remember
that before a European could be appointed
physician to a prince,” wrote the Venetian
merchant Niccolo Manucci who arrived in
India in 1654 at the age of 15, “he had to
undergo a prolonged probationary period
since these princes are extremely wary and
exacting in this regard.” The wealth of the Indian pharmacopoeia and the manifest achievements of Ayurvedic medicine greatly impressed the adventurer physicians from Europe who could only boast the three
basic weapons in the European arsenal: bloodletting, purging, and theriac. Theriac was probably the world’s
longest-lived and most popular drug, a universal panacea and antidote containing some 40 to 50 ingredients whose formula dated back to the Greeks in the 1st century AD. It found its way to China during
the Tang dynasty (667), and was still being dispensed in Europe as late as 1884. On the other hand, the
Indians were greatly impressed by European surgery, in particular lithotomy, wound cleansing, and military surgery.2,10
Among the French physicians who established themselves in India in the 17th century, four names stand
out: Bernier, Saint-Jacques, Destremau, and Dellon. They shared a taste for adventure and were all curious
to experience different civilizations and ways of life. They did not set out to make their fortune, and nor in
the main did they achieve it, with only Destremeau dying a conspicuously wealthy man. However, they all
relied on their art for an income during the journey and on arrival in India. Subsequently, they became
tempted by much more lucrative activities, such as trade, diamond dealing, and diplomacy. We are indebted to them for leaving detailed writings on the civilization, botany and ethnography of Mughal India.2
François Bernier: a sophisticated observer
François Bernier (1625-1688), the son of farmers in the Anjou, was orphaned at an early age and brought
up by his uncle, a priest. At the age of 15, he went to Paris, where he studied at the Collège de Clermont,
and made the acquaintance of the mathematician, theologian, astronomer, and philosopher Pierre Gassendi
(1592-1655). In 1652, he graduated from a 3-month intensive course at the Montpellier medical school
that granted degrees on the understanding that recipients would not practice medicine in France (!) Fascinated by philosophy, he gained fame with his 8 volume “introduction” to the work of Gassendi, whose
aide and secretary he had become. A year after the death of Gassendi, Bernier, with no attach left in France,
set off for Constantinople and Aleppo. He stayed for a year in Syria, Palestine, and Egypt where he caught
Glazed earthenware
pharmacy jar for storing
Theriac (1641), used by
Italian Jesuits. © Science
Museum/Science &
Society Picture Library.
94
MEDICOGRAPHIA, VOL 31, No. 1, 2009
Vaidya Dhanvantari,
avatar of Vishnu and
god of Ayurvedic
medicine. © Bridgeman Art Library.
French physicians in 17th-century Mughal India – Régnier
A TOUCH
OF
FRANCE
the plague. After being imprisoned for 6 weeks in Jeddah, he reached the west coast of India in early 1659,
landing at Surat, in the state of Gujarat, where the British East India Company had opened a trading post
in 1608.2,11,12 Journeying to Delhi, Bernier was appointed court physician to the Mughal Emperor, Aurangzeb
(literally, “Adorning the Crown”) upon the recommendation of another French physician, Saint-Jacques
(about whom more later), who had practiced at the court during the previous decade. The new emperor,
who had just eliminated his three brothers in a war of succession, had himself crowned under the title
Alamgir (literally, “Conqueror of the Universe”). Bernier thus became a privileged witness to historic events
such as the public humiliation of Dara, the emperor’s defeated brother, and the sumptuous welcome to
the Persian ambassador.
Aurangzeb, who reigned from 1658 to 1707, espoused a strict interpretation of Islam. Bernier reports
that the Emperor caught what was probably diphtheria: “He fell extremely ill, with a continuous raging
fever that caused periods of confusion. His tongue was so paralyzed that he could barely speak and his
Aurangzeb
(1618-1707), ruler
of the Mughal
Empire in India
for 48 years, from
1658 until his
death. Portrait by
Pierre Duflos,
1780. © Stapleton
Collection/Corbis.
Map of Kashmir, from the Amsterdam edition (3rd edition) of François Bernier’s
account of his voyages. All rights reserved.
physicians feared for his life.” By the end of 1659, Bernier had virtually given up practicing medicine in
India. His notes on his medical practice are few and far between, and brief in the extreme. Later in 1659,
he made the acquaintance of a wealthy scholar, Danishmand Khan, who took him under his protection.
Bernier taught him European science in Persian, dissecting a sheep to demonstrate the circulation of the
blood and lymph. In return, Bernier was tutored by a Hindu scholar among his protector’s retinue in the
basics of Hindu philosophy and religion.2,11,12
Between 1662 and 1665, Bernier joined the 150 000-strong caravan that took Emperor Aurangzeb to
convalesce in Kashmir. It included 35 000 horsemen, thousands of camels, and hundreds of elephants.
Kashmir was totally unknown to Europeans. “From all that I have just said,” wrote Bernier, “it can be
concluded that I am somewhat enamored of Kashmir, and that I believe there may be nothing similar nor
so beautiful.” It was during this journey that he met a Tibetan physician “who had a book of concoctions
that he consistently refused to sell me.”
Bernier observed the practice of Hindu and Muslim physicians, remaining noncommittal as to its efficacy. “I leave this to our learned Doctors to determine,” he wrote, not without irony. On the other hand, he
observed that “where anatomy is concerned we can say that the Hindus know nothing at all; they simply
spew out impertinent nonsense. It is therefore not surprising that they are so ignorant since they never
open the body of man or animal.” 2,11,12 Bernier’s observations of public health were more detailed:
The abstinence from wine observed in these parts, combined with the country’s everyday sobriety and the sweat
and perspiration constantly exuding through the pores, explain why, to my mind, gout, the stone, backache,
catarrh, and quartan fever are virtually unknown here, while those who, like myself, have brought such afflictions with them, are finally delivered from them; and even the pox, despite being very common, runs a less
cruel and harmful course, with the result that ordinary life is generally much healthier here than at home.11
Bernier also observed frequent cases of filariasis in Indians and visitors and described the technique used
to extract the worm by winding it a little further each day outside the body around a small stick.
Before leaving India, at the express request of the director of the French East India Company, Bernier
compiled a Mémoire sur l’établissement du commerce dans les Indes [Report on establishing trade in
India]. Dated March 10, 1668, it was addressed to Louis XIV’s minister of finance Jean-Baptiste Colbert.
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Centuries-old method of extracting treating dracunculiasis
(aka, guinea worm disease, or Medina worm), once the parasite
has emerged from the skin, by inching it out, day after day, coiling
it around a stick, a painful process that can take up to a month.
© Institut Pasteur.
Having returned to Paris, Bernier resumed his passion for philosophy and very nearly got thrown into jail for supporting René Descartes.
In 1685, he traveled to England, then the Netherlands where he visited French philosopher and critic Pierre Bayle, an exiled Protestant.
Bernier died in 1688, aged 68, from a stroke apparently induced by
heated philosophical debate.
Bernier left one of the most detailed accounts ever written of the political, economic, and religious organization of Mughal India. Blessed
with an elegant and precise style, and inspired by an educator’s desire to present an honest account of contemporary Indian history and
civilization, Bernier maintained copious notes and correspondence
throughout his 10-year stay. His Voyages de François Bernier contenant la description des États du Grand Moghol was published in 1670-1671, less than two years after his
return, and translated into English the same year [Travels in the Moghul Empire A.D. 1657-1668] by the
first secretary of the Royal Society. Bernier’s letters were known to contemporary luminaries such as Jean
de La Fontaine, Racine, and Boileau. Two centuries later, his writings were to draw praise from unexpected
quarters: on June 2, 1853, Karl Marx wrote to Friedrich Engels: “No one has written with more brilliance,
detail, and power on the development of oriental cities than old François Bernier.” Marx relied on Bernier’s
analysis of the absence of landownership to account for the decline and fall of Mughal India.2,11,12
Saint-Jacques, physician to the Great Mughal
Few hard facts are available on the life of the French physician
Saint-Jacques (1628-1694)—aka Jacques Seuillet or Jacques de
La Palisse — who played a prominent role at the court of Emperor Aurangzeb. His name was mentioned by many travelers,
merchants, East India Company agents, diplomats, missionaries,
and other French physicians present in India at the time. He was
unfailingly hospitable and never hesitated to play his princely
cards when interceding on his compatriots’ behalf. He enjoyed
well-recognized status at the Great Mughal’s court. Louis XIV
wrote to him on October 29, 1664, asking for his help in securing a fitting welcome from Aurangzeb for the ambassador François La Boullaye Le Gouz. Bernier described Saint-Jacques as
A consummate man of intrigue perfectly attuned to the political choreography of the durbar [Mughal court]. He can provide
much intelligence and be of assistance in prosecuting business.
