Nationwide Survey of Catheter Ablation for Atrial Fibrillation: The Japanese Catheter Ablation Registry of Atrial Fibrillation (J-CARAF)

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1 Circulation Journal Official Journal of the Japanese Circulation Society LATE BREAKING COHORT STUDIES (JCS 2014) Nationwide Survey of Catheter Ablation for Atrial Fibrillation: The Japanese Catheter Ablation Registry of Atrial Fibrillation (J-CARAF) Report of 1-Year Follow-up Yuji Murakawa, MD, PhD; Akihiko Nogami, MD; Morio Shoda, MD; Koichi Inoue, MD; Shigeto Naito, MD; Koichiro Kumagai, MD; Yasushi Miyauchi, MD; Teiichi Yamane, MD; Norishige Morita, MD; Ken Okumura, MD on behalf of the Japanese Heart Rhythm Society Members Background: A nationwide survey of catheter ablation for atrial fibrillation (AF) was conducted in Japan to determine the mid-term performance of the therapy from analysis of the 1-year outcome of registered patients. Methods and Results: A total of 2,137 patients who underwent AF ablation in September 2011 and March 2012 were initially registered. In 2013, the 1-year follow-up data of 1,208 patients (56.5% of 2,137) from 119 centers were collected. Average age was 61.9±10.7 years. Patients with paroxysmal AF () constituted 64.3%. Persistent AF () and long-standing (LS-) were 20.4% and 15.3%, respectively. For all patients, 76.7% underwent their first AF ablation. At 1 year after AF ablation, 70.9%, 61.4%, and 56.2% of,, and LS- patients, respectively, were free from AF or clinical/partial success ( vs. or LS-: P<0.01). Re-ablation was performed in 11.3%, 16.3%, and 17.3%, respectively. Multivariate logistic regression analysis revealed that procedure time (odds ratio [OR] 0.82, P=0.000), and results of AF induction test (OR 1.36, P<0.02) were significantly related to successful outcome. Conclusions: Approximately 70% of and 60% of non patients were free from AF recurrence or had clinical/ partial success status. Shorter procedure time and elimination of AF inducibility were independent predictors of midterm success of AF ablation. (Circ J 2014; 78: ) Key Words: Ablation; Atrial fibrillation; Catheter ablation; Follow-up studies; Outcomes Catheter ablation has become an effective, but still evolving, treatment for atrial fibrillation (AF). Advantages and disadvantages of AF ablation have been assessed from various aspects such as the incidence of complications, long-term outcome, or cost effectiveness. 1 4 Because novel techniques and devices are being constantly introduced into clinical practice, continuous effort is necessary to confirm whether the treatment in each country conforms to the international standard. 5 The Japanese Heart Rhythm Society (JHRS) initiated a nationwide registry of AF ablation (the Japanese Catheter Ablation Registry of Atrial Fibrillation [J-CARAF]), 6 8 with the aim of obtaining a perspective of the performance and safety of this treatment in Japan. Although some clinical studies have reported that AF ablation is a better choice than antiarrhythmic drug (AD) therapy for the maintenance of sinus rhythm, 9 11 no small number of Received January 28, 2014; revised manuscript received March 10, 2014; accepted March 11, 2014; released online March 21, 2014 Time for primary review: 23 days Fourth Department of Internal Medicine, Teikyo University, Kawasaki (Y. Murakawa); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba (A.N.); Department of Cardiology, Tokyo Women s Medical University, Tokyo (M.S.); Cardiovascular Center, Sakurabashi Watanabe Hospital, Osaka (K.I.); Division of Cardiology, Gunma Prefectural Cardiovascular Center, Maebashi (S.N.); Heart Rhythm Center, Fukuoka Sanno Hospital, Fukuoka (K.K.); Division of Cardiology, Nippon Medical School, Tokyo (Y. Miyauchi); The Department of Cardiology, The Jikei University School of Medicine, Tokyo (T.Y.); Division of Cardiology, Tokai University Hachioji Hospital, Hachioji (N.M.); and Division of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki (K.O.), Japan This paper was presented at the 78 th Annual Scientific Meeting of the Japanese Circulation Society, Late Breaking Cohort Studies 2-4 (March 22, 2014, Tokyo, Japan). Mailing address: Yuji Murakawa, MD, PhD, Fourth Department of Internal Medicine, Teikyo University School of Medicine, Mizonokuchi, Takatsu-ku, Kawasaki , Japan. murakawa@med.teikyo-u.ac.