Böhm M, Borer JS, Camm J, et al.
European Journal of Heart Failure 2015; doi:10.1002/ejhf.258

Background

Heart failure (HF) is related to increased sympathetic activity and reduced vagal activity, which results in an increase in heart rate (HR) with reduced heart rate variability (HRV) [1-3]. Improvement in HRV is associated with beneficial outcomes in HF patients [4-6].
The SHIFT trial (Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial) evaluated the effect of the specific HR-slowing drug ivabradine, on top of guideline-based background therapy, in patients with moderate to severe HF, a left ventricular ejection fraction (LVEF) ≤35%, and resting HR ≥70 b.p.m. Ivabradine acts by inhibiting the I_f current in the sinoatrial node and its addition resulted in a reduction in cardiovascular death or hospitalisation for worsening HF [7].
The present pre-specified SHIFT substudy aimed to: 1) evaluate the effect of ivabradine compared with placebo on HRV and safety parameters (24-h Holter ECG recordings), and 2) detect conduction or rhythm disorders with ivabradine treatment. The 24-h Holter monitoring was conducted in systolic HF patients (New York Heart Association (NYHA) class II, III, and IV) with at baseline and 8 months after randomisation to ivabradine (n = 298) or matching placebo (n = 304).

Main results

• Mean HR at baseline was 75.2±10.1 b.p.m. (similar in the two groups).  Mean 24-h HR was reduced by 9.5±10.0 b.p.m in ivabradine treated patients vs. 1.2±8.9 b.p.m. in placebo-treated patients (P <0.0001).
• At 8 months, more ivabradine-treated patients had episodes of bradycardia with HR <40 b.p.m. than patients treated with placebo (21.3% vs. 8.5%; P < 0.0001). 
• RR intervals between 2 and 2,5 seconds occurred more frequently in the ivabradine group (than in the placebo group. 1.2% of the ivabradine treated patients had RR intervals >2.5 s vs. 1.6% in the placebo group. No RR intervals >3 s were identified in patients taking ivabradine.
• The HR lowering by ivabradine showed similar effects on resting, asleep, awake, and 24-h HR, suggesting that these Holter parameters are potentially suitable for identification of HF patients with HR ≥70 b.p.m. and candidates for treatment with ivabradine.
• Ivabradine yielded beneficial effects on HRV, without significant increases in supraventricular or ventricular arrhythmias.

Conclusions

The SHIFT Holter substudy showed that ivabradine safely lowered HR and improved HRV parameters in patients with systolic HF. Ivabradine, on top of beta-blockers and ACE inhibitors or ARBs, improved autonomic imbalance in HF without inducing significant bradycardia, ventricular arrhythmias, or supraventricular arrhythmias. As these results were based on two 24-hour Holter recordings, arrhythmic incidents may have remained undetected.
HRV improvements in HF patients treated with ivabradine may be associated with a prolonged diastole leading to improved cardiac blood supply and LV filling, beneficial effects on LV remodelling, or reduced sympathetic influence and enhanced vagal tone, improving sympathovagal balance. The 24-h Holter parameters in the present study are potentially suitable for identification of HF patients with HR ≥70 b.p.m. and candidates for treatment with ivabradine.

Find this article online at European Journal of Heart Failure

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