Optimizing riociguat therapy for pulmonary hypertension: A systematic review and meta-analysis of dose variability, safety, and efficacy

Background: Pulmonary hypertension (PH) is a progressive, life-threatening condition characterized by elevated pulmonary arterial pressure, often culminating in right heart failure. Despite existing therapies, optimizing treatment efficacy and safety remains a clinical challenge. Riociguat, a soluble guanylate cyclase stimulator, has shown promise in managing PH, particularly in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). This meta-analysis aims to evaluate the optimal dosing of riociguat to maximize therapeutic benefits while minimizing adverse effects. Methods: This systematic review and meta-analysis followed PRISMA guidelines. A comprehensive search of PubMed, Cochrane Central, Embase, and Google Scholar was conducted to identify randomized controlled trials (RCTs) comparing riociguat with placebo in adult PH patients. Eligible studies included double-arm RCTs with riociguat dosages ranging from 0.5 to 2.5 mg. Primary outcomes included changes in 6-minute walk distance (6-MWD), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and NT-proBNP levels. Secondary outcomes were adverse events and clinical worsening. Study quality was assessed using the Cochrane risk of bias tool. Statistical analysis used RevMan 5.4 with a random-effects model. Heterogeneity was evaluated using χ 2 and I 2 tests, and meta-regression assessed the impact of age and BMI. Results: Ten RCTs involving 1109 PH patients were included. Riociguat significantly improved 6-MWD (MD: 27.23 m; 95% CI: 8.28–46.18; P = .005), reduced mPAP (MD: −2.61 mm Hg; 95% CI: −4.60 to −0.63; P = .01), lowered PVR (MD: −90.27 dynes·s·cm −5 ; 95% CI: −119.30 to −61.23; P < .00001), and decreased NT-proBNP levels (MD: −256.77 pg/mL; 95% CI: −491.99 to −21.55; P = .03). Meta-regression showed age and BMI significantly influenced treatment effects. Conclusions: Riociguat demonstrates dose-dependent efficacy in improving functional and hemodynamic parameters in PH, with the 2.5 mg thrice-daily dose showing consistent benefit. BMI impacted functional outcomes but not hemodynamic measures. These findings support tailored dosing strategies for optimized patient outcomes. Further research is needed to confirm dose-response effects and address residual heterogeneity.