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Introduction
Treatment with angiotensin converting enzyme (ACE) inhibitor benefits many patients with
cardiovascular diseases [1]. Over the last three decades, clinical pharmacy has evolved ACE
inhibitors as antihypertensive agents as they produce vasodilation through their effect on cardio
renal and cardiovascular system [2]. Their advantage in this population not only lies in secondary
beneficial effects of reduction in levels of angiotensin II but also in decreased catecholamine
levels and vascular remodeling, among others [3]. Some researchers have proposed
differentiating among ACE-Is based on tissue binding and suggest that blood pressure correlates
better with tissue ACE levels than with circulating ACE, which could relate to improved
outcomes suggesting the class effect of ACE-Is [4]. All ACE inhibitors are cardio protective and
they have shown clinical efficacy against placebo in patients with myocardial infarction. Recent
clinical trials have raised the questions regarding the classical effects of ACE inhibitors among
the patients at high risk of complications from coronary artery disease with or without evidence
of heart failure [2]. Among a population with MI and low left ventricular ejection fraction
(LVEF), those who developed heart failure (HF) had increased mortality. All ACE inhibitors are
used universally in treatment of heart failure patients with evidence indicating 25% reduction in
mortality and 35% reduction in hospitalization [1].Most of the data on ACE inhibition and heart
failure after MI have limited follow up duration [3]. And different ACE-Is have not been studied
uniformly with MI, heart failure and left ventricular dysfunction [2]. Therefore more studies are
required to determine whether all ACE inhibitors are equal in treating patients with manifestation
of myocardial infarction with or without heart failure.
Diabetes mellitus is one of the strongest and individual risk factor for cardiovascular and renal
disease [5]. Various epidemiological studies show that the risk of cardiovascular mortality is two
to three times higher in men and three to five times higher in women with diabetes mellitus than
in people without diabetes mellitus [5]. People with type 2 diabetes mellitus develop severe
cardiovascular and renal diseases prematurely especially in those having urinary albumin
excretion i.e. microalbuminuria causing diabetic nephropathy and proteinuria or overt
nephropathy leading to end stage renal disease (ESRD). The association of high urinary albumin
excretion with poor cardiovascular prognosis is well established [5]. Inhibition of renin
angiotensin aldosterone system (RAAS) in patients with type 1 and type 2 diabetes mellitus
reduces high urinary albumin excretion and improves the renal outcome in addition to lowering
blood pressure.
Many trials have shown that not only inadequate diabetes control but Hypertension,
dyslipidemia, cigarette smoking, old age, insulin resistance, male sex, Afro – Caribbean, Asian
or native American origin are strong risk factors for the development of Diabetic nephropathy
(DN). In normal subjects, an elevated proglomerular vascular resistance protects the glomerular
microcirculation from systemic BP variation. In patients with DN, this protective mechanism is
blunted and vasodilatation of the afferent vessels occurs, permitting systemic BP variation to be
transmitted to the glomerular bed. Hence strict BP control is mandatory to avoid glomerular
damage [3].
In diabetic nephropathy, typical reversible histological progressive changes in the glomerular
structure can be found which first leads to microalbuminuria, followed by selective albuminuria
and later non selective irreversible proteinuria with progressive decline in renal function and end
stage renal failure. At first, it was thought that proteinuria reduction and renal protection induced
by ACE inhibitions were primarily due to vasodilatation of the efferent arterioles with
subsequent in the glomerular pressure [3].
Hypertensive patients, per se, a high risk of developing de novo type 2 diabetes and this
particularly true for patients taking beta-blockers and diuretics. Conversely, the risk is reduced
by blockade by RAS, either by ACE-Is as indicated by CAPP [6], ALLHAT [7], ANBP [8] and
SOLVD [9] studies or by ARBs as indicated by LIFE [10], CHARM [11] and ALPINE [12]
study.
