Abstract
Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research.
Highlights
Composite endpoints are increasingly used as primary efficacy measures in heart failure clinical trials (Supplementary material online, Table S1)[1] to provide a comprehensive picture of the treatment effect, and to improve trial efficiency by increasing the event rate and reducing the required sample size
This paper summarizes the key insights and discussions, suggests approaches for using composite endpoints, and identifies knowledge gaps that need to be addressed by further research
Based on results from the Valsartan Heart Failure Trial (Val-HeFT), valsartan was approved by the Food and Drug Administration (FDA) to reduce hospitalization for heart failure, with no indication for improvement in mortality because it reduced only one of the two primary endpoints: (i) all-cause mortality and (ii) the composite of all-cause mortality or cardiac arrest with resuscitation, hospitalization for heart failure, or administration of intravenous inotropes or vasodilators for ≥4 h without hospitalization
Summary
Composite endpoints are increasingly used as primary efficacy measures in heart failure clinical trials (Supplementary material online, Table S1)[1] to provide a comprehensive picture of the treatment effect, and to improve trial efficiency by increasing the event rate and reducing the required sample size. Health-related quality of life as measured by instruments such as the Minnesota Living With Heart Failure (MLWHF) or the Kansas City Cardiomyopathy Questionnaire (KCCQ) might be considered as endpoints and have been used in many studies, but the FDA has specific standards that must be met when patient-reported outcomes are used to support labelling claims.[35,36] While health-related quality of life assessments are clinically relevant and can be informative, the methodological problems of using such scores in efficacy assessments (e.g. potential for bias in unblinded studies, procedures for handling missing data) are well known.[35] Whether regulatory agencies would accept the MLWHF or KCCQ scores as supportive evidence of efficacy remains to be seen and would probably need to be considered on an individual trial basis Another important consideration is the health technology assessment of new drugs after regulatory approval. Involve regulators early in discussion of which components will be included in a composite endpoint; may differ between acute and chronic heart failure trials
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