Heart failure endpoints in Food and Drug Administration pivotal trials

Numerous medications have been approved to treat heart failure (HF). Given the risk of irreversible morbidity and mortality in chronic HF, medication approval was traditionally based upon reductions in cardiovascular death or HF hospitalization. However, expanding use of effective medicines has reduced hospitalization and mortality rates. This incremental reduction in 'hard' outcomes has made endpoints that capture how patients feel or function attractive for new medicine development as efficacy can potentially be demonstrated in smaller trials of shorter duration than cardiovascular outcome trials. Moreover, while inpatient hospitalization is the traditional vehicle for managing acute HF, dedicated infusion centres, observation units, and emergency departments now provide alternative outpatient venues. This changing clinical practice landscape prompts consideration of certain outpatient HF events as reasonable for inclusion in a primary composite endpoint, though these events span a broad spectrum of severity of worsening HF. At the high severity margin, outpatient events approximate a hospitalization equivalent, i.e. but for the existence of alternative venues, patients would have been hospitalized. At the opposite end of the continuum are changes in care without direct contact, e.g. increasing oral diuretics after a brief telephone call. Both events ostensibly represent clinical worsening yet differ markedly in patient relevance. Building upon previous guidance documents, a contemporary regulatory perspective is presented on innovating, standardizing, and streamlining HF trials. Adoption of these principles may improve trial efficiency while ensuring new therapies possess unambiguous public health benefits.