Author + information
- Received April 27, 1999
- Revision received February 11, 2000
- Accepted March 6, 2000
- Published online July 1, 2000.
- Volker Kühlkamp∗,* (, )
- Alexander Schirdewan†,
- Karl Stangl‡,
- Michael Homberg§,
- Matthias Ploch∥ and
- Otto A Beck¶
- ↵*Reprint requests and correspondence: Volker Kühlkamp, Eberhard-Karls-Universität, Medizinische Klinik III, Otfried Müller Strasse 10, 72076 Tübingen, Germany
The primary objective of the present study was to assess the efficacy of metoprolol CR/XL to reduce the risk of relapse after cardioversion of persistent atrial fibrillation to sinus rhythm.
Indirect data from studies with d,l sotalol provide evidence that the beta-blocking effects of the compound are important in maintaining sinus rhythm after cardioversion of atrial fibrillation.
After successful conversion to sinus rhythm, 394 patients with a history of persistent atrial fibrillation were randomly assigned to treatment with metoprolol CR/XL or placebo. The two treatment groups were similar with respect to all pretreatment characteristics. Patients were seen on an outpatient basis for recording of resting electrocardiogram (ECG) after one week, one, three and six months of follow-up or whenever they felt that they had a relapse into atrial fibrillation or experienced an adverse event.
In the metoprolol CR/XL group, 96 patients (48.7%) had a relapse into atrial fibrillation compared with 118 patients (59.9%) in the placebo group (p = 0.005). Heart rate in patients after a relapse into atrial fibrillation was significantly lower in the metoprolol group (98 ± 23 beats/min) than in the placebo group (107 ± 27 beats/min). The rate of adverse events reported was similar in both groups when the difference in follow-up time was taken into account.
The results of this double-blind, placebo-controlled study in patients after cardioversion of persistent atrial fibrillation showed that metoprolol CR/XL was effective in preventing relapse into atrial fibrillation or flutter.
Atrial fibrillation is the most common persistent arrhythmia in the population, increasing in incidence with age (1,2). In the Framingham study, cardiac disease and cardiovascular risk factors were the predominant predisposing factors for atrial fibrillation (3). Exercise capacity is significantly reduced with chronic atrial fibrillation when compared with sinus rhythm (4). Hence, restoration and maintenance of
sinus rhythm are important therapeutic goals. It has been shown that drugs with class 1a, class 1c, and class 3 antiarrhythmic properties are suitable for maintaining sinus rhythm (5–14). However, especially with class 1 antiarrhythmic drugs, there is concern that these drugs may increase mortality (5,15–18). The risk of proarrhythmia is not associated with beta-blocker treatment.
A nonselective beta-blocker with class 3 antiarrhythmic activity, d,l sotalol, proved to be as effective as quinidine in maintaining sinus rhythm after direct current cardioversion (19); d-sotalol, the dextrorotatory optical isomer of the racemate d,l sotalol, blocks the rapid component of the delayed-rectifier current (IKr) and lacks clinically significant beta-blocking properties (20). A study comparing d,l sotalol, d-sotalol and placebo supported the finding that d,l sotalol was effective in maintaining sinus rhythm. However, the efficacy of d-sotalol was not significantly different from placebo (21). Hence, there is indirect evidence that beta-blockade is important for maintaining sinus rhythm after cardioversion. However, placebo-controlled data on the value of beta-blockade after cardioversion of persistent atrial fibrillation or atrial flutter not associated with open heart surgery are lacking. We therefore conducted a multicenter, placebo-controlled, randomized, double-blind trial to test the hypothesis that metoprolol CR/XL (controlled release), a selective beta1 adrenoceptor blocking drug, is effective in preventing relapse into atrial fibrillation following cardioversion.
