Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study
Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study
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DOI：
10.1016/s2213-2600(16)30307-1
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发表时间：
2016-11-01
影响因子：
76.2
通讯作者：
Vachiery, Jean-Luc
中科院分区：
文献类型：
--
作者：
Hoeper, Marius M.;McLaughlin, Vallerie V.;Vachiery, Jean-Luc
背景 在初治肺动脉高压患者中，与单药治疗相比，安立生坦和他达拉非的初始联合治疗可降低临床失败事件的风险。我们进行了二次分析，以进一步研究联合治疗对生存的影响。方法我们分析了肺动脉高压患者 (AMBITION) 试验中安立生坦和他达拉非改良意向治疗人群的生存数据。 AMBITION 是一项多中心、随机、双盲研究，其中未接受治疗的肺动脉高压患者以 2:1:1 的比例随机分配，并接受安贝生坦和他达拉非、安贝生坦和安慰剂、或他达拉非和安慰剂的联合治疗。我们对从随机分组到研究结束的所有死亡事件进行了预先指定的分析，包括停止指定治疗的患者。在事后分析中，我们分析了每位患者随机治疗结束后 7 天的生存率。我们使用 Cox 比例风险回归、Kaplan-Meier 生存估计和分层对数秩检验来比较接受初始联合治疗或初始单一治疗的患者的生存率。 结果 研究人群由 605 名肺动脉高压患者组成，他们被随机分配并接受联合治疗 (n = 302) 或单一治疗 (n = 303；152 名患者分配至安立生坦单药治疗，151 名患者接受他达拉非单药治疗)。研究结束时，联合治疗组 302 名患者中有 29 名（10%）死亡，而单药治疗组 303 名患者中有 41 名（14%）死亡（风险比 0.67，95% CI 0.42-1.08；分层对数秩 p=0.10）。随机治疗结束后 7 天，与单药治疗组（303 例患者中的 13 例 [4%]；风险比 0.21，95% CI 0.06-0.73）相比，联合治疗组的患者死亡人数较少（302 例患者中的 3 例 [1%]）。 解释 这些数据表明，对于新诊断的肺动脉高压患者，与初始单药治疗相比，初始联合治疗可能与生存优势相关。这一假设需要在未来的研究中得到解决。
Background In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival.Methods We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with ambrisentan and tadalafil, ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy.Findings The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0.67, 95% CI 0.42-1.08; stratified log-rank p=0.10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0.21, 95% CI 0.06-0.73).Interpretation These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies.