Author + information
- Received September 27, 2002
- Revision received February 20, 2003
- Accepted February 25, 2003
- Published online June 4, 2003.
- Michael A Lee, MD, FACC*,* (, )
- Richard Weachter, MD, FACC†,
- Scott Pollak, MD, FACC‡,
- Mark S Kremers, MD, FACC§,
- Ajay M Naik, MD∥,
- Russell Silverman, MD, FACC¶,
- Joann Tuzi, RN**,
- Wayne Wang, MS**,
- Linda J Johnson, PhD**,
- David E Euler, PhD**,
- ATTEST Investigators
- ↵*Reprint requests and correspondence:
Dr. Michael A. Lee, 365 Hawthorne Avenue, #201, Oakland, California 94609, USA.
Objectives The Atrial Therapy Efficacy and Safety Trial (ATTEST) was a prospective, randomized study to evaluate preventive pacing and antitachycardia pacing (ATP) in patients with symptomatic atrial fibrillation (AF) or atrial tachycardia (AT).
Background The effect of the combination of atrial prevention and termination algorithms on AT/AF burden and frequency in pacemaker patients is unknown.
Methods A DDDRP pacemaker (AT500, Medtronic Inc., Minneapolis, Minnesota) with three atrial preventive pacing algorithms and two ATP algorithms was implanted in 368 patients. Patients were randomized one-month post-implant to all prevention and ATP therapies ON or OFF and followed for three months. The OFF group had DDDR pacing at a lower programmed rate of 60 ppm. The AT/AF burden and frequency were determined from daily device counters in 324 patients treated according to protocol.
Results In 17,018 episodes with stored electrograms, appropriate detection was confirmed in 17,004 (99.9%). The median percentage of atrial pacing was 98% in the ON group versus 75% in the OFF group (p < 0.001). Using device-defined criteria for successful termination, ATP terminated 8,590 (54%) of 15,789 treated episodes. The median AT/AF burden during the three-month study period was 4.2 h/month ON versus 1.1 h/month OFF (p = 0.20). The median AT/AF frequency was 1.3 episodes/month ON versus 1.2 episodes/month OFF (p = 0.65). System-related, complication-free survival at four months was 90.2% (Kaplan-Meier estimate).
Conclusions This DDDRP pacemaker is safe, has accurate AT/AF detection, and provides ATP with 54% efficacy as defined by the device. The atrial prevention and termination therapies combined did not reduce AT/AF burden or frequency in this patient population.
There is considerable interest in the use of atrial pacing to prevent and treat atrial tachyarrhythmias. There is evidence that atrial pacing in pacemaker patients reduces the incidence of atrial tachyarrhythmias compared to VVI pacing (1–3). To increase the ability of atrial pacing to suppress the onset of atrial tachyarrhythmias, sophisticated algorithms have been developed that increase the percentage of atrial pacing (4–6). In addition to pacing algorithms for prevention, device-based antitachycardia pacing (ATP) has been shown to effectively terminate atrial tachyarrhythmias (6,7). The purpose of this prospective randomized study was to evaluate the efficacy and safety of prevention and termination therapies in a DDDRP pacemaker. Using the diagnostic features of the device to measure daily atrial tachyarrhythmia burden and frequency, the hypothesis was that activation of the prevention and termination therapies would reduce the burden and frequency of atrial tachyarrhythmias.
The device (AT500, Medtronic Inc., Minneapolis, Minnesota) features include DDDR pacing and DDIR mode switch during atrial tachyarrhythmias. Atrial tachyarrhythmias are detected when the median atrial cycle length (12 beats) is less than the programmed atrial tachycardia (AT) or atrial fibrillation (AF) detection interval, and the atrial:ventricular (A:V) ratio is >1:1 for at least 24 ventricular beats. The detection algorithm rejects atrial events resulting from far-field R waves and classifies the rhythm as AF or AT based on cycle length and cycle length regularity (6,7). The device stores an atrial electrogram as well as event markers for up to 35 episodes between interrogations. In addition, the number of daily AT/AF events and total duration of AT/AF episodes per day are stored by the device for up to 14 months (Fig. 1).
For episode termination, two rate-adaptive atrial ATP therapies are available (Burst+ and Ramp) to treat AT episodes (6,7). The device classifies a therapy as successful only if five consecutive sinus beats or paced beats with a normal A:V pattern are detected before AT/AF redetection within a 3-min window. If AT/AF is redetected before five consecutive sinus beats, the therapy is considered unsuccessful. The redetection of AT/AF after a therapy requires at least 32 ventricular beats, and this usually occurs within 20 to 30 s. If AT/AF is redetected after five consecutive sinus beats, the therapy is considered successful and the device logs a new episode. If AT/AF is not redetected and five consecutive sinus beats are not detected within 3 min, the detection algorithm considers the episode to have terminated and the therapy is classified as unsuccessful.
The device also has three pacing algorithms designed to prevent AT/AF recurrence. These include an atrial overdrive algorithm designed to maintain the programmed atrial escape interval just ahead of the intrinsic rate (atrial preference pacing), a temporary atrial overdrive mode designed to prevent short-long intervals after a premature atrial contraction (atrial rate stabilization), and a post-mode-switch overdrive pacing mode designed to inhibit the early recurrence of AT/AF after episode termination (6,7).
Study design and patient population
Eligible patients were those having American College of Cardiology/American Heart Association class I or II indications for a standard dual-chamber pacemaker (8)and a history of AT/AF. Patients were required to have at least one episode of paroxysmal or persistent AT/AF documented by electrocardiogram within the past year and one symptomatic episode in the past three months. Patients with permanent AF, an indication for an implantable defibrillator, or New York Heart Association functional class IV heart failure were excluded. All patients gave written informed consent according to a protocol approved by the local human subjects committee at the implanting center.
Bipolar right atrial and ventricular leads were required at implant, with ≤10 mm interelectrode spacing recommended. Atrial detection was programmed ON at implant in all patients, and DDDR pacing was programmed at a lower rate of 60 ppm and an upper rate of 120 ppm. A one-month run-in period was allowed for lead fixation and drug stabilization. At the one-month visit, patients were randomized to all prevention and termination therapies ON or OFF (Table 1) and followed for three months.
The effect of atrial therapies on AT/AF burden and total AT/AF frequency was the primary efficacy end point. Burden was calculated by summing the daily time spent in AT/AF and dividing by the follow-up duration (Fig. 1). Total frequency was calculated by summing the daily number of AT/AF episodes logged by the device and dividing by the duration of follow-up. To be included in the final analysis, patients needed ≥28 days of follow-up with strict programming compliance (Table 1). In addition, patients were excluded if they developed chronic AF before randomization that persisted throughout the study period.
Secondary efficacy end points included the accuracy of the detection algorithm, ATP efficacy, and symptomatic AT/AF frequency. The accuracy of the detection algorithm was determined by investigator review of stored AT/AF episodes. The ATP efficacy was expressed as the incidence of successful terminations based on the device counters. Symptomatic frequency was determined similar to total frequency except that only episodes were counted that were associated with one or more manual symptom markers (Fig. 1).
The primary safety end point was system-related, complication-free survival in all patients enrolled. System-related complications were defined as clinical events with potential adverse effects requiring invasive interventions specifically related to the device, the implanted leads, or the implant procedure. Adverse clinical events were analyzed and classified by an independent physician advisory committee.
Statistical analyses were performed using SAS statistical software (SAS Institute, Cary, North Carolina). Continuous data were reported as the mean ± SD or as the median along with the 25th to 75th percentile. A Kaplan-Meier estimate was obtained for complication-free survival. Comparisons between groups were performed using a Wilcoxon rank-sum test for unpaired data, a Wilcoxon signed rank test for paired data, or a chi-square test. For the evaluation of ATP efficacy and the efficacy of the detection algorithm, the generalized estimating equation (GEE) method was used with an exchangeable correlation structure (9). This technique adjusts for multiple episodes in a single patient and yields an average estimate that is based on the number of patients as well as the number of episodes per patient. For all statistical comparisons, the null hypothesis was rejected when p ≤ 0.05.
There were 370 patients enrolled at 28 centers worldwide and 368 devices implanted. The atrial leads were implanted in the atrial appendage (70%), the lateral free wall (12%), the high right atrium (11%), or the interatrial septum (0.5%). There were 324 patients included in the efficacy cohort. Reasons for exclusion included: <28 days of follow-up with all atrial therapies programmed according to protocol (n = 19), chronic AF before randomization (n = 12), death before randomization (n = 6), inadequate pacing and/or sensing (n = 3), explant before randomization (n = 2), and patient consent withdrawn before randomization (n = 1). The average follow-up time during the study period was 82 ± 13 days in the ON group and 85 ± 16 days in the OFF group (p = 0.96).
The demographics of the patients in the efficacy cohort are shown in Table 2. There were no significant differences in baseline characteristics between the ON and OFF groups. The antiarrhythmic drugs used are shown in Table 3. There were no significant differences in the use of drugs between the ON and OFF groups at either follow-up time, and there were no significant changes in drug use over time in the two groups.
Detection of atrial episodes
There were 271 patients who had 17,018 AT/AF episodes with a stored electrogram (8 s) available for review during the four-month follow-up period. The positive predictive accuracy of the detection algorithm was 99.9% (GEE-adjusted estimate, 99.7%), based on 17,004 episodes classified as appropriate by the investigators.
