Assessment of Atrioventricular Junction Ablation and VVIR Pacemaker Versus Pharmacological Treatment in Patients With Heart Failure and Chronic Atrial Fibrillation
A Randomized, Controlled Study
Background—Uncontrolled studies have suggested that atrioventricular junction ablation and pacemaker implantation have beneficial effects on quality of life in patients with chronic atrial fibrillation (AF).
Methods and Results—We performed a multicenter, controlled, randomized, 12-month evaluation of the clinical effects of atrioventricular junction ablation and VVIR pacemaker (Abl+Pm) versus pharmacological (drug) treatment in 66 patients with chronic (lasting >6 months) AF who had clinically manifest heart failure and heart rate >90 bpm on 3 standard ECGs recorded at rest during stable clinical conditions on different days. Before completion of the study, withdrawals occurred in 8 patients of the drug group and in 4 patients of the Abl+Pm group. At the end of the 12 months, the 28 Abl+Pm patients who completed the study showed lower scores in palpitations (−78%; P=0.000) and effort dyspnea (−22%; P=0.05) than the 26 of the drug group. Lower scores, although not significant, were also observed for exercise intolerance (−20%), easy fatigue (−17%), chest discomfort (−50%), Living with Heart Failure Questionnaire (−14%), New York Heart Association functional classification (−4%), and Activity scale (−12%). The intrapatient comparison between enrollment and month 12 showed that in the Abl+Pm group, all variables except easy fatigue improved significantly from 14% to 82%. However, because an improvement was also observed in the drug group, the difference between the 2 groups was significant only for palpitations (P=0.000), effort dyspnea (P=0.01), exercise intolerance (P=0.005), easy fatigue (P=0.02), and chest discomfort (P=0.02). Cardiac performance, evaluated by means of standard echocardiogram and exercise test, did not differ significantly between the 2 groups and remained stable over time.
Conclusions—In patients with heart failure and chronic AF, Abl+Pm treatment is effective and superior to drug therapy in controlling symptoms, although its efficacy appears to be less than that observed in uncontrolled studies because some improvement can also be expected in medically treated patients. Cardiac performance is not modified by the treatment.
Although a few uncontrolled studies1 2 3 4 have suggested the beneficial effect of atrioventricular (AV) junction ablation during long-term follow-up in patients with chronic AF, these did not include a control group of patients with similar arrhythmias treated without catheter ablation. A single controlled trial showed that ablation was superior to medical therapy in improving specific symptoms 15 days after ablation.5 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 al6 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. The main aim of this study was to test the hypothesis that AV junction ablation and VVIR pacemaker (Abl+Pm) treatment is superior to pharmacological therapy in improving quality of life and controlling specific symptoms during a long-term follow-up period in patients affected by manifest heart failure and chronic AF. 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 and conventional drug therapy. Each patient was followed up for 12 months. Comparison was performed at the end of this study period. The study protocol had been 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 caused by 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.
Patients were recruited from September 1993 to June 1996 among subjects referred to our institutions from the emergency room, inpatient service, and outpatient arrhythmia clinic. The study was terminated in July 1997.
Consecutive patients affected by chronic AF (lasting >6 months) who met all the following criteria were considered eligible for inclusion: (1) clinically manifest heart failure responsible for episodes of congestive heart failure or pulmonary edema or persistent severe symptoms including palpitations, dyspnea, easy fatigue, and chest discomfort that limited daily life and were intolerable for the patient; (2) evidence of structural heart disease; and (3) heart rate >90 bpm on 3 standard ECGs recorded at rest during stable clinical conditions on different days.
The following were criteria for exclusion from the study: end-stage heart failure; patients in class IV of the functional classification of the New York Heart Association; acute cardiovascular diseases during the previous 6 months, for example, myocardial infarction, unstable angina, or stroke; associated severe general medical illnesses; significant renal or hepatic disease; history of sustained ventricular tachyarrhythmias; follow-up not possible.
