Combined endpoints: can we use them?

Abstract

Analysing specific non-fatal events in isolation may lead to spurious conclusions about efficacy unless the events considered are combined with all-cause mortality. The use of combined endpoints has therefore become widespread, at least in cardiovascular disease trials. Combining all-cause mortality with selected non-fatal events is useful because event-free survival, an important criterion in therapy evaluation, is addressed in this manner. In many clinical trials, symptoms, signs or paraclinical measures (for example, blood pressure, exercise duration, quality of life scores) are used as endpoints. If the patient died before the endpoint was measured, or it was otherwise not possible to perform follow-up assessments as planned, the effect of treatment on these endpoints may be distorted if the patients concerned are ignored in the analysis. Examples are given of how distortion can be avoided by including all patients randomized in an analysis that uses a ranked combined endpoint based both on clinical events and on paraclinical measures. A distinction is made between a pseudo intention-to-treat analysis that disregards study medication status at the time of endpoint assessment but is confined to patients with data, and a true intention-to-treat analysis that takes into account all patients randomized based on a ranked combined endpoint.