Assessment of Atrioventricular Junction Ablation and DDDR Mode-Switching Pacemaker Versus Pharmacological Treatment in Patients With Severely Symptomatic Paroxysmal Atrial Fibrillation
A Randomized Controlled Study
Background The purpose of the study was to evaluate the effect of AV junction ablation and pacemaker implantation on quality of life and specific symptoms in patients with paroxysmal atrial fibrillation (AF) not controlled by drugs.
Methods and Results We performed a multicenter, randomized, 6-month evaluation of the clinical effects of AV junction ablation and DDDR mode-switching pacemaker (Abl+Pm) versus pharmacological treatment in 43 patients with intolerable, recurrent paroxysmal AF of three or more episodes in the previous 6 months not controlled with three or more antiarrhythmic drugs. Before completion of the study, 3 patients in the drug group withdrew because of the severity of their symptoms and 1 patient assigned to the Abl+Pm group in whom the ablation procedure failed. At the end of the 6 months, the 21 patients of the Abl+Pm group who completed the study showed, in comparison with the 18 of the drug group, lower scores in the Living with Heart Failure Questionnaire (−51%, P=.0006), palpitations (−71%, P=.0000), effort dyspnea (−36%, P=.04), exercise intolerance score (−46%, P=.001), and easy fatigue (−51%, P=.02). The scores for rest dyspnea, chest discomfort, and NYHA functional classification were also lower (−56%, −50%, and −17%, respectively) in the Abl+Pm group, although not significantly. At the end of the study, palpitations were no longer present in 81% of the Abl+Pm group and in 11% of the drug group (P=.0000). AF was documented in 31 of 122 visits (25%) in the Abl+Pm group and in 9 of 107 examinations (8%) in the drug group (P=.0005); chronic AF developed in 5 (24%) and 0 (0%) in the two groups, respectively (P=.04).
Conclusions In patients with paroxysmal AF not controlled by pharmacological therapy, Abl+Pm treatment is highly effective and superior to drug therapy in controlling symptoms and improving quality of life. The discontinuation of drug therapy exposes patients to further recurrences of paroxysmal AF and the risk of developing permanent AF.
Although a few small, uncontrolled studies1 2 3 4 have suggested the beneficial effects of AV junction ablation in patients with symptomatic paroxysmal AF, these did not include a control group of patients with similar arrhythmias treated without catheter ablation. Rigorous quantification of the impact of ablation therapy on specific symptoms and on the total well-being of the person, including physical and psychological aspects, has been performed only recently by Bubien et al4 in a wide variety of tachyarrhythmias. After ablation, the patients with AF exhibited persistently lower quality-of-life scores than those with the other types of arrhythmia. However, baseline values were also significantly worse in AF patients; moreover, chronic and paroxysmal AF were considered together, and the type of cardiac pacing was not specified. The main aim of the present study was to test the hypothesis that Abl+Pm treatment is superior to pharmacological therapy in improving quality of life and controlling specific symptoms in patients affected by severely symptomatic paroxysmal AF not controlled by pharmacological therapy. Secondary aims were to evaluate the effect of ablation and pacemaker implantation on cardiac performance and to assess the clinical complications of such treatment.
This prospective, randomized, multicenter trial was designed to compare the clinical efficacy of Abl+Pm treatment with that of conventional antiarrhythmic drug therapy. Each patient was followed up for 6 months. Comparison was performed at the end of this study period. The study protocol was approved by the Ethics Committee of the Hospital of Reggio Emilia and by the institutional review committees of the hospitals participating in the study. The enrolled subjects gave informed consent.
Assignment and Blinding
Randomization was effected centrally, blocking on study centers to minimize possible biases due to differences in patient characteristics between centers. The allocation of sequences was computer generated, and the intervention assignments were hidden from participants in the trial until the time of allocation.
Consecutive patients affected by paroxysmal (electrocardiographically documented) AF who met all the following criteria were considered eligible for inclusion: (1) tachyarrhythmic episodes that caused severe symptoms, including palpitations, dyspnea, easy fatigue, and chest discomfort, that were intolerable for the patient as a consequence of their frequency or as a manifestation of cardiac failure; (2) failure of three or more antiarrhythmic drugs (including amiodarone) to maintain stable sinus rhythm or to control symptoms; (3) three or more episodes of paroxysmal tachyarrhythmia during the previous 6 months; (4) duration of tachyarrhythmic episodes >1 year; and (5) age >50 years.