He strikes me as a man not to be ignored, either at the present
time or in the future.2,7
Saint-Jacques is thought to have arrived in India around
1648—whether overland or by sea is unknown. There is no eviFrontispiece of an 1830 edition of Frandence that he was a physician or had ever studied medicine. He çois Bernier’s “Relation of a Voyage Made
may have picked up some medical knowledge from missionar- in the Year 1664, With the Great Mughal
ies. Hard evidence for his presence was provided by Jean-Baptiste Aurangzeb to Dehli, Lahore, Bombay, and
Kashmir.” All rights reserved.
Tavernier who in Delhi in 1665 met “a French surgeon de La
Palisse, known as Saint-Jacques; he speaks Indian well and is married to the daughter of a Portuguese. The
Nawab is very fond of this surgeon.” Whatever his background, Saint-Jacques practiced medicine in India,
and had no other employment. When implementing Islamic law in 1668, Emperor Aurangzeb banished
all Christians except physicians and goldsmiths to at least one league from Delhi. Saint-Jacques was one of
those who stayed put.2,13 In a letter dated December 27, 1678, to his Superior in the Society of Jesus, the
Portuguese priest Joseph Freyre wrote:
In the city of Delhi lived a Christian by the name of Saint-Jacques, a Frenchman by nationality and physician
by profession, to whom the palace gates had been opened in recognition of the excellence of his art. For the perfection of the care that he administered he was rewarded with the King’s gratitude complete with the title of
Macebdar and an allowance of 6000 rupees a year, all of which gave him much standing and respect at Court.
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Saint-Jacques stayed in India for nearly 40 years and witnessed many political and military events. He
married a mixed-race Portuguese woman who bore him two children. His private life appears to have been
more than colorful, extending to the attempted poisoning of his wife, and as such attracting much contemporary comment. Saint-Jacques made several attempts to flee back to France, and eventually obtained
the Grand Mughal’s permission to leave India in 1688. Having received substantial emoluments over the
years, bought large quantities of diamonds, and sedulously advertised his appreciation of recompense for
his services as a go-between, he is unlikely to have returned to France empty-handed. Saint-Jacques died
on December 23, 1694.
Emperor Aurangzeb
hunting nilgais antelopes.
St Petersburg Album.
© Royal Ontario
Museum/Corbis.
Antoine Destremau, sultan’s surgeon and diamond dealer
Antoine Destremau (1636-1685) from southwest France (Armagnac) learned basic surgery with his brother Lucas in a brotherhood, or guild, in the adjoining province of the Béarn. According to a baptismal registry from March 10, 1687: “he served his surgery apprenticeship locally before traveling across France,
as surgeons customarily do to hone their skills, then left our region around 30 years ago and never returned.” He probably left for India around 1660. Three years later, the wealthy Tavernier took him as his
servant on his sixth voyage to India. Destremau was a Calvinist, like his master, and accompanied him
throughout his travels in India until 1666. This gave the young surgeon the opportunity of rubbing shoulders with all the better-known Frenchmen who were visiting India or had made it their temporary home
during this period, as confirmed by his name cropping up in their various accounts.2,7
Destremau spent almost 20 years in the sultanate of Golconda (Hyderabad) and was surgeon to Sultan
Abul Hasan from 1672 to 1685. Being well introduced at court, he enjoyed a considerable income. A priest
from one of the foreign missions, Father Jean Joret, testified as much in a letter dated December 27, 1682:
“We lodged in the city with Mr Destremont, a Frenchman who is physician to the King, and a great friend
of the King’s brother-in-law, who is fond of the French.” The sultanate of Golconda was courted by the
Dutch and British for its diamonds, silver, copper, tin, and lead, as well as for spices such as pepper and cinnamon. Since he spoke Persian, Portuguese, and Dutch, Destremau was probably working for the French
East India Company, while not hesitating to act on behalf of British interests as well. In October 1684,
François Martin, director of the French East India Company’s Pondicherry trading post, confirmed that
Destremau was the Company’s agent at the court of the sultan of Golconda. Of the three known letters in
Destremau’s writing, not one refers to medical activity, but only to matters of trade or diplomacy. The French
surgeon also dealt in diamonds, which was a highly lucrative activity. He soon amassed a considerable fortune, since he was able to come to the assistance of Admiral Jacob Blanquet de La Haye, leader of the French
flotilla besieged near Madras in March 1673.2,14
Destremau died after a long fever on July 17, 1685, at the age of 49, bequeathing a substantial fortune
and stipulating that he be buried in the Dutch cemetery. His will, written in Portuguese, set aside sums
for the poor of his birthplace, La Houga (Gers), his brother Lucas, his sister’s children, and his friend and
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fellow diamond dealer/jeweler François Guesty, whom he also appointed as his executor. Guesty was unscrupulous enough to embezzle part of the legacy, for which he was pursued by the local judiciary. In
January 1689, the French naval minister undertook his own investigation into the whereabouts of the surgeon’s assets, some of which were returned to France 3 years later.14
Charles Dellon, the most medical of India’s French physicians
Born in Agde (Hérault), Charles Dellon (1650-1710) embarked at the age of 17 as second surgeon on board
the Royal India Company ship, La Force. In 1673, he became a physician north of Bombay, in Daman, Portuguese India, treating the inhabitants and their governor Manuel Furtado de Mendonça:
From this moment onwards, I began seeing patients at the hospital and in their homes. At that time Daman
only had a few Pandits, or Indian physicians, with very limited skills. Generally speaking, the only knowledge
possessed by such physicians consisted of a few remedies that they dispensed as prescribed by tradition rather
than reason. Furthermore, since Europeans enjoy high esteem in the Orient, and since I was not lacking in
boldness myself, my services were called upon not only by the Portuguese, but even by the Indians who used to send for me from
10 leagues away (…) As the town of Daman is not particularly
large, I was soon a familiar figure everywhere.2,12,15
Man condemned
by the Inquisition of
Goa to be burned
at the stake. Late
18th-century color
engraving. Bibliothèques des Arts
Décoratifs, Paris,
France. © Bridgeman Art Library.
In a plot hatched by the Portuguese governor of Daman,
the Indian secretary of the Inquisition, and a Dominican
friar, Dellon was accused on a trumped-up charge of heresy
for having blasphemed against the adoration of a crucifix.
