The effect of atrial pacing therapies on atrial tachyarrhythmia burden and frequency

Results of a randomized trial in patients with bradycardia and atrial tachyarrhythmias

Device characteristics

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).

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Figure 1

Cardiac compass report. The atrial pacing therapies were activated on January 20. The vertical dashed lineindicates the last device interrogation. The atrial tachycardia (AT)/atrial fibrillation (AF) Patient Check indicates the days that the patient used his or her activator because of symptoms. The patient received the activator at the time of randomization. CV = cardioversion.

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.

Data analysis

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

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.

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).

Atrial ATP

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.

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Figure 2

An atrial tachycardia (AT) episode that was terminated by Ramp therapy. The graph shows the intervals between atrial (A-A) and ventricular (V-V) events at episode onset, detection, first therapy, and termination. The Ramp therapy was initiated 3.8 min after detection and resulted in the immediate termination of the atrial tachyarrhythmia. AF = atrial fibrillation.

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.

Episode duration

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).

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Figure 3

Histogram of atrial tachycardia/atrial fibrillation episode duration. The median episode frequency in each duration band was compared between the ON and OFF groups, and no significant differences were observed (p ≥ 0.17).

Safety

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).

Study limitations

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.