Composite Endpoints in Cardio-Renal Clinical Outcome Trials

Abstract

Over the last several decades, major adverse clinical outcomes have been studied in the form of composite endpoints in cardiovascular and renal trials. Great utilities and challenges in the use of composite endpoints are well known and have been discussed in statistical and medical literature. For regulatory applications, unique issues relating to marketing claims necessitate additional considerations and discussions on how to define proper estimands related to the clinical questions, how to handle intercurrent events, and what statistical inferences need to be incorporated in order to result in proper interpretation of trial results. Two key issues with component-specific analyses concern handling of dependent competing risk endpoints and multiple endpoint testing. These issues may arise even in the analysis of the time to the first occurrence of composite or component endpoint, as to be discussed later in this article using the RENAAL study as an illustrative example. For developing treatments to relieve disease burden, much attention has been called to the potential value of considering all disease-related events such as all hospitalizations, rather than only one or the first event occurrence, in statistical analysis. In that case, discussion of estimands and intercurrent events will be much more challenging.

Keywords:

• Component endpoint
• Competing risk
• Closed test
• Disease burden
• Estimand

Acknowledgments

The authors are grateful to the reviewers for their comments that improve the presentations of this article. This article reflects the views of the authors and should not be construed to represent the views or policies of the U.S. Food and Drug Administration.