This was a prospective randomized, double-blind, parallel group multicenter study comparing oral metoprolol CR/XL with placebo after cardioversion of persistent atrial fibrillation. The study protocol was approved by the Institutional Review Board at each of the 71 participating centers. Informed written consent was obtained from each patient. Patients were eligible if they had the persistent form of atrial fibrillation that had lasted for a minimum of three days and up to one year. The terminology used in the description of atrial fibrillation in this report follows the recently suggested recommendations (22). Patients had to be successfully converted to sinus rhythm either by direct current (DC) cardioversion or therapy with class 1 antiarrhythmic drugs. Whether a patient underwent cardioversion or not, and whether DC or a class 1 antiarrhythmic drug was used, was left to the discretion of the physician at each site; however, the use of DC cardioversion was recommended. A sufficient anticoagulation before, and for at least one month after, cardioversion was strongly recommended. The method of anticoagulation (oral phenprocoumon or IV heparin) was decided by the investigator at each site. After cardioversion of atrial fibrillation, patients were randomized to either metoprolol CR/XL (controlled release) or placebo. Patients were allocated treatment according to a computer-generated randomization list common to all centers.
The metoprolol CR/XL formulation is characterized by its ability to produce an even plasma concentration over 24 h (23). The metoprolol CR/XL tablets (50 mg and 100 mg) and matching placebo were manufactured, packed, labeled and distributed by the sponsor of the study (AstraZeneca RD, Mölndal, Sweden). The placebo tablets were identical in size, weight, color, and taste to the metoprolol CR/XL tablets. Tablets were packed in bottles for each patient. Compliance with the study medication was checked by pill count at each visit.
The initial dose was 100 mg metoprolol CR/XL or placebo given once daily. It was recommended to increase the dose to 200 mg once daily. If the investigator felt it necessary, however, the dose could be maintained at 100 mg once daily or decreased to 50 mg once daily. Concomitant drug therapy was not restricted. However, concomitant therapy with any class 1 or class 3 antiarrhythmic drug, beta-blockers or calcium channel blockers such as verapamil or gallopamil, was considered as an exclusion criterion. Patients were followed on an outpatient basis and were seen at one week, one month, three months and six months following inclusion or at the time of a relapse of atrial fibrillation or in the case of adverse events. Patients were encouraged to obtain an electrocardiogram (ECG) if they had symptoms suggestive of a recurrence of atrial fibrillation. At each visit, a resting ECG was obtained. After study closure, all ECGs were evaluated blindly at a central core laboratory with respect to the prevailing rhythm and heart rate at each visit. In the case of sinus rhythm, heart rate was calculated as the mean of three consecutive beats, and in the case of atrial fibrillation, as the mean of six consecutive beats.
Major exclusion criteria were: contraindications to treatment with beta-adrenergic blocking agents (i.e., presence or history of AV-block II/III, sick sinus syndrome, asthma), chronic oral treatment with amiodarone within six months prior to inclusion, concomitant treatment with any class 1 or 3 antiarrhythmic drug within five half-lives of that drug, cardiac surgery in the previous two months, clinical need for concomitant treatment with beta-blockers, and untreated thyroid dysfunction. Excluded from the study were patients with the paroxysmal form of atrial fibrillation or a history of paroxysmal atrial fibrillation, defined as recurrent episodes of atrial fibrillation alternating with sinus rhythm (22).
The primary end point of the study was to assess the efficacy of metoprolol CR/XL, compared with placebo, with respect to the cumulative number of patients relapsing into atrial fibrillation or flutter during a period of six months following cardioversion to sinus rhythm. Secondary objectives were to compare the effects of metoprolol CR/XL and placebo on the ventricular rate in patients with relapse of atrial fibrillation or flutter and to assess the tolerability of metoprolol CR/XL.
At baseline, a two-dimensional echocardiogram was obtained in the left parasternal short axis and the left apical four-chamber view. Left ventricular end-systolic and end-diastolic diameter, the thickness of the interventricular septum and the posterior wall, fractional shortening, and left atrial diameter were all determined.
The power calculation for the primary end point, namely relapse of atrial fibrillation/flutter, indicated that 200 patients per group were needed. This power calculation (80% power, α = 0.05, two-sided) was made on the assumption that 70% of patients in the placebo group would have a relapse over the six-month follow-up period and that metoprolol CR/XL would decrease this number to 55%.
