EDITORIAL
European Heart Journal (2014) 35, 480–481 doi:10.1093/eurheartj/eht476
Slowing down the heart rate in permanent atrial fibrillation Joachim R. Ehrlich 1* and Eli Ovsyshcher 2 1 Division of Cardiology, Deutsche Klinik fu¨r Diagnostik, Aukammallee 33, D-65191 Wiesbaden, Germany; and 2Ben Gurion University, Cardiology, Soroka University Medical Center, Beer Sheva, Israel
Online publish-ahead-of-print 19 November 2013
Ventricular rate control for atrial fibrillation (AF) is almost as old as the first records of the disease. While digitalis has been the focus of classical observations,1 this substance is currently losing relevance for AF ventricular rate control owing to uncertainties regarding its prognostic value. Recent studies and retrospective analyses of older trials have shed an unfavourable light on digitalis in AF patients, in particular if serum concentrations are elevated.2,3 In general, rate control aims at reducing symptoms and improving exercise capacity. It is recommended as initial treatment for all patients with AF.4 While symptomatic patients with paroxysmal and persistent AF should subsequently undergo further rhythm control actions, patients with permanent AF (as per definition) will remain on rate control medication. Rate control is non-inferior to rhythm control with respect to mortality in patients with different types of AF and with or without heart failure (HF).5,6 Data regarding the impact of rate control on mortality are limited by several shortcomings regarding unsystematic, non-randomized use of drugs or suboptimal oral anticoagulation, and may not be representative of contemporary treatment modalities with extended interventional techniques in AF management. A recent, large-scale observational study suggested prognostic benefit of rate control only during the first year after AF diagnosis.7 Previous observations from the RATAF study (Rate Control in Atrial Fibrillation) found rate control with diltiazem to be more effective in terms of reducing patients’ symptoms than betablockers.8 A substudy of RATAF which has been conducted by Ulimoen et al. indicates the interesting finding that calcium channel blockers work favourably in terms of peak oxygen uptake during exercise and reduce N-terminal pro brain natriuretic peptide (NT-proBNP) levels at rest and during exercise in comparison with beta-blockers.9 This is an important and novel finding
supporting the use of calcium channel blockers in patients with permanent AF and no or minimal structural heart disease. In this study, patients (aged a median of 71 years) were treated with four different rate-controlling drug regimens in a randomized and investigatorblinded order, demonstrating superiority of diltiazem or verapamil treatment. In terms of patient characteristics, only 41.7% of patients in this trial had arterial hypertension. This is unusually low for an AF population. For instance, the prevalence of hypertension in a recent large trial of dronedarone in patients with permanent AF was 84.6%.2 Nevertheless, patients had mildly elevated mean blood pressure and near normal systolic ejection fraction (EF), providing information on the type of patient included in the trial. With this study, there is now evidence for first-line use of calcium channel blockers to control ventricular rate in patients with no or minimal structural heart disease (Figure 1A). Patients with relevant structural heart disease in terms of ischaemic cardiomyopathy or HF were excluded from RATAF.9 It is nevertheless important to look at a target heart rate and drugs for rate control for such patients as rate control is an important treatment option in HF patients.6 AF occurs frequently with HF or underlying ischaemic heart disease, and even more so with worse functional class.10 Beta-blocker therapy is established and clearly beneficial in patients with ischaemic heart disease or systolic HF.11 Accordingly, the question of the type of drug to be used in permanent AF with HF will remain controversial until addressed in a prospective randomized trial. It can be speculated that calcium channel antagonists may be inferior to beta-blockers in HF. There is good evidence that the target resting heart rate should be ,110 b.p.m. in patients with permanent AF (excluding those with unstable HF, recent cardiac surgery, or stroke).12 In the ‘Rate-control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate-control II’ (RACE-II) study, patients with reduced systolic left ventricular function (EF ,40%) were only a minority (15.1% of 614 patients). However, HF defined as New York Heart Association (NYHA) functional class .II or EF ,40% or previous HF hospitalization was present in 47%. Using this definition, a recent post-hoc analysis of RACE-II demonstrated a similar
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi:10.1093/eurheartj/eht429.
* Corresponding author. Tel: +49 611 577 613, Fax: +49 611 577 325, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 16, 2015
This editorial refers to ‘Calcium channel blockers improve exercise capacity and reduce N-terminal Pro-B-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation’†, by S.R. Ulimoen et al., on page 517
Editorial
outcome of lenient rate control in stable HF.13 In order to interpret these results in the context of the present data, the high prevalence of beta-blocker therapy (65.6% alone or in combination) in RACE-II has to be kept in mind (Figure 1B). Rate control therapy in permanent AF may need to be tailored to the type of underlying cardiac disease. It is necessary to differentiate between various target heart rates and means to achieve these in specific patient populations. For patients with no or minimal structural heart disease, the present study suggests that calcium channel blockers should be used as first-line treatment. There is a need for trials on drugs and target heart rates for patients with permanent AF and relevant structural heart disease. Conflict of interest: none declared.
References 1. Mackenzie J. Diseases of the Heart. 3rd ed. London: Oxford Medical Publications; 1914.
2. Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum A, Blomstrom P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacretaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB, Heidbuchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsanyi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;365:2268 –2276. 3. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289:871–878. 4. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31: 2369 –2429. 5. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825 –1833. 6. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG, Hohnloser SH, Lambert J, Le Heuzey JY, O’Hara G, Pedersen OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG, Thibault B, Waldo AL. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358: 2667 –2677. 7. Ionescu-Ittu R, Abrahamowicz M, Jackevicius CA, Essebag V, Eisenberg MJ, Wynant W, Richard H, Pilote L. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch Intern Med 2012;172:997 –1004. 8. Ulimoen SR, Enger S, Carlson J, Platonov PG, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, Tveit A. Comparison of four single-drug regimens on ventricular rate and arrhythmia-related symptoms in patients with permanent atrial fibrillation. Am J Cardiol 2013;111:225 – 230. 9. Ulimoen SR, Enger S, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, Tveit A. Calcium channel blockers improve exercise capacity and reduce N-terminal ProB-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation. Eur Heart J 2014;35:517 –523. 10. Ehrlich JR, Nattel S, Hohnloser SH. Atrial fibrillation and congestive heart failure: specific considerations at the intersection of two common and important cardiac disease sets. J Cardiovasc Electrophysiol 2002;13:399 –405. 11. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure. N Engl J Med 1999;353:2001 –2007. 12. Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM, Hillege HL, Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA, Van Veldhuisen DJ, Van den Berg MP. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363 –1373. 13. Mulder BA, Van Veldhuisen DJ, Crijns HJ, Tijssen JG, Hillege HL, Alings M, Rienstra M, Groenveld HF, Van den Berg MP, Van Gelder IC. Lenient vs. strict rate control in patients with atrial fibrillation and heart failure: a post-hoc analysis of the RACE II study. Eur Heart J 2013;in press.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 16, 2015
Figure 1 This schematic represents an approach to rate control in haemodynamically stable patients with permanent AF. Lenient rate control is defined as ,110 b.p.m. at rest. Drugs suggested for first-line use are green, and alternative (or additional) drugs are yellow. (A) It is reasonable to initiate lenient rate control with a calcium channel blocker in patients with permanent AF with no or minimal structural disease. Should symptoms persist, a stricter rate control approach or use of an alternative drug may be indicated. (B) Patients with relevant structural heart disease [heart failure patients with preserved or reduced systolic left ventricular function (ejection fraction ,40%) or patients with ischaemic heart disease] may potentially benefit more from initial beta-blocker treatment.
481
European Heart Journal (2014) 35, 480–481 doi:10.1093/eurheartj/eht476
Slowing down the heart rate in permanent atrial fibrillation Joachim R. Ehrlich 1* and Eli Ovsyshcher 2 1 Division of Cardiology, Deutsche Klinik fu¨r Diagnostik, Aukammallee 33, D-65191 Wiesbaden, Germany; and 2Ben Gurion University, Cardiology, Soroka University Medical Center, Beer Sheva, Israel
Online publish-ahead-of-print 19 November 2013
Ventricular rate control for atrial fibrillation (AF) is almost as old as the first records of the disease. While digitalis has been the focus of classical observations,1 this substance is currently losing relevance for AF ventricular rate control owing to uncertainties regarding its prognostic value. Recent studies and retrospective analyses of older trials have shed an unfavourable light on digitalis in AF patients, in particular if serum concentrations are elevated.2,3 In general, rate control aims at reducing symptoms and improving exercise capacity. It is recommended as initial treatment for all patients with AF.4 While symptomatic patients with paroxysmal and persistent AF should subsequently undergo further rhythm control actions, patients with permanent AF (as per definition) will remain on rate control medication. Rate control is non-inferior to rhythm control with respect to mortality in patients with different types of AF and with or without heart failure (HF).5,6 Data regarding the impact of rate control on mortality are limited by several shortcomings regarding unsystematic, non-randomized use of drugs or suboptimal oral anticoagulation, and may not be representative of contemporary treatment modalities with extended interventional techniques in AF management. A recent, large-scale observational study suggested prognostic benefit of rate control only during the first year after AF diagnosis.7 Previous observations from the RATAF study (Rate Control in Atrial Fibrillation) found rate control with diltiazem to be more effective in terms of reducing patients’ symptoms than betablockers.8 A substudy of RATAF which has been conducted by Ulimoen et al. indicates the interesting finding that calcium channel blockers work favourably in terms of peak oxygen uptake during exercise and reduce N-terminal pro brain natriuretic peptide (NT-proBNP) levels at rest and during exercise in comparison with beta-blockers.9 This is an important and novel finding