Atrial and ventricular pacing
The number of atrial and ventricular paced and sensed beats were determined from the daily trend counters (atrial beats were not counted during an AT/AF episode) and summed over the study period in each patient. The median amount of atrial pacing was 98% (25th to 75th percentile, 97% to 99%) in the ON group and 75% (25th to 75th percentile, 38% to 95%) in the OFF group (p < 0.001). The median amount of ventricular pacing was 99% (25th to 75th percentile, 95% to 100%) in the ON group and 98% (25th to 75th percentile, 81% to 100%) in the OFF group (p = 0.005).
A total of 94 patients in the ON group experienced 54,976 AT/AF episodes during the three-month study period, and 15,789 of these episodes were treated with ATP in 85 patients. There were 8,590 treated episodes that were classified by the device as successfully terminated, yielding an efficacy of 54.4% (GEE adjusted estimate, 41.4%). An example of an episode treated successfully by ATP is shown in Figure 2.
Burden and frequency
The median burden and frequency during the run-in and study periods for the efficacy cohort are shown in Table 4. There were no significant differences in burden, total frequency, or symptomatic frequency between the ON and OFF groups during the study period. The AT/AF episodes were detected during the study period in 61% of patients in the ON group and 60% in the OFF group (p = 0.84). Symptomatic episodes were logged in 33% of patients in the ON group and 31% in the OFF group (p = 0.84). The burden and frequency during the run-in period were also analyzed to ensure that the two treatment groups were similar before randomization. The burden and frequency during the run-in period were not significantly different between the two groups. A paired analysis was also performed to compare the burden and frequency observed during the study period with the burden and frequency observed during the run-in period. The analysis was performed in both the ON and OFF groups, and no significant differences were observed (p ≥ 0.70).
Although burden and frequency were not altered by the therapies in the overall study population, it is possible that the inclusion of patients who had no episodes during the run-in period may have influenced the study outcome. Therefore, a retrospective analysis of burden and frequency was performed after stratifying the patients on the basis of the presence of episodes during the run-in period. The atrial therapies did not significantly alter burden or frequency in patients with or without AT/AF episodes during the run-in period (p ≥ 0.40).
It is also conceivable that there may have been a subgroup of patients receiving a particular type of antiarrhythmic drug or with a certain demographic profile that may have derived benefit from the therapies. Therefore, multiple subgroup analyses were performed after stratifying patients on the basis of their baseline characteristics (Table 2) or the use of antiarrhythmic drugs at one month (Table 3). The results of these analyses did not identify a responder subgroup.
Figure 3shows a histogram of AT/AF episodes based on duration. The device counters automatically grouped episodes into eight duration bands. Only seven bands are displayed because episodes lasting <1 min were not eligible to receive ATP. There were 28,735 episodes <1 min in the ON group and 20,395 episodes in the OFF group. There were 26,241 episodes ≥1 min in the ON group and 28,229 episodes in the OFF group. The majority of all episodes (≥80%) terminated within 10 min in both groups. Only 60% of the episodes ≥1 min in the ON group were treated with ATP therapy. For each patient in the ON and OFF groups, the number of episodes in each duration band was divided by the follow-up time. This yielded eight band-specific AT/AF frequencies. The median frequency in each band was compared between the ON and OFF groups (Wilcoxon rank-sum test), and no significant differences were observed (p ≥ 0.17).
There were 39 system-related complications reported in 36 patients during the four-month follow-up period. The most common were atrial lead dislodgement (n = 11), ventricular lead dislodgement (n = 5), and pericardial effusion (n = 4). The Kaplan-Meier estimate of system-related, complication-free survival at four months post-implant was 90.2% with a 95% confidence interval of 86.7% to 92.8%.
There were nine deaths over the course of the four-month follow-up period; six occurred before randomization and one was classified as procedure related. Causes of death included cardiac arrest (n = 3), cardiogenic shock (n = 2), congestive heart failure (n = 1), ventricular arrhythmia (n = 1), and renal failure (n = 1). One death was classified as unknown owing to inability of the site to acquire patient records from an outlying facility.
There were 65 external cardioversions to treat AT/AF in 59/368 patients during the four-month follow-up period. The largest number of cardioversions occurred at the time of implant (48%). In the efficacy cohort, there were 7 (4.6%) cardioversions in the ON group and 2 (1.2%) in the OFF group during the study period (p = 0.13).