The primary end point was the evaluation of quality of life and specific symptoms during the 12th month after randomization.
Secondary end points were intrapatient comparison of quality of life and specific symptoms between enrollment and month 12; recording of major clinical events occurring during the 12-month study period, for example, death and major morbidities, complications of the treatment, and number of hospitalizations; and objective assessment of cardiac performance at the beginning and end of the study.
These were made at the time of enrollment and at the end of the 12-month study period.
A comprehensive evaluation of the patient’s quality of life was made with the Minnesota LHFQ.7 This 21-item, self-administered questionnaire comprehensively covers physical, socioeconomic, and psychological impairments occurring 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 maximum possible score is 105. In patients with heart failure refractory to conventional therapy, the median score proved to be 52; this decreased to 10 in asymptomatic patients with heart disease.7 In patients with severely symptomatic paroxysmal AF uncontrolled by conventional drugs, the mean score was 50 and decreased to 20 after AV junction ablation and DDDR mode-switching pacemaker treatment.8 The reliability and validity of this questionnaire in detecting therapeutic benefits has been previously demonstrated.8 9 10 11
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 atrial fibrillation both in sequential and in case-control studies.5 It consists of a self-administered semiquantitative questionnaire. Each patient is asked to quantify by means of a score scale (0=absence, 10=maximum score) each of the following symptoms occurring 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.
New York Heart Association Classification
Functional capacity was also assessed objectively by the investigators on enrollment and at the end of the study period, using the 4-class functional classification of the NYHA.
Specific Activity Scale
The Specific Activity Scale assigns 1 to 4 functional classes on the basis of the single most difficult activity the patient can perform from a list of specific activities. It has been shown in particular to be better than the NYHA classification for the evaluation of true class II patients and less likely to underestimate treadmill performance.12
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 patients received a single-chamber rate-responsive pacemaker. Unless otherwise indicated, devices were programmed to the VVIR mode, a lower rate of 80 bpm, an upper rate limit of 120 bpm. The other programmable parameters were set as appropriate for each individual patient.
Patients from both groups underwent the commonly accepted conventional treatments for heart failure, including digitalis, diuretics, angiotensin-converting enzyme inhibitors and nitrates. The patients assigned to the drug arm were also treated with calcium-antagonists, sotalol, and amiodarone when necessary to control rapid ventricular heart rates. During the 12-month study period, changes in drug therapy were permitted to minimize the patient’s discomfort and to further improve the treatment. β-Blockers, amiodarone, and calcium-antagonists were also used in the Abl+Pm group when clinically indicated for other reasons. Antithrombotic therapy was used in accordance with the published guidelines.13 Anticoagulants were prescribed whenever possible at a therapeutic value of INR of 2.5 (tolerance limits 2 to 3). Antiplatelet therapy or no therapy was prescribed when anticoagulants were contraindicated. In patients older than 75 years, the decision to adopt anticoagulant therapy was taken on the basis of careful risk/benefit evaluation.
Patients were seen at the outpatient clinic every 3 months for 12 months. The follow-up visit included the gathering of data on clinical status, symptoms, drug treatments, and side effects. Moreover, on enrollment and at the 12-month visit, the patients underwent 24-hour Holter recording, echocardiography, and exercise stress testing.
This study was performed on ≈30 patients per group. On the basis of a previous study,5 we assumed that the Abl+Pm group had a 60% reduction in palpitations and a 50% reduction in effort dyspnea scores compared with the drug group. This sample size provided 80% power to show difference between groups 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⇓. Sixty-six patients were enrolled. Screening logs were not maintained throughout the trial, but we used data from intermittent surveys to calculate that ≈250 patients affected by heart failure and high rate chronic AF were initially screened. The most frequent reason for noneligibilty was a decrease of heart rate from an initial value >90 bpm to a value <90 bpm during the run-in phase. Baseline characteristics of the study population are shown in Table 1⇓.