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 1092 MURAKAWA Y et al. Table 1. Comparison of the Clinical Features of Patients With,, or LS- Undergoing AF Ablation LS- (n=777) (n=246) (n=185) vs. vs. LS- vs. LS- Age (years) 62.1± ± ±10.2 Sex (M/F) 586 (75.4%)/ (76.4%)/ (82.7%)/32 Previous history of AAD 630 (81.0%) 197 (80.8%) 121 (65.4%) <0.01 <0.01 CHA2DS2-VASc score 1.60± ± ±1.34 Lone AF 194 (25.0%) 42 (17.1%) 44 (23.8%) <0.05 LVEF (%) 64.9± ± ±9.9 <0.001 <0.001 LAd (mm) 38.8± ± ±5.7 <0.001 <0.001 <0.002 AAD, antiarrhythmic drug; LAd, left atrial dimension; LS-, long-standing persistent atrial fibrillation; LVEF, left ventricular ejection fraction;, paroxysmal atrial fibrillation;, persistent atrial fibrillation. patients require ADs or repeat ablation after initial AF ablation. Furthermore, because persistent AF () and long-standing (LS-) have come to be extensively treated by catheter ablation, there have emerged concerns about how to identify or LS- cases suitable for ablation. 12 In this report, we assessed the 1-year outcome of ablation therapy for paroxysmal AF () and non ( and LS-), and analyzed the association between clinical or procedural features and mid-tem outcome. The goal of the study was to offer a perspective of the current status of AF ablation in Japan, and to elucidate the factors related to favorable outcome. Methods Patients Characteristics The study s methods and the list of participating institutes have been reported. 6 In short, the survey was performed retrospectively using an online questionnaire to JHRS members. Clinical profiles and procedural information of AF ablation in patients who underwent AF ablation in September 2011 or May 2012 were collected. Clinical profiles included age, sex, previous AF ablation, AF type (,, or LS-), thromboembolic risk factors, structural heart disease, echocardiographic parameters, and pre- and postprocedural pharmacological treatments. Procedural data, such as the method of pulmonary vein isolation (PVI) and supplementary modification of the atrial substrate, were also collected. When programmed stimulation failed to induce 5-min AF at the end of ablation, AF inducibility was considered eliminated. The number of procedures performed in each institution, namely, 10 or more procedures per month, was used to identify high-volume centers. 1-Year Follow-up From April to October in 2013, detailed data during the year after the index AF ablation of each patient were collected. Arrhythmic status, use of ADs and other related agents such as oral anticoagulants, AF recurrence, and re-ablation were reported. The time to recurrence was expressed in months based on symptom and/or ECG documentation. In patients with AF recurrence confirmed 1 year after ablation but without a reliable clue to the date of recurrence, the time to recurrence was considered to be 12 months for the sake of analytical convenience. A blanking period of 3 months was taken into consideration. 13 Successful 1-year outcome included both freedom from AF/ AFL (atrial flutter)/at (atrial tachycardia) recurrence and clinical/partial success defined by the 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation. 