Volume 346:2062-2068

June 27, 2002

Number 26

Implantable Devices for the Treatment of Atrial Fibrillation

Joshua M. Cooper, M.D., Michael S. Katcher, M.D., and Michael V. Orlov, M.D., Ph.D.

Atrial fibrillation is a common arrhythmia that causes symptoms such as palpitations and dyspnea but is also associated with stroke, heart failure, and an increased risk of hospitalization and death.^1,2 The incidence of atrial fibrillation increases markedly with age. As the average age of the general population increases, the overall prevalence of atrial fibrillation is also increasing. Among the most common approaches to management are rate control plus anticoagulation and rhythm control with antiarrhythmic medications. Neither of these two strategies is ideal. Anticoagulation does not eliminate the risk of stroke, and the antiarrhythmic drugs often do not maintain sinus rhythm.^3,4 Both approaches also entail a risk of side effects and complications. In some cases, antiarrhythmic drugs appear to have led to life-threatening ventricular arrhythmias.^5,6 One new therapeutic option — pacemakers and defibrillators — is beginning to influence the management of atrial fibrillation.

Ventricular Pacing during Atrial Fibrillation

During atrial fibrillation, the atrioventricular node is bombarded with electrical impulses, which typically result in rapid ventricular rates. The rate at which signals are transmitted to the ventricles depends on the electrical properties of the conduction system; these properties can be influenced by medications and autonomic input. The ventricular response may be slow in patients with intrinsic conduction-system disease, in those who are taking rate-controlling pharmacologic agents, or in patients with a high vagal tone. Permanent pacemakers have long been used to treat symptomatic bradycardia caused by any of these factors.

If rapid ventricular rates persist after pharmacologic therapies for atrial fibrillation have proved unsuccessful or intolerable to the patient, permanent ablation of the atrioventricular node is an effective therapy.⁷ An ablation catheter is introduced through a femoral vein and positioned at the atrioventricular node under fluoroscopic and electrocardiographic guidance. Radio-frequency energy is delivered to this site, destroying the underlying conduction tissue and thus producing permanent heart block and eliminating tachycardia. This procedure is irreversible and typically leaves the patient with only a slow escape rhythm, necessitating the implantation of a permanent pacemaker. In patients with atrial fibrillation that is refractory to drug therapy, atrioventricular-node ablation decreases the incidence of palpitations, dyspnea, and fatigue by controlling the ventricular rate and also increases exercise tolerance.^8,9,10 This approach eliminates the need for rate-controlling medications. The restoration of a regular ventricular rhythm with pacing may also have an important role,¹¹ since cardiovascular hemodynamics are impaired by an irregular ventricular rhythm.^12,13

Although ventricular pacing can be used to treat either spontaneous or treatment-induced bradycardia, it has no effect on the fibrillation in the atria or on the associated risk of thromboembolism.

Prevention of Atrial Fibrillation with Atrial Pacing

The first evidence that permanent pacing could potentially affect atrial pathophysiology was derived from retrospective analyses of patients who had pacemakers implanted for the sick sinus syndrome. Patients with atrial or dual-chamber pacemakers had fewer episodes of atrial fibrillation than those with ventricular pacemakers alone.^14,15,16 Although retrospective studies are subject to bias, the data suggested a beneficial effect of pacing the atrium. In one retrospective analysis of patients who were followed for up to 12 years after receiving a pacemaker, atrial fibrillation developed in 26 percent of those with ventricular pacemakers but in only 5 percent of those with dual-chamber devices.¹⁴

These retrospective data led to several prospective trials^{17,18,19,20,21,22,23,24} that evaluated whether atrial or dual-chamber pacemakers led to a lower incidence of atrial fibrillation than did ventricular pacemakers (Table 1). The Canadian Trial of Physiologic Pacing prospectively followed patients with symptomatic bradycardia who had either a ventricular or a dual-chamber pacemaker implanted. Dual-chamber pacing decreased the incidence of both atrial fibrillation and progression to chronic atrial fibrillation, although these effects were not seen until two years after the pacemakers had been implanted.^19,20 The Pacemaker Selection in the Elderly trial also prospectively followed patients with either ventricular or dual-chamber pacemakers. Dual-chamber pacing was associated with a lower incidence of atrial fibrillation in patients with sinus-node dysfunction but not in patients with atrioventricular block.²¹ The contrasting outcomes in these two groups suggest that the mechanisms of progression to atrial fibrillation differ among patients with different types of conduction disturbances.

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Table 1. Results of Prospective, Randomized Trials of Atrial, Dual-Chamber, and Ventricular Pacemakers.

