(Circulation. 2003;108:2608.)
© 2003 American Heart Association, Inc.
Mini-Review: Expert Opinions |
From the Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (C.D.F.), and the Cardiovascular Health Research Unit, Department of Medicine, Epidemiology, and Health Sciences, University of Washington, Seattle, Wash (B.M.P.).
Correspondence to Curt D. Furberg, MD, PhD, Department of Public Health Sciences, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1063. E-mail cfurberg{at}wfubmc.edu
| Introduction |
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The placebo-controlled Heart Outcome Prevention Evaluation (HOPE) trial2 documented that ramipril (10 mg/d) reduced the risk of all-cause mortality (-16%), acute myocardial infarction (MI) (-20%), and stroke (-32%) in patients with evidence of vascular disease or diabetes plus one cardiovascular risk factor. In another placebo-controlled trial, Acute Infarction Ramipril Efficacy (AIRE), ramipril in the same daily dose reduced all-cause mortality by 27% in survivors of acute MI with clinical evidence of heart failure.3
The clinical trial experience with 2 other ACEIs is different. Compared with placebo, quinapril in the recommended dose of 20 mg daily had no effect on the risk of cardiac ischemic events in a 3-year trial of 1750 patients after angioplasty.4 Perindopril in the recommended dose of 4 mg/d lowered systolic and diastolic blood pressure by just 4.9/2.8 mm Hg compared with placebo in patients with a history of cerebrovascular disease in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),5 and it had no significant effect on the risk of stroke or coronary events.
On the basis of this clinical trial evidence, would it be appropriate to conclude that quinapril and perindopril in their approved and recommended doses are interchangeable with 10 mg of ramipril? What about the other 7 ACEIs on the US market?
| The Scientific Evidence |
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Seven of the ACEIs also have been approved for the indication of heart failure or left ventricular dysfunction/heart failure after infarction (Table). Three of thesefosinopril, lisinopril, and quinaprilwere approved solely on the basis of their ability to improve hemodynamic measurements, exercise tolerance, or symptoms. Notably, the other 4captopril, enalapril, ramipril, and trandolaprilhave also improved long-term survival or clinical outcomes compared with placebo in large randomized clinical trials, as indicated in the labeling. Ramipril has the broadest FDA approval, which includes reduction in risk for MI, stroke, and death from cardiovascular causes.1
Five ACEIs have not been shown to reduce mortality/morbidity for any indication.1 Three of these agentsbenazepril, fosinopril, and moexiprilhave not been tested in large, long-term trials for a mortality/morbidity benefit. In a small placebo-controlled trial of benazepril in patients with various renal diseases, 8 of the 9 deaths occurred in the benazepril group.7 The remaining 2 agentsquinapril and perindoprilwere tested in their FDA-approved dosages and failed to show a reduction in clinical events. One possible explanation for the failure to reduce events could be that the recommended doses were too low. Because effective doses for event reduction can be determined only in large, long-term outcome trials, new trials are needed to test that hypothesis.
The observed benefit of ramipril applies to the daily dose of 10 mg. One can reasonably assume that the outcome of HOPE might well have been different if the trial dose had been 5 or 2.5 mg/d. A strong dose-response relationship between enalapril and rehospitalization within 3 months of admission for congestive heart failure has been reported.8 Thus, prescribing the full daily dose of a documented drug is importantcaptopril (150 mg), enalapril (40 mg), lisinopril (40 mg), ramipril (10 mg), and trandolapril (4 mg).
In the absence of comparative mortality/morbidity data, any judgment of equipotency has to rely on a surrogate measure of efficacy. For the class of ACEIs, we are limited to the blood pressurelowering effects. There is good evidence to suggest that the event reduction with ACEIs in patients with heart failure or acute MI may be independent of blood pressure reduction. Therefore, it is difficult to estimate the dose of an unproven ACEI that, if effective, would prevent morbidity and mortality.
Drug safety is an additional consideration. Unfortunately, there are few reliable surrogates for long-term drug safety. Small and short-term trials conducted to document surrogate efficacy and to obtain regulatory approval are inadequate for evaluation of long-term safety. There are many examples of cardiovascular drugs that were approved on the basis of surrogate efficacy and subsequently withdrawn because of serious adverse eventscerivastatin, troglitazone, encainide, and mibefradil.
In short, solid scientific evidence of mortality/morbidity benefit, symptomatic relief, and long-term safety is available for 5 of the 10 ACEIs currently marketed in the United States.
| Under What Conditions Would an Extrapolation From a Proven to an Unproven Drug Be Appropriate? |
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| What Are the Clinical Advantages of the Class Effect Concept? |
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| What Are the Clinical Disadvantages of the Class Effect Concept? |
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The other major issue is equipotency, which is difficult to establish in the absence of relevant outcome data. For the unproven ACEIsbenazepril, fosinopril, moexipril, perindopril, and quinaprilwe do not know the clinically optimal daily dosages. This dilemma is illustrated by the quinapril and perindopril experience (see above). Dose selection becomes hypothesis based rather than evidence based.
| What Are the Potential Solutions to the Class Effect Dilemma? |
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| Summary |
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Addendum
The results of the EUROPA study (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease)10 underscore the critical role of ACEI dosing. In EUROPA, perindopril (8 mg/d) reduced major coronary heart disease mortality and morbidity by 20%, which is in sharp contrast to the lack of health benefit of perindopril (4 mg/d) in PROGRESS. This also illustrates the fallacy of basing regulatory recommendations about drug dose on a surrogate outcome (blood pressure lowering).
| Footnotes |
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| References |
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