Physicians' Academy for Cardiovascular Education

AF and bradycardia do not worsen outcome in ivabradine-treated SIGNIFY patients

Literature - Fox K, Eur Heart J. 2015

Bradycardia and atrial fibrillation in patients with stable coronary artery disease treated with ivabradine: an analysis from the SIGNIFY study

Fox K, Ford I, Steg PG, et al.
Eur Heart J. 2015 Sep 17. pii: ehv451. [Epub ahead of print]


The SIGNIFY study analysed the effect of heart rate lowering with the If inhibitor ivabradine in patients with coronary artery disease (CAD) without clinical heart failure (HF) and with preserved left ventricular function [1]. Heart rate lowering with ivabradine did not reduce the primary composite endpoint of CV death or non-fatal myocardial infarction (MI), when using an aggressive regimen, starting at 7.5 mg twice daily and up-titrating to 10 mg twice daily to achieve heart rate of 55-60 bpm.
Patients with limiting angina (Canadian CV Society (CCS) class >2) appear to respond worse to ivabradine than to placebo, with regard to outcomes. There was, however, evidence of symptomatic improvement with ivabradine treatment in patients with angina.
The most frequent CV adverse  events were symptomatic and asymptomatic bradycardia and atrial fibrillation (AF), and were more often seen in the ivabradine group. This analysis examines the role of bradycardia and AF in the SIGNIFY trial, in data of 19083 patients, with a median follow-up of 27.8 months, to explore whether this can explain the worse outcomes in these patients.

Main results

  • In the total population, 3572 (37.2%) patients had emergent bradycardia with ivabradine. Among those in whom bradycardia was recorded, 211 (5.9%, 2.5% per year) experienced a primary composite endpoint, as compared with 338 patients (5.8%, 2.9% per year) without emergent bradycardia.
  • 2242 of patients with CCS class >2 had emergent bradycardia on ivabradine (37.4%). Among those, 149 patients (6.7%, 2.8% per year) had a primary composite endpoint, as compared with 243 (6.6%, 3.2% per year) in patients without emergent bradycardia.
  • In the whole population, 754 cases of emergent AF were seen (438 on ivabradine: 4.6% or 2.2% per year and 316 on placebo: 3.3% or 1.5% per year, P<0.001). In those in whom emergent AF was recorded on ivabradine, 14% (10.9% per year) experienced a primary composite endpoint, as compared with patients with emergent AF on placebo (13.9%, 11.2% per year). Fatal and non-fatal stroke occurred after emergent AF was recorded in  4.6% and 4.2% in the ivabradine and placebo groups respectively.
  • In patients with CCS class >2 angina, 469 patients had emergent AF, of which 277 on ivabradine (4.6%, 2.2% per year) and 102 on placebo (3.2%, 1.5% per year). In these patients, a primary composite endpoint occurred after emergent AF in 15.2% (11.5% per year) of patients on ivabradine and in 13.5% (10.8% per year) on placebo.
  • No difference was seen in the frequency of the primary composite endpoint in patients with limiting angina between treatments and between groups with or without emergent AF.


The frequency with which emergent bradycardia was recorded was greater in the SIGNIFY study than previously described for treatment with ivabradine, which was to be expected due to the more aggressive treatment regimen. The current results do not suggest that emergent bradycardia (<50 bpm on resting ECG) is associated with adverse outcomes (CV death or non-fatal MI).
Although the outcome of patients who developed AF was worse than of those who did not, this did not depend on the type of treatment they received.
Find this article online at Eur Heart J


1. Fox K, Ford I, Steg PG, et al.. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014;371:1091–1099.

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