依伐布雷定治疗慢性心力衰竭的疗效评价（SHIFT）：一项随机、安慰剂对照研究

Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.

机构信息

Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.

出版信息

Lancet. 2010 Sep 11;376(9744):875-85. doi: 10.1016/S0140-6736(10)61198-1.

DOI:10.1016/S0140-6736(10)61198-1

PMID:20801500

Abstract

BACKGROUND

Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure.

METHODS

Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a β blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7.5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960.

FINDINGS

6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22.9 (IQR 18-28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 0.82, 95% CI 0.75-0.90, p<0.0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 [21%] placebo vs 514 [16%] ivabradine; HR 0.74, 0.66-0.83; p<0.0001) and deaths due to heart failure (151 [5%] vs 113 [3%]; HR 0.74, 0.58-0.94, p=0.014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0.025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p<0.0001). Visual side-effects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p<0.0001).

INTERPRETATION

Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder.

FUNDING

Servier, France.

摘要

背景

慢性心力衰竭与高死亡率和高发病率相关。静息心率升高是不良结局的危险因素。我们旨在评估选择性窦房结抑制剂伊伐布雷定降低心率对心力衰竭患者结局的影响。

方法

如果患者有症状性心力衰竭且左心室射血分数为 35%或更低、窦性心律且心率为 70 次/分钟或更高、在过去一年内因心力衰竭住院、并且正在接受稳定的背景治疗（如果耐受，则包括β受体阻滞剂），则符合参加这项随机、双盲、安慰剂对照、平行组研究的条件。患者通过计算机生成的分配方案随机分配至伊伐布雷定滴定至最大剂量 7.5mg 每日两次或匹配的安慰剂。患者和研究者对治疗分配均不知情。主要终点是心血管死亡或因心力衰竭恶化而住院的复合终点。分析采用意向治疗。该试验已注册，注册号为 ISRCTN70429960。

结果

6558 例患者被随机分配至治疗组（伊伐布雷定 3268 例，安慰剂 3290 例）。伊伐布雷定组 3241 例和安慰剂组 3264 例患者的数据可用于分析。伊伐布雷定组的中位随访时间为 22.9（IQR 18-28）个月。伊伐布雷定组有 793 例（24%）患者和安慰剂组有 937 例（29%）患者发生主要终点事件（HR 0.82，95%CI 0.75-0.90，p<0.0001）。这些效果主要归因于因心力衰竭恶化而住院的患者（安慰剂组 672 例[21%] vs 伊伐布雷定组 514 例[16%]；HR 0.74，0.66-0.83；p<0.0001）和心力衰竭死亡患者（安慰剂组 151 例[5%] vs 伊伐布雷定组 113 例[3%]；HR 0.74，0.58-0.94，p=0.014）。伊伐布雷定组发生严重不良事件（3388 例事件）的人数少于安慰剂组（3847 例事件）（p=0.025）。伊伐布雷定组有 150 例（5%）患者出现有症状的心动过缓，而安慰剂组有 32 例（1%）（p<0.0001）。伊伐布雷定组有 89 例（3%）患者报告出现视觉副作用（光幻视），而安慰剂组有 17 例（1%）（p<0.0001）。