International Journal of Cardiology 171 (2014) 174–178
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Documentation of pulmonary vein isolation improves long term efficacy of persistent atrial fibrillation catheter ablation☆,☆☆ Emanuele Bertaglia a,⁎,1, Giuseppe Stabile b,1, Gaetano Senatore c,1, Claudio Pratola d,1, Roberto Verlato e,1, Martin Lowe f,1, Pekka Raatikainen g,1, Filippo Lamberti h,1, Pietro Turco i,1, on the behalf of the CACAF 2 Study Investigators a
Department of Cardiological, Thoracic, and Vascular Sciences, University of Padua, Padova, Italy Casa di Cura Mediterranea, Napoli, Italy c Ospedale Civile, Ciriè, Italy d Ospedale Sant'Anna, Ferrara, Italy e Ospedale Civile Cosma, Camposampiero, Italy f Heart Hospital, London, United Kingdom g University of Tampere, Tampere, Finland h Ospedale San Giovanni, Roma, Italy i Casa di Cura San Michele, Maddaloni, Italy b
a r t i c l e
i n f o
Article history: Received 19 August 2013 Received in revised form 22 October 2013 Accepted 23 November 2013 Available online 4 December 2013 Keywords: Persistent atrial fibrillation Catheter ablation Pulmonary vein isolation Transtelephonic monitoring
a b s t r a c t Background: The aim of this study was to investigate the efficacy of catheter ablation in the treatment of persistent atrial fibrillation (AF) and the predictors of arrhythmia recurrence. Methods: Absence of atrial tachyarrhythmia (AT) recurrence during a mid-term follow-up was correlated with several clinical and procedural characteristics in a population of 82 patients aged 20–70 years who had experienced at least one documented relapse of persistent AF during a single trial of antiarrhythmic drug therapy. Electrophysiological success of ablation was declared when all identified PVs were isolated (confirmation of entry and exit block). Patients were followed for a maximum of 24 months after the blanking period with outpatient visits, ECG recordings, 24-hour Holter monitoring, and weekly transtelephonic monitoring for 30 s. Results: Electrophysiological success was documented in 38/82 (46.3%) patients. During a mean follow-up of 24.7 ± 4.2 months, 69/82 (84.1%) patients presented at least one episode of AT after the 2 month blanking period. According to univariate and multivariate logistic regression analyses, only an electrophysiologically successful ablation significantly correlated with the absence of documented AT relapse (OR 5.32, 95% CL 1.02–27.72; p = .0472). Conclusions: Mid-term outcome of a single procedure of catheter ablation without the adjunction of antiarrhythmic drug therapy is poor in patients with persistent AF. Documented PV isolation is useful to increase the success rate of circumferential PV ablation even in persistent AF patients. © 2013 Published by Elsevier Ireland Ltd.
1. Introduction According to the most recent HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation (AF) [1], ablation strategies which target pulmonary veins (PVs) or PV antra are the cornerstone for most AF ablation procedures, and if PVs
☆ The study was supported by Biosense Webster EMEA. ☆☆ E.B. received grant for consultancy from Biosense Webster. ⁎ Corresponding author at: Via Ca'Rossa, 35, 30173 Mestre, VE, Italy. Tel.: + 39 3470548576; fax: +39 0498212309. E-mail address: [email protected] (E. Bertaglia). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ijcard.2013.11.055
are targeted, complete electrical isolation should be the goal. PV isolation has been an effective means of preventing tachyarrhythmia recurrences particularly when AF is paroxysmal, that is when triggers have a predominant role [2–7]. On the contrary, the role of PV isolation is still debated when AF is persistent or “long standing”: not only is PV isolation not enough to treat these forms of AF [8,9], but also, according to some reports, PV isolation does not seem necessary to prevent AF recurrences [10–13]. Catheter Ablation for the Cure of AF (CACAF-2) Study was a prospective, randomized trial designed to compare the efficacy of radiofrequency catheter ablation with combined lesions in the right and left atria, in preventing AF recurrences among patients with recurrent, persistent AF refractory to 1 antiarrhythmic drug, in comparison to the best pharmacological therapy [14]. In this sub-study we investigated the role of
E. Bertaglia et al. / International Journal of Cardiology 171 (2014) 174–178
several clinical and procedural parameters for predicting mid-term (up to 26 months) freedom from atrial tachyarrhythmia (AT), among population of CACAF-2 Study. 2. Methods
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the recording to a monitoring center [15]. The transtelephonic monitoring (TTM) period started immediately after the blanking period, and continued for 24 months. The patients were asked to record a 30 second ECG once a week, and a 30 second ECG in the event of palpitation. Patients were also proactively followed by the monitoring center. Transthoracic echocardiograms were performed at the first day post-procedure and at 5, 14, and 26 months to collect information regarding pericardial effusion, volume parameters, and valve abnormalities.