This study demonstrated the safety and efficacy of a DDDRP pacemaker with atrial tachyarrhythmia prevention and termination therapies in a patient population with bradycardia and symptomatic AT/AF. The device was implanted in 99.5% of patients enrolled, and the four-month system-related, complication-free survival was 90.2%. The most frequent system-related complications were lead dislodgements. The positive predictive accuracy for atrial arrhythmia detection was 99.9%. The results on safety and detection accuracy in the present study confirm previous findings in a similar patient population (6).
The atrial prevention and termination therapies combined did not significantly alter burden, total frequency, or symptomatic frequency. The median burden was higher in the ON group during the study period, but this was also observed during the run-in period. The atrial therapies failed to reduce burden and frequency despite an increase in the relative amount of atrial pacing from a median of 75% to 98% and an ATP efficacy of 54%. It is possible that the high proportion of ventricular pacing (median = 99%) may have exerted a deleterious effect and limited any benefit from the atrial therapies. The ATP efficacy of 54% confirms the results of previous findings with this device in patients with bradycardia and AT/AF (6). Although a neutral effect of the atrial therapies on burden and frequency was reported in the previous study, patients were not randomized and the analysis was retrospective (6). In the present study, the effect of the atrial therapies on burden and frequency was evaluated prospectively with strict regulation of device programming. Because the outcome of the prospective analysis was neutral, several retrospective analyses were performed that stratified patients on the basis of demographics, antiarrhythmic drug use, or the presence of episodes during the run-in period. These retrospective analyses failed to identify a responder subgroup.
The failure of the atrial therapies to reduce burden stands in contrast to a previous study that evaluated burden in patients with a history of both atrial and ventricular tachyarrhythmias implanted with a device that had atrial defibrillation capabilities as well as pacing therapies (10). In that study, the median AT/AF burden was significantly reduced from 2.7 to 0.1 h/month in a highly selected subgroup of patients (41/269) who had atrial pacing (prevention and termination) therapies programmed ON, but did not receive atrial shocks. Although the explanation for the difference in the outcome of the two studies is not clear, several factors may have been operative. There were differences in the study designs, patient populations, antiarrhythmic drug use during follow-up, and the pacing algorithms employed for prevention and termination. In addition, episodes with cycle lengths <220 ms were not treated with ATP in the present study but were treated with ATP and/or 50-Hz burst pacing in the previous study (10).
Given the inclusion criteria of at least one symptomatic episode in the three months before implant in the present study, it was interesting that about 40% of the patients in both groups had no episodes during the study period. Because bradycardia may play a role in the initiation of AT/AF, DDDR pacing may have suppressed AT/AF in some patients. Moreover, changes in type or dosage of antiarrhythmic drugs before randomization may have played a role in AT/AF suppression during follow-up.
In addition to providing information on burden and frequency, the device also generated a histogram that grouped episodes into eight different duration bands. Because the precise duration of each episode was not stored, it was not possible to directly link the histogram to burden in a given patient. The histogram showed that the majority of episodes (≥80%) in both groups terminated within 10 min. The atrial therapies did not have a significant effect on the frequency of episodes in any of the eight duration bands. The lack of a significant effect of the atrial therapies on the duration histogram is consistent with the lack of an effect of the therapies on burden.
There are several important limitations of this study. The device stores 35 episodes between interrogations and, thus, only about 10% of all episodes logged by the daily counters were available for review. The daily counters did not store the episode type (AT or AF); thus, it was not possible to distinguish AT burden from AF burden. The daily counters also did not store the time of each episode; therefore, the time interval between episodes could not be evaluated. There was no mechanism in place to ensure that patients used their patient activators to log all symptomatic episodes during the study period; therefore, the number of true symptomatic episodes may have been underestimated. Furthermore, a three-month follow-up period after randomization may have been insufficient to adequately characterize burden and frequency.
The results of this prospective, randomized clinical trial show that this DDDRP pacemaker is safe in patients with bradycardia and symptomatic AT/AF. The dual-chamber algorithm was effective in detecting 99.9% of AT/AF episodes, and the ATP efficacy as defined by the device was 54%. Activation of the prevention algorithms increased the relative amount of atrial pacing from 75% to 98%. The atrial prevention and termination therapies combined did not reduce burden, total frequency, or symptomatic frequency. The failure of the atrial therapies to reduce burden or frequency may have been partially due to the suppression of bradycardia-induced AT/AF by DDDR pacing.
☆ This study was supported by a grant from Medtronic Inc., Minneapolis, Minnesota. J. Tuzi, W. Wang, L. J. Johnson, and D. E. Euler are employees of Medtronic Inc.
- atrial fibrillation
- atrial tachycardia
- antitachycardia pacing
- generalized estimating equation
- Received September 27, 2002.
- Revision received February 20, 2003.
- Accepted February 25, 2003.
- American College of Cardiology Foundation
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