Alternative endpoints for mortality in studies of patients with atrial fibrillation: the AFFIRM study experience.

OBJECTIVES: The purpose of this study was to examine possible alternatives for death, particularly hospitalization for cardiovascular reasons (CV hospitalization), as an endpoint in studies of atrial fibrillation (AF) using the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) database.

BACKGROUND: AF is associated with increased mortality, but large numbers of patients are needed to demonstrate even a moderate effect of a therapy on mortality.

METHODS: AFFIRM studied 4,060 patients with AF, randomized to either rate-control or rhythm-control strategy with death as the primary endpoint.

RESULTS: Only CV hospitalization occurred more frequently than death. Like death, CV hospitalization was more frequent in the rhythm-control arm (46% vs 36%, P < .001) overall but not in a cohort that attempted to exclude those CV hospitalizations possibly related to treatment strategy (e.g., cardioversion, 24% vs 27%). In either model there was no interaction of CV hospitalization (analyzed as a time-dependent covariate) with treatment arm (P = .18 and P = .21, respectively). CV hospitalization was highly predictive of death in both treatment arms (P < .001) in either model, but after this event, there was no difference in time to death. A composite endpoint of CV hospitalization combined with death might increase power and reduce the size of trials of therapy for AF in such patients.

CONCLUSIONS: In patients with AF such as those in the AFFIRM study, CV hospitalization has many attributes of a surrogate for mortality. More research on CV hospitalization, alone or as part of a composite endpoint, is warranted.