He was incarcerated for 18 months by the Inquisition in
Goa, excommunicated, stripped of his possessions, and sentenced to 5 years’ hard labor in Brazil and Portugal. On his
return to France in 1677, he began writing his memoir,
Relation de l’Inquisition de Goa [An account of the Goa
Inquisition]. Published in 1687, it proved an immense
popular success. It was promptly translated into German,
Dutch, and English—and placed on the Vatican’s Index of
banned books in 1690. Republished several times in the
18th century, it was the inspiration behind several passages
in Candide by the French philosopher Voltaire in 1759.12,15
Dellon was clearly an able physician despite holding no
recognized university degrees. He was one of the only
French physicians in India to publish a work of medicine
(Traité des maladies particulières aux pays orientaux, et
dans la route, et leurs remèdes, Paris, 1685 [Treatise on the diseases specific to the Orient and travel thereto, their remedies]). Its 62 pages deal with the diseases commonly encountered during the voyage and in
India itself, such as scurvy, vomiting, cholera, smallpox, snakebites, and filariasis, as well as the “exhaustion caused by sexual excess.” In addition to extolling bleeding and purging, Dellon recommended some
Indian treatments such as betel leaf, betel nut, and congee, a salted ground-rice porridge for diarrhea. He
also published a botanical work Curiosités [Curiosities] in 1703.12 In 1685, he became physician to the
Prince of Conti, one of the Royal India Company’s major subscribers. Little is known of his final years and
he is believed to have died around 1710.
Epilogue
Other genuine or self-certified French physicians were present in India in the 17th century, such as Biron,
author of a learned medical treatise on Indian botany, and Séguineau, whom the French nicknamed “Doctor Too bad/So much the better,” and who was in India from 1669 to 1673. Others who should be mentioned
include the surgeons of the Royal India Company based in Pondicherry, although their reputation was
often disastrous.
The European medicine of the 17th century deserved the ridicule heaped on it by Molière. There was
little chance of it impressing anyone, Indians included, either through the success of its treatments or the
acuteness of its observations. For the men who set out for India as adventurers, explorers, and fortuneseekers, medicine remained, above all, a useful prop, calling card, or fallback. 98
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REFERENCES
1. Braudel F. Civilisation matérielle, économie et capitalisme –
XVe-XVIIIe siècle. Vol. 3: Les temps du monde. Paris, France:
Armand Colin; 1979. [Braudel F. Civilization and capitalism,
15th-18th century. Vol. III: The perspective of the world. New
York, USA: Harper Collins; 1985].
2. Valence F de. Médecins de fortune et d’infortune? Des aventuriers français en Inde au XVIIe siècle. Paris, France: Maisonneuve & Larose; 2000 [free to p. 93: http://books.google.co.uk/
books?id=xYn9bCIMnmsC&pg=PA89&dq=Macebdar&ei=7BPSIr-LJDwsgPk4_DrDA#PPP1,M1]
3. Braudel F. Civilisation matérielle, économie et capitalisme –
XVe-XVIIIe siècle. Vol. 1: Les structures du quotidien. Paris,
France: Armand Colin; 1979. [Braudel F. Civilization and capitalism, 15th-18th Century. Vol. I: The structures of everyday life.
New York, USA: Harper Collins; 1985].
4. Castonnet des Fosses H. L’Inde française avant Dupleix. Paris,
France: Challamel aîné; 1887.
5. Dupuis J. Histoire de l’Inde. Paris, France/Pondicherry, India:
Éditions Kailash; 1996.
6. Weber H. La Compagnie française des Indes (1604-1875). Paris,
France: Éditions Arthur Rousseau; 1904.
7. Vincent R (ed). L’aventure des Français en Inde, XVIIe-XXe
siècles. Paris, France/Pondicherry, India: Éditions Kailash; 1998.
8. Modave de Féderbe LL. Voyage en Inde du comte de Modave,
1773-1776 (nouveaux mémoires sur l’état actuel du Bengale et
de l’Indoustan). Edited & annotated by Jean Deloche. Paris,
France: École française d’Extrême-Orient, 1971. [Féderbe, LL de,
comte de Modave. Comte de Modave’s account of Bengal, 17731774. Translated by Ghosh PN. Baharu, India: Harinath De Centre
for Language Training and Research; 1992].
9. Chardin J. Voyage en Perse et autres lieux de l’Orient (1735 et
1811). Stéphane Yerasimos, ed (based on the 1811 edition). Paris,
France: La Découverte; 1983. [Chardin J. The travels of Sir John
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Chardin into Persia, and the East-Indies, through the Black-Sea,
and the countrey of Colchis: describing Mingrelia, Imiretta, Georgia and several other countries unknown to these parts of Europe: with a new map of the Black-Sea: and also divers curious
descriptions of many cities and towns on copper plates: to which
is added, The coronation of this present King of Persia, Solyman
the Third. London, UK: Moses Pitt; 1686].
10. Manucci N. Un Vénitien chez les Moghols. Niccolo Manucci.
Valence F de, Sctrick R, presenters, editors and translators from
the Italian. Paris, France: Phébus; 1995.
11. Bernier F. Un libertin dans l’Inde moghole: Les voyages de
François Bernier (1656-1669). Tinguély F (ed). Paris, France: Éditions Chandeigne; 2008 [Bernier F. Travels in the Moghul Empire A.D. 1657-1668. Westminster, UK: Archibald Constable & Co;
1891. Available in near-entirety at http://books.google.co.uk/
books?id=_oGHt7Z8o4sC&pg=PA477&dq=bernier+english+
translation+1671&ei=Gvv9SMKiKZ_qtgOYtpC4DA#PPR12,M1].
12. Sigaléa R. La médecine traditionnelle de l’Inde. Doctrine prévédique, védique, âyurvédique, yogique et tantrique. Les Empereurs Moghols, leurs maladies et leurs médecins. Geneva, Switzerland: Olizane; 1995.
13. La Boullaye Le Gouz F. Voyages et observations. Paris, France:
Kimé, 1985.
14. Fabry P. La relève de l’escadre de Perse. Paris, France: Ginkgo; 2005.
15. Dellon C. L’Inquisition de Goa. Paris, France: Chandeigne;
1997 [Dellon C. The history of the Inquisition as it is exercised
at Goa. Written in French, by the Ingenious Monsieur Dellon,
who laboured five years under those serverities. With an Account
of his Deliverance. Translated into English by Henry Wharton
(1664-1695), vicar of Chartham. London, UK: James Knapton,
1688. Republished: Dellon’s Inquisition at Goa. London, UK: Baldwin, Craddock, and Joy; 1815].
ÉPICES, DIAMANTS ET MÉDECINE AYURVÉDIQUE
MÉDECINS FRANÇAIS EN INDE MOGHOLE AU XVIIE SIÈCLE
L
a fascination des Européens pour les Indes Orientales décupla au XVIe siècle lorsque la voie maritime fut ouverte. L’Inde était non seulement le foyer de civilisations et de religions multiples et
contrastées mais surtout un formidable réservoir d’épices et de diamants. Les premiers contacts
entre Européens et autorités indiennes furent avant tout dictés par des impératifs économiques
et commerciaux, d’où la politique des comptoirs qui permettait d’établir des têtes de pont sans
avoir à occuper militairement le territoire. Les aventuriers européens qui se rendirent en Inde par
voie terrestre ou par mer comptaient des marchands, des mercenaires, des missionnaires, des agents diplomatiques, des employés des « compagnies », des savants parmi lesquels des médecins (et des chirurgiens
encore rattachés à la profession des barbiers). La médecine européenne était encore très doctrinale et certainement inférieure à son homologue ayurvédique quant à l’efficacité thérapeutique. Seuls les chirurgiens jouissaient d’une certaine estime dans leur exercice auprès des empereurs moghols. Pour autant,
la médecine permettait à certains aventuriers de s’introduire dans les cours royales et d’y exercer une
influence diplomatique ou commerciale. Les Français arrivèrent peu après les Portugais, les Anglais et les
Hollandais. Quelques médecins français marquèrent de leur empreinte de leur passage en Inde, notamment Bernier, Destremeau, Saint-Jacques de Lapalisse et Dellon. Ces premiers Européens aux Indes Orientales ont laissé des récits de voyage, des manuscrits, des lettres, des rapports, des journaux, des dessins,
fascinant le lecteur européen friand d’exotisme.
