Ivabradine: pre-clinical and clinical evidence in the setting of ventricular arrhythmias

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REVIEW ARTICLE

Hippokratia 2022, 26(2): 49-54

Bazoukis G1,2, Hill B3, Tse G4,5, Naka KK6
1Department of Cardiology, Larnaca General Hospital, Larnaca, Cyprus, 2Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus, 3Department of Medicine, Queen’s University, Kingston, Ontario, Canada, 4Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China, 5Kent and Medway Medical School, Canterbury, Kent, United Kingdom, 6Second Department of Cardiology and Michaelidion Cardiac Center, Medical School University of Ioannina, Ioannina, Greece

Abstract

Background: Ivabradine, an agent lowering the heart rate, acting as a funny current (If) specific inhibitor, is responsible for the sinoatrial node’s spontaneous depolarization. According to current guidelines, it is indicated in specific heart failure populations and as a second-line treatment option to improve angina in chronic coronary syndromes.

Review of literature: The role of ivabradine in the setting of ventricular arrhythmias has been studied in both experimental and clinical studies. Specifically, experimental studies have examined the role of ivabradine in acute myocardial ischemia, reperfusion, digitalis-induced ventricular arrhythmias, and catecholaminergic polymorphic ventricular tachycardia showing promising results. In addition, clinical studies have shown a beneficial role of ivabradine in reducing ventricular arrhythmias. Ivabradine reduced premature ventricular contractions in combination with beta-blockers in dilated cardiomyopathy patients. Similarly, in catecholaminergic polymorphic ventricular tachycardia, ivabradine reduced dobutamine-induced premature ventricular complexes and improved ventricular arrhythmias burden. On the other hand, current data show no beneficial role of ivabradine in reducing ventricular arrhythmias in myocardial ischemia.

Conclusions: Randomized clinical trials are needed to elucidate the role of ivabradine in reducing the burden of ventricular arrhythmias in various clinical settings. HIPPOKRATIA 2022, 26 (2):49-54.

Keywords: Ivabradine, ventricular tachycardia, ventricular arrhythmias

Corresponding author: George Bazoukis, MD, MSc, PhD, Department of Cardiology, Larnaca General Hospital, Inomenon Polition Amerikis, Larnaca, Cyprus, tel: +37524800500, e-mail: gbazoykis@yahoo.gr

Introduction

Ivabradine is an agent lowering the heart rate (HR), acting as a specific inhibitor of the cardiac pacemaker or “funny” current (If). At present, ivabradine is indicated in patients with symptomatic heart failure (HF)  and an ejection fraction (EF) lower than 35 % and a heart rate >70 beats per minute in sinus rhythm, despite treatment with an evidence-based dose of beta-blocker, angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor neprilysin inhibitor (ARNI), and a mineralocorticoid receptor antagonist (MRA), to reduce the risk of HF hospitalization and cardiovascular death1,2. Ivabradine should be considered in these patients even if they have contraindications or cannot tolerate beta-blocker therapy2,3. Furthermore, ivabradine should be considered a second-line treatment in chronic coronary syndrome to reduce the frequency of angina and improve exercise tolerance4. Pre-clinical studies have demonstrated the potential use of ivabradine in reducing the incidence and inducibility of atrial fibrillation (AF) in animal models5-8. However, multiple large placebo-controlled randomized clinical trials have provided evidence of an increased incidence of AF in coronary artery disease and HF patients treated with ivabradine1,9,10. This has been further corroborated by three meta-analyses which suggest that ivabradine therapy increases the relative risk of AF by 15-24 %11-13. Despite these findings, some clinical studies noted a reduced incidence of AF when ivabradine was administered in combination with bisoprolol or metoprolol in patients undergoing cardiac surgery14,15. Additional evidence suggests that ivabradine use may reduce the risk of AF in patients with severe HF with left ventricular ejection fraction (LVEF) ≤35-40 %12,16. As such, the current literature regarding the association of ivabradine with AF remains inconclusive. Clinical studies suggest that ivabradine may increase the relative risk and incidence of AF in patients, despite limited pre-clinical and clinical studies proposing an opposite effect. The mechanism of ivabradine’s potential effect in inducing AF remains uncertain, although several hypotheses have been proposed. One such theory is the possibility of ivabradine-induced bradycardia shifting the autonomic balance toward sympathetic activation, stimulating sympathetic-vagal dysregulation and the development of AF12. This review aims to present pre-clinical and clinical studies that provide data regarding the role of ivabradine in ventricular arrhythmias (VA).

