Treatment of atrial fibrillation with an implantable atrial defibrillator — long term results

J.Christoph Gellera,*, Sven Reeka, Carl Timmermansb, Torsten Kayserc, Hung-Fat Tsed, Christian Wolperte, Werner Jungf, A.John Cammg, Chu-Pak Laud, Hein J.J. Wellensb and Helmut U. Kleina

a University Hospitals of Magdeburg, Magdeburg, Germany
b Academic Hospital Maastricht, Maastricht, Netherlands
c Guidant Inc. Europe, Brussels, Belgium
d Queen Mary Hospital, University of Hong Kong, Hong Kong China
e University of Mannheim, Mannheim, Germany
f Academic Hospital Villingen, Villingen, Germany
g St. George's Hospital, London, UK

* Correspondence to: J. Christoph Geller, M.D., Division of Cardiology, University Hospitals, Otto-von-Guericke University, Leipzigerstrasse 44, 39120 Magdeburg, Germany. Tel: ++49-391-671 3203; Fax: +49-391-671 3202
E-mail address: christoph.geller{at}medizin.uni-magdeburg.de

Received 25 March 2003; revised 26 August 2003; accepted 18 September 2003

Abstract

Objectives To evaluate the long-term outcome with an implantable atrial defibrillator (IAD) in patients with recurrent atrial fibrillation (AF).

Background Maintenance of sinus rhythm using repeated internal cardioversion shocks has been shown to be effective and safe in short-term studies but long term follow-up is unknown.

Methods Since 1995, 136 patients (30 women) with symptomatic, drug-refractory atrial fibrillation were implanted with an IAD (METRIX, InControl). This analysis was performed after a median of 40 (range 7–66) months after implantation.

Results In 26 patients, the programmed mode was not documented during last follow-up, four patients had died. Of the remaining 106 patients (mean age 58±10, range 34 – 79 years), 39 were actively delivering therapy with the device, in 14 patients the device was used to monitor the arrhythmia but no shocks were delivered, and in 53 patients it was turned off or explanted. Increases in defibrillation thresholds (n=7), patient intolerance of multiple cardioversion shocks (n=15), and significant bradycardia requiring dual-chamber pacing (n=12) were the main reasons for discontinuation of therapy in addition to battery depletion (n=19). After explantation, efforts to maintain sinus rhythm were continued in 17 patients whereas rate control was attempted in 36 patients.

Conclusions A strategy of maintaining sinus rhythm long-term with an IAD is feasible in a proportion of patients. However, patient selection is critical, and technical improvements (i.e. higher shock energies, dual-chamber pacing and additional preventive and anti-tachycardia pacing algorithms) are required to increase the number of patients having long term benefit, and frequent arrhythmia recurrences and patient intolerance to repeated cardioversion shocks remain a major limitation.

Key Words: Atrial fibrillation • Heart assist device • Defibrillation

1. Introduction

Electrical cardioversion is effective in restoring sinus rhythm in patients with atrial fibrillation (AF) in >90% of patients.1However, long-term maintenance of sinus rhythm is difficult despite the use of prophylactic antiarrhythmic drug therapy,2–4partly due to electrical changes in the atrium induced by the arrhythmia, summarized as ‘electrical remodelling’,5–7which render the atria more vulnerable to AF recurrence.

A strategy of repeated early electrical cardioversion may increase the number of patients achieving long-term maintenance of sinus rhythm.2,8Thus, after intracardiac electrodes for cardioversion of AF had been shown to be feasible and effective9–13and given the success of ventricular implantable defibrillators for patients at risk for sudden cardiac death or recurrent ventricular tachycardia, the application of device therapy to patients with AF was started in the mid-1990s.

In the initial clinical studies, implantable atrial defibrillators have been shown to be both effective and safe for termination of AF in patients without significant structural heart disease.14–17However, the long-term use and patient tolerance of repeated cardioversion shocks have not been reported.

Therefore, the goal of this analysis was to assess the long-term outcome after implantation of the METRIX atrioverter system (InControl Inc. Redmond, Washington, now Guidant Corp, St. Paul, MN) in patients with recurrent symptomatic AF.

