Europace

Europace 2004 6(4):343-350; doi:10.1016/j.eupc.2004.04.001
© 2004 by European Society of Cardiology

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Beta-blockers prevent subacute recurrences of persistent atrial fibrillation only in patients with hypertension

Trudeke Van Noord^a,*, Robert G. Tieleman^b, Hans A. Bosker^a,c, Tsjerk Kingma^a, Dirk J. Van Veldhuisen^a, Harry J.G.M Crijns^b and Isabelle C. Van Gelder^a

^aUniversity Hospital Groningen The Netherlands; ^bUniversity Hospital Maastricht The Netherlands; ^cRijnstate Hospital Arnhem The Netherlands

Manuscript submitted 7 November 2003. Accepted after revision 4 April 2004.

^*Corresponding author. University Hospital Groningen, Cardiology, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Phone: +31503612355. E-mail address: E-mail address: t.van.noord{at}thorax.azg.nl

	Abstract

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
AIM: Differential drug treatment guided by the underlying heart disease may improve outcome of rhythm control therapy. In the present study we investigated in a well-defined group with either lone atrial fibrillation (AF) or hypertension whether there were differences in rhythm control outcome between both groups in relation to the use of cardiovascular drugs.

METHODS AND RESULTS: One hundred sixty-two patients were included after successful cardioversion of persistent AF. None of the patients was given a class I or III antiarrhythmic drug. Patients' heart rhythm was checked 3 times a day, using transtelephonic monitoring for 1 month after cardioversion. One month after cardioversion up to 68% of patients had a recurrence of persistent AF. During the first 3 days almost no recurrences were seen on beta-blocker therapy whereas recurrences peaked on day 2–3 in the absence of beta-blockers. Univariate analysis showed that the use of beta-adrenergic receptor blockers and the presence of hypertension were associated with a lower recurrence rate at 1 month. Multivariate logistic regression analysis demonstrated that beta-blockade was the only statistically significant parameter predicting sinus rhythm at 1 month (OR 0.40, 95% CI 0.19–0.86, P=0.02).

CONCLUSIONS: Compared with lone AF patients, patients in the setting of hypertension maintain sinus rhythm much better after cardioversion when treated with a beta-blocker. Beta-blockade protects, in particular, against the early subacute recurrences. These findings underscore the importance of a differential approach towards drug prevention of post-cardioversion recurrences depending on the underlying heart disease.

Key Words: atrial fibrillation, cardioversion, beta-adrenergic receptor blockers, hypertension

	Introduction

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Therapy of persistent atrial fibrillation (AF) aims at (1) restoration and (2) subsequent maintenance of sinus rhythm (SR). With biphasic defibrillation the success of DC electrical cardioversion (ECV) is high; SR can be restored in 90–95% of patients [1]. However, the second goal is less easy to achieve. In the first two weeks after cardioversion 20–50% of patients suffer from a so-called subacute recurrence [2–4]. This is one of the major reasons that long-term maintenance of SR is low, even with serial antiarrhythmic drug therapy. Maintenance of SR is influenced by several factors. Other than age and previous duration of AF, underlying heart disease is an important determinant of recurrences. It has been shown that, e.g., patients with hypertension, mitral valve disease and decreased LV function have a very poor arrhythmia outcome [5,6]. It may be hypothesized that different underlying aetiologies have different AF initiation and perpetuation mechanisms. Therefore, it may be suggested that differential drug treatment guided by the underlying heart disease improves arrhythmia outcome. In the present study, we investigated in a well-defined patient group with either lone AF or hypertension whether there were differences in arrhythmia outcome between the groups in relation to use of cardiovascular drugs.

