Europace Advance Access originally published online on January 5, 2006
Europace 2006 8(2):107-112; doi:10.1093/europace/euj004
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ATRIAL FIBRILLATION
Right atrial overdrive pacing for prevention of symptomatic refractory atrial fibrillation
Department of Cardiology, Thoraxcenter, University Medical Center GroningenUniversity of Groningen PO Box 30.001, 9700 RB Groningen The Netherlands
Manuscript submitted 19 July 2004. Accepted after revision 14 August 2005.
Corresponding author. Tel: +31 50 3612355; fax: +31 50 3614391. E-mail address: i.c.van.gelder{at}thorax.umcg.nl
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Abstract |
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Aims Our aim was to investigate whether right atrial overdrive pacing is effective for the prevention of atrial fibrillation (AF) in patients without bradyarrhythmias.
Methods and results Patients with symptomatic paroxysmal or persistent AF refractory to at least two Class I or III antiarrhythmic drugs and without bradyarrhythmias were included. Successful therapy was defined as the combination of (a) a reduction of AF burden with or without AAD use >75%, (b) total AF burden 
5% per year, and (c) less than one electrical cardioversion per year. Lower rate was set at 70 b.p.m. Additional AF prevention and termination features were used in case of no success.After a median follow-up of 18 (10–55) months, therapy was effective in 19 of the 36 included patients (53%). In 74% of the successfully treated patients, additional antiarrhythmic drugs were used. In successfully treated patients, the AF burden was reduced from 15% (5–100%) to 0% (0–4%). Multivariate analysis showed that the concomitant use of a Class I or III antiarrhythmic drug, a lower AF burden before implantation and the use of an angiotensin converting enzyme inhibitor were predictors of successful therapy.
Conclusion Right atrial overdrive pacing in combination with antiarrhythmic drugs seems an attractive treatment option in drug refractory symptomatic AF patients.
Key Words: Atrial fibrillation, Pacing, Antiarrhythmic drugs
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Introduction |
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In atrial fibrillation (AF), rate control is an accepted primary treatment strategy.1
,2 However, rhythm control remains indicated in (severely) symptomatic AF patients. Patients suffering from symptomatic paroxysmal or persistent AF are initially treated with serial antiarrhythmic drugs with or without cardioversions. Despite optimal antiarrhythmic drug treatment, 50% of these patients have frequent recurrences.3 If unsuccessful and symptoms persist, the next step may be radiofrequency ablation,4,5 Cox's maze surgery6 or atrioventricular (AV) node ablation.7
Another option may be (dual site) right atrial, biatrial or single site alternative pacing sites (septal, bundle of Bachmann) overdrive pacing. So far, several studies showed varying success of pacemaker therapy on AF burden and AF episode frequency in symptomatic AF patients with and without bradyarrhythmias.8–21
The objectives of this study were to investigate whether right atrial overdrive pacing is effective for the prevention of AF in patients with drug refractory symptomatic AF without bradyarrhythmias and to determine predictors of successful treatment.
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Methods |
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Patient population
In this study, we included patients with a history of severely symptomatic paroxysmal AF who were refractory or intolerant to at least two Class I or III antiarrhythmic drugs. In all patients underlying heart disease was adequately treated. Patients with a sick sinus syndrome or AV node disease were excluded. Also patients with severe underlying (heart) disease (i.e. clinically significant valve disease, unstable angina pectoris, advanced chronic heart failure New York Heart Association (NYHA) Class III or IV, or malignancy) or alcohol and drug abuse were excluded.
Device characteristics
Patients received a DDDRP pacemaker (AT500TM, Medtronic Inc., Minneapolis, MN, USA). This pacemaker has three special algorithms to prevent AF, an anti-tachycardia pacing (ATP) algorithm, and is capable of measuring the AF burden.8 The three pacing algorithms to prevent a recurrence of AF are (a) atrial overdrive algorithm for maintenance of a pacing rate just above the intrinsic rate (atrial preference pacing, APP), (b) an atrial overdrive mode designed to avoid short–long intervals following a premature atrial complex (atrial rate stabilization, ARS), and (c) the post-mode switch overdrive pacing (PMOP) algorithm which is designed to inhibit the early recurrence of atrial tachyarrhythmias following termination of atrial arrhythmias by transiently pacing at a higher rate.9 The last algorithm (c) was programmed off during the whole study in all patients. In addition, the ATP algorithm was used, which can detect and terminate a fast atrial tachycardia, which is not rarely the onset of AF.10 The settings of the pacemaker are shown in Table 1.
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Study design
The patients were asked to register the number and duration of symptomatic AF episodes during 1 month before pacemaker implantation. This was the ‘estimated’ AF burden before implantation. Symptoms were investigated with the use of our standard arrhythmia question list. Routine transthoracic echocardiography was performed before implantation in all patients. After implantation, all the pacemakers were set on DDDR lower rate of 70 b.p.m. and the antiarrhythmic drug(s) in use was continued during the study unless adverse effects necessitated discontinuation. Patients with persistent AF at the moment of implantation underwent an electrical cardioversion (ECV). In case of recurrent, AF prevention features (ARS and APP) were activated. If this was still unsuccessful, the AF termination feature (ATP) was also activated (Figure 1). An episode of persistent AF was treated by an ECV. Patients were seen every 4 months at the arrhythmia department of our hospital. Patients were asked for complaints and AF burden was measured. In addition, the estimated AF burden was assessed.
