CLIN. AND EXPER. HYPERTENSION, 2 1 (5&6), 835-845 (1 999)

SUMMARY OF RANDOMIZED TRIALS OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS

Salim YusuP and Eva Lorn* and Jackie Bosch* and Hertzel Gerstein** Division of Cardiology* and Endocrinology* *

McMaster University and The Hamilton Health Sciences Corporation Research Centre

Hamilton, Ontario, L8L 2x2, Canada

Key Words: ACE-inhibitors, Heart failure, Randomized trials

ABSTRACT

Angiotensin converting enzyme (ACE) inhibitors have been shown to reduce the risk of death, worsening heart failure and recurrent infarction in patients with left ventricular dysfunction and heart failure. They have also been shown to reduce mortality in the acute phase of myocardial infarction. They have been demonstrated to reduce major vascular events and progression of renal disease in diabetes with hypertension, compared to placebo and to calcium channel blockers. Current trials are evaluating their role in preventing major vascular events in patients with coronary artery disease, strokes and Type I1 diabetes who are normotensive.

INTRODUCTION

Angiotensin-converting enzyme (ACE) inhibitors inhibit angiotensin I1

generation and bradykinin degradation. Animal and human experimental

835

Copyright 0 1999 by Marcel Dekker, Inc. www.dekker.com

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836 YUSUF ET AL.

studies demonstrate that ACE-inhibitors are effective blood pressure-

lowering agents, that they reduce cardiac hypertrophy, favourably influence

ventricular remodelling following myocardial infarction, can lead to coronary

vasodilation and decrease sympathetic tone( 1). These multiple mechanisms

of action contribute to the benefits associated with the use of ACE-inhibitors

in hypertension, myocardial infarction, heart failure, diabetes and renal

disease. The main purpose of this article is to summarize the available

randomized trials of ACE-inhibitors in CV disease.

ACE-INHIBITORS IN HEART FAILURE. ASYMPTOMATIC LEFT

VENTRICULAR DYSFUNCTION AND MYOCARDIAL INFARCTION

WITH LOW EJECTION FRACTION

ACE-inhibitors have been clearly shown to decrease mortality and

hospitalizations for heart failure and acute ischemic events in patients with

symptomatic heart failure. Mortality benefits have been demonstrated in

patients with severe (2) and moderate symptoms (3). These findings are

supported by the results of a systematic overview of randomized trials of

ACE- inhibitors in patients with heart failure (4). This meta-analysis of 32

trials including 3870 patients with symptomatic heart failure randomized to

ACE- inhibitor therapy and 3235 controls reveals a 23% reduction in total

mortality and a 35% reduction in the combined end-point of mortality or

hospitalization for congestive heart failure in the ACE-inhibitor group.

Furthermore, similar benefits were observed with several different ACE-

inhibitors suggesting a functional class effect across various subgroups

defined by age, gender, etiology of heart failure and NYHA class.

Patients with asymptomatic left ventricular dysfunction were studied in

the SOLVD (Studies of Left Ventricular Dysfunction) prevention trial which

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RANDOMIZED TRIALS OF ACE-INHIBITORS 837

shows a trend towards a lower mortality among patients treated with enalapril

and a significant reduction in hospital admissions for congestive heart failure

(5). Trials in patients with recent myocardial infarction and moderate

reductions in left ventricular ejection fraction, including the SAVE (Survival

and Ventricular Enlargement Trial)(6), AIRE (Acute Infarction Ramipril

Efficacy Study)(7) and TRACE (Trandolapril Cardiac Evaluation Study

group)(8) trials, also demonstrate significant mortality benefits for patients

treated with ACE-inhibitors.

Therefore, the available data from the trials of ACE-inhibitors clearly

demonstrate that these agents reduce mortality and morbidity in patients with

compromised left ventricular function. A recent meta-analysis based on

individual patient data from SOLVD, SAVE, TRACE and AIRE on a total of

about 12,500 patients indicates that over a follow-up of about 4 to 5 years,

there is a 20% relative risk reduction in mortality (p<O.OOOO 1) and a 2 1 'YO

RRR for myocardial infarction (p<O.OOOl) (9). There was no impact on

stroke, but few patients had an elevated blood pressure. Subgroup analysis

confirmed that the benefits in preventing death, CHF hospitalization and

myocardial infarction were similar in men and women, those with or without

concomitant use of diuretics, aspirin or beta-blockers and those with a variety

of patient characteristics. However, the benefits were greatest among those

with the greatest impairment of left ventricular function (9).