	Methods

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Patient population and study design
We included 162 patients after successful ECV of persistent AF. Routinely, all patients had undergone echocardiographic evaluation and laboratory tests and all patients were on proper anticoagulation (INR 2.0–3.5) for 4 weeks before and after cardioversion. This study was part of the MEDCAR study in which we investigated prospectively the recovery of electrical remodelling (for participating centres see Appendix) [7]. In that study patients with significant underlying heart disease including valvular disease, severe left ventricular dysfunction, previous myocardial infarction, angina, sick sinus syndrome, thyroid dysfunction or previous unsuccessful ECV were excluded. However, for the current study we excluded 19 patients with coronary artery disease from the MEDCAR database to obtain a well-defined group of patients with either hypertension or lone AF. Hypertension was defined as a history of untreated systolic blood pressure >160 mmHg and/or untreated diastolic blood pressure >95 mmHg. ECV was performed according to a previously described protocol [5]. Successful cardioversion was defined as the presence of SR at least 4 h after cardioversion. The study was approved by the local ethical committee and informed consent was obtained from all participants. Before inclusion patients started negative chronotropic and anti-hypertensive drugs, including beta-adrenergic receptor blockers, depending on the heart rate during AF and the presence of hypertension. After inclusion, no changes in drug therapy were made during 1 month of follow up. None of the patients was given a class I or III antiarrhythmic drug. Patients' heart rhythm was checked 3 times a day, using transtelephonic monitoring (TTM) for 1 month after ECV to detect any recurrence of AF. Recordings were made between 8:00 and 10:00 hrs, 16:00 and 18:00 hrs, and between 22:00 and 24:00 hrs. Additional recordings were made in case of symptoms suggesting a recurrence of AF. Based on the patients' symptoms and TTM recordings an estimate was made of the time of relapse of AF. Recurrences of AF detected by TTM were confirmed by a 12-lead ECG at the hospital (median 23 h after start of recurrence (range 2–512 h).

	Statistical analysis

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
Quantitative variables were compared between groups using a Student's two-tailed t-test for normally distributed variables or a Wilcoxon two-sample test for skewed distribution of variables. For qualitative variables (categorical or ordered), group differences were evaluated using a Fisher's exact test or a Chi-square test. Accordingly, baseline characteristics are given in mean ± SD, median and range (min–max) or percentages.

To determine the predictive factors for recurrence of AF, a univariate logistic regression analysis was performed using the relevant baseline predictors. Variables with a P-value <0.20 were selected for the multiple logistic regression analysis to derive a model with statistically significant predictors, by using a backward selection method. All P-values are two-sided and a P-value of <0.05 was considered statistically significant. SAS version 6.12 (Cary, NC) was used for all statistical evaluations.

	Results

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
Clinical characteristics
Patient characteristics are listed in Table 1. Subacute recurrences were frequent: up to 68% of patients had a recurrence of persistent AF within the first month after ECV (Fig. 1). Table 2 compares clinical characteristics of patients with and without a recurrence. Note that there was no difference in the systolic and diastolic blood pressure among the groups. Heart rate at inclusion was significantly lower in the beta-blocker treated patients in comparison with patients without beta-blockade (64±15 vs. 76±14 respectively, P<0.001). There were no differences in heart rate in the beta-blocker group between patients with and without a recurrence of AF.

View larger version (9K): [in this window] [in a new window]   Figure 1 Time course of recurrences of atrial fibrillation for 1 month after ECV. ECV = electrical cardioversion.

 

View this table: [in this window] [in a new window]   Table 1 Baseline characteristics

 

View this table: [in this window] [in a new window]   Table 2 Baseline characteristics, groups divided in arrhythmia outcome

 
Determinants of AF recurrence
Univariate analysis showed that the use of beta-adrenergic receptor blockers and the presence of hypertension were associated with a lower recurrence rate at 1 month (Table 2). As a consequence, since no other underlying heart disease was present, lone AF was associated with an increased recurrence frequency. Hypertensive patients did not differ in patient characteristics and echocardiographic parameters in comparison with lone AF patients. Subdividing the groups according to type of associated heart disease and beta-blocker use showed that patients with hypertension on beta-blocker therapy had the best chance of maintenance of SR: 65% of 26 patients with hypertension treated with a beta-blocker were in SR after 1 month, while only 24% of 76 patients with lone AF who were not using beta-blockers were in SR after 1 month (P<0.001) (Fig. 2, Table 3). Multivariate analysis demonstrated that only patients on beta-blocker therapy showed a significantly better outcome 1 month after ECV (odds ratio 0.400, confidence interval 0.186–0.860, P=0.0189) (Table 4).

View larger version (16K): [in this window] [in a new window]   Figure 2 Kaplan–Meier plots depicting the probability of maintenance of sinus rhythm for 1 month after ECV. AF = atrial fibrillation; BB = beta-blocker; ECV = electrical cardioversion; SR = sinus rhythm.

