盐酸伊伐布雷定治疗中国慢性心力衰竭患者的有效性及安全性评价：SHIFT研究中国亚组数据分析

Efficacy and safety analysis of ivabradine hydrochloride treatment of Chinese patients with chronic heart failure：subgroup analysis of Chinese patients in the SHIFT study

目的分析伊伐布雷定与慢性心力衰竭（心衰）预后研究（SHIFT研究）中国亚组数据，评估中国慢性心衰患者使用伊伐布雷定的有效性和安全性。方法SHIFT研究为随机、双盲、平行组设计、安慰剂对照、国际多中心临床研究，共纳入6 558例有症状的慢性心衰患者。患者满足年龄≥18岁，窦性心律，静息心率≥70次/min，左心室射血分数（LVEF）≤35%，入选前接受最佳剂量的慢性心衰药物治疗并且至少持续4周未更改，过去12个月内曾因心衰恶化入院治疗。本研究对入组患者中心率≥75次/min的中国患者进行了亚组事后分析。全部入选患者按计算机生成的分配方案通过电话互动语音应答系统随机分为2组，即伊伐布雷定组（5 mg每日2次起始，递增至最大剂量7.5 mg每日2次）和匹配的安慰剂组。收集入选者的临床基线特征。主要疗效终点为心血管死亡或心衰恶化所致再入院的复合终点，主要安全性终点包括研究中观察到的总不良事件数、心动过缓以及视觉不良反应（眼内闪光）。结果研究共入选2008年4月至2010年3月在中国49家中心就诊的心率≥75次/min的慢性心衰患者225例，其中伊伐布雷定组106例，安慰剂组119例，平均随访时间（15.6±5.1）个月。至研究结束时，伊伐布雷定组患者平均心率显著低于安慰剂组（71.0次/min比80.3次/min，P〈0.05），主要终点事件发生率显著低于安慰剂组[18.9%（20/106）比31.9%（38/119），HR＝0.56，95%CI 0.33～0.97，P＝0.039]，纽约心脏协会（NYHA）心功能分级改善的患者比例显著高于安慰剂组[52.8%（56/106）比34.5%（41/119）, P＝0.006 1]。伊伐布雷定组患者总不良事件数（129次，49.6%患者年）少于安慰剂组（203次，50.8%患者年），伊伐布雷定组和安慰剂组分别有2例（1.9%）和0例发生心动过缓，3例（2.9%）和1例（0.8%）发生视觉不良反应（眼内闪光）。结论伊伐布雷定减慢心率的治疗作用可改善中国慢性心衰患者临床预后和心功能，且不伴有明显不良反应，本亚组分析与SHIFT总体研究结果保持一致。

ObjectiveTo evaluate the efficacy and safety of ivabradine for the treatment of Chinese patients with chronic heart failure based on the Chinese subgroup data of the systolic heart failure treatment with the If inhibitor ivabradine trial （SHIFT）.MethodA total of 6 558 stable outpatients who presented symptoms of heart failure, with a left ventricular ejection fraction （LVEF） ≤35%, sinus rhythms with a heart rate ≥70 bpm participated in the randomized, double-blind, placebo-controlled, international multicenter clinical study.The subset of Chinese patients with heart rate ≥75 bpm was enrolled in the post-hoc subgroup analyses.Patients were randomly allocated by computer-generated assignment through a telephone interactive voice response system to ivabradine group （starting dose 5 mg bid, which was then uptitrated to the maximum 7.5 mg bid） or matched placebo group.The clinical baseline characteristics of participants were obtained and analyzed.The primary outcome endpoint was a composite endpoint of cardiovascular death or hospitalization resulting from worsening HF.The primary safety endpoint included total incidence of adverse events during the study, bradycardia, and adverse visual reaction （phosphenes）.ResultsA total of 49 Chinese centers enrolled a total of 225 patients with chronic heart failure, of whom, 106 patients were randomized to the ivabradine group and the other 119 patients to the placebo group, and the mean follow-up time was （15.6±5.1） months.By the end of the study, mean heart rate （71.0 bpm vs. 80.3 bpm, P〈0.05） and incidence of the primary endpoint events （18.9% （20/106） vs. 31.9%（38/119）, HR=0.56, 95%CI 0.33-0.97, P=0.039） were significantly lower, while the percentage of patients with improvement in heart functional class NYHA （53.8% （56/106） vs. 34.5% （41/119）, P=0.006 1） was significantly higher in the ivabradine group than in the placebo group.The total number of adverse events （129 events, 49.6% PY） in the ivabradine group was lower than that in the placebo group （203 events, 50.8% PY）. In the ivabradine group and the placebo group, there were respectively 2 patients （1.9%） and 0 patients experienced bradycardia, 3 patients （2.9%） and 1 patient （0.8%） experienced adverse visual reaction （phosphenes）.ConclusionsIvabradine significantly reduced heart rate and improved the clinical outcomes and NYHA function class in Chinese patients with chronic heart failure, these beneficial effects are achieved without inducing remarkable adverse reactions.The results of Chinese subgroup analysis were thus consistent with the overall results of the SHIFT study.