International Journal of Cardiology 179 (2015) 27–28
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Ivabradine for rate control in atrial fibrillation Jedrzej Kosiuk ⁎, Sabrina Oebel, Silke John, Sebastian Hilbert, Gerhard Hindricks, Andreas Bollmann Department of Electrophysiology, Heart Center Leipzig, Leipzig, Germany
a r t i c l e
i n f o
Article history: Received 15 October 2014 Accepted 20 October 2014 Available online 22 October 2014 Keywords: Ivabradine Atrial fibrillation Rate control
Ivabradine is a selective If current inhibitor frequently used to reduce heart rate in patients with heart failure or with cardiovascular disease [1,2]. Since the If current is mainly expressed in the sinus node, ivabradine use was originally restricted to patients in sinus rhythm. Moreover, large trials designed to detect the reduction of heart rate in patients in sinus rhythm deliberately omitted patients with atrial fibrillation (AF). Therefore, no scientific evidence is available with respect to ivabradine's effect in patients with this common arrhythmia. However, recent histological and molecular studies suggest that channels mediating If are ubiquitous expressed in the myocardium and also the atrioventricular node in mice, rats, and humans [3–5]. Those findings suggest that ivabradine might also have effects on atrioventricular conduction. This hypothesis has recently found support in an animal model of AF in which an intravenous ivabradine application of 0.5 mg/kg significantly reduced ventricular rate during AF by 39.5% [6]. Importantly, the drug lengthened the PR interval by increasing the atrial-His interval in a rate-dependent manner without affecting the His-ventricle interval or arterial pressure. This new evidence opens up a discussion if ivabradine might successfully be used for rate control in patients with AF. Such agent with a broad therapeutic index, few pharmacokinetic interactions, and selective maximal heart rate reduction without causing symptomatic bradycardia would be a desirable alternative for currently used medications. In that context, we read with great interest the recent letter by Moubarak and colleagues [7] describing an increase of heart rate during weaning of ivabradine in one patient with AF. Consequently, we wish to report comparable observations and present the first case of ivabradine ⁎ Corresponding author at: Department of Electrophysiology, Heart Center Leipzig, Strümpellstr. 39, 04289 Leipzig, Germany. E-mail address: [email protected] (J. Kosiuk).
http://dx.doi.org/10.1016/j.ijcard.2014.10.062 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
initiation for significant heart rate reduction in a patient with persistent AF. A 59 year old patient with persistent AF was admitted to our institution due to resting heart rate over 100 bpm. He was diagnosed with tachycardiomyopathy with a left ventricular ejection fraction (LVEF) of 35%. Because of previous drug failures, alternative treatment options were discussed and the patient was put on “off label” medication with 10 mg/d ivabradine. Continuous Holter ECG recordings during drug initiation documented a continued decrease of the mean heart rate up to day 3 when a steady state was reached (Fig. 1). Importantly, the effect of ivabradine was restricted to higher rate range as the minimal rate was not affected and no pauses over 2.5 s were observed during the whole recording period. Furthermore, in a treadmill test during the same stress level before and after medication, maximal heart rate during exercise also decreased (169 vs 153 bpm) but no effects on arterial pressure (160/80 vs 163/93 mm Hg) were observed. An echocardiographic examination revealed also a significant improvement of LVEF to 50%. In light of recent publications reporting an association between increased mortality and digoxin as one of the most widely used rate control agents [8,9], those encouraging first clinical experiences with a potentially effective and presumably safe drug open new perspectives and demand further systematic study in larger and finally randomized trials. References [1] J.C. Tardif, I. Ford, M. Tendera, M.G. Bourassa, K. Fox, Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina, Eur. Heart J. 26 (2005) 2529–2536. [2] K. Swedberg, M. Komajda, M. Bohm, et al., Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study, Lancet 376 (2010) 875–885. [3] S. Herrmann, B. Layh, A. Ludwig, Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart, J. Mol. Cell. Cardiol. 51 (2011) 997–1006. [4] Y. Ou, X.L. Niu, F.X. Ren, Expression of key ion channels in the rat cardiac conduction system by laser capture microdissection and quantitative real-time PCR, Exp. Physiol. 95 (2010) 938–945. [5] I.D. Greener, O. Monfredi, S. Inada, et al., Molecular architecture of the human specialised atrioventricular conduction axis, J. Mol. Cell. Cardiol. 50 (2011) 642–651. [6] R.L. Verrier, M.F. Sobrado, V.P. Pagotto, et al., Inhibition of I(f) in the atrioventricular node as a mechanism for dronedarone's reduction in ventricular rate during atrial fibrillation, Heart Rhythm. 10 (2013) 1692–1697. [7] G. Moubarak, D. Logeart, S. Cazeau, Solal A. Cohen, Might ivabradine be useful in permanent atrial fibrillation? Int. J. Cardiol. 175 (2014) 187–188. [8] M.G. Whitbeck, R.J. Charnigo, P. Khairy, et al., Increased mortality among patients taking digoxin—analysis from the AFFIRM study, Eur. Heart J. 34 (2013) 1481–1488. [9] M.P. Turakhia, P. Santangeli, W.C. Winkelmayer, et al., Increased mortality associated with digoxin in contemporary patients with atrial fibrillation findings from the TREAT-AF study, J. Am. Coll. Cardiol. 64 (2014) 660–668.
J. Kosiuk et al. / International Journal of Cardiology 179 (2015) 27–28
Fig. 1. Heart rate profile after begin treatment with ivabradine (arrow).
