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The role of pacemakers in the prevention of atrial fibrillation

The role of pacemakers in the prevention of atrial fibrillation
Author:
Rod Passman, MD, MSCE
Section Editor:
Bradley P Knight, MD, FACC
Deputy Editor:
Nisha Parikh, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Nov 22, 2019.

INTRODUCTION — The principal reason to place a pacemaker in a patient with atrial fibrillation (AF) is to treat symptomatic bradycardia. Pacing has not been shown to prevent the development of AF.

This topic will review the role of pacemakers in the prevention of AF. Brief mention will be given to implantable cardioverter defibrillators. The utility of other nonpharmacologic strategies for preventing AF is discussed separately. (See "Atrial fibrillation: Catheter ablation" and "Atrial fibrillation: Surgical ablation".)

PATIENTS WITHOUT AN INDICATION FOR A PACEMAKER — In patients with a history of atrial fibrillation (AF), pacing from one or both atria has been suggested as a means to reduce AF recurrences. There is no conclusive evidence to support the implantation of an atrial pacemaker to prevent AF in patients with a history of AF but no indication for pacing [1]. Similar to societal guidelines, we do not recommend the insertion of an atrial pacemaker for this purpose [2]. (See 'Overdrive (antitachycardia) atrial pacing' below.)

PATIENTS WITH SYMPTOMATIC BRADYCARDIA — Many patients with atrial fibrillation (AF) have sinus node dysfunction with symptomatic bradycardia requiring pacemaker placement. Moreover, antiarrhythmic drug treatment may lead to sinus or atrioventricular nodal dysfunction that may require pacing in order to permit up-titration of drug dose. The appropriate pacing modes for patients with sinus node dysfunction are discussed separately. (See "Sinus node dysfunction: Treatment", section on 'Treatment'.)

In patients who require permanent pacing, only physiologic pacing from the right atrium has been shown to prevent episodes of AF.

Physiologic pacing — The term "physiologic pacing" has historically been used to describe the maintenance of atrioventricular (AV) synchrony. For patients with non-permanent AF who require permanent pacing, we place a dual chamber pacemaker and program it to physiologic pacing, which is discussed below. Physiologic pacing results in a significantly lower rate of AF.

Sinus rhythm leads to a predictable myocardial activation sequence of different regions of the heart. This sequence optimizes cardiac output. Isolated right ventricular (RV) pacing disrupts the normal sequence of activation of the atria and ventricles in patients in normal sinus rhythm. The failure to activate the atria before the ventricles with RV pacing is termed AV dyssynchrony and may promote AF. This becomes part of the rationale for atrial pacing in patients with paroxysmal AF. In addition, RV pacing causes the RV to contract before the left ventricle (LV) and causes the septum to contract before the lateral wall of the LV, simulating the effects of left bundle branch block. This phenomenon is referred to as ventricular dyssynchrony or asynchrony and can also lead to AF. This risk can be reduced by maintaining AV synchrony (physiologic pacing) and by minimizing the amount of ventricular pacing [3]. A beneficial role of His bundle pacing in the prevention of AF or the reduction in AF burden in those with pacing indications has not yet been established [4]. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Physiologic pacing' and "Modes of cardiac pacing: Nomenclature and selection", section on 'Modes to minimize ventricular pacing'.)

Several mechanisms may contribute to the benefit of physiologic pacing in preventing AF in patients who are treated with standard dual-chamber pacing. (See "The electrocardiogram in atrial fibrillation".)

Maintenance of AV synchrony, which lowers the potential for AF by preventing the development of right atrial electrical and left atrial mechanical remodeling [5-7].

Reductions in the dispersion of refractoriness, perhaps due in part to lowering average atrial pressure and therefore stretch-related changes [8], and suppression of ectopic atrial premature beats that may initiate AF [9,10].

The potential benefit of physiologic pacing, as discussed directly above, on the development of AF has been evaluated in a number of clinical trials [11-21]. Physiologic pacing may be accomplished with atrial or AV pacing, which is also referred to as dual chamber.

A 2006 meta-analysis of randomized trials of physiologic versus ventricular pacing included 7231 patients and over 35,000 patient-years of follow-up [11]. Most patients assigned to physiologic pacing received a dual-chamber (DDD) pacemaker, and some received AAI pacing. Physiologic pacing resulted in a significantly lower rate of AF (hazard ratio 0.80, 95% CI 0.72-0.89). However, there was no significant reduction in mortality or heart failure. Other trials not included in the meta-analysis have come to similar conclusions [16].

