Contribution of individual components to composite end points in contemporary cardiovascular randomized controlled trials - 26/11/20

Doi : 10.1016/j.ahj.2020.09.001

Asim Shaikh, MBBS ^a, Rohan Kumar Ochani, MBBS ^a, Muhammad Shahzeb Khan, MD ^b,^{^⁎} , Haris Riaz, MD ^c, Safi U. Khan, MD ^d, Jayakumar Sreenivasan, MD, MSc ^e, Farouk Mookadam, MD ^f, Rami Doukky, MD ^b, Javed Butler, MD, MPH, MBA ^g, Erin D. Michos, MD, MHS ^h, Ankur Kalra, MD ⁱ, Richard A. Krasuski, MD ^j
^a Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan
^b Department of Internal Medicine, John H Stroger Jr Hospital of Cook County, Chicago, IL
^c Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
^d Department of Internal Medicine, Robert Packer Hospital, Sayre, PA
^e Department of Cardiovascular Medicine, Westchester Medical Center/New York Medical College, White Plains, NY
^f Department of Cardiovascular Medicine, Mayo Clinic, Phoenix, AZ
^g Department of Medicine, University of Mississippi, Jackson, MS
^h Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD
ⁱ Division of Cardiology, Cleveland Clinic, Cleveland, OH
^j Department of Cardiovascular Medicine, Duke University Health System, Durham, NC

^⁎Reprint requests: Muhammad Shahzeb Khan, MD, Department of Internal Medicine, John H Stroger Jr Hospital of Cook County, 1900 W Harrison St, Chicago, IL 60601.Department of Internal MedicineJohn H Stroger Jr Hospital of Cook County, 1900 W Harrison StChicagoIL60601

Background

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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Plan

What is already known about this subject?

•	Up to 50% of cardiovascular trials use composite outcomes.
•	Cardiovascular composite outcomes combine different end points with varying levels of clinical importance like revascularization and death to increase trial power.
•	The contribution made to the overall composite outcome by less clinically important end points is understudied; hence, we conducted this study to find out which type of end points have the biggest impact on the estimates of effect of the treatment as measured by the composite.

What does this study add?

•	Our study suggests that revascularization had the biggest impact on the composite outcome, whereas death, arguably the most important clinical end point, had the least.
•	The results of our study support the conclusion that some improvements to the designing of composite outcomes need to be made, specifically assigning weights to individual components depending on their clinical importance.

How might this impact on clinical practice?

•	Trials using composite outcomes may have misleading results because large sizes of treatment effects may only be relevant to less important end points. Incorporating additional tools in composite outcome designing, such as assigning weights, may be warranted.

Wilbert S. Aronow, MD, served as guest editor for this article.

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Vol 230

P. 71-81 - décembre 2020 Retour au numéro

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Contribution of individual components to composite end points in contemporary cardiovascular randomized controlled trials - 26/11/20

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