ClinicalAtrial FibrillationIvabradine for controlling heart rate in permanent atrial fibrillation: A translational clinical trial
Graphical abstract
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.
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List of BRAKE-AF Investigators is in the Online Supplement.