Who, when and how to rate control for atrial fibrillation Michiel Rienstra and Isabelle C. Van Gelder

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1 Who, when and how to rate control for atrial fibrillation Michiel Rienstra and Isabelle C. Van Gelder Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Correspondence to Isabelle C. Van Gelder, MD, Department of Cardiology, Thoraxcenter, University Medical Center Groningen, University of Groningen, PO Box , 9700 RB Groningen, the Netherlands Tel: ; fax: ; Conflicts of interest: None. Current Opinion in Cardiology 2008, 23:23 27 Purpose of review The aim of this review is to provide a perspective on rate control in atrial fibrillation, in the era after the large randomized trials comparing rate and rhythm control. This review emphasizes the indications for rate control, the optimal heart rate and the different treatment modalities. Recent findings Large studies have shown that rate control is not inferior to rhythm control with regard to cardiovascular morbidity and mortality. Rate control may now be instituted earlier during the course of the disease, even as first-choice therapy in some patients, particularly those with hypertension and underlying heart diseases, and those who are not (severely) symptomatic. The goals of rate-control therapy are to reduce symptoms, improve quality of life, minimize the development of heart failure, and prevent thromboembolic complications. An important negative aspect of rate-control therapy is the side effects of drugs. The optimal heart rate during atrial fibrillation has not yet been carefully investigated. Several approaches to control rate during atrial fibrillation are available, including pharmacological rate control and atrioventricular nodal ablation with pacemaker implantation. Summary Understanding the indications for rate control, treatment goals and options will gain the largest benefit for the individual patient with atrial fibrillation. Keywords atrial fibrillation, drug treatment, heart rate, rate control, symptoms Curr Opin Cardiol 23:23 27 ß 2008 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction After the development of atrial fibrillation, the first step in its treatment is to search for and treat underlying heart diseases. Thereafter, atrial fibrillation itself should be treated. Therapy should be aimed at reducing symptoms, improving quality of life, and preventing cardiovascular morbidity and mortality. In general, there are two treatment strategies: rhythm-control and rate-control treatment. The goal of rhythm control is achieving and maintaining sinus rhythm by serial cardioversions and antiarrhythmic drugs, or by non-pharmacological approaches, e.g. atrial catheter ablation. The problem with pharmacological rhythm-control treatment is that recurrences of atrial fibrillation frequently occur. In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and the RAte Control versus Electrical cardioversion for persistent atrial fibrillation (RACE) studies, rhythm-control treatment was effective in maintaining sinus rhythm in only 39 63% of patients after a mean of years [1,2]. The efficacy of catheter ablation of atrial fibrillation is increasing and evolving rapidly. This is indicated, however, in patients who are symptomatic with arrhythmia and not in elderly patients with longstanding atrial fibrillation [3]. An alternative to rhythm control is rate-control treatment, i.e. acceptance of atrial fibrillation, achieving adequate ventricular rate control and preventing thromboembolic complications. The AFFIRM and RACE studies have shown that current rate-control treatment is not inferior to rhythm-control treatment with regard to cardiovascular morbidity and mortality [1,2]. In those studies, predominantly elderly patients with underlying heart diseases were included. Most patients had at least one previous electrical cardioversion and only a small number of patients with paroxysmal atrial fibrillation were included. Patients with (severely) symptomatic atrial fibrillation and advanced heart failure were excluded. Since then, rate-control treatment has been adopted more frequently, even as first-choice therapy, and not only when rhythm-control treatment fails as was the case before the large rate versus rhythm-control trials. In the present review we will discuss for whom rate control is indicated, when and how. Indications for rate control As mentioned above, large randomized trials have shown that the two major treatment strategies for patients with ß 2008 Wolters Kluwer Health Lippincott Williams & Wilkins