In all 32 patients assigned to the Abl+Pm arm, the ablation end point (production of complete, persistent AV block) was reached without complications, with a median of 2 burns (range 1 to 31) at 30 to 40 W. Right-sided ablation was successful in 27 patients and a sequential approach (right- and left-sided ablation) in the other 5. In 3 patients, AV conduction resumed after a few days, and a second procedure was rapidly performed that achieved persistent AV block. Four patients assigned to the drug arm did not complete the study period because of the occurrence of severe symptoms and received ablation and pacemaker treatment after 1, 1, 4, and 6 months.
Primary End Point
At the end of the 12-month study period, the Abl+Pm group patients showed significantly lower scores in palpitations (−78%) and effort dyspnea (−22%) in comparison with those of the drug group (Table 2⇓). When adjusted for baseline values, exercise intolerance, easy fatigue, and chest discomfort also showed significantly lower scores in the Abl+Pm group. Lower scores, although not significant, were also observed for LHFQ, NYHA functional classification, and activity scale.
Secondary End Points
The intrapatient comparisons between enrollment and month 12 are shown in Table 2⇑. There was some improvement in both groups. In the Abl+Pm group all variables improved significantly, except for easy fatigue, from 14% to 82%. In the drug group the scores for LHFQ, palpitation, rest dyspnea, and easy fatigue improved significantly. NYHA class improved in 46% and 37% of the patients and worsened in 7% and 19%, respectively. Activity scale improved in 36% and 33% of the patients and worsened in 7% and 12%, respectively (not significant).
Clinical events occurring during the study period are reported in Table 3⇓. Complications related to ablation occurred in 2 patients: In a patient with severe heart failure an episode of ventricular fibrillation occurred 12 hours after ablation; this was possibly related to inappropriate programming of his permanent pacemaker (inadvertent night-rate drop to a rate of 50 bpm); in the other patient, pulmonary embolism occurred 2 days after ablation, with subsequent full recovery. No complications related to pacemakers were observed during the follow-up.
Cardiac performance, evaluated by means of standard echocardiography and exercise testing, did not differ significantly between the 2 groups and remained stable over time (Table 4⇓). In the subgroups of patients with ejection fraction ≤40% on enrollment, the ejection fraction value was seen, at the month-12 visit, to have increased by 4±10 points in the Abl+Pm group and by 4±16 in the drug group (not statistically different).
As a consequence of the pacemaker, on the month-12 Holter recording, minimum and mean heart rate were higher and maximum heart rate was lower in the Abl+Pm group (Table 4⇑). Antiarrhythmic and cardiovascular drugs administered throughout the study are shown in Table 5⇓. Therapy remained stable during the study period, with a predominance of calcium-antagonist therapy in the drug group and of nitrate therapy in the Abl+Pm group.
Secondary Ablation and Pacemaker Treatment
In the drug group, a total of 10 patients received ablation and pacemaker treatment because of worsening of their symptoms, 4 before the completion of the study and 6 immediately after the month-12 visit, and continued to be followed-up. In 7 of these, outcome measurements were obtained at the time of ablation and 1 year later (Table 6⇓). Ablation and pacemaker treatment caused not only an improvement compared with the time of ablation but also a significant improvement over the initial evaluation on enrollment, being of similar magnitude to that observed in the Abl+Pm group.
To date, ablation and pacemaker treatment of chronic AF have not been evaluated against a control group of medically treated patients during a long follow-up period. We enrolled a heterogeneous population affected by heart failure and AF with a relatively high ventricular rate that caused severe symptoms of heart failure. The characteristics of the population were similar to those of other studies. For example, the mean LHFQ score before ablation was as high as that of 38 to 48 registered by patients with heart failure refractory to conventional therapy who were undergoing studies on the effects of new pharmacological agents.9 10 11 The 1-year mortality rate of our population was 11%, which is very similar to that of the large series of patients affected by AF and mild-to-moderate heart failure enrolled in the V-HeFT II study.14
The main result of this study is that Abl+Pm treatment was effective and superior to drug therapy in controlling specific symptoms, although its efficacy was lower than that observed in the intrapatient comparison, as some improvement was also observed in the medically treated patients. Improvement was greater for the specific symptoms of the disease than for the indexes of health-related quality of life, namely LHFQ, NYHA, and activity scale, which failed to prove a statistically significant benefit. Whether this finding was due to a low sensitivity of these outcome measurements is open to question. However, the absolute decrease of 11 points in LHFQ score observed in the present study in the Abl+Pm group was slightly superior to the 5- to 8-point decrease observed with new inotropic agents in patients with severe heart failure10 11 but inferior to the 30-point decrease observed in patients with paroxysmal AF treated with ablation and pacemaker treatment.8 Given the lack of correlation between change in functional status and improvement in cardiac performance (evaluated by means of echocardiographic and exercise indexes), which remained stable during follow-up, one could suppose that the treatment had a greater effect on those symptoms more directly linked to rapid and irregular rhythm than on the outcome of the underlying heart disease.15 This is supported by the slight (not significant) reduction in adverse clinical events observed in the Abl+Pm group during the study period.
Ablation and pacing treatment is relatively simple to perform, elicits no complications, is safe, and does not cause impairment of cardiac performance, serious adverse effects, or increased risk of death in the 12 months after ablation.
Comparison With Previous Uncontrolled Studies
All previous studies showed that after ablation and pacemaker implantation, patients did better and had improved indexes of quality of life of a similar magnitude to that observed by us in the Abl+Pm group. For example, Natale et al4 ranked palpitations, effort dyspnea, rest dyspnea, exercise intolerance, and easy fatigue, and, after 12 months, found an improvement ranging from 46% to 88%. In our previous study,5 the items of the Specific Symptom Scale had improved by 48% to 96% (3 months from ablation). Geelen et al16 evaluated LHFQ at the baseline and after 6 months and found a 39% decrease (from 36 to 22) in this index. Ellenbogen et al17 found an improvement of 37% in their Physical Function score, of 135% in Physical Limits, and of 46% in Functional Quality of Life, 12 months after ablation. Fitzpatrick et al2 observed a 94% increase in their Quality of Life index; moreover, the pooled score of All Activities increased by 26%. A significant decrease in NYHA class has also been observed.4 5 17 Because of its controlled design, our study demonstrates that not all the benefits were due to ablation and pacemaker treatment per se, as some improvement occurred also in the conventional treatment group. Several factors other than ablation and pacemaker therapy may have contributed to determining the final results on outcome, including more thorough examinations during the study than before, higher motivation of the patients to treat their disease, and an unrecognized clinical instability at the time of enrollment. However, it is well known that many patients, even those affected by end-stage heart failure, may experience an unexpected reversal of their heart failure.18
Several previous studies have suggested that ablation and pacemaker treatment may cause an improvement in cardiac performance as a consequence of rhythm regularization and better rate control. A prospective hemodynamic study16 showed a significant increase in cardiac output from 1.9 to 2.3 L/m2 (6 months after ablation). In a controlled study involving patients in whom the ventricular rate was believed to be well controlled (but irregular), Daoud et al19 found that an increase in cardiac output could be achieved by regularization of the rhythm. The negative hemodynamic consequences of irregular sequences of R-R intervals during AF has been found to be independent of heart rate.20 In case report studies, the reversal of tachyarrhythmia-induced cardiomyopathy has been observed after ablation21 as well as after control of heart rate by means of medical therapy.22 23 24 Echocardiographic left ventricular diameters have been shown