 

View this table: [in this window] [in a new window]   Table 3 Chi-square analysis; arrhythmia outcome according to associated heart disease and use of beta-blockers

 

View this table: [in this window] [in a new window]   Table 4 Multivariate analysis

 
Timing of recurrences
TTM data show that most recurrences happen during the first 2 weeks after ECV, especially the first 10 days (Fig. 1). There were no differences in time course of recurrences between patients with and without hypertension. However, it was remarkable that none of the patients in the beta-blocker group had a recurrence within the first 3 days after ECV (Fig. 3). In the no beta-blocker group the incidence of daily recurrences peaked at day 2 and 3 with a gradual decline thereafter. By contrast, in the patients on a beta-blocker recurrences peaked at day 4 with a more rapid decay. Fig. 4 shows the diurnal distribution of recurrences in patients with and without beta-blocker treatment. There were no differences in diurnal distribution.

View larger version (12K): [in this window] [in a new window]   Figure 3 Time course of recurrences: beta-blocker vs. no beta-blocker therapy. BB = beta-blocker; ECV = electrical cardioversion.

 

View larger version (15K): [in this window] [in a new window]   Figure 4 Diurnal incidence of recurrences: beta-blocker vs. no beta-blocker therapy. BB = beta-blocker.

 

	Discussion

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
The main result of this study is that beta-blockers may help to prevent subacute recurrences of persistent AF after ECV. Beta-blockade suppresses recurrences in particular during the first 3 days after the shock. In patients with hypertension—but not in lone AF patients—this effect was sustained thereafter.

The role of hypertension and beta-blockers in maintenance of SR
Previous studies showed that hypertension is associated with arrhythmia intractability [5,6]. By contrast, in the present study, compared with lone AF, hypertension was not associated with an increased but rather a decreased rate of relapses when patients were treated with beta-blockade. The present study suggests that the main mechanisms responsible for reinitiation of lone AF are not amenable to beta-blockade in contrast to the mechanisms which cause relapses in hypertensive patients.

Suppression of recurrences by beta-blockade has been described previously by others [8,9]. Considering the arrhythmia free survival curves from the study of Kühlkamp et al., metoprolol appeared most effective in suppressing subacute recurrences, i.e. those occurring in the first 2–4 weeks after the cardioversion. Similar to our results, there was no catch-up of the recurrence rate thereafter. However, in their study metoprolol did not affect the incidence of relapses in the first 5 days after the shock. This is in contrast to the present findings, which obviously relates to a difference in drug regimens. In the previous studies beta-blocker treatment was only started after conversion to SR, whilst our patients were pretreated. Therefore our data underscore the importance of initiating beta-blockade before restoration of SR is undertaken.

Mechanisms by which beta-blockers prevent recurrences of AF
The fact that recurrences cluster in the subacute phase after cardioversion probably relates to transient hyper-vulnerability. It has been suggested that during this time period specific arrhythmogenic mechanisms play a role [10–14]. These include frequent atrial premature beats which serve as a trigger for the recurrence. Beta-blockers may suppress these triggers especially if they are adrenergic dependent. Conversely, beta-blockade may enhance bradycardia, which may predispose to bradycardia-dependent trigger beats or bradycardia induced AF, especially during the night. The diurnal distribution of recurrences in relation to modality of treatment did, however, not support either of these mechanisms. However, the fact that beta-blockers prevent the subacute recurrences in the first 3 days after cardioversion suggests that the subacute recurrences can be divided in adrenergic dependent recurrences and recurrences caused by other mechanisms.

Another arrhythmogenic mechanism may relate to (recovery of) electrical remodelling and restoration of the abnormal calcium handling [15–18]. It is tempting to assume that by reducing the adrenergic drive, restoration of cellular calcium handling is less turbulent and therefore less arrhythmogenic in the presence of beta-blockade. Other arrhythmogenic mechanisms during reversed remodelling include spatially non-uniform increase of AERP creating temporarily excess dispersion [17,19,20].

