Development and Evolution of a Hierarchical Clinical Composite End Point for the Evaluation of Drugs and Devices for Acute and Chronic Heart Failure

Abstract

Traditional approaches to the assessment of new treatments for heart failure have generally evaluated individual components of the syndrome at fixed points in time or have relied on surrogate physiological measures that are poorly correlated with the clinical status of patients. Conventional time-to-event trials that focus on morbidity and mortality represent an important methodological advance, but they generally assign undue weight to clinical events of less importance and are insensitive to difference in functional capacity among individuals who do not experience a clinical event during follow-up. Twenty years ago, a hierarchical clinical composite was developed to address these limitations; it aims to assess the clinical course of patients as a physician would in practice by combining a symptomatic assessment of the patient at each visit with an evaluation of the clinical stability of the patient between visits. The composite does not generate a numeric score by summing arbitrarily assigned weights to certain symptoms or events; instead, the composite ranks relevant measures and outcomes according to clinical priority. In doing so, the clinical composite minimizes the biases created by noncompleting patients in the assessment of symptoms or exercise tolerance while expanding the range of patients who contribute to the treatment difference in a typical morbidity and mortality trial. When applied appropriately, the hierarchical clinical composite end point has reliably distinguished effective from ineffective treatments. The composite may have particular advantages in the evaluation of new devices and transcatheter interventions in chronic heart failure and of new drugs for acute heart failure. Recent modifications enhance its discriminant characteristics and its ability to accurately assess the efficacy of novel interventions for heart failure.