Use and Misuse of Surrogate Outcomes in Arrhythmia Trials

Abstract

Rigorous design and careful execution of clinical trials have led to major advances in cardiovascular medicine over the past few decades. A pivotal design feature of any trial is the choice of outcomes. We place great value on reduction of mortality and somewhat less on outcomes, such as myocardial infarction, that lead to major morbidity and death. Changes in quality of life and functional capacity are harder to measure but are clinically meaningful in many situations. On the other hand, surrogate outcomes have very low status in this hierarchy. These are outcomes that “stand in” for more clinically relevant outcomes. The key feature of a surrogate outcome is that unproven assumptions are necessary to connect a change in the surrogate to a change in the accepted clinical outcome. The problem of using surrogate outcomes has been highlighted by situations in which the assumptions have been subsequently discredited. In the early 1980s, on the basis of numerous studies that demonstrated an association between ventricular premature depolarization (VPD) frequency and mortality in post-myocardial infarction (MI) patients, VPD suppression became an accepted method for antiarrhythmic drug selection in clinical practice. Even though VPDs were usually asymptomatic, VPD suppression served as a primary outcome measure in clinical trials that resulted in regulatory approval of antiarrhythmic drugs.1 The underlying assumption that VPD suppression was associated with a reduction in mortality was totally upended when the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that several drugs, which were highly effective at VPD suppression, actually increased mortality after MI.2 Article p 776 It is not always possible or desirable to perform a full-scale trial with the most highly clinically relevant outcomes. Surrogate outcomes are particularly useful in the early stages of development of a new drug or device when the main goal is to prove a …