In patients with persistent atrial fibrillation (AF), an extensive antiarrhythmic drug (AAD) therapy using class III AADs and class I AADs might be more effective in restoring sinus rhythm than class I or III AADs alone. However, the significance and efficacy of this treatment before radiofrequency catheter ablation is unclear. The present study included 51 consecutive patients with long-lasting persistent AF (>12 months) in whom ≥2 previous AADs had failed to restore sinus rhythm (SR). Before performing extensive pulmonary vein isolation, extensive AAD therapy for >3 months was attempted. Before ablation, AF had converted to SR in 33 patients (65%; SR group) and had continued in 18 (35%; AF group). The left ventricular ejection fraction had increased (p <0.01) in association with the improved left atrial diameter (p <0.05) and brain natriuretic peptide plasma level (p <0.001) in the SR group. However, these parameters had not improved in the AF group. The AF-free rate without any AADs at 14 months after a single ablation procedure was greater in the SR group (61%) than in the AF group (22%; hazard ratio 2.62, 95% confidence interval 1.22 to 5.63; p = 0.013). No restoration of SR with extensive AAD therapy (odds ratio 4.493, 95% confidence interval 1.143 to 17.658; p <0.05) and sustained AF lasting for >3 years (odds ratio 4.574, 95% confidence interval 1.027 to 20.368; p <0.05) before ablation were associated with AF recurrence after ablation. In conclusion, restoration of SR with improved cardiac function and structural remodeling after extensive AAD therapy might predict favorable outcomes after ablation in patients with long-lasting, persistent AF.
Persistent atrial fibrillation (AF) can cause atrial and ventricular remodeling, with chamber dilation and dysfunction. However, the restoration and maintenance of sinus rhythm (SR) with antiarrhythmic drug (AAD) therapy or catheter ablation can improve those adverse changes. Left atrial (LA) volume and ventricular function are reported to be predictors of outcome after ablation. We hypothesized that, in patients with long-lasting, persistent AF, the restoration and maintenance of SR using extensive AAD therapy, with resultant improvement in cardiac size and function before ablation, would result in favorable, long-term outcomes after ablation. We also believed that maintenance of SR after ablation would result in additional improvement in cardiac size and function. Accordingly, the purpose of the present study was to clarify the efficacy and safety of this hybrid therapy using an extensive AAD regimen consisting of class I AADs and class III AADs before catheter ablation in patients with long-lasting, persistent AF.
Methods
The present study included 51 consecutive patients with drug-resistant, persistent AF (7 women, mean age 60 ± 9 years, range 36 to 74; Table 1 ). These 51 patients underwent combined therapy with class III and I AADs (extensive AAD therapy) before undergoing catheter ablation. All patients had had long-lasting, persistent AF, defined as continuous AF lasting for >12 months before enrollment in the present study. The mean duration of AF was 36 ± 40 months (range 12 to 180). All patients had a history of treatment with a single class I AAD (n = 39) or class III AAD (n = 3) alone, or both, with different AADs during a different period (n = 9) that had failed to restore SR ( Table 1 ). The exclusion criteria were (1) New York Heart Association class III or IV congestive heart failure, (2) myocardial infarction or revascularization procedure within the previous 3 months, (3) previous catheter ablation for AF, (4) a history of sinoatrial node dysfunction, (5) a history of syncope due to polymorphic ventricular tachycardia or AAD therapy, (6) severe hepatic disease (total bilirubin >2.0 mg/dl) or renal dysfunction (serum creatinine >1.5 mg/dl), and (7) corrected QT interval of >500 ms on the baseline electrocardiogram (ECG). All patients had received warfarin as anticoagulation therapy. The institutional review committee had given ethical approval, and all patients gave their written informed consent before participation.
