Clin. Cardiol. Vol. 23 (Suppl. IV), IV-15–IV-19 (2000)

Class Effects and Evidence-Based Medicine

Curt D. Furberg, M.D., Ph.D.

Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

Summary: Drugs grouped into a therapeutic class on the basis of a common mechanism of action often have considerably different pharmacodynamic and pharmacokinetic properties. Among angiotensin-converting enzyme (ACE) inhibitors, differences with potential clinical relevance include potency, whether the drug is an active compound or requires metabolic activation, lipophilicity, route(s) of elimination, and half-life. Large clinical trials have documented the clinical benefits of several ACE inhibitors in various patient populations, and many clinical effects of ACE inhibitors are likely to be the same. However, there are possible quantitative differences among ACE inhibitors that may alter the overall therapeutic benefits for specific patient populations and indications. Equipotency in terms of clinical efficacy is difficult to determine. Since the concept of "class effect" is a term of convenience that has no universally accepted definition and subsequently should not form the basis for the practice of evidence-based medicine, untested drugs of a "class" should be considered to be unproven drugs.

Key words: angiotensin-converting enzyme inhibitor, pharmacokinetic, pharmacodynamic, cardiovascular morbidity and mortality, Heart Outcomes Prevention Evaluation study, lipophilicity

Introduction

"Class effect" is a concept that has gained widespread use in the recent decades. Third-party payers and institutions with formulary systems rely on it to control drug expenditure by limiting the number of drugs from a specific therapeutic class that can be prescribed for patients and/or reimbursed by the payer. While the driving force is often cost, the underlying premise is that compelling findings from large clinical trials of one member of a therapeutic class are applicable to all other members of the same class.

There is, however, no standard definition of "class effect." Instead, a related term, "class labeling," is used by the Food and Drug Administration (FDA). Class labeling "assumes that all products within a class are closely related in chemical structure, pharmacology, therapeutic activity, and adverse reactions." Two important caveats inherent in this definition are that the drugs are assumed, but not necessarily shown, to be closely related, and that the characteristics of the drugs that confer their close relation(s) are not defined. Two sets of criteria are used to determine class effect: the regulatory criteria used by the FDA to determine class labeling, and the pragmatic clinical criteria, the latter being concerned with therapeutic benefit, long-term safety, cost, and comparative efficacy among members of a class.

The recently published Heart Outcomes Prevention Evaluation (HOPE) study on ramipril¹ (10 mg once daily) raised anew the question of class effects for angiotensin-converting enzyme (ACE) inhibitors. While there are pharmacologic similarities among ACE inhibitors, there are also salient differences. By definition, all ACE inhibitors inhibit the conversion of the relatively inactive angiotensin I to the active metabolite angiotensin II.² But within the group, specific drugs are approved for the treatment of hypertension, heart failure, myocardial infarction, asymptomatic left ventricular dysfunction, and diabetic nephropathy.

Chemical Structure

All ACE inhibitors share an important feature--the bind-ing of the functional group to the zinc component of the ACE active site³--and it is this commonality that divides the class into its three subgroups: the sulfhydryl-containing ACE inhibitors for which captopril is the prototype; the carboxyl- or dicarboxyl-containing ACE inhibitors, which is the largest group of ACE inhibitors and for which enalapril and ramipril are representative members; and the phosphorous-containing or phosphinyl ACE inhibitors, which are structurally related to fosinopril (Fig. 1).^2–4

Fig. 1 Chemical structures of angiotensin-converting enzyme (ACE) inhibitors according to functional group.

In general, the overall benefit of a drug is determined by the sum of its desired and untoward (adverse) effects. Experience with other classes of agents such as nonsteroidal anti-inflammatory drugs has shown that while efficacy among members of a class tend to be similar, there can be marked differences in safety. Notably, small differences in chemical structure may sometimes produce profound pharmacologic differences.

Pharmacology and Pharmacokinetics

Pharmacologic differences among ACE inhibitors include variations in potency.^2–4 The potency of an ACE inhibitor relates to the affinity of the functional group for the zinc component as well as a number of additional binding sites on ACE. Another pharmacologic difference among ACE inhibitors is whether ACE inhibition is a result of the drug itself or dependent on conversion from a prodrug to an active metabolite.^2–4 Only captopril and lisinopril are active drugs that do not require hepatic activation; all other ACE inhibitors are prodrugs. Conversion from the prodrug to the active metabolite may be delayed or incomplete in patients with severe hepatic dysfunction.

There are also differences in the pharmacokinetics of ACE inhibitors (Table I),⁴ which affect their dosing schedule. Drug lipophilicity is a physico-chemical characteristic that not only influences pharmacokinetics, but indicates the extent of drug tissue penetration. For ACE inhibitors, greater drug lipophilicity correlates with greater inhibition of tissue ACE in animal and ex vivo studies.⁵ However, differences in lipophilicity have not yet been shown to be associated with differences in clinical effects.^{3, 4} Differences in lipophilicity and the inhibition of tissue ACE may be clinically relevant.

The route of elimination for ACE inhibitors is also of potential clinical relevance. Since most ACE inhibitors are excreted predominantly by the kidneys, plasma clearance and elimination is diminished in patients with impaired renal function, thereby requiring a reduction in dose. There are, however, exceptions: fosinopril and spirapril have balanced renal/hepatic elimination, trandolapril has a renal-hepatic elimination ratio of 30 to 70, and ramipril has a renal-hepatic elimination ratio of 70 to 30.^2–4 The duration of action of a drug determines dosing frequency; drugs with a longer duration of action require fewer daily doses. All ACE inhibitors except captopril can be dosed once daily,⁴ which generally improves patient compliance.