For the primary end point, cumulative incidences were compared using the log-rank test, with nominal two-tailed p values. Patients were included in the statistical analysis according to the intention-to-treat approach. Data on patients with sinus rhythm were censored at the date of the last follow-up visit. Data on heart rate were compared using the t-test, and descriptive statistics were given for all other variables.
Characteristics of the patients
Four hundred three patients were enrolled into the trial. For the final evaluation, nine patients (5 randomized to metoprolol CR/XL and 4 randomized to placebo) were withdrawn from analysis because they had only a baseline ECG, without any follow-up information (Fig. 1). Hence, 394 patients were available for the intention-to-treat analysis. One hundred and ninety-seven patients were assigned to the metoprolol group and 197 to the placebo group. The two treatment groups were similar with respect to all pretreatment characteristics (Tables 1 and 2). ⇓⇓In particular, there was no difference in the duration of atrial fibrillation prior to cardioversion and the proportion of patients with prior antiarrhythmic or DC cardioversion. The majority of patients were cardioverted by means of DC cardioversion (n = 325, 82.5%). The subgroup cardioverted by class 1 antiarrhythmic drugs (n = 69, 17.5%) was not different in baseline characteristics, compared with the patients cardioverted electrically. Most patients received 100 mg metoprolol CR/XL (n = 122, 62%) or the corresponding dose of placebo (n = 131, 67%) once daily. The dose of metoprolol was reduced to 50 mg once daily in 36 patients (18.3%) from the metoprolol CR/XL group and in 12 patients (6.1%) from the placebo group. In 33 patients (16.8%), metoprolol was increased to 200 mg daily, whereas 50 patients (25.4%) in the placebo group had a dose increase.
Primary end point
The intention-to-treat analysis showed that 118 patients (59.9%) in the placebo group and 96 patients (48.7%) in the metoprolol CR/XL group relapsed into atrial fibrillation or flutter (p = 0.005, Fig. 2). In the group of patients in which electrical cardioversion was performed, 106 of 163 patients (65.0%) in the placebo group relapsed into atrial fibrillation, compared with 82 of 162 patients (50.6%) in the metoprolol group (p = 0.002, Fig. 3). The median time to relapse of atrial fibrillation was 7.5 days in the placebo group and 13.0 days in the metoprolol CR/XL group (p = 0.001). Mean follow-up in the placebo group was 73 ± 80 days, versus 93 ± 81 days in the metoprolol group.
The ability of metoprolol CR/XL to prevent a relapse to atrial fibrillation was demonstrated in all subgroups analyzed. However, because the number of patients included in our study was not sufficient to analyze subgroups, only descriptive statistics for this comparison are given (Tables 3 and 4). ⇓⇓The duration of atrial fibrillation prior to cardioversion and its impact on the efficacy of metoprolol CR/XL to prevent a relapse to atrial fibrillation was analyzed only in the subgroup with a documented duration of atrial fibrillation.
Secondary end point and effect on heart rate
Mean heart rate of patients who relapsed into atrial fibrillation or flutter in the placebo group was 107 ± 27 beats/min, compared with 98 ± 23 beats/min in the metoprolol group (p = 0.015). In patients remaining in sinus rhythm, mean heart rate at study closure decreased from 74 ± 14 beats/min to 64 ± 11 beats/min in the metoprolol CR/XL group. The corresponding figure in the placebo group was 70 ± 11 beats/min versus 72 ± 13. The difference in heart rate between the two study groups during follow-up was highly significant (p = 0.0001).
Safety and tolerability of treatment
Serious adverse events and adverse events causing withdrawal from the study were seen in 20 patients in the metoprolol group and in 6 patients in the placebo group (Fig. 1 and Table 3). However, follow-up time was longer in the metoprolol group than in the placebo group. The main reasons for premature discontinuation of study medication in the metoprolol CR/XL group were dizziness, AV-block II and exertional dyspnea (Table 5). The number of patients included in the safety analysis was not the same as that included in the efficacy analysis. The safety population includes 399 patients (199 placebo and 200 metoprolol CR/XL) and is defined as all patients who received at least one dose of study drug, and for whom post-dose data were available.
