Comparative Effectiveness of Sotatercept and Approved Add-On Pulmonary Arterial Hypertension Therapies: A Systematic Review and Network Meta-Analysis

Abstract Background There are no direct comparisons of sotatercept to add-on therapies approved for pulmonary arterial hypertension (PAH). Objective This study aimed to compare the efficacy and safety of add-on sotatercept versus other add-on therapies using a network meta-analysis. Data Sources We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov until April 15, 2023, for randomized trials involving patients with PAH who were treated with add-on sotatercept or other add-on PAH therapies. Data Extraction Data extraction and risk-of-bias assessments were performed independently and in duplicate using the Cochrane RoB 2.0 tool. We performed a frequentist random-effects network meta-analysis using the restricted maximum-likelihood estimator and assessed the certainty of evidence using the GRADE (grading of recommendations assessment development, and evaluation) approach. Synthesis Our search found 18 trials (5,777 patients) eligible for analysis. Sotatercept reduces clinical worsening as compared with placebo (relative risk [RR], 0.21; 95% confidence interval [CI] = 0.11–0.41; with high certainty). Sotatercept probably reduces clinical worsening more, compared with add-on endothelin receptor antagonists (RR, 0.28; 95% CI = 0.14–0.55), inhaled prostanoid (RR, 40.21; 95% CI = 0.07–0.67), and prostanoid taken orally (RR, 0.32; 95% CI = 0.16–0.67; all with moderate certainty). Sotatercept probably improves 6-minute-walk distance compared with placebo (mean difference [MD], 36.89 m; 95% CI = 25.26–48.51). Although sotatercept probably improves 6-minute-walk distance more than add-on endothelin receptor antagonists (MD, 18.38 m; 95% CI = 5.92–30.84) and prostanoid taken orally (MD, 25.66 m; 95% CI = 13.71–37.61), it did not exceed the minimal clinically important difference of 33 m (both with moderate certainty). Conclusions Sotatercept is an effective add-on therapy for PAH, likely superior to many approved add-on PAH therapies in reducing clinical worsening.