Randomized Crossover Comparison of DDDR Versus VDD Pacing After Atrioventricular Junction Ablation for Prevention of Atrial Fibrillation
Background—Some clinical data suggest that atrial-based pacing prevents paroxysmal atrial fibrillation (AF). This study tested the hypothesis that DDDR pacing compared with VDD pacing prevents AF after atrioventricular (AV) junction ablation.
Methods and Results—Patients were randomized to DDDR pacing (n=33) or to VDD pacing (n=34) after AV junction ablation and followed every 2 months for 6 months. Patients then crossed over to the alternate pacing mode and were followed for an additional 6 months. Primary analysis included the time to first recurrence of sustained AF (duration >5 minutes), total AF burden, and the development of permanent AF. The time to first episode of AF was similar in the DDDR group (0.37 days, 95% CI 0.1 to 1.3 days) and the VDD pacing group (0.5 days, 95% CI 0.2 to 1.7 days, P=NS). AF burden increased over time in both groups (P<0.01). At the 6-month follow-up, AF burden was 6.93 h/d (95% CI 4.37 to 10.96 h/d) in the DDDR group and 6.30 h/d (95% CI 3.99 to 9.94 h/d) in the VDD group (P=NS). Twelve (35%) patients in the DDDR group and 11 (32%) patients in the VDD group had permanent AF within 6 months of ablation. Within 1 year of follow-up, 43% of patients had permanent AF.
Conclusions—DDDR pacing compared with VDD pacing does not prevent paroxysmal AF over the long term in patients in the absence of antiarrhythmic drug therapy after total AV junction ablation. Many patients have permanent AF within the first year after ablation.
Atrioventricular (AV) junction ablation is a therapeutic option for the treatment of patients with paroxysmal atrial fibrillation (AF) who are unresponsive to or intolerant of antiarrhythmic therapy.1 2 3 4 Ventricular function and quality of life have been reported to be improved in patients after AV junction ablation.4 5 6 Recently, quality of life has been reported to improve in patients after AV junction ablation compared with patients treated with antiarrhythmic drug therapy.3 6 The appropriate choice of pacing mode after ablation is uncertain because many patients may progress to permanent AF, particularly if antiarrhythmic drug therapy is discontinued.3 7 8 Atrial-based pacing reduces the incidence of paroxysmal AF and chronic AF in the pacemaker population.9 10 It has been suggested that atrial-based pacing might prevent paroxysmal AF by eliminating bradycardia-induced dispersion of atrial repolarization that provides the substrate for AF and by overdrive suppression of supraventricular premature beats, which provide the trigger for AF.11 12 13 14 However, whether atrial pacing prevents paroxysmal AF or impedes the progress to permanent AF after ablation is unknown. Furthermore, it is unknown whether AV sequential pacing in the DDDR mode is superior to atrial-sensed ventricular synchronous pacing in the VDD mode after ablation. Although both are “physiological” pacing modalities and maintain AV synchrony, DDDR pacing provides the ability to pace the atrium and thus to isolate the potential benefits of atrial pacing from those of AV synchronization. We have previously reported that atrial pacing over a 3-month follow-up period did not prevent paroxysmal AF in patients without symptomatic bradycardia.14 The present study evaluates the effects of DDDR versus VDD pacing on AF recurrence over the long term in patients after AV junction ablation and cessation of antiarrhythmic drug therapy.
The present study tested the hypotheses that (1) DDDR pacing would reduce the time to first recurrence of paroxysmal AF compared with VDD pacing in patients after AV junction ablation and (2) that DDDR pacing would reduce the recurrence of paroxysmal AF and total burden of AF over time compared with VDD pacing in patients after AV junction ablation.
The study population consisted of patients with a history of paroxysmal AF who had ≥3 episodes of paroxysmal AF within the year before pacemaker implantation. Patients also had to be refractory to or intolerant of medical therapy because of significant adverse effects and hence had undergone a total AV junction ablation. Patients enrolled in this study had participated in the initial phase of the Atrial Pacing Peri-Ablation for Prevention of Atrial Fibrillation (PA3) Trial.14 Those proceeding to AV junction ablation participated in this second phase of the PA3 Trial. The study was approved by all the medical ethics review boards of the participating institutions (see Appendix).
