Composite Outcomes in Cardiovascular Research: A Survey of Randomized Trials

4 November 2008 | Volume 149 Issue 9 | Pages 612-617

Background: Composite end points are common in clinical trials.

Objective: To describe how composite outcomes are used, constructed, and reported in cardiovascular trials and to evaluate the contribution of individual end points to the composite estimate of effect in those trials.

Design: Review of 2-group, parallel-design, randomized cardiovascular trials that used composite end points and were published in 14 clinical journals from 1 January 2000 to 1 January 2007.

Setting: Published randomized trials in cardiovascular medicine and surgery.

Participants: Two-group, parallel-design trials published in 14 leading general medical, cardiology, and cardiothoracic surgery journals from 1 January 2000 to 1 January 2007.

Measurements: The types and numbers of individual events included in the composite outcome and P values and risk estimates for the composite outcome.

Results: Of 304 trials published that used composite outcomes, 221 (73%) reported a composite primary outcome and 83 (27%) reported a composite secondary outcome. Composite outcomes comprised a median of 3 (interquartile range, 3 to 4) individual outcomes; death was the most common individual outcome. The total number of individual events and the total number of events represented by the composite outcome differed in 79% of trials. P values for composite outcomes were less than 0.050 more frequently than they were 0.050 or greater. Death as an individual end point made a relatively minimal contribution to estimates of effect summarized by the trials' composite end points, whereas revascularization made a greater contribution.

Limitation: All-cause and cardiovascular mortality were not distinguished, and the findings might not apply to trials in other fields.

Conclusion: Composite outcomes in cardiovascular trials are frequent and commonly comprise 3 to 4 individual end points that vary in clinical significance. Discrepancies between the total number of individual events in a trial and those reported for composite outcomes are common. Individual outcomes do not contribute equally to composite measures, so the overall estimate of effect for a composite measure cannot be assumed to apply equally to each of its individual outcomes.

Editors' Notes Context Many trials combine several events into a single composite outcome when reporting the effect of an intervention. Contribution Of cardiovascular trials published over 7 years, 37% used composite outcomes. The individual events making up the composite differed in their clinical significance and in their influence on the composite estimate of effect. Caution The findings may not apply to trials in other specialties. Implication Composite outcomes are used commonly in cardiovascular trials and rely on end points that vary in their clinical significance. The overall estimate of effect for a composite measure cannot be assumed to apply equally to each individual outcome. The Editors

 

Author and Article Information

From Papworth Hospital and Addenbrooke's Hospital, Cambridge, and the Centre for Statistics in Medicine, Oxford, United Kingdom.

Potential Financial Conflicts of Interest: None disclosed.

Reproducible Research Statement: Study protocol: Not available. Statistical code: Available from Dr. Lim (e-mail, e.lim{at}rbht.nhs.uk). Data set: Available subject to approval by the study committees by contacting Dr. Lim (e-mail, e.lim{at}rbht.nhs.uk).

Requests for Single Reprints: Eric Lim, MBChB, MSc, MD, Imperial College and Academic Division of Thoracic Surgery, Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom; e-mail, e.lim{at}rbht.nhs.uk.

Current Author Addresses: Dr. Lim: Imperial College and Academic Division of Thoracic Surgery, Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom.

Drs. Brown and Helmy and Mr. Mussa: Department of Cardiothoracic Surgery, Papworth Hospital, Papworth Everard, Cambridge CB23 8RE, United Kingdom.

Dr. Altman: Centre for Statistics in Medicine, Wolfson College Annexe, Linton Road, Oxford OX2 6UD, United Kingdom.

Author Contributions: Conception and design: E. Lim.

Analysis and interpretation of the data: E. Lim, D.G. Altman.

Drafting of the article: E. Lim, A. Helmy, S. Mussa, D.G. Altman.

Critical revision of the article for important intellectual content: E. Lim, A. Helmy, S. Mussa, D.G. Altman.

Final approval of the article: E. Lim, A. Helmy, S. Mussa, D.G. Altman.

Statistical expertise: E. Lim, D.G. Altman.

Administrative, technical, or logistic support: A. Helmy, S. Mussa.

Collection and assembly of data: E. Lim, A. Brown, A. Helmy, S. Mussa.

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