Clinical Significance of Early Recurrence After Pulmonary Vein Antrum Isolation in Paroxysmal Atrial Fibrillation

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1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Arrhythmia/Electrophysiology Clinical Significance of Early Recurrence After Pulmonary Vein Antrum Isolation in Paroxysmal Atrial Fibrillation Insight Into the Mechanism Shinsuke Miyazaki, MD; Hiroshi Taniguchi, MD; Hiroaki Nakamura, MD; Takamitsu Takagi, MD; Jin Iwasawa, MD; Hitoshi Hachiya, MD; Yoshito Iesaka, MD Background: Early recurrence of atrial fibrillation (ERAF) is common after pulmonary vein antrum isolation (PVAI); however, the definition, study population, and lesion set are not uniform in prior studies. We examined ERAF for paroxysmal AF while complying with the definition in the latest guidelines. Methods and Results: We included 471 patients undergoing empirical PVAI for paroxysmal AF. ERAF was observed in 180 patients (38.2%) including 49, 16, and 115 within 3, 4 7 days, and 8 90 days, respectively, after the index procedure. ERAF (hazard ratio 6.872; 95% confidence interval ; P<0.0001) was the strongest factor associated with recurrence beyond 3 months (LR) in the multivariable model, and ERAF patients had worse outcomes than those without, regardless of the time to the first ERAF episode. There were no significant differences in the prevalence of PV reconnections and non-pv foci among 29 and 62 patients, respectively, who underwent redo procedures for ERAF within and more than 3 months after the index procedure, and 21 who underwent redo procedures for LR. Re-ablation was associated with a greater freedom from LR (HR 0.443; 95% CI ; P=0.015). Conclusions: ERAF occurred in 38.2% of patients and was strongly associated with LR regardless of the time to the first ERAF episode. Re-ablation for ERAF significantly improved the freedom from recurrent atrial arrhythmias, regardless of the time to the first ERAF episode. (Circ J 2015; 79: ) Key Words: Catheter ablation; Early recurrence; Paroxysmal atrial fibrillation; Pulmonary vein isolation Catheter ablation is an established therapy for drugresistant atrial fibrillation (AF), 1 4 and paroxysmal AF (PAF) is the most eligible indication. Electrical pulmonary vein antrum isolation (PVAI) is a widely accepted strategy for PAF, and the success rate seems to be satisfactory. However, immediate and early recurrence of atrial arrhythmias is common after AF ablation and the mechanism is still under debate This observation is universal, regardless of the energy source, such as radiofrequency (RF) 5 11 or cryothermal energy, 12 and regardless of whether a catheter procedure 5 12 or surgical procedure. 13 The latest guidelines state that recurrent atrial arrhythmias, the blanking period, and early recurrence of AF (ERAF) should be defined as atrial arrhythmias at least 30 s in duration that are documented following catheter ablation, in the first 3 months post-procedure, and recurrence within the first 3 months post-procedure, respectively. 14 Although previous studies reported a correlation between ERAF and recurrence beyond the blanking period, there are substantial differences in several important points. The definition of ERAF, the blanking period, recurrence and endpoints of the procedure are non-uniform and not according to the latest guidelines. In addition, the vast majority of studies had heterogeneous populations with different types of AF (paroxysmal, non-paf) despite considerable differences in the arrhythmia mechanisms and clinical outcome. In the present study, while complying with the definition from the latest guidelines, we aimed to investigate (1) the proportion of patients with ERAF after contemporary PVAI using RF, (2) the effect of ERAF on the clinical outcome, (3) the clinical variables associated with ERAF and recurrence beyond the blanking period, (4) the association of the time to the first ERAF episode and clinical outcome, (5) the association of the time to the first ERAF episode and arrhythmia focus during the repeat procedure, and (6) the effect of re-ablation on the subsequent clinical outcome, in patients undergoing empiric PVAI for PAF. Methods Study Population The study was a retrospective observational study, and consisted Received April 29, 2015; revised manuscript received July 23, 2015; accepted August 3, 2015; released online September 7, 2015 Time for primary review: 25 days Cardiovascular Center, Tsuchiura Kyodo Hospital, Tsuchiura, Japan Mailing address: Shinsuke Miyazaki, MD, Cardiology Division, Cardiovascular Center, Tsuchiura Kyodo Hospital, 11-7 Manabeshin-machi, Tsuchiura , Japan. mshinsuke@k3.dion.ne.