Validity of composite end points in clinical trials

Abstract

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? 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 caseConsider a 76 year old man who has disabling angina despite taking 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 myocardial infarction, and hospital admission for acute coronary syndrome) was much lower in the revascularisation group (25.5%) than in the medical management arm (64.2%; hazard ratio 0.31, 95% confidence interval 0.21 to 0.45).Although the overall result suggests invasive treatment would be beneficial, marked differences existed in the absolute reduction in risk across components (table 1). In the invasive group, five more patients died but there were six fewer myocardial infarctions and 78 fewer hospital admissions. How should you interpret these results and inform the patient? Evaluating composite end pointsClinicians can use three questions to help decide whether to base a clinical decision on the effect of treatment on a composite end point or on the component end points (box). We will not expand on statistical issues here, but box A on bmj.com gives a brief outline. Importance of individual components to patientsWhen all components of a composite end point are of equal importance to the patient, it will not be misleading to assume that the effect of the int...

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