| Variable | Total (n = 51) | SR Group (n = 33) | AF Group (n = 18) | p Value |
|---|---|---|---|---|
| Age (years) | 60 ± 9 | 59 ± 10 | 60 ± 7 | 0.70 |
| Men | 44 (86%) | 27 (82%) | 17 (94%) | 0.40 |
| Structural heart disease | 3 (6%) | 2 (6%) | 1 (6%) | 1.00 |
| Duration of sustained atrial fibrillation (mo) | 33 ± 42 | 24 ± 34 | 52 ± 50 | <0.05 |
| Total No. of antiarrhythmic drugs used previously | 2.5 ± 0.8 | 2.6 ± 0.7 | 2.4 ± 1.0 | 0.44 |
| Other drugs | ||||
| Angiotensin-converting enzyme inhibitor/angiotensin receptor antagonist | 33 (65%) | 19 (58%) | 14 (78%) | 0.22 |
| β blockers | 33 (65%) | 22 (67%) | 11 (61%) | 0.76 |
| Statins | 10 (35%) | 8 (24%) | 2 (11%) | 0.46 |
| Hypertension | 27 (53%) | 19 (58%) | 8 (44%) | 0.40 |
| Diabetes mellitus | 4 (8%) | 4 (12%) | 0 (0%) | 0.28 |
| Total bilirubin (mg/dl) | 0.8 ± 0.3 | 0.7 ± 0.3 | 0.8 ± 0.4 | 0.58 |
| Creatinine (mg/dl) | 0.9 ± 0.1 | 0.9 ± 0.1 | 0.9 ± 0.2 | 0.35 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 68 ± 12 | 68 ± 12 | 68 ± 12 | 0.99 |
| Echocardiography parameters | ||||
| Left atrial diameter (mm) | 44.3 ± 6.7 | 44.0 ± 6.7 | 44.7 ± 6.7 | 0.76 |
| Left ventricular ejection fraction (%) | 57.7 ± 10.0 | 58.2 ± 9.7 | 56.5 ± 11.1 | 0.63 |
| Left ventricular end-diastolic diameter (mm) | 49.0 ± 4.8 | 49.1 ± 4.1 | 48.8 ± 6.3 | 0.86 |
| Plasma brain natriuretic peptide level (pg/ml) | 133 ± 102 | 122 ± 75 | 172 ± 160 | 0.22 |
| Extensive antiarrhythmic drug therapy before catheter ablation | ||||
| Bepridil | 27 (53%) | 24 (73%) | 3 (17%) | <0.001 |
| Plus flecainide | 21 (41%) | 20 (61%) | 1 (6%) | <0.001 |
| Plus aprindine | 4 (8%) | 2 (6%) | 2 (11%) | 0.61 |
| Plus pilsicainide | 1 (2%) | 1 (3%) | 0 (0%) | 1.00 |
| Plus propafenone | 1 (2%) | 1 (3%) | 0 (0%) | 1.00 |
| Amiodarone | 24 (47%) | 9 (27%) | 15 (83%) | <0.001 |
| Plus flecainide | 8 (16%) | 3 (9%) | 5 (28%) | 0.11 |
| Plus aprindine | 5 (10%) | 2 (6%) | 3 (17%) | 0.33 |
| Plus pilsicainide | 3 (6%) | 1 (3%) | 2 (11%) | 0.28 |
| Plus propafenone | 8 (16%) | 3 (9%) | 5 (28%) | 0.11 |
| Electrocardiographic findings | ||||
| Before antiarrhythmic drug therapy | ||||
| Heart rate (beats/min) | 84 ± 17 | 83 ± 15 | 87 ± 22 | 0.47 |
| Corrected QT (ms) | 419 ± 33 | 418 ± 36 | 421 ± 27 | 0.74 |
| After treatment with antiarrhythmic drugs | ||||
| Heart rate (beats/min) | 60 ± 11 | 57 ± 8 | 68 ± 17 | <0.05 |
| Corrected QT (ms) | 446 ± 34 | 451 ± 30 | 433 ± 41 | 0.10 |
Before ablation, whether SR had been spontaneously restored with ≥3 months of extensive AAD therapy (class I and III AADs) was evaluated. Flecainide (100 to 150 mg/day), aprindine (20 to 40 mg/day), pilsicainide (75 to 100 mg/day), and propafenone (75 to 100 mg/day) were the class I AADs, and bepridil (100 to 200 mg/day) and amiodarone (100 to 200 mg/day) were the class III AADs.
All patients were followed up at least once per month at the outpatient clinic of Tsukuba University Hospital. On each visit, the patients underwent 12-lead electrocardiography to evaluate whether the SR had been restored and to not miss any findings of an overdose of the AADs. Twelve-lead electrocardiography and/or 24-hour Holter electrocardiography were also performed if the patient reported dizziness or near-syncope, suggestive of torsades de pointes or bradycardia. If the QT interval was prolonged (corrected QT >500 ms) within 1 month after extensive AAD therapy, bepridil or amiodarone was discontinued, or the dose was decreased. No external transthoracic cardioversion to restore SR was performed in any of the patients while they were receiving extensive AAD therapy.
At least 3 months after the initiation of extensive AAD therapy, extensive pulmonary vein (PV) isolation was performed in each patient using the double-Lasso technique, as previously described. All antiarrhythmic medications were discontinued 5 half-lives before the procedure, with the exception of amiodarone, which was discontinued ≥2 weeks before catheter ablation. After transseptal catheterization, two 7Fr 10-polar ring catheters (Lasso, Biosense Webster, Diamond Bar, California) and a 7Fr quadripolar ablation catheter with an 8-mm distal electrode and deflectable tip (Ablaze, Japan Lifeline, Tokyo, Japan) were positioned in the left atrium. After selective PV angiography, 2 Lasso catheters were positioned inside the upper and lower PVs, within 5 mm of the ostium, to map the PV potentials. Before ablation, internal cardioversion was attempted to restore SR in all patients with AF. If the cardioversion failed to restore SR, we began ablation during ongoing AF. After completing extensive PV isolation, we performed a repeat cardioversion to achieve SR. The end point of the extensive PV isolation was the creation of an extensive ipsilateral bidirectional conduction block from the atrium to the PVs and vice versa.