One of the largest prospective trials to date, the Mode Selection Trial, followed more than 2000 patients with the sick sinus syndrome.²⁵ Patients were randomly assigned to receive either a ventricular or a dual-chamber pacemaker, and the primary end points were mortality and stroke. Although the two groups did not differ significantly with respect to the primary end points, dual-chamber pacing had a clear effect on the incidence of atrial fibrillation. There was almost a 50 percent decrease in the likelihood of a first episode of atrial fibrillation and a reduction in the risk of progression to chronic atrial fibrillation with dual-chamber pacing. Currently, it is common to implant either an atrial or a dual-chamber device in patients with the sick sinus syndrome who require a pacemaker.

The benefits of dual-chamber pacing over ventricular pacing are both mechanical and electrical. Atrial pacing allows coordinated contraction of the chambers, which in turn lowers average atrial pressure and decreases any stretch-related changes that might be induced in atrial tissue.^26,27 Pacing the atrium also prevents pauses and thus reduces the risk of atrial fibrillation that is associated with increased vagal tone and bradycardia.²⁸ Lastly, atrial pacing may suppress ectopic atrial beats that can precipitate bouts of atrial fibrillation.^29,30

Because all patients in the prospective trials just described received a pacemaker, the results cannot be compared with those in patients without devices. Although atrial pacing was associated with a lower incidence of atrial fibrillation than was isolated ventricular pacing, it is unclear whether this finding was due to the beneficial effects of pacing the atrium or to the deleterious effects of pacing the ventricle. It is possible, for example, that retrograde activation of the atria during ventricular pacing increases the likelihood of atrial fibrillation. Only studies that compared atrial pacing with no pacing could prove that pacing the atria had a truly protective effect.

Alternative-Site and Dual-Site Atrial Pacing

In healthy atrial tissue, each sinus beat initiates the rapid, synchronous depolarization of the atria and is present as a P wave on the surface electrocardiogram. In diseased atrial tissue, however, electrical conduction is slower and more variable, resulting in less coordinated atrial depolarization and a broader P wave. This slowed, nonuniform conduction may provide an ideal substrate for reentrant wavelets and atrial fibrillation.³¹

In an effort to promote more synchronized atrial activation in patients with atrial fibrillation, investigators have studied the effects of pacing the atria at novel sites. Attaching a pacing lead to the interatrial septum or to the opening of the coronary sinus allows both atria to be stimulated simultaneously, resulting in a narrower P wave.^32,33,34 A similar result can be achieved by pacing at Bachmann's bundle, which is a band of tissue that electrically connects the right and left atria.³⁵ Among patients with paroxysmal atrial fibrillation who required a pacemaker, patients in whom the atrial lead was placed at Bachmann's bundle³⁶ or on the interatrial septum³⁷ had a lower incidence of paroxysmal and chronic atrial fibrillation than those in whom the lead was positioned in the traditional right atrial appendage.

Another way to resynchronize the atria is to pace two sites simultaneously.³⁸ The most common configuration is a lead attached to the right atrial appendage in order to stimulate the right atrium and a lead placed in the coronary sinus in order to stimulate the left atrium. When two sites are paced concurrently, there is greater synchronization of the atrial tissue during depolarization. In the electrophysiology laboratory, this electrical coordination immediately reduces the ability to provoke atrial fibrillation.³⁹ The clinical relevance of this pacing strategy has been evaluated in studies of patients who have undergone cardiac surgery, a high-risk group with an incidence of postoperative atrial fibrillation of 25 to 50 percent.^40,41,42,43 In these studies, patients were randomly assigned to receive single-site or dual-site atrial pacing postoperatively. In three of the studies,^40,41,42 patients with simultaneous pacing from right and left atrial wires had a significant reduction in the occurrence of atrial fibrillation (Table 2).

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Table 2. Results of Prospective, Randomized Trials of Dual-Site and Single-Site Atrial Pacing.

Whereas these four studies evaluated the effect of dual-site pacing on the incidence of atrial fibrillation during a brief, high-risk period, other trials have examined the effects in the general population of patients with atrial fibrillation (Table 2).^44,45 A study of patients who had a prolonged P wave consequent to delayed atrial activation found that simultaneous pacing from two atrial sites shortened the P wave and significantly decreased the rate of progression to persistent atrial fibrillation.⁴⁴ In a recently completed crossover study of 120 patients with atrial fibrillation, long-term dual-site atrial pacing combined with treatment with antiarrhythmic drugs reduced the incidence of atrial fibrillation by 34 percent.⁴⁶

The role of dual-site pacing in the long-term management of atrial fibrillation is unclear, since medical therapy alone can usually control the symptoms of atrial fibrillation. Placing a second atrial lead can be technically challenging, and there is a risk of coronary-sinus lead dislodgement. In addition, the presence of two atrial leads creates unique sensing issues: native atrial beats may be counted twice, leading to an inappropriate pacemaker response. In patients who require a pacemaker for concomitant bradycardia, single-site atrial pacing remains the standard of care. If future improvements reduce the problems associated with the implantation of dual atrial leads, however, this approach could become a useful adjunctive therapy, particularly in patients with a delay in interatrial conduction.

Overdrive Atrial Pacing

The fundamental function of a pacemaker is to prevent the heart rate from falling below a certain threshold. The amount of pacing that actually occurs depends on the relation between the programmed lower limit and the native heart rate. The faster the setting of the pacemaker, the more it will override the intrinsic rate (referred to as "overdrive"). In addition to influencing the pattern of atrial depolarization, atrial pacing most likely also suppresses premature atrial beats, which precede and trigger episodes of atrial fibrillation.^29,30 Both these effects reduce the initiation of atrial fibrillation, particularly when atrial pacing predominates over native atrial activity.

Several prospective studies have demonstrated that a faster atrial pace results in a higher percentage of paced beats and fewer episodes of atrial fibrillation. In one small trial in which the atrial pacing rate was 10 beats per minute faster than the mean heart rate,⁴⁷ the incidence of atrial arrhythmias was significantly reduced over a 30-day period, and atrial fibrillation was eliminated in 14 of the 22 patients. In another study, patients who had a higher percentage of paced beats had a lower incidence of atrial arrhythmia.⁴⁸ In other studies, however, fixed atrial pacing did not significantly suppress atrial fibrillation.⁴⁹ These negative trials did not achieve as much of an increase in the level of atrial pacing, suggesting that atrial pacing needs to predominate over intrinsic atrial activity to reduce the initiation of atrial fibrillation.

In an attempt to increase the effectiveness of atrial pacing as an antiarrhythmic therapy without the use of excessive rates of pacing, complex algorithms have been developed.^50,51 These approaches advocate continuous monitoring of native atrial activity and the use of a pacing rate that is slightly faster than the sinus or ectopic atrial rate. The goals of these algorithms include achieving a higher degree of atrial pacing and reducing the sudden rate change that occurs after premature beats. In several studies, the use of sophisticated pacing strategies led to rates of atrial pacing of more than 80 percent and to a more consistent ability of the pacemaker to suppress bouts of atrial fibrillation.^52,53 A recent trial achieved a rate of atrial pacing of 93 percent with the use of a dynamic-atrial-overdrive algorithm and decreased the number of days during which atrial fibrillation occurred by 25 percent.⁵⁴ The use of this algorithm has been approved by the Food and Drug Administration, and devices with this feature are now being used in clinical practice. Clinical studies of overdrive atrial pacing in patients who do not meet the traditional criteria for the implantation of a pacemaker are now under development.

High-Frequency Pacing and Electrical Cardioversion

Although aggressive atrial pacing may help to prevent atrial fibrillation, it has no effect on atrial fibrillation once it occurs. Sinus rhythm should be restored soon after the onset of atrial fibrillation in order to minimize the risk of stroke, rapidly restore physiologic hemodynamics, and avoid the electrical changes in the atria that tend to maintain a fibrillatory substrate.^55,56 The concept of using an implanted device to terminate supraventricular arrhythmias is not new. In the past, these devices were used exclusively to treat supraventricular tachycardias that were electrically organized, such as atrioventricular-node reentry and atrial flutter, and therefore amenable to termination by rapid atrial pacing.^57,58 The problem with these early antitachycardia devices, however, was that rapid pacing did not terminate atrial fibrillation.

The goal of detecting and promptly treating symptomatic atrial fibrillation inspired the development of the implantable atrial defibrillator. The first of these devices (the Metrix Atrioverter, InControl) was implanted in a small group of patients but is no longer manufactured. It consisted of two atrial defibrillation leads, one in the right atrium and one in the coronary sinus, as well as a ventricular pacing lead, which was used to synchronize shocks to the QRS complex. The device was programmed to detect atrial fibrillation and administer a shock to restore sinus rhythm. Because atrial fibrillation is usually not immediately life-threatening, the shock can be discharged under manual control or after a delay. In the initial trial, this device was used only to deliver shocks under a physician's supervision,⁵⁹ and patients were sedated, since atrial shocks may be painful. The device was also tested in an outpatient setting; almost half the patients were permitted to trigger the delivery of shocks at home. The overall efficacy of the device in terminating atrial fibrillation was 90 percent, with almost one third of episodes requiring more than one shock.⁶⁰ Although the patients experienced moderate discomfort from the shocks, they reported a high degree of satisfaction with the device. There were no instances of ventricular proarrhythmia.

