Effects of Right Atrial Pacing Preference in Prevention of Paroxysmal Atrial Fibrillation

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1 Circ J 2008; 72: Effects of Right Atrial Pacing Preference in Prevention of Paroxysmal Atrial Fibrillation Atrial Pacing Preference Study (APP Study) Hideyuki Ogawa, MD; Toshiyuki Ishikawa, MD; Kouhei Matsushita, MD; Katsumi Matsumoto, MD; Tomoaki Ishigami, MD; Teruyasu Sugano, MD; Kazuaki Uchino, MD; Satoshi Umemura, MD; Shinichi Sumita, MD*; Kazuo Kimura, MD*; Takeshi Nakagawa, MD**; Makoto Shimizu, MD ; Hideo Nishikawa, MD ; Atsunobu Kasai, MD ; Yukio Kioka, MD Background Several preliminary studies have indicated that atrial pacing can prevent atrial tachyarrhythmias. The suggested mechanisms by which pacing may be effective include suppression of premature atrial beats. Methods and Results The Atrial Pacing Preference (APP; Guidant, St Paul, MN, USA) algorithm allows the pacemaker to maintain a pacing rate slightly higher than the sinus rate. The preventive effects of APP on paroxysmal atrial fibrillation (AF) were studied in 51 patients (70±11 years). Nine patients did not complete the protocol. The pacemaker was programmed in random order to APP off and APP on at 3 different settings (ie, 8, 16 and 32 cycles) for 4 weeks each, using a cross-over design. Percentage atrial pacing was lower in APP off than at the other settings. Premature beat counts were greater in APP off than at the other settings. There was a significant difference in mode switch episode counts between APP off and the most effective setting (3,818±15,356 vs 596±1,719; p<0.01). Conclusions The APP algorithm is a promising method for preventing atrial tachyarrhythmia in patients with an implanted pacemaker and AF. Optimizing the setting of the APP algorithm is an important issue in the prevention of AF. (Circ J 2008; 72: ) Key Words: Atrial fibrillation; Overdrive pacing; Pacemaker; Pacemaker algorithm Atrial fibrillation (AF) occurs as a result of various mechanisms. 1 The initiating mechanisms of AF are considered to be bradycardia, that is, premature atrial contraction (PAC). Pharmacological treatment by class I or III antiarrhythmic drugs is usually effective. 2 3 Nonetheless, some patients are refractory to antiarrhythmic agents. Atrial pacing has been shown to prevent paroxysmal AF. 4 7 Overdrive atrial pacing is thought to prevent AF triggered by bradycardia and premature atrial beats. The Atrial Pacing Preference (APP; Guidant, St Paul, MN, USA) algorithm allows the pacemaker to maintain a pacing rate slightly higher than the sinus rate. However, the efficacy and optimal setting of APP are unclear. The present multicenter study evaluates the efficacy of APP for the prevention of AF and the importance of optimal APP search interval setting in (Received July 22, 2007; revised manuscript received November 19, 2007; accepted December 11, 2007) Division of Cardiology, Yokohama City University Hospital, *Division of Cardiology, Yokohama City University School Medical Center, **Division of Cardiology, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Division of Cardiology, Yaizu City Hospital, Yaizu, Division of Cardiology, Yamada Red Cross Hospital, Ise and Division of Cardiovascular Surgery, Fukuyama City Hospital, Fukuyama, Japan Mailing address: Hideyuki Ogawa, MD, Division of Cardiology, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama , Japan. h-ogawa@fukuhp.yokohama-cu. ac.jp All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp patients with sick sinus syndrome (SSS) and AF. Methods Patient Selection The inclusion criteria were those of the American College of Cardiology/American Heart Association class I or II pacemaker indications, together with a history of paroxysmal episodes of AF. Each patient underwent implantation of 2 permanent pacing leads. RA leads were placed at the RA appendage, and RV leads were placed at the RV apex. The exclusion criteria were: presence of chronic AF, <20 years old, pregnancy, undergoing dialysis, chronic renal failure, and severe heart failure. Antiarrhythmic drug therapy remained essentially unchanged in all patients. Written informed consent was obtained from all patients. The local ethics committee approved the study. Device Characteristics All patients received a Model 1280 (Guidant) combined with bipolar atrial and ventricular pacing leads. The device features included DDDR pacing and DDIR mode switch during atrial tachyarrhythmias and APP algorithm. The APP algorithm allows the pacemaker to maintain a pacing rate slightly higher than the sinus rate. When a P- wave is detected, the next pacing interval is shortened by 8ms. When the pacing state is maintained for search intervals (ie, programmable cycles), the pacing interval is prolonged by 8 ms. The APP pacing rate is limited to the

2 Effect of Atrial Pacing Preference 701 Fig 1. Overall design of follow up. The pacemaker was programmed in random order to atrial pacing preference (APP) off (setting a) and APP with 3 different search interval settings (ie, 8 cycles for setting b, 16 cycles for setting c, and 32 cycles for setting d) for 4 weeks each, using a cross-over design. Table 1 Programmed Parameters Basic setting Mode DDD Rate response Off Lower rate 60 ppm Max pacing rate 120 ppm AV delay 150 ms Mode switching ATR start 170 ppm Entry count 3 cycles Exit count 3 cycles ATR lower rate 60 ppm Setting a Basic setting only Setting b Basic setting+app APP search interval 8 cycles Setting c Basic setting+app APP search interval 16 cycles Setting d Basic setting+app APP search interval 32 cycles AV, atrio ventricular; ATR, atrial tachycardia response; APP, atrial pacing preference. Fig 2. Comparison of percentage of atrial pacing among 4 settings. Comparing atrial pacing preference (APP) off with APP on, atrial pacing percentage was lower in APP off (setting a) than in any of the APP maximum pacing rate. When a PAC is detected, the APP algorithm does not change the V A interval. PAC was defined by a spontaneous atrial sense interval <750 ms and an adjacent atrial sense interval shortened by 25% or less. As a result, a high percentage of atrial pacing is achieved. The pacemaker Holter monitor was reset before each study period and interrogated at the end of a 1-month pacing period to assess the number and total duration of AF episodes. The pacemaker was programmed in random order to APP off (setting a) and APP on with 3 different search interval settings (ie, 8 cycles at setting b, 16 cycles at setting c, and 32 cycles at setting d) for 4 weeks each, using a cross-over design. The overall design is shown in Fig 1. A total of 51 patients participated. The indications for pacing were atrio-ventricular block in 4 patients, and SSS in 47 patients. The pacemaker and algorithm programming settings for the patients included in the analysis are shown in Table 1. The pacemaker was programmed in random order to either: the basic setting only (setting a); the basic setting+app search interval for 8 cycles (setting b); the basic setting+app search interval 16 cycles (setting c); or the basic setting+app search interval for 32 cycles (setting d), using a cross-over design. Atrial tachyarrhythmia response (ATR) is a system to change from DDD to DDI mode. Clinical evaluation items were atrial pacing percentage, number of PAC, and ATR total time. APP on settings (ie, settings b, c and d) (45.6±30.7 vs 86.8±16.7, p< 0.01; 86.6±20.3, p<0.01; 86.2±21.3, p<0.01 for each setting, respectively). Statistical Analysis Baseline descriptive statistical data are presented as the mean ± SD. Differences between groups were evaluated using Friedman or non-parametric tests, Wilcoxon or Mann Whitney s U-test. Results Forty-two patients completed the 5-month follow up (mean age, 70±11 years; 17 men). Nine patients did not complete the protocol. The reasons for withdrawal from the study were persistent AF in 4 cases, far-field sensing in 4 cases, and 1 patient decided to discontinue. No major adverse clinical events were observed. Antiarrhythmic therapy included sodium channel blockers in 13 patients, potassium channel blockers in 5 patients, -blocking agents in 4 patients, calcium channel blockers in 2 patients, and digitalis in 7 patients. Comparing APP off with APP on, atrial pacing percentage was lower in APP off (setting a) than in the APP on settings (ie, settings b, c and d) (45.6±30.7 vs 86.8±16.7, p<0.01; 86.6±20.3, p<0.01; 86.2±21.3, p<0.01 for each setting, respectively; Fig 2). Ventricular pacing percentage was 88% in setting a, and more than 94% in each of settings b, c, and d. There was no

3 702 OGAWA H et al. Fig 3. Comparison of number of premature atrial contraction among 4 settings. Premature beat counts were greater in atrial pacing preference (APP) off (setting a) than in the APP on settings (ie, settings b, c and d) (72,034±157,237 vs 40,507±89,714, p<0.01; 39,363±99,668, p<0.01; 41,380±104,381, p<0.01 for each setting, respectively). Fig 5. Comparison of atrial tachyarrhythmia response total time among 4 settings. There was no significant difference in total duration of atrial tachyarrythmia between atrial pacing preference (APP) on and APP off (setting a: 2,373±6,083; setting b: 1,855±3,893; setting c: 1,960±4,070; setting d: 2,164±4,622). Fig 4. Comparison of number of atrial tachyarrhythmia response among 4 settings. The number of atrial tachyarrythmias tended to be reduced by atrial pacing preference on, but the reduction did not reach statistical significance (setting a: 3,720±15,006; setting b: 1,382±3,823; setting c: 1,653±3,564; setting d: 1,644±3,926). Fig 6. Comparison of atrial tachyarrhythmia response total time between atrial pacing preference (APP) off and the most effective setting. There was a significant difference in mode switch episode counts between APP off and the most effective setting (3,818±15,356 vs 596±1,719; p<0.01). significant difference of ventricular pacing percentage in each