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Medicines Q&As
Q&A 297.3
What is the rationale and evidence for combining angiotensin
converting enzyme inhibitors with angiotensin II receptor
antagonists for treating hypertension and for preventing vascular
events?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Published: August 2014
Summary


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To date there is no convincing evidence to support the use of an ACE inhibitor in
combination with an ARB in patients with vascular diseases such as cardiovascular
disease or diabetes mellitus (high risk vascular patients) and post MI patients.
Similarly the available evidence indicates no additional benefit of combining an ACE
inhibitor with an ARB for patients with mild to moderate hypertension.
The MHRA advises against combining any two renin-angiotensin system (RAS) blocking
agents. Healthcare professionals are advised to review the treatment of all patients
currently taking a combination of RAS blocking agents at a routine appointment and
carefully consider if combination use is appropriate.
If such a combination is considered absolutely necessary, it should be used under a
specialist’s supervision with close monitoring of kidney function, fluid and salt electrolyte
balance (particularly potassium) and blood pressure. Consideration should be given to
monitoring patients when combination use is started and on a monthly basis thereafter,
and also after changing dose and during intercurrent illness.
Background
This Q&A is the first of a series of two Q&As on the rationale and evidence for combining
angiotensin converting enzyme inhibitors with angiotensin II receptor antagonist.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have
similar clinical effects but differ in their pharmacology: ACE inhibitors block the conversion of
angiotensin I to angiotensin II and prevent the breakdown of bradykinin whilst ARBs selectively
block the AT1 receptor (1). Excessive amounts of angiotensin II leads to vasoconstriction and
increased aldosterone secretion causing further sodium and water retention, while bradykinin,
acting on receptors in the vascular endothelium, promotes release of vasodilators including nitric
oxide (2). The pharmacology of ACE inhibitors and ARBs is represented in Figure 1.
An ACE inhibitor alone may not fully block the renin-angiotensin system. The continued production
of angiotensin II is incompletely understood but may be associated with alternate synthesis
pathways (see fig 1) (1). Therefore by utilising the combination of an ACE inhibitor and an ARB
you would expect to gain a more complete blockade of the renin-angiotensin system.
The question is: in practice does this translate into an improved clinical outcome for the patient?
Available through NICE Evidence Search at www.evidence.nhs.uk
Medicines Q&As
Figure 1: Interaction of ACE inhibitors and ARBs with renin-angiotensin system (RAS) (1).
Answer
The MHRA issued a Drug Safety Update in June 2014 on the combination use of medicines from
different classes of renin-angiotensin system (RAS) blocking agents (3). The MHRA’s advice was
based on a review by the Pharmacovigilance Risk Assessment Committee (PRAC) at the
European Medicines Agency (EMA), which looked at the risk of combining different classes of
medicines that act on the renin-angiotensin system (ACE-inhibitors, ARBs, or aliskiren). (4). The
review was initiated due to concerns that these combinations could increase the risk of
hyperkalaemia, hypotension and renal failure compared to their use as monotherapies. (13) In
particular, there was concern that the combinations might not lead to the anticipated benefits and
therefore risk may outweigh benefits. The review found that the risk was likely to be greater than
the benefits.