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Dominique CAMUS, Journalist
6, rue du Porche
76590 Manéhouville, FRANCE
(e-mail: [email protected])
West meets East
Pondicherry and the French
East India Company
by D. Camus, France
T
he rise and fall of the European trading posts that dotted each
coast of the Indian subcontinent reflected the commercial rivalries and colonial ambitions of the European powers as well as political rivalries between Indian princes. The reason why many Europeans settled on the otherwise uninviting Coromandel Coast was that
it represented an important staging post on trade routes between the
Mediterranean and the Far East. Pondicherry (modern Puducherry), which
acted as the capital of French India under Joseph François Dupleix (16971763), slipped back into anonymity after the Treaty of Paris in 1763.
Coat of arms of the
French East India Company. The motto reads
“Florebo Quocumque
Ferar” “I will flower
wherever I am taken.”
All rights reserved.
The India Companies
European rulers granted their merchants trading monopolies in Asia and America, creating the East and
West India Companies, respectively. The West India Companies lasted only decades, whereas the East India
Companies remained active for a century, and in some cases longer. Thus, the French West India Company,
set up by minister of finance Jean-Baptiste Colbert in 1664, was dissolved in 1674, while its Dutch counterpart managed to survive from 1621 to 1667. In Asia, the situation proved quite different. The English
East India Company, founded in 1600, lasted until 1858, and its Dutch counterpart from 1602 to 1795;
the French East India Company, set up in 1664, suspended in 1769 and reorganized in 1784, finally lost
its monopoly in 1791.
T
he five trading posts of the French East India Company were Pondicherry (modern Puducherry),
its smaller districts of Karaikal, Yanam, and Mahé, and Chandernagore (modern Chandannagar)
in the then wealthy Bengal. Pondicherry on the Coromandel Coast, where the French were granted
leave of settlement by the Mughal emperor in 1673, was the French capital of southern India, enjoying huge prestige in the 1750s. Fertile Karaikal fed Pondicherry and supplied it with cloth. Mahé on the
west coast produced pepper. Chandernagore was commercially the most active. These highly coveted trading posts were subject to the vicissitudes of European politics and their repercussions in Asia. The
French East India Company took advantage of the declining Mughal Empire to intervene in Indian politics and protect its interests. The governors resided in Pondicherry. Their initial task was to contain the
Dutch (1693), but their most bitter struggles were against the British, who destroyed the city in 1761.
Pondicherry was returned to the French at the Treaty of Paris (1763) and rebuilt within two years. In 1902,
when stepping ashore on Pondicherry beach, the writer Pierre Loti described “the melancholy induced
by arriving in this distant and charming town where an entire French past dozes behind cracked walls.”
Joseph François Dupleix (1697-1763) and the Marquis de Bussy-Castelnau (1718-1785) were “remarkable
administrators or war leaders who dreamed of a French empire in India, but it was a dream unshared by
the French government.” The five trading posts were ceded back to India between 1949 and 1956.
www.medicographia.com
Medicographia. 2009;31:100-110.
100 MEDICOGRAPHIA, VOL 31, No. 1, 2009
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Mughal India
India was a vast empire when the French under Louis XIV
decided to establish a number of commercial outposts in
the second half of the 17th century. The subcontinent was
ruled by the Timurid Mughals, a Sunni Muslim dynasty of
Turko-Mongol origin from Samarkand. Although descended from the notorious Timur (Tamerlane), they no longer
carried his warrior genes. From the reign of Babur (15261530) to that of Shah Jahan (1627-1658), India became dotted with remarkable palaces, renowned for the refined
lifestyle and brilliant civilization of an aristocracy that not
infrequently viewed Europeans as “barbarians.”
In the era in which France turned its attention to India,
the Mughal empire was foundering from a combination of
sheer vastness and oversophistication. Dynastic decline
proceeded apace under Aurangzeb (1658-1707). While quick
to seize the opportunities on offer, France was slow to digest the long-term consequences. The protectorate policy—invented by Dupleix almost despite himself, admirably
pursued by Bussy, and imitated by the British with leg- Jean-Baptiste Colbert (1619-1683). Painting by
endary success — was never understood or supported by Claude Lefebvre, 1666. Oil on canvas, 1.3 0.96 m.
Versailles. © RMN / Gérard Blot.
the French government. Paris was even shocked to discover that Pondicherry was its counterpart in Southern India, playing a capital city’s role with all the pomp
that this implied at the time. Unlike Britain or the Netherlands, France was primarily a land power. It
lacked the money to develop and modernize its fleet, which was only half that of Great Britain and the
Netherlands. Being relatively powerless at sea, it was never really in a position to defend its overseas colonies.
In all attempts to do so, it prioritized the French West Indies and Canada. Lukewarm commitment to India
explained why at the Treaty of Aix-la-Chapelle (1748)
France swapped Madras for Louisbourg on Cape Breton
Island (Canada), in a deal that put Pondicherry in jeopardy. Understandably, the settlement of Pondicherry felt
abandoned: in 1750, French influence in Southern India
was immense, as was the prestige of Pondicherry itself.
A show of support was all that it required to strengthen
its position, but Paris was oblivious. Reinforcements were
sent with the sole aim of “fighting off the British.”
Mughal Emperor Aurangzeb (1658-1707) and courtiers.
Attributed to Bhawani Das, around 1710. © The Trustees of
the Chester Beatty Library, Dublin / Bridgeman Art Library.
West meets East: Pondicherry and the French East India Company – Camus
The rush for India in the 17th century
Indian riches had always attracted foreign merchants.
The Portuguese discovered the route to India in 1498. In
the 17th century the Dutch, British, and Danes arrived
on the Coromandel Coast to offset the Portuguese settlements in Goa and along the Bengali coast. Trade was
the sole motive behind the Portuguese presence in Asia.
Goa was their Asian capital. Symbolic of their determination to remain masters of trade with the East was the
hanging in Goa in 1602 of two Zeeland merchants for
having attempted to sell pepper.
In the 17th century bitter rivalry pitted the British
against the Dutch, at a time when both were attempting to oust the Spanish and Portuguese from Asia. The
British were notorious for privateering and plundering,
with bases at Masulipatam on the Coromandel Coast,
Bantam (modern Banten) on the western tip of Java, and
Surat in the state of Gujurat, a major port with multiple
connections to Indian Ocean countries.
In 1639 Francis Day—“Day of Madras”—who headed
the British East India Company factory in Masulipatam,
was exploring the southern coastline when he negotiMEDICOGRAPHIA, VOL 31, No. 1, 2009 101
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French and other
European settlements
in India (1501-1739).
http://en.Wikipedia.org/
wiki/Frencmh_East_
India-Company.
All rights reserved.
ated the concession of some land near São-Tomé, occupied by the Portuguese. He asked the local chief, or
nayak, to finance the building of a fort, promising reimbursement once the Company was installed and
providing employment for the region’s weavers and dyers. Less than a year later, the new trading post of
Madras was born, comprising 80 substantial houses under the imposing walls of Fort St George, which
itself was not completed until 1653.
Delayed French interest in India
The French were slow to take interest in India. All through the 17th century, they read accounts by travelers attracted by this mysterious yet fascinating subcontinent: “They discovered the adventures of the
Goan mercenary François Pyrard de Laval, the reflections of François Bernier, who had become doctor to
a Mughal prince, the memoirs of the jeweler Jean-Baptiste Tavernier, or the descriptions by Melchidesec
Thévenot.” 1 But actual French settlement in India was a less simple matter.
The turning point came in 1661, when Louis XIV assumed effective control of government. Envying
the Dutch their commercial success, he closed the French markets to them and used the newly founded
French East India Company to encourage rival colonial companies. In 1666, the Mughal emperor Aurangzeb
granted France permission to establish a trading post in Surat. François Caron, the recently appointed director general of the French East India Company, arrived there in 1668 with substantial funds, and asked for
logistic support and warships. In 1670 an impressive flotilla commanded by Admiral Jacob Blanquet de
La Haye embarked from La Rochelle to
show the Dutch that the French meant
business in Asia. However, its attempts
to take Ceylon (modern Sri Lanka) or to
hold on to São-Tomé after its initial capture were to prove unsuccessful.