Three patients died, all in the metoprolol group. One of the patients had dilated cardiomyopathy and experienced sudden death. Another patient died from ischemic stroke, and a third patient died from hemorrhagic stroke one week after relapse of atrial fibrillation, while on oral anticoagulation with phenprocoumon.
Adverse events, not necessarily leading to discontinuation of the study medication and observed in at least two patients, are listed in Table 5. Dizziness, vertigo, nausea and bradycardia were more commonly reported in the metoprolol CR/XL group than in the placebo group.
Our study shows that the proportion of patients relapsing into atrial fibrillation during the study period of six months was significantly lower on metoprolol CR/XL than on placebo.
Proarrhythmia: comparison with class 1 and class 3 antiarrhythmic drugs
This study may have a potentially important impact on drug treatment to maintain sinus rhythm after cardioversion. As mentioned above, class 1 antiarrhythmic drugs bear the risk of proarrhythmia and might increase mortality, at least in patients with organic heart disease (5,15,17,18). Treatment with d,l sotalol is effective in maintaining sinus rhythm after cardioversion, although this treatment is associated with a significant risk of proarrhythmia (19,24). Torsades de pointes has been described with two new class 3 antiarrhythmic drugs. However, this was not associated with an increased mortality (12,14). Similarly, amiodarone has not been shown to be associated with an increased mortality (25–27). Severe noncardiac side effects, however, require withdrawal of the drug in a substantial proportion of patients (25–27). Hence, although amiodarone seems to be very effective in maintaining sinus rhythm, it is not the drug of first choice in the majority of patients with chronic atrial fibrillation (28–31).
It has been shown, however, that beta-blocking drugs are safe and improve the prognosis in patients with hypertension, after myocardial infarction and in patients with heart failure (32–37). Thus, the use of beta-blocking agents does not raise safety concerns. This study is the first to clearly show that metoprolol CR/XL is effective in preventing a relapse of atrial fibrillation after cardioversion to sinus rhythm (Figs. 2 and 3).
Efficacy of treatment
Our findings are in accordance with a recently published observational study reporting a marked reduction of the risk for atrial fibrillation if patients were treated with a beta-blocker (38). The effect of metoprolol CR/XL cannot be attributed solely to a better control of the underlying cardiac disease, because the ability of metoprolol CR/XL to prevent a relapse to atrial fibrillation was of similar magnitude in all subgroups analyzed (Table 4). Although a direct comparison of different studies is difficult, the efficacy of metoprolol CR/XL to prevent a relapse into atrial fibrillation was found to be similar to that obtained in studies with class 1 or class 3 antiarrhythmics (29).
Importance of the placebo group
One of the most important points in our study design was the use of a placebo group. Many studies published in recent years have compared different active drug regimens for prevention of a relapse to atrial fibrillation in patients with persistent atrial fibrillation but have included no control group. Placebo-controlled studies in patients with atrial fibrillation have been published only for quinidine in 1981 and 1984 (39,40). About 50% of patients included in the controlled studies using quinidine had atrial fibrillation associated with rheumatic heart disease (5). In our study, only 14 patients (3.6%) had valvular heart disease. This is similar to some recent studies and may reflect a temporal decline in rheumatic heart disease and/or a change in the treatment of patients with atrial fibrillation associated with rheumatic disease (15,19,41). It is questionable whether data obtained in a patient population with valvular heart disease as the main cardiac diagnosis can be applied to a general patient population with cardiac disease, where valvular heart disease is present only in a minority of individuals.
