Vizza Carmine Dario, Jansa Pavel, Teal Simon, Dombi Theresa, Zhou Duo
Unita' di Ipertensione Polmonare, Dipartimento di Scienze Respiratorie e Cardiovascolari, Universita' degli Studi di Roma La Sapienza, Viale del Policlinico, 155, Rome, Italy.
Charles University, Ovocný trh 3-5, 116 36 Praha 1, Prague, Czech Republic.
BMC Cardiovasc Disord. 2017 Sep 6;17(1):239. doi: 10.1186/s12872-017-0674-3.
Few controlled clinical trials exist to support oral combination therapy in pulmonary arterial hypertension (PAH).
Patients with PAH (idiopathic [IPAH] or associated with connective tissue disease [APAH-CTD]) taking bosentan (62.5 or 125 mg twice daily at a stable dose for ≥3 months) were randomized (1:1) to sildenafil (20 mg, 3 times daily; n = 50) or placebo (n = 53). The primary endpoint was change from baseline in 6-min walk distance (6MWD) at week 12, assessed using analysis of covariance. Patients could continue in a 52-week extension study. An analysis of covariance main-effects model was used, which included categorical terms for treatment, baseline 6MWD (<325 m; ≥325 m), and baseline aetiology; sensitivity analyses were subsequently performed.
In sildenafil versus placebo arms, week-12 6MWD increases were similar (least squares mean difference [sildenafil-placebo], -2.4 m [90% CI: -21.8 to 17.1 m]; P = 0.6); mean ± SD changes from baseline were 26.4 ± 45.7 versus 11.8 ± 57.4 m, respectively, in IPAH (65% of population) and -18.3 ± 82.0 versus 17.5 ± 59.1 m in APAH-CTD (35% of population). One-year survival was 96%; patients maintained modest 6MWD improvements. Changes in WHO functional class and Borg dyspnoea score and incidence of clinical worsening did not differ. Headache, diarrhoea, and flushing were more common with sildenafil.
Sildenafil, in addition to stable (≥3 months) bosentan therapy, had no benefit over placebo for 12-week change from baseline in 6MWD. The influence of PAH aetiology warrants future study.
ClinicalTrials.gov NCT00323297 (registration date: May 5, 2006).
很少有对照临床试验支持肺动脉高压（PAH）的口服联合治疗。
将正在服用波生坦（62.5或125毫克，每日两次，稳定剂量≥3个月）的PAH患者（特发性[IPAH]或与结缔组织病相关[APAH-CTD]）随机分组（1:1），分别给予西地那非（20毫克，每日3次；n = 50）或安慰剂（n = 53）。主要终点是第12周时6分钟步行距离（6MWD）相对于基线的变化，采用协方差分析进行评估。患者可继续参加为期52周的延长期研究。使用协方差分析主效应模型，该模型包括治疗、基线6MWD（<325米；≥325米）和基线病因的分类项；随后进行敏感性分析。
在西地那非组和安慰剂组中，第12周时6MWD的增加相似（最小二乘均值差异[西地那非-安慰剂]，-2.4米[90%CI：-21.8至17.1米]；P = 0.6）；在IPAH（占总体的65%）中，相对于基线的平均±标准差变化分别为26.4±45.7米和11.8±57.4米，在APAH-CTD（占总体的35%）中分别为-18.3±82.0米和17.5±59.1米。一年生存率为96%；患者的6MWD保持适度改善。世界卫生组织功能分级、Borg呼吸困难评分的变化以及临床恶化的发生率没有差异。西地那非组头痛、腹泻和面部潮红更为常见。
除了稳定（≥3个月）的波生坦治疗外，西地那非在使6MWD相对于基线在12周内发生变化方面并不比安慰剂更具优势。PAH病因的影响值得未来研究。
ClinicalTrials.gov NCT00323297（注册日期：2006年5月5日）。