Map of Pondicherry. Engraving, 1782. Private Collection. © Bridgeman Art Library.
102 MEDICOGRAPHIA, VOL 31, No. 1, 2009
The founding of Pondicherry
The founding of Pondicherry was to
engrave an otherwise unsuccessful expedition in French memory. When dispatched by Admiral La Haye to seek food
and munitions from local rulers, Louis
Auguste Bellanger de Lespinay obtained
permission from the sultan’s governor,
Sher Khan Lodi, to establish an outpost
at Pudu Cherry (“new village”), a small
fishing and trading village south of SãoTomé. Once the French had taken it
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over, François Martin, commissioner of the French East India Company, was the driving force behind its
rapid growth, beginning in 1674. He began by raising two brick and stone bastions to carry eight cannon.
The site was constantly threatened. The hinterland was a battleground between Indian princes and it suffered incursions from Marathi marauders. Martin had to pay the princes protection money while maintaining enough soldiers to repulse any attack.
Franco-Indian trade
In the 17th and 18th centuries it was India’s luxury products that mainly interested France. But because
India had no need for French products, the resulting trade imbalance created a deficit, which France attempted to offset by shipping precious metals to India. Like other European East India Companies, except
for the Dutch, the French exported cargoes of gold bars and silver pieces.
View of Pondicherry.
18th-century engraving,
showing the French
East India Company
warehouses in the
port of Pondicherry.
© Frédécric Soltan /
Sygma / Corbis.
Shipments from France to Asia
The French East India Company operated its precious-metal route by sending ships to Hispaniola (the
island comprising modern Haiti and the Dominican Republic), which was rich in Spanish gold, or to
Louisiana, bordering Mexico; alternatively, it bought piasters in Cadiz, the home port of the galleons returning from the West Indies and also a port of call for those on their way to India. On other occasions the
Company bought a little gold in Portugal. “Over the period from 1725 to 1770, for which data are available,
France carried close on 6 million marks to Asia, roughly equivalent to one quarter of the kingdom’s metal reserves on the eve of the Revolution.” 2
These shipments were supplemented by wines and spirits: “Pondicherry needed 8000 to 10 000 liters of
Bordeaux a year, 20 000 liters of brandy and 200 000 liters of madeira,” 2 as well as fabrics such as twilled
woolen cloth from Sedan and Amiens. Shipments also comprised occasional luxury items such as gold
thread and coral.
Shipments from Asia to France
Shipments for the return journey consisted of fabrics, white cloths, and muslins. Between 1730 and 1750,
Company ships returned to France with 250 000 to 300 000 lengths of fabric yearly. These goods entered
the kingdom freely provided they were labeled with the Company’s name. Conversely, when the Company
bought “painted” or “dyed” fabrics, also known as “Indian fabrics,” it was allowed to sell them anywhere
except in France, a measure designed to protect French manufacturers. To enforce the law, special checks
were carried out on ships arriving from Asia. An excise sloop would meet the incoming ship, officials
would climb aboard and place seals on the crew’s sea-chests and bags. Once in port, usually Lorient, nothing could be unloaded without being checked. Painted/dyed fabrics were stored in warehouses under armed
guard. Despite all these precautions, every device was used to smuggle the prized Indian fabrics ashore
undetected. Boats would meet the incoming ships out at sea, before the excise sloop reached them. The
delightful Indian fabrics with their leaf and bright-plumed bird designs won over the French, who found
them more attractive than their own geometric and floral patterns. The Lyon silk manufacturers asked
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the ban to be extended to the importation of silks for the same protective reasons. Duly implemented in
the late 17th century, the ban soon generated its own contraband market, as with the regular fabrics. As
for food imports, pepper was by far the most important commodity, with 400 000 to 500 000 pounds being
shipped from Mahé annually. Minor items included cardamon and rhubarb, for use in preparing medicines,
and, more minor still, cinnamon, alum, and aloes. The two main heavy goods were Bengali saltpeter and
the Maldive cowrie shells that were used as a slave trade currency and were in particular demand along the
coast of Guinea. Rattan and dyewood served as ballast and also helped to keep the fabrics and pepper dry.
The annual sale
All ships left India with their return cargo in January, during the winter monsoon season, which was the
best time of year for crossing the Indian Ocean. The imported goods were sold yearly in October. In the
17th century, the sale took place in Paris, then in Le Havre; in the 18th century in Saint-Malo, Nantes, and
then Lorient. The major sale was followed by a “little sale,” featuring curios and spoiled goods. Up to 1730,
according to Philippe Haudrère, sales barely reached 10 million livres tournois (1 livre tournois = 0.31 g
fine gold). Turnover then doubled from 1730 to 1755, at which point
the Company was running head to head with the British East India
Company, except during the War of the Austrian Succession. After
1760 and the Seven Years War, the Company experienced financial difficulties, with sales falling back below 10 million.
The booming trading post of Pondicherry
Under François Martin, the fishing village expanded into a town.3
Having completed the fortifications, his main concerns were to
strengthen ties with Sher Khan Lodi and establish regular trading
links with the home country. The population grew with the arrival of
Indians fleeing local conflicts. French expansion continued in Bengal
with the founding of Chandernagore by Martin’s son-in-law, BourreauDeslandes, in 1688. The Surat outpost was abandoned.
In 1701, the creation of a sovereign council chaired by Martin gave
Pondicherry the preeminence that it was to retain, even over the
commercially more active Bengali settlements. The expansion of
French presence in India was weakened by conflicts in Europe and
the policy of Louis XIV, who redeclared war on the Netherlands in
1689. Martin was unable to repulse the Dutch troops and was forced
to capitulate in 1693. Peace came with the Treaty of Ryswick in 1697,
John Law (1671-1729). Scottish financier, fought a duel
but
the Dutch only returned Pondicherry in 1699, after much hesitaover a woman, killed his opponent and had to flee to the
Continent. Credited with introducing paper money to
tion. Having already been weakened in this war, the French East India
France. Established the Mississippi Company to develop
Company was then hit by another, the War of the Spanish Succession
the French Colony of Louisiana. Made Comptroller Gen(1701-1714). Trade suffered in consequence. Nevertheless, at Martin’s
eral of Finances in 1720. When his bank crashed he became an object of popular hatred and died destitute in
death in 1706, France was left with sizeable settlements along the
Venice. Painting by Casimir de Balthazar, 1843. Oil on
Coromandel Coast and in Bengal. Pondicherry, the Company’s politcanvas, 0.79 0.65 m, Versailles. © RMN / Gérard Blot.
ical and administrative capital, had a population of 60 000.
The Peace of Utrecht in 1713 that put an end to the War of the Spanish Succession left the Company
ruined. Martin’s successors failed to match his mettle. Hébert, for example, falsified his accounts to make
the Indians appear as embezzlers, enabling him to impound their goods. Once unmasked he was forcibly
repatriated to France in 1718. After his departure, Pondicherry slipped further downwards, threatening
Martin’s whole achievement. However, once the Company was taken over by the Compagnie d’Occident,
founded by John Law (1671-1729)—“Law of Lauriston,” France’s Scottish-born Comptroller-General of
Finances— it was ready to make a fresh start.
French expansion (1721-1741)
The new Company registered two decades of increasing prosperity, thanks partly to the peace and stability that had returned to Europe. New trading posts were founded, including Mahé (1721), on the Malabar
Coast (the western counterpart of Coromandel) where France already held the outpost of Calicut (modern
Kozhikode), a crucial link in the pepper trade. The British, who owned the neighboring trading post of
Tellicherry (modern Thalassery), found the French presence unwelcome and riposted with a series of hostilities via Indian intermediaries: incursions across Mahé’s borders, seizing of ships at sea, and blockade.
