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Randomized Clinical Trials Using a Hierarchical Composite Primary End Point: A Scoping Review
Selina Ehrenzeller1, Amos J de Jong2, Yonas Martin3
1CLEAR Methods Center, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
JAMA Network Open
|July 28, 2026
Summary
Hierarchical composite end points (HCEs) are increasingly used in randomized clinical trials (RCTs). However, their construction, analysis, and reporting methods lack standardization, necessitating development of new guidelines.
Area of Science:
- Clinical Trials Methodology
- Biostatistics
- Evidence Synthesis
Background:
- Hierarchical composite end points (HCEs) integrate multiple outcomes into a single measure for randomized clinical trials (RCTs).
- Their application as primary outcomes in RCTs has seen a notable increase.
- Understanding current practices in HCE construction, analysis, and reporting is crucial.
Purpose of the Study:
- To describe the frequency of HCEs used as primary outcomes in RCTs.
- To examine how these HCEs are constructed, analyzed, and reported.
- To identify trends and variations in HCE implementation.
Main Methods:
- A scoping systematic review was conducted, searching MEDLINE, Embase, CENTRAL, and Web of Science.
- Included RCTs used an HCE as their primary outcome, identified by self-declaration or specific analytical methods.
- Data on trial characteristics, endpoint composition, hierarchy justification, and analysis were extracted and summarized descriptively.
Main Results:
- 92 RCTs, involving over 79,000 participants, met the inclusion criteria.
- HCE use has surged, with 78.3% of trials starting recruitment in the last decade.
- Most HCEs comprised a median of 4 components, often prioritizing mortality, yet hierarchy justification was frequently unreported (82.2%).
- Generalized pairwise comparison was common (57.3%), but result presentation lacked standardization.
Conclusions:
- The use of HCEs in RCTs is expanding across various medical disciplines.
- Significant heterogeneity exists in HCE construction, analytical methods, and reporting practices.
- Further research and development of methodological and reporting standards for HCEs are essential.
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