SOPRANO: Macitentan in patients with pulmonary hypertension following left ventricular assist device implantation

Abstract

Macitentan is a dual endothelin receptor antagonist (ERA) approved for treating pulmonary arterial hypertension (PAH). SOPRANO evaluated the efficacy and safety of macitentan versus placebo in pulmonary hypertension (PH) patients after left ventricular assist device (LVAD) implantation. SOPRANO was a phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients with an LVAD implanted within the prior 90 days who had persistent PH (i.e., mean pulmonary arterial pressure ≥25 mmHg, pulmonary artery wedge pressure [PAWP] ≤18 mmHg, and pulmonary vascular resistance [PVR] >3 Wood units [WU]) were randomized (1:1) to macitentan 10 mg or placebo once daily for 12 weeks. The primary endpoint was change in PVR. Secondary endpoints included change in right-heart catheterization hemodynamic variables, N-terminal prohormone of brain natriuretic peptide levels, World Health Organization functional class, and safety/tolerability. Fifty-seven patients were randomized to macitentan (n = 28) or placebo (n = 29). A statistically significant reduction in PVR from baseline to Week 12 was observed with macitentan versus placebo (placebo-corrected geometric mean ratio, 0.74; 95% confidence interval, 0.58-0.94; p = .0158). No statistically significant differences were observed in secondary endpoints. In a post-hoc analysis, 66.7% of patients receiving macitentan achieved PVR <3 WU versus 40.0% receiving placebo (p = .0383). Macitentan was generally well tolerated; adverse events were consistent with those in previous PAH studies with macitentan. In conclusion, macitentan showed promising tolerability and significantly reduced PVR in PH patients with persistently elevated PVR after LVAD implantation. ClinicalTrials. gov identifier: NCT02554903.

Keywords: SOPRANO; left ventricular assist device; macitentan; pulmonary hypertension; pulmonary vascular resistance.

Figure 1

Patient disposition. Abbreviations: AE, adverse event; D/C, discontinued; HD, hemodynamics; LVAD, left ventricular assist device; RHC, right‐heart catheterization. ^aOther reasons included: not randomized within 14 days of baseline RHC (n = 1); not stable within 48 h before baseline RHC (n = 1); LVAD not implanted ≤90 days before randomization (n = 2); no written informed consent (n = 1); reason not available (n = 11). ^bOne patient experienced cerebral hemorrhage unrelated to the study drug. ^cOne patient reported acute kidney injury (unrelated) and worsening right‐heart failure (unrelated). ^dOne patient experienced hemorrhagic stroke (unrelated).

Figure 2

Post‐hoc analysis of the proportion of patients achieving a PVR <3 WU. Abbreviations: PVR, pulmonary vascular resistance; WU, Wood unit. Data are presented only for patients with both baseline and post‐baseline values. ^aThe p‐value was calculated based on Cochran–Mantel–Haenszel statistics by adjusting for baseline PVR category.