Comparative Efficacy of Balloon Pulmonary Angioplasty and Pharmacological Therapies in Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Network Meta-Analysis

Background Inoperable or residual chronic thromboembolic pulmonary hypertension treatment modalities remain challenging due to limited comparison of alternatives between BPA and pharmacological agents. Objective To compare the relative efficacy and safety of BPA and pharmacological treatments in patients with inoperable or residual CTEPH. By integrating both direct and indirect comparisons, the study aims to provide a hierarchised, evidence-based framework to inform personalised treatment selection and guideline development for this high-risk population. Methods A systematic search of major databases through November 2024 identified randomized trials evaluating BPA, Riociguat, endothelin receptor antagonists (Bosentan, Ambrisentan, Macitentan), PDE-5 inhibitors (Sildenafil), and prostacyclin analogs (Selexipag). Outcomes included pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index (CI), 6-minute walk distance (6MWD), NT-proBNP, and Borg Dyspnea Index (BDI). A frequentist random-effects model was applied using the netmeta R package. Results Nine studies with 839 participants were analyzed. BPA showed the greatest reduction in PVR (MD -444.02 dyn·s·cm⁻⁵, 95% CI -606.99 to -281.05) and mPAP (MD -16.17 mmHg), with the highest SUCRA scores across outcomes. Riociguat ranked second overall, improving PVR, 6MWD, and CI. Macitentan and selexipag significantly improved CI, while bosentan reduced NT-proBNP. Ambrisentan and sildenafil did not demonstrate significant benefits over placebo. High heterogeneity was observed for PVR and BDI outcomes. Conclusions Ballon Pulmonary Angioplasty (BPA) demonstrates the most robust and consistent improvements in hemodynamics as evidenced by PVR, mPAP and mRAP measurements as well in functional and biomarker improvements (6MWD and NT-proBNP) in patients with inoperable CTEPH while Riociguat remains the most effective pharmacologic agent, offering significant benefits across multiple domains including PVR, 6MWD, mPAP and CI. Macitentan and Selexipag showed promising improvements in cardiac output while Bosentan provided NT-proBNP and pVR benefit. Ambrisentan and Sildenafil did not demonstrate significant advantages over placebo in this population. These findings support BPA as the most effective intervention for inoperable CTEPH, with Riociguat as the preferred pharmacologic therapy. However, limited direct comparisons and heterogeneity in some endpoints warrant long-term outcome studies to refine treatment sequencing, combination strategies and the consideration for future head-to-head trials between advanced oral therapies and BPA.