Europace Advance Access originally published online on November 12, 2008
Europace 2009 11(1):62-69; doi:10.1093/europace/eun294
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Atrial Fibrillation
Reduction of atrial fibrillation burden by atrial overdrive pacing: experience with an improved algorithm to reduce early recurrences of atrial fibrillation
1 Internal Department/Division of Cardiology, Public Hospital Elisabethinen, Academic Teaching Hospital, Fadingerstraße 1, A-4010 Linz, Austria; 2 National Institute of Cardiovascular Diseases, Bratislava, Slovakia; 3 Maasland Ziekenhuis, Sittard, The Netherlands; 4 Medical Center Alkmaar, Alkmaar, The Netherlands; 5 Lund University Hospital, Lund, Sweden; 6 Artur Koblitz, s.r.o., Regional Hospital Pardubice, Czech Republic; 7 Zentral Klinik Bad Berka, Bad Berka, Germany; 8 Tweesteden Ziekenhuis, Tilburg, The Netherlands; 9 Medtronic Bakken Research Center, Maastricht, The Netherlands
Manuscript submitted 25 August 2008. Accepted after revision 8 October 2008.
* Corresponding author. Tel: +43 732 7676 4917. E-mail address: helmut.puererfellner{at}elisabethinen.or.at
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Abstract |
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Aims: Two independent studies have revealed a potential limitation of post-mode switch overdrive pacing (PMOP), which is its delayed start.
Methods and results: We conducted a prospective, randomized, single blind, crossover design study (the post-long pause overdrive pacing study) to test the efficacy of an improved version of PMOP (PMOPenhanced). A total of 45 patients were enrolled, of whom 41 were analysed. The median number of atrial tachycardia/atrial fibrillation (AT/AF) episodes per day (1.38 vs. 1.19), the median number of early recurrences of atrial fibrillation (ERAF) per day (0.56 vs. 0.51), and the median AT/AF burden (time per day spent in AT/AF) (2.47 vs. 2.51 h) were not significantly different during the control and active study periods. Based on the median number of episodes per week recorded 90 days prior to enrolment, the patients were stratified by the median and then split into two groups, Group A (lower 2-Quartiles) and Group B (upper 2-Quartiles). The median AT/AF burden was significantly lower in Group B during the active study period (3.71 vs. 1.71 h, P = 0.02).The median number of AT/AF episodes per day and the median number of ERAF per day in Group B showed a trend towards reduction when the algorithm was turned on (3.79 vs. 2.44 and 2.77 vs. 1.86, respectively). In contrast, in Group A we did not demonstrate any difference in AT/AF frequency, ERAF frequency, or burden.
Conclusion: The main finding of this study is that temporary overdrive pacing at 90 bpm for 10 min starting just prior to device-classified AT/AF termination does not show a positive effect on the overall study population. However, when enabled in patients who suffer from a high percentage of ERAF, a significant reduction in the AT/AF burden could be demonstrated. Based on these findings, further prospective studies on a more targeted patient population are needed to confirm our results.
Key Words: Atrial tachyarrhythmias, Atrial fibrillation, Early recurrence of atrial fibrillation, Atrial overdrive pacing, AT500, Pacing algorithm
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Introduction |
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The phenomenon of early recurrences of atrial fibrillation (ERAF) has been a major topic of investigation recently. Early recurrences of atrial fibrillation occur not only after spontaneous atrial tachycardia/atrial fibrillation (AT/AF) termination,1
but also frequently after cardioversion.2–7 Comparing the results of different trials is difficult due to differences in the study design and definitions used. Some investigators refer to ERAF as the episodes that start within 2 min8 after a previous episode. Others have used a 10 min window. Early recurrences of atrial fibrillation have been attributed to a highly vulnerable phase in atrial electrophysiological properties, because immediately after restoration of the sinus rhythm the atrial refractory period is shorter than normal for 