supporting the use of calcium channel blockers in patients with permanent AF and no or minimal structural heart disease. In this study, patients (aged a median of 71 years) were treated with four different rate-controlling drug regimens in a randomized and investigatorblinded order, demonstrating superiority of diltiazem or verapamil treatment. In terms of patient characteristics, only 41.7% of patients in this trial had arterial hypertension. This is unusually low for an AF population. For instance, the prevalence of hypertension in a recent large trial of dronedarone in patients with permanent AF was 84.6%.2 Nevertheless, patients had mildly elevated mean blood pressure and near normal systolic ejection fraction (EF), providing information on the type of patient included in the trial. With this study, there is now evidence for first-line use of calcium channel blockers to control ventricular rate in patients with no or minimal structural heart disease (Figure 1A). Patients with relevant structural heart disease in terms of ischaemic cardiomyopathy or HF were excluded from RATAF.9 It is nevertheless important to look at a target heart rate and drugs for rate control for such patients as rate control is an important treatment option in HF patients.6 AF occurs frequently with HF or underlying ischaemic heart disease, and even more so with worse functional class.10 Beta-blocker therapy is established and clearly beneficial in patients with ischaemic heart disease or systolic HF.11 Accordingly, the question of the type of drug to be used in permanent AF with HF will remain controversial until addressed in a prospective randomized trial. It can be speculated that calcium channel antagonists may be inferior to beta-blockers in HF. There is good evidence that the target resting heart rate should be ,110 b.p.m. in patients with permanent AF (excluding those with unstable HF, recent cardiac surgery, or stroke).12 In the ‘Rate-control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate-control II’ (RACE-II) study, patients with reduced systolic left ventricular function (EF ,40%) were only a minority (15.1% of 614 patients). However, HF defined as New York Heart Association (NYHA) functional class .II or EF ,40% or previous HF hospitalization was present in 47%. Using this definition, a recent post-hoc analysis of RACE-II demonstrated a similar
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi:10.1093/eurheartj/eht429.
* Corresponding author. Tel: +49 611 577 613, Fax: +49 611 577 325, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 16, 2015
This editorial refers to ‘Calcium channel blockers improve exercise capacity and reduce N-terminal Pro-B-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation’†, by S.R. Ulimoen et al., on page 517
Editorial
outcome of lenient rate control in stable HF.13 In order to interpret these results in the context of the present data, the high prevalence of beta-blocker therapy (65.6% alone or in combination) in RACE-II has to be kept in mind (Figure 1B). Rate control therapy in permanent AF may need to be tailored to the type of underlying cardiac disease. It is necessary to differentiate between various target heart rates and means to achieve these in specific patient populations. For patients with no or minimal structural heart disease, the present study suggests that calcium channel blockers should be used as first-line treatment. There is a need for trials on drugs and target heart rates for patients with permanent AF and relevant structural heart disease. Conflict of interest: none declared.
References 1. Mackenzie J. Diseases of the Heart. 3rd ed. London: Oxford Medical Publications; 1914.
2. Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum A, Blomstrom P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacretaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB, Heidbuchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsanyi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;365:2268 –2276. 3. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289:871–878. 4. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31: 2369 –2429. 5. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825 –1833. 6. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG, Hohnloser SH, Lambert J, Le Heuzey JY, O’Hara G, Pedersen OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG, Thibault B, Waldo AL. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358: 2667 –2677. 7. Ionescu-Ittu R, Abrahamowicz M, Jackevicius CA, Essebag V, Eisenberg MJ, Wynant W, Richard H, Pilote L. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch Intern Med 2012;172:997 –1004. 8. Ulimoen SR, Enger S, Carlson J, Platonov PG, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, Tveit A. Comparison of four single-drug regimens on ventricular rate and arrhythmia-related symptoms in patients with permanent atrial fibrillation. Am J Cardiol 2013;111:225 – 230. 9. Ulimoen SR, Enger S, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, Tveit A. Calcium channel blockers improve exercise capacity and reduce N-terminal ProB-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation. Eur Heart J 2014;35:517 –523. 10. Ehrlich JR, Nattel S, Hohnloser SH. Atrial fibrillation and congestive heart failure: specific considerations at the intersection of two common and important cardiac disease sets. J Cardiovasc Electrophysiol 2002;13:399 –405. 11. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure. N Engl J Med 1999;353:2001 –2007. 12. Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM, Hillege HL, Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA, Van Veldhuisen DJ, Van den Berg MP. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363 –1373. 13. Mulder BA, Van Veldhuisen DJ, Crijns HJ, Tijssen JG, Hillege HL, Alings M, Rienstra M, Groenveld HF, Van den Berg MP, Van Gelder IC. Lenient vs. strict rate control in patients with atrial fibrillation and heart failure: a post-hoc analysis of the RACE II study. Eur Heart J 2013;in press.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 16, 2015
Figure 1 This schematic represents an approach to rate control in haemodynamically stable patients with permanent AF. Lenient rate control is defined as ,110 b.p.m. at rest. Drugs suggested for first-line use are green, and alternative (or additional) drugs are yellow. (A) It is reasonable to initiate lenient rate control with a calcium channel blocker in patients with permanent AF with no or minimal structural disease. Should symptoms persist, a stricter rate control approach or use of an alternative drug may be indicated. (B) Patients with relevant structural heart disease [heart failure patients with preserved or reduced systolic left ventricular function (ejection fraction ,40%) or patients with ischaemic heart disease] may potentially benefit more from initial beta-blocker treatment.
481
