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The Role of Pacing in the Management of
Paroxysmal Atrial Fibrillation

Paul A. Levine, MD

St. Jude Medical CRMD, Sylmar and Loma Linda University School of Medicine,
CA, USA

INTRODUCTION
   Atrial fibrillation (AF) is the most common significant cardiac arrhythmia, affecting an estimated four million people worldwide. Its rapid and uncoordinated atrial rhythm significantly compromises hemodynamics, decreases cardiac output, predisposes to ventricular arrhythmias, and sets the stage for thromboembolic complications. Contributing mechanisms are presumed to be the occurrence of long-short cycles, an increased temporal dispersion of refractoriness, and atrial ectopic activity. Its incidence increases with age, affecting 4% of those over 60, and up to 15% of those over 70.(1,2) Although it can occur in the absence of other conditions ("lone" AF), it is most often associated with a number of complicating conditions, including hypertension, organic heart disease, coronary artery disease and others.

   While the natural history of atrial fibrillation has not been conclusively established, it appears to start with brief paroxysmal episodes that are self-terminating. The next stage is persistent and more prolonged episodes that require intervention to terminate. Finally a chronic stage develops where attempts to terminate the rhythm and restore normal sinus rhythm are essentially abandoned in favor of controlling the resulting ventricular rate and managing other consequences (3).

   The health care costs associated with this arrhythmia are enormous. It has been reported to account for one-third of hospital days for all patient discharges where arrhythmia was the primary diagnosis (4), with an estimated cost of over $1 billion annually in the United States alone.

   Historically, because of the absence of truly curative interventions and the risks and costs associated with repeated cardioversion, therapy has focused on management of the arrhythmia's consequences. Primary among these have been ventricular rate control, anticoagulation therapy and, where feasible, pharmacologic agents in an effort to maintain sinus rhythm. Pharmacologic therapies have been widely used with varying degrees of success. According to the American Heart Association, several drugs effectively restore and maintain sinus rhythm in patients with AF but usually in the range of 30-45%. However, to date, little data is available to confirm the superiority of one particular drug over another for this purpose except for Amiodarone which is associated with potentially significant side effects and the recently available Dofetilide. Agents, such as digitalis, verapamil, diltiazem, and b-adrenergic blockers may be useful during AF to decrease the ventricular response that occurs over the atrioventricular (AV) node. They rarely terminate AF. (5) In addition, various ablative and surgical techniques have been employed to restore and maintain sinus rhythm but with varying degrees of success. These techniques continue to mature.

PACING AND ATRIAL FIBRILLATION PREVENTION
   A subset of patients with paroxysmal AF is the bradycardia-tachycardia syndrome which commonly warrants bradycardia pacing. A considerable body of research, both retrospective and prospective, has examined the effects of pacing on this arrhythmia. Some of the early pertinent research initially focused on the long-term results of single-chamber ventricular vs. atrial or dual-chamber pacing. Sasaki (6) reported on 103 patients with sick sinus syndrome, divided into unpaced, ventricular paced and physiologically (atrial or dual chamber) paced groups. The VVI group exhibited significantly more complications overall than the physiologically paced group; chief problems were AF in 36% and thromboembolism in 20%. Stangl (7) reported on 222 patients with sick sinus syndrome; 110 received AAI pacing, and 112 VVI pacing. The incidence of chronic AF was over three times higher in the VVI group. Feuer (8) reported on 220 patients paced for sinus node disease and AV block; half were VVI-paced, and half were DDD/DDI paced. Again, AF developed more frequently in the VVI group. The authors suggested that both preservation of AV synchrony and electrical stabilization of the sinus node and atrium might account for the apparently protective effect of dual-chamber pacing. Reporting on a larger group (950 patients) of pacemaker recipients followed for up to eight years, Hesselson (9) found chronic AF developed significantly more frequent in the VVI group (80%) than in the DDD and DVI-paced patients (10%) over an 8 year follow-up period. More recently, these findings were confirmed by Andersen (10) in the first prospective randomized trial comparing AAI to VVI, confirmed the apparent protective effect of atrial pacing on the subsequent development of AF: cumulative indices of both paroxysmal AF and chronic AF were significantly lower in the atrially paced group. This was only demonstrable after a follow-up period of 5+ years. A prospective multicenter randomized trial in the United States (11), the Pacing Mode Selection in the Elderly (PASE) trial was focused on quality of life. One of the secondary endpoints was the incidence of atrial fibrillation and while the study demonstrated a trend favoring dual chamber pacing over VVI pacing with respect to the incidence of atrial fibrillation, this did not reach statistical significance. It should be noted that the mean follow-up was less than 2 years and the programmed base rate was usually 50 ppm. A second multicenter randomized trial, the Canadian Trial on Physiologic Pacing (CTOPP) (12) involved thousands of patients. Although the development of atrial fibrillation was not one of the primary endpoints, there was a statistically significant reduction in the incidence of atrial fibrillation with DDDR pacing as compared to VVIR pacing after 4 years of follow-up with an 18% reduction in the risk of atrial fibrillation.