A combined atrial and ventricular defibrillator (the Jewel AF device, Medtronic) was approved by the Food and Drug Administration to treat either drug-refractory atrial fibrillation or ventricular arrhythmias. It demonstrated a high degree of discrimination between atrial and ventricular tachyarrhythmias, resulting in cardioversion of 76 percent of rhythms identified as atrial fibrillation.⁶¹ An updated version of the device (the GEM III AT, Medtronic) is currently in use. The shocks for atrial fibrillation can be activated by the patient or can be programmed to occur automatically in the early morning while the patient is asleep, thus ensuring that a shock is delivered within 24 hours after the onset of atrial fibrillation. Theoretically, prompt cardioversion may prevent thrombus and stroke, although this outcome has not yet been studied. This device can also deliver rapid atrial pacing to treat atrial arrhythmias. High-frequency (burst) pacing terminates atrial fibrillation about 17 percent of the time, suggesting that painful shocks can occasionally be avoided.⁶¹ These various therapies for atrial arrhythmias have been very safe, with no reported instances of ventricular proarrhythmia.

Evaluation of the electrogram strips stored in implantable defibrillator devices has provided new insights into the mechanisms of the initiation of atrial fibrillation. In one study, all the patients had had clinical atrial fibrillation before the device was implanted, but only 19 percent of device-detected atrial arrhythmias were found to be atrial fibrillation.⁶² The rest were other types of atrial tachyarrhythmias, suggesting that episodes of atrial fibrillation may often be preceded by more organized rhythms. These organized arrhythmias are much more amenable to termination by rapid atrial pacing, with success rates of about 50 percent.^63,64,65

Atrial-defibrillator therapy is currently suitable only for a small subgroup of patients with symptomatic, drug-refractory atrial fibrillation, since there is no evidence that treating asymptomatic episodes of atrial fibrillation has clinical benefit. The frequency of atrial fibrillation is another important variable. The episodes should be frequent enough to warrant the implantation of a device, but not so frequent that the patient would experience many shocks. The ideal patient population for this invasive antiarrhythmic strategy has not yet been defined. Because approximately 25 percent of patients who receive an implantable defibrillator for ventricular arrhythmias also have paroxysmal atrial fibrillation,⁶⁶ a combined treatment device may also be appropriate.

Conclusions

Implantable pacemakers and defibrillators are undergoing rapid evolution. Currently used devices combine pacing and cardioversion therapies both to prevent and to treat atrial fibrillation (Figure 1). Recent studies have shown that these devices can significantly decrease the incidence of atrial fibrillation⁶³ and improve the quality of life.⁶⁷ Although the current guidelines for the management of atrial fibrillation predominantly encompass pharmacologic strategies,⁶⁸ implantable devices are likely to have an increasing role in the near future, particularly when they are used in combination with other treatments.

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Figure 1. Devices Used to Treat Atrial Fibrillation. Dual-site atrial pacing (Panel A) can resynchronize the atria when atrial conduction is slow. One lead paces the right atrium, and the second lead is placed in the coronary sinus to pace the left atrium. The result is a narrower P wave on the electrocardiogram. Ventricular pacing (Panel B) can prevent symptomatic bradycardia, which may be due to intrinsic conduction-system disease, medications that block the atrioventricular node, or ablation of the atrioventricular node. Atrial pacing (Panel C) is associated with less frequent atrial fibrillation than ventricular pacing. Overdrive atrial pacing (Panel D) can suppress premature beats and other triggers of atrial fibrillation. Atrial defibrillators (Panel E) can detect atrial fibrillation and deliver a shock to restore sinus rhythm. The right atrium is depolarized by the proximal electrode (shown as a coil), and the energy subsequently depolarizes the rest of the myocardium and reenters the distal electrode (shown as a coil in the right ventricle).

Source Information

From the Cardiovascular Division, Brigham and Women's Hospital, Boston (J.M.C.); and Division of Cardiology, Veterans Affairs Boston Healthcare System, Veterans Affairs Medical Center, West Roxbury, Mass. (M.S.K., M.V.O.).

Address reprint requests to Dr. Katcher at Cardiology 111A, VA Boston Healthcare System, 1400 VFW Pkwy., West Roxbury, MA 02132.

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Edward E. Rylander, M.D.

Diplomat American Board of Family Practice.

Diplomat American Board of Palliative Medicine.

Edward E. Rylander, M.D.

Diplomat American Board of Family Practice.

Diplomat American Board of Palliative Medicine.