2. Methods

2.1. Patients
Beginning in October of 1995, implantation of an atrial defibrillator was performed in 42 hospitals in nine European countries and in Hong Kong, China, in symptomatic patients with drug-refractory paroxysmal or persistent AF. The patient characteristics have been previously described.14–17METRIX devices (model 3000 and 3020, In Control, Redmond, now Guidant Inc., Minneapolis, USA) were used which have been described in detail elsewhere.15–17Briefly, the device incorporates a stand-alone atrial defibrillator, able to deliver biphasic truncated exponential (3ms/3ms or 6ms/6ms) shocks of a maximum of 3 or 6J, using an atrial shock vector between one defibrillation coil in the distal coronary sinus and the other in the right atrium, and a right ventricular lead for shock synchronization and pacing (Fig. 1). It also has VVI (back-up) pacing capabilities but no atrial pacing or additional preventive pacing options in the atrium.



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Fig. 1 Schematic view of the implanted METRIX device, showing the two atrial shock leads, one in the right atrium and one in the coronary sinus, and the right ventricular lead for shock synchronization and pacing.

 
Using the stored information of the programmed mode during a follow-up visit in 2000 and a questionnaire to all the participating centers of the initial studies in 2001, this analysis was performed a median of 40 (range 7–66) months after implantation of the system.

2.2. Definitions
The patients were divided into three groups, depending on their device status at the time of last follow-up: (1) device programmed in the patient-activated or the automatic shock delivery mode; (2) device used in the monitoring mode but not for (patient activated or automatic) shock delivery; (3) device inactive or explanted.

If the device was no longer used, (1) the reason(s) for discontinuation of therapy, (2) the duration of active use of the device (time from implantation to reprogramming to an inactive mode or to explantation), and (3) the alternative treatment after inactivation or explantation of the device (i.e. continued attempts to maintain sinus rhythm vs. rate control) were evaluated.

Time variables are expressed as median values and the range.

3. Results

3.1. Patients
The initial search at the time of the follow-up visit identified 136 patients (30 women) with symptomatic drug-refractory paroxysmal (n=78) or persistent (n=58) AF implanted with a METRIX device in 42 centres in Europe and in Hong Kong. The majority of them did not have significant structural heart disease.14–17

At the time of follow-up, four patients had died, and in 26 cases, there was no record of the programmed mode. These patients were excluded from further analysis. In the remaining 106 cases, we were able to collect information about (1) rhythm status; (2) the programmed mode of the device, (3) the duration of use of the device, (4) the alternative therapy after inactivation or explantation of the METRIX device at the time of last follow-up. The mean age of these patients was 58±10 (range 31–79) years, there were 26 women. At the last follow-up, 75 patients were in sinus rhythm, 31 patients were in AF.

3.2. Device status during follow-up visit
The device status at the time of last follow-up, 40 (range 7–66) months after implantation, is summarized in Fig. 2. Thirty-nine patients (37%) were delivering therapy using the implanted device, either automatically after detection of AF by the device (n=1) or in the patient-activated shock delivery mode (n=38). In 14 patients (13%), the implanted device was used to monitor for arrhythmia recurrence but no (automatic or patient-activated) therapy was delivered. If AF recurred, cardioversion shocks were applied under physician supervision during office visits, either using the implanted device or external DC cardioversion. In 53 patients (50%), defibrillator therapy was abandoned and the device was turned off or explanted.



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Fig. 2 Programmed mode of the device at the time of last follow-up. 39 patients (37%) were still actively delivering therapy with the device, 14 patients (13%) were programmed in the monitor mode, and in 53 patients (50%), the device was turned off or explanted.

 
3.3. Time of active use
Mainly for safety reasons, all patients initially used the device in the monitor mode without actively delivering out-of hospital shocks with the device. During active use of the device (median 20 months, range 1–43), patients were programmed in the monitor mode for 13 (range 1–56) months. The out-of-hospital therapy mode was used in 45 patients (42%) for 15 (range 1–45) months. Of these 45 patients, only six did not continue delivering shocks via the device (three were reprogrammed to monitor-only mode and three devices were explanted) (Fig. 3). The median time from implant to battery depletion (voltage indicator or interrogation impossible) was 42 (range 12–64) months.



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Fig. 3 Therapy after discontinuation of use/explantation of the METRIX device. In 17 patients, efforts to maintain sinus rhythm were continued whereas in 36 patients, rate controlling therapy was performed.

 
3.4. Reasons for inactivation/explantation
The reason for premature (before end of battery life) discontinuation of therapy were (1) increases in the defibrillation threshold so that the device could no longer effectively terminate an episode of AF (n=7), (2) patient intolerance to multiple cardioversion shocks due tofrequent AF recurrences (n=15), and (3) significant bradycardia (either spontaneously or during additional antiarrhythmic drug therapy) requiring dual-chamber pacing (n=12), a capability the device used in this study did not have.