Mechanism of action
The mechanism by which a plain beta-blocker prevents relapse into atrial fibrillation remains speculative. An increased sympathetic drive has been shown to provoke atrial tachyarrhythmias (42). This accords with our finding that the effect of metoprolol was more pronounced in patients with a sinus rate above 80/min, as compared with the group with a sinus rate below 80/min (Table 4). In addition, beta-adrenergic stimulation shortens the action potential duration by increasing the magnitude of IK(43). In pacing-induced atrial fibrillation, shortening of the atrial refractoriness is thought to be an important mechanism by which atrial fibrillation perpetuates itself (44). Furthermore, it has been shown recently that the ultrarapid delayed rectifier K+ current (IKUR) plays an important role in human atrial repolarization (45). This current is increased by isoproterenol and the effect of isoproterenol is reversed by the addition of propranolol (46). An increase of IKUR decreases action potential duration. Hence, there is evidence from experimental observations that stimulation of adrenoceptors might facilitate the induction and perpetuation of atrial fibrillation.
Some limitations of the present study should be noted. It is known from patients with paroxysmal atrial fibrillation that asymptomatic episodes are frequent (47). In a recent study, atenolol was found to be equivalent to d,l sotalol in reducing the number of episodes of symptomatic atrial fibrillation (48). Paroxysmal atrial fibrillation or a history of it were exclusion criteria in our study. All patients in our study required DC cardioversion or treatment with class 1 antiarrhythmic drugs to convert to sinus rhythm. It seems unlikely, therefore, that we inadvertently recruited a significant number of patients with paroxysmal atrial fibrillation. Furthermore, recurrences of atrial fibrillation were homogeneously distributed over time, and they were not more frequently observed at the visits during long-term follow-up. Therefore, it seems unlikely that metoprolol CR/XL treatment masked symptoms of relapse into atrial fibrillation. Although it cannot be ruled out that we might have missed asymptomatic episodes of atrial fibrillation that terminated spontaneously, the main goal of treatment in atrial fibrillation is the reduction of symptomatic episodes, as it has never been shown that atrial stabilization, for example, reduces the risk of stroke. Asymptomatic episodes might have been detected had we used frequent transtelephonic monitoring, as suggested in two published trials in patients with frequent paroxysmal atrial fibrillation (10,11).
A further limitation of our study is that the results cannot be applied to all patients with atrial fibrillation. The mean age of the patients in this trial was about 60 years, whereas in the general population the mean age of patients with atrial fibrillation is about 75 years (19). However, this might reflect the practice of avoiding cardioversion and prescribing antiarrhythmic drugs to maintain sinus rhythm in the elderly (15), at least in the setting of a clinical trial.
Finally, the 40% placebo efficacy at the six-month follow-up is higher than previously reported; therefore, it has not been proven that metoprolol CR/XL is as effective in a group of patients with a high risk for a recurrence of atrial fibrillation after cardioversion.
It is concluded that metoprolol CR/XL is superior to placebo for prevention of relapse into atrial fibrillation after cardioversion to sinus rhythm. Because therapy with beta-adrenergic blocking drugs has been shown to be safe, treatment with metoprolol CR/XL may become the treatment of first choice in patients with atrial fibrillation who require drug therapy to maintain sinus rhythm.
We would like to thank all investigators and study nurses who contributed to the successful completion of this study. We thank Professor John Wikstrand, MD, PhD, the Assistant Director of the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg University, who is also Senior Medical Advisor at AstraZeneca RD, Mölndal, Sweden, for his comments and help during preparation of the manuscript.
ECG core laboratory.
We also thank Eva-Lena Alenhag, Anna Frödén, and Caroline Schmidt, laboratory technologists, Inger Wendelhag, PhD, and Nils Edvardsson, MD, PhD, at the Wallenberg Laboratory for cardiovascular research, Sahlgrenska University Hospital, Göteborg University, Sweden, for analysis of all ECGs in the study.
Thomas Lanz, PhD, Astra Germany, Isabella Florén, and Margareta Thimell, AstraZeneca RD, Mölndal, Sweden.
Jonas Carlsson AstraZeneca RD, Mölndal Sweden.
☆ The study was supported by a grant from AstraZeneca RD, Mölndal, Sweden, and BMBF Förderprojekt 01EC9405 (Volker Kühlkamp).
- direct current
- Received April 27, 1999.
- Revision received February 11, 2000.
- Accepted March 6, 2000.
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