Zuanetti et al 1993, Granger et al 1993, Malmberg et al 1996, Mark et al 1997 demonstrated that
diabetic hypertensive patients are considered high risk with markedly increased mortality after
AMI, almost double that of patients without diabetes and these excess mortality seems to be
related to congestive heart failure and reinfarction periods [3]. Cohn et al 2000 showed that ACE
inhibition is beneficial in such patients through prevention of LV remodeling. Addition to
prevention of renal function, improvement in fibrinolytic balance, endothelial function,
sympatho-vagal balance and glycemic control also contributes to reduce the mortality in diabetic
hypertensive patients [3].
Even numerous national and international guidelines JNC-7 [13], KDOQI [14], ADA [15]
suggest the use of either ACE-Is or ARBs as initial therapeutic agents in hypertensive patients
with type 2 diabetes mellitus for reducing the progression to diabetic nephropathy.
Nowadays, the use of ACE-Is is recommended in guidelines on the management of hypertension,
stable coronary artery disease, myocardial infarction and heart failure [16].
Do all ACE inhibitors differ in their clinical outcomes?
Nevertheless, all ACE inhibitors differ in chemical structure, potency, bioavailability, plasma
half-life, tissue affinity and to some extent in pharmacological actions also but difference in their
clinical outcomes has not been explored besides lowering blood pressure when used in
appropriate dosage [1]. As the earlier studies of different ACE-Is ascertained them beneficial in
different cardiovascular population and revealed their class effects no longer clinical trials
compared the efficacy of one ACE-I with another to determine which one best improves
survival.
There are imperative lessons to be learned different ACE inhibitor studies. The result of the
Heart Outcome Prevention Evaluation (HOPE) study [17] with ramipril led many physicians to
believe that class effect of ACE-I is so powerful that any ACE-I would be beneficial in any of
the indications that had been studied with specific individual ACE-I. Even European Trial on the
reduction of Cardiac events (EUROPA) with perindopril led to similar impact of class effect of
ACE-Is. But the failure of Prevention of events with Angiotensin Converting Enzyme Inhibition
(PEACE) study [18] with trandolapril challenged this concept of class effect. The class effect of
different ACE-Is is always a central topic of debate.
This article reviews the effect of different ACE-Is on diabetic nephropathy and long term
cardiovascular mortality and hospitalization in patients after a myocardial infarction.
Impact of different ACE-Is on diabetic nephropathy with long term follow up
Many ACE-Is have been so far studied for their effect on urinary albumin excretion in both type
1 and type 2 diabetes mellitus.
HOPE and MICRO-HOPE study [5] investigators studied the long term cardiovascular effects of
ramipril on patients having a past history of cardiovascular disease, aged 55 years or above and
having at least one cardiovascular risk factor i.e. diabetes or hypertension or dyslipidemia or
microalbuminuria or current smoking. The aim of the MICRO-HOPE study was to investigate
whether ACE inhibition with ramipril (10 mg/day) can lower the risk of cardiovascular and renal
disease in type 2 diabetes patients. The main outcome of the study was overt nephropathy and
primary outcome of the study was myocardial infarction, stroke or cardiovascular death. The
mean follow up period of the study was 4.5 years (Figure 1). The reduction in the systolic and
diastolic blood pressure at 1 month was 5.3 mmHg and 2.6 mmHg respectively whereas at the
end of the study, the mean reduction was 2 mmHg and 3.3 mmHg respectively. Ramipril showed
statistically and clinically significant result on urinary albumin excretion compared to placebo.
Ramipril lowered the risk of overt nephropathy in patients who did or did not have baseline
microalbuminuria. Moreover, ramipril treatment led to a lower albumin/creatinine ratio than
placebo at one year and at the end of the study. Ramipril reduced the development of overt
nephropathy by 24% (95% CI, 3-40, p=0.027) compared to placebo.