Mechanism of action

The sinoatrial node generates repetitive spontaneous action potentials, which facilitate the pacemaker ability of the heart. This depolarization is initiated by the opening of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels within sinoatrial nodal cells which conduct a slow, inward-depolarizing sodium-potassium current, the If current4. Ivabradine exerts its therapeutic effect through selective inhibition of the intracellular aspect of HCN channels, disrupting sodium and potassium ion movement through the channel and thus controlling the flux through the HCN channels. This leads to a prolonged diastolic depolarization phase and thereby slows HR17. As the activity of ivabradine is dependent on its inhibition of HCN channels in their open state, it is, therefore, more potent at faster HRs18. Furthermore, ivabradine inhibits HCN channels in a dose-dependent manner, preventing adverse reductions in HR as its activity saturates at higher concentrations19.

Experimental studies

Baseline characteristics and key outcomes of the included experimental studies and clinical trials are presented in Table 1. Experimental models have studied the role of ivabradine in the following clinical settings: acute myocardial ischemia, reperfusion, digitalis-induced VAs and catecholaminergic polymorphic ventricular tachycardia (CPVT).

The impact of metoprolol and ivabradine has been studied in acute non-reperfused myocardial infarction in rat models. Both ivabradine and metoprolol reduced arrhythmic mortality and VAs in post‐myocardial infarction rats and also reduced QTc prolongation20. In another model, ivabradine reduced the combined ventricular tachycardia/ventricular fibrillation (VT/VF) incidence and arrhythmic mortality in the setting of acute myocardial infarction (AMI)21. Vaillant et al showed that ivabradine induced a 2.9-fold increase in VF threshold and prevented ischemia-induced monophasic action potential duration compared to controls. At the same time, a significant reduction was noted in the hypoxic area22. Mechanisms proposed for the ivabradine-related cardioprotection from ischemia-induced VF include the associated reduction in HR, increased regional myocardial blood flow, and preservation of cardiomyocyte and mitochondrial ultrastructure22,23. In another experimental study, ivabradine, but not propranolol, delayed the onset of ischemia-induced VF by preserving myocardial energy status24. An additional experimental study showed that ivabradine might be useful to prevent reperfusion arrhythmias if given early during acute myocardial ischemia before percutaneous interventions25. Specifically, the authors showed that ivabradine administered throughout ischemia and reperfusion reduced reperfusion VF incidence through HR reduction25.

Frommeyer et al provided data about the role of ivabradine in digitalis-induced VAs. In this setting, ivabradine demonstrated potent anti-arrhythmic properties by increasing the effective refractory period and post-repolarization refractoriness. Using a standardized pacing protocol, a significant suppression of VF following the infusion of ivabradine was noted26. In the setting of CPVT, ivabradine did not reduce in vivo ventricular tachyarrhythmias in transgenic CPVT mice27. As a result, ivabradine showed to have no role in this setting. 

Clinical data

Ivabradine has been found to reduce premature ventricular contractions (PVCs) in various clinical settings. Rayan et al28 regarding ivabradine’s safety and efficacy in idiopathic dilated cardiomyopathy patients using ivabradine as an add-on therapy to the maximally tolerated beta-blocker. PR, QTc, or QRS durations were not prolonged at three months’ follow-up, while ventricular ectopic activity was significantly reduced28. Mughal et al29 described the impact of ivabradine in ventricular ectopic beats in a patient with non-ischemic dilated cardiomyopathy. Specifically, carvedilol was changed to ivabradine, and the 24-hour Holter monitor revealed a significant reduction in the burden of ventricular ectopic beats from over 20 % to 4 %29. Recently, a case report demonstrated the efficacy of ivabradine in the reduction of PVCs burden originating from the left ventricular summit30. Although oral beta-blocker, verapamil, flecainide, and amiodarone were not efficacious, administering ivabradine reduced the PVC burden30.

Ivabradine has also been used in the setting of CPVT31. Specifically, in a young female with CPVT, ivabradine completely suppressed VAs31. In addition, in a young boy with CPVT, adding ivabradine to flecainide reduced premature ventricular beats during the exercise test31. Kohli et al32, described an 18-year-old male with CPVT refractory to flecainide, nadolol, and sympathectomy. In this case, VAs were successfully suppressed after the initiation of ivabradine32.

Ivabradine has been reported to have a beneficial role in dobutamine-induced VAs. Specifically, ivabradine was studied in decompensated HF patients requiring inotropic support, with LVEF <35 %, and sinus rhythm. Compared to the control group, ivabradine at 5 μg/kg/min of dobutamine dose reduced PVCs by 43 % and at 10 μg/kg/min by 38 %. However, ivabradine did not attenuate the arrhythmogenic effect of dobutamine at high dobutamine doses (15 μg/kg/min)33.

