Author + information
- Received January 3, 2003
- Revision received February 24, 2003
- Accepted March 12, 2003
- Published online August 20, 2003.
- Mark D Carlson, MD, MA*,* (, )
- John Ip, MD†,
- John Messenger, MD‡,
- Scott Beau, MD§,
- Steven Kalbfleisch, MD∥,
- Pierre Gervais, MD¶,
- Douglas A Cameron, MD#,
- Aurelio Duran, MD**,
- Jesus Val-Mejias, MD††,
- Judith Mackall, MD*,
- Michael Gold, MD, PhD‡‡,
- ADOPT Investigators
- ↵*Reprint requests and correspondence:
Dr. Mark D. Carlson, Department of Medicine, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio, USA 44106.
Objectives The Atrial Dynamic Overdrive Pacing Trial (ADOPT) was a single blind, randomized, controlled study to evaluate the efficacy and safety of the atrial fibrillation (AF) Suppression Algorithm (St. Jude Medical Cardiac Rhythm Management Division, Sylmar, California) in patients with sick sinus syndrome and AF.
Background This algorithm increases the pacing rate when the native rhythm emerges and periodically reduces the rate to search for intrinsic atrial activity.
Methods Symptomatic AF burden (percentage of days during which symptomatic AF occurred) was the primary end point. Patients underwent pacemaker implantation, were randomized to DDDR with the algorithm on (treatment) or off (control), and were followed for six months.
Results Baseline characteristics and antiarrhythmic drugs used were similar in both groups. The percentage of atrial pacing was higher in the treatment group (92.9% vs. 67.9%, p < 0.0001). The AF Suppression Algorithm reduced symptomatic AF burden by 25% (2.50% control vs. 1.87% treatment). Atrial fibrillation burden decreased progressively in both groups but was lower in the treatment group at each follow-up visit (one, three, and six months) (p = 0.005). Quality of life scores improved in both groups. The mean number of AF episodes (4.3 ± 11.5 control vs. 3.2 ± 8.6 treatment); total hospitalizations (17 control vs. 15 treatment); and incidence of complications, adverse events, and deaths were not statistically different between groups.
Conclusions The ADOPT demonstrated that overdrive atrial pacing with the AF Suppression Algorithm decreased symptomatic AF burden significantly in patients with sick sinus syndrome and AF. The decrease in relative AF burden was substantial (25%), although the absolute difference was small (2.50% control vs. 1.87% treatment).
Atrial fibrillation (AF) affects an estimated 2.3 million individuals, causes significant morbidity, and is associated with $1 billion in health costs each year in the U.S. (1). Despite the development and use of class IC and class III antiarrhythmic drugs, AF recurs in many patients (2). Furthermore, antiarrhythmic drugs are associated with side effects that may increase mortality or require that therapy be terminated.
Previous studies suggested that dual-chamber or atrial pacing decreases the risk for AF in patients who require permanent pacing for sinus node dysfunction (3,4). Potential mechanisms responsible for an antiarrhythmic effect attributed to atrial pacing include rate dependent effects on refractoriness, reduction of ectopy, prevention of pauses, and remodeling of the electrophysiologic substrate.
A new rate adaptive atrial pacing algorithm (AF Suppression Algorithm, St. Jude Medical Cardiac Rhythm Management Division, Sylmar, California) was designed to provide a high percentage of atrial paced beats while allowing for the normal diurnal variation in the heart rate. The algorithm increases the pacing rate when the native rhythm emerges and periodically reduces the rate gradually to search for intrinsic atrial activity. The Atrial Dynamic Overdrive Pacing Trial (ADOPT) was designed to assess the clinical efficacy and safety of the AF Suppression Algorithm in patients with AF, sick sinus syndrome, and an indication for permanent pacing. The primary objectives were to determine whether the algorithm in combination with DDDR pacing is safe and effective in reducing symptomatic AF compared with DDDR pacing alone.
