Elsevier

Heart Rhythm

Volume 20, Issue 6, June 2023, Pages 822-830
Heart Rhythm

Clinical
Atrial Fibrillation
Ivabradine for controlling heart rate in permanent atrial fibrillation: A translational clinical trial

https://doi.org/10.1016/j.hrthm.2023.02.012Get rights and content

Background

Pharmacological options for rate control in atrial fibrillation are scarce. Ivabradine was postulated to reduce the ventricular rate in this setting.

Objectives

The objectives of this study were to evaluate the mechanism of inhibition of atrioventricular conduction produced by ivabradine and to determine its efficacy and safety in atrial fibrillation.

Methods

The effects of ivabradine on atrioventricular node and ventricular cells were studied by in vitro whole-cell patch-clamp experiments and mathematical simulation of human action potentials. In parallel, a multicenter, randomized, open-label, phase III clinical trial compared ivabradine with digoxin for uncontrolled permanent atrial fibrillation despite β-blocker or calcium channel blocker treatment.

Results

Ivabradine 1 μM inhibited “funny” current and rapidly activating delayed rectifier potassium channel current by 28.9% and 22.8%, respectively (P < .05). The sodium channel current and L-type calcium channel current were reduced only at 10 μM. Ivabradine slowed the firing frequency of a modeled human atrioventricular node action potential by 10.6% and induced a minimal prolongation of ventricular action potential. Thirty-five (51.5%) patients were randomized to ivabradine and 33 (49.5%) to digoxin. The mean daytime heart rate decreased by 11.6 beats/min (−11.5%) in the ivabradine arm (P = .02) vs 19.6 (−20.6%) in the digoxin arm (P < .001), although the noninferiority margin of efficacy was not met (Z = −1.95; P = .97). The primary safety end point occurred in 3 patients (8.6%) on ivabradine and in 8 (24.2%) on digoxin (P = .10).

Conclusion

Ivabradine produced a moderate rate reduction in patients with permanent atrial fibrillation. The inhibition of funny current in the atrioventricular node seems to be the main mechanism responsible for this reduction. Compared with digoxin, ivabradine was less effective, was better tolerated, and had a similar rate of serious adverse events.

Introduction

Atrial fibrillation (AF) provokes a rapid heart rate (HR) in most patients. HR control strategy involves the use of negative chronotropic drugs that slow conduction through the atrioventricular node (AVN): β-blockers (BBs), non-dihydropyridine calcium channel blockers (non-DHP CCBs), and/or digoxin. Despite its broad use, digoxin has important limitations, such as a narrow therapeutic range and a high rate of adverse events and drug interactions. Additionally, a possible increase in long-term mortality related to digoxin has been described.1

Ivabradine is a selective blocker of the hyperpolarization-activated cyclic nucleotide-gated channel (HCN4) responsible for the pacemaker “funny” current (If) of the sinoatrial node,2 although it can also inhibit atrioventricular conduction.3 Several observational studies,4,5 1 open-label pilot study,6 and 1 small randomized clinical trial7 showed that ivabradine reduced the ventricular rate in patients with persistent and/or permanent AF. However, the ionic mechanisms responsible for the ivabradine-induced slowing of atrioventricular conduction leading to a reduction in ventricular rate during AF remain unclear since it can be related to If inhibition or may involve additional currents at the AVN and/or ventricular level. Additionally, the performance of ivabradine compared with other negative chronotropic agents is not known.

The translational study “IvaBRAdine blocK of funny current for heart rate control in pErmanent Atrial Fibrillation (BRAKE-AF)” (ClinicalTrials.gov identifier NCT03718273) aims to evaluate the role of ivabradine as a second-line drug for controlling HR in AF.

Section snippets

Methods

BRAKE-AF is a Spanish independent research project conducted at 10 hospitals and the Complutense University of Madrid. The in vitro studies were approved by the Committee on the Care and Use of Animals at the Complutense University and conformed to the Guide for the Care and Use of Laboratory Animals. The clinical trial was approved by our drug research ethics committee. All participants signed an informed consent form. Further details of the study design can be found elsewhere8 and in the

Effects of ivabradine on cardiac ionic currents

Ivabradine 1 μM significantly decreased the amplitude of If (control: −98.2 ± 8.4 pA/pF at −140 mV) by 28.9% ± 5.4% (P < .05) and of the IKr (control: 2.72 ± 0.24 pA/pF) by 22.8% ± 5.4% (P < .05), but not the amplitude of INa (7.2% ± 3.0%) or ICaL (≤5%) (Figure 1). At 10 μM, ivabradine decreased the amplitude of INa (control: −72.0 ± 7.6 pA/pF) by 22.3% ± 3.5% and ICaL (control: −3.4 ± 0.6 pA/pF) by 14.3% ± 5.4% (P < .05 for both). However, even at concentrations up to 10 μM, ivabradine did not

Discussion

BRAKE-AF is the largest clinical trial conducted with ivabradine for HR control in AF, the first one to compare it with an active drug, and the first to be designed with a translational perspective from in vitro studies.

Conclusion

Ivabradine essentially decreased the amplitude of If and IKr and reduced the AVN firing rate by 10.6% in silico. Translated to humans, ivabradine did not meet the primary efficacy end point compared with digoxin, although it produced a moderate and dose-dependent reduction in mean daytime HR (−11.6 beats/min) in patients with uncontrolled permanent AF, with a similar rate of serious adverse events and better tolerance. The inhibition of If seems to be involved in ivabradine-induced slowing of

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Funding Sources: This study was funded by project PI17/01272 from the Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness), cofounded by the European Regional Development Fund.

Disclosures: The authors have no conflicts of interest to disclose.

1

List of BRAKE-AF Investigators is in the Online Supplement.

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