A local ruler, the Rajah of Badagara (modern Vatakara), conspired with the British and in 1724 ordered the
French garrison to evacuate Mahé. It returned strengthened six months later and defeated the Rajah’s
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Joseph François Dupleix (1697-1763), member of the
French East India Company Council in Pondicherry in 1720,
became Superintendent at Chandernagore in 1730, and was
appointed Governor General of all the French Indies in 1741.
© Frédéric Soltan / Sygma / Corbis.
forces. On March 10, 1728, the French and British Companies
agreed to stop attacking each other’s forts and ships once they
were in sight of Mahé or Tellicherry. The agreement held until
1760, despite wars at home between the two countries.
Subsequently the French settled at Yanam in 1723 and at
Karaikal in 1739, remaining in each case until 1954, interspersed by periods of British rule. Conflicts erupted after the
death of Emperor Aurangzeb and Indians often called upon the
French to help rid them of their enemies. Sahaji, the king of
Tanjore (modern Thanjavur), requested support from Pierre
Benoît Dumas, the governor of Pondicherry (1735-1741), offering money and the rice-growing region of Karaikal in return.
Dumas set up a corps of 5000 Indian auxiliaries or sepoys, organized along European lines. French prestige was boosted when fearsome pillaging warriors, the Marathis,
invaded the territory of the Nawab of the Carnatic, Dost Ali Khan (reign: 1732-1740), killing him in battle.
His widow asked Dumas for shelter. When the Marathis came to Pondicherry to demand the widow and
her gems, Dumas refused to hand her over. Not only did the Indian princes esteem him all the more, but
a son of Dost Ali Khan was so moved by the nobility of this gesture that he gifted him some land in thanks.
Dupleix: from glory to disgrace
BertrandFrançois Mahé
de la Bourdonnais
(1699-1753). Painting
by Antoine Graincourt,
18th century. Lorient,
Musée de la Compagnie
des Indes. © RMN /
Hervé Lewandowski.
Dutch decline in late 17th century India strengthened the presence of the French and British. In the 18th
century rival interests brought them into armed conflict on several occasions. The history of France in
India was to reach its peak in the era of Joseph François Dupleix (1697-1763), but ultimately “his policy
cost dearly, leading to the loss and ruin of French influence and a corresponding consolidation of the
British presence.” 4 Dupleix was the most celebrated and controversial of his country’s governors.
In order to protect trade, Dupleix sought to avoid conflict with Britain. When the French declared war on
Britain in 1744, he made an agreement with the British Company: no hostile acts by either
Company east of the Cape of Good Hope. But the Anglo-French entente cordiale in India
could never hold. When British naval officers broke the agreement by capturing several
French ships, Dupleix decided to attack Madras, sending an engineer into the city to
reconnoiter its weakest points, and securing the dispatch by the governor of Mauritius of ten vessels and 2300 European troops under the command of BertrandFrançois Mahé de la Bourdonnais.
Its preparations complete, the French squadron launched the siege of Madras on
September 14-15, 1746. Taken by surprise, the British were unprepared and surrendered on September 21. La Bourdonnais offered to return the city for a ransom,
the exact amount of which would be subject to a gentleman’s agreement. He backed
his undertakings with his word of honor. But French victory was weakened by disagreement between La Bourdonnais and Dupleix, who believed that his role was that
of overall commander. La Bourdonnais, on the other hand, felt that where the fate of
Madras was concerned, he himself should have the last word. In this clash of viewpoints,
Dupleix refused to countenance talk of ransom, since he was all too conscious of the prize
that Madras represented. His aim was to cripple the city and he had no hesitation in breaking
the agreement entered into by La Bourdonnais. In the ensuing trial of strength between the two men,
meteorological chance came to the aid of Dupleix: a cyclone laid waste the fleet commanded by La Bourdonnais and it limped back to Mauritius. Dupleix seized on the opportunity to push forward with his plans.
But without La Bourdonnais and his fleet, he had to ask the Nawab of the Carnatic to attack Madras. The
British were masters of the sea and mounted a vigorous riposte. Not only did they establish a blockade
along the coast, but in 1748 a British squadron under Admiral Edward Boscawen landed in Pondicherry
with 8000 men. The city fought back and the British withdrew after a siege lasting 40 days, having lost 1675
men versus only 393 French dead. The treaty of Aix-la-Chapelle (1748) restored the ante bellum status
quo: Madras was returned to the British in a sorry state following its partial destruction by Dupleix.
Dupleix had brilliantly defended Pondicherry, but his policies were aggressive and the local inter-Indian
wars played against him. The Indian princes found it expensive to maintain troops after the war against
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the British. They asked Dupleix for help in exchange for territorial concessions and economic benefits.
In 1749, Dupleix backed the coalition of Chanda Shahib, a friend of France, against Anaverdi Khan, the
king of the Carnatic. The French and their Indian allies won the battle, with Anaverdi Khan dying on the
field. An outstanding French officer was the Marquis Charles de Bussy-Castelnau who arrived in India in
1746 and set out to “learn the language, study the customs, and familiarize himself with the competing
political interests.” The situation between the French and English turned ugly. In the Carnatic, Dupleix
had to grapple with a bitter enemy, Mohammed Ali, backed by the British. Bussy meanwhile was strengthening his position in the Deccan Plateau, obtaining land along the Orissa coast, by the Bay of Bengal. This
took him too far to be of assistance to Dupleix. “So long as Dupleix was successful on the battlefield, the
Company was happy to give him free rein, but it became concerned after the defeats at Trichinopoly in
1753. France, which was now at peace with Britain, was
worried by the Anglo-French conflict in India and decided to bring Dupleix home.” 4
The weakening of French India
In 1754, France sent Charles Godeheu to Pondicherry
to begin negotiations with the British. The two Companies agreed to take no further part in inter-Indian
conflicts, to abandon their territorial ambitions, and to
retain territories of similar size around Pondicherry
and Madras. “Godeheu’s agreement with the British in
India proved to be worth no more than the paper it was
written on, since as soon as he left the British simply
resumed the same expansionist policy that had been
followed by Dupleix.” 4
The peace intended by the Godeheu treaty proved
short-lived indeed: war between France and Britain—
the French and Indian War or Seven Years War—broke
out in 1756, although it took until October for the news
Lifting of the siege of Pondicherry, in 1748. Engraving, 1789.
to reach India. The French had around one thousand
© Bridgeman Art Library.
men, the British twice that. This imbalance produced
some decisive British victories, notably in Bengal with the capture of Chandernagore (1757), which was
razed to the ground. The most bitter fighting was in the Carnatic where the French under General Thomas
Arthur Lally-Tollendal and Bussy tried in vain to retake Madras (1759). Bussy was made prisoner and Lally
found refuge behind the ramparts of Pondicherry which the British then set out to starve into surrender.
The besieged inhabitants survived on cats and rats, and many soldiers deserted. In 1760, fourteen British
ships surrounded Pondicherry. The French held out for a year until, exhausted, they capitulated unconditionally in 1761. The British then razed the European city.
The Treaty of Paris (February 16, 1763) restored peace between France and Britain. The trading posts of
Pondicherry, Karaikal, Yanam, Mahé, and Chandernagore were returned, but the British held on to the
territories they had conquered. They were particularly strong in Bengal where they banned the French
from restoring the fortifications at Chandernagore. The Treaty of Paris was deeply hurtful to the French
because it left them with mere scraps of territory and trading posts that were largely demolished. Lally was
accused of high treason, condemned to death, and executed on May 9, 1766.
1763-1778: a new lease on life for the trading posts
When Baron Jean/John Law of Lauriston, a distant cousin of the original John Law, took back Pondicherry
in 1765 in the name of France, the city was but a heap of ruins. The combination of longstanding neglect
by Paris and a catastrophic financial situation had compounded its destruction by the British. But thanks
to Law, the European city was rebuilt within two years, complete with administrative buildings, private
houses, and elaborate fortifications. Yet French commercial and military power was on the wane.