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 2354 MIYAZAKI S et al. Table 1. Characteristics of the Study Population of Patients With PAF n 471 Age, years 62.4±11.1 PAF, n (%) 471 (100%) Female, n (%) 131 (27.8%) Structural heart disease, n (%) 53 (11.2%) Hypertension, n (%) 196 (41.6%) Body mass index, kg/m ±3.7 CHADS2 score 0.79±0.94 CHA2DS2-VASc score 1.56±1.40 LA diameter, mm 40.3±5.8 LV ejection fraction, % 66.4±7.2 Pro-BNP, pg/ml 340±1,015 High-sensitivity CRP, mg/dl 0.24±0.78 egfr, ml/min 71.4±19.2 AF, atrial fibrillation; BNP, B-type natriuretic peptide; CRP, C-reactive protein; egfr, estimated glomerular filtration rate; LA, left atrium; LV, left ventricle; PAF, paroxysmal atrial fibrillation. of 471 consecutive patients with PAF who underwent electrical PVAI between October 2010 and September AF was classified according to the guidelines. 14 All patients gave their written informed consent and the study protocol was approved by the hospital s institutional review board. Mapping and Ablation Protocol All antiarrhythmic drugs were discontinued for at least 5 halflives prior to the procedure. The bipolar electrograms were filtered from 30 to 500 Hz. A 7Fr 20-pole 3-site mapping catheter (BeeAT, Japan-Life-Line, Tokyo, Japan) was inserted through the right jugular vein for pacing, recording and internal cardioversion. The electrophysiological study was performed under mild sedation obtained with pentazocine and hydroxyzine pamoate. The ablation was performed according to the strategy described previously. 15 In brief, after a transseptal puncture, PVAI was performed with a 3.5-mm ablation catheter with an externally-irrigated tip (Thermocool, Biosense-Webster, Diamond Bar, CA, USA) using the double-lasso technique under the guidance of a 3D mapping system (CART03, Biosense- Webster). During the procedure, the activated clotting time was maintained at s. The endpoint of the PVAI was achievement of bidirectional conduction block between the left atrium (LA) and the PVs, and any dormant PV conduction revealed by adenosine triphosphate was eliminated. Complete block along the cavotricuspid isthmus was created if common atrial flutter was detected before or during the procedure. During the repeat procedure, the previous lesion set was consolidated. Next, a pacing protocol was undertaken to identify any non-pv triggers during an isoproterenol infusion and by an adenosine injection. Cardioversion of sustained AF was also undertaken to identify any non-pv foci. Follow-up No antiarrhythmic drugs were prescribed after the procedure. The patients underwent continuous, in-hospital ECG monitoring for 2 4 days following the procedure. The first outpatient clinic visit was 3 weeks after the ablation procedure. Subsequent follow-up visits consisted of a clinical interview, ECGs, and 24-h Holter monitoring every 3 months at the cardiology clinic. Patients with palpitations were encouraged to use a patient-activated event recorder. For the detection of any asymptomatic events, we used an external loop recorder (Spider Flash, Sorin, France), which enabled automatic detection of any atrial tachyarrhythmias for 14 consecutive days. 16 Recurrence was defined if an arrhythmia lasting longer than 30 s was documented. A repeat procedure was strongly recommended for patients with recurrence. Statistical Analysis Continuous data are expressed as the mean ± standard deviation for normally distributed variables or as the median [25th, 75th percentiles] for non-normally distributed variables, and were compared using Student s t-test or