   As this pattern emerged, investigators examined the characteristics of atrial pacing more closely, and overdrive appears to be a likely mechanism, particularly in the setting of an underlying bradycardia. However, even when an underlying bradycardia was not present, a beneficial effect of pacing has been suggested. Ragonese (13) examined a small group of pacemaker recipients who had surgical repair of complex congenital heart disease and atrial reentrant tachycardias unresponsive to conventional therapy. Pacemakers were specifically programmed to a rate 20% higher than the mean intrinsic rate previously determined via Holter recording. Eighty-three percent of the patients were arrhythmia-free at the end of the study. Stabile (14) found that atrial pacing markedly reduced AF using DDDR pacemakers programmed to a lower rate of 75 min-1, with rate response parameters programmed to help assure continuous pacing by having the paced rate always faster than the underlying sinus rate. Garrigue (15) also evaluated atrial overdrive in 22 patients with DDD pacemakers, and found no atrial arrhythmias in 14, and a reduction in the number and duration of arrhythmias in the remaining eight compared to the baseline studies.

   Others have used a variety of overdrive algorithms that are self-adjusting but usually limited to some degree. There has been variable success. In one recently published study, the percent atrial pacing increased from 60% to 72% but there was no significant difference in the number of mode switch episodes being used as the marker for the incidence of paroxysmal atrial fibrillation (16).

   Continuing clinical research and technological evolution have produced still other device-based technologies in an attempt to control AF. The atrial defibrillator (17) has been studied, as has bi-atrial pacing (18) and multi-site atrial pacing (19-21) from two right atrial foci. The excellent results reported by Saksena and colleagues with respect to dual-site atrial pacing has not been able to be reproduced by others (22). While one or more of these newer approaches may prove practical, they are problematic at present:. Internal atrial defibrillation is uncomfortable for patients who are, after all, not experiencing a life-threatening arrhythmia and treats but does not prevent the atrial fibrillation. Multi-site pacing requires significantly more hardware, pulse generator adaptation and is far more complex than a standard implant. Further, support for the role of atrial resynchronization comes from two acute studies (23,24) that studied post-op open heart patients. These patients are likely to have a different electrophysiologic mechanism for their atrial fibrillation than individuals with sinus node dysfunction. Recent work by Padeletti and colleagues (25) provides additional support to the concept that site of activation and resulting activation sequence is important, even without special overdrive algorithms although with special algorithms, the results may be even better.

   By controlling the proposed mechanisms responsible for AF (long-short cycles, increased temporal dispersion of refractoriness, frequent atrial ectopic beats), the combination of overdrive pacing in conjunction with factors controlling the activation sequence appears to be a promising technique to postpone if not totally prevent the development of chronic AF. The reduction in the incidence of paroxysmal atrial fibrillation is a valuable endpoint. However, sustained pacing at a high base rate without allowing for the normal circadian variation and slowing in the heart rate may have adverse hemodynamic consequences as suggested by Chew and colleagues (26).