2.1. Patients 2.4. Definitions The enrollment criteria, rationale and power calculation for CACAF-2 Study have been previously reported [14]. In summary, patients between 20 and 70 years of age who had experienced at least one documented relapse of persistent AF during a single trial of antiarrhythmic drug were enrolled in the study. Each patient was randomized to catheter ablation (Ablation group) or antiarrhythmic drug therapy alone (Control group) in a 2:1 manner. In summary: 87 patients were randomized to the Ablation group and 42 patients to the Control group. Among patients randomized to the Ablation group, 82 underwent transcatheter ablation and represent the study population discussed in this manuscript (Fig. 1).
Primary endpoint: total absence of any documented AT, including AF and atrial tachycardia/flutter, lasting N30 s during the first 24 months after the 2-month blanking period, in the absence of antiarrhythmic drugs, after a single ablation procedure. Electrophysiological success: isolation of all identified PVs, with documentation of entry and exit block. AF history: time since the first diagnosis of arrhythmias was detected.
3. Statistical methods
2.2. Catheter ablation Patients had to be on oral anticoagulant therapy for at least 1 month before ablation. Left atrium and PVs were explored using a transseptal approach. Real-time 3D left atrial maps were reconstructed using a nonfluoroscopic navigation system (CARTO®, Biosense Webster Inc., Diamond Bar, California). Maps were acquired during AF or pacing from the coronary sinus. Radiofrequency pulses were delivered using a 3.5-mm NAVISTAR® THERMOCOOL® catheter (Biosense Webster Inc., Diamond Bar, California) with a temperature limitation of 45 °C and a radiofrequency energy up to 42 W. Radiofrequency energy was delivered up to 120 s until local electrogram amplitude was reduced by ≥80%. To reduce the risk of the catheter tip overheating, a fine back-and-forth movement of the catheter was recommended during radiofrequency delivery at the ablation site. The ablation lines consisted of contiguous focal lesions deployed at a distance ≥5 mm from the ostia of the PVs, creating a circumferential line around each PV. In addition, the left inferior PV was connected to the mitral annulus (mitral isthmus), and a left atrial roof line connecting the superior encirculations of the PVs' ostia was created. Demonstration of conduction block through the lines was not required. PV isolation had to be checked at the end of anatomical circumferential ablation after spontaneous restoration of normal sinus rhythm or after electrical cardioversion. A circular decapolar mapping catheter (LASSO®, Biosense Webster Inc., Diamond Bar, California) was used to check PV isolation. Each PV ostium was considered completely isolated when: 1) PV potentials disappeared or were disconnected (entry block); and 2) pacing from at least 3 points inside the encircled PV with a stimulus of 10 mA of amplitude and 2 ms of duration allowed local capture without left atrium capture (exit block). PV isolation after circumferential ablation was not mandatory. Patients with conduction along the cavo-tricuspid isthmus underwent inferior vena cava–tricuspid annulus isthmus ablation after completion of the left atrium ablation, in the same session.
Continuous measurements were expressed as mean ± SD (range), and were compared by means of Student's t-test with equal or unequal variances. The normality of distribution of continuous variables was assessed by visual inspection of the histograms. Discrete variables were analyzed by Fisher's exact test using the Monte Carlo estimation of the exact p-value when appropriate. Among patients with successful ablation the actuarial probability of freedom from AF after ablation was calculated with the method of Kaplan and Meier. Differences between the curves were tested for significance by the log-rank statistic. A p value b 0.05 was considered statistically significant. Logistic regression analysis was conducted to study the effects of baseline characteristics, medical history, medication history, left atrial diameter, status of procedure success and study sites on the success of the endpoint. Univariate logistic regression models were conducted for each of the potential predictors. A p-value b0.20 was used for the purpose of screening covariates. Forward, backward and Stepwise selection algorithms were used for selecting the covariates into the multivariate logistic regression model. Only covariates with a p-value b0.05 remained in the final model. Odds ratio and 95% confidence limit were calculated. Analysis was performed by means of SAS 9.2.
2.3. Follow-up
4. Results
A blanking period of 2 months was scheduled in order to allow the consolidation of radiofrequency lesions and resolution of any pericarditis secondary to the RFA. Before the end of the blanking period, one electrical cardioversion was allowed to restore sinus rhythm in the event of persistent AF, and one transcatheter ablation in the event of intolerable recurrent atrial flutter/tachycardia. Patients were followed for a maximum of 24 months after the blanking period with outpatient visits and ECG recordings at 2, 5, 8, 11, 14, 17, 20, 23 and 26 months and 24-hour Holter monitor recordings at 2, 5, 8, 14, 20, and 26 months. In order to exclude asymptomatic AT recurrences, each patient was provided with a personal device that had the capability of recording a single-lead ECG during an event and also transmitting
Demographic data of the 82 study patients are presented in Table 1. The majority (80.5%) of our patients were male. Most of them suffered from structural heart disease (mainly hypertensive cardiopathy, 57.5%). 4.1. Catheter ablation PV ablation was electrophysiologically successful in 38/82 (46.3%) patients. There were 77 subjects (77/82, 93.9%) where left atrial linear
Fig. 1. Diagram of the accountability of subjects.
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Table 1 Demographic data.
Table 2 Summary of covariates. Study group (n = 82)
Age, years (mean ± SD) Male gender Diabetes mellitusa Hypertensive cardiopathya Other structural heart diseasesa Previous antiarrhythmic class I drug trieda Previous antiarrhythmic class II drug trieda Previous antiarrhythmic class III drug trieda Baseline left atrial dimension, mm (mean ± SD)b Duration of AF history, years (mean ± SD)c a b c
57.2 ± 9.1 66 (80.5%) 4 (5.0%) 46 (57.5%) 2 (2.5%) 45 (54.9%) 8 (9.8%) 27 (32.9%) 44.3 ± 5.2 2.4 ± 2.5
Data available for 80 patients. Data available for 76 patients. Data available for 72 patients.
lesions were placed. In these 77 subjects, 28 of them (28/77, 36.4%) had bidirectional block across the line confirmed. Mean procedural time resulted of 180.5 ± 74.1 min; mean fluoroscopy time of 34.5 ± 25.1 min; and mean duration of RF ablation applications of 48.2 ± 18.5 min. 4.2. Follow-up Mean follow-up duration was 24.7 ± 4.2 months (range 9–26). A total of 7554 TTM ECG recordings were collected during the study. The mean interval between TTM ECG recordings was 5.6 ± 3.7 days (range 1–95). After the blanking period, 69/82 (84.1%) patients presented with at least one episode of documented AT. Persistent ATs were observed in 28/69 (40.1%) patients, while in 41/69 (59.9%) patients a paroxysmal arrhythmia was the first observation. Atrial flutter/tachycardia was the AT observed in 5/69 (7.2%) patients. Nine out of 69 patients (13.0%) with documented ATs were completely asymptomatic. During the follow-up 17 subjects (17/82, 20.7%) underwent more than 1 procedure: 15 subjects (15/82, 18.3%) had 2 procedures while 2 subjects (2/82, 2.4%) had 3 procedures. Finally, a mean of 1.2 ± 0.5 procedures per patient was performed during the study. Including redo procedures, 24/82 (29.3%) patients were free from any documented atrial tachyarrhythmias without AAD. With the reintroduction of AAD and/or repetition of catheter ablation, 62/82 (75.6%) patients were in sinus rhythm at the end of follow-up.