Mann-Whitney U-test, respectively. Categorical variables were compared using the chi-square test. Parameters with a significance <0.05 in the univariate analysis were entered into a multiple logistic regression analysis. The multivariate Cox method was used to determine the predictors of recurrent arrhythmias. Variables with a P-value <0.05 in the univariate analyses were included in the multivariate Cox regression model. A Kaplan-Meier analysis was used to determine the percentage of patients free from recurrence. The difference in the arrhythmia-free survival was evaluated using the log-rank test. The following variables were evaluated in association with arrhythmia freedom after the procedure: age, sex, body mass index, presence of structural heart disease, hypertension, duration of AF, LA diameter, left ventricular ejection fraction, CHADS2, CHA2DS2-VASc score, pro-b-type natriuretic peptide level, high-sensitivity C-reactive protein level, and estimated glomerular filtration rate (egfr). P<0.05 indicated statistical significance. Results Patients Characteristics and ERAF The baseline characteristics of the 471 patients who underwent successful PVAI are presented in Table 1. The mean followup period was 15.8±11.0 months. Figure 1A shows the freedom from recurrent arrhythmias after a single procedure without applying a blanking period. The first ERAF episode was observed within 3 days, between 4 7 days, and 8 90 days post-procedure in 49, 16 and 115 patients, respectively. In total, 180 (38.2%) had ERAF after the index procedure, and the period to the first ERAF episode was a median 15.0 [ ] days. A larger LA was the sole factor correlated with ERAF as identified by the multivariable analysis (hazard ratio [HR] 1.036; 95% confidence interval [CI] ; P=0.036). Age, CHA2DS2-VASc score and egfr correlated with a recurrence within the first 3 days post-procedure as identified by the univariate analysis, but they were not significant in the multivariable model (Table 2). Other factors, including the clinical characteristics, echocardiographic parameters, and serological parameters, did not correlate with the ERAF. Recurrence Beyond the Blanking Period During a mean follow-up of 15.8±11.0 months, 39 patients (8.3%) experienced recurrence of atrial arrhythmias after the 3-month blanking period. Increased age, female sex, and ERAF were associated with a greater risk of recurrence after the blanking period in the univariate analysis, and ERAF (HR 6.872; 95% CI ; P<0.0001) and female sex (HR 1.229; 95% CI ; P=0.015) were significant in the multivariable model (Table 2). Figure 2 shows the freedom from recurrence after a single procedure in the patients without and with ERAF stratified by the time to the first ERAF episode. Regardless of the period to the first ERAF, the patients with

3 Early Recurrence After PAF Ablation 2355 Figure 1. Freedom from recurrent arrhythmias after a single (A) and last ablation procedure (B). Table 2. Univariate and Multivariable Factors Associated With Recurrence After AF Ablation as Stratified by the Timing of Recurrence Univariate analysis Multivariate analysis HR 95% CI P value HR 95% CI P value After single procedure Recurrence <3 days Age, years CHA2DS2-VASc score egfr, ml/min ERAF (recurrence <3 months) LA diameter, mm Recurrence >3 months Age, years Female ERAF < < All recurrences Female LA diameter, mm After last procedure Age, years Female < CHA2DS2-VASc score CI, confidence interval; ERAF, early recurrence of atrial arrhythmias; HR, hazard ratio. Other abbreviations as in Table 1. ERAF had a worse outcome than those without. Larger LA (HR 1.032; 95% CI ; P=0.007) and female sex (HR 1.510; 95% CI ; P=0.005) were the factors that correlated with any recurrence after a single procedure as identified by the multivariable analysis (Table 2). Re-Ablation and the Clinical Outcome Among 180 patients with ERAF, 29 (16.1%) and 62 (34.4%) patients underwent a second procedure within and more than 3 months, respectively, after the initial procedure. The characteristics of these patients are shown in Table 3. No significant differences were observed with regard