Circ Heart Fail. 2025 Mar 11:e011381. doi: 10.1161/CIRCHEARTFAILURE.123.011381. Online ahead of print.
ABSTRACT
BACKGROUND: Despite favorable hemodynamic and neurohormonal effects, endothelin receptor antagonists have not improved outcomes in patients with heart failure (HF), possibly because they cause fluid retention.
METHODS: In this randomized, double-blind, multicenter trial (SERENADE [Macitentan in Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease]), we evaluated the effects of an endothelin receptor antagonist, macitentan, in patients with HF, left ventricular ejection fraction ≥40%, and pulmonary vascular disease. After a 4-week placebo run-in (to ensure clinical stability), followed by a 5-week single-blind macitentan run-in, patients who did not exhibit fluid retention were randomized to macitentan or placebo. The primary end point was change in NT-proBNP (N-terminal pro-B-type natriuretic peptide; baseline to 24 weeks); secondary end points included change in KCCQ (Kansas City Cardiomyopathy Questionnaire) clinical summary score (baseline to 24 weeks) and time to worsening HF by 52 weeks.
RESULTS: Of 230 patients enrolled, 28 were excluded during the placebo run-in, 60 excluded during the macitentan run-in, and 142 were randomized. Macitentan had no effect on change in NT-proBNP (geometric mean ratio [macitentan/placebo], 1.02 [90% CI, 0.88-1.19]; P=0.79) or on secondary end points (placebo-corrected change in KCCQ clinical summary score, -3.5 [90% CI, -8.2 to +1.2]; P=0.22). Worsening HF occurred in 20 (28%) patients assigned to macitentan and 13 (18%) assigned to placebo (hazard ratio, 1.48 [90% CI, 0.83-2.67]; P=0.24). More macitentan-treated patients developed fluid retention (16 [23%] versus 10 [14%]) and cardiac adverse events (33 [46%] versus 22 [31%]) versus placebo.
CONCLUSIONS: Despite a novel enrichment trial design to target pulmonary vascular disease and exclude treatment-related fluid retention in patients with HF and preserved/mildly reduced left ventricular ejection fraction, macitentan neither lowered NT-proBNP nor improved HF outcomes.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03153111 and NCT03714815.
PMID:40066571 | DOI:10.1161/CIRCHEARTFAILURE.123.011381
