Fast track — ArticlesIvabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study
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
References (26)
- et al.
Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial
Lancet
(2008) - et al.
Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers
Am J Cardiol
(2008) Funny channels in the control of cardiac rhythm and mode of action of selective blockers
Pharmacol Res
(2006)- et al.
Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy
Lancet
(1993) - et al.
Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program
J Am Coll Cardiol
(2008) - et al.
Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial
Lancet
(2008) - et al.
Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure—COMET
Am Heart J
(2005) - et al.
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM)
Eur J Heart Fail
(2008) - et al.
Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003: a population study of 5.1 million people
Circulation
(2009) - et al.
Survival trends in men and women with heart failure of ischaemic and non-ischaemic origin: data for the period 1987–2003 from the Swedish Hospital Discharge Registry
Eur Heart J
(2009)
Beta-blockers in chronic heart failure
Circulation
Ventricular remodeling in heart failure and the effect of beta-blockade
Am J Cardiol
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)
Lancet
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