2–8 min.3 Accordingly, prevention of ERAF may significantly improve the success rate of maintaining the sinus rhythm in patients with paroxysmal AT/AF. In AT/AF patients who have a pacemaker implanted, ERAF may be reduced by overdrive pacing the atrium. Overdrive pacing can be obtained by programming the lower rate of the device to an elevated rate, i.e. DDD 100 bpm. However, this implies that the patient's heart rate will never decrease below 100 bpm, which is usually not well tolerated by the patient. It is therefore more desirable to overdrive pace only in the vulnerable time period, e.g. several minutes after an AT/AF episode. Some devices offer an algorithm that automatically applies temporary overdrive pacing to prevent ERAF with a programmable rate and duration after AT/AF termination, i.e. the post-mode switch overdrive pacing (PMOP) feature. It was found in previous work that one in three episodes is prevented during the 10 min overdrive period.9 Israel et al.10 reported that automatic overdrive pacing at 120 bpm after AT/AF termination did not reduce the total number of AT/AF episodes or the AT/AF burden. In addition, they reported that 29% of episodes started during PMOP intervention and 18% of episodes started even before PMOP was initiated.10 They concluded that PMOP did not prevent ERAF, mainly due to insufficient overdrive suppression and the delay between AT/AF termination and PMOP intervention. The results of our previous work are similar; 29% of episodes started during the overdrive period and 31% of episodes started even before the overdrive rate was reached.9 Thus up to 30% of episodes are not prevented due to the slow start of the feature. In order to prevent these episodes also, overdrive pacing should start earlier. Therefore, we have improved the PMOP algorithm (PMOPenhanced). The present post-long pause overdrive pacing (PLOP) study is a prospective, randomized, crossover trial evaluating the efficacy of this improved algorithm in patients with drug refractory device documented AT/AF. |
Methods |
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Study population
Our study population consisted of patients with a standard pacemaker indication, who had been implanted with a Medtronic AT500TM (Medtronic Inc., Minneapolis, MN, USA) at least 90 days prior to enrolment, and who had device documented paroxysmal AT/AF with an AT/AF burden between 0.5 and 60% within the last 90 days. Patients were excluded if they were younger than 18 years, not expected to remain on stable anti-arrhythmic drugs during the whole study period, and unwilling to have all other preventive algorithms and atrial pacing (AP) therapies turned off. All patients gave written informed consent and the protocol was approved by the Local Ethical Committees.
Device programming
All patients had their device implanted at least 90 days prior to enrolment. The atrial and ventricular leads were implanted at conventional sites. The AT500TM offers three different algorithms for preventive pacing (Atrial Preference PacingTM, Atrial Rate StabilizationTM, and Post Mode switch Overdrive PacingTM) together with atrial anti-tachycardia pacing, all of which have been described in detail elsewhere.10,11 During the entire study period, all preventive algorithms and AP therapies were turned off. The AF detection zone was programmed between 100 and 200 ms and the AT detection zone between 200 and 360 ms or more if slow AT episodes were detected. Paced and sensed AV delay were not changed at enrolment and were programmed in some patients up to 300 ms (median value 210 and 180 ms, respectively), and the post-ventricular atrial refractory period was set to 310 ms. The last 35 episodes were stored in the episode log.
PMOPenhanced
The purpose of the algorithm is to provide a period of constant overdrive pacing in the atrium in response to one or more consecutive long pauses within an AT/AF episode (PLOP). The length of this pause as well as the number of pauses is programmable (pause length: 400–600 ms and number of pauses: 1–4). The algorithm is very similar to the existing PMOP algorithm. However, it is designed to be more ‘aggressive’ and to deploy after one or more long pauses during an AT/AF episode, meaning, to start earlier and quicker. In contrast, PMOP deploys 12 beats after device-determined episode termination, which requires five sinus beats.
During the PLOP study, the algorithm was programmed to deploy after two consecutive intervals longer than 400 ms after AT/AF detection. When the deployment criteria of the PMOPenhanced algorithm were satisfied, the algorithm responded with a transient period with a constant, overdrive pacing rate, programmed for 10 min at 90 bpm. In contrast to the current PMOP, no decrement was used at the onset of algorithm deployment to allow the rate to increase quickly. An increment of 20 ms per pacing interval was used at the end of the overdrive period providing a more gradual return to the basal pacing rate than provided by the current PMOP algorithm (70 ms decrement).
The PMOPenhanced user interface (UI) provides settings for the algorithm status (ON or OFF) and overdrive rate. The PMOPenhanced software includes diagnostics presenting the following data for patients programmed to the algorithm ON arm as well as to the OFF arm (monitor mode only):
- PMOPenhanced criteria met count: the total number of times that the algorithm deployment criteria were met since the application started or last clear data operation minus the number of times that the algorithm was deactivated by an ongoing AT/AF episode (deactivated by ongoing AT/AF count).
