Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document

Abstract

Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all‐cause mortality, cause‐specific mortality, relevant non‐fatal morbidity (e.g. all‐cause and cause‐specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient‐reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA‐ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12–13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.

Variability in use of IV nitrates and diuretics in acute HF: a ‘virtual patient’ clinical decision-making study

“…However, their design presents a number of challenges in terms of patient enrolment, the timing of treatment administration and selection of appropriate measures of success ('outcome endpoints'). 92 Trials assessing the effects of therapies on the symptoms of acute heart failure require early patient enrolment and rapid treatment administration, within hours of admission. 92 Allowing later enrolment 1-2 days after admission means that early treatment effects cannot be assessed, and could also affect the characteristics of the patient population.…”

“…92 Trials assessing the effects of therapies on the symptoms of acute heart failure require early patient enrolment and rapid treatment administration, within hours of admission. 92 Allowing later enrolment 1-2 days after admission means that early treatment effects cannot be assessed, and could also affect the characteristics of the patient population. For example, many patients experience improvements in acute dyspnoea within 3-24 hours with current therapies; the subsequent enrolment of symptomatic patients could capture a disproportionately high proportion of those with refractory symptoms and a particularly poor prognosis.…”

“…For example, many patients experience improvements in acute dyspnoea within 3-24 hours with current therapies; the subsequent enrolment of symptomatic patients could capture a disproportionately high proportion of those with refractory symptoms and a particularly poor prognosis. 92 Patient enrolment in the emergency department can, however, prove challenging. Study protocols need to ensure that staff are available to identify and enrol patients effectively, with careful consideration given to obtaining informed consent, as this may prove difficult in acutely ill patients.…”

“…93 A wide range of outcome measures is potentially of interest in acute heart failure, Acute heart failure has diverse causes and consequences, so evaluating the efficacy of new treatments is complex and care is needed to select the most appropriate endpoints for the aims of the trial (Figure 4.1). 92 Death from cardiovascular causes or from all causes offer the most rigorous endpoints, but it is not known whether a short-term therapy for acute heart failure would be capable of reducing longterm death rates (for example by preventing damage to heart muscle). 92 Assessment of symptoms such as breathlessness (dyspnoea) may be an alternative endpoint; however, the ability to detect changes in dyspnoea depends on how it is measured and on variations in patient disease characteristics.…”

In‐hospital worsening heart failure: a clinically relevant endpoint?

“…The growing awareness of in‐hospital WHF as a clinical endpoint has been strengthened by its inclusion in a European Society of Cardiology consensus document on clinical trial endpoints for HF 26. The document highlights that (i) WHF during the index hospitalization may be used as a component of the primary composite endpoint; (ii) in‐hospital WHF may capture important, non‐fatal events occurring prior to discharge; (iii) consistent capturing of in‐hospital WHF events across trial sites is important; and (iv) specific criteria for the diagnosis must be pre‐defined 26…”