Hierarchical composite endpoints analyzed through pairwise comparisons more accurately reflect multifaceted treatment benefit than time-to-first-event composites, but transparent outcome prioritization, patient involvement in ranking, and reporting of Net Treatment Benefit remain underutilized despite their importance to interpretation.
For decades, many cardiovascular clinical trials were designed around mortality, from thrombolysis after myocardial infarction to ACE inhibitors in heart failure. When death rates were higher and treatment options more limited, reducing mortality was the clearest demonstration of clinical benefit. As death rates fell and background therapy improved, trials powered on mortality alone became impractically large, and composite endpoints combining death with nonfatal events became the standard.