PRAC advises against combining medicines from any two of these classes (4). Healthcare
professionals are advised to review the treatment of all patients currently taking a combination of
RAS blocking agents at a routine appointment and carefully consider if combination use is
appropriate (3). If such a combination is considered absolutely necessary, it should be used under
a specialist’s supervision with close monitoring of kidney function, fluid and salt electrolyte balance
(particularly potassium) and blood pressure. Consideration should be given to monitoring patients
when combination use is started and on a monthly basis thereafter, and also after changing dose
and during intercurrent illness (3).
High risk for Vascular Disease
The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial
(ONTARGET) (n= 25,620) looked at whether the combination of telmisartan and ramipril was
superior to ramipril alone as a treatment to prevent vascular events in high risk patients who had
cardiovascular disease or diabetes mellitus but did not have heart failure (5). The study also
Available through NICE Evidence Search at www.evidence.nhs.uk
Medicines Q&As
evaluated whether telmisartan was non-inferior to ramipril for the same indication. Patients were
randomised to receive either 80mg telmisartan (n=8542) or 5mg ramipril (titrated up to 10mg)
(n=8576) or a combination of the two drugs (n= 8502). The median follow up period was 56
months.
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The primary composite outcome was death from cardiovascular causes, myocardial
infarction, stroke or hospitalisation for heart failure. In the combination therapy group the
primary outcome occurred in 1386 patients (16.3%; relative risk 0.99; 95% CI 0.92-1.07)
as compared to 1412 patients in the ramipril group (16.5%).
The main secondary outcome, composite of death from cardiovascular causes, myocardial
infarction or stroke, was the same in the combination group and in the ramipril group
(14.1%).
Discontinuations due to hypotensive symptoms were higher in the combination group
(4.8%) than the ramipril group (1.7%). Renal dysfunction was higher in the combination
therapy group (13.5%) compared to the ramipril group (10.2%, (p<0.001).
The combination therapy was not found to be significantly better than either monotherapy used in
preventing serious outcomes in patients with known vascular disease or diabetes. In addition,
patients taking dual blockade had higher rates of renal dysfunction, hyperkalaemia and
hypotension. The study concluded that the combination of the two drugs in this group of patients
did not offer any additional clinical benefits.
Post Myocardial Infarction
The benefit of treatment with the combination of an ACE inhibitor and an ARB was not confirmed
in the only published trial carried out in post-myocardial infarction (MI) patients. The Valsartan in
Acute Myocardial Infarction (VALIANT) trial (n=14,703) included patients who had myocardial
infarction (0.5 to 10 days previously) complicated by left ventricular systolic dysfunction, heart
failure, or both and were randomised to receive valsartan (n=4909), valsartan plus captopril
(n=4885) or captopril (4909) which was titrated to target doses and adjusted according to patients
clinical status (6). More patients discontinued treatment in the combination group (19%) than in the
valsartan group (15.3%) and captopril group (16.8%), p=0.007 for the comparison between
captopril and combination group. A p value was not given for the difference between the valsartan
group vs. combined group as the study was not designed for this comparison. The proportion of
patients taking target doses were 56% for valsartan (160mg twice daily), 47% for valsartan and
captopril (80mg twice daily and 50mg three times daily respectively), and 56% for valsartan (50mg
three times daily) treatment.

