Education And Debate

Validity of composite end points in clinical trials

BMJ 2005; 330 doi: http://dx.doi.org/10.1136/bmj.330.7491.594 (Published 10 March 2005) Cite this as: BMJ 2005;330:594
  1. Victor M Montori, assistant professor1,
  2. Gaietà Permanyer-Miralda, senior consultant (gpermany@vhebron.net)2,
  3. Ignacio Ferreira-González, research fellow3,
  4. Jason W Busse, research associate4,
  5. Valeria Pacheco-Huergo, general practitioner6,
  6. Dianne Bryant, instructor4,
  7. Jordi Alonso, head7,
  8. Elie A Akl, research assistant professor8,
  9. Antònia Domingo-Salvany, senior scientist7,
  10. Edward Mills, director of research9,
  11. Ping Wu, research assistant9,
  12. Holger J Schünemann, associate professor8,
  13. Roman Jaeschke, clinical professor5,
  14. Gordon H Guyatt, professor4
  1. 1 Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
  2. 2 Cardiology Service, Epidemiology Unit, Hospital General Vall d'Hebron, Barcelona 08035, Spain
  3. 3 Department de Medicina, Universitat Autònoma de Barcelona, Hospital General Vall d'Hebron
  4. 4 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON L8N 3Z5, Canada
  5. 5 Department of Medicine, McMaster University
  6. 6 Primary Care Centre TurÓ, EAP Vilapicina, Institut Català de la Salut, Barcelona, Spain
  7. 7 Health Services Research Unit, Institut Municipal d'InvestigaciÓ Mèdica, Barcelona, Spain
  8. 8 Department of Medicine and of Social and Preventive Medicine, University at Buffalo, Buffalo, NY 14214, USA
  9. 9 Department of Research, Canadian College of Naturopathic Medicine, Toronto, Canada M2K 1E2
  1. Correspondence to: G Permanyer-Miralda
  • Accepted 10 January 2005

Use of composite end points as the main outcome in randomised trials can hide wide differences in the individual measures. How should you apply the results to clinical practice?

Introduction

Improvements in medical care over the past two decades have decreased the frequency with which patients with common conditions such as myocardial infarction develop subsequent adverse events. Although welcome for patients, low event rates provide challenges for clinical investigators, who consequently require large sample sizes and long follow up to test the incremental benefits of new treatments. Clinical trialists have responded to these challenges by relying increasingly on composite end points, which capture the number of patients experiencing any one of several adverse events—for example, death, myocardial infarction, or hospital admission.1

Use of composite end points is usually justified by the assumption that the effect on each of the components will be similar and that patients will attach similar importance to each component.1 But this is not always the case. In this article we provide a strategy to interpret the results of clinical trials when investigators measure the effect of treatment on an aggregate of end points of varying importance.

Example case

Consider a 76 year old man who has disabling angina despite taking β blockers, nitrates, aspirin, an angiotensin converting enzyme inhibitor, and a statin. His doctor suggests cardiac catheterisation and possible revascularisation. The patient is reluctant to have invasive management, and wonders how much benefit he might expect from surgery.

The trial of invasive versus medical therapy in elderly patients (TIME) is relevant.2 The study randomised 301 patients aged 75 years or older with resistant angina to optimised drug treatment or cardiac catheterisation and possible revascularisation. Although the groups showed no difference in quality of life at 12 months, the frequency of a composite end point (death, non-fatal …

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