2 24 Arrhythmias Table 1 Criteria for choice of pharmacological treatment strategy in persistent atrial fibrillation Rhythm control Rate control First episode of atrial fibrillation (Severely) symptomatic atrial fibrillation Young age Poor ventricular rate control during atrial fibrillation Reversible tachycardiomyopathy Heart failure (?) Possible discontinuation of anticoagulation No or minor complaints of atrial fibrillation (also lone atrial fibrillation) Older age (> 75 years) High-risk recurrence of atrial fibrillation (severe atrial fibrillation) Indication for anticoagulation irrespective of the rhythm Certain subgroups (women, hypertensive patients) atrial fibrillation are equally effective, at least in large persistent atrial fibrillation populations. In daily clinical practice, it is important to translate the results of these trials to the individual patient. The wide heterogeneity in the presentation and underlying causes of atrial fibrillation calls for an individual approach to therapy. Such an approach requires the selection of appropriate rhythmcontrol or rate-control strategies depending on the nature, intensity, and frequency of symptoms, patient preferences, co-morbid conditions, and the risk of recurrent atrial fibrillation [4]. Additional analyses of prespecified subgroups of patients in the AFFIRM study showed that patients of 65 years and older and patients without a history of chronic heart failure had significantly better outcomes (lower all-cause mortality) with rate-control therapy (P < 0.01) [5]. Subanalyses of the RACE study showed enhanced cardiovascular morbidity and mortality in hypertensive patients and women treated with rhythm control [6,7 ]. Depending on the symptoms, rate control may be a reasonable initial therapy in older patients, especially women with persistent atrial fibrillation who have hypertension or other underlying heart diseases (Table 1). It is currently unknown whether patients with atrial fibrillation in the setting of chronic heart failure will benefit from a rate or rhythm-control approach. Previous small studies have shown that conversion to sinus rhythm improved left ventricular function and reversed tachycardiomyopathy [8,9]. Comparable data were observed in a RACE substudy. In 335 patients included in the RACE study, echocardiography was performed at baseline and 1 and 2 years of follow-up. Echocardiography was compared between patients randomly assigned to rate (n ¼ 160) and rhythm control (n ¼ 175), and in the rhythm-control group between patients with atrial fibrillation versus sinus rhythm at the study end. The maintenance of sinus rhythm was associated with improvement in left ventricular function and a reduction of atrial sizes [10]. Pharmacological rhythm control often fails, however, especially in patients with chronic heart failure [11 13]. Furthermore, antiarrhythmic drugs may cause proarrhythmia and increase sudden cardiac death, also particularly in heart failure patients. Although rhythm control by atrial catheter ablation in heart failure patients is promising, it is currently certainly not a treatment option in the majority of such patients [14]. Data from the AF-CHF trial, investigating rate versus rhythm control in patients with atrial fibrillation and chronic heart failure, are eagerly awaited [15]. Optimal rate-control target The goal of rate-control therapy is to reduce symptoms, improve quality of life, minimize the development of heart failure, and prevent thromboembolic complications. Intuitively, strict rate control should be associated with fewer symptoms, better quality of life, a lower incidence of heart failure, and better survival. An important negative aspect of strict rate-control therapy is the side effects of rate-control drugs, eventually leading to pacemaker implantation (Table 2). At present, the optimal heart rate during atrial fibrillation is unknown (Figure 1). Few retrospective analyses have been carried out to study this important topic. In the AFFIRM trial a strict rate-control approach was used, consisting of a resting heart rate of less than 80 beats per minute (bpm), and either a 6-min walk test heart rate of 110 bpm or less, or a mean heart rate on a 24-h Holter recording of 100 bpm or less, in combination with a maximum heart rate of up to 110% of the predicted maximum heart rate [1]. The rate-control target was achieved in two-thirds of patients, mostly with betablocker therapy [16]. In 5% of patients, however, an atrioventricular node ablation was necessary, and in 6% a pacemaker was implanted because of bradycardia. In the RACE trial a more lenient rate-control approach was applied, consisting of a more lenient resting heart rate of 100 bpm or less [2]. In that trial, in only 1% of the patients was an atrioventricular node ablation performed. In both trials severe adverse effects of rate-control drugs were rare. A pooled analysis of the AFFIRM and RACE studies included 1091 patients, 874 from AFFIRM and 217 from RACE. The mean resting heart rate during study follow-up was lower in AFFIRM (76 versus Table 2 Presumed benefits and disadvantages of strict ratecontrol treatment strategy in atrial fibrillation Pro Fewer symptoms Improved quality of life Lower incidence of heart failure Fewer strokes Improved prognosis Contra Irregular heart rate still present More drug-related adverse effects (Preventable) pacemaker implantations Higher costs

