End points in chronic heart failure clinical trials

Selection of end points for outcomes is an important step in a randomized clinical trial. The primary end point defines the research question and should ideally be clinically relevant, easily ascertainable in all patients, capable of unbiased assessment, sensitive to the hypothesized effects of the treatment, and inexpensive to measure. Mortality is currently regarded as the most important true end point for evaluation of new heart failure drugs. However, the diminishing rates of these events in sequential trials means that progressively larger sample sizes are needed to display benefit from the next therapeutic agent. This explains the increasing use of composite end points and surrogate end points. The latter are substitutes for true end points for the purpose of comparing specific interventions in a clinical trial; they have no direct importance to the patient, but are biologically relevant and are supposed to show a strong and consistent relationship with clinical benefit. Another, perhaps more important, aspect is that surrogate end points increase our understanding of the disease process and mechanisms of action of drugs and thus may help take a more enlightened approach to managing patients. We review the potentials and limitations of the true and surrogate end points in clinical studies of patients with chronic heart failure.