Of the 15 patients not tolerating repeated shock delivery, six had persistent AF and nine had (frequent recurrences of) paroxysmal AF. Six patients had early recurrence of AF (ERAF) after initially successful termination of an episode (all paroxysmal AF), resulting in >1 shock being delivered per episode, and nine patients experienced frequent recurrences of AF not due to ERAF, requiring very frequent shock delivery that was not tolerated long-term. Both changes in the antiarrhythmic drug regimen and different attempts of sedation and/or anxiolytic therapy did not improve long-term tolerance of shock therapy in the setting of frequent arrhythmia recurrence, independent of whether it was due to ERAF or not.

In 19 patients, battery depletion was the reason that made exchange of the device necessary. Seven of these patients refused implantation of a new defibrillator because of intolerance of therapy shocks.

3.5. Alternative therapy after explantation
When the device was turned off or explanted, efforts to maintain sinus rhythm were continued in 17 Patients (Fig. 3): a second generation dual-chamber defibrillator was implanted in nine patients, a dual-chamber pacemaker (sometimes with additional preventive and anti-tachycardia pacing algorithms) was implanted in six patients, and antiarrhythmic drug therapy was attempted in two patients (one with an additional MAZE procedure).

Efforts to maintain sinus rhythm were discontinued and rate control alone was instituted in 36 patients (Fig. 3), 13 of these received His bundle ablation and VVI-R pacemaker implantation.

4. Discussion

This is the first long-term (median follow-up 40 months) study showing that device-based therapy using repeated internal cardioversion shocks to maintain sinus rhythm is feasible in a proportion of patients with recurrent symptomatic AF: 50% of the patients continued to use the device either to treat or to monitor AF, and attempts to maintain sinus rhythm were continued in two-thirds of patients.

The duration of use of the implanted device was approximately 4 years, close to the calculated life-span of the device battery. The majority of patients initially used the device in the monitor mode, mainly for safety reasons this was a requirement of the initial clinical studies.14–18Forty-five patients were later programmed in the out-of-hospital shock delivery mode. Of these 45 patients, only six patients discontinued shock delivery via the device, emphasizing that patient selection is critical in order to identify those patients who will be ableto tolerate repeated shocks long-term. Patients with (frequent episodes of) paroxysmal AF may not be ideal candidates for atrial defibrillator therapy for a number of reasons, in particular the high incidence of ERAF, and for these patients catheter ablation19may be the preferred therapy.

The main reasons for premature (before the end of battery life-span) termination of using the device were (1) increase in the energy requirements for successful cardioversion so that shock failure with the maximum output of the implanted device no longer allowed restoration of sinus rhythm, (2) patient intolerance to repeated cardioversion shocks due to frequent AF recurrences, partly due to ERAF, and (3) significant bradycardia, either spontaneous or after additional antiarrhythmic drug therapy (the METRIX device did not incorporate dual chamber bradycardia pacingcapabilities).

4.1. Alternative therapy after explantation
After explantation of the METRIX device, efforts to maintain sinus rhythm were continued in 17 patients whereas in 36 patients the goal of maintaining sinus rhythm was no longer pursued and rate controlling therapy was begun. Thus, attempts to maintain sinus rhythm were continued in 66% of patients for approximately 3 years (either with the METRIX device or using an alternative therapy after explantation of the device).

These results compare favourably with other therapeutic options attempting to maintain sinus rhythm in patients with recurrent AF. In particular, antiarrhythmic drug therapy is limited by high recurrence rates and additional side effects (i.e. pro-arrhythmia, negativeinotropic effects, and non-cardiac organ toxicity), resulting in long-term maintenance of sinus rhythm in <50%.2–4

4.2. Previous studies
Implantable atrial defibrillators have been shown to be both effective and safe for the termination of AF in patients without significant structural heart disease.14–18However, most of the previously published studies did not deal with the long-term outcome of a strategy using repeated atrial cardioversion shocks.

Timmermans et al.17described the follow-up of 260±144 days in 51 patients who received a METRIX defibrillator. In this study, a decrease in the number of episodes requiring therapy and an increase in the time between episodes were observed.