3 Rate control in atrial fibrillation Rienstra and Van Gelder 25 Figure 1 Hypothetical curve of optimal heart rate control during atrial fibrillation Risk 50 Window of optimal rate control Heart rate (bpm) Adverse effects of rate control on pacemaker implantations; costs; symptoms of atrial fibrillation, impaired quality of life, incidence of coronary heart failure; risk of stroke; applicability. 83 bpm). This post-hoc analysis showed that the stringency of the approach to rate control between both trials was not associated with an important difference in clinical events (Figure 2) [17 ]. In addition, a retrospective analysis of the AFFIRM study demonstrated that the heart rate achieved was not related to cardiovascular hospitalization, overall survival, quality of life, and functional status [17,18]. Figure 2 Composite endpoint, i.e. death, cardiovascular hospitalization or myocardial infarction, event-free survival in AFFIRM and RACE studies Event-free 100 survival (%) Log rank statistic = 2.71 P = Time (years) n at risk Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study; RAte Control versus Electrical cardioversion for persistent atrial fibrillation (RACE) study. The present American College of Cardiology/American Heart Association/European Society of Cardiology guidelines state, in the absence of any randomized trial, that the criteria for rate control vary with patient age, but usually involve achieving heart rates between 60 and 80 bpm at rest and 90 and 115 bpm during moderate exercise [19]. Currently, no standard method for the assessment of rate control has been established to guide the management of patients with atrial fibrillation. As is stated in the guidelines, the assessment of heart rate response during minor exercise is more relevant than investigating heart rate during maximal exercise because this level of exercise is generally performed by these (elderly) persistent atrial fibrillation patients. Furthermore, no difference is made between rate-control therapy in patients with atrial fibrillation in the setting of a normal versus a (severely) impaired cardiac function [20 22]. Currently, the RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient versus strict rate control in patients with and without heart failure (RACE II) trial is being conducted [23 ]. The primary hypothesis of the RACE II study is that lenient (heart rate < 110 bpm at rest) rate control is not inferior to strict (heart rate < 80 bpm at rest and heart rate during minor exercise < 110 bpm) rate control in patients with permanent atrial fibrillation, with or without heart failure, in terms of cardiovascular mortality and morbidity, quality of life and costs. Rate control can be achieved using betablockers, calcium antagonists, and digoxin, alone or in combination. At present, all 619 patients are included. Follow-up will be 2 3 years. Data are awaited by the end of Pharmacological rate control Ventricular rate control during atrial fibrillation can be achieved by the use of beta-blockers, non-dihydropyridine calcium antagonists, digoxin, and amiodarone, alone or in combination. In general, it is thought that rate control is relatively easy to achieve. In the AFFIRM study, however, the opposite was demonstrated, at least to obtain strict rate control. Frequent dose adjustments and medication changes were needed, and their strict rate-control target (resting heart rate 80 bpm and exercise heart rate 110 bpm or mean heart rate on Holter monitoring 100 bpm) was only achieved in 70% of all patients [16]. Which rate-control drug or combination is the most effective is at present uncertain. A comparative evaluation of rate-control drugs is difficult. There is a wide heterogeneity between trials in terms of objectives, patient selection, agents and doses used, the duration of therapy, outcome measures (both quantitative and qualitative) and trial size [24]. Farshi et al. [22] compared the effects of five standard drug regimens consisting of digoxin, diltiazem, atenolol, the combination digoxin/ diltiazem and the combination digoxin/atenolol on the mean 24-h heart rates, circadian patterns of ventricular

