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INTRODUCTION

This JAMA Guide to Statistics and Methods reviews the use of composite outcome measures in clinical trials and discusses how their use should influence interpretations of trial results.

There are many harmful manifestations of atherosclerotic cardiovascular disease (ASCVD). Because all of these manifestations are undesirable, combining the most important ones into a single study outcome measure can simplify efforts to measure the overall effect of the disease on health outcomes. For example, ASCVD can result in myocardial infarction (MI), stroke, or death. Each of these is to be avoided, and how well an intervention reduces the risk of any of these occurring can be measured by combining all of these clinical outcomes into a single composite end point. A composite end point is an outcome that is defined as occurring if 1 or more of the components occur. For ASCVD, one of the most common composites is called major adverse cardiovascular events (MACE). Because a composite outcome occurs more frequently than its individual components, composites can reduce the number of study participants required to achieve the desired power of a study, making it easier and less expensive to conduct a clinical trial.

A study by Kavousi et al1 demonstrates the benefits and limitations of composite outcomes. This study assessed the utility of coronary artery calcification (CAC) testing for estimating the probability of incident ASCVD in low-risk women using a composite end point that included nonfatal MI, coronary heart disease (CHD) death, and stroke. Overall, the authors found that CAC “was associated with an increased risk of ASCVD and modest improvement in prognostic accuracy compared with traditional risk factors.”1

WHY ARE COMPOSITE END POINTS USED IN CLINICAL STUDIES?

Composite end points may be used in a clinical trial (or in observational studies) if the target disease has several clinically important consequences and the study is intended to examine the effects (or association) of an intervention on (or exposure with) more than 1 consequence or end point. In this case, a composite end point provides a summary measure for the treatment effect. Composite end points, such as MACE, may also be used when a single outcome of interest (eg, CHD death in a low-risk population) is rare, making it impractical to conduct studies that are adequately powered to demonstrate an effect of an intervention on its occurrence.2 For rare outcomes, researchers often combine several types of events (CHD death, MI, and stroke) in a single composite end point. Because the frequency of the composite end point is greater than any of its components, this facilitates the design of studies of reasonable size and duration that have sufficient statistical power. If only 1 infrequent outcome were considered, such as CHD death, studies to determine the effect of an intervention on those outcomes could be unreasonably large or take too long to complete.

LIMITATIONS OF COMPOSITE END ...

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