Background and Aims 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. Methods 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. Results 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. Conclusions 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.

中文翻译：

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肺动脉高压治疗：个体参与者数据网络荟萃分析

背景和目标针对三种主要信号通路的有效疗法被批准用于治疗肺动脉高压（PAH）。然而，很少有大型患者水平的研究来比较这些途径的有效性。该分析的目的是比较 PAH 治疗途径的有效性并评估治疗异质性。方法 使用来自 20 项 PAH 治疗 III 期随机临床试验的 6811 名 PAH 患者的个体参与者数据进行网络荟萃分析，这些试验已提交给美国食品和药物管理局。各个药物按以下治疗途径分组：内皮素、一氧化氮和前列环素途径。结果样本平均年龄（±标准差）为49.2（±15.4）岁；78.4% 为女性，59.7% 患有特发性 PAH，36.5% 正在接受背景 PAH 治疗。协变量调整后，针对内皮素+一氧化氮途径{β: 43.7 m [95%置信区间(CI): 32.9, 54.4]}、一氧化氮途径[β: 29.4 m (95% CI: 22.6, 36.3)]，内皮素途径 [β: 25.3 m (95% CI: 19.8, 30.8)] 和前列环素途径 [口服/吸入 β: 19.1 m (95% CI: 14.2, 24.0)，静脉/皮下 β: 24.4 m (95% CI : 15.1, 33.7)] 与安慰剂相比，第 12 或 16 周时 6 分钟步行距离显着增加。治疗还显着降低了临床恶化事件的可能性。年龄、体重指数、高血压、糖尿病和冠状动脉疾病的治疗效果存在显着异质性。结论 针对三种传统治疗途径的药物可显着改善 PAH 的预后，但对于患有某些合并症的患者，治疗具有显着的异质性。随机临床试验有必要通过个性化方法确定最有效的治疗策略。