Acute Mvocardial Infarction

A recent systematic overview, including almost 100,000 individual

patients' data from randomized trials of ACE-inhibitor treatment, started in

the acute phase of myocardial infarction and continued for a short time,

revealed a modest but statistically significant 7% proportional reduction in

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YUSUF ET AL. 838

30-day mortality among ACE-inhibitor allocated patients, representing

avoidance of about 5 deaths per 1000 patients treated and supporting the use

of ACE-inhibitors early in acute myocardial infarction( 10). The absolute

benefits appear to be larger in higher-risk patients such as those with anterior

infarction, sinus tachycardia, previous myocardial infarction, diabetes or

Killip class I1 and 111. Some controversy persists as to whether all patients

with acute myocardial infarction should receive ACE-inhibitor therapy, or

whether this treatment should be reserved for those at highest risk for adverse

outcomes, such as patients with large infarcts and early evidence of heart

failure. A reasonable approach would be to initiate ACE-inhibitors early in

the acute phase of myocardial infarction in all patients without contra-

indications for these agents and to withdraw treatment in lower-risk subsets at

about 6 weeks. In the high-risk subgroups of patients, treatment with an

ACE-inhibitor should be continued indefinitely.

Hyperte nsion

The use of ACE-inhibitors in the treatment of hypertension is also clearly

established as a single drug therapy or in combination with other agents, in

particular with diuretics. In general, the blood pressure reduction with ACE-

inhibitors is similar to that achieved with other agents. The recent Sixth

Report of the Joint National Committee on Prevention, Detection, Evaluation

and Treatment of High Blood Pressure lists use of ACE-inhibitors as the

preferred initial drug therapy in patients with hypertension in the presence of

heart failure, myocardial infarction with systolic dysfunction, type I diabetes

mellitus with proteinuria and renal insufficiency of other causes in the

absence of significant bilateral renal artery stenosis (1 1). These

recommendations are supported by the trials reviewed and by a number of

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RANDOMIZED TRIALS OF ACE-INHIBITORS 839

recent trials in diabetic nephropathy and other forms of renal disease. Lewis

et al. (1 2) studied 409 patients with insulin-dependent diabetes mellitus and

proteinuria (urinary protein excretion of 3500 ug.day) but no advanced renal

failure (serum creatinine 1221 umol.1) who were randomly allocated to

treatment with captopril or placebo. Captopril treatment significantly

retarded the rate of loss of renal function and was associated with a 50%

reduction in risk of the combined end-points of death, dialysis and

transplantation. This marked benefit appeared independent of the overall

small differences in blood pressure between the treatment groups. ACE-

inhibitor therapy was found to be protective against progression of renal

insufficiency also in patients with renal disease of diverse etiologies but in

the absence of diabetes and is recommended as preferred therapy in

hypertensive patients with renal disease (1 3). For type I1 diabetes mellitus

patients with proteinuria current recommendations suggest the use of ACE-

inhibitors is the therapy of choice. More recent evidence demonstrates

improved cardiovascular outcomes in these patients when treated with ACE-

inhibitors rather than with calcium channel antagonists. Thus, the FACET

study (Fosinopril Amlodipine Cardiovascular Events Trial) conducted in 3 80

hypertensives with non-insulin-dependent diabetes followed up to 3.5 years

reported a significantly lower risk of major cardiovascular events in those

treated with fosinopril as compared with those receiving amlodipine (RR =

0.49; 95% CI - 0.26-0.95, p=0.03) (14). Similarly, a recently reported

subgroup analysis of the ABCD (Appropriate Blood pressure Control in

Diabetes) trial indicated that the rates of fatal and nonfatal myocardial

infarction among those assigned nisoldipine (a calcium channel blocker) was

significantly higher than those assigned enalapril (RR=9.5, 95% CI of 2-3 -

2 1.4%) (1 5) . The recent GLANT study also indicated a trend towards a

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840 YUSUF ET AL.

higher rate of adverse events with a calcium channel blocker compared to an

ACE-inhibitor (1 6). It is not clear at present whether these differences

observed are real or due to selective reporting of trials that observed a

difference. Never the less, it would be prudent to use ACE-inhibitors in

preference to calcium channel blockers in patients with diabetes until the

results of future large, comparative trials such as ALLHAT (Antihypertensive

therapy and Lipid Lowering Heart Attack prevention Trial) are available. In

the CAPPP (Captopril Prevention Project) study, which compared

conventional therapy with a diureticbeta-blocker versus an ACE-inhibitor,

there was no overall differences in outcomes. However, the former regimen

was superior to the latter regimen in reducing strokes, although the latter was

superior to the former in reducing the development of diabetes and

macrovascular complications in this subgroup of patients (1 7). These data

are supported by the UK PDS (1 8), which recently demonstrated a clear

reduction of macrovascular and microvascular complications in patients with

diabetes with blood pressure lowering, which was similar with the two

antihypertensive regimen used (beta-blockers and ACE-inhibitors).

