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European Heart Journal Advance Access originally published online on February 28, 2007
European Heart Journal 2007 28(11):1351-1357; doi:10.1093/eurheartj/ehl544
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Maintenance of sinus rhythm with metoprolol CR initiated before cardioversion and repeated cardioversion of atrial fibrillation: a randomized double-blind placebo-controlled study

Anna K Nergårdh*, Mårten Rosenqvist, Rolf Nordlander{dagger} and Mats Frick

Department of Cardiology, Karolinska Institutet at Stockholm South Hospital, Stockholm S-118 83, Sweden

Received 14 July 2006; revised 18 December 2006; accepted 25 January 2007; online publish-ahead-of-print 28 February 2007.

* Corresponding author. Tel: +46 8616 30 88; fax: +46 8616 30 40. E-mail address: anna.nergardh{at}sodersjukhuset.se


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Aims: To assess the effect of metoprolol in combination with repeated cardioversion on maintenance of sinus rhythm (SR).

Methods and results: Consecutive outpatients with persistent atrial fibrillation (AF) were randomized to treatment with metoprolol CR or placebo in a double-blind fashion. Study treatment was started at least one week before direct current (DC) cardioversion. Patients were followed once a week during the first 6 weeks after cardioversion. In case of relapse during this period, a second cardioversion was performed. Total treatment time was 6 months. A total of 168 patients were randomized to metoprolol (n = 83) or placebo (n = 85). The dose of study treatment at cardioversion was 169 ± 47 mg in the metoprolol group and 180 ± 40 mg in the placebo group (P = 0.12). In an intention-to-treat analysis, 46 patients (55%) in the metoprolol group and 34 patients (40%) in the placebo group (P = 0.04) had SR 1 week after cardioversion, and 38 patients (46%) in the metoprolol group compared with 22 patients (26%) in the placebo group had SR after 6 months (P < 0.01).

Conclusion: A treatment strategy of metoprolol CR started before cardioversion in combination with prompt second cardioversion in case of early relapse (1–6 weeks) significantly increases the proportion of patients in SR during six months of follow-up.

Key Words: Atrial fibrillation • Cardioversion • Metoprolol • Arrhythmias

{dagger} Deceased 3 June 2006. Back


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the population, and its prevalence increases with age.1 AF may cause disabling symptoms as well as an increased risk of tromboembolic events.2 Current recommendations concerning rate or rhythm control of AF mainly depend on patient symptoms. Exercise capacity is significantly reduced by chronic AF when compared with sinus rhythm (SR), and restoration and maintenance of SR often are important therapeutic goals for symptomatic reasons.3 However, even with the use of class I and III antiarrhythmic drugs, the recurrence rate of AF after direct current (DC) cardioversion is ~50% after 6 months.4,5 Due to their adverse effects and risk of pro-arrhythmias, treatment with antiarrhythmic drugs of class I and III is not generally advised in patients scheduled for their first DC cardioversion.6 Present evidence for using ß-blockers in order to reduce relapse into AF is limited and ß-blockers are generally assumed to be less effective for this purpose.7,8 However, in the previous study from our department, the use of ß-blockers as well as a short duration of AF were found to be independent predictors for maintenance of SR.9 The highest incidence of recurrence of AF is observed during the first weeks after cardioversion, particularly within the first week.10 One explanation for these early relapses is remodelling of the atria, where AF causes progressive structural and electrophysiological changes.11–14 A strategy of repeated cardioversions without changes in drug therapy in patients with early relapse has been evaluated and showed positive results, however without pre-specified time to second cardioversion.15 The high incidence of relapse into AF after restoration of SR in combination with the pro-arrhythmic risks with more effective antiarrhythmic drugs clearly show a need for evaluating more potent strategies without pro-arrhythmic side effects.