The study design is outlined in Figure 1⇓. Consenting patients received a Medtronic Thera DR pacemaker before AV junction ablation. The Thera DR device can store information on the time, date, and duration of up to 15 consecutive episodes of an atrial tachyarrhythmia in the device memory. This information was retrieved with the use of the pacemaker programmer during follow-up visits. After pacemaker implantation, antiarrhythmic drugs were usually discontinued and patients were randomly assigned to pacing in the DDDR or VDD modes. The programmed parameters for the 2 modes used in this study are shown in Table 1⇓. Patients randomized to the DDDR mode were programmed to a lower rate of 70 bpm to ensure that the atrium would be paced most of the time. Patients randomized to the VDD mode were programmed to a lower rate of 60 bpm. This rate was chosen to preserve AV synchrony most of the time. If the sinus rate fell below 60 bpm, then asynchronous ventricular pacing would result.
All patients completed a 2-week stabilization phase to allow antiarrhythmic drugs to wash out. The high-rate atrial episode diagnostic data were retrieved and the counters were cleared at the 2-week follow-up visit. Patients were then assessed at subsequent follow-up visits scheduled 2, 4, and 6 months after ablation. At each visit, the high-rate atrial episode data were retrieved. These data were used to determine the primary outcome event of the study. At the 6-month follow-up visit, patients were crossed over to the alternate pacing mode and followed every 2 months for an additional 6 months. Ambulatory ECGs were obtained at each follow-up visit.
Study Outcome Events
The primary study outcome event was time to first recurrence of sustained AF lasting at least 5 minutes and occurring ≥2 weeks after randomization. Since the time course of recurrence may not be completely random, the intervals between first and second episodes and between second and third episodes of paroxysmal AF were also determined.15 Other outcome measures included AF burden, which was defined as hours of AF per day and the proportion of patients in whom permanent AF (which was defined as an AF burden of 24 h/d) would develop. AF burden was calculated as the total duration of AF detected during the follow-up period. In the case when the event counters were filled before completion of the total follow-up duration, AF burden was calculated as the total duration of AF during the time to detection of the first 15 episodes of sustained AF.
The high-rate atrial tachycardia detection feature of the Thera DR was used for AF detection in this study. This feature has been reported to have a high sensitivity and specificity for the detection of atrial tachyarrhythmias,14 16 17 and we have validated this detection algorithm previously.14 In the present study, validation of appropriate detection of AF was carried out with the use of an enhanced Marker channel feature of the device to download to one channel of the ambulatory ECG, with marker signals representing what the device interpreted as atrial and ventricular electrograms. Appropriate detection of episodes of AF was observed in all 35 patients who had AF during ambulatory ECG monitoring during follow-up visits.
All episodes of AF detected by the pulse generator were reviewed by 2 observers who were blinded to the programmed pacing modality. Specific rules had been developed previously to diagnose oversensing of near-field P waves or far-field R waves or competitive atrial pacing based on characteristic beat-to-beat intervals during an episode.14 17 Of 3061 episodes of AF detected in the study population, only 4 episodes caused by oversensing (0.1%) were inappropriately detected as AF. These episodes were excluded in the final data analysis.
Analysis was performed according to the intention-to-treat principle. The time to occurrence of the first episode of sustained AF and the second episode of sustained AF were determined by means of the Kaplan-Meier method.18 Differences in the survival curves were compared by means of the log-rank test.19 Geometric mean data were calculated following a log transformation, and these differences were compared by means of a 2-way ANOVA or ANOVA for repeated measures where appropriate. Differences in proportions were compared by means of χ2 analysis. Data are presented as mean±1 SD or geometric mean and 95% CI when log transformation was used. A value of P<0.05 for 2-sided comparisons was considered significant.
Thirty-three patients were randomized to the DDDR group and 34 patients were randomized to the VDD group. The clinical characteristics of the 2 groups were similar (Table 2⇓). Interrogation of the pacemaker at the 2-month follow-up visit revealed that the atrium was paced 41±29% of the time and the ventricle was paced 99.7±0.3% of the time in patients randomized to the DDDR group and that the ventricle was paced 99.8±0.2% of the time in the patients randomized to the VDD group. The low proportion of atrial pacing in the DDDR group reflects the high AF burden observed.
Early Crossovers to DDDR From VDD Mode
Five patients randomized to the VDD group were crossed over to DDDR pacing before completion of the 6-month follow-up period because of hemodynamic symptoms or feeling unwell. These patients were included in the VDD group for the intention-to-treat analysis.
Time to First and Second AF
Survival free of recurrent sustained AF after the 2-week stabilization period based on intention-to-treat analysis is shown in Figure 2⇓. There was no significant difference between the 2 groups (P>0.3). Since the time to first event assumes that AF occurs randomly, which may not be the case,15 event-free survival of the interval between the first and second episodes of sustained AF were also compared on the basis of intention-to-treat analysis. These data were censored to adjust for those who remained in AF and hence were not at risk to have a second episode. No differences were observed between the 2 groups (Figure 3⇓).