The Role Of ACE-Inhibitors In The Prevention Of Myocardial Infarction

The potential for ACE-inhibitors to prevent major acute ischemic events

has been brought into focus by the results of the SOLVD trials and the SAVE

study, which separately demonstrated a significant reduction in the incidence

of acute myocardial infarction in patients with documented cardiovascular

disease and low ejection fraction treated with ACE-inhibitors for

approximately 40 months (1 9,20). Pooled results of the SOLVD Treatment

trial, the SOLVD Prevention trial, SAVE, AIRE and TRACE indicate a 2 1 YO (95% CI, 11-29%; p=O.OOl) relative risk reduction (RRR) for myocardial

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RANDOMIZED TRIALS OF ACE-INHIBITORS 84 1

infarction associated with ACE-inhibitor therapy. In addition, other major

ischemic endpoints, specifically hospitalizations for unstable angina in the

combined SOLVD trials (RRR=20%; 95% CI, 9-29%, p=O.OOl) and

revascularization procedures in the SAVE trial ( m = 2 4 % , 95% CI, 6-39%;

p=0.014) were also significantly reduced in patients treated with enalapril and

captopril respectively.

PREVENTION OF DIABETIC COMPLICATIONS

There is a substantial amount of data that ACE-I reduce the degree of

microalbuminuria in patients with diabetes. This has been observed in

patients with Type I diabetes (see earlier reference to Lewis et d) where

patients with proteinuria had a substantially reduced rate of development of

endstage renal failure or death compared to an alternative regimen for BP

control. In Type I1 diabetes, a number of studies have demonstrated a

reduction in the degree of microalbuminuria. However, these studies have

not been designed to study either the reduction in development of diabetic

nephropathy among those with microalbuminuria in those diabetics without

microalbuminuria. Both hypotheses are being tested in the MICRO-HOPE

(Microalbuminuria, Cardiovascular and Renal Outcomes in the Heart

Outcomes Prevention Evaluation trial) (2 1) substudy of HOPE (Heart

Outcomes Prevention Evaluation trial). ACE-inhibitors have also been used

in patients with non-diabetic renal disease.

PREVENTION OF DIABETIC RETINOPATHY

In the EUCLID(EUROD1AB Controlled trial of Lisinopril in Insulin-

dependent Diabetes mel1itus)study , 1 59 patients were randomized to receive

ACE-inhibitors and 165 were randomized to controls (22). There was a 50%

reduction (p<0.02) in progression of diabetic retinopathy with ACE-

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842 YUSUF ET AL.

inhibitors, a 73% RRR in progression of retinopathy by two levels (p=0.05), a

large reduction in development of progression to proliferative retinopathy

(p=0.03). A similar benefit was observed among Type I1 diabetics in the UK

PDS.

CONCLUSIONS

ACE-inhibitors are currently well established and accepted agents in the

treatment of patients with heart failure, left ventricular dysfunction without

overt heart failure symptoms within the settings of recent myocardial

infarction or chronic ischemic cardiac disease, hypertension and acute

myocardial infarction. These drugs have also been clearly shown to reduce

the progression of renal disease in insulin-dependent diabetes mellitus with

proteinuria.

Promising information, supported by basic research, epidemiological and

genetic links, as well as by clinical trials in patients with low left ventricular

ejection fraction, indicate a potent new emerging important role for ACE-

inhibitors in reducing the risk for myocardial infarction and other major

ischemic events in a broader range of high-risk patients with preserved left

ventricular function. Ongoing clinical trials will clearly answer these

hypotheses over the next few years and will also provide insights into the

impact of prolonged ACE-inhibitor therapy on atherosclerosis progression.

Potentially, the findings of these clinical investigations will impact on a large

number of patients with coronary artery disease and could therefore have

important public health implications.

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RANDOMIZED TRIALS OF ACE-INHIBITORS 843

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