We have conducted a placebo-controlled, randomized, double-blind trial in patients with first time persistent AF to test the hypothesis that metoprolol controlled release (CR) initiated at least 1 week before cardioversion, in combination with prompt repeat cardioversion in the case of early relapse is effective in maintaining SR after DC cardioversion.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Consecutive patients referred to the Cardiology Department of South Hospital in Stockholm with symptomatic persistent AF with duration of up to 1 year and with no history of earlier DC cardioversion were eligible. In this study, persistent AF was defined as AF in repeated ECG recordings prior to referral, and confirmed with a 24 h Holter recording prior to inclusion in all patients. Major exclusion criteria were: contraindications to treatment with beta-blocking agents, i.e. a history of AV-block II/III, sick sinus syndrome or asthma, and poorly controlled congestive heart failure, untreated thyroid dysfunction, cardiac surgery within the previous two months as well as absolute indications for ß-blocker treatment such as known coronary artery disease (CAD). Treatment with any class I or III anti-arrhythmic drug or calcium channel blockers such as verapamil was also considered as an exclusion criterion. A complete medical history, physical examination, ECG and an examination of the medical notes including a review of available ECG recordings were performed in all patients in an attempt to determine the duration of AF. All patients underwent transthoracic echocardiography prior to inclusion. All patients were treated with warfarin, INR at levels between 2.1 and 3.0, for at least 3 weeks before and 6 weeks after cardioversion. In total, 615 patients were screened for inclusion. The most common reasons for not entering the study was unwillingness to participate, absolute indication for beta-blocking treatment, and AF shown to be paroxysmal.

Study treatment
At the time of inclusion at least 7 days prior to cardioversion, patients were randomized to either metoprolol CR or placebo. The metoprolol CR tablets (100 mg) and matching placebo were manufactured, packed, labeled, and distributed by AstraZeneca RD, Mölndal, Sweden. Patients were allocated treatment according to a computer-generated randomization list. The placebo tablets were identical in size, weight, colour, and taste to the metoprolol CR tablets. Tablets were packed in bottles for each patient. Compliance with the study medication was checked by pill counts. Initial dose was 50 mg of metoprolol or placebo given once daily, with 50 mg stepwise increase to a target dose of 200 mg once daily.

Cardioversion
DC cardioversion was performed on an elective basis according to standard clinical practice. Light general anaesthesia was induced with intravenous propofol. Paddles were placed in the right second intercostal space and in a left-sided lateral position along the mid-axillary line. Delivery of biphasic waveform shocks was started with 120 J and if unsuccessful followed by at least two attempts at 200 J. Selective ß1-blockers were given intravenously to patients with rapid ventricular rates or high blood pressure. Patients were observed 2 h following cardioversion. A pre-discharge 12-lead ECG was obtained for 2 h after cardioversion.

Follow-up
Patients were followed on an outpatient basis and were seen once a week during the first 6 weeks following DC cardioversion. At each visit, a 12-lead ECG was obtained. The patients were also instructed to contact the hospital in case of symptoms indicating recurrence of AF between the scheduled visits. If relapse was diagnosed during the first 6 weeks after DC cardioversion, the patients were scheduled for repeat cardioversion within 7 days, without any change in study treatment. These patients re-entered the once-a-week visit scheme. After the first 6 weeks, the patients had scheduled visits three and six months after DC cardioversion. At each visit, a resting ECG was obtained.

The primary endpoint of the study was to assess the efficacy of metoprolol CR compared with placebo in combination with prompt repetition of cardioversion in case of early relapse, with respect to the number of patients in SR 6 months following the first DC cardioversion. Secondary objectives were to compare the effects of metoprolol CR and placebo on the number of patients showing early re-initiation of AF (ERAF) after cardioversion, the number of patients in SR at 6 weeks, the ventricular rates in patients with relapse of AF, and to assess the tolerability of metoprolol CR.

Statistical analysis
The power calculation for the primary endpoint, namely SR 6 months after DC cardioversion, indicated that 74 patients per group were needed. This power calculation (80% power, {alpha} = 0.05, two-sided) was made on the assumption that 25% of patients in placebo group would have SR 6 months after DC cardioversion. We assumed a success rate at DC cardioversion of 90%, and included a total of 168 patients. For the primary endpoint, data were compared using the Pearson's {chi}2 test. Patients were included in the statistical analysis according to the intention-to-treat approach. Cumulative incidence was compared using the log-rank test.