The British were ahead in many fields, discouraging the French from launching any commercial ventures. In addition, they were devoid of scruples: “in January 1774, they had the Indian commander of
the guard of the French outpost publicly flogged at every intersection in Dacca [modern Dhaka], and
they made known, to trumpet blasts, that anyone claiming to live under the French flag would be summarily impaled. In December of the same year, they published, to drum rolls, a ban on weavers working
for the French, on pain of death by hanging!” 5 —hardly a propitious climate for the revival of French power
in India.
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From 1778 to 1962
The American War of Independence (1775-1783) hastened the collapse of French India after France intervened in the conflict pitching Britain against its American colonies. The immediate effect of this intervention was the loss of the French outposts in India. The British attacked Pondicherry and the fragile
alliances that the French forged with Indian princes disappeared in smoke. After two periods of British
occupation (1778-1785 and 1792-1814), Pondicherry was returned to the French in 1816. At the Treaty of
Paris (1814), the British gave France back its five trading posts, but none were to shine with their former
prestige. Nevertheless, a royal college was established in Pondicherry in 1826. It was the first academic
institution in the French Empire, and was followed by a School of Law (1838) and the first Alliance française
(1893). Chandernagore reverted to India in 1948, the year after independence, followed de facto on November 1, 1954, by the four trading posts forming the territory of Pondicherry. Although the formal transfer
treaty was signed between France and India in May 1956, de jure transfer did not take place until 1962.
Daily life in the trading posts
In terms of daily life, the trading posts were embryonic French communities, from the founding of Surat
onwards, according to its description by François Martin: “a little Babylon… where you see people from
virtually all conceivable generations…. The streets are always chock-full with carts, elephants, camels,
beasts of burden, coaches, horses, and palanquins… Such a mixture gives an impression of greatness and
wealth yet the city is very badly built, dirty, and in several places even putrid.”
Pondicherry soon sped ahead of the other trading posts, Masulipatam, Balasore, and even Chandernagore,
none of which had “a typically French cityscape or colonial community, no doubt because they were much
less commercially active. Things were quite different in Pondicherry.” 6
More than one historian was surprised by Bellanger de l’Espinay’s decision to settle this fishing village in 1673. The writer Robert Challe, traveling as ship’s purser, confided to his diary in 1690: “This is
the most wretched and barren site along the Coromandel Coast,” adding “I fail to understand the intentions of the first Frenchmen who settled a place so difficult
of access from the sea, so open to access from the land, and
so uncomfortable in which to live.” 7
Although there was much common sense in these criticisms, Pondicherry’s location was not as bad as it was painted.
Its shipping roads were among the best along Coromandel;
the mouth of the Ariyankuppam river offered ships a safe
haven; the water was excellent; and the local weavers manufactured cotton goods that delighted the French. Travelers
also agreed that the location had its charm: “the coastline of
fields alternating with woods is pleasing to the eye, being quite
beautiful, even and flat.”
This therefore was where François Martin founded Pondicherry: “a French city enshrined in the magical colors of Oriental vegetation,” according to the Pondicherry-born soldier
of mixed race Édouard de Warren. Martin was to govern with
intelligence and diplomacy. By undertaking to respect ways
and customs, he inaugurated what was to be known until 1954
as France’s policy towards indigenous communities. He made
generous tax exemptions to weavers and granted lands to the
soldier-colonists. To ensure that the city could defend itself,
he completed the rectangular Fort Barlong. Between them,
Capuchins, Jesuits, and foreign missions built four churches. François-Martin, agent for the French East
The Company director and officers lived in the fort and sever- India Company, acquiring Pondicherry in
1674. © Roger-Viollet.
al Frenchman had “decently built single-storey whitewashed
houses.” Challe was particularly impressed by the whitewash, which he likened to “white marble.” When
the Dutch occupied the city (1693-1699), they built a wall with six fortified turrets around the Indian city
and laid the city’s checkerboard ground plan.
After they left, Martin came back to Pondicherry where he pursued his goal of transforming the city into
a genuine capital. By 1702, he’d built a new fort around the old one: “a copy of the pentagonal fort at
Tournai in France… the only fort in the colonies that was built to a design by Vauban.” Between 1699 and
his death in 1706, Martin created a major thoroughfare, the rue des Français (modern Dumas Road), and
the rue des Capucins (modern Romain Rolland Street). To the north stretched the Indian quarter with its
pagodas “and beautiful long tree-lined avenues.”
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Europeans gradually began to build homes in this part of the city. Martin’s successors did not inherit
his interest in town planning, and not until Pierre Lenoir did someone seek to carry his work forwards.
To strengthen the city’s defenses, Lenoir built a new wall with powerful bastions.
Pondicherry, which numbered “200 Frenchmen and an indigenous population of several thousand in
1690…, grew to 30 000 inhabitants in 1705, 60 000 in 1718 and 100 000 en 1725.” 8 The two main districts
came to be known as “the white city and the black city, until the former was dubbed the business district
and the latter the red light district.” 9
New thoroughfares were built. The long rue Madras (modern Mahatma Gandhi Road) crossed the city
from north to south, and the rue Valdaour (modern Nehru Street) from east to west. At this time righthanded castes banned left-handed castes from crossing their streets on horseback or by palanquin. Lenoir
did away with this ban and “proclaimed free movement of all castes on the main thoroughfares because
the king wished no distinction to be made between his subjects, whatever their beliefs, race, wealth or
poverty.” 10
To ensure that buildings stayed hygienic and attractive, Lenoir insisted on the use of bricks and tiles.
Some visitors were impressed, others hoped for improvements: “it is difficult to get about in the sandy
streets, some of the Indian houses are dilapidated…” Dumas strengthened the fortifications and developed
the southern district where he built a hospital, a mint, and a new church (Notre Dame des Anges), as well
as laying out splendid public gardens.
His successor, Dupleix, found Pondicherry “one of the most beautiful cities on the Coromandel Coast.” 10
Before becoming governor of Pondicherry he had spent over ten years in Bengal where he had turned
Chandernagore, a village of huts set among weeds, into a “a large town with two churches, two mosques,
several pagodas, a hospital, quays, an arsenal, and strong fortifications. Where there were once wattle and
daub huts, there were now 6000 houses, including over 2000 in brick.” 11 In 1740 Chandernagore’s population reached 30 000.
During the first years of his governorship of Pondicherry, Dupleix completed the works undertaken by
Dumas. He restored the town after the 6-week siege in 1748, when over 60000 cannonballs had rained upon
its walls. As a henceforth victorious city, Pondicherry shone like the capital of a vast empire and its gov-
THE FRENCH INSTITUTE OF PONDICHERRY
(www.ifpindia.org - [email protected])
In 2005 the French Institute of Pondicherry celebrated its 50th birthday. The Institute was set up in
1955 after the agreement that ceded the French trading posts to India. From the start, in the words of
Pandit Jawaharlal Nehru, it was considered “a window open on France.” It had three Departments:
French Language and Civilization, as in the French Institutes in some other countries; Sciences, at
the request of the host nation eager to develop a new India; and Indology, headed by the director of the
French School of the Far East. Beginning in 1958, the French Language and Civilization Department
has been run by the Alliance Française in Pondicherry. The Sciences Department has undertaken a
vegetation mapping project on a scale of 1/10 6, built up a herbarium containing 40000 specimens (including many endemic species), collected tropical pollens (to form one of the world’s richest biological archives for reconstructing the local paleo-environment), and gathered soil samples. The Indology
Department has collected manuscripts on palm-leaves and published as well as translated Sanskrit
and Tamil manuscripts.
Over the years, the Institute has come into its own. It has played a leading role in scientific cooperation between France and India. Indeed, India offers a privileged field for research in this regard,
particularly in its position as the second most populated country on the planet.