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Definition of successful therapy
Successful pacing therapy was for the purpose of this study defined as the combination of (a) a reduction of AF burden >75% with or without antiarrhythmic drugs, (b) a total AF burden of
5% per year, and (c) less than one ECV per year. We chose this definition because this means an important reduction of AF in patients who suffered before very frequently from the arrhythmia. In clinical practice, this an acceptable approach. A comparison was made between the successful (success group) and unsuccessful treated patients (failure group).
Statistical analysis
Baseline descriptive statistics are the mean±standard deviation (SD) or median (range) for continuous variables and counts with percentages for categorical variables. Differences between groups were evaluated by Student's t-test or Mann–Whitney U test, depending on normality of the data, for continuous data and by Fisher's exact test or 
2 test for categorical data. Univariate and multivariate logistic regression analyses were performed to determine predictors of successful treatment. Cut-off points of the variables of interest were chosen on the basis of clinical relevance or the median value. All univariate variables with P<0.2 were added to the multivariate model. In the multivariate model, interaction was investigated. In all analyses, a value of P<0.05 was considered statistically significant. Correlation between the estimated AF burden and the AF burden derived from the pacemaker was evaluated by the Spearman correlation test. All analyses were performed using statistical software (SPSS 11.0, SPSS Inc., Chicago, IL, USA).
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Results |
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Patients
A total of 36 consecutive patients was included between January 2001 and January 2003 (Table 2). All atrial leads were implanted in the right atrial appendage. The mean age of the patients was 61±10. All included patients had a history of paroxysmal AF. During the last month before implantation, conversion from paroxysmal to persistent AF occurred in eight patients (22%). The median estimated AF burden in the month before implantation was 30% (2–100%).
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Outcome
According to predetermined definition, pacing therapy was effective in 19 patients (53% of the total population) after a follow-up of 18 (10–55) months. In 13 of these 19 patients (68%), no single episode of AF was observed during the last year of follow-up. Fourteen of the 19 successfully treated patients (74%) were concomitantly treated with Class I or III antiarrhythmic drugs. In two patients, antiarrhythmic drug therapy could be discontinued because of successful suppression of AF. In four of the successfully treated patients (21%), one ECV was performed during follow-up. In the successfully treated patients, AF burden was reduced from 15% (5–100%) to 0% (0–4%) (Figure 2A). Successfully treated patients were paced with a lower rate of 70 b.p.m. alone (11%), lower rate of 70 b.p.m. and prevention features on (42%), or lower rate of 70 b.p.m., prevention and termination features on (47%).
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According to the definition, 17 patients failed therapy (failure group), despite concomitant use of antiarrhythmic drugs in seven of the 17 (41%) patients. AF burden did not change in these patients (from a median of 33% (2–100) to 32% (0–100), respectively) (Figure 2B). AF progressed to permanent AF in seven patients (19%). AV node ablation was not performed. We also estimated the AF burden during follow-up as we did at baseline. There was a strong correlation between the estimated AF burden and the AF burden derived from the pacemaker (R=0.82, P<0.001).
Predictors of success of right atrial overdrive pacing
Multivariate analysis revealed that an AF burden at baseline >10% was a predictor of unsuccessful outcome, whereas concomitant treatment with a Class I or III antiarrhythmic drug and the use of an angiotensin converting enzyme inhibitor were independent predictors of success of therapy (Table 3).
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Complications
After implantation, four events in 36 patients (11%) related to the procedure or system occurred: pericardial effusion necessitating cardiac surgery (n=1), pneumothorax requiring pleural drainage (n=1), pocket haematoma occurring 24 h after the procedure and after the start of heparin prompting evacuation (n=1), and atrial lead dislodgment (n=1).
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Discussion |
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Main findings
This study shows that right atrial overdrive pacing with or without AF prevention algorithms and ATP can successfully be performed in 53% of drug refractory symptomatic AF patients without bradyarrhythmias. In 74% of the successfully treated patients, concomitant antiarrhythmic drugs were used. Except for a lower AF burden before the start of pacing therapy, concomitant treatment with Class I or III antiarrhythmic drugs and the use of an angiotensin converting enzyme inhibitor improved success of pacing therapy.
Comparison with previous studies
So far, studies showed varying success of atrial (overdrive) pacing therapy on AF burden and AF episode frequency in symptomatic AF patients with and without bradyarrhythmias.8–24 Results between studies differ, because patient groups and devices were often not comparable. Furthermore, antiarrhythmic drugs were not always continued, and different preventive pacing algorithms were used. Finally, continuous atrial pacing was not always achieved.