Continuous variables are given as mean ± SD values. The unpaired t-test was used for analysis of statistical differences in variables between the groups. In comparisons of two proportions Pearson's {chi}2 test was used, and in the case of small numbers Fisher's exact test analysis was performed. A P-value < 0.05 was considered statistically significant. Calculations were performed with the statistical computer package STATISTICA 7.0 (StatSoft Inc.,Tulsa, Oklahoma).

Ethics
This study was approved by the Ethics Committee of Karolinska Institute, and all patients gave their informed consent to participate. The study was initiated by the investigators, and Astra-Zeneca, Sweden, had no involvement in the collection, analysis, or interpretation of data, in writing the report or in the decision to submit the paper for publication. The design, conduction, and interpretation of the study were undertaken by the authors. The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Acknowledgements
 References
 
Patient characteristics
A total of 168 patients were included in the study (Figure 1). Eighty-three patients were randomized to treatment with metoprolol and 85 patients to placebo. The two treatment groups were similar with respect to all pre-treatment characteristics (Table 1). Before scheduled DC cardioversion, four patients in the metoprolol group and four patients in the placebo group discontinued treatment (Figure 1). In the metoprolol group, one patient developed bradycardia < 40 beats/min, and one patient died after a cerebral haemorrhage. Two patients chose to discontinue treatment for personal reasons. In the placebo group, four patients chose to discontinue treatment for personal reasons.


Figure 1
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  		Figure 1 Flow diagram of the study. AE: Non-serious adverse event; SAE: Serious adverse event.

 

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  		Table 1 Baseline clinical characteristics

 
Cardioversion
Seventy-nine patients in the metoprolol group and 81 patients in the placebo group underwent DC cardioversion. Mean dose of study treatment (±SD) at the time of cardioversion was 169 ± 47 mg in the metoprolol group compared with 180 ± 40 mg in the placebo group (P = 0.12). Mean duration treatment time before cardioversion was 29.1 ± 16 and 26.3 ± 15 days (P = 0.26) in metoprolol and placebo groups, respectively. Fifty patients (60%) in the metoprolol and 61 patients (72%) in the placebo groups reached the target dose of 200 mg, as shown in Table 2.


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  		Table 2 Doses of metoprolol/placebo

 
Four patients in the metoprolol group (5%) and six patients (7%) in the placebo group never restored SR at DC cardioversion (Figure 1). One of the patients in the metoprolol group developed bradycardia after cardioversion, and was given atropine intravenously. This patient was later treated with permanent pacemaker. In the metoprolol group, 11 patients (13%) received an intravenous ß-blocker (metoprolol) at the time of cardioversion because of rapid ventricular rates or high blood pressures, compared to 27 patients (32%) in the placebo group (P < 0.01).

Early relapse and repeated cardioversion
No patients in the metoprolol group showed ERAF, defined as relapse into AF prior to the discharge ECG 2 h after cardioversion. By contrast, seven patients in the placebo group showed ERAF (P < 0.01), five of whom had been given intravenous ß-blocker treatment at time of cardioversion. Forty patients (47%) in the placebo group and 41 patients (49%) in the metoprolol group had a second DC cardioversion, i.e. relapsed during the first 6 weeks after their initial DC cardioversion (P = 0.8), as shown in Figure 1. The median duration from the detected relapse in AF until the second cardioversion was 1 (range 0–7) and 2 (range 0–7) days in the metoprolol and in the placebo groups, respectively. Ten patients were subjected to their second cardioversion after more than 7 days (10–26 days), because of non-therapeutic INR values. Nine of these patients were treated with metoprolol and two with placebo. At this second cardioversion, two patients developed ERAF, one treated with metoprolol and one with placebo.

Primary endpoint, effect of study treatment
An intention-to-treat analysis of all patients with a first successful cardioversion shows that 6 months after primary DC cardioversion, 22 patients (26%) in the placebo group and 38 patients (46%) in the metoprolol group were in SR (P < 0.01, Table 3). The difference in proportion of patients in SR between the two study groups was significant along 1 week after primary cardioversion, and remained highly significant through out the follow-up period (Table 3). In patients who converted to SR at the first DC cardioversion, a log-rank test of equality over treatment groups regarding time to second relapse during first 6 weeks after primary DC or first relapse more than 6 weeks after primary DC cardioversion yielded a P-value = 0.02 (Figure 2).


