Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH):: randomised, double-blind, placebo-controlled trial
Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH):: randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s0140-6736(04)16723-8
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发表时间：
2004-07-24
期刊：
影响因子：
168.9
通讯作者：
Lüscher, TF
中科院分区：
文献类型：
--
作者：
Anand, I;McMurray, J;Lüscher, TF
背景内皮素受体阻滞剂在实验性和临床心力衰竭中提供血流动力学益处。我们的目的是测量长期内皮素阻断对慢性心力衰竭患者左心室（LV）重构和临床结局的影响。方法642例慢性心力衰竭患者在标准治疗的基础上，在一项随机、双盲、安慰剂对照试验在50-300 mg组中，达卢生坦在6周内上调剂量。主要终点是24周时通过MRI测量的LV收缩末期容积（LVESV）较基线的变化。所有在基线和随访时可评估MRI扫描的患者均纳入分析。在基线和6个月时，可在485例（76%）具有配对MRI数据的患者中评估LVESV。在任何剂量下，LVESV的变化均与安慰剂组无显著差异（10 mg剂量组与安慰剂的平均差异为1.27 mL [95% CI -9.9至12-4]，25 mg组为-1.84 mL [-13.0至9.3]，50 mg组为-5.68 mL [-16.9至5.6]，100 mg时为-4.05 mL [-15.5至7.4]，300 mg时为-4.34 mL [-15.7至7.0]）。71例（11.1%）患者心力衰竭恶化，30例（4.7%）在研究期间死亡，两组之间无差异。解释在接受血管紧张素转换酶抑制剂、β受体阻滞剂或醛固酮拮抗剂的慢性心力衰竭患者中，使用达卢生坦阻断内皮素（A）并不能改善心脏重塑或临床症状或结局。因此，内皮素（A）阻断不太可能作为此类患者的辅助治疗。
Background Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure.Methods 642 patients with chronic heart failure were assigned the oral endothelin(A)-antagonist darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50-300 mg groups, darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis.Findings Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1.27 mL [95% CI -9.9 to 12-4] with 10 mg dose, -1.84 mL [-13.0 to 9.3] with 25 mg, -5.68 mL [-16.9 to 5.6] with 50 mg, -4.05 mL [-15.5 to 7.4] with 100 mg, and -4.34 mL [-15.7 to 7.0] with 300 mg). Heart failure worsened in 71 (11.1%) patients, and 30 (4.7%) died during the study with no difference between groups.Interpretation Endothelin(A) blockade with darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, beta blocker, or aldosterone antagonist. Thus, endothelin(A) blockade is unlikely to be useful as an add-on treatment in such patients.