Similarly, DIABHYCAR study was carried out to investigate whether ACE inhibition with
ramipril (1.25 mg/day) lowers the risk of cardiovascular and renal events in type 2 diabetes
patients with microalbuminuria or proteinuria. The primary outcome measure was the combined
incidence of cardiovascular death, non-fatal myocardial infarction, stroke, heart failure leading to
hospital admission and end stage renal disease. A total of 4912 patients were followed for a
mean of 4 years. A low dose of ramipril was able to reduce the systolic and diastolic blood
pressure by 1.89 mmHg and 1.34 mmHg respectively after 1 year whereas at the end of the study
ramipril lowered the mean reduction was 3.61 mmHg and 2.37 mmHg respectively. in the
DIABHYCAR study, there was a trend towards more regression from proteinuria (UAE > 200
mg/l) and microalbuminuria (20 – 200 mg/l) to normal (UAE < 20 mg/l) or microalbuminuria
among patients taking ramipril than those taking placebo (RR 14%, 95 % CI, -4 – 28, p < 0.07).
Likewise, the BENEDICT [3] (Bergamo NEphrologic Diabetes Complication Trial) evaluated
whether a combination therapy of ACE inhibitor with Calcium Channel Blocker (CCB) was
better than either class alone or placebo in decreasing the progression toward microalbuminuria
in normoalbuminuric patients with type 2 diabetes mellitus and hypertension. In BENDICT,
1204 patients were randomized to either a combination of trandolapril and verapamil,
trandolapril alone or verapamil alone or placebo. Mean follow up was 3.6 years (Figure 2). At
the end of study, patients in trandolapril group (alone or in combination with verapamil) had
lower blood pressure than patients with verapamil group alone. Persistent microalbuminuria was
reached in 5.8% of subjects who received trandolapril based therapy and 10.9% in subjects who
did not. This difference was statistically significant (p < 0.001) even after the adjustment for age,
sex, smoking status and diastolic blood pressure.
Similarly, PROCOPA study [3] was designed to compare whether the magnitude of proteinuria
reduction with different class of antihypertensive agents differs, while similar BP reduction is
achieved. PROCOPA was a prospective, double blind, randomized trial including patients having
blood pressure > 130/85 mmHg, proteinuria > 1 g/day, creatinine clearance > 50 ml/min and
primary renal disease. All the patients were randomized to atenolol, trandolapril, verapamil or
combination of trandolapril and verapamil for 6 months. There was no statistically significant
difference in blood pressure reduction in between groups but there was significant urinary
albumin excretion in trandolapril based both the strategy, suggesting that in spite of adequate and
similar blood pressure control by all class of agents, only ACE inhibition reduces proteinuria in
primary renal disease.
Impact of Different ACE-Is on AMI with long term follow up
An impressive number of clinical trials have evaluated the effect of different ACE-Is in patients
surviving AMI for varying period of time. Hansen ML et al [1] in 2007 compared the effect of
different ACE inhibitors on mortality rate in patients surviving MI for a period of 5 years.
All patients aged >30 years hospitalized first time with MI and who were alive 30 days after
discharge were identified using National Patient registry in Denmark. The preferred end points of
interest were mortality due to recurrent MI and readmission due to MI.
A total of 16,068 patients who claimed at least one prescription of ACE inhibitor from the
pharmacy within 30 days after surviving MI were included. During the study trandolapril and
ramipril were the agents most frequently used, each accounting for 30% of all ACE-Is, followed
by enalapril (13%), captopril (12%) and perindopril (7%). During the study, prescription pattern
changed, with use of enalapril and captopril declining steadily and use of trandolapril, ramipril
and perindopril increasing. The average daily dosage for patients using trandolapril, ramipril,
enalapril, captopril and perindopril were 2, 5, 10, 37.5, 4 mg respectively [1].
The following (Figure3) illustrates the all cause of mortality curves among patients who claimed
at least one prescription of CE-I within 30 days of discharge after MI.
After Hansen MJ et al none of the research group has published another likely comparative study
with different ACE-Is. But Ariel Diaz and Anique Ducharme [3] in 2008 reviewed an update on
the use of trandolapril in the management of cardiovascular disorders. Pernille Buch et al [19]
reviewed the clinical effectiveness of trandolapril in patients with LV dysfunction after
myocardial infarction with a follow up of 12 years.