Clinical trials in myocardial ischemia have not shown a positive effect of ivabradine in reducing VAs. In the SIGNIFY trial, administering ivabradine in stable coronary artery disease (CAD) patients without HF did not improve outcomes9. Regarding the safety outcomes of this study, the occurrence of severe VAs did not differ significantly between the ivabradine and control groups9. Steg et al34, studied the impact of intravenous ivabradine on HR in patients with ST-elevation myocardial infarction (STEMI)34. The authors concluded that ivabradine might be used safely in this setting. Furthermore, no significant differences in the occurrence of VAs were found between ivabradine and control groups34. 

Conclusions

Experimental studies have demonstrated the beneficial role of ivabradine in acute myocardial ischemia, reperfusion, and digitalis-induced VAs. Furthermore, clinical data have provided evidence that ivabradine may reduce dobutamine-induced VAs and arrhythmias in the setting of CPVT and dilated cardiomyopathy. However, randomized clinical trials are needed to elucidate the role of ivabradine in reducing the burden of VAs in various clinical settings.

Conflicts of interest

The authors declare no conflicts of interest. 

Acknowledgments

We want to thank Dr. Athanasios Saplaouras, Prof. Tong Liu, Dr. Konstantinos P Letsas, Dr. Konstantinos Vlachos, and Dr. Michael Efremidis for their valuable comments on this manuscript.