to decrease, especially in patients with baseline depressed function, thus leading to improvements in the indexes of systolic function, namely ejection fraction and fractional shortening.3 4 5 17 25 26 27 Exercise capacity has also been seen to improve after ablation.5 27 28 Contrary to these studies, we were unable to show significant modifications of echocardiographic parameters and exercise stress testing either in intergroup or intrapatient comparisons. Even though in patients with depressed left ventricular function we observed a slight increase in the value of the ejection fraction after 12 months, this increase was also observed in the control group, thus making it unlikely that it was due to a beneficial effect of ablation, as supposed in many uncontrolled studies.3 5 17 25 26 The lack of improvement in exercise capacity was also observed in the Ellenbogen study.17 The reason for these differences is unclear. Admittedly, our study did not have the power to show slight differences, if any, in cardiac performance, and we recognize the limitations inherent in the method of assessment of cardiac performance. Indeed, comparing echocardiographic data from several different investigators and between different underlying rhythms and the heterogeneous pathogenesis of the population might have generated confounding results. Furthermore, the low maximal heart rate achieved during stress testing in the Abl+Pm group may have contributed to lower stress tolerance in that population. Moreover, the mean heart rate of our population, evaluated by means of Holter monitoring, was not particularly high and might have been lower than that observed in other studies. On the other hand, the beneficial hemodynamic effect of regularization and rhythm control might have been counteracted by the deleterious effect of asynergic ventricular contraction caused by right apical ventricular pacing.29 30
No case of overt reversal of cardiac dysfunction was observed, suggesting that tachycardia-induced cardiomyopathy is rare in an unselected population of elderly patients with a ventricular rate not particularly elevated and known cause of heart disease. Indeed, tachycardia-induced cardiomyopathy seems to be more likely in patients without evidence of known heart disease and with a very high ventricular rate.21 22 23 24 On the other hand, fortunately, we did not observe any case of severe hemodynamic deterioration caused by severe mitral regurgitation, as occurred after ablation in the population of Vanderheyden et al.31 One explanation could be that we excluded from enrollment the patients with end-stage heart failure and those in NYHA functional class IV, who were probably those at highest risk of adverse outcome. Moreover, the patients who had recurrent episodes of heart failure, worsening of symptoms, or cardiac death were balanced in the Abl+Pm and drug groups, thus suggesting that the natural course of the underlying disease, and not an adverse effect of ablation, was the cause of the unfavorable outcome.
Finally, the results of the study did not evidence an increased risk of death, especially sudden death, either early or late after ablation. Early studies described sudden death in patients after DC ablation of the AV junction.32 33 Life-threatening ventricular arrhythmias and procedure-related death have been observed in the immediate time period after radiofrequency ablation.33 34 35 36 Concern has also been expressed over the high mortality rate late after ablation, along with the uncertainty whether this should be attributed to the natural course of the underlying disease or to an adverse effect of the ablation and pacemaker treatment.13 34 37 However, several authors33 36 37 38 39 have identified DC ablation, postablation bradycardia, failure of temporary pacing, very severe heart failure, and hypokalemia as factors able to predict these complications. Our results suggest that when the above-mentioned factors are under control, life-threatening ventricular tachyarrhythmias are unlikely to occur, that long-term survival is similar to that observed in patients treated with conventional therapy, and that the sudden death rate is slightly lower in ablated patients. However, this conclusion needs further evidence because our study did not have the power to show any slight differences in mortality rates. To summarize, the different results of this study compared with the previous uncontrolled studies give further demonstration of the need to perform clinical trials including a control group before considering a new treatment as established.
In patients with heart failure and chronic AF, the control of rapid and irregular heart rate achieved by ablation and pacemaker treatment can be proposed, in addition to conventional pharmacological therapy, as an efficacious means of improving quality of life without exposing patients to serious adverse effects, complications, or death. However, this study was unable to show a benefit of the treatment on cardiac performance or on the progression of the disease.
- Received January 12, 1998.
- Revision received April 13, 1998.
- Accepted April 27, 1998.
- Copyright © 1998 by American Heart Association
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