Covariate
Gender Male Female Hypertensive cardiopathy Yes No Diabetes mellitus Yes No Other structural heart diseases Yes No Previous class I AAD Yes No Previous class II AAD Yes No Previous class III AAD Yes No Electrophysiologically successful ablation Yes No Age, years (mean ± SD) Baseline LA diameter, mm (mean ± SD) Duration of AF history, years (mean ± SD)
Freedom from AT Yes
No
13 (19.7%) 0 (0.0%)
53 (80.3%) 16 (100.0%)
5 (10.9%) 7 (20.6%)
41 (89.1%) 27 (79.4%)
1 (25.0%) 11 (14.5%)
3 (75.0%) 65 (85.5%)
0 (0.0%) 12 (15.4%)
2 (100.0%) 66 (84.6%)
8 (17.8%) 4 (11.4%)
37 (82.2%) 31 (88,6%)
1 (12.5%) 11 (15.3%)
7 (87.5%) 61 (84.7%)
3 (11.1%) 9 (17.0%)
24 (88.9%) 44 (83.0%)
10 (26.3%) 3 (6.8%) 52.8 ± 11.9 45.9 ± 2.4 1.3 ± 0.7
28 (73.7%) 41 (93.2%) 58.3 ± 8.1 44.5 ± 5.5 2.6 ± 2.7
p-Value
.0624
.3428
.4851
1.0000
0.5360
1.0000
.7418
.0309
.1443 .1023 .0044
AAD: antiarrhythmic drugs; LA = left atrial; AF = atrial fibrillation.
During the 24 months of follow-up, the rate of sinus rhythm maintenance resulted significantly higher in patients with electrophysiologically successful ablation than in patients without electrophysiologically successful ablation (Log Rank p = .04; Fig. 2). 5. Discussion 5.1. Main findings Main findings of this study are: 1) mid-term outcome of a single procedure of catheter ablation without the adjunction of AAD is poor in patients with persistent AF; 2) in this study population, acute demonstration of bidirectional electrical disconnection of PV increases the success rate of circumferential ablation; and 3) most of the patients experienced a paroxysmal AF recurrence after catheter ablation.
4.3. Adverse events
5.2. Previous studies
One (1.2%) procedure-related adverse event was reported: one cardiac tamponade during ablation of the right superior PV which required percutaneous drainage. Three iatrogenic left atrial flutters were observed, which were treated with a repeat ablation during the blanking period. A probable device-related event (dyspnea during a hypertensive crisis) was observed in one patient (1.2%).
Since the initial description of PVs as triggers of AF [2], our hope was that PV isolation by means of catheter ablation could cure all types of AF. Unfortunately, over time, we have learned that when we face “long standing” persistent AF, PV isolation alone may not be enough [8,9]. Other strategies were added to PV isolation in order to increase the success rate in these patients, including creation of linear lines along the left atrial roof or the mitral isthmus [8,16,17], elimination of those areas of the left atrium displaying continuous electrical activity, complex fractionated activity, locally short cycle length, temporal gradient between the distal and the proximal dipoles of the ablation catheter, centrifugal activation [17–20], and complete isolation of the posterior left atrium [21,22]. Nevertheless, PV isolation remains the cornerstone of AF treatment in all these strategies [1] despite the fact that, according to some reports, PV isolation did not seem necessary for ablation treatment of persistent or “long standing” AF [10–13]. The controversy over the role of PV isolation in persistent AF patients was fomented in the recent past by the results of Pratola et al. [12]. In contrast with previous publications in
4.4. Predictors of successful follow-up Several demographic and clinical procedural variables were analyzed to determine whether they were correlated with the absence of documented AT relapse during the follow-up (Table 2). Results of univariate logistic regression analysis are presented in Table 3. Only an electrophysiologically successful ablation correlated with the absence of documented AT relapse (26.3% with electrophysiologically successful ablation vs 6.8% without electrophysiologically successful ablation, p = .0309). The data were confirmed at the multivariate logistic regression analysis (OR 5.32, 95% CL 1.02–27.72; p = .0472).
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Table 3 Univariate and multivariate logistic regression analyses of potential predictors for freedom from any documented atrial tachyarrhythmias. Variable
Age Gender Hypertension Diabetes mellitus Structural heart disease Previous class I AAD Previous class II AAD Previous class III AAD Procedural success Baseline LA dimension Duration of AF history
Univariate logistic regression
Multivariate logistic regression
p-Value
OR (95% CL)
p-Value
OR (95% CL)
.0653 .9625 .2356 .5721 .9808 .4334 .8350 .4899 .0240 .3125 .1538
0.94 (0.89–1.00) –a 0.47 (0.14–1.64) 1.97 (0.19–20.69) –a 1.68 (0.46–6.10) 0.79 (0.09–7.09) 0.61 (0.15–2.47) 4.88 (1.23–19.33) 0.94 (0.83–1.06) 0.60 (0.30–1.21)
.3174
0.97, CL 95% 0.91–1.03
.0472
5.32, 95% CL 1.02–27.72
.0826
0.83, 95% CL 0.67–1.03
AAD: antiarrhythmic drugs; LA = left atrial; AF = atrial fibrillation. a The maximum likelihood estimation is not available due to the sparseness of the data (zero cell).
which recovered PV conduction after the initial procedure was a dominant finding in patients with recurrent AT [23–25], Pratola concluded that in persistent AF patients, sinus rhythm could persist after ablation despite the recovery of PV conduction [12]. Our results may resolve this controversy as they suggest that acute demonstration of bidirectional electrical disconnection of PV increases the efficacy of circumferential PV ablation in persistent AF patients. To the best of our knowledge our study finding is unique on this issue for three reasons: 1) the study population consisted entirely of persistent AF patients; 2) the length of follow-up was very long (mean 24.7 ± 4.2 months); and 3) collection of over 7500 TTM ECG recordings in order to identify asymptomatic AT relapse. This differs from previously published studies in which paroxysmal AF patients were well represented, asymptomatic AF recurrences after ablation were not collected, and follow-up was shorter [6,10,26].
5.3. Other predictors of successful persistent AF ablation In previous studies onmid-term follow-up of persistent AF ablation, left atrial size and duration of AF history result significantly correlated with a bad outcome [27–29]. In the present study duration of AF history results significantly correlated with AT recurrences during the followup at the univariate analysis, but not at the multivariate analysis. Left atrial size did not appear to correlate with the mid-term outcome even at the univariate analysis. This could be the result of the strict exclusion criteria we adopted at enrollment: patients with AF as the sole rhythm for N 6 months, or with a left atrial diameter N50 mm were excluded from the study [14].
5.4. Mid-term outcome of persistent AF ablation Clinical outcome of our patients appears poor, because only 15.6% remained free of any AT recurrence during the 24 months of followup. This result is in contrast with a previous randomized study on circumferential ablation of chronic AF patients, where 74% of patients maintained sinus rhythm 12 months after ablation [26]. However, in Oral and Pappone's paper patients were followed for only 12 months, and many patients repeated ablation during the study or were on antiarrhythmic drugs. Most recently, in a randomized comparison between catheter ablation and surgical ablation in patients who had already failed one catheter ablation procedure or had a mild enlarged left atrium, only 36.0% of persistent AF patients maintained sinus rhythm without AAD 12 months after the second catheter ablation [30]. The poor outcome of our study has several explanations. 1) Most of our patients (about 60%) presented with paroxysmal AF as their recurrent AT: being the presence of a trigger the principal reason of this kind of relapse, if in all our patients electrophysiological PV isolation was achieved, most of these recurrences could be avoided. Moreover, paroxysmal recurrences could have been unrecognized in previous studies without an intensive follow-up as in our study. 2) Creation of linear lesions along the roof and the mitral isthmus might increase the success rate of persistent AF ablation when completeness of lines is assessed [31]. On the contrary, bidirectional block across the line was confirmed only in one third of our patients. 3) In clinical practice, most persistent AF patients could benefit from continuation of AADs, as was documented in the CACAF Study [32]. 4) Repeat ablation could increase outcome of these patients too. In fact, at 24-month follow-up 75.6% of our patients were in sinus rhythm at final visit. Importantly, during repeated procedures ablation strategies in addition to PV isolation are often required [33]. 6. Limitations With extensive use of TTM we could detect AT in 9 completely asymptomatic patients. However, we cannot exclude the possibility that other asymptomatic AT relapses could have been undetected. Despite a low percentage of documented PV electrical isolation, during the follow-up we observed a rate of organized tachyarrhythmias (7.2%) not superior to those reported in Literature [34]. The small numbers did not allow us to find a correlation between assessment of PV isolation and occurrence of atrial flutter/tachycardia. 7. Conclusions
Fig. 2. Kaplan–Meier estimates of the time to atrial fibrillation occurrence in the patients with electrophysiologically successful ablation (red line) and without electrophysiologically successful ablation (blue line).
In conclusion, our data further support the assessment of PV isolation also in persistent AF patients.
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Appendix A Chairman: Emanuele Bertaglia, MD. Steering Committee: Emanuele Bertaglia, MD (Chairman); Gaetano Senatore, MD; Giuseppe Stabile, MD. Safety Monitoring Committee: Hein Heidbuchel, MD; Stephan Willems, MD; Harry Crijns, MD. Participating centers (listed in alphabetical order): Camposampiero—Italy (R. Verlato, P. Baccillieri, P. Turrini); Ciriè—Italy (G. Senatore, G. Donnici, M. Fazzari); Cotignola— Italy (P. Turco, B. El Jamal); Ferrara—Italy (C. Pratola, E. Baldo, R. Ferrari, P. Notarstefano); Florence—Italy (A. Colella, L. Padeletti); London Heart Hospital—UK (M. Lowe); London St. Mary's Hospital—UK (N. Peters, W. Davies, V. Markides, P. Kanagaratnam); Maddaloni—Italy (G. Stabile, A. De Simone); Mirano—Italy (E. Bertaglia, P. Pascotto, F. Zerbo, F. Zoppo); Oulu—Finland (P. Raatikainen); Rome—Italy (F. Lamberti, R. Nardo); Trento—Italy (M. Del Greco, M. Disertori); Treviso—Italy (R. Mantovan, V. Calzolari, P. Stritoni).
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Documentation of pulmonary vein isolation improves long term efficacy of persistent atrial fibrillation catheter ablation☆,☆☆ Emanuele Bertaglia a,⁎,1, Giuseppe Stabile b,1, Gaetano Senatore c,1, Claudio Pratola d,1, Roberto Verlato e,1, Martin Lowe f,1, Pekka Raatikainen g,1, Filippo Lamberti h,1, Pietro Turco i,1, on the behalf of the CACAF 2 Study Investigators a
Department of Cardiological, Thoracic, and Vascular Sciences, University of Padua, Padova, Italy Casa di Cura Mediterranea, Napoli, Italy c Ospedale Civile, Ciriè, Italy d Ospedale Sant'Anna, Ferrara, Italy e Ospedale Civile Cosma, Camposampiero, Italy f Heart Hospital, London, United Kingdom g University of Tampere, Tampere, Finland h Ospedale San Giovanni, Roma, Italy i Casa di Cura San Michele, Maddaloni, Italy b
a r t i c l e
i n f o
Article history: Received 19 August 2013 Received in revised form 22 October 2013 Accepted 23 November 2013 Available online 4 December 2013 Keywords: Persistent atrial fibrillation Catheter ablation Pulmonary vein isolation Transtelephonic monitoring
a b s t r a c t Background: The aim of this study was to investigate the efficacy of catheter ablation in the treatment of persistent atrial fibrillation (AF) and the predictors of arrhythmia recurrence. Methods: Absence of atrial tachyarrhythmia (AT) recurrence during a mid-term follow-up was correlated with several clinical and procedural characteristics in a population of 82 patients aged 20–70 years who had experienced at least one documented relapse of persistent AF during a single trial of antiarrhythmic drug therapy. Electrophysiological success of ablation was declared when all identified PVs were isolated (confirmation of entry and exit block). Patients were followed for a maximum of 24 months after the blanking period with outpatient visits, ECG recordings, 24-hour Holter monitoring, and weekly transtelephonic monitoring for 30 s. Results: Electrophysiological success was documented in 38/82 (46.3%) patients. During a mean follow-up of 24.7 ± 4.2 months, 69/82 (84.1%) patients presented at least one episode of AT after the 2 month blanking period. According to univariate and multivariate logistic regression analyses, only an electrophysiologically successful ablation significantly correlated with the absence of documented AT relapse (OR 5.32, 95% CL 1.02–27.72; p = .0472). Conclusions: Mid-term outcome of a single procedure of catheter ablation without the adjunction of antiarrhythmic drug therapy is poor in patients with persistent AF. Documented PV isolation is useful to increase the success rate of circumferential PV ablation even in persistent AF patients. © 2013 Published by Elsevier Ireland Ltd.