References

  1. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010; 376: 875-885.
  2. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Rev Esp Cardiol (Engl Ed). 2022; 75: 523.
  3. Swedberg K, Komajda M, Böhm M, Borer J, Robertson M, Tavazzi L, et al. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol. 2012; 59: 1938-1945.
  4. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020; 41: 407-477.
  5. Verrier RL, Bonatti R, Silva AF, Batatinha JA, Nearing BD, Liu G, et al. If inhibition in the atrioventricular node by ivabradine causes rate-dependent slowing of conduction and reduces ventricular rate during atrial fibrillation. Heart Rhythm. 2014; 11: 2288-2296.
  6. Frommeyer G, Sterneberg M, Dechering DG, Ellermann C, Bögeholz N, Kochhäuser S, et al. Effective suppression of atrial fibrillation by ivabradine: Novel target for an established drug? Int J Cardiol. 2017; 236: 237-243.
  7. Li YD, Ji YT, Zhou XH, Jiang T, Hong YF, Li JX, et al. Effects of ivabradine on cardiac electrophysiology in dogs with age-related atrial fibrillation. Med Sci Monit. 2015; 21: 1414-1420.
  8. Wang J, Yang YM, Li Y, Zhu J, Lian H, Shao XH, et al. Long-term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization-activated cyclic nucleotide gated channel overexpression. J Cardiovasc Electrophysiol. 2019; 30: 242-252.
  9. Fox K, Ford I, Ferrari R. Ivabradine in stable coronary artery disease. N Engl J Med. 2014; 371: 2435.
  10. Tendera M, Talajic M, Robertson M, Tardif JC, Ferrari R, Ford I, et al. Safety of ivabradine in patients with coronary artery disease and left ventricular systolic dysfunction (from the BEAUTIFUL Holter Substudy). Am J Cardiol. 2011; 107: 805-811.
  11. Tanboğa İH, Topçu S, Aksakal E, Gulcu O, Aksakal E, Aksu U, et al. T The Risk of Atrial Fibrillation With Ivabradine Treatment: A Meta-analysis With Trial Sequential Analysis of More Than 40000 Patients. Clin Cardiol. 2016; 39: 615-620.
  12. Wang Z, Wang W, Li H, Zhang A, Han Y, Wang J, et al. Ivabradine and Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials. J Cardiovasc Pharmacol. 2022; 79: 549-557.
  13. Martin RI, Pogoryelova O, Koref MS, Bourke JP, Teare MD, Keavney BD. Atrial fibrillation associated with ivabradine treatment: meta-analysis of randomised controlled trials. Heart. 2014; 100: 1506-1510.
  14. Iliuta L, Rac-Albu M. Ivabradine Versus Beta-Blockers in Patients with Conduction Abnormalities or Left Ventricular Dysfunction Undergoing Cardiac Surgery. Cardiol Ther. 2014; 3: 13-26.
  15. Abdel-Salam Z, Nammas W. Atrial Fibrillation After Coronary Artery Bypass Surgery: Can Ivabradine Reduce Its Occurrence? J Cardiovasc Electrophysiol. 2016; 27: 670-676.
  16. Bocchi EA, Rassi S, Guimarães GV. Safety profile and efficacy of ivabradine in heart failure due to Chagas heart disease: a post hoc analysis of the SHIFT trial. ESC Heart Fail. 2018; 5: 249-256.
  17. Bocchi EA, Salemi VMC. Ivabradine for treatment of heart failure. Expert Opin Drug Saf. 2019; 18: 393-402.
  18. Badu-Boateng C, Jennings R, Hammersley D. The therapeutic role of ivabradine in heart failure. Ther Adv Chronic Dis. 2018; 9: 199-207.
  19. Koruth JS, Lala A, Pinney S, Reddy VY, Dukkipati SR. The Clinical Use of Ivabradine. J Am Coll Cardiol. 2017; 70: 1777-1784.
  20. Marciszek M, Paterek A, Oknińska M, Mackiewicz U, Mączewski M. Ivabradine is as effective as metoprolol in the prevention of ventricular arrhythmias in acute non-reperfused myocardial infarction in the rat. Sci Rep. 2020; 10: 15027.
  21. Mackiewicz U, Gerges JY, Chu S, Duda M, Dobrzynski H, Lewartowski B, et al. Ivabradine protects against ventricular arrhythmias in acute myocardial infarction in the rat. J Cell Physiol. 2014; 229: 813-823.
  22. V Vaillant F, Timour Q, Descotes J, Manati W, Belhani D, Bui-Xuan B, et al. Ivabradine induces an increase in ventricular fibrillation threshold during acute myocardial ischemia: an experimental study. J Cardiovasc Pharmacol. 2008; 52: 548-554.
  23. Vaillant F, Dehina L, Mazzadi A, Descotes J, Chevalier P, Tabib A, et al. Heart rate reduction with ivabradine increases ischaemia-induced ventricular fibrillation threshold: role of myocyte structure and myocardial perfusion. Resuscitation. 2011; 82: 1092-1099.
  24. Vaillant F, Dehina L, Dizerens N, Bui-Xuan B, Tabib A, Lauzier B, et al. Ivabradine but not propranolol delays the time to onset of ischaemia-induced ventricular fibrillation by preserving myocardial metabolic energy status. Resuscitation. 2013; 84: 384-390.
  25. Ng FS, Shadi IT, Peters NS, Lyon AR. Selective heart rate reduction with ivabradine slows ischaemia-induced electrophysiological changes and reduces ischaemia-reperfusion-induced ventricular arrhythmias. J Mol Cell Cardiol. 2013; 59: 67-75.
  26. Frommeyer G, Weller J, Ellermann C, Bögeholz N, Leitz P, Dechering DG, et al. Ivabradine Reduces Digitalis-induced Ventricular Arrhythmias. Basic Clin Pharmacol Toxicol. 2017; 121: 526-530.
  27. Bueno-Levy H, Weisbrod D, Yadin D, Haron-Khun S, Peretz A, Hochhauser E, et al. The Hyperpolarization-Activated Cyclic-Nucleotide-Gated Channel Blocker Ivabradine Does Not Prevent Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia. Front Pharmacol. 2020; 10: 1566.
  28. Rayan M, Tawfik M, Alabd A, Gamal A. Ivabradine, a novel heart rate slower: is it a sword of double blades in patients with idiopathic dilated cardiomyopathy? Anadolu Kardiyol Derg. 2011; 11: 402-406.
  29. Mughal LH, Houghton AR, Khoo J. Significant suppression of premature ventricular ectopics with ivabradine in dilated cardiomyopathy. Br J Cardiol. 2019; 26: 36-37.
  30. Çinier G, Hayıroğlu Mİ, Özcan KS, Pay L, Tekkeşin Aİ, Gürkan K. The use of ivabradine in a patient with idiopathic ventricular arrhythmia originating from the left ventricular summit. J Electrocardiol. 2022; 71: 32-36.
  31. Vaksmann G, Klug D. Efficacy of ivabradine to control ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia. Pacing Clin Electrophysiol. 2018; 41: 1378-1380.
  32. Kohli U, Aziz Z, Beaser AD, Nayak HM. Ventricular arrhythmia suppression with ivabradine in a patient with catecholaminergic polymorphic ventricular tachycardia refractory to nadolol, flecainide, and sympathectomy. Pacing Clin Electrophysiol. 2020; 43: 527-533.
  33. Mert KU, Mert GÖ, Morrad B, Tahmazov S, Mutlu F, Çavuşoglu Y. Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias. Kardiol Pol. 2017; 75: 786-793.
  34. Steg P, Lopez-de-Sà E, Schiele F, Hamon M, Meinertz T, Goicolea J, et al. Safety of intravenous ivabradine in acute ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention: a randomized, placebo-controlled, double-blind, pilot study. Eur Heart J Acute Cardiovasc Care. 2013; 2: 270-279.