AF Recurrence Characteristics
The characteristics of recurrences of AF are shown in Table 3⇓. The majority of patients (94%) had sustained AF during the initial 6-month follow-up period, and most patients had multiple episodes of AF. There were no significant differences in the time to first episode of AF, the interval between first and second episodes of AF, and the burden of AF (P=NS). The AF burden increased significantly over time in both groups (P<0.01, Figure 4⇓). Twelve (35%) patients in the DDDR group and 11 (32%) patients in the VDD group had permanent AF at the completion the 6-month follow-up period.
Patients crossed over to the alternate pacing modality after 6 months of follow-up. However, because of the high proportion of patients who had permanent AF before the 6-month follow-up visit, the number of patients actually being paced in the DDDR or VDD pacing modes during the last 6 months of follow-up was small. The AF burden continued to increase during the last 6 months after crossover to the alternate pacing modality (Figure 4⇑). AF burden was similar in both groups 1 year after ablation.
The proportion of patients who were in AF at each follow-up visit and the proportion of patients in whom permanent AF developed increased significantly after AV node ablation in all patients (Figure 5⇓, P<0.001). Within 1 year of AV node ablation, 43% of the study population had permanent AF.
Present therapeutic strategies for the management of AF, which include pharmacological maintenance of sinus rhythm or heart rate control of AF, are unsatisfactory for many patients.20 AV junction ablation with implantation of a VVIR or DDDR pacemaker alleviates symptoms of uncontrolled or irregular heart rates and may result in improved hemodynamic function.1 2 3 4 5 6 At present, it is uncertain whether the DDDR pacing modality is indicated after AV junction ablation, particularly if antiarrhythmic drug therapy is discontinued. Some studies have reported a high progression to permanent/chronic AF after total AV junction ablation in patients with AF.3 7 8 The present study is the first to assess whether atrial-based pacing might prevent the development of chronic AF over the long term after total AV junction ablation and to isolate the potential benefits of atrial pacing over preservation of AV synchrony.
The rationale that AV sequential pacing might be indicated in such patients is based on clinical and experimental data, suggesting that physiological pacing prevents the development of AF.9 10 11 12 13 14 It has been suggested that atrial pacing might prevent AF by eliminating bradycardia-induced dispersion of atrial repolarization, which is believed to provide the electrophysiological substrate for AF, and by overdrive suppression of supraventricular premature beats, which provide the trigger for AF. In our previous study, we have shown that over the short term, atrial pacing did not prevent AF.14 In the present study, atrial-based pacing did not prevent AF over the long term in this highly symptomatic patient population. Nor did we observe a benefit of DDDR pacing over VDD pacing on AF recurrence. This suggests that prevention of relative bradycardia in the atrium is not an important approach for the prevention of AF. This is in keeping with observations that bradycardia immediately preceding the onset of AF is observed in only 8% to 10% of episodes.13 21 The minimal atrial pacing rate evaluated in the present study was 70 bpm and thus it is possible that atrial pacing at higher baseline rates might have been beneficial. It is also possible that pacing algorithms designed to ensure atrial pacing the majority of the time might have been beneficial. The present study is the first to assess the impact of atrial pacing for prevention of AF over the long term. Since patients had frequent AF, the electrophysiological substrate predisposing to recurrent AF probably persisted over time and contributed to the development of permanent AF in some.22 It is thus possible that atrial pacing might allow recovery of the electrophysiological substrate for AF over time in patients with fewer episodes of AF.
No attempt was made to maintain antiarrhythmic drug therapy, therefore the present study must be considered a trial of atrial pacing in the absence of adjunctive antiarrhythmic drug therapy. The results of this study may not apply to the situation in which antiarrhythmic drug therapy is continued after AV junction ablation. It is possible, as suggested by other investigators, that combined pacing and pharmacological therapy might have been beneficial in this group.12
The choice of pacing mode after AV junction ablation remains controversial. Some investigators have elected to use the simple, less costly VVIR pacing system. Others have suggested implantation of a dual-chamber, rate-responsive system with mode switching capabilities, based on the assumption that atrial pacing and/or maintenance of AV synchrony would prevent the progression to chronic AF. Mitchell et al23 retrospectively studied the atrial rhythm in 49 patients after AV junction ablation for paroxysmal AF. At a mean follow-up of 18.6 months, 67% were in sinus or atrial paced rhythm. Brignole et al3 reported that 24% of 21 patients had permanent AF 6 months after AV junction ablation, whereas none of the 18 patients randomized to antiarrhythmic therapy had permanent AF. Gianfranchi et al8 followed 63 patients with paroxysmal AF for 23±16 months after AV junction ablation and reported that permanent AF developed in 35%. The actuarial rate of progression to permanent AF was 22%, 40%, and 56% at 1, 2, and 3 years, respectively, after ablation. Gribbin et al7 reported that 42% of 62 patients had permanent AF over a mean follow-up of 30 months after AV junction ablation. Marshall et al6 reported that 12 of 37 patients receiving DDDR pacemakers had permanent AF within 6 weeks of AV junction ablation compared with none of 19 patients treated with antiarrhythmic drug therapy. Buys et al24 suggested that VDD pacing is an acceptable modality after AV junction ablation because only 4 of 17 patients had permanent AF during a mean follow-up of 18 months. In the present study, the time course of development of permanent AF was independent of the pacing modality DDDR versus VDD. The rate of progression to permanent AF in the present study was more rapid than reported by most investigators. This may reflect a patient population with a higher disease burden of AF compared with other studies.