setting. Premature beat counts were greater in APP off (setting a) than in each of the APP on settings (ie, settings b, c and d) (72,034±157,237 vs 40,507±89,714, p<0.01; 39,363±99,668, p<0.01; 41,380±104,381, p<0.01 for each setting, respectively; Fig 3). The number of atrial tachyarrythmias tended to be reduced by APP on, but the reduction did not reach statistical significance (Fig 4). Similarly, no significant difference in total duration of atrial tachyarrythmia was found between APP on and APP off (Fig5). ATR total time was not reduced significantly in the AVB cases. The prevalence of AF tended to be higher in patients with SSS than in those with AVB. 8 But it should be noted that the number of patients with AVB was only 4 in the present study; hence, we cant verify whether the tendency is caused by the difference between SSS and AVB. Discussion We considered that the optimal APP search interval setting would be different for each patient. We compared APP off with the most effective APP search interval setting. There was a significant difference in mode switch episode counts between APP off and the most effective setting (3,818±15,356 vs 596±1,719, p<0.01; Fig 6). ATR total time corresponds approximately to AF burden. However, ATR is not specific for AF because it may occur after a few premature atrial beats or as the result of far-field sensing (Fig 7). Therefore, all recordings from the event recorders were analyzed manually. We examined electrograms and ruled out ATR events by far-field sensing. AF is associated with significant morbidity and mortality. It is found to be a risk factor for death independent of other cardiovascular conditions. 9 There are several mechanisms for the development of AF. 1 The Pacemaker Selection in the Elderly (PASE) trial has reported that AF is not affected significantly by pacing mode or the indication for pacing (SSS vs atrioventricular block). 10 In contrast, the Canadian Trial of Physiological Pacing (CTOPP) showed a significant reduction in AF with physiological pacing. 11 The differences in outcome between these studies might be attributable to differences in design. Atrial pacing could reduce AF by pre-

4 Effect of Atrial Pacing Preference 703 Fig 7. Detectable deflections of ventricular far-field signal in atrial channel after a paced ventricular event. AP, atrial pace; AS, atrial sense; VP, ventricular pace. venting the changes in refractoriness caused by pauses or bradycardia, reducing intra-atrial conduction time, reducing dispersion of atrial refractoriness or reducing atrial ectopy. The results of many prospective and retrospective studies have shown significant antiarrhythmic effects Nonetheless, some patients require relatively faster atrial pacing at a rate of 90beats/min, which may be poorly tolerated on a long-term basis Basic rate programming does not usually allow atrial pacing percentages higher than 80%. 24 When a preventive effect on AF is expected by overdrive pacing, a high pacing percentage is needed. The role of a true overdrive atrial pacing algorithm was first evaluated by Murgatroyd et al, who found that the APP algorithm provides additional benefit. 7 This algorithm allows the pacemaker to maintain a pacing rate slightly higher than the sinus rate. As a result, a high percentage of atrial pacing is achieved. The APP algorithm has been developed to perform continuous atrial overdrive pacing so that pacing percentages greater than 85% can be obtained. A high percentage of atrial pacing is important to produce a clinical effect. No major adverse effects were observed. In the current study, the total duration of atrial tachyarrythmia tended to be reduced by APP, but the reduction did not reach statistical significance during 4 settings (ie, APP off and APP on with 3 different search intervals). We hypothesized that the optimal APP search interval setting was different for each patient, and then compared APP off with the most effective search interval setting in each individual. The total duration of atrial tachyarrythmia was reduced significantly by the most effective APP search interval setting. It is not yet apparent as to how to decide the optimal overdrive setting. The arrival time interval to basic sinus rate may be different for each person. The APP search interval setting may influence the effect of APP, so the most effective APP search interval setting should be selected. Conclusions The results of this prospective clinical trial show that the APP algorithm is safe in patients with paroxysmal AF. The APP algorithm is a promising method for preventing atrial tachyarrhythmia in patients with an implanted pacemaker and AF. The optimal APP search interval setting is an important issue in the prevention of AF. References 1. Waldo AL. Mechanisms of atrial fibrillation. J Cardiovasc Electrophysiol 2003; 14(Suppl): S267 S274 (review). 2. Miyaji K, Tada H, Kusano K, Hashimoto T, Kaseno K, Hiramatsu S, et al. 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