13 Statistical Analysis Continuous variables with a normal distribution are expressed as the mean ± SD. The comparison of categorical variables was done using Tukey s test. Kaplan-Meier curves of AF-free survival were generated. Comparisons between and non patients were done by 2-sided log-rank test. Logistic regression analysis was applied to determine how each clinical variable related to the outcome. Variables with a <0.1 in the univariate analysis were selected for multivariate logistic regression analysis. In addition, patients with and those with non were separately analyzed to assess whether predictive factors for the mid-term outcome of AF ablation varied among the different AF types. Relative risks are expressed as odds ratio (OR) with 95% confidence interval (CI). P<0.05 was considered statistically significant. Results Comparison of Clinical Backgrounds In total, 158 institutes reported their data of AF ablation. A total of 2,137 cases were registered and 1-year follow-up data were obtained for 1,208 of them from 119 centers. Average patient age was 61.9±10.7 years, and 76.7% (n=927) were male. Of all sessions, 76.3% were first AF ablations, 20.2% were second sessions, and 3.5% were subsequent sessions. Patients with constituted 64.3% (n=777), while and LS- were 20.4% and 15.3% (n=246 and 185), respectively. Clinical profiles of the 3 AF types are shown in Table 1. Left ventricular ejection fraction in patients was greater than that of non subjects. Left atrial diameter (LAd) in patients was smaller than in non patients. Comparison of Ablation Methods and Procedural Results Table 2 lists the differences in AF ablation procedures among the AF types. Procedure time for patients (mean: 3.36 h) was shorter than that required to ablate non (3.81 h and 3.60 h). Continuous fractionated atrial electrogram (CFAE) ablation and left atrial (LA) linear ablation were more frequently adopted in non- patients (CFAE: 4.9%, 19.5%, 33.0%, LA linear ablation: 15.4%, 26.4%, 48.1%, P<0.01 between any paired comparison). The number of electrical defibrillations required in patients was smaller than that needed in non- patients. Table 3 compares the postprocedural AF inducibility. Elimination of inducible AF was confirmed in 359 of 443 patients in whom AF induction was attempted (81.0%). Inducible AF was absent in 79.5% of patients and 69.2% of LS- patients (P<0.05 vs. ) in whom the postprocedural AF induction test was performed.

3 Nationwide Survey of AF Ablation 1-Year Follow-up 1093 Table 2. Procedural Data for AF Ablation Among Patients With 3 Types of AF (n=777) (n=246) LS- (n=185) First session 598 (76.9%) 189 (76.8%) 135 (73.0%) vs. vs. LS- vs. LS- Procedure time 3.36± ± ±1.25 <0.001 <0.02 CFAE ablation 38 (4.9%) 48 (19.5%) 61 (33.0%) <0.01 <0.01 <0.01 LA linear ablation 120 (15.4%) 65 (26.4%) 89 (48.1%) <0.01 <0.01 <0.01 No. of electrical defibrillation 0.63± ± ±1.88 <0.001 <0.001 <0.001 CFAE, complex fractionated atrial electrogram; LA, left atrial. Other abbreviations as in Table 1. Table 3. Postprocedural Inducibility Among Patients With 3 Types of AF (n=777) (n=246) LS- (n=185) Inducible 84 (10.8%) 26 (10.6%) 28 (15.1%) Not inducible 359 (46.2%) 101 (41.1%) 63 (34.1%) Not tested 334 (42.9%) 119 (48.4%) 94 (50.8%) Rate of non-inducibility 81.0%* 79.5% 69.2% *Rate of non-inducibility is the ratio of subjects in who AF was not induced to those tested in each AF type. Rate of non-inducibility is significantly higher in than LS- (P<0.05). Abbreviations as in Table 1. Table 4. Medications at the Time of Discharge of Patients With 3 Types of AF Undergoing Ablation LS- (n=777) (n=246) (n=185) vs. vs. LS- vs. LS- Statin 131 (16.9%) 40 (16.3%) 39 (21.1%) ACEI or ARB 200 (25.7%) 74 (30.1%) 67 (36.2%) <0.05 β-blocker 207 (26.6%) 85 (34.6%) 49 (26.5%) <0.05 Oral anticoagulant 747 (96.1%) 241 (96.8%) 181 (97.8%) Antiarrhythmic agent 339 (43.6%) 160 (65.0%) 131 (70.8%) <0.01 <0.01 ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker. Other abbreviations as in Table 1. Figure. Freedom from AF/AFL/AT or clinical/partial success. Kaplan-Meier curves showing arrhythmic status following index AF ablation session for patients and that for non patients. Comparison of curves was made by the log-rank test.

