Efficacy and Safety of Riociguat in Early Pulmonary Vascular Disease

BACKGROUND: Pulmonary arterial hypertension therapies have not been systematically studied in early disease stages, despite potential benefit. RESEARCH QUESTION: Is riociguat safe, well tolerated, and potentially effective in early pulmonary vascular disease? STUDY DESIGN AND METHODS: This was a prospective, multicenter, double-blind phase 2a trial. Adults with early pulmonary vascular disease, defined as mean pulmonary arterial pressure ≥ 25 mm Hg with pulmonary vascular resistance (PVR) ≥ 2 to < 3 Wood units (WU), or mean pulmonary arterial pressure 21 to < 25 mm Hg with PVR ≥ 2 WU, were randomized to receive 1:1 riociguat or placebo for 24 weeks. The primary end point was change in PVR from baseline to week 24. Secondary end points, evaluated hierarchically, comprised changes in cardiac index, total pulmonary resistance, diffusing capacity of the lung for carbon monoxide, 6-minute walking distance, World Health Organization functional class, and quality of life. Complementary parameters were analyzed in an exploratory manner, and safety was monitored throughout. RESULTS: Of 261 prescreened patients, 35 eligible patients were randomized to treatment (97% female; mean age, 65.5 ± 6.9 years; 77.1% connective tissue disease-associated pulmonary arterial hypertension); 32 completed the trial. Reasons for ineligibility were documented. Riociguat significantly improved the primary end point of change in PVR (riociguat -0.73 ± 0.67 WU vs placebo -0.02 ± 0.67 WU; P = .043; 27% placebo-adjusted reduction). No significant differences were observed in secondary end points. Of the exploratory end points, only cardiac output showed a trend toward improvement under riociguat (0.35 ± 0.86 L/min vs placebo -0.19 ± 0.75 L/min; P = .084). Only mild to moderate adverse events were observed, and serious events were not considered treatment related. INTERPRETATION: Despite the limited number of participants, treatment with riociguat was safe and significantly improved the primary end point PVR over 24 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT05339087; URL: www. CLINICALTRIALS: gov).