to the patients charac- teristics. On the other hand, among 38 patients with recurrence beyond the blanking period after the initial procedure, 21 (55.3%) underwent second procedures. In total, 112 (23.8%) patients underwent second procedures. During the second procedure, PV reconnections were observed in the unilateral and bilateral ipsilateral PVs in 48 (43.8%) and 53 (47.3%) patients, respectively, and ablation targeting non- PV foci was required in 22 (19.6%) patients. There were no significant differences in terms of the prevalence of PV reconnections and non-pv foci among the patients who underwent redo procedures for ERAF within and more than 3 months after the initial procedure and who underwent redo procedures

4 2356 MIYAZAKI S et al. Figure 2. Freedom from recurrent arrhythmias after single ablation procedures in patients with ERAF stratified by the time to the first ERAF episode and those without ERAF. ERAF, early recurrence of atrial arrhythmias. Table 3. Characteristics of Subjects With ERAF Who Underwent an Early or Late Re-Ablation and Those Who Did Not Undergo Re-Ablation ERAF with early redo ERAF with late redo ERAF without redo P value n 29 (16.1%) 62 (34.4%) 89 (49.4%) Age, years 65.7± ± ± Female, n (%) 9 (31.0%) 22 (35.5%) 25 (28.1%) Structural heart disease, n (%) 5 (17.2%) 4 (6.5%) 12 (13.5%) Hypertension, n (%) 13 (44.8%) 22 (35.5%) 35 (39.3%) Body mass index, kg/m ± ± ± CHADS2 score 1.03± ± ± CHA2DS2-VASc score 1.97± ± ± LA diameter, mm 41.4± ± ± LV ejection fraction, % 67.3± ± ± Pro-BNP, pg/ml 407± ± ±1, High-sensitivity CRP, mg/dl 0.10± ± ± egfr, ml/min 66.5± ± ± Abbreviations as in Tables 1,2. for recurrence beyond 3 months after the initial ablation (Figure 3). All PVs were successfully re-isolated during the second procedure. The location of non-pv foci was the right atrium, LA, atrial septum, superior vena cava, and coronary sinus ostium in 6, 3, 4, 4, and 1 patient, respectively. In the remaining 4 patients, the precise location could not be identified. Figure 1B shows the freedom from recurrent arrhythmias after the last ablation procedure. Increased age, higher CHA2DS2-VASc score, and female sex correlated with recurrence after the last procedure as identified by the univariate analysis, and female sex was the sole significant factor in the multivariable model (HR 1.598; 95% CI ; P=0.0004, Table 2). ERAF and Re-Ablation Freedom from recurrent atrial arrhythmias after the last procedure was significantly lower in the ERAF group not undergoing re-ablation when compared with either the group of patients who experienced ERAF and underwent a re-ablation, or the group of patients not experiencing ERAF (P<0.0001; Figure 4). Among 180 patients with ERAF, re-ablation (adjusted HR 0.443; 95% CI ; P=0.015) was independently associated with a lower risk of recurrence after the blanking period in the multivariable analysis. Although age, CHA2DS2- VASc score and female sex were significantly correlated with recurrence after the blanking period in the univariate analysis, they were not significant in the multivariable model (Table 4).

5 Early Recurrence After PAF Ablation 2357 Figure 3. Prevalence of PV reconnections (A) and non-pv foci (B) during the second procedure in patients who underwent redo procedures for ERAF within and more than 3 months after the initial procedure and in patients who underwent redo procedures for recurrence beyond 3 months after the initial procedure. ERAF, early recurrence of atrial arrhythmias; PV, pulmonary vein. Figure 4. Freedom from recurrent arrhythmias after a single ablation procedure in patients with and without ERAF (A). Freedom from recurrent arrhythmias after the last ablation procedure in patients who did and did not undergo redo procedures for ERAF and those without ERAF (B). ERAF, early recurrence of atrial arrhythmias. Table 4. Univariate and Multivariate Factors Associated With Recurrence After the Last Procedure Among Patients With ERAF (n=180) Univariate analysis Multivariate analysis HR 95% CI P value HR 95% CI P value Age, years Female sex CHA2DS2-VASc score Re-ablation Abbreviations as in Tables 1,2.

