Twenty-four-hour heart rate lowering with ivabradine in chronic heart failure: insights from the SHIFT Holter substudy

AimsAnalysis of 24-h Holter recordings was a pre-specified substudy of SHIFT (Systolic Heart Failure Treatment with the I-f Inhibitor Ivabradine Trial) for exploring the heart rhythm safety of ivabradine and to determine effects of ivabradine on 24-h, daytime, and night-time heart rate (HR) compared with resting office HR. Methods and resultsThe 24-h Holter monitoring was performed at baseline and 8months after randomization to ivabradine (n = 298) or matching placebo (n = 304) titrated maximally to 7.5mg b.i.d. in patients with baseline HR 70 b.p.m. Patients received guideline-based optimized heart failure therapy including ACE inhibitors and/or ARBs in 93% and beta-blockers at maximally tolerated doses in 93%. After 8months, HR over 24h decreased by 9.510.0 b.p.m. with ivabradine, from 75.4 +/- 10.3 b.p.m. (P < 0.0001), and by 1.2 +/- 8.9 b.p.m. with placebo, from 74.8 +/- 9.7 b.p.m. (P < 0.0001 for difference vs. ivabradine). HR reduction with ivabradine was similar in resting office and in 24-h, awake, and asleep recordings, with beneficial effects on HR variability and no meaningful increases in supraventricular or ventricular arrhythmias. At 8months, 21.3% on ivabradine vs. 8.5% on placebo had 1 episode of HR <40 b.p.m. (P < 0.0001). No episode of HR <30 b.p.m. was recorded; 3 (1.2%) patients had RR intervals >2.5s on ivabradine vs. 4 (1.6%) patients on placebo. No RR intervals >3s were identified in patients taking ivabradine. Conclusion Ivabradine safely and significantly lowers HR and improves HR variability in patients with systolic heart failure, without inducing significant bradycardia, ventricular arrhythmias, or supraventricular arrhythmias.