The ADOPT was a single blind, prospective, controlled, multicenter, randomized clinical trial. Patients were enrolled between December 11, 1998 and December 31, 2000.
The principal inclusion criteria were: 1) symptomatic paroxysmal or persistent AF with at least two symptomatic episodes in the month preceding implant on a stable antiarrhythmic drug and/or atrioventricular nodal blocking agent (or no drugs) and at least one episode in the 12 weeks preceding implant documented by electrocardiogram (ECG) or rhythm strip; 2) sinus node dysfunction with a 1998 American College of Cardiology/American Heart Association class 1 bradycardia indication for a dual-chamber pacemaker (5); and 3) written informed consent for participation and willingness and ability to comply with follow-up testing and evaluation procedures. The protocol was reviewed and approved by the institutional review board of each participating center. The principal exclusion criteria were presence of another arrhythmia control device, cardiac surgery in the last six months, or expected cardiac surgery during the six-month study period.
Atrial fibrillation was defined as a minimum of 30 s of continuous irregular ECG baseline with no discrete P waves and variable R-R intervals. Paroxysmal AF was defined as an episode of AF that terminates spontaneously. Persistent AF was defined as that which required cardioversion to restore normal sinus or paced atrial rhythm after at least 24 h of continuous arrhythmia.
Patient history, implantation, and follow-up
Pre-implant assessment consisted of medical history, physical examination, 12-lead ECG and quality of life assessment. Randomization was conducted via sequentially numbered sealed envelopes that were distributed to and maintained by each investigational center. Each envelope was opened sequentially, and contained the patient's treatment assignment.
All patients received a Trilogy DR+/DAO (model 2360L or 2364L) or an Integrity AFx (model 5346) pacemaker (St. Jude Medical, Cardiac Rhythm Management Division) combined with existing or newly implanted market-approved bipolar atrial and ventricular pacing leads. Devices were programmed to DDDR pacing with a base rate of 60 ppm randomized to the AF Suppression Algorithm on (treatment group) or off (control group). The algorithm increased the pacing rate when two intrinsic atrial events were detected within 16 cycles. Four discrete programmable algorithm components controlled the overdrive pacing rate, the duration of overdrive pacing, and the rate at which the pacing rate decreases after an episode of overdrive pacing. The lower rate overdrive (LRO) defined the number of beats/min that the algorithm increased the pacing rate if the intrinsic rate was between 45 and 59 beats/min. Upper rate overdrive (URO) determined the number of beats/min that the algorithm increased the paced rate when the intrinsic rate exceeded 150 beats/min. The increase in overdrive rate between LRO and URO was based on a sliding scale between these two. Once stable pacing was achieved, the system continued to pace at the overdrive rate for a programmable number of cycles. If, during a period of overdrive pacing, additional intrinsic P waves were detected, the algorithm increased the pacing rate again. If no intrinsic P waves were detected during the overdrive pacing period, the algorithm progressively extended the interval between successive atrial paced complexes, gradually slowing the effective pacing rate to either the programmed base rate or the sensor-defined rate. The recovery rate was the fourth parameter in the algorithm. It defined the cycle length increase on successive cycles. Two values were provided, separated by a colon. The first and second values identified the millisecond increase in cycle length, when the pacing rate was above and below 100 ppm, respectively. Programming of these components was stipulated for patients in the treatment group.
Before hospital discharge, each patient received a cardiac event recorder (Card Guard model 2206 or equivalent; Card Guard Scientific Survival, Rehovot, Israel) and was instructed in its use. Patients were asked to record every symptomatic episode during the six months following pacemaker implantation. Follow-up visits were scheduled for 30 days, 90 days, 6 months, 9 months, and 12 months post-implant, and every 6 months thereafter. In addition to standard pacemaker follow-up procedures, the following data were collected: 1) SF-36 Health Survey: patients were asked to complete the questionnaire before interacting with healthcare personnel; 2) pacemaker diagnostic data, including the percentage of atrial paced beats; 3) antiarrhythmic drug therapy at implant and changes during follow-up; and 4) information regarding hospitalizations and cardioversions.
