What Should be the Primary Treatment in Atrial Fibrillation: Ventricular Rate Control or Sinus Rhythm Control with Long-term Anticoagulation?

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1 The Journal of International Medical Research 2009; 37: What Should be the Primary Treatment in Atrial Fibrillation: Ventricular Rate Control or Sinus Rhythm Control with Long-term Anticoagulation? B OKCUN 1, Z YIGIT 1, A YILDIZ 2, I UZUNHASAN 1, K ORTA 1, M BASKURT 1, A KAYA 2 AND S KUCUKOGLU 1 1 Institute of Cardiology, Istanbul University, Istanbul, Turkey; 2 Department of Cardiology, 29 Mayis Hospital, Istanbul, Turkey Recent trials have favoured ventricular rate control in atrial fibrillation (AF) management, however the present study investigated whether the restoration and maintenance of sinus rhythm with longterm anticoagulation therapy was superior in terms of embolic events and death in 534 patients with an AF duration > 48 h. Patients were randomized and received sinus rhythm control with either aspirin (group 1) or warfarin (group 2), or they were given ventricular rate control (group 3). Cardioversion to sinus rhythm was attempted in 425 patients and was successful in 387 (91.1%) of them. After 3 years follow-up there were 12, two and 15 embolic events in groups 1, 2 and 3 respectively (significant difference between groups 1 and 2, and 2 and 3) and overall mortalities were four, two and 12, respectively (significant difference between groups 2 and 3). It is concluded that patients with an AF duration > 48 h might benefit considerably from sinus rhythm restoration and long-term warfarin therapy in terms of embolic events and mortality. KEY WORDS: WARFARIN; ASPIRIN; ANTICOAGULANTS; ATRIAL FIBRILLATION; EMBOLISM; MORTALITY Introduction Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, occurring in 0.4% of the adult population. 1 3 Its prevalence is age-related and increases significantly to 1 4% after the sixth decade of life. 4 A significantly higher risk of systemic embolism, congestive heart failure and death is associated with AF. 1 5 The management of patients with AF involves restoration and maintenance of sinus rhythm, ventricular rate control and antithrombotic therapy. 6 8 Cardioversion to sinus rhythm is commonly used to relieve symptoms, improve cardiac function and decrease the incidence of thrombus formation. 3,5 8 In 2002, however, the results of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and Rate Control versus Electrical Cardioversion (RACE) and Strategies of Treatment in Atrial Fibrillation (STAF) trials showed that sinus rhythm control was not superior to ventricular rate control in terms 464

2 of mortality and embolic event rates In these trials, anticoagulation was discontinued when sinus rhythm had been maintained for 1 month in the rhythm control arm of the study and most of the strokes that occurred were in these patients The purpose of the present study was to determine whether a strategy that attempts to restore and maintain sinus rhythm with long-term warfarin therapy will improve survival and decrease embolic events in patients with AF. Patients and methods PATIENTS Patients > 18 years of age with persistent AF for > 48 h were included in the study. AF was defined as the absence of P waves, coarse or fine fibrillatory waves and completely irregular RR intervals. Patients with valvular heart disease, coronary artery disease, heart failure, thyroid disease, renal failure, sick sinus syndrome, pulmonary embolism, acute pericarditis, diabetes mellitus, chronic obstructive lung disease, hypertrophic obstructive cardiomyopathy or atrial thrombus were excluded from the study. Ethics approval for the study was obtained from Istanbul University. All patients gave informed verbal consent. STUDY DESIGN Patients were randomized to three groups. Group 1 comprised those patients who successfully cardioverted to sinus rhythm and for whom warfarin therapy (international normalized ratio [INR] ) was discontinued at the end of the first month after cardioversion but aspirin (325 mg) once daily was given for the 3-year follow-up study period (aspirin sinus rhythm control group). Group 2 also comprised patients who successfully cardioverted to sinus rhythm but warfarin therapy (INR ) as well as aspirin (325 mg, once daily) were both continued for the 3 year follow-up study period (warfarin sinus rhythm control group). Group 3 comprised those patients in whom cardiovertion to sinus rhythm was attempted but was unsuccessful and also those patients for whom cardioversion was not attempted. In this group, digoxin, verapamil and metoprolol were used for ventricular rate control, the target heart rate being < 80 beats/min at rest and they were also treated with warfarin (INR ) plus aspirin (325 mg, once daily) for the 3 year follow-up study period (ventricular rate control group). CARDIOVERSION PROCEDURE At baseline, a resting 12-lead electrocardiogram (ECG) was obtained and transthoracic echocardiography (TTE) and transoesophageal echocardiography (TEE) were performed. The TTE and TEE studies were performed with an Acuson 128 XP/5 ultrasound system (Acuson Corp., Mountain View, CA, USA). M-mode TTE was used to measure the left atrial diameter at endsystole and the left ventricular ejection fraction, according to the recommendations of the American Society of Echocardiography. 16 Food consumption was halted at least 4 h before carrying out TEE. Patients received local pharyngeal anaesthesia (1% lidocaine spray) as the only pre-medication and were given effective anticoagulation either with heparin or warfarin (INR of or activated partial thromboplastin time of s, twice that of a normal control) before TEE. Patients with no detectable thrombus on TEE were cardioverted to sinus rhythm. For cardioversion, amiodarone was given intravenously (300 mg over 1 h, then mg/kg for the remaining 23 h). If cardioversion could not be achieved after intravenous loading, electrical cardioversion 465