4 1094 MURAKAWA Y et al. Table 5. Clinical Status of Patients With 3 Types of AF Undergoing Ablation at 1 Year After Ablation AD Re-ablation (n=777) (n=246) LS- (n=185) AF/AFL/AT freedom or clinical/partial success 533 (68.6%) 147 (59.8%) 100 (54.1%) + 44 (5.7%) 17 (6.9%) 12 (6.5%) + 18 (2.3%) 4 (1.6%) 4 (2.2%) (3.7%) 11 (4.5%) 8 (4.3%) Poor control or AF/AFL/AT recurrence 15 (1.9%) 12 (4.9%) 12 (6.5%) + 25 (3.2%) 16 (6.5%) 21 (11.4%) Undetermined 113 (14.5%) 39 (15.8%) 28 (15.1%) Successful outcome 551 (70.9%)* 151 (61.4%) 104 (56.2%) No. of patients with re-ablation 88 (11.3%) 40 (16.3%) 32 (17.3%) Use and non-use of antiarrhythmic drugs (AD) at 1 year after AF ablation are expressed by + and, respectively. *P<0.01 vs. and LS-. AFL, atrial flutter; AT, atrial tachycardia. Other abbreviations as in Table 1. Table 6. Univariate Comparison of Relevant Factors Between Patients With and Without Successful Outcome at 1 Year After AF Ablation AF/AFL/AT freedom or clinical/partial success Others No. of patients 806 (66.7%) 402 (33.3%) Patient profile Age (years) 61.9± ± Sex (M/F) 629 (78.0%)/ (74.1%)/ First session (Yes/No) 616 (76.4%)/ (76.1%)/ /non 551 (68.4%)/ (55.8%)/ Lone AF (Yes/No) 187 (23.2%)/ (23.1%)/ CHA2DS2-VASc score 1.60± ± LVEF (%) 63.6± ± LAd (mm) 40.1± ± AF ablation Procedure time (h) 3.37± ± D imaging system (Used/not used) 749 (92.9%)/ (94.0%)/ CFAE (Done/not done) 82 (10.2%)/ (16.2%)/ LA linear ablation (Done/not done) 161 (20.0%)/ (28.1%)/ Cavotricuspid isthmus ablation (Done/not done) 496 (61.5%)/ (59.7%)/ Non-inducible AF*/Inducible or not tested 377 (46.8%)/ (36.3%)/ High-volume center (Yes/No) 523 (64.9%)/ (62.2%)/ Treatment at discharge Oral anticoagulant 775 (96.2%)/ (98.0%)/ Antiarrhythmic drug 392 (48.6%)/ (59.2%)/ Statin 116 (14.4%)/ (23.4%)/ ACEI or ARB 217 (26.9%)/ (30.9%)/ β-blockade 223 (27.7%)/ (29.4%)/ *Non-inducible AF indicates the number of subjects in whom AF was not inducible after ablation. Abbreviations as in Tables 1,2,5. Pharmacological Treatment at the Time of Discharge In total, 1,169 of 1,208 patients (96.8%) were discharged under oral anticoagulant (OAC) therapy. Approximately half of the patients (52.2%) were treated with 1 or 2 ADs (Table 4). A larger proportion of the non patients were given ADs than in the group. 1-Year Outcome The Figure shows Kaplan-Meier curves comparing recurrence-free survival between and non subjects. Clinical status at 1 year after the index ablation is shown in Table 5. Successful outcome was maintained in 70.9%, 61.4%, and 56.2% of,, and LS- patients, respectively ( vs. : P<0.01. vs. LS-: P<0.01). Re-ablation was performed in 11.3 %, 16.3%, and 17.3% of,, and LS- patients, respectively. Adverse events during the 1-year follow-up occurred in 10 subjects: hemorrhagic stroke (n=1), symptomatic ischemic stroke (n=4), pacemaker implantation for sick sinus syndrome (n=2), phrenic nerve injury (n=1), gastroparesis (n=1), and left lower pulmonary vein occlusion (n=1). The latter 3 events were apparently related to AF ablation. Thus, the incidence of clinically overt complications during the year after discharge was 0.25%.