   If one carefully examines Holter monitor studies in a patients with normal heart rates, the mean resting heart rate during the daytime is in the range of 80 bpm while the normal circadian rhythm variation results in a nighttime rate approximately 60 bpm. In that many patients are bothered by a persistent relatively high rate even if this is effective in suppressing atrial fibrillation, there have been two studies specifically evaluating the combination of a high daytime base rate combined with a lower nighttime rest rate. Programming requires a rest rate algorithm that is based on sensor activity so that it both automatically and dynamically adjusts the rate based on a surrogate for rest. The PROVE study (27) sponsored by ELA Medical studied 25 patients and demonstrated a trend towards a lower incidence of paroxysmal atrial fibrillation but did not reach statistical significance. The Circadian Overdrive Pacing (COP) (28) trial sponsored by St. Jude Medical compared a number of different settings comparing a higher base rate / rest rate combination to fixed rates. The combination of a base rate of 80, rest rate of 65 reduced the incidence of mode switch episodes by 50% which was significant at the p < 0.05 level.

   The Dynamic Atrial Overdrive (DAO) algorithm was developed which would allow for the normal circadian variation while still providing overdrive using the intrinsic atrial rhythm as the guide for the overdrive rate (29). If the rhythm were totally under the control of the pacemaker (sensor based), the rate could still fluctuation in a manner similar to circadian variation using the dynamic adjustment of the rest rate based on relative sensor activity (30,31). Increases in atrial paced rate would be based on a relative increase in native atrial activity which could be either sinus or APBs. To minimize frequent fluctuations, at least two native events had to be detected within a 16 cycle window as an increase in atrial ectopy is often demonstrated as preceding the development of atrial fibrillation. The DAO was subjected to a prospective multicenter randomized trial comparing the effects of DAO added to standard DDDR pacing to that of standard DDDR pacing. All subjects required pacing support for the bradycardia tachycardia syndrome with documented recurrent episodes of paroxysmal atrial fibrillation prior to the device implantation. Over 399 patients were enrolled with the study being completed in December, 2000. The results have been presented at the Late Breaking Clinical Trials session at NASPE (May 5, 2001). The endpoint was atrial fibrillation burden defined as ECG documented episodes of atrial fibrillation. In fact, the definition was very conservative in that any episode of atrial fibrillation occurring during a given day was considered as "one day of atrial fibrillation." Hence, a 20 second episode was virtually equal to hours of atrial fibrillation. This would bias the results against the algorithm. All patients carried a transient arrhythmia monitor for documentation of symptomatic episodes. The results were presented based on a intention to treat analysis with the DAO group having a 25% reduction in atrial fibrillation burden compared to the group with the algorithm disabled. When the patients who had no episodes of atrial fibrillation during the first thirty days following pacemaker implantation were excluded from both groups, the group with the DAO algorithm enabled had a 35% reduction in atrial fibrillation burden than the group with the algorithm disabled.

FOLLOW-UP DOCUMENTATION:
   Assessing the effectiveness of any of these techniques must rely on the diagnostic event counters (32-36) integral to the implanted device. One must be reasonably certain that the event counter diagnostics are appropriate and are not reporting inappropriate numbers of AMS episodes due to far field R wave oversensing or failing to detect the atrial fibrillatory signals and hence, not mode switching. Other characteristics of these episodes such as duration of each episode or atrial rate which will trigger the episode and the total percentage of time that the system functioned in a nontracking as compared to a tracking mode is helpful in further assessing the effectiveness of these new algorithms. The specific capability of the diagnostic event counters varies between manufacturers and even between pacemaker models from the same manufacturers.

SUMMARY
   The role of device therapy involving special overdrive algorithms of varying complexity combined with unique sites of stimulation looks to be very promising in helping to stabilize the atrium reducing the incidence of paroxysmal atrial fibrillation and hopefully delaying the development of chronic atrial fibrillation. The underlying disease process is likely to continue. As such, pacing will be an effective but temporary therapy and not a permanent cure. The likelihood is that hybrid therapy will be required consisting of a variety of pharmacologic agents in conjunction with stimulation and even ablation therapies. Still, reducing the number and duration of paroxysmal atrial fibrillation episodes and delaying the eventual development of chronic atrial fibrillation offers major benefits to patients. Just as automatic mode switching algorithms are now considered standard therapy in all DDD[R] pacemakers, atrial fibrillation preventive algorithms are likely to be an integral component of future devices. Whether or not stimulation therapy will prove to have a primary therapeutic role in patients who do not already need a pacemaker for a symptomatic bradycardia remains fertile grounds for future study.

REFERENCES

1. Ostrander LD, Brandt RL, Kjelsberg MO et al. Electrocardiograph findings among the adult population of a total natural community, Tecumseh, Michigan. Circulation 1965; 31:888-898.

2. Kannel WB, Abbot RD, Savage DD, et al. Epidemiologic features of chronic atrial fibrillation: The Framingham study. N Engl J Med 1982; 306:1018-1022.

3
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4. Bialy D, Lehmann H, Schumacher DN, et al. Hospitalization for arrhythmias in the United States: Importance of atrial fibrillation. (abstract) J Am Coll Cardiol 1992; 19 (Supplement A):41A.

5. Prystowsky EN, Benson WD, Jr., Fuster V, et al. Management of patients with atrial fibrillation: A statement for healthcare professionals from the subcommittee on electrocardiography and electrophysiology, American Heart association. Circulation 1996; 93: 1262-1277.

6. Sasaki Y, Shimotori M, Akahane K, et al, Long-term follow-up of patients with sick sinus syndrome: A comparison of clinical aspects among unpaced, ventricular inhibited paced and physiologically paced groups, PACE 1988; 11: 1575-1583.

7. Stangl K, Seitz K, Wirtzfeld A, et al. Differences between atrial single chamber pacing (AAI) and ventricular single chamber pacing (VVI) with respect to prognosis and antiarrhythmic effect in patients with sick sinus syndrome. PACE 1990; 13:2080-2085.

8. Feuer JM, Shandling AH, Messenger JC. Influence of cardiac pacing mode on the long-term development of atrial fibrillation. Am J Cardiol 1989; 64:1376-1379.

9. Hesselson AB, Parsonnet V, Bernstein AD, et al. Deleterious effects of long-term single chamber ventricular pacing in patients with sick sinus syndrome: the hidden benefits of dual-chamber pacing. J Am Coll Cardiol 1992; 19:1542-1549.

10. Anderson HR, Nielsen JC, Thomsen PEB, et al, Long-term follow-up of patients from a randomised trial of atrial versus ventricular pacing for sick sinus syndrome, Lancet, 1997; 350: 1210-1216.

11. Lamas G, Orav EJ, Stambler BS, et al, Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared to dual-chamber pacing, New Engl J Med 1998; 338: 1097-1104.

12. Connolly SJ, Kerr CR, Gent M, et al, Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes, New Engl J Med 2000; 342: 1385-1391.

13. Ragonese P, Drago F, Guccione P, et al, Permanent overdrive atrial pacing in the chronic management of recurrent postoperative atrial reentrant tachycardia in patients with complex congenital heart disease, PACE 1997; 20: 2917-2923.

14. Stabile G, Senatore G, De Simone A, et al, Determinants of efficacy of atrial pacing in preventing atrial fibrillation recurrences, J Cardiovasc Electrophysiol 1999; 10: 2-9.

15. Garrigue S, Barold SS, Cazeau S, et al, Prevention of atrial arrhythmias during DDD pacing by atrial overdrive, PACE 1998; 21: 1751-1759.

16. Murgatroyd FD, Nitzche R, Slade AKB, et al, A new pacing algorithm for overdrive suppression of atrial fibrillation, PACE 1994; 17: 1966-1973.

17. Lau CP, Tse H, Lok N, et al, Initial clinical experience with an implantable human atrial defibrillator, PACE 1997; 20: 220-225.

18. Daubert C, Mabo P, Berder V, Arrhythmia prevention by permanent atrial resynchronization in advanced interatrial block, Eur Heart J 1990; 11: 237-242.