The following were criteria for exclusion from the study: (1) symptomatic bradycardia in the bradycardia-tachycardia form of the sick sinus syndrome; (2) the need for a pacemaker implant for reasons other than tachyarrhythmia control; (3) acute clinical diseases during the previous 6 months; and (4) associated severe general medical illnesses.
The primary end point was the evaluation of quality of life and specific symptoms during month 6 after randomization.
Secondary end points were (1) intrapatient comparison of quality of life and specific symptoms between enrollment and month 6; (2) recording of major clinical events occurring during the 6-month study period, ie, complications of the treatment, development of permanent AF, number of hospitalizations and/or electrical cardioversions; and (3) objective assessment of cardiac performance at the beginning and end of the study.
These were done at the time of enrollment and at the end of the 6-month study period.
A comprehensive evaluation of the patient’s quality of life was made by use of the Minnesota LHFQ.5 This 21-item, self-administered questionnaire comprehensively covers physical, socioeconomic, and psychological impairments that occurred during the previous month that patients often relate to their heart disease. A score based on how each person ranks each item on a common scale is used to quantify the extent of impairment and how it is affected by therapeutic intervention. The content of the questionnaire is reported in the “Appendix.” The maximum possible score is 105. In patients refractory to conventional therapy, the median score proved to be 52; this decreased to 10 in asymptomatic patients with heart disease.5 The reliability and validity of this questionnaire in detecting therapeutic benefits has been demonstrated previously.6 7 8
Specific Symptoms Scale
The Specific Symptoms Scale was developed as a disease-specific instrument to measure the patient’s perception of the frequency and severity of arrhythmia-related symptoms. This instrument has been demonstrated to discern changes in the symptoms of patients with AF both in sequential and in case-control studies.9 It consists of a self-administered semiquantitative questionnaire. Each patient was asked to quantify by means of a score scale (0=absence, 10=maximum score) each of the following symptoms that occurred during the previous month: palpitations, effort dyspnea (shortness of breath during physical activity), rest dyspnea (shortness of breath at rest), exercise intolerance (fatigue during mild physical activity), easy fatigue at rest, and chest discomfort.
Moreover, functional capacity was also assessed objectively by the investigators on enrollment and at the end of the study period according to the four-class functional classification of the NYHA.
Ablation Procedure and Pacemaker Implantation
The ablation end point was the production of complete, persistent AV block. The ablation procedure was followed, after 1 hour, by pacemaker implantation during the same session. All the patients received a dual-chamber rate-responsive pacemaker (Diamond, Vitatron) equipped with a single algorithm, which is able to identify pathological atrial rhythms and to differentiate them from physiological variations in sinus rate, irrespective of their frequency. The algorithm is based on the heart rate as a whole and on the beat-to-beat change in atrial rate. Gradual increases in atrial rate are identified as physiological and do not result in a change in pacing mode; rapid increases in atrial rate, even if the absolute rate is not particularly high, are classified as pathological and result in a beat-to-beat mode switching from DDDR to DDIR. The pathological atrial rhythm, therefore, no longer needs to exceed the upper rate limit before automatic switching of the pacing mode is activated. Unless otherwise indicated, devices were programmed to mode-switching “auto,” a lower rate of 70 bpm, an upper rate limit of 130 bpm, bipolar atrial sensitivity of 1 mV, atrial refractory period of 260 ms, and atrial blanking of 100 ms. The other programmable parameters were set as appropriate for each individual patient.
On enrollment, the patients assigned to the drug arm were treated with the antiarrhythmic drug regimen that had shown the best efficacy during the patient’s history. During the 6-month study period, changes in drug therapy were permitted in order to minimize the patient’s discomfort and to further improve the best treatment.
The patients assigned to the Abl+Pm arm had their antiarrhythmic drugs discontinued at the time of enrollment, except for 4 patients who were taking digitalis (patient 3) or β-blockers (patient 1) for other reasons. Anticoagulants and aspirin were prescribed in 7 and 8 patients, respectively, of the Abl+Pm arm and in 5 and 8 patients of the drug arm.