28
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Ivabradine for rate control in atrial fibrillation Jedrzej Kosiuk ⁎, Sabrina Oebel, Silke John, Sebastian Hilbert, Gerhard Hindricks, Andreas Bollmann Department of Electrophysiology, Heart Center Leipzig, Leipzig, Germany
a r t i c l e
i n f o
Article history: Received 15 October 2014 Accepted 20 October 2014 Available online 22 October 2014 Keywords: Ivabradine Atrial fibrillation Rate control
Ivabradine is a selective If current inhibitor frequently used to reduce heart rate in patients with heart failure or with cardiovascular disease [1,2]. Since the If current is mainly expressed in the sinus node, ivabradine use was originally restricted to patients in sinus rhythm. Moreover, large trials designed to detect the reduction of heart rate in patients in sinus rhythm deliberately omitted patients with atrial fibrillation (AF). Therefore, no scientific evidence is available with respect to ivabradine's effect in patients with this common arrhythmia. However, recent histological and molecular studies suggest that channels mediating If are ubiquitous expressed in the myocardium and also the atrioventricular node in mice, rats, and humans [3–5]. Those findings suggest that ivabradine might also have effects on atrioventricular conduction. This hypothesis has recently found support in an animal model of AF in which an intravenous ivabradine application of 0.5 mg/kg significantly reduced ventricular rate during AF by 39.5% [6]. Importantly, the drug lengthened the PR interval by increasing the atrial-His interval in a rate-dependent manner without affecting the His-ventricle interval or arterial pressure. This new evidence opens up a discussion if ivabradine might successfully be used for rate control in patients with AF. Such agent with a broad therapeutic index, few pharmacokinetic interactions, and selective maximal heart rate reduction without causing symptomatic bradycardia would be a desirable alternative for currently used medications. In that context, we read with great interest the recent letter by Moubarak and colleagues [7] describing an increase of heart rate during weaning of ivabradine in one patient with AF. Consequently, we wish to report comparable observations and present the first case of ivabradine ⁎ Corresponding author at: Department of Electrophysiology, Heart Center Leipzig, Strümpellstr. 39, 04289 Leipzig, Germany. E-mail address: [email protected] (J. Kosiuk).
http://dx.doi.org/10.1016/j.ijcard.2014.10.062 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
initiation for significant heart rate reduction in a patient with persistent AF. A 59 year old patient with persistent AF was admitted to our institution due to resting heart rate over 100 bpm. He was diagnosed with tachycardiomyopathy with a left ventricular ejection fraction (LVEF) of 35%. Because of previous drug failures, alternative treatment options were discussed and the patient was put on “off label” medication with 10 mg/d ivabradine. Continuous Holter ECG recordings during drug initiation documented a continued decrease of the mean heart rate up to day 3 when a steady state was reached (Fig. 1). Importantly, the effect of ivabradine was restricted to higher rate range as the minimal rate was not affected and no pauses over 2.5 s were observed during the whole recording period. Furthermore, in a treadmill test during the same stress level before and after medication, maximal heart rate during exercise also decreased (169 vs 153 bpm) but no effects on arterial pressure (160/80 vs 163/93 mm Hg) were observed. An echocardiographic examination revealed also a significant improvement of LVEF to 50%. In light of recent publications reporting an association between increased mortality and digoxin as one of the most widely used rate control agents [8,9], those encouraging first clinical experiences with a potentially effective and presumably safe drug open new perspectives and demand further systematic study in larger and finally randomized trials. References [1] J.C. Tardif, I. Ford, M. Tendera, M.G. Bourassa, K. Fox, Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina, Eur. Heart J. 26 (2005) 2529–2536. [2] K. Swedberg, M. Komajda, M. Bohm, et al., Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study, Lancet 376 (2010) 875–885. [3] S. Herrmann, B. Layh, A. Ludwig, Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart, J. Mol. Cell. Cardiol. 51 (2011) 997–1006. [4] Y. Ou, X.L. Niu, F.X. Ren, Expression of key ion channels in the rat cardiac conduction system by laser capture microdissection and quantitative real-time PCR, Exp. Physiol. 95 (2010) 938–945. [5] I.D. Greener, O. Monfredi, S. Inada, et al., Molecular architecture of the human specialised atrioventricular conduction axis, J. Mol. Cell. Cardiol. 50 (2011) 642–651. [6] R.L. Verrier, M.F. Sobrado, V.P. Pagotto, et al., Inhibition of I(f) in the atrioventricular node as a mechanism for dronedarone's reduction in ventricular rate during atrial fibrillation, Heart Rhythm. 10 (2013) 1692–1697. [7] G. Moubarak, D. Logeart, S. Cazeau, Solal A. Cohen, Might ivabradine be useful in permanent atrial fibrillation? Int. J. Cardiol. 175 (2014) 187–188. [8] M.G. Whitbeck, R.J. Charnigo, P. Khairy, et al., Increased mortality among patients taking digoxin—analysis from the AFFIRM study, Eur. Heart J. 34 (2013) 1481–1488. [9] M.P. Turakhia, P. Santangeli, W.C. Winkelmayer, et al., Increased mortality associated with digoxin in contemporary patients with atrial fibrillation findings from the TREAT-AF study, J. Am. Coll. Cardiol. 64 (2014) 660–668.
J. Kosiuk et al. / International Journal of Cardiology 179 (2015) 27–28
Fig. 1. Heart rate profile after begin treatment with ivabradine (arrow).
28
