Pulmonary Arterial Hypertension-Targeted Therapy for Pulmonary Hypertension Associated With Left Heart Disease: Bayesian and Frequentist Meta-Analysis of Randomized Controlled Trials.

Pulmonary hypertension associated with left heart disease (PH-LHD) is the most prevalent form of pulmonary hypertension. Despite the recent advances in medications for pulmonary artery hypertension (PAH), it remains unclear whether PAH-targeted therapy is effective in patients with PH-LHD. We searched PubMed and EMBASE through October 1, 2025 for randomized controlled trials comparing PAH-targeted therapy (i.e., endothelin receptor antagonist and phosphodiesterase-5 inhibitor) and placebo for patients with PH-LHD. The primary outcome was all-cause mortality, and secondary outcomes included adverse events and heart failure hospitalization. First, we performed Bayesian random-effects meta-analysis with weakly informative priors, using study-specific effect estimates and standard errors, with subgroup analysis for heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Additionally, we conducted frequentist meta-analysis. We identified 8 randomized controlled trials in a total of 775 patients. In Bayesian meta-analysis, we estimated the probability that PAH-targeted therapy increased all-cause mortality at 79.9% (risk ratio [RR]: 1.55; 95% credible interval [0.51 to 4.36]) and adverse events at 94.8% (RR: 1.13; 95% credible interval [0.96 to 1.38]), compared with placebo. In the subgroup analysis, no material difference was observed between heart failure with reduced ejection fraction and HFpEF, with HFpEF demonstrating a 62% probability of a smaller risk increase. In frequentist meta-analysis, there was no significant difference in all-cause mortality, while PAH-targeted therapy was associated with significantly increased adverse events, compared with placebo (RR: 1.15; 95% CI 1.04 to 1.28). In conclusion, PAH-targeted therapy was associated with a moderate probability of increased mortality and a high probability of increased adverse events.