Pulmonary arterial hypertension treatment: an individual participant data network meta-analysis

• Published in: European heart journal Vol. 45; no. 21; pp. 1937 - 1952
• Main Authors: Moutchia, Jude, McClelland, Robyn L, Al-Naamani, Nadine, Appleby, Dina H, Holmes, John H, Minhas, Jasleen, Mazurek, Jeremy A, Palevsky, Harold I, Ventetuolo, Corey E, Kawut, Steven M
• Format: Journal Article
• Language: English
• Published: England 01.06.2024
• Subjects: Antihypertensive Agents - therapeutic use; Clinical Trials, Phase III as Topic; Endothelins - metabolism; Epoprostenol - therapeutic use; Female; Humans; Hypertension, Pulmonary - drug therapy; Male; Middle Aged; Network Meta-Analysis; Nitric Oxide - metabolism; Pulmonary Arterial Hypertension - drug therapy; Randomized Controlled Trials as Topic; Treatment Outcome; Treatment heterogeneity; Treatment pathway; Comparative effectiveness; Network meta-analysis; Pulmonary arterial hypertension
• ISSN: 0195-668X; 1522-9645; 1522-9645
• DOI: 10.1093/eurheartj/ehae049

Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity. A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways. The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {β: 43.7 m [95% confidence interval (CI): 32.9, 54.4]}, nitric oxide pathway [β: 29.4 m (95% CI: 22.6, 36.3)], endothelin pathway [β: 25.3 m (95% CI: 19.8, 30.8)], and prostacyclin pathway [oral/inhaled β: 19.1 m (95% CI: 14.2, 24.0), intravenous/subcutaneous β: 24.4 m (95% CI: 15.1, 33.7)] significantly increased 6 min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease. Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach.