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. 2007 Apr 14;334(7597):786.
doi: 10.1136/bmj.39136.682083.AE. Epub 2007 Apr 2.

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

Ignacio Ferreira-González  1 , Jason W Busse, Diane Heels-Ansdell, Victor M Montori, Elie A Akl, Dianne M Bryant, Pablo Alonso-Coello, Jordi Alonso, Andrew Worster, Suneel Upadhye, Roman Jaeschke, Holger J Schünemann, Gaietà Permanyer-Miralda, Valeria Pacheco-Huergo, Antònia Domingo-Salvany, Ping Wu, Edward J Mills, Gordon H Guyatt
Affiliations

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

Ignacio Ferreira-González et al. BMJ. .

Abstract

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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Conflict of interest statement

Competing interests: None declared.

Figures

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Fig 1 Stages of systematic review of cardiovascular randomised controlled trials. CEP=composite end point; RCT=randomised controlled trial
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Fig 2 Variability in magnitude of the effect of intervention across categories of importance to patients
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Fig 3 Comparison of irbesartan with amlodipine in the diabetic nephropathy study
See this image and copyright information in PMC

Comment in

References

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    1. Montori VM, Permanyer-Miralda G, Ferreira-Gonzalez I, Busse JW, Pacheco-Huergo V, Bryant D, et al. Validity of composite end points in clinical trials. BMJ 2005;330:594-6. - PMC - PubMed
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