The Second Follow-up Serial Infusions of Nesiritide (FUSION II) trial for advanced heart failure: Study rationale and design

Background: Patients with persistently symptomatic advanced heart failure have limited treatment options after appropriate use of standard evidence-based therapies. Current recommendations from the American College of Cardiology/American Heart Association guidelines for treatment of stage C/D heart failure beyond standard therapy include ventricular replacement, investigational agents, and palliative interventions. Given the elevated risk of this patient population, additional treatment options seem warranted. Natriuretic peptides are protean compounds that provoke vasodilation, natriuresis, neurohormonal antagonism, and reverse remodeling, but they have an uncertain risk-benefit profile affecting serum creatinine and clinical events. In the pilot, open-label FUSION I trial, the adjunctive administration of nesiritide with standard therapy for patients with advanced heart failure, was demonstrated to have a neutral effect on outcomes with no evidence of increased risk. Within a prespecified subset of high-risk patients, a potential signal of benefit on a combined end point of mortality and cardiovascular hospitalization was identified. Study Design: FUSION II is a 900-patient randomized, placebo-controlled, double-blind, phase IIb trial designed to further assess the safety, efficacy, and optimal dosing frequency of outpatient nesiritide for advanced heart failure. The primary end point is a composite of all-cause mortality and cardiorenal hospitalization. Conclusions: If a confirmatory signal of benefit is identified in FUSION II, a definitive phase III mortality/quality of life trial will be warranted. Additional issues related to the influence of disease management, the logistics of outpatient parenteral therapy administration, and future iterations of natriuretic peptide therapy will need to be investigated.