McGoon Michael D, Frost Adaani E, Oudiz Ronald J, Badesch David B, Galie Nazzareno, Olschewski Horst, McLaughlin Vallerie V, Gerber Michael J, Dufton Chris, Despain Darrin J, Rubin Lewis J
Mayo Clinic, Rochester, MN.
Baylor College of Medicine, Houston, TX.
Chest. 2009 Jan;135(1):122-129. doi: 10.1378/chest.08-1028. Epub 2008 Sep 23.
Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population.
Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs.
Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed.
Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities.
Clinicaltrials.gov Identifier NCT00423592.
一些内皮素受体拮抗剂（ERA）与肝功能检查（LFT）结果异常有关。然而，安立生坦血清转氨酶水平超过正常上限（ULN）三倍的发生率，与未接受ERA治疗的肺动脉高压（PAH）患者中观察到的情况相似。由于安立生坦可能对因LFT异常而停用ERA治疗的PAH患者有益，我们评估了安立生坦在该患者群体中的安全性和有效性。
因LFT异常而先前停用波生坦和/或西他生坦的患者接受安立生坦治疗，起始剂量为2.5mg每日一次，持续4周，随后为5mg/天，持续8周。主要终点是研究者认为与安立生坦相关且导致停药的转氨酶水平超过ULN三倍的发生率。次要终点包括转氨酶水平超过ULN五倍需要停药以及超过ULN三倍需要减量，以及6分钟步行距离（6MWD）、Borg呼吸困难指数、世界卫生组织功能分级和简明健康调查36项量表（Short Form-36）评分的变化。患者在12周终点后继续治疗，每月监测LFT。
36例先前停用波生坦（n = 31）、西他生坦（n = 2）或两者（n = 3）的患者入组。基线时，69.4%的患者接受前列环素和/或西地那非治疗。没有患者的转氨酶水平超过ULN三倍而需要停用安立生坦。1例患者转氨酶水平短暂超过ULN三倍，在临时减量后恢复正常。长期治疗（中位暴露时间102周）未观察到额外的转氨酶水平超过ULN三倍的情况，尽管超过一半的患者剂量增加至每日10mg。观察到6MWD和其他疗效评估有显著改善。
对于因LFT结果异常而停用波生坦和/或西他生坦治疗的患者，安立生坦治疗可能是一种选择。
Clinicaltrials.gov标识符NCT00423592。