Mortality from any cause, the primary outcome, was similar in the three treatment groups;
19.9% in the valsartan group, 19.3% in the combination group and 19.5% in the captopril
group. The hazard ratio for the combination group compared to captopril group was 0.98
(97.5% CI 0.89-1.09, P=0.73).
 The rate of the secondary end point of death from cardiovascular causes, recurrent
myocardial infarction, or hospitalisation for heart failure was also similar in the three
groups (31.1%, 31.1% and 31.9% respectively).
 Rates of hospitalisation for heart failure and myocardial infarction were numerically lower
in the combination group: 17.1% in the combination group, 18.7% in the valsartan group,
and 19.3% in the captopril group, the difference was statistically significant (p=0.007)
between the combination and captopril group.
 The highest rate of adverse events occurred in the combination treatment group (9%) and
the lowest in the valsartan group (5.8%).
The study concluded that combination treatment did not reduce mortality or cardiac outcomes
despite additional lowering of blood pressure.
Hypertension
The current guidelines from NICE and the British Hypertension Society do not recommend the
combination of an ACEI inhibitor and an ARB in the management of hypertension (7). A few small
trials have demonstrated that using this combination is more effective at reducing blood pressure
Available through NICE Evidence Search at www.evidence.nhs.uk
Medicines Q&As
than monotherapy (8;9). A meta-analysis of 14 small RCTs involving 434 patients compared the
combination of ACE inhibitors and ARBs with either an ACE inhibitor or ARB alone in the
treatment of hypertension. The combination of an ACE inhibitor with an ARB reduced 24-hour
ambulatory blood pressure by 4.7/3.0 mmHg (95% CI, 2.9 to 6.5/1.6 to 4.3) when compared with
ACE monotherapy and by 3.8/2.9mmHg (95% CI, 2.4 to 5.3/0.4 to 5.4) when compared to ARB
monotherapy. Similarly, the combination reduced clinical blood pressure (sitting or supine) by
3.8/2.7 mmHg (95% CI, 0.9 to 6.7/0.8 to 4.6) and 3.7/2.3mmHg (95% CI, 0.4 to 6.9/0.2 to 4.4)
when compared with an ACE inhibitor and ARB respectively. However many of the trials used suboptimal doses or once daily doses of short acting ACE inhibitors and when larger doses or long
acting ACE inhibitors were used, there was generally no additive effect on blood pressure when an
ARB was added (10).
Long term effects over 12 months of dual blockade therapy on blood pressure were examined in
the CALM II study (n=75) where hypertensive type 1 and 2 diabetic patients received 16mg
candesartan and 20mg lisinopril (n=38) or high-dose 40mg lisinopril (n=37) (11). Dual blockade
treatment tended to be more effective than lisinopril monotherapy in lowering 24-hour and night
systolic blood pressure although the difference was not statistically significant. The mean
differences between treatments were: daytime, 5.6mmHg (95% CI -0.4 to 11, p=0.07); night-time,
2.2mmHg (-3.1 to 7.4, p=0.4) and 24-hour systolic BP, 3.9mmHg (-1.6 to 9.5, p=0.16). No
difference in the effect on diastolic BP was observed between the two treatment groups. A total of
15 patients (8 lisinopril and 7 dual blockade) had to be treated with thiazide diuretics due to
insufficient blood pressure reduction. Both treatments were generally well tolerated and no serious
drug related events were noted. More patients in the dual blockade group were also treated with
thiazides at baseline (20/38 vs. 8/37, p<0.05): whether this affected the results can only be
speculated. Conversely, the dual-blockade group may have had more severe hypertension at
baseline. The study concluded that reduction in blood pressure for dual therapy was similar to
dosage up-titration with the ACE inhibitor.
The largest study identified is the ONTARGET study (see ‘High risk for Vascular Disease’ section).
Blood pressure monitoring throughout the study showed that average blood pressure reductions
were lower in both the telmisartan group (a 0.9/0.6mmHg average reduction) and the combination
group (a 2.4/1.4mmHg average reduction) compared to the ramipril group although the statistical