Why beta-blockade appeared effective only in patients with hypertension is unclear. This is especially remarkable since hypertension—due to pressure overload of the left atrium—may lead to significant (ultra)structural remodelling. Excessive atrial wall stretch, e.g. due to diastolic dysfunction, has been shown to be arrhythmogenic [21,22]. In that setting, beta-blockade may be antiarrhythmic by lengthening diastole and enhancing ventricular filling, thereby ameliorating stretch related arrhythmogenic mechanisms.

Distribution of recurrences
In both the beta-blocker and the no beta-blocker group, the diurnal distribution of recurrences was the same. This is an important finding, since it was presumed that recurrences of AF might be related to nocturnal vagotonia or to sympathetic activity during daytime [23]. The diurnal distribution in the absence of beta-blockers shows that recurrences of AF do not depend on sympathetic or vagal activity. Beta-blockade was not associated with a different diurnal pattern of recurrences compared with no beta-blockade. This suggests that beta-blockers do not necessarily act by suppressing recurrences due to sympathetic activity in awake patients.

Considering the diurnal distribution of recurrences, induction of recurrences due to bradycardia and vagotonia during the night by beta-blocker treatment, does not seem to play a role. On the other hand, it may be that sympathetic activity is instrumental in causing the very early (24–72 h after ECV) recurrences. As appears from the TTM data, irrespective of underlying disease beta-blockers prevent recurrences during the first 3 days after ECV.

	Limitations

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
Patients were started on beta-blockers in a non-randomized fashion. This precludes firm conclusions concerning efficacy of beta-blockade in relation to type of associated cardiac condition. However, this is the first study to suggest that in patients with persistent AF an individual treatment strategy guided by the type of underlying heart disease might be worthwhile to enhance cardioversion outcome. Furthermore, this is the first study with beta-blockers commenced before ECV which is important since this study shows that the beneficial effects can in great part be ascribed to the prevention of recurrences during the first 3 days after cardioversion. The present population was rather young and the patients had lone AF or only hypertension as underlying heart disease. The conclusions, therefore, apply to this subgroup of AF patients and not to all persistent AF patients.

	Clinical relevance

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
Beta-blocker therapy prevents subacute recurrences of AF, especially during the first 3 days after cardioversion. After this period, patients with hypertension remain free from AF recurrences while lone AF patients are not protected by beta-blockade. These different recurrence phases argue in favour of a differential antiarrhythmic approach guided by underlying heart disease and type of recurrence.

	Conclusion

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
We advocate pretreatment with a beta-blocker in persistent AF patients considered for electrical cardioversion, especially if patients suffer from hypertension. Furthermore, this study supports the notion that subacute recurrence should be divided in an adrenergic dependent early phase and a late phase, of which the mechanism is still not well understood.

	Appendix

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
Participating Clinical Centres of the MEDCAR study: RG Tieleman, MD, IC Van Gelder, MD, T Kingma, MSc, HJGM Crijns MD, University Hospital Groningen; HA Bosker, MD, Rijnstate Hospital Arnhem; AAM Wilde, MD, AMC Amsterdam; CJHJ Kirchhof, MD, University Hospital Maastricht; JH Bennekers, Martini Hospital, Groningen; FALE Bracke, Catharina Hospital Eindhoven; B Cernohorsky, MD, St Antonius Hospital Sneek; M Bijl, MD, Wilhelmina Hospital Assen; AMJ Lucassen, MD, University Hospital Nijmegen; NM van Hemel, Antonius Hospital Nieuwegein; JW Roos-Hesselink, MD, Dijkzigt Hospital Rotterdam; LHR Bouwels, MD, Canisius Wilhelmina Hospital Nijmegen, MA Allessie, Department of Physiology, University of Maastricht, The Netherlands.

	Acknowledgements

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
The MEDCAR study was supported by grant 95.184 of the Netherlands Heart Foundation, The Hague, The Netherlands. We thank the technicians from the TTM laboratory, University Hospital Groningen. We thank Mrs Corine Baljé-Volkers from the Trial Coordination Center, University Hospital Groningen, for the statistical analysis.

	Footnotes

 
Presented in part at the 22nd Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology, May 2001, Boston MA.

	References

Top Abstract Introduction Methods Statistical analysis Results Discussion Limitations Clinical relevance Conclusion Appendix Acknowledgements References

 
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