Patients were seen at the outpatient clinic every month for 6 months. For each month during this period, patients were given a diary and were asked to record in it whether they had had episodes of paroxysmal tachyarrhythmia (see “Definitions”). This question was included to determine the number of patients affected by clinically relevant paroxysmal tachyarrhythmia likely to be, but not surely, of atrial origin. The follow-up visit included the gathering of data on clinical status, symptoms, drug treatments, adherence to the study regimen, and side effects. Each patient’s diary data and cardiac rhythm at the time of the visit were recorded. Moreover, in the Abl+Pm arm, the pacemaker was interrogated and data concerning pathological atrial rhythms (as defined by the pacemaker algorithm) and device operations were examined.
Permanent AF was defined as AF that had been present during the last two follow-up visits (months 5 and 6).
Paroxysmal tachyarrhythmias were defined as episodes of rapid palpitations lasting more than 1 minute with abrupt onset and termination that occurred during the follow-up and were not documented by the ECG.
This study was performed with 20 patients per group. On the basis of previous studies,5 9 we assumed that the Abl+Pm group had an 80% reduction in palpitation and rest dyspnea scores and a 50% reduction in Minnesota LHFQ score. This sample size provided 90% power to show a 50% rate of difference between this group and the drug group, with a probability of 95%.
Comparison between continuous variables was obtained by paired and unpaired Student’s t test, as appropriate; comparison between proportions was obtained by Fisher’s exact test.
Participant Flow and Follow-up
Progress through the various stages of the trial, including flow of participants, withdrawals, and timing of primary and secondary outcome measures, are shown in the Figure⇓. Baseline characteristics of the study population are shown in Table 1⇓.
In all 22 patients assigned to the Abl+Pm arm, the ablation end point (production of complete, persistent AV block) was reached without complications, with a mean of 7±5 burns (range, 1 to 20) at 30 to 40 W. Right-sided ablation was successful in 15 patients and a sequential approach (right- and left-sided ablation) in the other 6. In 1 patient, AV conduction resumed after a few days, and the patient refused a second procedure. Three patients assigned to the drug arm did not complete the study period owing to the occurrence of severe symptoms. They withdrew from the study and immediately received ablation and pacemaker implantation.
Primary End Point
At the end of the 6-month study period, the Abl+Pm group patients showed significantly lower scores in LHFQ (−53%), palpitations (−71%), effort dyspnea (−36%), exercise intolerance (−46%), and easy fatigue (−51%) in comparison with those of the drug group (Table 2⇓). The scores for rest dyspnea, chest discomfort, and NYHA classification were also lower in the ablation group (−51%, −50%, and −17%, respectively), although not significantly.
Secondary End Points
The intrapatient comparisons between enrollment and month 6 are shown in Table 2⇑. In the Abl+Pm group, all variables except chest discomfort decreased significantly; in the drug group, only palpitation scores decreased significantly.
Clinical events that occurred during the study period are reported in Table 3⇓. Both the documented episodes of AF and the number of patients with permanent AF were higher in the Abl+Pm group. By contrast, the subjective perception of atrial tachyarrhythmias and the number of hospitalizations or electrical cardioversions were higher in the drug group. The data yielded by interrogation of the pacemakers (in the Abl+Pm group) revealed that pathological atrial rhythms (as defined from the specific pacemaker algorithm) had occurred for 24%, 21%, 23%, 25%, 26%, and 30% of the time during each of the 6 months of the study period, respectively; overall, the patients had had a mean of 47 days (25%) of pathological atrial rhythms out of a total duration of the study period of 187 days.
No complication related to ablation or pacemaker occurred during the study. Cardiac performance remained stable over time in both groups (Table 4⇓).
Clinical Failure of Ablation and Pacemaker Therapy
Clinical failure occurred in 3 (14%) of the Abl+Pm group patients, who stated that they had not received any benefit from the therapy. By contrast, the other 18 patients in this group reported improvement in their status. These 3 patients claimed to have had a total of 409 episodes of paroxysmal tachyarrhythmias during the study period; although pacemaker recordings revealed periods of pathological atrial rhythm in all, the temporal correlation between their symptomatic episodes and documented pathological atrial rate was weak. Psychiatric evaluation revealed a severe depressive status in 2 of the 3. These patients had already had a history of depression.
Changes in Treatments During the Study Period
In the drug group, 5 of 18 patients (28%) required changes in their antiarrhythmic drug regimen during the study period. Antiarrhythmic treatments throughout the study period are shown in Table 5⇓.
In the Abl+Pm group, 6 of 21 patients (29%) required arrhythmia-related reprogramming of pacemaker parameters during the study period: in 5 patients, atrial sensitivity was increased to 0.5 mV to obtain a better sensing of AF waves; in 1 patient, the VVIR mode was adopted after the development of permanent AF.
To date, no nonpharmacological treatments of paroxysmal AF have been evaluated against a control group of medically treated patients. We enrolled a small, severely symptomatic population. Apart from palpitation, patients had many symptoms that usually are encountered in patients with heart failure, as shown by the high scores recorded in both LHFQ and Specific Symptoms. The mean LHFQ score before ablation was higher than the 38 to 48 score registered by patients with heart failure refractory to conventional therapy who were undergoing studies on the effects of new pharmacological agents.6 7 8
The main result of this study is that, in a small population of patients affected by severely symptomatic paroxysmal AF not controlled by pharmacological therapy, Abl+Pm treatment is highly effective and superior to drug therapy in controlling symptoms and improving quality of life during the following 6 months. After ablation, the mean improvement varied from 36% to 71% according to the indexed parameter, and the LHFQ score approached that of asymptomatic subjects.5 Palpitations, the most specific symptom of paroxysmal AF, was virtually abolished in 81% of patients at the end of the 6-month study period. Although arrhythmia is paroxysmal, patients are also expected to report a great improvement in general, physical, emotional, and social indexes of their health-related quality of life and not only in arrhythmia-specific parameters. Moreover, the discontinuation of drug therapy exposes patients to further recurrences of paroxysmal AF and the risk of developing permanent AF, although these events do not have a negative impact on the short-term outcome. Ablation and pacing treatment is relatively simple to perform, elicits no complications, is safe, and shows no impairment of cardiac performance at 6 months.
Several factors may have contributed to determining the results of the study. These concern both the choice of the medical treatment and the choice of the pacing modalities.
The use of antiarrhythmic drugs has been demonstrated to significantly increase the probability of maintaining sinus rhythm. For example, in seven comparative trials10 11 12 13 14 15 16 in which a no-drug or placebo regimen was compared with active drug therapy after cardioversion for AF, the use of quinidine, disopyramide, flecainide, or amiodarone increased the proportion of patients remaining in sinus rhythm. Sotalol and propafenone have been found to have efficacy comparable to that of quinidine.17 18 Several studies19 20 21 22 23 24 have suggested that amiodarone may be effective when other agents have failed. Crijns et al25 and Antman et al26 have suggested that the sequential use of flecainide, quinidine, propafenone, sotalol, and amiodarone, when one has failed to maintain sinus rhythm, increases the proportion of patients successfully treated. In the present study, patients were treated in a similar manner; the results suggest that the sequential antiarrhythmic drug therapy was superior to no drug treatment in preventing recurrences of paroxysmal AF and the development of permanent AF, even in a selected population with very severe AF that had been considered to be resistant to multiple pharmacological treatment.
On 6-month intrapatient comparison, the drug group patients showed a significant improvement in palpitation score and a trend toward improvement in some other symptoms (Table 2⇑). The final effects of antiarrhythmic drugs on outcome probably depend on the sum of various factors, including a better control of arrhythmic recurrences, more thorough examinations during the study than before, higher motivation of the patients to treat their disease, the negative impact (as perceived by the patient) of antiarrhythmic drugs on quality of life, and the potential toxicity and side effects of the drugs. The study was not designed to investigate whether the better outcome observed in the Abl+Pm group was due to the beneficial effect of the nonpharmacological treatment per se or also to the discontinuation of the antiarrhythmic drugs.
The pacing modalities after ablation are likely to have influenced the clinical outcome. In the literature, various pacing modes (VVI, VVIR, DDD, DDDR), algorithms of recognition of atrial tachyarrhythmias, and modes of switching have been proposed.1 2 3 27 28 29 30 31 32 This study was not designed to compare different devices or different modalities of pacing; therefore, the results do not necessarily apply to other pacing modes and algorithms. In patients with paroxysmal AF, AV junction ablation creates an iatrogenic effect only rarely found in patients without ablation, namely, the presence, at one and the same time, of total AV block and paroxysmal atrial tachyarrhythmias.27 28 We preferred the DDDR to the VVIR and DDD modes, because it theoretically restores AV synchrony during sinus rhythm, prevents the development of AF, and provides adequate ventricular rate increase during physical activity in the presence of atrial tachyarrhythmias. To overcome ventricular tracking of rapid atrial activity, various mode-switching algorithms have been developed that are able to change pacing modality automatically from an AV synchronous mode during sinus rhythm to a non-AV synchronous mode during AF. For this purpose, the pacemakers must have an algorithm that is able to identify pathological atrial arrhythmias and to differentiate them from physiological variations in rate. The fast mode-switching devices have been reported to be more effective than the medium and slow mode-switching devices.33 We preferred a fast mode-switching system, which is able to identify pathological atrial rhythms on a beat-to-beat change in atrial rate. In a short-term study,27 this system proved to be able to lower the percentage of abnormal ventricular tracked beats during AF to <4% of total ventricular beats.
In the present study, contrary to the excellent results observed in most cases, the treatment was clinically unsuccessful in 3 patients (14%). A careful analysis of these patients suggested that AF recurrences were only partially responsible for the subjective perception of palpitations. It is quite possible that their symptoms after ablation were also related to DDDR pacing per se or to its inappropriate programming. Weber and Kapoor34 found that psychiatric illness accounts for the cause of palpitations in nearly one third of all patients with palpitations. It is possible that a depressive status (which was present in 2 of our patients) may decrease the threshold of subjective perception of nonphysiological rhythms.
Conclusions and Future Perspectives
At present, in patients in whom drugs are unable to maintain a stable sinus rhythm, the control of rapid heart rate achieved by ablation and pacemaker treatment can be proposed as the preferable mode of treatment. Owing to the higher rate of recurrences of AF (both paroxysmal and permanent) in patients off drugs, one could infer that the results of ablation and pacemaker treatment may be improved by adding pharmacological therapy or by developing more sophisticated pacing modalities able to reduce the recurrence rate of AF. Whether this approach is cost-effective remains to be demonstrated. New nonpharmacological approaches to the prevention of AF, including surgery and endocardial catheter ablation, atrial pacing or implantable atrial defibrillators, or control of rapid ventricular rate by means of AV junction modulation are encouraging, but too few data are available and their recommendation for use awaits results from clinical trials.35 Their efficacy should probably be compared with the definitively proven treatment, namely Abl+Pm.
Several unresolved issues remain regarding the efficacy and safety of Abl+Pm treatment in the long term. The first concerns the long-term effect of the hemodynamic modifications caused by asynchronous ventricular activation as a result of right ventricular apex stimulation and the loss of AV synchrony in the cases in which chronic AF develops. Although some data indicate no increased risk of death or complications during long-term follow-up36 and cardiac performance has proved to be unchanged or improved during an intermediate follow-up, especially in those patients with preablation left ventricular dysfunction,2 3 36 too few data are available on the long-term outcome of these patients to recommend a larger prescription of this treatment for patients with less severe or short-duration AF.
Selected Abbreviations and Acronyms
|Abl+Pm||=||AV junction ablation and DDDR automatic mode-switching pacemaker|
|LHFQ||=||Living with Heart Failure Questionnaire|
Content of the Minnesota LHFQ
These questions concern how your heart condition has prevented you from living as you wanted to during the last month. These items listed below (Table 6⇓) describe different ways in which some people are affected. If you are sure an item does not apply to you or is not related to your heart condition, then circle 0 (No) and go on to the next item. If an item does apply to you, then circle the number rating how much it prevented you from living as you wanted. Remember to think about only the last month.
The authors wish to thank the following cardiologists, whose contribution was essential for the collection of patient data: D. Oddone, G. Gaggioli (Lavagna); N. Bottoni, C. Tomasi (Reggio Emilia); G. Fucà, S. Scarfò, M. Dinelli (Cento); R. Mureddu, A. Ranise (Imperia); F. Vernazza, G. Arena, E. Soldati (Pisa); G.B. Magenta (Milano); M. Gasparini, A. Bonso (Mestre).
- Received February 13, 1997.
- Revision received May 5, 1997.
- Accepted May 28, 1997.
- Copyright © 1997 by American Heart Association
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