ECG collection and classification
Electrocardiograms collected from patient-initiated cardiac event recordings of symptomatic episodes constituted the entire record of AF episodes in the study. Patients were instructed to transmit ECGs via telephone to a central receiving center. Two cardiac electrophysiologists reviewed and classified each rhythm. The reviewers were blinded to therapy and classified the rhythms independently. Periodic meetings were held to resolve any disagreements. A third cardiologist participated in the review and discussion of any classification discrepancies between the two primary readers.
The primary end points of the study were symptomatic AF burden and adverse events. Atrial fibrillation burden was defined as the total number of AF days divided by the cumulative follow-up days. An AF day was one during which a patient transmitted a recording classified as AF. Atrial fibrillation burden was chosen (rather than time to first symptomatic AF episode or time between AF episodes) because it provides information about the frequency of symptomatic AF during the entire follow-up period. Episodes were documented by event recorders. The number and duration of the mode-switch episodes were not utilized as end points in this study because of a lack of direct ECG correlation with the reported mode-switch episodes precluding accurate identification of atrial fibrillation episodes. Secondary end points included the number of symptomatic AF episodes, hospitalizations, cardioversions, and quality of life.
Statistical calculations were made using the SAS (SAS Institute Inc., Cary, North Carolina), S-Plus (S-Plus Insightful Corporation, Seattle, Washington), and BUGS (MRC Biostatistics Unit, Cambridge, United Kingdom) statistical packages, and all analyses were based on an intention to treat principle. The sample size was based on determining whether, during the first six months of follow-up, patients treated with DDDR pacing with the algorithm on would have at least a 30% decrease in AF episodes versus patients treated with DDDR pacing alone. The log likelihood test using Poisson distribution resulted in 104 patients per arm at 5% significance level and 80% statistical power. Therefore, analysis of secondary end points may lack the requisite statistical power to detect differences between the treatment groups.
Homogeneity of the treatment groups was assessed by comparing demographic and baseline characteristics, with continuous variables summarized by their mean, standard deviation, minimum and maximum, and categorical variables summarized through frequency or percent. The primary efficacy end point was analyzed using the statistical method for extended generalized linear models based on a binomial specification (6). The statistical analysis of overall improvement of the treatment was based on the data collected at the time points of 30 days, 90 days, and 6 months when patients were scheduled for follow-up visits. By using these time points, direct correlations could be made to secondary end points (i.e., quality of life). Other end points including number of AF episodes, hospitalization, cardioversion, adverse events, and automatic mode switching were also analyzed. For continuous variables, comparisons were evaluated for significance with the use of the Wilcox rank-sum test. For categorical end points, a chi-square test was used to compare the two treatment groups. Survival was evaluated by the Kaplan-Meier method along with the log-rank test.
A total of 319 patients (163 men and 156 women) with a mean age of 71.3 ± 9.9 years were enrolled in the study and completed 6 months follow-up. Of these, 288 (158 control and 130 treatment) were included in the analysis. Reasons for not including patients were all prospective and included 26 whose devices were programmed incorrectly at implant, 4 who were unable to demonstrate ability to use the event recorder by recording a baseline ECG, and 1 in whom the investigator could not implant the atrial lead.
There were no significant differences in baseline characteristics between the treatment group and the control group (Table 1). Antiarrhythmic drugs used in both groups were similar at baseline and during follow-up (Table 2and Table 3). Based on pacemaker diagnostic data, the treatment group experienced a significantly higher percentage of atrial pacing (mean of 92.9% vs. 67.9%; p < 0.0001). Lead function (sensing, impedance, and pacing thresholds were similar in both groups. Overall, the total patient population experienced 2,412 episodes of symptomatic atrial arrhythmias during follow-up; 2,180 (90.4%) classified as AF, 110 (4.6%) as atrial flutter, and 122 (5%) as atrial tachycardia.
