马西替坦可减少肺动脉高压发病和死亡

《新英格兰医学杂志》8月29日在线发表的一项Ⅲ期临床试验结果显示，马西替坦(macitentan)可降低肺动脉高压(PAH)患者的发病率和死亡率，且主要是通过减缓疾病进展发挥作用(N. Engl. J. Med. 2013 Aug. 29 [doi:10.1056/NEJMoa1213917 ])。

墨西哥Ignacio Chavez国立心脏研究所的TomásPulido博士及其同事报告称，马西替坦是一种双向内皮素受体拮抗剂，是在波生坦的基础上进行结构改造而开发出的一种有效性和安全性更佳的药物。在39个国家151家医学中心开展的SERAPHIN试验(内皮素受体拮抗剂改善肺动脉高压患者临床结局的研究)对2种剂量的马西替坦与安慰剂进行了对比研究。受试者为≥12岁的特发性或遗传性PAH，或与结蹄组织疾病、修复后先天性体-肺分流、HIV感染、药物应用或毒物暴露等相关的PAH患者。

受试者被随机分组，分别给予3 mg马西替坦(250例)、10 mg马西替坦(242例)或安慰剂(250例)治疗，1次/日，中位治疗时间为115周。主要终点指标为PAH事件或全因死亡。

结果显示，3 mg马西替坦组和10 mg马西替坦组分别有38%和 31%的患者达到主要终点，而安慰剂组为46%。药物治疗组PAH住院率或死亡率也显著小于安慰剂组，分别为26%、21%和34%。治疗组6分钟步行距离分别增加7.4 m和12.5 m，而安慰剂组减少9.4 m。

同样，治疗组WHO心衰功能分级改善比例高于安慰剂组，分别为20%、22%和13%。此外，与安慰剂组相比，治疗组肺血管阻力显著下降，心脏指数也显著提高。

SERAPHIN试验由爱可泰隆制药公司(Actelion Pharmaceuticals)资助，Pulido博士报告与爱可泰隆、辉瑞、礼来、拜耳、联合治疗及吉利德公司存在利益关系，其同事也报告与数家业内公司存在关联。

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By: MARY ANN MOON, Cardiology News Digital Network

Macitentan reduced morbidity and mortality in patients who had pulmonary arterial hypertension in an industry-sponsored phase III clinical trial, chiefly by slowing progression of the disease, according to a report published online Aug. 29 in the New England Journal of Medicine.

Two doses of macitentan, a dual endothelin receptor antagonist developed by altering the structure of bosentan to enhance efficacy and safety, were tested against placebo in 742 patients treated at 151 medical centers in 39 countries. The study subjects were patients aged 12 and older who had idiopathic or heritable pulmonary arterial hypertension (PAH), or PAH related to connective tissue disease, repaired congenital systemic-to-pulmonary shunts, HIV infection, drug use, or toxin exposure, said Dr. TomásPulido of Ignacio Chavez National Heart Institute, Mexico City, and his associates in SERAPHIN (Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome).

The study subjects were randomly assigned to receive 3-mg macitentan (250 patients), 10-mg macitentan (242 patients), or placebo (250 patients) once daily for a median treatment period of 115 weeks. The primary end point, a composite of a PAH event or death from any cause, was reached by 38% of patients receiving 3-mg macitentan and 31% of those receiving 10-mg macitentan, compared with 46% of patients receiving placebo.

Rates of hospitalization or death due to PAH also were significantly lower in patients who received active treatment, at 26% for 3-mg macitentan and 21% for 10-mg macitentan, compared with 34% for placebo. Six-minute walk distance increased by 7.4 m with 3-mg macitentan and by 12.5 m with 10-mg macitentan, but decreased by 9.4 m with placebo, the investigators said (N. Engl. J. Med. 2013 Aug. 29 [doi:10.1056/NEJMoa1213917]).

Similarly, WHO heart failure functional class improved in 20% of patients receiving 3-mg macitentan and 22% of those receiving 10-mg macitentan, compared with only 13% of those receiving placebo. And patients in both active treatment groups showed significant reductions in pulmonary vascular resistance as well as significant increases in the cardiac index, compared with those in the placebo group.

SERAPHIN was funded by Actelion Pharmaceuticals. Dr. Pulido reported ties to Actelion, Pfizer, Eli Lilly, Bayer, United Therapeutics, and Gilead, and his associates reported ties to numerous industry sources.