BACKGROUND Heart rate reduction as a therapeutic target has been investigated in adults with heart failure (HF). Ivabradine has shown promising efficacy, but has not been evaluated in children. Currently, treatment recommendations for chronic pediatric HF are based mainly on chronic HF guidelines for adults. OBJECTIVES The authors explored the dose-response relationship of ivabradine in children with dilated cardiomyopathy and symptomatic chronic HF. The primary endpoint was ≥20% reduction in heart rate from baseline without inducing bradycardia or symptoms. METHODS This was a randomized, double-blind, placebo-controlled, phase II/III study with 12 months of follow-up. Children (n = 116) receiving stable HF therapy were randomized to either ivabradine or placebo. After an initial titration period, the dose was adjusted to attain the primary endpoint. Left ventricular function (echocardiography), clinical status (New York Heart Association functional class or Ross class), N-terminal pro-B-type natriuretic peptide, and quality of life (QOL) were assessed. RESULTS The primary endpoint was reached by 51 of 73 children taking ivabradine (70%) versus 5 of 41 taking placebo (12%) at varying doses (odds ratio: 17.24; p < 0.0001). Between baseline and 12 months, there was a greater increase in left ventricular ejection fraction in patients taking ivabradine than placebo (13.5% vs. 6.9%; p = 0.024). New York Heart Association functional class or Ross class improved more with ivabradine at 12 months than placebo (38% vs. 25%; p = 0.24). There was a trend toward improvement in QOL for ivabradine versus placebo (p = 0.053). N-terminal pro-B-type natriuretic peptide levels decreased similarly in both groups. Adverse events were reported at similar frequencies for ivabradine and placebo. CONCLUSIONS Ivabradine safely reduced the resting heart rate of children with chronic HF and dilated cardiomyopathy. Ivabradine's effect on heart rate was variable, highlighting the importance of dose titration. Ivabradine treatment improved left ventricular ejection fraction, and clinical status and QOL showed favorable trends. (Determination of the efficacious and safe dose of ivabradine in paediatric patients with dilated cardiomyopathy and symptomatic chronic heart failure from ages 6 months to 18 years; ISRCTN60567801).

中文翻译：

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伊伐布雷定用于扩张型心肌病和有症状的慢性心力衰竭儿童

背景已在患有心力衰竭(HF)的成人中研究了作为治疗目标的心率降低。伊伐布雷定已显示出有希望的疗效，但尚未在儿童中进行评估。目前，慢性儿科 HF 的治疗建议主要基于成人慢性 HF 指南。目的 作者探讨了伊伐布雷定对扩张型心肌病和症状性慢性 HF 儿童的剂量反应关系。主要终点是心率从基线降低 20% 以上，而不会引起心动过缓或症状。方法 这是一项随机、双盲、安慰剂对照、II/III 期研究，随访 12 个月。接受稳定 HF 治疗的儿童（n = 116）随机接受伊伐布雷定或安慰剂。在最初的滴定期后，调整剂量以达到主要终点。评估了左心室功能（超声心动图）、临床状态（纽约心脏协会功能分级或罗斯分级）、N 端前 B 型利钠肽和生活质量 (QOL)。结果 以不同剂量服用伊伐布雷定的 73 名儿童中的 51 名 (70%) 达到了主要终点，而服用不同剂量的安慰剂的 41 名儿童中的 5 名 (12%) 达到了主要终点（优势比：17.24；p < 0.0001）。在基线和 12 个月之间，与安慰剂相比，服用伊伐布雷定的患者左心室射血分数的增加更大（13.5% 对 6.9%；p = 0.024）。纽约心脏协会功能分级或罗斯分级在 12 个月时使用伊伐布雷定比安慰剂改善更多（38% 对 25%；p = 0.24）。伊伐布雷定与安慰剂相比，QOL 有改善的趋势（p = 0.053）。两组的 N 端前 B 型利钠肽水平下降相似。伊伐布雷定和安慰剂的不良事件报告频率相似。结论 伊伐布雷定安全地降低了慢性 HF 和扩张型心肌病儿童的静息心率。伊伐布雷定对心率的影响是可变的，突出了剂量滴定的重要性。伊伐布雷定治疗改善左心室射血分数，临床状态和 QOL 显示出良好的趋势。（确定 6 个月至 18 岁患有扩张型心肌病和有症状的慢性心力衰竭的儿科患者伊伐布雷定的有效和安全剂量；ISRCTN60567801）。结论 伊伐布雷定安全地降低了慢性 HF 和扩张型心肌病儿童的静息心率。伊伐布雷定对心率的影响是可变的，突出了剂量滴定的重要性。伊伐布雷定治疗改善左心室射血分数，临床状态和 QOL 显示出良好的趋势。（确定 6 个月至 18 岁患有扩张型心肌病和有症状的慢性心力衰竭的儿科患者伊伐布雷定的有效和安全剂量；ISRCTN60567801）。结论 伊伐布雷定安全地降低了慢性 HF 和扩张型心肌病儿童的静息心率。伊伐布雷定对心率的影响是可变的，突出了剂量滴定的重要性。伊伐布雷定治疗改善左心室射血分数，临床状态和 QOL 显示出良好的趋势。（确定 6 个月至 18 岁患有扩张型心肌病和有症状的慢性心力衰竭的儿科患者伊伐布雷定的有效和安全剂量；ISRCTN60567801）。