3 was attempted. This was initiated at 200 J and was repeated if necessary. If still unsuccessful, an attempt was made at 360 J and this was repeated if necessary. The electrical cardioversion procedure was brought to an end after the restoration of sinus rhythm or after two attempts at 360 J. All patients in the rhythm control groups received amiodarone (200 mg four times daily) during the follow-up period. To detect early recurrence of arrhythmia, electrocardiographic monitoring was performed in all patients during the first 24 h in hospital. Sinus rhythm lasting > 24 h was considered to indicate successful cardioversion. FOLLOW-UP Patients were observed for a minimum follow-up period of 3 years with regular weekly visits in the first month and once a month thereafter. A 12-lead ECG was also taken at every visit during the 3 year followup study period. The end points of the study were embolism and death. Causes of mortality were classified as progressive heart failure, haemorrhage, embolism, sudden death and other. STATISTICAL ANALYSIS Differences between groups were evaluated by analysis of variance, the χ 2 test and Student s t-test. Kaplan Meier analysis was performed to estimate the cumulative rates of survival and embolic events. A P-value 0.05 was considered statistically significant. Results The numbers of patients in each group at each stage of the study are summarized in Fig. 1. The study population consisted of 534 patients with AF duration > 48 h. There were initially 425 patients in the sinus rhythm control groups (groups 1 and 2) and 109 patients in the ventricular rate control group (group 3). A total of 38 patients in groups 1 and 2 could not be cardioverted and they were transferred to the ventricular rate control group. Thus, a total of 387 patients were finally allocated to sinus rhythm control and 147 patients to ventricular rate control. Of the patients allocated to sinus rhythm control, 175 (45.2%) were still in sinus rhythm after 3 years and, of these, 88 were in the aspirin sinus rhythm control group (group 1) and 87 were in the warfarin sinus rhythm control group (group 2). There were no significant differences between the three groups with regard to age, gender, left atrial diameter, left ventricular ejection fraction and left ventricular diameter, and baseline characteristics of ischaemic heart disease, hypertension and diabetes mellitus were also similar in the three groups (Table 1). There were 12 embolic events and four deaths in group 1, two embolic events and two deaths in group 2, and 15 embolic events and 12 deaths in group 3 by the end of the 3-year follow-up period (Table 2). The rates of embolic events and overall mortality were similar in groups 1 and 3, and mortality also did not differ significantly between groups 1 and 2 (Table 2; Figs 2 and 3). The embolic event rate was significantly higher in group 1 than in group 2 (P = 0.013) and in group 3 than in group 2 (P = 0.046) (Table 2; Fig. 2). The mortality rate was significantly higher in group 3 than in group 2 (P = 0.049) (Table 2; Fig. 3). No major bleeding occurred in group 1 during the 3-year follow-up period and there was one intracranial haemorrhage in each of groups 2 and 3 (no significant difference between the three groups). The numbers of patients with minor bleeding episodes were two (2.3%) in group 1, six (6.9%) in group 2 and nine (6.1%) in group 3 (Table 2). 466

