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Abstract：
Background and Objectives: Cancer therapy containing anthracyclines is associated with cancer-treatment-related cardiac dysfunction and heart failure (HF). Conventional cardioprotective medications can be frequently complicated by their blood-pressure-lowering effect. Recently, elevated resting heart rate was shown to independently predict mortality in patients with cancer. As a heart rate-lowering drug without affecting blood pressure, ivabradine could present an alternative management of anthracyclines-induced cardiotoxicity. Materials and Methods: This study aimed to investigate the probable protective effects of ivabradine in cancer patients with elevated heart rate (>75 beats per minute) undergoing anthracycline chemotherapy. Patients referred by oncologists for baseline cardiovascular risk stratification before anthracycline chemotherapy who met the inclusion criteria and had no exclusion criteria were randomly assigned to one of two strategies: ivabradine 5 mg twice a day (intervention group) or controls. Electrocardiogram, transthoracic echocardiogram with global longitudinal strain (GLS), troponin I (Tn I), and N-terminal natriuretic pro-peptide (NT-proBNP) were performed at baseline, after two and four cycles of chemotherapy and at six months of follow-up. The primary endpoint was the prevention of a >15% reduction in GLS. Secondary endpoints were effects of ivabradine on Tn I, NT-proBNP, left ventricular (LV) systolic and diastolic dysfunction, right ventricle dysfunction, and myocardial work indices. Results: A total of 48 patients were enrolled in the study; 21 were randomly assigned to the ivabradine group and 27 to the control group. Reduced GLS was detected 2.9 times less often in patients receiving ivabradine than in the control group, but this change was non-significant (OR [95% CI] = 2.9 [0.544, 16.274], p = 0.208). The incidence of troponin I elevation was four times higher in the control group (OR [95% CI] = 4.0 [1.136, 14.085], p = 0.031). There was no significant change in NT-proBNP between groups, but the increase in NT-proBNP was almost 12% higher in the control group (OR [95% CI] = 1.117 [0.347, 3.594], p = 0.853). LV diastolic dysfunction was found 2.7 times more frequently in the controls (OR [95% CI] = 2.71 [0.49, 15.10], p = 0.254). Patients in the ivabradine group were less likely to be diagnosed with mild asymptomatic CTRCD during the study (p = 0.045). No differences in right ventricle function were noted. A significant difference was found between the groups in global constructive work and global work index at six months in favour of the ivabradine group (p = 0.014 and p = 0.025). Ivabradine had no adverse effects on intracardiac conduction, ventricular repolarization, or blood pressure. However, visual side effects (phosphenes) were reported in 14.3% of patients. Conclusions: Ivabradine is a safe, well-tolerated drug that has shown possible cardioprotective properties reducing the incidence of mild asymptomatic cancer-therapy-induced cardiac dysfunction, characterised by a new rise in troponin concentrations and diminished myocardial performance in anthracycline-treated women with breast cancer and increased heart rate. However, more extensive multicentre trials are needed to provide more robust evidence.
摘要：
背景和目的：含蒽环类药物的癌症治疗与癌症治疗相关的心功能不全和心力衰竭（HF）有关。常规的心脏保护药物经常因其降低血压的作用而变得复杂。最近,静息心率升高可独立预测癌症患者的死亡率.作为一种不影响血压的降低心率的药物，伊伐布雷定可以提供蒽环类药物引起的心脏毒性的替代治疗。材料和方法：本研究旨在研究伊伐布雷定对蒽环类化疗患者心率升高（>75次/分钟）的可能的保护作用。符合纳入标准且没有排除标准的蒽环类化疗前由肿瘤学家转诊的基线心血管风险分层患者被随机分配到两种策略之一：伊伐布雷定每天两次（干预组）或对照。心电图,经胸超声心动图整体纵向应变（GLS），肌钙蛋白I(TnI),和N末端利钠肽前体（NT-proBNP）在基线进行，经过2个周期和4个周期的化疗和6个月的随访。主要终点是防止GLS降低>15%。次要终点是伊伐布雷定对TnI的影响，NT-proBNP,左心室（LV）收缩和舒张功能障碍，右心室功能障碍,和心肌工作指数。结果：共纳入48例患者，21例随机分配到伊伐布雷定组，27例随机分配到对照组。在接受伊伐布雷定的患者中，GLS降低的频率比对照组低2.9倍，但这一变化并不显著(OR[95%CI]=2.9[0.544，16.274]，p=0.208）。肌钙蛋白I升高的发生率是对照组的四倍(OR[95%CI]=4.0[1.136,14.085],p=0.031)。组间NT-proBNP无明显变化，但NT-proBNP的增加在对照组中几乎高出12%(OR[95%CI]=1.117[0.347,3.594],p=0.853)。在对照组中发现左心室舒张功能障碍的频率增加2.7倍（OR[95%CI]=2.71[0.49,15.10]，p=0.254）。在研究期间，伊伐布雷定组的患者不太可能被诊断为轻度无症状CTRCD（p=0.045）。右心室功能无差异。在六个月时，两组在全球建设性工作和全球工作指数方面存在显着差异，有利于伊伐布雷定组（p=0.014和p=0.025）。伊伐布雷定对心内传导没有不良影响，心室复极,或血压。然而,14.3%的患者报告了视觉副作用(膦).结论：伊伐布雷定是安全的，耐受性良好的药物，显示出可能的心脏保护特性，减少轻度无症状癌症治疗引起的心功能不全的发生率，以蒽环类药物治疗的乳腺癌患者的肌钙蛋白浓度新的升高和心肌功能下降和心率增加为特征。然而,需要更广泛的多中心试验来提供更有力的证据.