The TRAndolapril Cardiac Evaluation (TRACE) study was designed to evaluate the effect of
Angiotensin Converting Enzyme (ACE) inhibition with trandolapril on cardiovascular morbidity
in patients surviving AMI with reduced LV function and overall mortality as well as
cardiovascular mortality. TRACE was a randomized, placebo controlled, double blind study
conducted in 27 Danish coronary units. In TRACE study, 2614 patients were screened by an
echocardiography derived wall motion score index (WMSI) < 1.2. A WMSI < 1.2 means ejection
fraction 35% (Heger et al 1980). A total of 1749 patients with LVD (ejection fraction < 35%)
were randomized to trandolapril (n = 876) or placebo (n = 873).
TRAndolapril Cardiac Evaluation (TRACE) study [19]
The TRAndolapril Cardiac Evaluation (TRACE) study was designed to evaluate the effect of
Angiotensin Converting Enzyme (ACE) inhibition with trandolapril on cardiovascular morbidity
in patients surviving AMI with reduced LV function and overall mortality as well as
cardiovascular mortality. TRACE was a randomized, placebo controlled, double blind study
conducted in 27 Danish coronary units. In TRACE study, 2614 patients were screened by an
echocardiography derived wall motion score index (WMSI) < 1.2. A WMSI < 1.2 means ejection
fraction 35% (Heger et al 1980). A total of 1749 patients with LVD (ejection fraction < 35%)
were randomized to trandolapril (n = 876) or placebo (n = 873).
The Kaplan – Meier plot (Figure 4) for mortality at 10 years of follow up was 71.5% in placebo
group compared to 69.5% in trandolapril group. For the entire follow up, trandolapril was found
to reduce the risk of death from any cause compared to placebo (RR 0.89, 95% CI, 0.80 – 0.99,
p=0.035).
During the on-treatment follow up, the death due to cardiovascular causes was significantly
lower in trandolapril (226) compared to placebo (288) (RR 0.78, 95% CI, 0.76 – 0.91, p=0.001)
(Figure 5).
A total of 9220 hospitalizations were registered during the entire follow up, 4634 in trandolapril
group and 4586 in placebo group. The adjusted rate ratio for all causes of hospitalization was
0.92 (95% CI, 0.88 – 0.96, p < 0.001) for the trandolapril group compared to placebo. There was
significant reduction in the cardiac hospitalization during the entire follow up period for patients
treated with trandolapril (RR 0.95, 95% CI, 0.91 – 1.00, p = 0.047) compared to placebo. The
decreased rate of cardiac hospitalization in trandolapril group was particularly evident for CHF
hospitalization (p < 0.001). These data suggest benefits of ACE inhibition by trandolapril after
MI. (Figure 6)
This long term findings by Buch P et al significantly recommend the use of trandolapril in MI
patients surviving MI as the data does not show significant increase in mortality rate even after
following trandolapril for a period of 10-12 years.
Discussion
Appropriate and optimal dosage with ACE inhibitor is more promising in cardiovascular diseases
[3]. This analysis is one of the fewest analysis to review a sustain benefit in mortality with ACE
inhibitor treatment during long term follow up. There is solid evidence from the hard endpoint
clinical trial for the optimal trandolapril, ramipril and perindopril dosage to use. Despite the fact
that most ACE inhibitors are recommended for once daily dose only trandolapril and ramipril
have trough-to-peak ratio in excess of 50% [3]. Other ACE inhibitors like perindopril have
obtained indication for heart failure and current US guidelines for the management of heart
failure acknowledges this problem and they do not establish a precise recommended dosage for
perindopril [3]. The European Society of Cardiology recommends only trandolapril 4 mg daily
precise evidence based dosage [20].