Impact of site and rate of atrial pacing — The impact of the site of atrial pacing was evaluated in the SAFE study of 385 patients with paroxysmal AF and sinus node dysfunction with an indication for long-term pacing [22]. Individuals were randomly assigned to pacing at the right atrial appendage or the right septum. These two groups were further stratified by whether a continuous overdrive pacing algorithm was "on" or "off." (see 'Overdrive (antitachycardia) atrial pacing' below). After a mean follow-up of 3.1 years, there was no difference in the rate of occurrence of persistent AF between the two sites.

Alternate strategies — As discussed above, we place a dual chamber pacemaker in patients with non-permanent AF who have symptomatic bradycardia and no indication for biventricular pacing. When possible, we pace from the right atrium only. While attempting physiologic pacing has been standard of care for decades, data suggests a physiologic benefit of His bundle pacing when feasible [4]. (See "Sinus node dysfunction: Treatment", section on 'Long-term management'.)

The ability of other atrial pacing systems to suppress AF recurrences has been evaluated in several studies and has not been found to prevent the development of AF.

Alternative-site, dual-site right atrial, and biatrial pacing — Based on the available evidence, we do not perform alternative site, dual-site right atrial, or biatrial pacing to prevent episodes of AF.

The atria can be paced at sites other than the right atrial appendage, such as at the high interatrial septum near Bachman’s bundle, or at two sites simultaneously to provide greater synchronization of atrial tissue, which might protect against AF. Biatrial pacing usually involves pacing simultaneously from a lead in the right atrial appendage to stimulate the right atrium and a lead in the coronary sinus to stimulate the left atrium [23]. Alternatively, two sites in the right atrium can be paced simultaneously (eg, the high right atrium and low on the interatrial septum near the coronary sinus ostium) [24].

Possible mechanisms by which arrhythmia recurrence rates are lowered with dual-site pacing include a reduction in atrial conduction delay and a smaller increase in the width of the atrial electrogram caused by an early premature beat, measured at the right posterior interatrial septum.

The relative efficacy of dual- versus single-site (right atrial) pacing has been evaluated in several small series [25-29] and the larger and randomized DAPPAF trial [24]. A meta-analysis of 12 randomized controlled trials enrolling 1146 patients compared right atrial appendage pacing with interatrial septum pacing. Compared with right atrial appendage pacing, interatrial septum pacing was associated with a reduction in the number of AF episodes and AF burden. However, the development of permanent AF and the prevalence of recurrent AF were similar between the two pacing modes [30].  

The following observations illustrate the range of findings:

In a crossover study of 30 patients with drug-refractory AF, both types of pacing were beneficial; however, dual-site pacing in combination with an optimized final drug was associated with significant increases in the proportion of patients free of AF recurrence (89 versus 62 percent with single-site pacing) and in the mean arrhythmia-free interval (195 versus 143 days) [25].

In the DAPPAF trial, 118 patients with paroxysmal symptomatic AF and a bradyarrhythmic indication for pacing were randomly assigned to each of three pacing modes: right atrial, dual-site right atrial, and support (DDI or VDI) pacing [24]. There was no overall benefit from dual-site compared to single-site atrial pacing. However, subgroup analysis suggested that dual-site pacing was more effective than single-site or support pacing in patients receiving a class I or III antiarrhythmic drug and in those with ≤1 symptomatic AF episode per week.

In the PASTA Trial, 142 patients with pacing indications were randomly assigned to pacing from either the free right atrial wall, right atrial appendage, coronary sinus ostium, or dual site right atrial pacing from the coronary sinus ostium and the right atrial appendage [29]. There was no statistically significant difference with respect to the occurrence of AF between the four groups after 24 months.

Overdrive (antitachycardia) atrial pacing — The rationale for overdrive or antitachycardia pacing that predominates over intrinsic atrial activity is that triggering of AF might be reduced by affecting the pattern of atrial depolarization and suppressing atrial premature beats. Initial studies produced variable results [23]. This was followed by the development of complex algorithms that keep the pacing rate slightly faster than the intrinsic atrial rate in an attempt to minimize the sudden rate change that occurs after premature beats.

Some combinations of proprietary pacing algorithms designed to both prevent AF by overdrive pacing and to pace-terminate AF at its onset have been shown to have a statistically significant positive impact on AF burden. However, their impact is clinically small, often leads to symptoms such as palpitations related to overdrive pacing, and should not be considered as a treatment option in patients who do not have a bradycardia indication for pacing. In addition, they do not compare to the efficacy of antiarrhythmic drug therapy or catheter ablation. We consider using this pacing modality in patients with frequent, symptomatic episodes of AF whose episodes have been difficult to manage with rate or rhythm control. (See 'Patients without an indication for a pacemaker' above.)

Some [31-34], but not all [22], of these algorithms appear to more effectively reduce the total number of episodes of AF or the burden of symptomatic AF compared to DDDR alone [31-34]. We do not routinely use any of these algorithms for overdrive atrial pacing.

The following studies are representative:

POT trial – The Prevention Or Termination trial studied the effect of antitachycardia pacing on AF burden when added to preventive pacing algorithms (PPA) [35]. The study consisted of 85 patients who received a DDDR (rate-adaptive dual-chamber pacemaker) with antitachycardia pacing (ATP) algorithms who had greater than 30 minutes per week of AF. They were randomly assigned either to PPA or to PPA with ATP for three months, and then they were crossed to the alternative therapy for the same amount of time with a one-month washout period. Both groups showed a significant decrease in AF burden at the end of the first period (64 versus 81 percent), but there was no further decrease in AF burden of the number of episodes when adding ATP to PPA.

SAFARI trial – The Study of Atrial Fibrillation Reduction (SAFARI) was designed to determine the impact of preventive pacing algorithms on patients with pacing indications and a history of paroxysmal AF. The study randomized 240 patients to receive either continuous overdrive and triggered overdrive pacing therapies (PPTs) or standard pacing. The primary efficacy end point was post-randomization AF burden, defined as the average number of hours per day spent in atrial tachyarrhythmia during the longest period of at least 90 days between the 4- and 10-month visits. There was no difference in the development of permanent AF between the PPTs ON group (0 percent) compared with the OFF group (2.5 percent). Patients randomized to the PPTs ON group had a median reduction in AF burden to 0.08 hours/day compared with no change in the OFF group [36].

ADOPT-A trial – The randomized Atrial Dynamic Overdrive Pacing Trial (ADOPT-A) trial assessed the efficacy of a pacemaker algorithm designed to pace the atrium at rates slightly faster than intrinsic in patients with a history of symptomatic paroxysmal or persistent AF and an indication for dual chamber pacing. The primary end points of the study were symptomatic AF burden and adverse events. A total of 319 patients were randomized. The burden of symptomatic atrial arrhythmias (defined as AF, atrial flutter, and atrial tachyarrhythmias) was reduced by 26.5 percent, from 2.6 percent in the control group to 1.9 percent in the treatment group. The mean number of AF episodes (4.3 ± 11.5 control versus 3.2 ± 8.6 treatment) and adverse event rates were not statistically different between groups.

ASSERT trial – The main objective of the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) was to evaluate the risk of stroke in patients with dual chamber pacemakers and ICDs and subclinical AF episodes lasting >six minutes. Patients with pacemakers were also randomly assigned to receive or not to receive continuous atrial overdrive pacing to evaluate long-term atrial arrhythmia risk. Of the 2451 pacemaker patients randomized, there was no difference in the annual rate of atrial tachyarrhythmia development (1.96 percent per year in patients randomized to receive atrial overdrive pacing versus 1.44 percent per year in control patients) and no difference in the combined end point of stroke, systemic embolism, myocardial infarction, death from vascular causes, or hospitalization for heart failure [37].

MINERVA trial – This trial evaluated a novel atrial antitachycardia pacing feature (DDDRP). In the study, DDDRP alone was compared with DDDRP with managed ventricular pacing (MVP) or with MVP alone in patients with bradycardia and previous atrial arrhythmias [38]. The reactive antitachycardia pacing algorithm used in the study continually monitors the atrial rhythm and delivers tiered pacing therapies based on atrial rate. The primary AF objective was to assess rates of permanent AF in the 1166 enrolled patients. At two years, permanent or persistent AF occurred in 19 percent of patients in the control DDDRP arm, 25 percent in the MVP arm, and 15.1 percent in the DDDRP + MVP arm [2].  

PATIENTS WHO REQUIRE ICD OR RESYNCHRONIZATION THERAPY — The number of patients with atrial fibrillation (AF) who are receiving an implantable cardioverter defibrillator (ICD) or who require cardiac resynchronization therapy is increasing.

Many patients who have ICD indications (eg, low left ventricular ejection fraction) may have a history of AF or may have subclinical AF detected on routine follow-up. In patients with a history of non-permanent AF and both pacing and ICD indications, a dual chamber ICD is recommended. In patients with no known AF history in whom an ICD is indicated, a single chamber device is recommended. An atrial sensing only (VDD) ICD lead is also available and may be useful in the diagnosis of AF in a patient with a single lead ICD. A stand-alone atrial defibrillator was previously evaluated but is no longer available due to the high risk of recurrent AF and the pain associated with shocks. These devices are capable of sensing within and defibrillating the right atrium. However, we do not recommend their placement to terminate AF nor do we use them for AF outside the hospital setting.

The use of cardiac resynchronization in patients with AF is discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation", section on 'Our approach'.)

RECOMMENDATIONS OF OTHERS — We agree with recommendations made by the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society guidelines and their focused updates [2,39,40].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient education: Pacemakers (The Basics)")

Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

In patients with atrial fibrillation (AF), we recommend NOT placing a permanent pacemaker to treat or reduce the frequency of AF in the absence of another indication for pacing (Grade 1B). (See 'Alternate strategies' above.)

Ventricular pacing can increase the risk of AF. In patients without chronic AF who require a pacemaker for bradycardia, we recommend dual-chamber or atrial pacing, rather than ventricular pacing (Grade 1A). (See 'Patients with symptomatic bradycardia' above.)

In patients with intact atrioventricular conduction who receive a dual-chamber device, we recommend the use of pacing modes/parameters that minimize right ventricular pacing (Grade 1B). (See 'Patients with symptomatic bradycardia' above.)

We do not use alternate-site, dual-right atrial, or biatrial pacing to prevent AF. (See 'Alternate strategies' above.)

We do not use overdrive (antitachycardia pacing) to prevent AF in patients who do not have a bradycardia indication for pacing. (See 'Overdrive (antitachycardia) atrial pacing' above.)

REFERENCES

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  21. Stambler BS, Ellenbogen KA, Orav EJ, et al. Predictors and clinical impact of atrial fibrillation after pacemaker implantation in elderly patients treated with dual chamber versus ventricular pacing. Pacing Clin Electrophysiol 2003; 26:2000.
  22. Lau CP, Tachapong N, Wang CC, et al. Prospective randomized study to assess the efficacy of site and rate of atrial pacing on long-term progression of atrial fibrillation in sick sinus syndrome: Septal Pacing for Atrial Fibrillation Suppression Evaluation (SAFE) Study. Circulation 2013; 128:687.
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  24. Saksena S, Prakash A, Ziegler P, et al. Improved suppression of recurrent atrial fibrillation with dual-site right atrial pacing and antiarrhythmic drug therapy. J Am Coll Cardiol 2002; 40:1140.
  25. Delfaut P, Saksena S, Prakash A, Krol RB. Long-term outcome of patients with drug-refractory atrial flutter and fibrillation after single- and dual-site right atrial pacing for arrhythmia prevention. J Am Coll Cardiol 1998; 32:1900.
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  28. Leclercq JF, De Sisti A, Fiorello P, et al. Is dual site better than single site atrial pacing in the prevention of atrial fibrillation? Pacing Clin Electrophysiol 2000; 23:2101.
  29. Spitzer SG, Wacker P, Gazarek S, et al. Primary prevention of atrial fibrillation: does the atrial lead position influence the incidence of atrial arrhythmias in patients with sinus node dysfunction? Results from the PASTA Trial. Pacing Clin Electrophysiol 2009; 32:1553.
  30. Zhang L, Jiang H, Wang W, et al. Interatrial septum versus right atrial appendage pacing for prevention of atrial fibrillation : A meta-analysis of randomized controlled trials. Herz 2018; 43:438.
  31. Israel CW, Lawo T, Lemke B, et al. Atrial pacing in the prevention of paroxysmal atrial fibrillation: first results of a new combined algorithm. Pacing Clin Electrophysiol 2000; 23:1888.
  32. Funck RC, Adamec R, Lurje L, et al. Atrial overdriving is beneficial in patients with atrial arrhythmias: first results of the PROVE Study. Pacing Clin Electrophysiol 2000; 23:1891.
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  34. Wiberg S, Lönnerholm S, Jensen SM, et al. Effect of right atrial overdrive pacing in the prevention of symptomatic paroxysmal atrial fibrillation: a multicenter randomized study, the PAF-PACE study. Pacing Clin Electrophysiol 2003; 26:1841.
  35. Mont L, Ruiz-Granell R, Martínez JG, et al. Impact of anti-tachycardia pacing on atrial fibrillation burden when added on top of preventive pacing algorithms: results of the prevention or termination (POT) trial. Europace 2008; 10:28.
  36. Gold MR, Adler S, Fauchier L, et al. Impact of atrial prevention pacing on atrial fibrillation burden: primary results of the Study of Atrial Fibrillation Reduction (SAFARI) trial. Heart Rhythm 2009; 6:295.
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  38. Boriani G, Tukkie R, Manolis AS, et al. Atrial antitachycardia pacing and managed ventricular pacing in bradycardia patients with paroxysmal or persistent atrial tachyarrhythmias: the MINERVA randomized multicentre international trial. Eur Heart J 2014; 35:2352.
  39. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. [corrected]. Circulation 2012; 126:1784.
  40. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125.
Topic 1044 Version 30.0

References

1 : Pacing therapy for prevention of atrial fibrillation.

2 : 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.

3 : Device-based therapies for atrial fibrillation.

4 : Impact of Physiologic Pacing Versus Right Ventricular Pacing Among Patients With Left Ventricular Ejection Fraction Greater Than 35%: A Systematic Review for the 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

5 : Electrical remodeling of the atria following loss of atrioventricular synchrony: a long-term study in humans.

6 : Mechanical remodeling of the left atrium after loss of atrioventricular synchrony. A long-term study in humans.

7 : Heart failure and echocardiographic changes during long-term follow-up of patients with sick sinus syndrome randomized to single-chamber atrial or ventricular pacing.

8 : Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation.

9 : The role of atrial ectopics in initiating paroxysmal atrial fibrillation.

10 : Regional right and left atrial activation patterns during single- and dual-site atrial pacing in patients with atrial fibrillation.

11 : Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data.

12 : Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators.

13 : Progression to chronic atrial fibrillation after pacing: the Canadian Trial of Physiologic Pacing. CTOPP Investigators.

14 : Ventricular pacing or dual-chamber pacing for sinus-node dysfunction.

15 : Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.

16 : Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease.

17 : Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome.

18 : Long-term follow-up of patients from a randomised trial of atrial versus ventricular pacing for sick-sinus syndrome.

19 : Incidence of atrial fibrillation and thromboembolism in a randomised trial of atrial versus dual chamber pacing in 177 patients with sick sinus syndrome.

20 : A randomized comparison of atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome.

21 : Predictors and clinical impact of atrial fibrillation after pacemaker implantation in elderly patients treated with dual chamber versus ventricular pacing.

22 : Prospective randomized study to assess the efficacy of site and rate of atrial pacing on long-term progression of atrial fibrillation in sick sinus syndrome: Septal Pacing for Atrial Fibrillation Suppression Evaluation (SAFE) Study.

23 : Implantable devices for the treatment of atrial fibrillation.

24 : Improved suppression of recurrent atrial fibrillation with dual-site right atrial pacing and antiarrhythmic drug therapy.

25 : Long-term outcome of patients with drug-refractory atrial flutter and fibrillation after single- and dual-site right atrial pacing for arrhythmia prevention.

26 : No incremental benefit of multisite atrial pacing compared with right atrial pacing in patients with drug refractory paroxysmal atrial fibrillation.

27 : Dual-site atrial pacing for atrial fibrillation in patients without bradycardia.

28 : Is dual site better than single site atrial pacing in the prevention of atrial fibrillation?

29 : Primary prevention of atrial fibrillation: does the atrial lead position influence the incidence of atrial arrhythmias in patients with sinus node dysfunction? Results from the PASTA Trial.

30 : Interatrial septum versus right atrial appendage pacing for prevention of atrial fibrillation : A meta-analysis of randomized controlled trials.

31 : Atrial pacing in the prevention of paroxysmal atrial fibrillation: first results of a new combined algorithm.

32 : Atrial overdriving is beneficial in patients with atrial arrhythmias: first results of the PROVE Study.

33 : A new pacemaker algorithm for the treatment of atrial fibrillation: results of the Atrial Dynamic Overdrive Pacing Trial (ADOPT).

34 : Effect of right atrial overdrive pacing in the prevention of symptomatic paroxysmal atrial fibrillation: a multicenter randomized study, the PAF-PACE study.

35 : Impact of anti-tachycardia pacing on atrial fibrillation burden when added on top of preventive pacing algorithms: results of the prevention or termination (POT) trial.

36 : Impact of atrial prevention pacing on atrial fibrillation burden: primary results of the Study of Atrial Fibrillation Reduction (SAFARI) trial.

37 : Subclinical atrial fibrillation and the risk of stroke.

38 : Atrial antitachycardia pacing and managed ventricular pacing in bradycardia patients with paroxysmal or persistent atrial tachyarrhythmias: the MINERVA randomized multicentre international trial.

39 : 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. [corrected].

40 : 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons.