Editorial
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Jan 26, 2015; 7(1): 1-5
Published online Jan 26, 2015. doi: 10.4330/wjc.v7.i1.1
Opportunities and challenges of clinical trials in cardiology using composite primary endpoints
Geraldine Rauch, Bernhard Rauch, Svenja Schüler, Meinhard Kieser
Geraldine Rauch, Svenja Schüler, Meinhard Kieser, Institute of Medical Biometry and Informatics, University of Heidelberg, D-69120 Heidelberg, Germany
Bernhard Rauch, Institut für Herzinfarktforschung, D-67063 Ludwigshafen, Germany
Author contributions: All authors contributed to this manuscript.
Conflict-of-interest: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Geraldine Rauch, Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany. rauch@imbi.uni-heidelberg.de
Telephone: +49-6221-561932 Fax: +49-6221-561932
Received: October 27, 2014
Peer-review started: October 27, 2014
First decision: November 27, 2014
Revised: December 19, 2014
Accepted: December 29, 2014
Article in press: January 4, 2015
Published online: January 26, 2015
Processing time: 96 Days and 4.3 Hours
Abstract

In clinical trials, the primary efficacy endpoint often corresponds to a so-called “composite endpoint”. Composite endpoints combine several events of interest within a single outcome variable. Thereby it is intended to enlarge the expected effect size and thereby increase the power of the study. However, composite endpoints also come along with serious challenges and problems. On the one hand, composite endpoints may lead to difficulties during the planning phase of a trial with respect to the sample size calculation, as the expected clinical effect of an intervention on the composite endpoint depends on the effects on its single components and their correlations. This may lead to wrong assumptions on the sample size needed. Too optimistic assumptions on the expected effect may lead to an underpowered of the trial, whereas a too conservatively estimated effect results in an unnecessarily high sample size. On the other hand, the interpretation of composite endpoints may be difficult, as the observed effect of the composite does not necessarily reflect the effects of the single components. Therefore the demonstration of the clinical efficacy of a new intervention by exclusively evaluating the composite endpoint may be misleading. The present paper summarizes results and recommendations of the latest research addressing the above mentioned problems in the planning, analysis and interpretation of clinical trials with composite endpoints, thereby providing a practical guidance for users.

Keywords: Composite endpoint; Competing risks; Multiple testing; Time-to-event; Adaptive designs

Core tip: When planning a clinical trial with a composite primary endpoint: (1) Be aware of planning uncertainties when calculating the sample size and incorporate them in an adequate way; (2) Include a multiple testing strategy for an improved interpretation of the study results; (3) Take into account competing risks when analyzing the individual components of a composite endpoint; and (4) Analyze subsequent events in an adequate multi-stage model.