Applying Exercise Capacity and Physical Activity as Single vs Composite Endpoints for Trials of Cardiac Rehabilitation Interventions: Rationale, Use-case, and a Blueprint Method for Sample Size Calculation.

Objective: To conceptualize a composite primary endpoint for parallel-group RCTs of exercise-based cardiac rehabilitation (CR) interventions and to explore its application and statistical efficiency.

Design: We conducted a statistical exploration of sample size requirements. We combined exercise capacity and physical activity for the composite endpoint (CE), both being directly related to reduced premature mortality in patients with cardiac diseases. Based on smallest detectable and minimal clinically important changes (change in exercise capacity of 15 W and change in physical activity of 10 min/day), the CE combines 2 dichotomous endpoints (achieved/not achieved). To examine statistical efficiency, we compared sample size requirements based on the CE to single endpoints using data from 2 completed CR trials.

Setting: Cardiac rehabilitation phase III.

Participants: Patients in cardiac rehabilitation.

Interventions: Not applicable.

Main Outcome Measure(s): Exercise capacity (P assessed by incremental cycle ergometry) and physical activity (daily minutes of moderate to vigorous physical activity assessed by accelerometry).

Results: Expecting, for example, a 10% between-group difference and improvement in the clinical outcome, the CE would increase sample size by up to 21% or 61%, depending on the dataset. When expecting a 10% difference and designing an intervention with the aim of non-deterioration, the CE would allow to reduce the sample size by up to 55% or 70%.

Conclusions: Trialists may consider the utility of the CE for future studies in exercise-based CR to reduce sample size requirements. However, perhaps surprisingly at first, the CE could also lead to an increased sample size needed, depending on the observed baseline proportions in the trial population and the aim of the intervention.