Comparable with this study, the PA3 study also included patients with antiarrhythmic drug refractory paroxysmal AF. In contrast to the present data, however, the PA3 study showed no favourable effect.11 This may relate to the fact that only DDIR pacing with a lower rate set at 70 b.p.m. was used as active treatment (versus DDI at a rate of 30 b.p.m.), no overdrive pacing was performed (the atrium was paced for 67% of the time) and no ATP was performed. In accordance with our data, Wiberg et al.12 showed a beneficial effect of right atrial overdrive pacing for the prevention of symptomatic paroxysmal AF in patients without bradyarrhythmias. The same holds for the AF Therapy Investigators who reported that a combination of atrial pacing algorithms of the Selection900TM (Vitatron, Dieren, The Netherlands) reduced AF burden in antiarrhythmic drug refractory AF patients without bradyarrhythmias.13 Also, the NIPP-AF Study, a small randomized, crossover, single blinded-study, showed a significant reduction in total AF burden (45±34 vs. 22±29%). In that study, dual-site right atrial overdrive pacing at a rate slightly above the sinus rate was combined with sotalol treatment in patients without a bradycardia indication for pacing.14
Until now, however, most studies have been performed in patients with AF and bradyarrhythmias necessitating pacemaker implantation.8,15–21 Some also showed beneficial effects of overdrive pacing.15,16,18,20 Others, however, have not confirmed these benefits. Israel et al.8 on behalf of the AT500TM Verification Study Investigators studied 325 patients for the efficacy of pacing prevention algorithms (ARS, APP, and PMOP) and ATP. Despite 97% of atrial pacing, no differences in the number of AF episodes and AF burden without or with preventive pacing were observed. The Atrial Septal Pacing Clinical Efficacy Trial Investigators randomized 298 patients to right atrial septal or non-septal pacing with an AT500TM with either the AF prevention algorithms programmed on or off (3 months followed by crossover for another 3 months).17 No significant reduction of the AF frequency nor burden was observed when the algorithms were programmed on. Patients with septal leads had fewer symptomatic episodes of AF confirming other studies that demonstrated clinical benefits of atrial septal pacing22–24 or dual-site right atrial pacing.14,20 In our study, patients were always paced with a single atrial lead in the right atrial appendage. Nevertheless, we observed a significant improvement of symptoms in more than half of the patients. As mentioned earlier, most other trials have evaluated patients with indications for pacing, whereas the present study included patients with severely symptomatic AF but no indication for pacing. It is conceivable that in patients without indication for pacing, as is the case in the present study group, there is a higher response rate than in patients with indications for pacing. Further randomized studies should be performed to attain more evidence on the efficacy of pacemaker treatment in symptomatic AF patients without bradyarrhythmias.
Predictors of success and failure of treatment
Comparable with the data of the group of Saksena22 and Manegold et al.25, our main finding was that ‘hybrid’ therapy, i.e. the combination of pacing and antiarrhythmic drugs, is effective for the prevention of symptomatic AF especially when the AF burden at inclusion is not too high, and concomitant angiotensin converting enzyme inhibitors are used. In contrast to their studies, however, we did not use additional ablation. The beneficial effect of angiotensin receptor blockers or an angiotensin converting enzyme inhibitor is in agreement with previously performed studies in patients with persistent AF.26,27
Possible underlying mechanism
The reduction of the AF burden in the present study may be due to a combination of the prevention of triggers (atrial premature complexes), termination of a regular atrial tachycardia that may induce AF by ATP, and eventually reversion of electrical and structural remodelling. Especially prevention of triggers, either by right atrial overdrive pacing alone or in combination with the rate smoothing post-atrial premature complexes algorithm and use of antiarrhythmic drugs may have been effective. At present, there are no data on the efficacy of the aforementioned algorithm. Also in this study, we have data neither on the efficacy of the latter algorithms nor on the efficacy of ATP. Eventually, the process of reversal of electrical and structural remodelling may have contributed to the success of the therapy.28,29 It is tempting to speculate that angiotensin converting enzyme inhibitors may have prevented the occurrence of severe, irreversible remodelling precluding unsuccessful pacing therapy or may have contributed to a faster reversion of the remodelling process. On the other hand, these drugs may also have reduced the number of triggers or set the stage for a slower atrial tachycardia or flutter which could successfully be terminated by ATP.
Study limitations
There are some important limitations of this study. First, this study was not a randomized study and did not use a crossover design. Secondly, there was no objective documentation of the AF burden in the month before pacemaker implantation. The patient-based AF burden before pacemaker implantation may be underestimated, because asymptomatic AF episodes were missed. On the other hand, it may also have been overestimated because of sinus tachycardia and the occurrence of either premature atrial or ventricular complexes. It would have been best to evaluate the patients after implantation with the pacemaker set at DDI or AAI 34 b.p.m. to get 1-month AF burden data prior to treatment. Furthermore, no objective quality of life data were assessed.
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Conclusion |
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This study shows that hybrid therapy with right atrial overdrive pacing and concomitant antiarrhythmic drugs, and angiotensin converting enzyme inhibitors may be an attractive treatment option for drug refractory AF patients without bradyarrhythmias.
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Acknowledgement |
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This study was supported by an educational grant from Medtronic.
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References |
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