The Institute is now recognized in international research circles as a particularly important observatory from which to study sustained development in South Asia. It also plays a major role in the network of cooperation that links France to India and, more generally, Europe to Asia. As a multidisciplinary institution with its own budget reporting to the Foreign Ministry, the Institute validated thirty
projects in 2005. It organizes symposia and seminars, trains young Indian, French, and other national
researchers, and awards doctoral grants to both Indian and European students. Since 2003, the Institute has undertaken an ambitious publication program on both paper (some 230 titles) and CD-ROM.
Not only does the sheer range of its activities set the French Institute of Pondicherry apart, but its
harnessing of modern technology has made it a powerful laboratory perfectly poised to research both
past and present India, given the rapid and radical mutation undergone by the subcontinent in the
last decades.
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ernor desired a palace worthy of his station. Begun in 1738 it was completed in 1752. Dupleix constantly
complained about the softness of his fellow-colonists. They’d not covered themselves with honor during the siege— far from it, their courage had melted in the heat. In May and June, the “land winds” blew
and transformed Pondicherry into an oven. Europeans had to contend with alternating seasons of cyclones
and heat. In Pondicherry, the most devastating hurricane (1745) destroyed over 2000 homes and caused
40 deaths. Weakened by the climatic extremes, the French also lived in fear of epidemics of cholera, smallpox, and leprosy. Crocodiles lurked in the rivers and cobras were common in Pondicherry, while panthers
and tigers prowled around Chandernagore.
But the major threat remained war, despite the French colonists getting on reasonably well with the
other European settlers in India in peacetime. Dupleix had cordial relations with Schitermann, head of
the Dutch trading post at Chinsurah, and with François de Schonamille from Antwerp, who managed the
Austrian trading post at Bankibazar.
Despite the climate and insecurity, life in the trading posts was far from unpleasant and its financial advantages were undeniable. Six hundred livres a year was enough to live in style. There was no dearth of
applicants. No Company employee earned less than this, and there was extra money to be made from trade
within India itself. Some Frenchmen made a fortune, while soldiers earned a more basic wage.
In what setting did the settlers live and what did they eat? Wealthy Frenchmen liked fine homes with
gardens and conservatories: “Some very luxurious homes were furnished with lacquer wardrobes with copper inlays, tables and consoles in local wood incrusted
with ivory or mother of pearl, and screens in papier de
Chine.” 12 The walls were lined in silk from Bengal, satin
from Tonkin, dyed cloth from Pondicherry or hung with
Chinese prints and Persian miniatures. Craftsmen, particularly cabinet-markers, developed a recognizable Pondicherry style of furniture. This mix of oriental sophistication and teak furniture crafted by French artisans
gave an undeniable charm to the interiors of the settler
houses.
In the larger settler homes, wives managed a team of
servants, some of whom had been bought from their families as slaves in times of famine. The Company had a vegetable garden for growing European as well as Indian
crops. French wine traveled badly, and Persian wine was
often preferred. The French also happily savored “the
delights of Indian cooking, the chutneys, raitas, and curries… the guava and ginger jams and tarts, and a host of
exquisitely tasting exotic dishes.”
Notre-Dame de
l’Immaculée Conception
Cathedral in the former
French colony of
Pondicherry, in 1996.
© Frédéric Soltan /
Sygma / Corbis.
Puducherry today
Today when strolling through this city with its old-world
charm, the eye lingers on ornate walls, ancient balconies,
colonnaded porches, and climbing bougainvillea. Visitors sense a relaxed rhythm of life unlike anywhere else. Maybe its older citizens dream back to the city’s
French past as they listen to the music of the monsoon rain on the mango leaves. At any event, France
remains present, not only in some fine buildings, but also in the activities of its cultural institutions such
as the Alliance française and the French Institute (see box). REFERENCES
1. Kroell A. Pondichéry (1674-1761), l’échec d’un rêve d’empire.
Paris, France: Autrement; 1993.
2. Haudrère P. Les Compagnies des Indes orientales. Paris,
France: Desjonquères; 2006.
3. Kaeppelin, P. Les origines de l’Inde française. La Compagnie
des Indes Orientales et François Martin. Étude sur l’histoire
du commerce et des établissements français dans l’Inde sous
Louis XIV (1664-1719). Paris, France: Challamel; 1908.
4. Le Treguilly P, Moraze M. L’Inde et la France: Deux siecles
d’histoire commune, XVIIe-XVIIIe siècles. Histoire, sources, bibliographie. Paris, France: CNRS Éditions; 2007.
5. A.N., Col. C2, fol. 97. Extracts from dispatches by Jean-Baptiste Chevalier (1729-1789), governor of Chandernagore.
6. Weber J. Pondichéry et les comptoirs de l’Inde après Dupleix:
La démocratie au pays des castes (L’Aventure coloniale de la
France). Paris, France: Denoel; 1996.
West meets East: Pondicherry and the French East India Company – Camus
7. Challe R. Journal d’un voyage fait aux Indes Orientales, 16901691. Deloffre F, Menemenciaglu M, eds. Paris, France: Mercure
de France; 1983.
8. Labernadie MV. Le vieux Pondichéry 1673-1815. Histoire d’une
ville coloniale française. Paris, France: Leroux; 1936.
9. Grand dictionnaire universel du XIXè siècle. Paris, France:
Larousse; 1874.
10. Abbé Guyon. Histoire des Indes orientales, anciennes et modernes. Paris, France: Desaint & Saillant; 1744.
11. Castonnet des Fosses H. L’Inde française au XVIIIè siècle.
Paris, France: Société de Géographie Commerciale; 1900.
12. Martineau A. Dupleix, sa vie et son œuvre. Paris, France:
Société d’éditions géographiques, maritimes et coloniales; 1932.
MEDICOGRAPHIA, VOL 31, No. 1, 2009 109
A T
OUCH
OF
FRANCE
QUAND L’OUEST RENCONTRE L’EST : PONDICHÉRY
ET LA COMPAGNIE FRANÇAISE DES INDES ORIENTALES
L
a Compagnie française des Indes orientales dispose de « loges », simples entrepôts, et de « comptoirs ». Pondichéry, dont dépendent Chandernagor, Kãrikãl, Yanaon et Mahé, seront les principaux « Établissements français en Inde ». Pondichéry, situé sur la côte de Coromandel, où les
Français sont autorisés à s’installer par l’empereur Moghol (1673), joue le rôle de « capitale »
française en Inde du Sud. Dans les années 1750 son prestige est immense. Chandernagor, situé
dans la riche province du Bengale, est le plus actif pour le commerce. Kãrikãl, au cœur d’une région fertile, ravitaille Pondichéry et regroupe des tisserands. Mahé, sur la côte occidentale, est au centre
d’une région productrice de poivre. Très convoités, ces comptoirs sont soumis aux aléas de la politique
européenne, et à leurs rebondissements en Asie. La Compagnie profite du déclin de l’Empire Moghol
pour intervenir dans les affaires politiques indiennes et protéger ses intérêts. Ces comptoirs sont placés
sous l’autorité d’un gouverneur résidant à Pondichéry. Il doit, dans un premier temps, se défendre contre
les Hollandais (1693), mais la lutte la plus acharnée sera avec les Anglais, en 1748, puis en 1761 où ils
détruisent la ville. Lors du Traité de Paris (1763), elle est rendue à la France et rebâtie en deux ans. En
1902, quand Pierre Loti débarque sur la plage de Pondichéry il évoque « la mélancolie d’arriver dans
cette ville lointaine et charmante, où sommeille entre des murailles lézardées tout un passé français ».
Dupleix et Bussy « remarquables administrateurs et chefs de guerre, ont rêvé d’un empire français en
Inde ; ce rêve a été le leur, pas celui du gouvernement de la France ». Les cinq comptoirs seront cédés à
l’Inde de 1949 à 1956.
110 MEDICOGRAPHIA, VOL 31, No. 1, 2009
West meets East: Pondicherry and the French East India Company – Camus
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