6 2358 MIYAZAKI S et al. The time to the first ERAF episode was not associated with recurrence after the blanking period. Discussion The results of the present study showed that (1) ERAF is common after PVAI and is the strongest predictor of recurrence after the blanking period in patients with PAF, (2) the clinical outcome beyond the blanking period is similarly worse in patients with ERAF regardless of the time to the first ERAF episode, (3) PV reconnections and non-pv foci are similarly observed during the second procedure regardless of the time to the first recurrent episode, (4) repeat ablation procedures significantly improve the clinical outcome in patients with ERAF, and (5) female sex is an independent predictor of arrhythmia recurrence after both a single and repeat ablation procedure. Clinical Factors Predicting ERAF and Recurrence Beyond the Blanking Period The present study demonstrated that the presence of ERAF was the strongest independent risk factor for arrhythmia recurrence beyond the blanking period. Conversely, the absence of ERAF was associated with a significantly lower risk of recurrence beyond the blanking period. A larger LA was associated with ERAF and any recurrence after a single procedure, presumably because an increased LA diameter was considered to represent advanced structural remodeling. Female sex was associated with recurrence beyond the blanking period, any recurrence after a single procedure, and also after the last procedure. Patel et al 17 showed that the outcomes were worse for females in a large study, and speculated that non-pv foci were one of the causes of a higher recurrence rate. 18 The contribution of the PVs to the mechanism of atrial arrhythmias seemed to be less in females than in males, and it is likely that the limitation of eliminating non-pv foci led to a lower success rate. Clinical Significance of ERAF in PAF Ablation A common clinical dictum is that ERAF often is caused by irritability and of little prognostic importance. In fact, several studies have reported that the majority of the patients with ERAF did not have recurrent arrhythmias after the blanking period. 5,11 However, our study has shown that the majority of patients with ERAF suffered recurrence after the blanking period, which was in line with other reports. 9,12 A possible explanation for these discrepant findings is the duration of the follow-up period and the monitoring intensity. It is likely that a short follow-up period and insufficient intermittent monitoring might miss recurrences beyond the blanking period. The ratio of symptomatic to asymptomatic AF episodes significantly decreases post-procedure, 19 and usually the follow-up intensity decreases with time after the procedure. Nevertheless, prior studies demonstrated that the arrhythmia-free rate continued to decrease during long-term follow-up. 20 Although the setting of the blanking period might be adequate, the use of the word delayed success should be limited to patients undergoing long-term, sufficiently rigorous monitoring after the ablation procedure. These data suggest that particular vigilance is required in monitoring patients with ERAF. In contrast, patients without ERAF can be encouraged that longer term AF freedom is likely. The latest guidelines 14 state that scheduled 7-day Holter ECG recordings or daily plus symptom activated event recordings are estimated to document approximately 70% of arrhythmia recurrences, and recommend intense monitoring after AF ablation procedures. Unfortunately, neither the use of implantable loop recorders for monitoring recurrent arrhythmias post- AF ablation, nor of 7-day Holter monitoring is approved in Japan. We used a 14-day auto-trigger event recorder to overcome this issue in the present study. Mechanism of Arrhythmia Recurrence The mechanism(s) of ERAF remain to be fully elucidated. Several groups 8,21,22 have investigated the role of inflammation during the acute phase post-af ablation, and the results strongly support inflammation playing a prominent role in the etiology of atrial arrhythmia recurrences within a few days post-af ablation, but not after that. Based on these results, it seems likely that the clinical outcome would differ between patients with a first ERAF episode within a few days and patients with a first ERAF episode more than a few days post-procedure. However, interestingly, the present study showed that (1) the clinical outcome was similar regardless of the time to the first ERAF episode in