5 Nationwide Survey of AF Ablation 1-Year Follow-up 1095 Factors Related to 1-Year Outcome Type of AF, LAd, procedure time, CFAE ablation, LA linear ablation, results of AF induction test, and use of OAC, ADs, and statins were related to outcome with <0.1 in the univariate analysis (Table 6). The proportion of patients with the status of AF/AFL/AT free or clinical/partial success among those from high-volume centers was 67.7% (523/773), which was comparable with that of patients from other hospitals (65.1% [283/435], P=0.357). As shown in Table 7, multivariate logistic regression analysis showed that procedure time (OR 0.82, P=0.000), elimination of inducible AF (OR 1.36, P=0.02), and statin therapy were significantly related to a successful 1-year outcome after AF ablation. When the patients were separately analyzed, LAd, procedure time, LA linear ablation, OAC, ADs, and statins were associated with 1-year outcome with P<0.01. Among these factors, procedure time (OR 0.73, P=0.000), OAC (OR 0.16, P<0.02), ADs (OR 0.62, P<0.01), and statins (OR 0,62, P<0.05) were factors related to outcome. Analysis of non patients revealed that sex (OR 1.69, P<0.05) and inducibility of AF (OR 1.98, P<0.01) showed significant relationships with the 1-year outcome. Discussion The principal findings of this study were as follows. (1) Initially, 2,137 cases of AF ablation were registered, and 1-year follow up data of approximate half of them were collected. (2) At the time of index AF ablation, there were significant differences in clinical features and procedural results among the 3 AF types. (3) The proportion of 1-year successful outcome was approximately 70% among patients, and approximately 60% among non patients. (4) Shorter procedural time, elimination of AF inducibility, and non-use of statins were associated with successful outcome 1-year after AF ablation. Baseline Characteristics of Patients AF ablation has become a feasible choice of treatment to restore and maintain sinus rhythm. In its early phase, AF ablation was intended only for drug-refractory. Thanks to technological and technical progress, and LS- with preserved cardiac structure can also be treated by ablation, if patients prefer that choice. 14,15 It is important to rationally select patients whose AF substrate is likely to be cured by PVI and/or by some supplemental ablation at sites other than the PV antrum. The LA size is known as 1 determinant of successful ablation, 16 and in the present study, although the mean LAd of the 3 AF types was statistically different, the LA in non patients was not markedly enlarged (mean: 42.8 mm and 44.7 mm). Also, the cardiac function of non patients was considerably preserved. These observations suggest that AF ablation in non patients is currently performed only in strictly selected patients. Procedure time in non subjects was longer than in. CFAE ablation and LA linear ablation were more frequently performed in non patients. Also, electrical defibrillation was more frequently required in non patients. These observations are consistent with the assumption that the AF substrate in non is more extensive and/or comprises multiple mechanisms than in. Postprocedural AF Inducibility and Pharmacological Treatment at the Time of Discharge As shown in Table 3, AF inducibility was assessed in approximately 60% of patients and 50% of non patients. The Table 7. Multivariate Logistic Regression Analysis for the Predictors of Successful 1-Year Outcome After Ablation in Patients With 3 Types of AF Odds ratio (95% CI) /non 1.3 ( ) LAd 0.99 ( ) Procedure time 0.82 ( ) CFAE ablation 0.87 ( ) LA linear ablation 0.84 ( ) Elimination of inducible AF 1.36 ( ) Oral anticoagulant 0.54 ( ) Antiarrhythmic drug 0.77 ( ) Statin 0.61 ( ) CI, confidence interval. Other abbreviations as in Tables 1,2. proportion of subjects in who sustained (>5 min) non-inducible AF was 81% of those tested. Interestingly, AF was not inducible in a comparable proportion of patients (101/127, 79.5%). Elimination of inducible AF was apparently more difficult in LS- patients. Considering the knowledge compiled by many earlier studies and clinical experience of individual physicians, 7 it seems natural that ADs are more frequently prescribed for non patients at the time of discharge. Although the proportions of statin, angiotensin-converting enzyme inhibitor, and angiotensin II receptor blocker use seem to be related to the prevalence of comorbidity, some physicians might have used these agents to ameliorate the remaining AF substrate or inflammatory changes in the myocardium. 