Composite Primary End Points in Cardiovascular Outcomes Trials Involving Type 2 Diabetes Patients: Should Unstable Angina Be Included in the Primary End Point?

Reductions in cardiovascular (CV) outcomes in recently reported trials, along with the recent approval by the U.S. Food and Drug Administration of an additional indication for empagliflozin to reduce the risk of CV death in type 2 diabetes patients with evidence of CV disease, have renewed interest in CV outcome trials (CVOTs) of glucose-lowering drugs. Composite end points are a pragmatic necessity in CVOTs to ensure that sample size and duration of follow-up remain reasonable. Combining clinical outcomes into a composite end point increases the numbers of events ascertained and thus statistical power and precision. Historically, composite CV end points in diabetes trials have included a larger number of components, while more recent CVOTs almost exclusively use a composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke—the so-called three-point major adverse CV event (3P-MACE) composite—or add hospitalization for unstable angina (HUA) to these three outcomes (4P-MACE). The inclusion of HUA increases the number of events for analysis, but noteworthy disadvantages include clinical subjectivity in ascertainment of HUA and its lower prognostic relevance compared with CV death, MI, or stroke. Furthermore, results from recent CVOTs indicate that glucose-lowering agents seem to have minimal impact on HUA. Its inclusion therefore potentially favors a shift of the hazard ratio (HR) toward the null, which is especially problematic in trials designed...

Source: Diabetes Care - August 22, 2017 Category: Endocrinology Authors: Marx, N.; McGuire, D. K.; Perkovic, V.; Woerle, H.-J.; Broedl, U. C.; von Eynatten, M.; George, J. T.; Rosenstock, J. Tags: Perspectives in Care Source Type: research