4 AF > 48 h duration 534 patients Sinus rhythm control (n = 425) Ventricular rate control (n = 109) Cardioversion Unsuccessfully cardioversed 38 patients Successfully cardioverted ( = 387 patients) 147 patients Ventricular rate control group (Group 3) 387 patients 175 patients in sinus rhythm after 3 years 212 patients were not in sinus rhythm at the end of the study 88 patients Aspirin-sinus rhythm control group (Group 1) 87 patients Warfarin-sinus rhythm control group (Group 2) FIGURE 1: Patient numbers and treatment outcomes in the present study designed to compare sinus rhythm control with ventricular rate control in patients with atrial fibrillation (AF) TABLE 1: Baseline characteristics of patients with atrial fibrillation who completed the study receiving aspirin sinus rhythm control (group 1), warfarin sinus rhythm control (group 2) or ventricular rate control (group 3) Statistical Group 1 Group 2 Group 3 significance No. of patients Age (years), mean ± SD 69 ± 5 68 ± ± 5.4 NS Female n, (%) 57 (64.8) 50 (57.4) 89 (60.5) NS Male n, (%) 31 (35.2) 37 (42.5) 58 (39.5) NS Hypertension n, (%) 64 (72.7) 74 (85.1) 107 (72.8) NS Diabetes n, (%) 16 (18.1) 12 (13.8) 28 (19.0) NS Ischaemic heart disease n, (%) 36 (40.9) 29 (33.3) 57 (38.8) NS LVEF (%), mean ± SD 61.3 ± ± ± 9.4 NS LA diameter (cm), mean ± SD 4.1 ± ± ± 3.7 NS LVEDD (cm), mean ± SD 5.0 ± ± ± 1.2 NS LA, left atrium; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NS, not statistically significant (P > 0.05). 467

5 TABLE 2: Clinical outcomes after 3 years of follow-up for patients with atrial fibrillation receiving aspirin sinus rhythm control (group 1), warfarin sinus rhythm control (group 2) or ventricular rate control (group 3) Statistical Group 1 Group 2 Group 3 significance No. of patients Minor bleeding n, (%) 2 (2.3) 6 (6.9) 9 (6.1) NS All embolic events n, (%) 12 (13.6) 2 (2.3) 15 (10.2) P = (group 1 vs 2) P = (group 2 vs 3) Cerebral embolism n, (%) 8 (9.1) 1 (1.2) 9 (6.1) NS Transient ischaemic attack n, (%) 4 (4.6) 1 (1.2) 4 (2.7) NS Peripherial embolism n, (%) (1.4) NS Death from all causes n, (%) 4 (4.6) 2 (2.3) 12 (8.2) P = (group 2 vs 3) Death from embolism n, (%) 2 (2.3) 1 (1.2) 3 (2.0) NS Death owing to pump failure n, (%) 2 (2.3) 0 7 (4.8) NS Sudden death n, (%) (0.7) NS Cerebral haemorrhage n, (%) 0 1 (1.2) 1 (0.7) NS NS, not statistically significant (P > 0.05). Embolic event free (%) Group 1 vs group 2 P = Group 1 vs group 3 P = NS Group 2 vs group 3 P = Group 1 Group 2 Group Follow-up duration (months) FIGURE 2: Percentage of patients with atrial fibrillation who remained free from embolic events following aspirin sinus rhythm control (group 1), warfarin sinus rhythm control (group 2) or ventricular rate control (group 3) during the 3-year study follow up period 468