The diagnostic data counters were used for detection of AF in the present study. It is possible that some episodes were not detected because of undersensing. However, ambulatory ECG monitoring validated detection of AF by the pacemaker in the study population. The low proportion of atrial pacing documented during follow-up in the DDDR group probably reflects the fact that many patients had persistent AF and that the AF burden was high in the remaining patients. It is also possible that the baseline sinus rate increased after ablation, after cessation of antiarrhythmic drugs. However, we cannot exclude the possibility that a higher programmed atrial pacing rate or other pacing algorithms designed to promote atrial pacing might have reduced the AF burden.
DDDR pacing compared with VDD pacing does not prevent recurrence of paroxysmal AF, nor does it delay the development of permanent AF in patients with frequent paroxysmal AF after total AV junction ablation. Given the high proportion of patients who have permanent AF within 12 months of ablation, a VVIR pacing system may be satisfactory for many patients.
The following participated in this study (listed in descending order of number of patients randomized): Hamilton General Hospital, Hamilton, Ontario, Canada: Stuart J. Connolly, Wesley James, Catherine LeFeuvre, Maryann Menard. Foothills Medical Center, Calgary, Alberta, Canada: Anne M. Gillis, D. George Wyse, John M. Rothschild, L. Brent Mitchell, Henry J. Duff, Karen Hillier, Charlotte Hale. Hôpital Notre Dame, Montreal, Quebec, Canada: Pierre Lacombe, Diane Therrin, Claude Provencal, Louise Patry. Institut de Cardiologie, Hôpital Laval, Quebec City, Quebec, Canada: François Philippon, Marcel Gilbert, Gilles O’Hara, Johanne Rompré. Institut de Cardiologie, Montreal, Quebec, Canada: Marc Dubuc, Mario Talajic, Dennis Roy, Eric Lavallee. St Paul’s Hospital Vancouver, British Columbia, Canada: Charles R. Kerr, John Boone, John Yeung-Wai-Lah, Sheila Flavelle, Susan Mooney. St Michael’s Hospital, Toronto, Ontario, Canada: David Newman, Paul Dorian, Jane Laslop, Linda DeBelias. University Hospital, London, Ontario, Canada: Raymond Yee, George Klein, Caro Norris. University Hospital, Edmonton, Alberta, Canada: Katherine M. Kavanagh, Shane Kimber, Ingrid Scott. Queen Elizabeth II Health Sciences Center, Victoria General Hospital, Halifax, Nova Scotia, Canada: Martin J. Gardner, Laurence Sterns, Marcia Shields. Hôpital du Sacre-Coeur, Montreal, Quebec, Canada: Teresa Kus, Franck Molin, Ginette Gaudette.
This study was supported by a grant-in-aid from Medtronic, Inc, Minneapolis, Minn. Dr Gillis is a Senior Scholar of the Alberta Heritage Foundation for Medical Research. The authors thank Ken Riff, MD, and Nick Jensen, DVM, Medtronic, Inc, for their advice on study design; Rahul Mehra, PhD, Michael Hill, PhD, and Stephanie Fitts, PhD, Medtronic, Inc, for help with validating the high-rate atrial episodes; Margot McDonald, Karen Hillier, Andrew Mah, and Catherine St George, study coordinators, and Ronda Ross for help with manuscript preparation.
Dr Gillis is a consultant to Medtronic, Inc; she is also a stockholder of that firm. Dr Yee is a member of an advisory committee for Medtronic, Inc.
- Received December 6, 1999.
- Revision received March 4, 2000.
- Accepted March 10, 2000.
- Copyright © 2000 by American Heart Association
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