The AF Suppression Algorithm reduced symptomatic AF burden from 2.50% in the control group to 1.87% in the treatment group, a relative difference of 25%. Atrial fibrillation burden decreased progressively during the course of the follow-up period (Fig. 1) in both groups but was lower in the group with the AF Suppression Algorithm on (p = 0.005) at each follow-up visit. The burden of symptomatic atrial arrhythmias (defined as AF, atrial flutter, and atrial tachyarrhythmias) was reduced by 26.5%, from 2.6% in the control group to 1.9% in the treatment group, and also decreased progressively over time (p = 0.008).
Secondary end points
Symptomatic episodes of AF occurred in 81 patients in the control group and 73 patients in the treatment group (p = NS). The treatment group required 63% fewer cardioversions post-implant (13 vs. 4), although the difference was not significant (p = 0.0925). The difference in hospitalizations between treatment and control groups in hospitalizations (15 vs. 17, respectively) was also not significant (p = 0.8439). Before randomization, patients were asked to recall the number of AF episodes they had experienced in the six months prior to enrollment. The mean number of AF episodes during that time was similar in both groups (8.0 ± 4.2 treatment vs. 8.3 ± 4.1 control; p = NS). During six months follow-up, the mean number of symptomatic AF episodes in the control and treatment groups was 4.3 ± 11.5 and 3.2 ± 8.6, respectively (p = NS). In both groups, the decrease in symptomatic AF frequency was significant (p = 0.0001).
In general, quality of life scores improved during follow-up (Table 4) in both patient groups. In comparison to values at implant (within group), the control group exhibited significant improvement during follow-up in five of the eight subscales and in the standardized mental component scales. The treatment group exhibited significant improvement during follow-up in four of eight subscales and both the standardized physical and mental component scales. The only statistically significant difference between the control and treatment groups was a higher social function score in the treatment group at six months.
The incidence of complications, observations or other reported events was not significantly different between the treatment and control groups. Lead dislodgment occurred in seven control and six treatment patients. Pneumothorax occurred in one control and one treatment patient. Myocardial perforation and system infection occurred in one treatment patient each. The only observation specifically related to the algorithm was intolerance to high rate pacing in three patients. There was no difference in the number of deaths in the treatment and control groups (5 vs. 1, respectively, p = 0.11). One patient in both the treatment and control groups died of heart failure. The remaining deaths were due to cardiac arrest, respiratory failure, shock (of undetermined etiology), and unknown cause.
Automatic mode switching
The duration of automatic mode switching was similar in the control and treatment groups at each follow up visit (Table 5) and for the duration of follow up (1,112 h vs. 1,209 h, respectively, p = NS). Automatic mode switching is not specific for AF because it may occur after a few premature atrial beats or as the result of far field R-wave sensing. Furthermore, automatic mode switching can occur multiple times during a single episode of AF and is dependent on pacemaker programming that was not controlled for in this study. Because the trial focused on symptomatic AF and because of the nonspecific nature of automatic mode switching, the latter was not included as an end point in this trial. Using prospectively defined rules to minimize inappropriate automatic mode switching occurrences (eliminating automatic mode switch events that were <1 min in duration and those in which the peak filtered atrial rate were at or slightly above the atrial tachycardia detection rate) the mean number of automatic mode switches/day was 2.5 in the treatment group and 4.8 in the control group (p = 0.14).
The ADOPT demonstrated that overdrive atrial pacing with the AF Suppression Algorithm decreases symptomatic AF burden in patients with sick sinus syndrome and paroxysmal AF. The study inclusion requirements (two symptomatic episodes during the month prior to implant with one episode documented by ECG or rhythm strip) were similar to those utilized in studies of drugs used to suppress AF and were used to ensure a sufficient frequency of the arrhythmia during follow-up to compare treatment and control groups appropriately.
