Elsevier

The Lancet

Volume 376, Issue 9744, 11–17 September 2010, Pages 875-885
The Lancet

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

https://doi.org/10.1016/S0140-6736(10)61198-1Get rights and content

Summary

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.

Introduction

Chronic heart failure is common, disabling, and serious. It affects roughly 2–3% of the population in many industrialised countries.1 Even with existing treatment, which has substantially improved outcomes in the past two decades,2, 3 prognosis is fairly poor. Development of novel therapeutic approaches for the treatment of this disorder is crucial. Standard pharmacological treatment includes β blockers and renin-angiotensin-aldosterone system (RAAS) antagonists.1 β blockers have reduced morbidity and mortality beyond what is achieved with RAAS antagonists alone.4 Additional benefits of these drugs in the management of chronic heart failure include improved left-ventricular remodelling5 and reduction in sudden deaths.6 These benefits seem to be linked, at least in part, to their heart-rate-lowering properties.7, 8 Heart-rate reduction could be particularly important in chronic heart failure—eg, by attenuating the effect of energy starvation of the myocardium.9 However, in addition to their attenuating effect on heart rate, β blockers have other undesired actions on the heart, including an effect on myocardial contractility.

Raised resting heart rate is a risk factor for mortality and cardiovascular outcomes in epidemiological and observational studies.10, 11 In patients with coronary artery disease and left-ventricular dysfunction, a heart rate of 70 beats per minute (bpm) or higher was associated with a 34% increased risk of cardiovascular death and a 53% increase in admission to hospital for heart failure compared with heart rate lower than 70 bpm.12 Heart rate is also directly related to risk of death, cardiovascular death, or admission to hospital in patients with heart failure,13 and heart-rate reduction is associated with improved outcomes.14 However, heart rate remains increased in most patients treated with β blockers,15 which constitutes a further reason to seek new therapeutic strategies.

Ivabradine is a specific inhibitor of the If current in the sinoatrial node.16 Results of studies in healthy hearts suggest that, at concentrations achieved during therapeutic use, ivabradine has no action on other channels in the heart or vascular system. Unlike β blockers, ivabradine does not modify myocardial contractility and intracardiac conduction, even in patients with impaired systolic function.17 We designed the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) with the aim of evaluating the effect of ivabradine in addition to guidelines-based treatment on cardiovascular outcomes, symptoms, and quality of life in patients with chronic heart failure and systolic dysfunction.

Section snippets

Study design and patients

SHIFT was an event-driven, multinational, randomised, double-blind, placebo-controlled, parallel-group clinical trial in patients with moderate-to-severe heart failure and left-ventricular systolic dysfunction. The study was undertaken in 677 centres in 37 countries. Eligible patients were men or women aged 18 years and older who were in sinus rhythm and had a resting heart rate of 70 bpm or higher, as measured on 12-lead electrocardiography (ECG) after at least 5-min rest on two consecutive

Results

Figure 1 shows the trial profile. 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Of these, no data were available for seven patients who were assigned to treatment, but not dispensed study drug. During follow-up, two centres (including their 46 patients) were removed from the trial before unmasking because of invalid data caused by misconduct as detected during study audit. Therefore, the results are based on 6505 patients (3241 ivabradine, 3264

Discussion

Our results show that ivabradine substantially and significantly reduced major risks associated with heart failure when added to guideline-based and evidence-based treatment. Thus, in patients treated with ivabradine, relative risk of the primary endpoint (cardiovascular death or hospital admission for worsening heart failure) fell by 18% compared with placebo treatment. This finding was mainly the result of a favourable effect on heart failure events (death or hospital admission due to heart

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  • Cited by (2118)

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