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Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials
Ignacio Ferreira-González1, Jason W Busse, Diane Heels-Ansdell
1Departament de Medicina, Universitat Autònoma de Barcelona, and Hospital Vall d'Hebron, Barcelona 08035, Spain.
Insights
Composite end points in cardiovascular trials often have components varying in patient importance and treatment effect. Less important components may show larger effects, potentially misrepresenting treatment impact.
Area of Science:
- Cardiovascular Medicine
- Clinical Trial Design
- Health Outcomes Research
Background:
- Composite end points are frequently used in randomized controlled trials (RCTs) to assess treatment efficacy.
- The relative importance of individual components within composite end points to patients is often not clearly defined.
- Variability in event rates and treatment effects across components can influence the interpretation of trial results.
Purpose of the Study:
- To investigate the variation in patient importance across components of composite end points in cardiovascular RCTs.
- To examine the frequency of events and relative risk reductions for different component categories.
- To assess the impact of component variability on the interpretation of treatment effects.
Main Methods:
- Systematic review of cardiovascular RCTs published in major medical journals between January 2002 and June 2003.
- Categorization of composite end point components based on patient importance (fatal, critical, major, moderate, minor).
- Analysis of event rates and relative risk reductions across component categories.
Main Results:
- 68% of identified RCTs reported complete component data for primary composite end points; 98% included a fatal end point.
- 54% of analyzed composite end points showed significant gradients in patient importance and treatment effect magnitude.
- More important components had lower event rates, while less important components demonstrated larger relative risk reductions.
Conclusions:
- Composite end points in cardiovascular trials often exhibit substantial gradients in patient-reported importance and treatment effect magnitude.
- The prominence of less important components with higher event rates and larger treatment effects can lead to misleading conclusions about treatment effectiveness.
- Careful consideration of component weighting and patient priorities is crucial for accurate interpretation of composite end point data.
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.
