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Contribution of individual components to composite end points in contemporary cardiovascular randomized controlled
Asim Shaikh1, Rohan Kumar Ochani1, Muhammad Shahzeb Khan2
1Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan.
Insights
Cardiovascular trials often use composite outcomes, including less significant "soft" endpoints. This can mislead interpretations of treatment effectiveness due to the varying clinical importance of individual components.
Area of Science:
- Cardiology
- Clinical Trials
- Health Outcomes Research
Background:
- Cardiovascular randomized controlled trials (RCTs) commonly employ composite endpoints to increase statistical power.
- The specific influence of individual components on the overall composite outcome is often not well understood.
Purpose of the Study:
- To analyze the composition and impact of individual endpoints within composite outcomes in cardiovascular RCTs.
- To assess the contribution of "hard" and "soft" endpoints to the overall effect estimates in cardiovascular trials.
Main Methods:
- Systematic search of MEDLINE for cardiovascular RCTs published between 2011-2017 in six high-impact journals.
- Included two-armed, parallel-design RCTs reporting composite outcomes, categorizing components as "hard" (mortality, MI, HF, stroke) or "soft" (hospitalization, angina, revascularization).
- Analyzed outcome type, event rates, and the contribution of each component to the composite effect estimate (R² change).
Main Results:
- Nearly 50% of cardiovascular RCTs (45.8%) utilized composite endpoints, with 79.4% designating them as the primary outcome.
- Death was the most frequent component (89.8%), followed by myocardial infarction (66.1%).
- Approximately 46.5% of trials included "soft" endpoints; revascularization significantly contributed to effect estimates (R² change=0.423), while death contributed minimally (R² change=0.005).
Conclusions:
- Composite endpoints in cardiovascular RCTs frequently incorporate "soft" endpoints, potentially impacting nearly half of all studies.
- The significant contribution of certain endpoints, like revascularization, over others, such as death, can lead to a misleading interpretation of treatment effects.
- Clinical significance of individual components must be considered when interpreting composite outcomes in cardiovascular research.
Abstract:
Cardiovascular randomized controlled trials (RCTs) typically set composite end points as the primary outcome to enhance statistical power. However, influence of individual component end points on overall composite outcomes remains understudied.
Methods:
We searched MEDLINE for RCTs published in 6 high-impact journals (The Lancet, the New England Journal of Medicine, Journal of the American Medical Association, Circulation, Journal of the American College of Cardiology and the European Heart Journal) from 2011 to 2017. Two-armed, parallel-design cardiovascular RCTs which reported composite outcomes were included. All-cause or cardiovascular mortality, myocardial infarction, heart failure, and stroke were deemed "hard" end points, whereas hospitalization, angina, and revascularization were identified as "soft" end points. Type of outcome (primary or secondary), event rates in treatment and control groups for the composite outcome and of its components according to predefined criteria.
Results:
Of the 45.8% (316/689) cardiovascular RCTs which used a composite outcome, 79.4% set the composite as the primary outcome. Death was the most common component (89.8%) followed by myocardial infarction (66.1%). About 80% of the trials reported complete data for each component. One hundred forty-seven trials (46.5%) incorporated a "soft" end point as part of their composite. Death contributed the least to the estimate of effects (R2 change = 0.005) of the composite, whereas revascularization contributed the most (R2 change = 0.423).
Conclusions:
Cardiovascular RCTs frequently use composite end points, which include "soft" end points, as components in nearly 50% of studies. Higher event rates in composite end points may create a misleading interpretation of treatment impact due to large contributions from end points with less clinical significance.
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