The patients remained hospitalized with continuous rhythm monitoring for about 1 week after the procedure. After discharge, the patients underwent follow-up at 2 weeks after the procedure and then every month at our cardiology clinic. On each visit, the patients underwent 12-lead electrocardiography and intensive questioning regarding any arrhythmia-related symptoms. A 24-hour Holter ECG was performed at least twice during the follow-up period. Portable electrocardiographic monitoring (HCG-901, Omuron, Kyoto, Japan) for 3 minutes was also performed twice daily (morning and night) for 3 consecutive days at 2 weeks and 1, 3, 6, and 14 months after ablation. Twelve-lead ECGs, 24-hour Holter ECGs, and portable electrocardiographic monitoring were also used if the patients reported palpitations. If any ECG documented an AF episode during the follow-up period, the patient was diagnosed with a clinical recurrence of AF, irrespective of the presence of symptoms. However, AF recurrence within the first month only was considered transient, and a blanking period of 4 weeks was applied.
Echocardiography was also performed at least twice (before AAD therapy and just before ablation). It was also performed >6 months after ablation in selected patients. The measurement variables of echocardiography were obtained 3 times at each examination, and each measurement was averaged. Echocardiography was performed and assessed by experienced physicians who were unaware of any clinical information on the patients. The plasma brain natriuretic peptide (BNP) level was measured periodically using an immunoradiometric assay and monoclonal antibodies specific to BNP.
All variables are expressed as the mean ± SD and were compared using Student’s t test. Categorical variables were compared using chi-square analysis and Yate’s correction, if necessary. Logistic regression analysis was used to identify the predictors of AF recurrence after ablation. The interval to AF recurrence was estimated using the Kaplan-Meier method, with comparisons made using the log-rank test. A p value <0.05 was considered statistically significant.
Results
By 44 ± 35 days (range 13 to 153) after extensive AAD therapy, AF had converted to SR in 33 patients (65%; SR group) but not in 18 patients (35%; AF group; Table 1 ). No difference was found in the baseline data in age, gender, prevalence of structural heart disease, echocardiographic parameters, or plasma BNP level between the 2 groups ( Table 1 ). However, the total duration of sustained AF was longer in the AF group than in the SR group (p <0.05; Table 1 ). The prevalence of AF for >3 years in the AF group was 44% compared to 21% in the SR group, although the difference was not statistically significant (p = 0.08).
In the SR group, the left ventricular ejection fraction had increased (p <0.01), and the LA diameter (p <0.05) and plasma BNP level (p <0.001) had decreased at the end of the extensive AAD therapy ( Figure 1 ). In contrast, in the AF group, no significant difference was found in these parameters before and after extensive AAD therapy.
During extensive AAD therapy, 4 patients (7.8%) experienced an adverse effect from the AADs. Two patients discontinued the class III AADs because of severe bradycardia (heart rate <40 beats/min). A marked prolongation of the QT interval (corrected QT >500 ms) was found in the remaining 2 patients. Of the latter 2 patients, 1 had been taking bepridil (200 mg/day) and flecainide (100 mg/day) and 1, bepridil (150 mg/day) and flecainide (150 mg/day). Both patients discontinued the class III AADs and continued taking the class I AADs. In 3 of these 4 patients, SR had been already restored when the adverse effect was found, and SR was maintained until catheter ablation. These 3 patients were included in the SR group. The remaining patient, in whom SR had not been restored before ablation was included in the AF group. No patient demonstrated any torsades de pointes during treatment.
Radiofrequency catheter ablation was performed 171 ± 81 days (range 94 to 444) after the initiation of extensive AAD therapy. Extensive PV isolation and the creation of a bidirectional block line at the cavotricuspid isthmus were achieved in all patients. The results and data from catheter ablation are listed in Table 2 . Extensive PV isolation was initially performed during AF in 7 patients (14%) because of failed cardioversion to restore SR (n = 3) or immediate recurrence of AF (n = 4) at the beginning of ablation. In 15 patients (28%) with no restoration of SR at the end of extensive PV isolation, additional ablation, including linear ablation at the LA roof, isolation of the superior vena cava, and/or ablation of the complex fractionated atrial electrograms was performed. Ten patients (19%) required cardioversion at the end of the ablation procedure. The prevalence of this requirement was less in the SR group (n = 3) than in the AF group (n = 7; p <0.05).
| Variable | SR Group (n = 33) | AF Group (n = 18) | p Value |
|---|---|---|---|
| Total duration of procedure (min) | 305 ± 71 | 345 ± 86 | 0.09 |
| Total duration of radiofrequency energy application (min) | 54 ± 17 | 63 ± 24 | 0.13 |
| Total radiofrequency energy applications | 84 ± 28 | 75 ± 29 | 0.27 |
| Prevalence of additional ablation | 10 (30%) | 5 (28%) | 1.00 |
| Roof line | 8 (24%) | 3 (17%) | 0.72 |
| Superior vena cava isolation | 5 (15%) | 2 (11%) | 1.00 |
| Complex fractionated atrial electrogram ablation | 3 (9%) | 3 (17%) | 0.66 |
| Cardioversion failed to restore SR or immediate atrial fibrillation recurrence present at beginning of ablation | 2 (6%) | 5 (28%) | 0.08 |
| Cardioversion required at end of catheter ablation | 3 (9%) | 7 (39%) | <0.05 |
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