significance of these results were not discussed. Overall effect of the combination, as discussed
earlier, did not offer any additional clinical benefit (5).
No studies have yet been carried out to demonstrate whether using this combination is as effective
in lowering blood pressure as combining an ACE inhibitor with another antihypertensive agent
such as a diuretic (9). Currently there appears to be no benefit in using the combination in mildmoderate hypertension. Most patients will achieve their target blood pressure using either agent as
monotherapy with maximal dose or by combining either agent with a diuretic. The data is less
conclusive with respect to severe hypertension in patients with diabetes and renal disease (12).
Meta-analysis
A recently published meta-analysis of 33 studies compared the long-term efficacy and safety of
dual blockade of the renin-angiotensin system for any indication (n=68,405) (13). Twenty-two of
the studies evaluated the combination of an ACE inhibitor and ARB (dual blockade) vs.
monotherapy. Subgroup analyses were carried out for patients with and without heart failure;
these included studies in which patients had been treated with an ACE inhibitor and ARB as well
as an ACE inhibitor or ARB and aliskiren.
The following efficacy outcomes were reported for the subgroup of patients without heart failure:
this group included patients with hypertension, with or without diabetes or chronic kidney disease.
In this group, up to 15,716 patients were treated with dual blockade and 26,054 treated with
monotherapy.
 All-cause mortality was increased in patients treated with dual blockade compared with
monotherapy (risk ratio 1.07, 95% CI 1.00 to 1.14, p=0.04).
Available through NICE Evidence Search at www.evidence.nhs.uk
Medicines Q&As
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There was no increase in cardiovascular mortality with dual blockade vs. monotherapy
(RR 1.04, 95% CI 0.90 to 1.20, p=0.61).
There was a trend towards a reduction in hospital admissions for heart failure with dual
rather than monotherapy (RR 0.91, 95% CI 0.82 to 1.01, p=0.07).
Four main safety outcomes were analysed.
 The risk of hyperkalaemia was significantly higher with dual blockade (RR 1.50, 95% CI
1.28 to 1.76, p<0.001).
 The incidence of hypotension was significantly higher with dual blockade (RR 1.63, 95%
CI 1.20 to 2.22, p=0.002).
 The risk of renal failure was not significantly increased (RR 1.04, 95% CI 0.80 to 1.35,
p=0.76).
 More patients treated with dual blockade discontinued therapy due to drug adverse events
than with monotherapy (RR 1.22, 95% CI 1.10 to 1.36, p<0.001).
The authors compared the safety risks of hyperkalaemia, hypotension, renal failure and withdrawal
due to drug-related adverse events for dual blockade vs. ACE inhibitor alone and vs. ARB alone
for the whole patient cohort (i.e. both subgroups). The risk of all adverse outcomes was
significantly greater with dual blockade than with ACE inhibitors alone, and hypotension and
withdrawal were significantly greater with dual blockade than with ARB alone.
Limitations
Many of the studies looking at combination ACE inhibitor and ARB therapy for hypertension have
small patient numbers and are of short duration. For the other indications discussed in this Q&A;
high risk for vascular disease and post MI, only one study for each was identified indicating
research in these areas is extremely limited.
References
(1)
Chiaventone K, Ou N. Cardiovascular Update: The role of combination ACE inhibitors and
angiotensin II receptor blockers. Pharm Times 2004;(Dec).
(2)
Opie.l.H, Poole-Wilson PA, Pfeffer M. Chapter 5. Angiotensin-Converting Enzyme (ACE) Inhibitors,
Angiotenin-II Receptor Blockers (ARBs), and Aldosterone Antagonists. In: Opie.l.H, Gersh.B.J,
editors. Drugs for the Heart. Philadelphia; Pennsylvania: Elsevier Saunders, 2005.
(3)
MHRA. Combination use of medicines from different classes of renin-angiotensin system blocking
agents. Drug Safety Update 2014; 7(11):A1.
(4)
Combined use of medicines affecting the renin-angiotensin system (RAS) to be restricted - CHMP