Development of a pacemaker algorithm to suppress AF was based on experimental and clinical experience, suggesting that atrial pacing offers a protective effect when compared with ventricular pacing. In previous retrospective and prospective studies of patients with sinus node dysfunction, atrial-based pacing (AAI or DDD) has been associated with a lower incidence of AF (3,7–10). Subsequent studies revealed that atrial overdrive pacing was likely to be responsible for the protective effect of pacing (11–13). Atrial overdrive pacing appears to address the fundamental mechanisms believed to give rise to AF, effectively controlling both rate and rhythm. Sufficiently rapid atrial pacing can eliminate the pauses following ectopic beats, overdrive ectopy, and reduce the dispersion of refractoriness that are thought to set the stage for AF.
Despite these reported effects, the evidence that atrial overdrive pacing decreases AF has been equivocal. A pilot study demonstrated that overdrive atrial pacing reduced atrial ectopy but was underpowered to detect a difference in AF (14). In recent studies, mode switch episodes and measures of functional status were similar in patients treated consecutively with standard pacing and overdrive pacing (15–17). Design differences between these studies and the current study may account for differences in outcomes. The sample sizes, the primary end point (mode switch episodes), the lower percentage of paced beats, the use of continuous high rate overdrive pacing in one study, and a relatively short crossover study design may have obscured beneficial effects of atrial overdrive pacing in these trials. Despite differences in study design, preliminary results from the Consistent Atrial Pacing (CAP) and the Prevention by Overdriving (PROVE) trials indicated that overdrive pacing reduced the frequency of AF (18,19).
The results of the current study are consistent with previous studies showing that conventional atrial pacing (without overdrive suppression) prevents AF in patients with sick sinus syndrome (3,4). Symptomatic AF burden decreased, AF episodes occurred less frequently, and several quality of life measures improved in both groups. Furthermore, ADOPT is the first study to show that symptomatic AF burden decreases progressively over time with dual-chamber pacing. The reason for this is unknown but it is consistent with the hypothesis that pacing or decreasing AF burden affects the atrial substrate that is responsible for the arrhythmia.
Whereas standard DDDR pacing decreased the frequency of AF, the AF Suppression Algorithm provided additional benefit. Differences in secondary end points (cardioversions and hospitalizations) did not reach statistical significance, possibly because the study was not sufficiently powered to do so. The AF suppression algorithm was safe; there was no difference in morbidity or mortality between the two groups.
Symptomatic AF burden was chosen as the primary end point because it provides information regarding arrhythmia frequency during the entire follow-up period. Symptomatic AF episodes were used rather than mode switch episodes to enhance the specificity of the measure. Mode switching can occur for atrial arrhythmias or signals other than AF, some of which may be very brief and clinically insignificant. Whereas this method for determining AF burden may not account for all AF episodes (an individual could have more than one episode in a day), it circumvents the problem of patients who may transmit more than once during a single episode.
A potential limitation was reliance on self-reporting by patients; patients determined what constituted a symptomatic episode, used the event recorder to record the ECG, and transmitted the resulting ECG. However, this technique has been used in studies of drugs for suppression of AF and it has been shown to be effective in both a meta-analysis (20)and an experimental comparison with Holter recording (21).
The focus on symptomatic AF burden as the primary measure of the algorithm's efficacy meant that the sample size was based exclusively on detecting the reduction in symptomatic AF episodes. This limits the statistical power of the secondary analyses. This study was not powered sufficiently to permit any assessment of the impact of the AF Suppression Algorithm on the incidence of hospitalizations or cardioversions in this patient population.
The prospectively defined requirement that pacemakers be programmed appropriately resulted in the exclusion of 26 patients from the trial, most of whom were in the treatment group. We cannot exclude the possibility that the exclusion of these patients increased or decreased the observed treatment effect.
