Use and misuse of composite endpoints in randomised clinical trials

Area of Science:

• Cardiology
• Clinical Trials
• Biostatistics

Background:

• Composite endpoints are frequently used in cardiovascular outcome trials, often termed major adverse cardiovascular events (MACE).
• Their popularity stems from statistical efficiency and the ability to capture multiple outcomes.
• However, definitions lack consensus, and their use can obscure treatment effects.

Purpose of the Study:

• To critically review the definition, interpretation, use, and misuse of composite endpoints in cardiovascular trials.
• To discuss the methodological advantages and limitations of composite endpoints.
• To explore alternatives to composite endpoints and aid trialists and readers in critical evaluation.

Main Methods:

• Literature review of composite endpoints in cardiovascular trials.
• Analysis of key landmark and topical cardiovascular studies using composite endpoints.
• Discussion of statistical and clinical implications of composite endpoint design and reporting.

Main Results:

• Composite endpoints offer statistical efficiency but can be driven by less significant events or dilute treatment effects.
• Lack of consensus on MACE definitions impacts interpretation.
• Overlooked limitations can affect clinical practice-changing trial interpretations.

Conclusions:

• Critical understanding of composite endpoints is essential for accurate interpretation of cardiovascular trial results.
• Careful consideration of composite endpoint design, definition, and reporting is crucial for future trials.
• Exploring alternatives may provide clearer insights into treatment efficacy.