endorses PRAC recommendation. European Medicines Agency Accessed via:
http://www.ema.europa.eu on 29/05/2014.
(5)
The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular
events. N Engl J Med 2008; 358(15):1547-1549.
(6)
Pfeffer MA, McMurray JJV, Velazquez EJ et al. Valsartan, captopril, or both in myocardial infarction
complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349(20):18931906.
(7)
Clinical Guideline 217. Hypertension: Clinical management of hypertension in adults in primary care.
August 2011. NICE and British Hypertension Society. Accessed via:
http://www.nice.org.uk/guidance/CG127 on 05/08/2014.
(8)
Kon Koh K, Quon MJ, Lee Y et al. Additive beneficial cardiovascular and metabolic effects of
combination therapy with ramipril and candesartan in hypertensive patients. Eur Heart J 2007;
28:1440-1447.
Available through NICE Evidence Search at www.evidence.nhs.uk
Medicines Q&As
(9)
van de Wal RMA, van Veldhuisen DJ, van Gilst WH et al. Addition of an angiotension receptor
blocker to full dose ACE-inhibition: controversial or common sense? Eur Heart J 2005; 26:23612367.
(10)
Doulton TWR, He FJ, MacGregor GA. Systematic review of combined angiotensin-converting
enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension 2005; 45:880886.
(11)
Anderson NH, Poulsen PL, Knudsen ST et al. Long-term dual blockade with candesartan and
lisinopril in hypertensive patients with diabetes. The CALM II study. Diabetes Care 2005; 28:273277.
(12)
Sica DA. The practical aspects of combination therapy with angiotensin receptor blockers and
angiotensin-converting enzyme inhibitors. JRAAS 2002; 3(2):66-71.
(13)
Makani H, Bangalore S, Desouza KA. Efficacy and safety of dual blockade of the renin-angiotensin
system: meta-analysis of randomised trials. Br Med J 2013; 346:f360.
(14)
Summary of Product Characteristics. Capoten tablets 25mg. Date of revision of the text: August
2013. E.R Squibb & Sons Limited. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(15)
Summary of Product Characteristics. Vascace Tablets. Date of revision of the text: 29/11/2013.
Roche Products Limited. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(16)
Summary of Product Characteristics. Innovace Tablets. Date of revision of the text: November 2013.
Merck Sharp & Dohme Limited. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(17)
Summary of Product Characteristics. Fosinopril sodium 20mg Tablets. Date of revision of the text:
21/09/2012. Actavis UK Limited. Accessed via: www.medicines.org.uk on 29/5/2014.
(18)
Summary of Product Characteristics. Tanatril 5, 10 & 20mg tablets. Date of revision of the text:
15/05/2010. Chiesi Limited. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(19)
Summary of Product Characteristics. Zestril 5mg, 10mg and 20mg tablets. Date of revision of the
text: 09/06/2014. AstraZeneca UK Limited. Accessed via: http://emc.medicines.org.uk on
05/8/2014.
(20)
Summary of Product Characteristics. Perdix 7.5mg film-coated tablets. Date of revision of the text:
April 2014. UCB Pharma Ltd Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(21)
Summary of Product Characteristics. Coversyl arginine. Date of revision of the text: August 2013.
Servier Laboratories Limited. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(22)
Summary of Product Characteristics. Accupro Tablets 5mg, 10mg, 20mg & 40mg. Date of revision of
the text: August 2013. Pfizer Limited. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(23)
Summary of Product Characteristics. Tritace 5mg tablets. Date of revision of the text: 14/02/2014.
Aventis Pharma Ltd. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(24)
Summary of Product Characteristics. Gopten. Date of revision of the text: 04/09/2012. Abbott
Healthcare Products Ltd. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(25)
Summary of Product Characteristics. Edarbi Tablets. Date of revision of the text: 22/05/2014.
Takeda UK Ltd. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(26)
Summary of Product Characteristics. Amias Tablets. Date of revision of text: 21/11/2013. Takeda
