Composite Endpoints in Contemporary Cardiovascular Trials: Trends in Phase 3 Trials and Key Issues in Regulatory Review

Abstract

Interpreting composite endpoints in cardiovascular drug development is a key challenge, particularly when events of different clinical relevance are combined into a single primary outcome. Previous reviews noted that conventional composite endpoints may mask clinically meaningful differences at the individual component level and be mainly driven by less clinically important “soft” events, raising concerns about how overall treatment effects should be understood. Despite these concerns, information remains limited on how composite endpoints are used in current cardiovascular drug development programs and how their interpretation influences regulatory decision-making. Thus, we conducted a descriptive review of cardiovascular phase III trial publications and ClinicalTrials.gov registries (2015–2024) that specified a composite primary endpoint and identified 173 trials. Hard endpoints such as death remain common; however, the range of events included in composite endpoints has increased in recent years. The examination of regulatory evaluations of composite endpoints in new drug applications for cardiovascular diseases—including chronic heart failure, transthyretin amyloid cardiomyopathy, and cardiovascular conditions requiring antithrombotic therapy—in Japan, the United States, and the European Union revealed that regulatory agencies consistently raised concerns across regions regarding differences in clinical importance among components and the interpretability of composite results. These findings highlight the need to consider differences in clinical importance among components and carefully interpret the composite endpoint results in the context of individual component outcomes, both in trial design and evaluation.