19. Levy T, Walker S, Rex S, Paul V, Does atrial overdrive pacing prevent paroxysmal atrial fibrillation in paced patients? International J Cardiology 2000: 75: 91-97.

20. Saksena S, Prakash A, Hill M, et al, Prevention of recurrent atrial fibrillation with chronic dual-site right atrial pacing, J Amer Coll Cardiol 1996; 28: 687-694.

21. Default P, Prakash A, Giorgberidze I, et al, The role of pacemaker therapy in the prevention of atrial fibrillation, Semin Intervent Cardiol 1997; 2: 219-225.

22. Ramdat Misier AR, Beukema WP, Oude HA, et al, Multisite atrial pacing: An option for atrial fibrillation prevention? Preliminary results of the Dutch dual-site atrial pacing for prevention of atrial fibrillation study, Amer J Cardiol 2000: 86 (suppl): 20K-24K.

23. Fan K, Lee KL, Chiu CSW, et al, Effects of biatrial pacing in prevention of postoperative atrial fibrillation after coronary artery bypass surgery, Circulation 2000; 102: 755-760.

24. Daoud EG, Dabir R, Archambeau M, et al, Randomized double-blind trial of simultaneous right and left atrial epicardial pacing for prevention of post-operative heart surgery atrial fibrillation, Circulation 2000; 102: 761-765.

25. Padeletti L, Cristina M, Michelucci A, et al, Interatrial septal pacing: A new approach to prevent recurrent atrial fibrillation, J Interventional Cardiac Electrophysiology, 1999; 3: 35-43.

26. Chew PH, Bush DE, Engel BT, et al, Overnight heart rate and cardiac function in patients with dual chamber pacemakers, PACE 1996; 19: 822-828.

27. Funck RC, Adamec R, Lurje L, et al, Atrial overdriving is beneficial in patients with atrial arrhythmias, First results of the PROVE study, PACE 2000; 23: 1891-1893.

28. De Vusser P, Mairesse GH, van Mieghem W, et al, Significant reduction in atrial fibrillation using circadian overdrive pacing at 80/65 ppm, PACE 2001; 24: 663 (abstract 498).

29. Levine PA, Sperzel J, Florio J, et al, Device management of paroxysmal atrial fibrillation using the Dynamic Atrial Overdrive algorithm, Herzschrittmacher 2000; 20: 86-95.

30. Bornzin GA, Arambula ER, Florio J, et al, Adjusting heart rate during sleep using activity variance, PACE 1994; 17: 1933-1939.

31. Levine PA, Isaeff DM, Role of sleep (rest) mode and its clinical assessment utilizing the diagnostic event counters intrinsic to the pacemaker, Herzschrittmacher 1999; 19: 53-62.

32. Levine PA, Holter and Pacemaker Diagnostics, in Aubert AE, Ector H, Stroobandt R (editors) Cardiac Pacing: A Bridge to the 21st Century, Kluwer Academic Publishers, 1994; Chpt 29: 309-324.

33. Machado C, Johnson D, Tahcker JR, Duncan JL, Pacemaker patient-triggered event recordings: accuracy, utility and cost for the pacemaker follow-up clinic, PACE 1996; 19: 1813-1818.

34. Levine PA, Markowitz T, Sanders R, Diagnostic Features of the Modern Pacemaker, in Ellenbogen K, Kay GN, Wilkoff BL (editors), Clinical Cardiac Pacing, Philadelphia, W. B. Saunders Publ, 1995; Chpt. 32: 639-655.

35. Levine PA, Bornzin GA, Hauck G, Florio J, Implementation of automatic mode switching in Pacesetter's Trilogy DR+ and Affinity DR pulse generators, Herzschr Elecktrophys 1999: 10: Suppl 1 I/46-I/57.

36. Levine PA, Isaeff DM, Wachsner R, Der nutzen der diagnostischen moglichkeiten von herschrittmachern, Herschrittmacher 1999; 19: 24-32

 

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2nd Virtual Congress of Cardiology

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Steering Committee
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Dr. Raúl Bretal
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Dr. Armando Pacher
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