doi: 10.1161/01.CIR.0000090572.51900.92
(Circulation. 2003;108:2608.)
© 2003 American Heart Association, Inc.
Mini-Review: Expert Opinions |
Should Evidence-Based Proof of Drug Efficacy Be Extrapolated to a "Class of Agents"?
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
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Introduction |
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 Top Introduction The Scientific EvidenceUnder What Conditions Would...What Are the Clinical...What Are the Clinical...What Are the Potential...SummaryReferences |
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Clinicians are frequently faced with selecting a specific drug from within a pharmacological class of agents. A common illustration for cardiologists is the selection of an angiotensin-converting enzyme inhibitor (ACEI). Here, we summarize the scientific evidence for 3 of the 10 marketed ACEIs in the United States.1
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?
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The Scientific Evidence |
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All 10 marketed ACEIs have been approved by the US Food and Drug Administration (FDA) for the indication "hypertension" (Table).1,6 This approval means that they all lower elevated blood pressure. The indication for hypertension does not mean that they have been shown to reduce the cardiovascular complications of hypertension, that they convey health benefits to patients with congestive heart failure or vascular disease, or that the recommended dosages for the ACEIs are optimal or equipotent. The perindopril experience in the PROGRESS trial illustrates this point.
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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 these—fosinopril, lisinopril, and quinapril—were approved solely on the basis of their ability to improve hemodynamic measurements, exercise tolerance, or symptoms. Notably, the other 4—captopril, enalapril, ramipril, and trandolapril—have 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 agents—benazepril, fosinopril, and moexipril—have 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 agents—quinapril and perindopril—were 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 important—captopril (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 pressure–lowering 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 events—cerivastatin, 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.
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Under What Conditions Would an Extrapolation From a Proven to an Unproven Drug Be Appropriate? |
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Extrapolations are not accepted by regulatory agencies. In fact, FDA regulations do not allow manufacturers to make marketing claims for unapproved indications. This principle ought to be an incentive for drug manufacturers to conduct large, long-term trials. However, because the practice of medicine is not regulated, clinicians are free to use an approved drug for unapproved indications. Many forces, such as marketing and restricted formularies, represent challenges to the adoption of evidence-based medical practice. The class effect concept often has been overinterpreted to mean that all members of a drug class are interchangeable. What are the clinical advantages and disadvantages of the class effect concept?
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What Are the Clinical Advantages of the Class Effect Concept? |
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With more than 9500 drugs on the US market,9 it makes sense to group drugs into classes or families. Grouping simplifies medical education and clinical practice. Each drug class often is defined by a common mechanism of action. The pharmaceutical industry can freely develop and market late-arriving members of a class, the so-called "me-too" drugs. By forgoing long-term mortality/morbidity trials, a company can reduce the costs of drug development, invest in marketing, and offer the unproven drug inexpensively. Because of a smaller financial investment, it can successfully compete with the older and better-documented members on the basis of price. For many policymakers, lower drug cost is an important consideration.
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What Are the Clinical Disadvantages of the Class Effect Concept? |
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The term class effect has never been defined—scientifically, clinically, or from a regulatory perspective1—and this lack of a consensus definition has led to varying interpretations of the term. All drugs have multiple mechanisms of action (Figure). The common actions—favorable or unfavorable—define the class. The actions that are specific to an individual agent within a class may add to, subtract from, or have a neutral effect on the efficacy or safety attributed to the common class actions. Ignoring the not-in-common effects of any individual drug has the potential to be misleading. The mechanisms mediated through the inhibition of the ACE enzyme define the class of ACEIs. The failure of quinapril and perindopril to reduce events might be explained by differences in not-in-common actions. Thus, the sum of all actions of these 2 ACEIs may be different from the sum of actions of the 5 ACEIs with documented mortality/morbidity benefit.
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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 ACEIs—benazepril, fosinopril, moexipril, perindopril, and quinapril—we 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.
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What Are the Potential Solutions to the Class Effect Dilemma? |
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First, a good scientific/clinical definition of class effect is needed. Second, efforts should be made to increase the use of the best-documented drugs within any drug class. They should be prescribed in the full dose. In other words, better adherence to the FDA-approved indications, as detailed in the label/package insert, is highly recommended. Third, prescription of a me-too drug with incomplete documentation and unknown fully effective dosing ought to be restricted. Fourth, if pharmaceutical companies want to claim comparability, there should be more properly designed event trials comparing drugs of the same family to establish comparability.
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Summary |
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TopIntroductionThe Scientific EvidenceUnder What Conditions Would...What Are the Clinical...What Are the Clinical...What Are the Potential...SummaryReferences |
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- In general, extrapolation of mortality/morbidity benefits from a proven drug to an unproven drug should be avoided. The FDA-approved indications offer valuable guidance.
- Specifically, in the case of ACEIs, 5 members have published mortality/morbidity data, and their use is strongly recommended.
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).
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionThe Scientific EvidenceUnder What Conditions Would...What Are the Clinical...What Are the Clinical...What Are the Potential...SummaryReferences |
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- Furberg CD, Pitt B. Are all angiotensin-converting enzyme inhibitors interchangeable? J Am Coll Cardiol. 2001; 37: 1456–1460.
[Abstract/Free Full Text]
- 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.
[Abstract/Free Full Text]
- The 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.[Medline]
[Order article via Infotrieve]
- 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.[CrossRef][Medline]
[Order article via Infotrieve]
- 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.[CrossRef][Medline]
[Order article via Infotrieve]
- Furberg CD, Herrington DM, Psaty BM. Are drugs within a class interchangeable? Lancet. 1999; 354: 1202–1204.[CrossRef][Medline]
[Order article via Infotrieve]
- Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med. 1996; 334: 939–945.
[Abstract/Free Full Text]
- Luzier AB, Forrest A, Adelman M, et al. Impact of angiotensin-converting enzyme inhibitor underdosing on rehospitalization rates in congestive heart failure. Am J Cardiol. 1998; 82: 465–469.[CrossRef][Medline]
[Order article via Infotrieve]
- National Institute for Health Care Management, Research and Educational Foundation. Prescription Drug Expenditures in 2001: Another Year of Escalating Costs. Revised May 6, 2002. Available at: http://www.nihcm.org/spending2001.pdf. Accessed October 6, 2003.
- Fox KM; 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.[CrossRef][Medline]
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