In contrast, others have not shown a decrease in the number of episodes using repeated cardioversion for AF recurrences.6,20,21The most likely explanation for this observation is that—in addition to electrical atrial remodelling (which is theoretically reversible)—structural remodeling of the atrium is observed even after relatively short episodes of AF,[5–7,22–27]and these structural changes are likely not reversible. Finally, the number of AF episodes triggered by foci in the pulmonary veins19may not decrease over time despite aggressive restoration of sinus rhythm.

Studies with a new generation dual-chamber defibrillator28–31have also shown the feasibility and safety of atrial defibrillator therapy in patients with drug-refractory recurrent AF. However, tolerance of shock therapy in these studies28–31seemed to be higher than in our longer follow-up study. The reasons for this observation are not completely clear, most likely differences in patient selection are responsible.

Patient discomfort associated with defibrillation has recently spurred interest in the development of painless methods of arrhythmia termination, assuming that the use of pacing therapies would reduce the need for shock therapy. Friedman and colleagues32described the experience with the Jewel AF in patients with a standard ICD indication and two episodes of atrial tachyarrhythmias in the year preceding ICD implantation. In their study, pacing and shock therapies for prevention and/or termination of AF were used in this group of patients who had significantly more advanced structuralheart disease than patients who received a METRIX device.14–16,18During a 3 month period, atrial therapies resulted in a significant reduction in ‘AF burden’ compared to a 3 month period when these therapies were turned off. However, no specific comment regarding shock tolerance in case of frequent AF recurrences was made. Interestingly, burden reduction persisted even when patients treated only with painless pacing therapies were considered.32These observations suggest that a device with both pacing and shock therapies may have much greater clinical utility than a shock-only device because the observed episode reduction (both number and duration) may enhance tolerability of device therapy for atrial arrhythmias.

4.3. Clinical implications
Device therapy should be considered for symptomatic patients with drug-refractory recurrent AF, most likely in combination with and not as a substitute to antiarrhythmic drug treatment. Some of the limitations of the first-generation device used in this study, mainly the insufficient defibrillation energies and the lack of dual-chamber pacing capabilities, have been overcome by improvements in device technology.28–32

However, the problem of patient intolerance to multiple painful cardioversion shocks encountered with the METRIX device remains. In contrast to the ventricular defibrillator which is designed to provide a very rapid response to a life-threatening arrhythmia, the atrialdefibrillator is designed to improve the patient's quality of life, by providing treatment to an often highly symptomatic but not life threatening arrhythmia. Because improvement of quality of life (and not necessarily improvement of prognosis) is the goal, the patient's perception of the therapy is central to its success. The first cardioversion shock needs to be highly successful in restoring sinus rhythm because shock energies for successful cardioversion with currently used shock waveforms and vectors are significantly higher than those reported to be tolerable without sedation or analgesia.11,18,28,30,33–36Therefore, the number of episodes requiring cardioversion is critical, and frequent arrhythmia recurrence may prevent long term use ofsuch a therapy. In this respect, the problem of ERAF6,16,29,30,37–43is of particular importance, and—unless solved—it will prevent more wide-spread use of device therapy for AF.

Nighttime delivery of shock therapy,31antiarrhythmic drug therapy (reducing the number of AF episodes and the incidence of ERAF, increasing shock efficacy, and reducing the energy requirements for successful cardioversion),44–49changes in shock waveform and shock vectors (decreasing the energy requirements for successful cardioversion),50–53and additional (preventive and anti-tachycardia) pacing capabilities28,32,54–57may be ways to increase patient tolerance of device therapy in the future.

4.4. Study limitations
The results of this study should be interpreted in light of certain methodologic limitations. The major limitation of the study is its observational character, this was not a randomized controlled trial. Therefore, more strict statistical analysis of the data is not possible. However, to the best of our knowledge, this is the first study to address the long-term tolerability of aggressive rhythm maintenance therapy in severely symptomatic patients outside of studies under clinical conditions.

5. Conclusions

Long-term use of an implantable atrial defibrillator to maintain sinus rhythm is feasible in a proportion of patients with symptomatic, drug-refractory paroxysmal or persistent AF. Second-generation devices, incorporating higher energy shocks, dual-chamber pacing capabilities, and additional non-shock treatment options may help to overcome most of the limitations of the device used in this study, and device therapy may become a valuable addition to the therapeutic armamentarium for patients with recurrent symptomatic AF.

However, patient selection will remain critical to achieve maximum benefit long term, and the problem of frequent AF recurrences remains the single most important obstacle for more wide-spread use of device-based therapy.

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