- PMOPenhanced terminated by a new AT/AF count: the number of times that a new AF/AT episode terminated the algorithm.
- PMOPenhanced deactivated by ongoing AT/AF count (PMOPenhanced false therapy counts): the number of algorithm deactivations due to an ongoing episode, i.e. a new episode occurred before the last episode was classified as being terminated after five sinus beats.
Study design
Eligible patients were randomized into two groups following the assignment provided in their randomization envelopes. All patients had the experimental software downloaded into their pacemaker at enrolment. Approximately half the patients were programmed initially to PMOPenhanced ON, whereas the remaining patients were programmed to monitor mode only, for the first 3 months of the study. All other preventive and termination therapies were disabled during the study. Collection of diagnostic data occurred in both arms. At the 3-month follow-up visit, all patients were crossed over to the opposite randomization programming.
Data collection
At enrolment, all devices were interrogated, data were saved, and device memory was cleared. The research software was downloaded in all devices. Patients were asked to complete a quality of life questionnaire [atrial fibrillation severity scale (AFSS)]. After 3 months, patients were asked to return to the clinic. During that visit, the devices were interrogated again, data were saved, device memory was cleared, and the patients crossed over to the other study arm. The patients were asked to complete the quality of life questionnaire and medication changes were documented. Patients returned to the clinic for a final device interrogation after another 3 months, the data saved to disk, and the patients were asked to complete the quality of life questionnaire. The PMOPenhanced UI was used to record the algorithm-specific parameters and finally, to remove the research software.
Quality of life
Quality of life was assessed using the University of Toronto AFSS. The AFSS is a 14-item disease-specific scale developed to capture subjective and objective ratings of the AF disease burden. A measure of total AF burden is obtained by combining measures of frequency, duration, and patient perceived severity; higher scores indicate a greater AF burden. For AF frequency, a lower score denotes more frequent AF, whereas for AF duration, a lower score denotes AF of longer duration. For global well-being, a higher score means better quality of life.12
Study endpoints
The primary endpoint of the study was to demonstrate a reduction of ERAF during the overdrive period (10 min), qualified as device-classified PMOPenhanced success. Success rate was provided as a crude estimate: (the total number of PMOPenhanced deployments minus the total number of ERAF divided by total number of PMOPenhanced deployments). From these values, the difference in success rate between the active and inactive phase, Delta-PMOPenhanced success rate, was calculated. Secondary endpoints included device-classified AT/AF frequency, device-classified burden, duration of sinus rhythm between episodes, safety/adverse events, and quality of life.
Finally, three algorithm-specific diagnostics were analysed between the ON and the OFF arms of the study, comparing the number of times the algorithm deployment criteria were satisfied, the terminated by the new AT/AF count, and the number of deactivated by ongoing counts.
Statistical methods and data analysis
Data were analysed using the SPSS 12.0 software package (SPSS, Chicago, IL, USA). Data are presented as median values with the inter-quartile range (IQR, 25th–75th percentiles).
A two-sided, non-parametric test (Wilcoxon signed ranks test) was performed to compare paired values. A Mann–Whitney U test was used to compare non-parametric data between two independent groups. Correlation between ERAF and other continuous variables was assessed using the Spearman's rank correlation method. A P-value of 
0.05 was considered statistically significant.
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Patients
We enrolled 45 patients from October 2004 to September 2005 (see Table 1). Patients were enrolled in the study if they had at least five AT/AF episodes and a burden between 0.5 and 60% stored in their device in the 90-day-period prior to enrolment. The median time since last device interrogation was 162.5 days. The median device-derived AT/AF burden was 10%, and the median number of AT/AF episodes was 1.59 per day. Three patients developed persistent AF, one during the active study phase and two during the control phase. One patient requested to exit the study. The remaining 41 patients were analysed.
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In all but two patients, the programming requirements to disable all other preventive and termination therapies were met; these two patients had ATP programmed on during the whole study period. In all but five patients, the anti-arrhythmic drug regime was kept stable. Two patients started amiodarone treatment. In the three other patients, sotalol therapy changed, in one patient the sotalol dose was increased, in another decreased, and a third patient started on sotalol. The analysis was done with an intention to treat, including the patients in whom the medication was changed, but excluding those who developed persistent AF (n = 3). We also performed the analysis by excluding the patients who had their medication changed during the course of the study; however, this did not affect the results.
Study endpoints
The primary endpoint of the PLOP study was to demonstrate a reduction of ERAF during the overdrive period (10 min), qualified as device-classified PMOPenhanced success. This primary endpoint was not met. The median Delta-success rate (7.36%) was not significantly different from zero; the same was true for the median Delta-ERAF (zero) (Figure 1).
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The median number of AT/AF episodes per patient per day (1.38 vs. 1.19), the median AT/AF burden (10% for both study periods), and the median number of ERAF during each follow-up period (0.56 vs. 0.51) were not significantly different during the control and active study periods.
To exclude time-dependent changes in AT/AF frequency, an additional analysis was performed to compare patients receiving PMOPenhanced pacing in the first (n = 18) vs. the second (n = 23) study phase. There was no difference in median AT/AF frequency (IQR) when comparing PMOPenhanced activated in the first study phase with PMOPenhanced activated in the second study phase, 7.88 (1.39–16.26) vs. 8.31 (2.83–39.04). There was also no significant difference when comparing the median AT/AF frequency (IQR) with PMOPenhanced inactive in the first study phase with the second study phase, 13.69 (2.49–29.99) vs. 6.25 (1.12–32.19).
Post hoc analysis
PMOPenhanced is a feature designed to prevent early recurrences of AF. The patient population that we studied had a median number of 1.38 episodes per day (all patients, PLOP OFF). With approximately one episode per day, the chance of having early recurrences is small. Therefore, we performed a secondary analysis. Because we found a positive correlation between the number of ERAF and the number of episodes (Spearman's 
correlation coefficient = 0.912, P = 0.01) in the entire population with PMOPenhanced inactive, we stratified the patients by the median and then split into two groups based on the average number of episodes per week recorded during 90 days prior to randomization.
In the subgroup of patients with relative frequent episodes and thus frequent ERAF (Group B), the median time per day spent in AT/AF (burden) was significantly reduced when PMOPenhanced was activated (3.71 vs. 1.71 h per day, P = 0.02 Wilcoxon signed ranks test, two-tailed, Figure 2). This significant reduction was accompanied by a trend towards reduction of the number of ERAF per day (2.77 vs. 1.86, P = 0.07) as well as a reduction in the total number of AT/AF episodes per day (3.79 vs. 2.44, P = 0.079). In contrast, no such difference could be demonstrated in Group A (Table 2).
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Time between episodes
Time between episodes can only be studied in the last 35 episodes stored. Data are collected in the device episode log at the end of each randomization phase. Every patient contributes the last 35 AT/AF episodes (maximum) prior to device interrogation. Time in sinus rhythm and/or paced rhythm between episodes is calculated as the time interval between device-reported episode termination and device-reported onset of the next AT/AF episode.
Five of these patients had no episodes during one (three patients) or two follow-up periods (two patients), and they were not included in the analysis. The remaining 36 patients had 1443 episodes, stored during the active phase and 1333 episodes stored during the monitoring phase. The time covered by these 35 episodes was a median of 28.82% (IQR: 6.86–82.36%) of total follow-up time. During the active treatment period, the time in sinus rhythm between episodes was significantly increased, 82.0 (IQR: 16.0–4925.5) vs. 50.5 s (IQR: 13.9–2566.9) ON vs. OFF ( P = 0.00 623, Mann–Whitney U test), which is an increment of 62.4%.
Safety and adverse events
During the study, 15 adverse events were reported. All adverse events were classified as not serious. None of the patients required a lower overdrive rate. Twelve of the reported events were arrhythmia related. The proportion of patients experiencing an arrhythmia-related adverse event (including development of persistent AF) during the two treatment periods could be considered equivalent at a 0.05 level, confidence interval 95%. Palpitations possibly related to the overdrive pacing rate (90 bpm) could not be excluded in four patients, because these events happened with PLOP programmed to ON.
Quality of life
The total AT/AF burden score at baseline for all patients (n = 41) was 17.59 ± 3.25; the average AT/AF frequency and duration scored were 7.07 ± 2.54 and 5.90 ± 1.89, respectively. The most recent AT/AF episode was scored 4.61 ± 2.84. The patients reported no difference in the score for total AT/AF burden, AT/AF frequency, AT/AF duration, and most recent AT/AF episode when comparing PMOPenhanced OFF vs. ON (Table 3).
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Algorithm-specific endpoints
Table 4 demonstrates that there were no significant differences between algorithm-specific endpoints when comparing ON vs. OFF in all patients. From the algorithm-specific endpoints, it was possible to calculate the percentage of episodes that could be classified ERAF. Activation of PMOPenhanced did not change the percentage of ERAF (Table 5).
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Percentage atrial and ventricular pacing
The percentages of AP (83 vs. 84%) and ventricular pacing (70 vs. 72%) were not significantly different during the control and active study periods.
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Discussion |
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We found no effect of temporary overdrive pacing in the whole study population. This finding is in line with other studies.13
–16 However, with a post hoc analysis we could demonstrate that overdrive pacing the atrium at 90 bpm for a 10 min period starting shortly before device-classified AT/AF termination is effective in reducing the AT/AF burden in patients who have had many early recurrences. In these patients, activation of the improved algorithm resulted in a positive trend towards a reduction in overall AT/AF frequency as well as ERAF frequency. Unlike other studies, the PLOP study did not demonstrate an improvement in patient symptoms when the algorithm was activated, although some individual patients reported improved quality of life with the algorithm turned on. This is, to the best of our knowledge, the first report to demonstrate a significant reduction in device-classified AT/AF burden caused by overdrive pacing alone. The reduction could only be demonstrated in patients with a high number of AT/AF episodes. In patients with a low number of AT/AF episodes, the AT/AF burden non-significantly increased during algorithm activation. When we excluded the patients who had their medications changed during the study period, we found a trend towards an increase in burden in this patient group. Although not significant, these results require further investigation. If indeed these observations are true it underlines a patient-tailored approach to AT/AF.
So far, only one report has demonstrated a positive result of atrial overdrive pacing reducing ERAF.9 This randomized study was the first to study the efficacy of PMOP with other preventive and anti-tachypacing therapies turned off. Moreover, this study looked at the efficacy of preventing early recurrences during the overdrive period. Other studies such as Aspect17 or Attest,18 have not demonstrated any effect of atrial prevention algorithms on device-classified AT/AF frequency or burden. These two trials, however, looked at the combined effect of all atrial prevention algorithms on AT/AF frequency and burden, whereas we studied the efficacy of a single algorithm only. Israel et al.8 tested the efficacy of atrial overdrive pacing at 120 bpm for 2 min to prevent immediate reinitiation of tachyarrhythmia in a patient population similar to ours (73% sick sinus syndrome); all other preventive and anti-tachycardia pacing functions were active and kept unchanged throughout the study. The median number of episodes per patient per day in that study was 0.34 vs. 0.37 (ON vs. OFF), and the median percentage of ERAF was 30 vs. 38%. These numbers are similar to those that we reported in our lower 2-Quartiles: median number of AT episodes per patient per day 0.32 vs. 0.37 (ON vs. OFF), and the median percentage of ERAF was 42 vs. 38.5% (ON vs. OFF). Israel et al. could not demonstrate any effect on burden, symptoms, and quality of life during PMOP OFF vs. ON. We found a similar result in the lower 2-Quartiles. Israel blamed the PMOP failures on insufficient overdrive suppression due to the slow start of PMOP. Based on our results, we believe that Israel et al. studied a patient population that did not suffer from enough ERAF.
Urban et al.19 published their retrospective analysis evaluating the impact of percentage of right ventricular pacing (RVP) and AP on AT/AF burden. They showed that the AT/AF burden significantly increased with more %RVP and decreased with more %AP. The ADOPT trial reported a significant reduction in the symptomatic AT/AF burden (2.5 vs. 1.87%) when reporting their results on the AF suppression algorithm. However, the treatment group experienced a higher %AP, which in line with Urban et al., could easily be the cause of the difference found. In our patient population, we did not find a difference in the percentage of AP or ventricular pacing with the algorithm active or inactive between the groups. Consequently, this could not have caused the observed difference in the AT/AF burden, number of atrial episodes, and %ERAF. Activation of the algorithm did not result in an increase in the percentage of atrial or ventricular pacing. This is also related to the fact that the algorithm is only active for a limited period of time (10 min in our study) when actually needed.
Pürerfellner et al.20 have reported on the accuracy of atrial detection in implantable devices such as AT500TM. They demonstrated appropriate AT detection in 95.3% and inappropriate episode termination in 16.3% in the AT500TM. Inappropriate termination was caused by (i) bigeminal flutter patterns, (ii) functional 2:1 under-sensing of flutter, and (iii) true under-sensing of AF. Undesirable deployment of the PMOPenhanced algorithm was prevented by addressing the potential interaction of the algorithm counter with under-sensing. Deployment of the algorithm occurs when two long pauses longer than 400 ms are detected. The risk exists that a long pause occurs due to under-sensing and not due to temporary termination of an episode. If PMOPenhanced is activated, the random access memory-ware checks whether AF is ongoing after the 10th ventricular event. If that is the case, the algorithm will immediately be deactivated, and that deactivated by the ongoing counter is incremented. In case the algorithm was activated and the atrial episode is not in progress any longer, the criteria met count is incremented. If a new atrial episode is detected, the algorithm is terminated and the terminated by new AT/AF counter is incremented.
Thus, in case of inappropriate algorithm activation due to under-sensing, the algorithm will only be activated for 10 ventricular beats. This has no effect on the episode, since it appeared in goats that pacing during AF does not increase the length of the episode (unpublished results). We found 12.13% fewer episodes when relying on PMOPenhanced counters when compared with AT500 episode counters. These data suggest that the episode count based on algorithm deployments is superior to the current AT500 count, which overestimates episode termination23.
The PLOP study is the first to include all episodes recorded during the entire follow-up in the analyses of ERAF, and not just the last 35 stored in the episode log. One limitation of looking at the last 35 stored episodes is that one assumes that the distribution of ERAF is normal. This assumption is not valid on an individual basis but may be reasonable on average, which requires a large patient population. In our patient population, the time covered by the stored episodes represented 28% (median, range 0.19–100%) of the whole follow-up period. Thus, conclusions drawn from the stored episodes from such a small patient population are not representative of all episodes. The PMOPenhanced algorithm collects diagnostic data during the whole follow-up period. From this diagnostic information, the percentage of ERAF during the entire follow-up period could be calculated. The algorithm did not affect the percentage of episodes that could be classified as ERAF (69 vs. 60% OFF vs. ON, respectively in the entire population). However, the algorithm did reduce the AT/AF frequency, as well as the ERAF frequency. In addition, we found a prolongation of time in normal sinus rhythm (NSR) between episodes (82 vs. 50.5 s PLOP ON vs. OFF, respectively) in the stored episode log. These results taken together are in accordance with the hypothesis that prevention of ERAF significantly improves the success rate of maintaining the sinus rhythm in patients with paroxysmal AT/AF and also prevents late recurrences. Thus, the improved PMOP algorithm, PMOPenhanced, may reduce the overall susceptibility to AT/AF by preventing not only early, but also late, recurrences.
Limitations
Unfortunately, the number of enrolled patients was relatively small. With more patients, the difference in ERAF and most probably the total number of episodes, may have reached significance. Another limitation of the study is that the analysis of time among episodes is based on the last 35 episodes stored. These 35 episodes are stored in 28% of the total follow-up period (range 0.19–100%), which indicates that these results cannot be taken as representative for all episodes. Although the diagnostics of the enhanced algorithm are improved over the current PMOP, it is still not possible to analyse the time in NSR during the entire follow-up period.
Finally, we did not have access to the electrogram recordings enabling an in-depth analysis of the episode termination; therefore our comment on the superiority of the PMOPenhanced deployment count vs. AT500 episode count is suggestive and needs further research.
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Conclusions |
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Data from this study do not demonstrate that atrial overdrive pacing effectively reduces the AT/AF burden in the overall PAF population. However, on the basis of the results of our post hoc analysis, we suggest that it is worthwhile to pay close attention to the patient population that will be enrolled in future studies on the reduction of the AF burden by means of overdrive pacing.
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Support for this study was provided by the Medtronic Bakken Research Center, Maastricht, The Netherlands.
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Acknowledgements |
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The authors greatly appreciate the co-operation with: F. Biedermann, E. Clausson, D. Daly, C. Eppacher, D. Erckens, T. Milata, and J. Veselovsky and the scientists: M. Hill, D. Hettrick, and P. Ziegler.
Conflict of interest: H.P. works as a consultant/advisor for Medtronic. L.K. and G.C.R.K. both work as scientists for Medtronic.
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References |
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