Is Improved Survival a Class Effect of Angiotensin-Converting Enzyme Inhibitors?

Randomized trials have shown that several but not all angiotensin-converting enzyme (ACE) inhibitors, when given at specific doses, increase survival in specific populations of patients with heart disease. Whether improved survival is a “class effect” of ACE inhibitors is a question of considerable clinical interest, and one that motivated the study by Pilote and colleagues in this issue (1). Clearly the answer to this question is not yet known, since the requisite head-to-head randomized trials have not been done. Unfortunately, such trials are not likely to be imminent because of the enormous size and expense of comparative trials of survival benefits of cardiovascular agents. How, then, should clinicians select an ACE inhibitor for survival benefit?

One important component of the “class effect” question is whether the survival benefits of proven ACE inhibitors should be extrapolated to ACE inhibitors lacking such evidence. One might reasonably assume as a null hypothesis either that all ACE inhibitors confer approximately the same benefit unless proven otherwise or, conversely, that any given ACE inhibitor has no survival benefit unless proven otherwise. A major potential advantage of extrapolating survival benefits is that it permits clinicians to select from a wider range of drugs, thereby potentially reducing treatment costs, provided that the unproven treatment is in truth similarly effective. Resulting cost savings can then be used to address other societal concerns, including other health issues. The major disadvantage of extrapolating is that if the unproven agent is substantially less effective than proven agents, patients receiving the unproven ACE inhibitor will not derive optimal benefit.

McAlister and colleagues (2) have proposed a scheme of evidence levels for extrapolating drug effects within a pharmacologic class. In their scheme, level 1 evidence consists of head-to-head randomized trials of clinical outcomes. These have not been performed …