4 26 Arrhythmias responses and on programmed exercise in patients with persistent atrial fibrillation. Least effective was the use of digoxin and diltiazem alone. The combination of digoxin and atenolol produced the most effective rate control, reflecting a synergistic effect on the atrioventricular node. Khand et al. [25] investigated in a randomized, doubleblinded study the effects of digoxin alone, carvedilol alone, or their combination on heart rate control in patients with persistent atrial fibrillation and heart failure. The combination of carvedilol and digoxin appeared to be superior to either carvedilol or digoxin alone. In the AFFIRM study, the most effective rate-control drugs to achieve the rate-control target were beta-blockers [16]. Although serious adverse effects from rate-control drugs are uncommon, the strategy is not without adverse effects [1,2]. Pacemaker implantations were more frequent in AFFIRM, using a strict rate-control approach, than in RACE, in which a more lenient rate-control approach was applied (11 versus 1%, respectively, P ¼ ). Pacemakers were mainly implanted in the setting of atrioventricular node ablation or bradycardia induced by rate-control drugs [17 ]. Atrioventricular node ablation The American College of Cardiology/American Heart Association/European Society of Cardiology guidelines state that non-pharmacological therapy should be considered when pharmacological measures fail [19]. Atrioventricular node ablation together with permanent pacemaker implantation provides highly effective rate control and improves symptoms in selected patients [26 30]. In general, patients most likely to benefit from this therapy are severely symptomatic patients, those with adverse effects and those with uncontrollable heart rates despite the use of negative chronotropic drugs [19,29]. This approach, however, has several limitations, including the need for pacemaker implantation and the permanent loss of atrioventricular nodal conduction. In addition, recent studies have shown that right ventricular pacing may be associated with an increased risk of heart failure [31,32], also after long-term (4 7 years of followup) right ventricular pacing after atrioventricular node ablation in patients with an initially normal left ventricular function [33,34]. It remains to be investigated whether this relates to right ventricular pacing or progression of the underlying heart disease. Whether biventricular pacing may reduce this risk still remains to be confirmed. A recent meta-analysis of three randomized trials with 347 patients compared cardiac resynchronization therapy with right ventricular pacing in atrial fibrillation patients treated with atrioventricular nodal ablation. The patients included were both those with permanent atrial fibrillation with drug-refractory, severely symptomatic, uncontrolled heart rates and those with permanent atrial fibrillation in the setting of heart failure [35]. No differences in survival, stroke, hospitalization, exercise capacity, or healthcare costs were found. Cardiac resynchronization therapy, however, was associated with an improvement in ejection fraction in two of the three trials, predominantly in patients with permanent atrial fibrillation in the setting of heart failure. Future approaches to control rate in atrial fibrillation Various alternatives to the induction of total atrioventricular blockade with atrioventricular node ablation have been or are currently being studied. Atrioventricular node modification was ineffective as complete atrioventricular node block was a frequent complication and long-term efficacy was poor [36,37]. Other approaches, such as selective vagal stimulation of the epicardial atrioventricular nodal fat pad, gene therapy, infusions with fibroblasts or acetylcholine, warrant further investigation [38 42]. Conclusion Rate control may now be adopted as a first-choice therapy in a variety of patients, especially older relatively asymptomatic patients with hypertension or other underlying heart diseases. The goal of rate-control therapy is to minimize symptoms, improve quality of life, minimize the development of heart failure, and prevent thromboembolic complications. An important negative aspect of rate-control therapy is the side effects of rate-control drugs. This seems to be especially the case if a strict ratecontrol target is intended. Remarkably, little research has been conducted on the optimal heart rate, evaluation tools, and rate-control drugs or drug combinations. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347: Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) task force on catheter and surgical ablation of atrial fibrillation. 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