(A-111) Efficacy and Safety of Pharmacological Interventions for Pulmonary Arterial Hypertension (PAH): A Systematic Review and Network Meta-Analysis (NMA) of Randomized Controlled Trials (RCTs)

Background: Pulmonary Arterial Hypertension (PAH) is a progressive condition characterized by pulmonary vascular remodeling, leading to increased pulmonary artery pressure, right heart failure, and premature death. Despite advances in pharmacotherapy, PAH management remains challenging, requiring effective interventions to improve outcomes.

Objectives: To evaluate the efficacy and safety of pharmacological interventions for PAH through a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs).

Methods: A systematic search was conducted in PubMed, Embase, and Cochrane CENTRAL up to December 2024. The protocol is registered with PROSPERO (CRD42025642025). Studies included patients with WHO Group 1 PAH receiving Endothelin receptor antagonists (Bosentan, Ambrisentan, Macitentan, Sitaxsentan), Phosphodiesterase-5 inhibitors (Sildenafil, Tadalafil, Vardenafil), Prostacyclin analogs Epoprostenol, Iloprost, Treprostinil, Beraprost), Non-prostanoid IP receptor agonists (Selexipag), or Soluble guanylate cyclase stimulators (Riociguat), compared with placebo or other treatments. Primary outcomes were clinical worsening, hospitalization, and mortality; secondary outcomes included adverse events (AEs). Risk of bias was assessed with the Cochrane Risk of Bias 2 tool. A frequentist random-effects NMA was conducted in R Studio (version 4.4.2) using the netmeta package, with treatment rankings assessed by surface under the cumulative ranking curve (SUCRA).

Results: A total of 31 RCTs with 7096 patients were included. Riociguat (OR: 0.19, 95% CI: [0.08, 0.41]), vardenafil (OR: 0.09, 95% CI: [0.01, 0.93]), and sildenafil (OR: 0.35, 95% CI: [0.17, 0.71]) significantly reduced clinical worsening (I² = 26.5%), with rankings favoring vardenafil (SUCRA: 0.838) and iloprost (SUCRA: 0.826). For hospitalization risk, riociguat (OR: 0.097, 95% CI: [0.010, 0.938]) and selexipag (OR: 0.535, 95% CI: [0.316, 0.905]) significantly reduced risk (I² = 24.1%), with the highest rankings for riociguat (SUCRA: 0.883) and selexipag (SUCRA: 0.812). No treatment significantly reduced mortality (I² = 36.5%), though vardenafil (SUCRA: 0.853) and sildenafil (SUCRA: 0.665) ranked highest for potential benefit. AEs, including flushing and headache, were more frequent with some therapies but had no impact on efficacy. The overall risk of bias in all RCTs was low.

Conclusions: Riociguat, vardenafil, and sildenafil significantly reduced clinical worsening and hospitalization, with selexipag also lowering hospitalization risk. Vardenafil ranked highest for mortality reduction, but no treatment showed a significant survival benefit. Despite AEs, efficacy remained unaffected. Further research is needed to confirm mortality outcomes.