BMJ  2007;334:786 (14 April), doi:10.1136/bmj.39136.682083.AE (published 2 April 2007)

Research

Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials

¹ Departament de Medicina, Universitat Autònoma de Barcelona, and Hospital Vall d'Hebron, Barcelona 08035, Spain, ² Cardiology Service, Epidemiology Unit, Hospital General Vall d'Hebron, ³ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada L8N 3Z5, ⁴ Department of Medicine, McMaster University, ⁵ Knowledge and Encounter Research Unit, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA, ⁶ Department of Medicine and of Social and Preventive Medicine, University at Buffalo, Buffalo, New York 14214, USA, ⁷ Unit of Clinical Research Development and INFORMAtion Translation/CLARITY Research Team, Department of Epidemiology, Italian National Cancer Institute Regina Elena, Rome 00144, Italy, ⁸ Faculty of Health Sciences, University of Western Ontario, Elborn College, London, ON, Canada N6G 1H1, ⁹ Iberoamerican Cochrane Centre, Department of Clinical Epidemiology and Public Health, Hospital de Sant Pau, Barcelona 08041, ¹⁰ Health Services Research Unit, Institut Municipal d'Investigació Médica (IMIM-hospital del mar), Barcelona E-08003, ¹¹ College of Naturopathic Medicine, Toronto, ON, Canada M2K 1E2, ¹² Global Health, Simon Fraser University, Vancouver, BC, Canada V5A 1S6

Objective To explore the extent to which components of composite end points in randomised controlled trials vary in importance to patients, the frequency of events in the more and less important components, and the extent of variability in the relative risk reductions across components.

Design Systematic review of randomised controlled trials.

Data sources Cardiovascular randomised controlled trials published in the Lancet, Annals of Internal Medicine, Circulation, European Heart Journal, JAMA, and New England Journal of Medicine, from 1 January 2002 to 30 June 2003. Component end points of composite end points were categorised according to importance to patients as fatal, critical, major, moderate, or minor.

Results Of 114 identified randomised controlled trials that included a composite end point of importance to patients, 68% (n=77) reported complete component data for the primary composite end point; almost all (98%; n=112) primary composite end points included a fatal end point. Of 84 composite end points for which component data were available, 54% (n=45) showed large or moderate gradients in both importance to patients and magnitude of effect across components. When analysed by categories of importance to patients, the most important components were associated with lower event rates in the control group (medians of 3.3-3.7% for fatal, critical, and major outcomes; 12.3% for moderate outcomes; and 8.0% for minor outcomes). Components of greater importance to patients were associated with smaller treatment effects than less important ones (relative risk reduction of 8% for death and 33% for components of minor importance to patients).

Conclusion The use of composite end points in cardiovascular trials is frequently complicated by large gradients in importance to patients and in magnitude of the effect of treatment across component end points. Higher event rates and larger treatment effects associated with less important components may result in misleading impressions of the impact of treatment.

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