Treatment with ACE inhibitor trandolapril in patients surviving MI with impaired left ventricular
function had a long term beneficial effect on survival and hospital admission rates. Both
cardiovascular and non-cardiovascular mortality was reduced in trandolapril group compared to
placebo. The lower morbidity in the trandolapril group was achieved through a reduction in CHF
hospitalization during on treatment phase. Treatment with trandolapril for a minimum of 2 years
in patients surviving MI will save approximately 20 lives per 1000 patients over a span of 10
years [3].
HOPE [5] finding suggests an angiotensin converting enzyme inhibitor, ramipril is beneficial in
broad range of patients with or without the clinical symptoms of left ventricular systolic
dysfunction or heart failure who are at high risk for cardiovascular events. Treatment with
ramipril reduces the overall mortality and myocardial infarction, stroke, cardiac arrest, coronary
revascularization, heart failure and risk of complications related to diabetes and of diabetes itself.
Treating 1000 patients with ramipril for 4 years prevents about 150 events in approximately 70
patients. HOPE also demonstrated a mark reduction in the incidence of complications related to
diabetes and new onset of diabetes. So the overall treatment with ramipril was beneficial even in
diabetic patients. These effects may be mediated by improved insulin sensitivity, decrease in
hepatic clearance of insulin, improved blood flow to pancreas, an anti-inflammatory effect or an
effect on abdominal fat.
The BENEDICT and PROCOPA study evaluated the comparative renoprotective effect among
ACE-I, calcium channel blockers, beta blockers and diuretics. The results of both study suggest
that the renoprotective effect was attributed to ACE-I i.e trandolapril only. The HOPE, MICROHOPE and DIABHCAR study result shows that ramipril is a very good clinical renoprotective
agent. All the studies reviewed in the present article suggest that use of ACE inhibitors not only
prevents the progression to overt nephropathy or ESRD in hypertensive diabetic patients but also
improved the renal function by delaying the onset of microalbuminuria in diabetic patients as
well as by lowering the urinary albumin excretion in microalbuminuric and proteinuric patients.
The results of the DIABHYCAR study show that there was a trend toward regression from
proteinuria
and
renoprotection.
microalbuminuria
to
normoalbuminuria
with
clinically
significant
A clinical review of different ACE-Is by Hansen MJ et al in 2007 [1] kept all ACE-Is with
clinical similar effectiveness in patients surviving MI. But the recent studies on trandolapril by
Ariel Diaz, Anique Ducharme, Buch P et al [3] reviewed the long term clinical effectiveness of
trandolapril in various cardiovascular populations. And the findings of the study further enforce
the use of trandolapril with clinically significant decline in mortality rate as well as
hospitalization due to MI. Additionally; there is no further studies are available that compare the
long term clinical effectiveness of ramipril, perindopril, enalapril and captopril. All of this to
total put trandolapril way ahead in the race of ACE-I for the treatment of in patients surviving
MI with or without clinical symptoms of heart failure. Even review by Ariel Diaz on the update
of trandolapril in different cardiovascular disorders further enforces the previous data on the use
of trandolapril in the management of cardiovascular disorders.
Conclusion
All ACE-Is with varying degrees of pharmaceutical properties were associated with similar
clinical outcomes. For the long term benefits for MI patients who need treatment with ACE-I,
focus on the continuing treatment with recommended dosage is most important, but initiating and
continuing therapy with trandolapril for longer period of time can improve the cardiovascular
outcomes. Although still an impressive number of studies on comparative effect of ACE-I is still
required.
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List of figures:
Figure 1: long term effect of ramipril on microalbuminuria
Figure 2: Comparative effect of on microalbuminuria with ACE inhibitor and No ACE inhibitor
in BENEDICT study.
Figure 3: Comparative effect of different ACE-Is on moratality rate in patients surviving MI
Figure 4: Kaplan – Meier curve for mortality from all causes in the trandolapril group compared
with the placebo group over 10 years of follow up
Figure 5: Kaplan – Meier curve for mortality from cardiovascular causes in the trandolapril
group compared with the placebo group over 10 years of follow up.
Figure 6: Kaplan – Meier curve for hospitalization from all causes in the trandolapril group
compared with the placebo group over 10 years of follow up.