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 conceptualise a composite primary endpoint for parallel-group RCTs of exercise-based cardiac rehabilitation 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, both being directly related to reduced premature mortality in cardiac patients. Based on smallest detectable and minimal clinically important changes (change in exercise capacity of 15W and change in physical activity of 10 min/day), the composite endpoint combines two dichotomous endpoints (achieved/not achieved). To examine statistical efficiency, we compared sample size requirements based on the composite endpoint to single endpoints using data from two completed cardiac rehabilitation trials.

SETTING: Cardiac rehabilitation phase III PARTICIPANTS: Cardiac rehabilitation patients INTERVENTIONS: Not applicable MAIN OUTCOME MEASURE(S): Exercise capacity (Pmax assessed by incremental cycle ergometry) and physical activity (daily minutes of moderate to vigorous physical activity assessed by accelerometry) RESULTS: Expecting, e.g., a 10% between-group difference and improvement in the clinical outcome, the composite endpoint would require a sample size increase 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 composite endpoint would allow to reduce the sample size by up to 55% or 70%.

CONCLUSIONS: Trialists may consider the utility of the composite endpoint for future studies in exercise-based cardiac rehabilitation, which could reduce sample size requirements. However, perhaps surprisingly at first, the composite endpoint 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.