patients with ERAF, (2) the prevalence of PV reconnections and non-pv foci were similar between patients with ERAF and those with recurrence beyond the blanking period, and a significant proportion of patients undergoing a repeat ablation had PV reconnections, and (3) the clinical outcome similarly significantly improved after a redo procedure in the patients with ERAF regardless of the time to the first ERAF episode, which suggested that PV reconnections are clinically relevant and responsible for ERAF. Recently, Jiang et al showed that the prevalence of PV reconnections and LA-PV conduction delays were similar in patients with and without arrhythmia recurrence after PAF ablation. 23 The data suggest that other factors, such as ganglionated plexus (GP), are associated with the manifestation of clinical recurrence. Several basic studies demonstrated that GPs are associated with PV firing, 24 and an additional GP ablation leads to a significant reduction in the arrhythmia recurrence after PAF ablation. 25 Given the published data and our data, we speculate that both substrate and stimulators are required for the clinical manifestation of recurrent arrhythmias. That is, the former might be associated with electrically reconnected PVs, and the latter might be caused by inflammation, GPs, etc. It is possible that the redo procedure similarly eliminated the substrate in these patients, which resulted in the similar longterm outcome after the redo procedure among the patients with different times to the first recurrent episode. It is not surprising that recurrence beyond the blanking period was observed in patients with ERAF when any stimulating factors were added to the remaining substrate. The incomplete understanding of the mechanisms and significance of post-ablation arrhythmias has resulted in controversy regarding the optimal therapeutic strategies, and the appropriate management of ERAF is still in debate. Although we demonstrated an independent association between re-ablation and improved long-term success, the appropriate timing of the redo procedure should be explored in individual cases based on clinical outcome irrespective of the period from the initial procedure. The risks of re-ablation should be balanced against a conservative strategy. Clinical Implications ERAF strongly correlated with clinical outcome beyond the blanking period. The data suggest that particular vigilance is required to state a delayed success. One also may be hesitant to withdraw anticoagulation therapy in such patients, given the poor long-term prognosis. Considering the frequent PV reconnections regardless of the time to the first recurrent episode

7 Early Recurrence After PAF Ablation 2359 post-ablation and significant improvement in the clinical outcome after the redo procedure, a repeat procedure might be proactively considered for patients with ERAF. Study Limitations This study is limited by its retrospective nature. As with all AF outcome studies, the monitoring of the arrhythmia recurrences was subject to practical limitations; however, we had careful follow-up data from a large consecutive series. Conclusions ERAF post-pvai is commonly observed and is the strongest predictor of recurrence beyond the blanking period in patients with PAF. Although the prevalence of ERAF was higher during the earlier period post-procedure, the long-term clinical outcome after a single procedure was similarly poor regardless of the time to the first ERAF episode. Reconnections of PVs and non-pv foci were similarly observed during the second procedure in the patients with ERAF and those with recurrence beyond the blanking period, and a redo procedure significantly improved the clinical outcome of patients with ERAF. Particular vigilance is required long-term in patients with ERAF, regardless of the time to the first ERAF episode. Acknowledgments We thank Mr John Martin for his help with preparation of the manuscript. Disclosures Conflicts of Interest: None. Financial Support: None. References 1. Haïssaguerre M, Jaïs P, Shah DC, Garrigue S, Takahashi A, Lavergne T, et al. Electrophysiological end point for catheter ablation of atrial fibrillation initiated from multiple pulmonary venous foci. Circulation 2000; 101: Nault I, Miyazaki S, Forclaz A, Wright M, Jadidi A, Jaïs P, et al. Drugs vs. ablation for the treatment of atrial fibrillation: The evidence supporting catheter ablation. Eur Heart J 2010; 31: JCS Joint Working Group. 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