Clinical Trial Data

Several ACE inhibitors have been shown to reduce the risk of cardiovascular morbidity and mortality in patients with cardiovascular disease.² They are currently indicated for the treatment of patients with hypertension, particularly those with diabetes, and postinfarction patients with left ventricular dysfunction or congestive heart failure. However, none of the commercially available ACE inhibitors have been studied in all of these patient populations in large clinical trials (Table II).^{1, 6–22} The magnitude of the benefit demonstrated with each ACE inhibitor varies among trials. In patients with congestive heart failure or left ventricular dysfunction, the reduction in all-cause mortality with ACE inhibitor treatment ranged from 8% with enalapril⁹ to 27% with ramipril,²⁰ while the risk reduction for myocardial infarction ranged from 11% with ramipril²⁰ to 25% for captopril.⁶ Studies in patients with coronary heart disease have shown similar variability: from no effect on disease progression and cardiovascular events with quinapril¹⁹ to a significant 25% reduction (p = 0.0004) with ramipril in a composite endpoint of myocardial infarction, stroke, and death from cardiovascular causes.¹

Such findings ostensibly suggest that ACE inhibitors cannot be assumed to be equivalent with respect to clinical effects. However, it is difficult to compare studies since there are differences not only in the drugs themselves and their dosages, but also in study populations, study design, outcome measures, concomitant therapy, and other variables. Direct comparative trials with various ACE inhibitors are necessary to determine whether they indeed have equivalent clinical effects. Until such studies are done, physicians should not assume that all members of the ACE inhibitor class are equivalent in terms of benefits. Another issue relates to dosing. Should we really assume that short-term changes in blood pressure are reliable determinants of the optimal drug dose for treatment of congestive heart failure?

Although the ability of ACE inhibitors to reduce the risk of chronic heart failure is largely a class effect, the optimal dose for each ACE inhibitor that will effectively reduce mortality and morbidity remains unknown.²³ The importance of a correct dose was demonstrated in a study that evaluated the risk of hospital readmission within 90 days for patients with heart failure.²⁴ The strongest predictor of readmission was not being prescribed an ACE inhibitor, and the second strongest predictor was an inadequate dose of an ACE inhibitor (Fig. 2). Increasing doses of an ACE inhibitor were associated with impressively lower readmission rates for patients with heart failure. Dose-response trials are needed to determine optimal dosing.

Fig. 2 Relative risk (RR) of hospital readmission for heart failure with respective 95% confidence intervals as a function of ACE inhibitor dose received expressed as mg of enalapril. Reprinted from the American Journal of Cardiology 1998; 82: 465–469 with permission from Excerpta Medica Inc.

In the United States, a drug has to be more effective than placebo to be approved. Newer compounds from the same therapeutic class typically need less stringent documentation for regulatory approval. Currently, 10 ACE inhibitors are approved for use in the United States. The approval of the most recently marketed ACE inhibitor, perindopril, was based on its ability, in two separate trials, to lower blood pressure in more than 350 patients with mild-to-moderate hypertension.^{25, 26} By mere inference to the major clinical trials of ACE inhibitors (Table II), perindopril and other less tested ACE inhibitors may, if the price is right, be selected by third-party payers and formulary committees as the ACE inhibitor of choice. However, comparative clinical trials that establish equipotent doses of ACE inhibitors for each indication ought to be required prior to marketing.

Conclusions

The health effects of a drug are determined by its favorable and unfavorable actions. The concept of class effect is a convenient term, but has no universally accepted definition. While it is useful to group drugs on the basis of chemical structure and common mechanisms of action, drugs within a therapeutic class may also have substantially different pharmacologic properties. These pharmacologic differences among ACE inhibitors of potential clinical relevance include potency of tissue ACE inhibition, lipophilicity, and adverse events associated with specific chemical structures. Pharmacokinetic differences include whether a drug is an active compound or a prodrug requiring conversion to an active metabolite, route(s) of elimination, and half-life. While large clinical trials that document the clinical effects of all ACE inhibitors for every indication have not yet been done, the qualitative clinical effects of ACE inhibitors are likely to be similar: reductions in the overall risk of cardiovascular disease as well as in cardiovascular morbidity and mortality in patients with established disease. However, there are likely to be quantitative differences because equipotent or optimal doses of ACE inhibitors that are of therapeutic benefit in the various indications are unknown.

Untested drugs with respect to morbidity and mortality outcomes should be considered unproven drugs. The practice of medicine, including third-party payer and formulary committee decisions, should be evidence based; the decision to prescribe specific drugs at given doses should be based on clinical trial experience. Thus, the results of the HOPE study with its unique population and findings of other important clinical trials, although impressive, should not be extended to the ACE inhibitors that have not been shown to reduce cardiovascular morbidity and mortality.

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Supported by a grant from Monarch Pharmaceuticals.

Address for reprints:
Curt D. Furberg, M.D., Ph.D.
Director of the Office of Academic Program Development
Wake Forest University School of Medicine
Medical Center Boulevard
Winston Salem, NC 27157-1063, USA