VARIANCE AND DISSENT Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns Ignacio Ferreira-Gonza ´lez a,b , Gaieta ` Permanyer-Miralda a, * , Jason W. Busse c , Dianne M. Bryant d , Victor M. Montori e , Pablo Alonso-Coello f , Stephen D. Walter c , Gordon H. Guyatt c a Servei de Cardiologia, Unitat d’Epidemiologia, Hospital Universitari Vall d’Hebron, Barcelona 08035, Spain b Department of Internal Medicine, Universitat Auto`noma de Barcelona, Barcelona, Spain c Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada d Faculty of Health Sciences, The University of Western Ontario, London, Canada e Division of Endocrinology, Diabetes, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA f Iberoamerican Cochrane Centre, Department of Clinical Epidemiology and Public Health, Hospital de Sant Pau, Barcelona, Spain Accepted 25 October 2006 Abstract Objective: To investigate the rationale, potential problems and solutions of using composite endpoints (CEPs) for the assessment of intervention effects. Study Design and Setting: This study is a systematic review. We searched MEDLINE, EMBASE, and the Science Citation Index, for publications appearing between 1980 and September 2005, and reviewed potentially informative textbooks. Eligible articles provided a commentary, analysis, or discussion of CEPs for any of the following areas: (1) rationale, (2) interpretation or meaning, (3) advantages, (4) limitations or conceptual problems, and (5) recommendations for use. Results: Seventeen articles and one textbook proved eligible. Decreases in sample size requirements and ability to assess the net effect of an intervention were the most commonly cited advantages. Authors noted the risk of misinterpretation when heterogeneity among com- ponents with respect to either patient importance or magnitude of treatment effects as the most salient disadvantage. There were discrep- ancies between authors concerning the usefulness of CEPs to avoid bias from competing risks and when the direction of the effect of therapy differs across components. Conclusion: Methodologists have given limited attention to CEPs and their views are sometimes contradictory. Further work is needed to establish the role of CEPs in research and in guiding clinical practice. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Composite endpoints; Combined outcomes; Clinical trials; Outcomes; Endpoints; Overview 1. Introduction The primary endpoint of a clinical trial is the outcome defined by the research question of interest. This endpoint should ideally be important to patients, be amenable to un- biased assessment and potentially influenced by the treat- ment [1]. Investigators testing experimental treatments often wish to determine the effect of interventions on more than a single primary endpoint. This goal raises a number of challenges, including the requirement for a sample size large enough to draw strong conclusions about each of the relevant primary endpoints. Investigators may deal with this problem by combining multiple primary endpoints into a single composite\variable, or composite endpoint (CEP). CEPs are defined as the occurrence of any event from among a given set of events after a certain period of fol- low-up. Patients experiencing any of the events from the eligible set (the components) are considered to have expe- rienced the CEP of interest [2]. For instance, in a clinical trial that includes the CEP ‘‘death or nonfatal myocardial infarction or nonfatal stroke,’’ patients experiencing any of these three endpoints during the follow-up are consid- ered to have experienced the CEP. The efficacy of the ther- apy can then be assessed in two different ways: (1) comparing the total rate of patients experiencing the CEP in the treatment group with that of the control group; and * Corresponding author. Tel.: þ34-93-2746177; fax: þ34-93-2746063. E-mail address: gpermany@vhebron.net (G. Permanyer-Miralda). 0895-4356/07/$ e see front matter Ó 2007 Elsevier Inc. All rights reserved. doi: 10.1016/j.jclinepi.2006.10.020 Journal of Clinical Epidemiology 60 (2007) 651e657