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  		Table 3 Number of patients in SR during follow-up

 

Figure 2
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  		Figure 2 Cumulative number of patients in SR, subdivided by treatment group. The log-rank test of equality over treatment groups included a total number of patients = 143, metoprolol = 75 and placebo = 68; i.e. all patients with successful primary DC cardioversion.

 
In patients who underwent one DC cardioversion during the study period (i.e. no relapse during the first 6 weeks after cardioversion), 28 out of 42 (67%) patients in the metoprolol group maintained SR at 6 months follow-up, compared with 19 out of 45 patients (42%) in the placebo group (P = 0.02). In patients who had a second DC cardioversion, 10 out of 41 patients (24%) in the metoprolol group and three out of 40 patients (8%) in the placebo group showed SR 6 months after their initial cardioversion (P = 0.03).

Effect on heart rate
Mean heart rate (±SD) at time for the first cardioversion was 76.1 beats/min (±13) and 88.2 (±14) in the metoprolol group and the placebo group, respectively (P < 0.01).

Mean heart rate (±SD) at relapse was 86.4 (±17) beats/min in the metoprolol treatment group compared with 97.9 (±22) beats/min in the placebo group (P = 0.02).

Safety and tolerability of treatment
Withdrawals from the study were seen in two patients in the metoprolol group because of serious adverse event and adverse event (one with hemorrhagic stroke 2 days after initiation of anticoagulation treatment and one with AV-block II, Figure 1). A side effect was registered if observed on at least at one occasion and occurring in two or more patients. Side effects were registered at each follow-up visit 1 week, 6 weeks, 3 months, and 6 months after primary DC cardioversion. The results of these reports are shown in Table 4. The number of patients included in the safety analysis was 166 patients, i.e. all patients who received at least one dose of study drug.


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  		Table 4 Most common adverse effects (occurring for two or more patients)

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Acknowledgements
 References
 
The main result of our study is that metoprolol CR in combination with prompt recardioversion in the case of early relapse significantly increases the proportion of patients in SR 6 months after primary DC cardioversion of persistent symptomatic AF.

ß-blockers and prevention of AF
The mechanism by which a ß-blocker might prevent relapse into AF remains unexplained. There is evidence from experimental observations that stimulation of adrenorececeptors facilitates both the induction and perpetuation of AF.16–18 Earlier studies comparing ß-blockers with sotalol have shown equality concerning prevention of relapse into AF.7,19 However, in the study by Plewan et al.7 the dose of sotalol was relatively low (160 mg/day), and since the class III anti-arrhythmic effect is less pronounced at low doses, this investigation may be interpreted as a comparisons between two ß-blockers. In a placebo-controlled multi-centre trial by Kühlkamp et al.,8 metoprolol showed a significant decrease in relapse of AF after DC cardioversion according to a log-rank test. However, the proportion of patients in SR at 6 months differed only modest between the treatment groups. In that investigation, the treatment with ß-blocker was started after DC cardioversion and the dose of metoprolol might have been suboptimal. Since relapse into AF is the most frequent during the first weeks after DC cardioversion,9,10 our results emphasize the importance of starting treatment with ß-blockers prior to DC cardioversion in order to inhibit early relapse into AF. Moreover, it is possible that the use of a higher dose of ß-blocker in our study compared to the doses used in the study by Kühlkamp et al.8 might have produced a more pronounced antiarrhythmic effect.

Atrial remodelling and repeated cardioversion
The rational for repeated cardioversion in the case of relapse is that the duration of AF has previously been described as an independent predictor for maintenance of SR.9 Persistent AF is known to cause electrophysiological changes in the atrial myocardium, which are thought to explain the progressive nature of the arrhythmia.11 The main mechanism for early relapses is thought to be atrial remodelling, and in particular perturbation in atrial electrophysiological properties, i.e. atrial electrical remodelling.10–14 In a investigation by Bertaglia et al.,15 a regime of repeated cardioversion (within 2–60 days after relapse in AF) was useful in achieving SR after 12 months in patients treated with class IC or III anti-arrhythmic drugs. However, as the authors point out, it has previously been demonstrated that in patients with persistent AF recovery from atrial electrical remodelling ranged from 12 to 72 h,20,21 and a positive effect of repeated cardioversion cannot therefore be solely explained by the prevention of atrial electrical remodelling. In our study, we found that patients in the placebo group who had relapsed into AF during the first 6 weeks and received prompt repeated cardioversion showed significantly higher rates of relapse to persistent AF during follow-up compared with patients who received metoprolol treatment. This is consistent with a trial by Fynn et al.,22 which demonstrated that early repeated internal cardioversion (within 35 h) in the case of recurrence of AF was of very limited value in patients without anti-arrhythmic treatment.

