Background: Current pulmonary arterial hypertension (PAH) therapies have not been systematically studied in early stages of PAH although they may lead to improved outcomes.
Methods: This prospective, multicenter, randomized, double-blind and placebo-controlled phase IIa trial assessed the efficacy, safety, and tolerability of riociguat (MK-4836) vs. placebo over 24 weeks in adult patients with early pulmonary vascular disease, defined as either (a) mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg with pulmonary vascular resistance (PVR) ≥ 2 to < 3 Wood Units, (WU), or (b) mPAP 21– < 25 mmHg with PVR ≥ 2 WU. Patients were randomized 1:1 to receive riociguat or placebo. The primary endpoint was the change in PVR from baseline to week 24. Secondary endpoints were evaluated hierarchically as change in (1) cardiac index (CI), (2) total pulmonary resistance, (3) change in diffusion capacity of the lung, (4) six-minute walking distance (6MWD), (5) WHO functional class (FC), (6) quality of life. Further parameters, including clinical assessment, hemodynamics and pulmonary function were tested exploratory. Safety and tolerability were assessed throughout the study.
Results: A total of 35 patients were enrolled and randomized (riociguat n = 17, placebo n = 18); 32 completed the trial. The majority of participants were female (97%) with a mean age of 65.54 ± 6.9 years; 74.3% had connective tissue disease–associated PAH. Treatment with riociguat resulted in a significant improvement of the primary endpoint PVR compared with placebo after 24 weeks (riociguat -0.69 ± 0.60 WU vs. placebo 0.89 ± 3.29 WU, p = 0.043). Multiple imputation confirmed this finding (p = 0.045). There were no significant between-group differences in the secondary or explorative endpoints as mPAP, CI, or cardiac output (CO), though a trend toward an improved CO (riociguat 0.35 ± 0.86 l/min vs. placebo -0.19 ± 0.75 l/min, p = 0.084) was observed with riociguat. Functional capacity (6MWD, FC) and N-terminal pro-brain natriuretic peptide remained stable in both groups, consistent with early-stage disease. Quality-of-life measures showed no meaningful difference except for a placebo-related improvement in one physical domain. Riociguat was well tolerated; adverse events were mild or moderate. No treatment-related serious adverse events occurred.
Conclusion: Riociguat treatment led to a significant improvement of the primary endpoint PVR after 24 weeks. Treatment was generally well tolerated, in line with the known safety profile of riociguat. These findings suggest that riociguat is a safe and effective treatment option for patients with early PAH. Further prospective studies are needed to confirm these results.