1-Year Outcomes As shown in the Figure, the proportion of successful outcome was dependent on the type of AF. This observation is identical to those of earlier studies. 17,18 In the randomized study by Wilber et al, 9 recurrence-free survival rate at 9 months after AF ablation was a little lower than 70%. Because the patients in their study consisted of both and newly-developed (lasting <30 days), the proportion of successful outcome in our study (70.9%) seems substantially comparable with that in their study. Use of ADs, supplementary ablation, procedure time, and AF type are inter-connected. Multivariate logistic regression analysis suggests the significance of procedure time and elimination of inducible AF for a favorable outcome. This observation is not fully consistent with an earlier study in which AF inducibility did not predict mid-term recurrence. 19 Also, the results failed to confirm the advantage of supplementary ablation, cavotricuspid isthmus ablation, CFAE ablation, and LA linear ablation. We could not elucidate the striking relationship between LAd and outcome. 20 This result may be explained by not so many patients with large LA undergoing AF ablation such that the impact of LA size could be decisively detected. Both the complexity of pathological substrate and skill level of the operator may be reflected in the procedure time. It is not possible to quantitatively estimate the skill level of each physician. We included the number of procedures per month into the analysis. Although the number of sessions/month is not a surrogate marker for skill, it may at least elucidate the volume of practice. As a result, successful outcome was observed in 67.7% of patients from high-volume centers and in 65.1% from other hospitals. Thus, our observation did not confirm the view that the frequency of practice has an appreciable influence on the

6 1096 MURAKAWA Y et al. mid-term outcome. Study Limitations Most of the earlier reports were based on the experiences of a single center or a few high-end centers that performed a largevolume of AF ablations. In contrast, J-CARAF is a nationwide registry and the present analysis was based on the data from centers with various backgrounds, different experience levels, and heterogeneous strategies of AF ablation. Thus, we hope that the present observations reflect the status of the real world to a considerable extent. On the other hand, follow-up data were obtained for only half of registered patients. It is undeniable that not a small number of patients who experienced an unfavorable outcome were missing. Pharmacological treatment, frequency of outpatient visit, and judgment of AF recurrence were entrusted to each physician. Extrapolation of the present observations to clinical settings in other countries where the post-ablation pharmacological therapy and follow-up strategy are different from those in Japan may be limited. Inducibility of AF depends on the site and intensity of electrical stimulation. Details of postprocedural AF induction were not included in our survey. It is possible that the prognostic significance of AF inducibility may differ among different stimulation methods. Conclusions There were significant differences in the clinical features and procedural results between and non patients. Approximately 70% of and 60% of non patients had freedom from AF/AFL/AT or clinical/partial success. Shorter procedure time and elimination of AF inducibility were independent predictors of successful outcome 1-year after AF ablation. Acknowledgments This survey was conducted with the voluntary support of the members of the Japanese Heart Rhythm Society. References 1. 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