Combination strategy
In our study, 46% of the patients in the metoprolol group compared with 26% in the placebo group were in SR 6 months after DC cardioversion using a strategy including pre-treatment with a ß-blocker and prompt repeated cardioversion in the case of early relapse. The beneficial effect of ß-blockers seems to be related partly to inhibition of AF for the first 2 h after cardioversion (ERAF) but also to the inhibition of subacute relapse into AF. The finding that pre-treatment with ß-blockers significantly reduced the incidence of ERAF is in accordance with earlier studies showing a reduction of early relapses in AF in subgroups of patients with ß-blockers and also with verapamil-treatment,23–25 thought to be partly due to restoration of abnormal intracellular calcium handling.12,26 However, our finding on ERAF also could be due to few patients, and more studies in this area are of need. There is a trend also in our study towards that patients with hypertension had more beneficial effect of ß-blocking treatment, however our material is too small for a significant result. In our study, the incidence of relapse after a second cardioversion was significantly lower in patients with ß-blocker treatment. One possible explanation is that on-going treatment with ß-blockers at the time for relapse might postpone electrical remodelling and thereby increase the chance of remaining in SR after the second cardioversion.

The results in our investigation regarding the proportion of patients in SR 6 months after DC cardioversion are comparable with earlier studies using class I and III anti-arrhythmic drugs as prophylactic treatment.4,5 These drugs, however, bear a substantial risk of pro-arrhythmic side effects.27,28 In our study, metoprolol, a ß-blocker, was well tolerated and safe for the patients even in higher doses. Withdrawal of treatment, even because of bradycardia, was seen only in a few patients. If so, this was seen when starting treatment, and only in one case revealed at time for cardioversion.

Our results favour this treatment strategy for patients with first time persistent symptomatic AF, with a proportion of patients in SR 6 months after DC cardioversion comparable with previous strategies but without a risk of drug-induced arrhythmias. This might be even more relevant in patient with ischaemic heart disease or congestive heart failure in whom ß-blockers have recognized beneficial properties. Using the strategy presented in this study, it might be possible to decrease the use of class I and III anti-arrhythmic drugs thereby avoiding potential risks for pro-arrhythmias.

Study limitation
Some limitations with the present study should be noted. Our results cannot be applied to all patients with persistent AF, since earlier cardioversion was an exclusion criterion.

Another limitation is that our study protocol does not allow us to state which part of the treatment, ß-blocker or prompt repeated cardioversion, is the isolated most effective. After cardioversion, the patients were followed once a week with 12 lead ECG. Episodes of asymptomatic AF are known to be common, and an alternative method could have been transtelephonic monitoring.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Acknowledgements
 References
 
In patients with symptomatic persistent first-time cardioverted AF, we advocate a strategy of pre-treatment with metoprolol CR in combination with prompt cardioversion in case of early relapse (1–6 weeks). This strategy significantly increases the number of patients in SR during 6 months of follow-up. The treatment is both safe and well tolerated, and our strategy offers an advantageous alternative to traditional antiarrhythmic treatment.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
References
 
We thank Ms Rigmor Härdén for skilled technical assistance. We express our gratitude to Associate Professor Andreas Sjögren for constructive criticism of the manuscript. This study was supported by a grant from the Swedish Heart and Lung Foundation and an unrestricted grant from Astra-Zeneca, Sweden.

Conflict of interest: M.R. has received reimbursement from Astra Zeneca as a national coordinator in clinical trials and for lecturing. He has also received research grants from Astra Zeneca.


   Footnotes
 
{dagger} Deceased 3 June 2006. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 

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