Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure Primary Results of the ENABLE Trials
Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure Primary Results of the ENABLE Trials
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DOI：
10.1016/j.jchf.2017.02.021
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发表时间：
2017-05-01
影响因子：
13
通讯作者：
Swedberg, Karl
中科院分区：
文献类型：
--
作者：
Packer, Milton;McMurray, John J. V.;Swedberg, Karl
目的 本临床试验的目的是评估波生坦拮抗内皮素受体对严重慢性心力衰竭患者发病率和死亡率的长期影响。 背景 内皮素可能在心力衰竭中发挥作用，但内皮素受体拮抗剂的短期临床试验报告的结果令人失望。缺乏长期试验。 方法 在 2 项相同的双盲试验中，我们将 1,613 名纽约心脏协会功能分级为 IIIb 级且射血分数 < 35% 的 IV 型心力衰竭患者随机分配至接受安慰剂或波生坦（目标剂量 125 mg，每天两次）治疗，中位治疗时间为 1.5 年。每项试验的主要结果是 9 个月时的临床状态（通过分层临床综合评估）；两项试验的主要结局是全因死亡或因心力衰竭住院。 结果 两项试验中波生坦均不影响 9 个月时的临床状态（p = 0.928 和 p = 0.263）。此外，安慰剂组有 321 名患者和波生坦组有 312 名患者死亡或因心力衰竭住院（风险比 [HR]：1.01；95% 置信区间 [CI]：0.86 至 1.18；p = 0.90）。波生坦组在前 2 至 4 周内出现液体潴留，表现为外周水肿增加、体重增加、血红蛋白减少以及心力衰竭住院风险增加，尽管背景利尿剂有所强化。随访期间，安慰剂组有 173 名患者死亡，波生坦组有 160 名患者死亡（HR：0.94；95% CI：0.75 至 1.16）。波生坦组中约 10% 的患者肝转氨酶显着升高，但没有人出现急性或慢性肝衰竭。 结论 波生坦没有改善严重慢性心力衰竭患者的临床病程或自然病程，但引起早期和重要的液体潴留。 (J Am Coll Cardiol HF 2017;5:317-26) (C) 2017 年，美国心脏病学会基金会。
OBJECTIVES The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure.BACKGROUND Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking.METHODS In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class Illb to IV heart failure and an ejection fraction < 35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure.RESULTS Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure.CONCLUSIONS Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention. (J Am Coll Cardiol HF 2017;5:317-26) (C) 2017 by the American College of Cardiology Foundation.