甲磺酸伊马替尼作为肺动脉高压的附加治疗：随机 IMPRES 研究的结果。
Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study.
机构信息
Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany.
出版信息
Circulation. 2013 Mar 12;127(10):1128-38. doi: 10.1161/CIRCULATIONAHA.112.000765. Epub 2013 Feb 12.
BACKGROUND
By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH).
METHODS AND RESULTS
Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥ 800 dyne·s·cm(-5) symptomatic on ≥ 2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12-52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm(-5) (95% confidence interval, -502 to - 255; P<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation.
CONCLUSIONS
Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174 (core study); NCT01392495 (extension).
背景
通过抑制血小板衍生生长因子信号，伊马替尼可能对治疗肺动脉高压（PAH）患者有效。
方法和结果
在肺动脉高压中使用伊马替尼的一项随机、疗效研究（IMPRES）是一项随机、双盲、安慰剂对照的 24 周试验，评估了伊马替尼在肺动脉阻力≥800 达因·秒·厘米^-5 的患者中的疗效，这些患者在接受≥2 种 PAH 治疗后仍有症状。主要终点是 6 分钟步行距离的变化。次要终点包括血流动力学、功能分级、血清 N 端脑钠肽水平的变化以及临床恶化时间。在核心研究完成后，患者可以进入开放标签的长期扩展研究。在 202 名入组患者中，41%的患者接受了 3 种 PAH 治疗，其余患者接受了 2 种治疗。24 周后，6 分钟步行距离的平均安慰剂校正治疗效果为 32 米（95%置信区间，12-52；P=0.002），在继续接受伊马替尼治疗的患者中，这种效果在扩展研究中得以维持。肺动脉阻力下降了 379 达因·秒·厘米^-5（95%置信区间，-502 至-255；P<0.001，组间差异）。治疗之间的功能分级、临床恶化时间和死亡率没有差异。伊马替尼的严重不良事件和停药率高于安慰剂（分别为 44%比 30%和 33%比 18%）。接受伊马替尼和抗凝治疗的患者中有 8 例（核心研究 2 例，扩展研究 6 例）发生硬膜下血肿。
结论
伊马替尼改善了晚期 PAH 患者的运动能力和血流动力学，但严重不良事件和研究药物停药较为常见。需要进一步研究伊马替尼在 PAH 患者中的长期安全性和疗效。
临床试验注册
网址：http://www.clinicaltrials.gov。唯一标识符：NCT00902174（核心研究）；NCT01392495（扩展）。
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