Whereas the absolute AF burden reduction (2.50% to 1.87%) is small, it represents a relative reduction of 25% and it occurred despite a decrease in AF frequency that occurred in both the treatment and the control groups. The reduction in AF frequency in the control group and the incremental reduction in the treatment group are similar to those reported for drug therapy to suppress AF. Furthermore, the reduction occurred in patients, many of whom were receiving antiarrhythmic drugs.
The ADOPT demonstrates that the AF Suppression Algorithm is safe and effective in patients with symptomatic AF and sick sinus syndrome. Given the apparent safety of the algorithm as it was programmed in the ADOPT and because it is an incremental therapy that can be programmed on or off in patients who are receiving a pacemaker for another reason, this therapy offers an attractive option for patients with the sick sinus syndrome and AF. The application of this algorithm to other patient populations requires further studies. This trial supports the concept that atrial repolarization alters development of AF (Appendix).
The authors express their appreciation to Paul Levine, MD, for his editorial assistance.
Other investigators of the ADOPT study are as follows: Islam Bolad, Harefield Hospital, Middlesex, United Kingdom; Gabriel Breur, Palm Beach Gardens Medical Center, Palm Beach Gardens, Florida; Hugh Calkins, Johns Hopkins Hospital, Baltimore, Maryland; Luis Constantin, Lehigh Valley Hospital, Allentown, Pennsylvania; Paul Dorian, St. Michael's, Toronto, Canada; Chris Fellows, Virginia Mason Clinic, Seattle, Washington; Michael Gammage, Queen Elizabeth Hospital, Birmingham, United Kingdom; Eli Gang, Cardiovascular Medical Group of Southern California, Beverly Hills, California; Michael Gold, University of Maryland, Baltimore, Maryland; Yisachar Greenberg, Maimonides Medical Center, Brooklyn, New York; Steven Greer, Arkansas Cardiology Clinic, Little Rock, Arkansas; Sajad Gulamhusein, Capital Health, Edmonton, Canada; Mark Harvey, Oklahoma Foundation for Cardiovascular Research, Oklahoma City, Oklahoma; Steven Klein, Moses Cone Memorial Hospital, Greensboro, North Carolina; Ching Lau, Sunnybrook Health Science Center, Toronto, Canada; Richard Leather, Victoria Heart Institute, Victoria, Canada; Charles Love, Ohio State University Medical Center, Columbus, Ohio; John Mandrola, Baptist Hospital East, Louisville, Kentucky; Frank McGrew III, Stern Cardiovascular Center, Memphis, Tennessee; John McKenzie III, Heart Institute of Glendale, Glendale, California; Pascal Patrick McKeown, Royal Victoria Hospital, Belfast, North Ireland; Stephen Prater, Atlanta Cardiology Group, Atlanta, Georgia; Russell Reeves, Cardiovascular Associates, Birmingham, Alabama; Mark Rosenthal, Abington Memorial Hospital, Abington, Pennsylvania; Anthony Tang; University of Ottawa Heart Institute, Ottawa, Canada; Bernard Thibault, Montreal Heart Institute, Montreal, Canada; Anthony Turi, St. Peter's Hospital, Albany, New York; Mark Wathen, Vanderbilt University Medical Center, Nashville, Tennessee; Steve Winters, Morristown Memorial, Morristown, New Jersey; Seth Worley, Lancaster Heart Group, Lancaster, Pennsylvania.
☆ This trial was supported by St. Jude Medical Cardiac Rhythm Management Division.
- Atrial Dynamic Overdrive Pacing Trial
- atrial fibrillation
- lower rate overdrive
- upper rate overdrive
- Received January 3, 2003.
- Revision received February 24, 2003.
- Accepted March 12, 2003.
- American College of Cardiology Foundation
- ↵Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults. National implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001; 2370–5
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