Editorials
Here Comes a Novel Heart-Rate Reducing Therapy in Heart Failure Treatment
2016 Volume 80 Issue 3 Pages 594-595
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2016 Volume 80 Issue 3 Pages 594-595
Ivabradine is a novel heart-rate reducing agent that inhibits the pacemaker current (If) of cardiac sinoatrial node cells with limited inotropic side effects. Ivabradine is a promising agent that prevents myocardial ischemia and treats symptoms in patients with stable angina pectoris, where heart-rate reducing is beneficial because it decreases the oxygen requirement of cardiac muscle.1 In the BEAUTIFUL trial, ivabradine did not show clinical benefit in patients with coronary artery disease and left ventricular systolic dysfunction (ejection fraction <40%) in sinus rhythm with heart rate ≥60 beats/min.2 The subgroup analysis suggested that ivabradine improved outcomes in patients who had a heart rate ≥70 beats/min.3 In the SHIFT trial, symptomatic heart failure (HF) patients with left ventricular systolic dysfunction (ejection fraction ≤35%) had a higher baseline heart rate ≥70 beats/min and a greater heart rate reduction by ivabradine than in the BEAUTIFUL trial, and ivabradine significantly reduced cardiovascular death or hospital admission for worsening HF. In the placebo group, risk for the primary endpoint events increased by 16% with every 5-beats/min increase from baseline heart rate.4 In the subgroup analysis of the SHIFT trial, there were significant treatment effects only in patients with a baseline heart rate higher than the median 77 beats/min.5
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The ESC guidelines recommend that ivabradine should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an ejection fraction ≤35%, a heart rate remaining ≥70 beats/min, and persistent symptoms (NYHA class II–IV) despite treatment with evidence-based medical treatment.6 Recently, the European Medicines Agency (EMA) approved ivabradine for treatment of patients with HF and systolic dysfunction receiving guideline-based recommended background therapy, including β-blockers or when β-blockers are contraindicated or poorly tolerated, provided the resting heart rate is ≥75 beats/min. The subgroup analysis of SHIFT using the cut off value recommended by EMA demonstrated that ivabradine significantly reduces all clinical outcomes in the ≥75 bpm group but not in the <75 bpm group.7 Further, the effect of ivabradine on outcomes is greater in the ≥75 beats/min group, with heart rates achieved of <60 beats/min or heart rate reduction of >10 beats/min predicting best risk reduction.
In this issue of the Journal, a placebo-controlled phase II study was designed to investigate the efficacy and safety of ivabradine in 126 Japanese patients with symptomatic HF and ejection fraction <35% in sinus rhythm with heart rate ≥75 beats/min.8 The initial dose was 2.5 or 5 mg twice daily (BID) of ivabradine, and the dose was increased up to a final dose of 7.5 mg BID in 73.8% in the 2.5-mg and in 84.6% in the 5-mg groups. The heart rate reduction of 16 beats/min after 6 weeks after ivabradine treatment was greater in this study compared with the BEAUTIFUL and SHIFT trials, which was comparable to data from the subgroup analysis of SHIFT (baseline heart rate ≥75 beats/min).7 Because ivabradine is an open-channel blocker and inhibits the If current in a use-dependent manner (Figure 1), it is reasonable that patients with high resting heart rates are suitable for ivabradine treatment.9
Effect of ivabradine on the If current in a use-dependent manner.
It is well known that resting heart rate is a strong predictor, as well as a risk factor, of mortality and morbidity in patients with HF.10 The CHART-2 study, one of the largest HF cohort studies in Japan, demonstrated that patients with systolic blood pressure <89 mmHg, or those with systolic blood pressure 89–115 mmHg and heart rate >76 beats/min, are defined as a high-risk group with a mortality rate >20% using CART analysis.11 Although β-blockers are widely used to reduce mortality in patients with HF and systolic dysfunction,12 patients with high resting heart rates despite usage of β-blockers or those with β-blocker intolerance because of low systolic blood pressure seem to have a poor prognosis. In this phase II study of ivabradine,8 117 (92.9%) patients had β-blocker therapy and 74 of 117 (63.3%) patients were treated with at least 50% of the target dose defined by the Japanese guidelines.13 Ivabradine can reduce heart rate without decreasing systolic blood pressure. Figure 2 shows the possible mechanism by which ivabradine improves cardiac function in patients with HF. Heart-rate reduction decreases energy expenditure, increases blood supply by prolonging diastole, improves force-frequency associations, and improves vascular elastance, resulting in left ventricular unloading.4
Possible mechanism by which ivabradine improves failing heart function. Heart rate reduction decreases energy expenditure, increases blood supply by prolonging diastole, and improves force-frequency associations. Furthermore, heart rate reduction improves vascular elastance, leading to left ventricular unloading.
The adverse events were fewer in the 2.5-mg group than in the 5-mg group although all adverse events were similar to those reported in the SHIFT trial.5 The incidence of phosphenes (9.5%) was higher in the present study compared with the SHIFT trial (2.8%), but phosphenes were mild and improved during the study. B-type natriuretic peptide (BNP) and NT-proBNP levels were significantly increased in the 5-mg group. Because the observation period was short and the number of patients was small, further study is required to elucidate whether this increase in biomarkers reflects clinical adverse events.
In the very recent SIGNIFY trial, ivabradine showed no clinical benefit in 19,102 patients with stable coronary artery disease without clinical HF in sinus rhythm with heart rates ≥70 beats/min.14 It was suggested that ivabradine has more effect in patients with non-ischemic HF than in those with ischemic HF.15 The present phase II study8 included more patients with non-ischemic HF (60% vs. 35%) compared with the SHIFT trial. Ivabradine may be a promising agent for Japanese patients with HF because the prevalence of non-ischemic HF is higher than that of ischemic HF in Japan.
