Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
Eur Heart J. 2024 Jun 1;45(21):1937-1952. 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.
已有针对肺高压（PAH）三种主要信号通路的有效治疗方法获批。然而，鲜有大规模的患者层面研究比较这些通路的有效性。本分析旨在比较 PAH 治疗通路的有效性，并评估治疗异质性。
使用美国食品药品监督管理局提交的 20 项 PAH 治疗 III 期随机临床试验的 6811 例 PAH 患者的个体参与者数据进行网络荟萃分析。个体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。
样本的平均（±标准差）年龄为 49.2（±15.4）岁；78.4%为女性，59.7%为特发性 PAH，36.5%正在接受背景 PAH 治疗。在协变量调整后，靶向内皮素+一氧化氮通路[β：43.7 m（95%置信区间：32.9，54.4）]、一氧化氮通路[β：29.4 m（95%置信区间：22.6，36.3）]、内皮素通路[β：25.3 m（95%置信区间：19.8，30.8）]和前列环素通路[口服/吸入β：19.1 m（95%置信区间：14.2，24.0），静脉/皮下β：24.4 m（95%置信区间：15.1，33.7）]与安慰剂相比，12 或 16 周时 6 分钟步行距离显著增加。治疗还显著降低了临床恶化事件的发生概率。治疗效果存在显著的异质性，与年龄、体重指数、高血压、糖尿病和冠状动脉疾病有关。
靶向三种传统治疗途径的药物显著改善了 PAH 的结局，但在某些合并症患者中存在显著的治疗异质性。有必要开展随机临床试验，以确定在个体化方法中最有效的治疗策略。