UK Ltd Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(27)
Summary of Product Characteristics. Teveten 300mg Flim-coated Tablets. Date of revision of the
text: 30/072013. Abbott Healthcare Products Limited. Accessed via: http://emc.medicines.org.uk on
05/8/2014.
Available through NICE Evidence Search at www.evidence.nhs.uk
Medicines Q&As
(28)
Summary of Product Characteristics. Aprovel 150mg film-coated tablets. Date of revision of the text:
04/10/2013. Sanofi. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(29)
Summary of Product Characteristics. Cozaar 12.5mg, 25mg, 50mg and 100mg Film-Coated Tablets.
Date of revision of the text: March 2014. Merck Sharp & Dohme Limited. Accessed via:
http://emc.medicines.org.uk on 05/8/2014.
(30)
Summary of Product Characteristics. Olmetec film-coated tablets. Date of revision of the text:
18/04/2013. Daiichi Sankyo UK Limited. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(31)
Summary of Product Characteristics. Micardis 20mg tablets. Date of revision of the text: December
2013. Boehringer Ingelheim Limited. Accessed via: http://emc.medicines.org.uk on 05/8/2014.
(32)
Summary of Product Characteristics. Diovan 160mg capsules. Date of revision of the text:
02/11/2012. Novartis Pharmaceuticals UK Ltd. Accessed via: http://emc.medicines.org.uk on
05/8/2014.
Quality Assurance
Prepared by
Updated by Alexandra Denby, London Medicines Information Service (Northwick Park Hospital)
Based on earlier work by Aya Mizukami and Helen Rowlandson, London Medicines Information
Service (Northwick Park Hospital)
Date Prepared
5th August 2014
Checked by
Varinder Rai, London Medicines Information Service (Northwick Park Hospital)
Date of check
August 11th 2014
Search strategy
 Embase: [*DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR/cb [cb=Drug Combination]
AND *ANGIOTENSIN RECEPTOR ANTAGONIST/cb [cb=Drug Combination]] AND
[CARDIOVASCULAR DISEASE/dt [dt=Drug Therapy] OR HEART INFARCTION/dt
[dt=Drug Therapy] OR *HYPERTENSION/dt [dt=Drug Therapy]] [Limit to: Human and
English Language and Publication Year 2012-2014]
 Embase: [*DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR/cb [cb=Drug Combination]
OR *ANGIOTENSIN RECEPTOR ANTAGONIST/cb [cb=Drug Combination]] AND
[CARDIOVASCULAR DISEASE/dt [dt=Drug Therapy] OR HEART INFARCTION/dt
[dt=Drug Therapy] OR *HYPERTENSION/dt [dt=Drug Therapy]] [Limit to: Human and
English Language and Publication Year 2012-2014]
 Medline DRUG THERAPY, COMBINATION/ and [*ANGIOTENSIN RECEPTOR
ANTAGONISTS/ or ANGIOTENSIN-CONVERTING ENZYME INHIBITORS/tu] and
[HYPERTENSION/ or *CARDIOVASCULAR DISEASES/dt]. Limit to: Human and English
Language and Publication Year 2012-Current.
 Cochrane Library “ace inhibitors” and “angiotensin”
Available through NICE Evidence Search at www.evidence.nhs.uk
Medicines Q&As
Appendix 1: UK licensed indications for ACE inhibitors and ARBs *Please refer to current
Summary of Product Characteristics (SPC), which can be accessed via
http://emc.medicines.org.uk for full dosing information.
ACE Inhibitors (trade
name)
Hypertension
Heart
failure
Captopril
(Capoten) (14)
Cilazapril
(Vascace) (15)
Enalapril
(Innovace) (16)






Fosinopril (17)


Imidapril (Tanatril)
(18)
Lisinopril (Zestril)
(19)
Moexipril (Perdix)
(20)
Perindopril
(Coversyl
Arginine) (21)
Quinapril
(Accupro) (22)
Ramipril (Tritace)
(23)
Trandolapril
(Gopten) (24)
Angiotensin II
receptor
antagonists
Azilsartan (Edarbi)
(25)
Candesartan
(Amias) (26)
Eprosartan
(Teveten) (27)
Irbesartan
(Aprovel) (28)
Losartan (Cozaar)
(29)
Olmesartan
(Olmetec) (30)
Telmisartan
(Micardis) (31)
Valsartan (Diovan)
(32)



Post MI
prophylaxis

Post MI
prophylaxis
with LV failure

Diabetic
nephropathy
(type 1)
Diabetic
nephropathy
(type 2)
Cardiovascular
disease, stroke
or peripheral
disease











Hypertension
Heart
failure





Post MI
prophylaxis
Post MI
prophylaxis
with LV failure



Diabetic
nephropathy
(type 1)
Diabetic
nephropathy
(type 2)
Cardiovascular
risk reduction
















Available through NICE Evidence Search at www.evidence.nhs.uk
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