6 Group 1 Group 2 Group 3 98 Survival (%) Group 1 vs group 2 P = NS Group 1 vs group 3 P = NS Group 2 vs group 3 P = Follow-up duration (months) FIGURE 3: Cumulative percentage survival in patients with atrial fibrillation following aspirin sinus rhythm control (group 1), warfarin sinus rhythm control (group 2) or ventricular rate control (group 3) during the 3-year study follow up period Discussion AF is the most common sustained arrhythmia encountered in clinical practice. 1,2 The prevalence of atrial fibrillation increases sharply with age, from 0.5% in the age group years to 4% in those years old and as high as 9% of those 70 years 17, and it is a major cause of stroke in the elderly. 5 AF is responsible for 7 31% of all ischaemic strokes 6 and 50 70% of patients with stroke associated with AF die or have a severe permanent neurological deficit. 18,19 There are two general approaches in the management of AF: 6,7 (i) ventricular rate control and the prevention of stroke; and (ii) restoration and maintenence of sinus rhythm. Adequate ventricular rate control in AF decreases the patient s symptoms and prevents tachycardia-induced cardiomyopathy. 6,7 For the prevention of stroke in patients with AF, prospective, randomized, controlled trials have shown that effective anticoagulation needs to be established. 6,7 They have also shown that a history of previous stroke or transient ischaemic attack, diabetes mellitus, hypertension, advanced age, congestive heart failure, rheumatic heart disease and coronary artery disease are independent risk factors for stroke in patients with AF and that warfarin treatment is recommended for these patients with AF who have any of these risk factors. 6,7 Adjusted-dose warfarin reduces the risk of stroke by about 60% compared with placebo, aspirin reduces the risk by about 20% compared with placebo, and warfarin reduces the risk by about 40% compared with aspirin. 6,7 The advantages of restoring sinus rhythm include marked relief of symptoms, improvement in cardiac haemodynamics and a decrease in thromboembolic events. 3,5 Restoration of sinus rhythm in AF patients was examined in the Pharmacological 469

7 Intervention in Atrial Fibrillation (PIAF), AFFIRM, the Rate Control versus Electrical Cardioversion (RACE) and STAF studies. 9 15,20 The PIAF study included 252 patients with AF followed up for 12 months and found no difference in quality of life between the groups allocated to control of ventricular rate or sinus rhythm. 20 The AFFIRM study included patients who had at least one risk factor other than AF for stroke and death These risk factors were age 65 years, systemic hypertension, diabetes mellitus, congestive heart failure, transient ischaemic attack, previous stroke, enlarged left atrium 50 mm, and left ventricular fractional shortening < 25% or left ventricular ejection fraction < 40%. Patients were followed up for approximately 5 years and no difference was found in terms of stroke and mortality between the ventricular rate control and sinus rhythm control groups. In the RACE trial, 512 patients with AF for > 24 h but <1 year were randomized to either ventricular rate control or sinus rhythm control and followed up for 3 years. 12,13 At the end of the study it was found that sinus rhythm control was not superior to ventricular rate control. The STAF trial also found no difference between ventricular rate or sinus rhythm control in morbidity and mortality among patients with AF. 15 These four studies showed that cardioversion in AF provided no benefit over rate control in terms of embolism, death and the relief of symptoms and, therefore, ventricular rate control was established as the primary therapy for AF patients. 9 15,20 In the AFFIRM and RACE trials most strokes occurred in patients whose warfarin therapy was stopped or in patients with INR < Anticoagulation was, therefore, recommended to all patients with risk factors for stroke. There has been no previous study comparing the three treatment strategies for AF of: (i) ventricular rate control plus longterm anticoagulation; (ii) sinus rhythm control plus anticoagulation for 1 month; and (iii) sinus rhythm control plus long-term anticoagulation. The present study is the first to compare these three treatment strategies in AF patients and the results are similar to those of studies such as AFFIRM, RACE and STAF in that sinus rhythm control plus anticoagulation for 1 month was not superior to ventricular rate control in terms of rates of mortality and embolic events. Sinus rhythm control plus anticoagulation for 3 years, however, improved survival and decreased embolic events in patients with AF compared with the other two treatment strategies. Thus, cardioversion to sinus rhythm did not decrease the incidence of thrombus formation without long-term warfarin anticoagulation therapy. In conclusion, the present study suggests that the restoration and maintenance of sinus rhythm with long-term anticoagulation therapy is superior in terms of reducing the incidence of embolic events and death compared with either cardioversion to sinus rhythm or the restoration and maintenance of sinus rhythm with short-term anticoagulation therapy in patients with AF duration > 48 h. This warrants further investigation in larger cohorts of patients with AF. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 27 October 2008 Accepted subject to revision 6 November 2008 Revised accepted 18 February 2009 Copyright 2009 Field House Publishing LLP 470

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