1. Introduction According to the most recent HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation (AF) [1], ablation strategies which target pulmonary veins (PVs) or PV antra are the cornerstone for most AF ablation procedures, and if PVs
☆ The study was supported by Biosense Webster EMEA. ☆☆ E.B. received grant for consultancy from Biosense Webster. ⁎ Corresponding author at: Via Ca'Rossa, 35, 30173 Mestre, VE, Italy. Tel.: + 39 3470548576; fax: +39 0498212309. E-mail address: [email protected] (E. Bertaglia). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ijcard.2013.11.055
are targeted, complete electrical isolation should be the goal. PV isolation has been an effective means of preventing tachyarrhythmia recurrences particularly when AF is paroxysmal, that is when triggers have a predominant role [2–7]. On the contrary, the role of PV isolation is still debated when AF is persistent or “long standing”: not only is PV isolation not enough to treat these forms of AF [8,9], but also, according to some reports, PV isolation does not seem necessary to prevent AF recurrences [10–13]. Catheter Ablation for the Cure of AF (CACAF-2) Study was a prospective, randomized trial designed to compare the efficacy of radiofrequency catheter ablation with combined lesions in the right and left atria, in preventing AF recurrences among patients with recurrent, persistent AF refractory to 1 antiarrhythmic drug, in comparison to the best pharmacological therapy [14]. In this sub-study we investigated the role of
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several clinical and procedural parameters for predicting mid-term (up to 26 months) freedom from atrial tachyarrhythmia (AT), among population of CACAF-2 Study. 2. Methods
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the recording to a monitoring center [15]. The transtelephonic monitoring (TTM) period started immediately after the blanking period, and continued for 24 months. The patients were asked to record a 30 second ECG once a week, and a 30 second ECG in the event of palpitation. Patients were also proactively followed by the monitoring center. Transthoracic echocardiograms were performed at the first day post-procedure and at 5, 14, and 26 months to collect information regarding pericardial effusion, volume parameters, and valve abnormalities.
2.1. Patients 2.4. Definitions The enrollment criteria, rationale and power calculation for CACAF-2 Study have been previously reported [14]. In summary, patients between 20 and 70 years of age who had experienced at least one documented relapse of persistent AF during a single trial of antiarrhythmic drug were enrolled in the study. Each patient was randomized to catheter ablation (Ablation group) or antiarrhythmic drug therapy alone (Control group) in a 2:1 manner. In summary: 87 patients were randomized to the Ablation group and 42 patients to the Control group. Among patients randomized to the Ablation group, 82 underwent transcatheter ablation and represent the study population discussed in this manuscript (Fig. 1).
Primary endpoint: total absence of any documented AT, including AF and atrial tachycardia/flutter, lasting N30 s during the first 24 months after the 2-month blanking period, in the absence of antiarrhythmic drugs, after a single ablation procedure. Electrophysiological success: isolation of all identified PVs, with documentation of entry and exit block. AF history: time since the first diagnosis of arrhythmias was detected.
3. Statistical methods
2.2. Catheter ablation Patients had to be on oral anticoagulant therapy for at least 1 month before ablation. Left atrium and PVs were explored using a transseptal approach. Real-time 3D left atrial maps were reconstructed using a nonfluoroscopic navigation system (CARTO®, Biosense Webster Inc., Diamond Bar, California). Maps were acquired during AF or pacing from the coronary sinus. Radiofrequency pulses were delivered using a 3.5-mm NAVISTAR® THERMOCOOL® catheter (Biosense Webster Inc., Diamond Bar, California) with a temperature limitation of 45 °C and a radiofrequency energy up to 42 W. Radiofrequency energy was delivered up to 120 s until local electrogram amplitude was reduced by ≥80%. To reduce the risk of the catheter tip overheating, a fine back-and-forth movement of the catheter was recommended during radiofrequency delivery at the ablation site. The ablation lines consisted of contiguous focal lesions deployed at a distance ≥5 mm from the ostia of the PVs, creating a circumferential line around each PV. In addition, the left inferior PV was connected to the mitral annulus (mitral isthmus), and a left atrial roof line connecting the superior encirculations of the PVs' ostia was created. Demonstration of conduction block through the lines was not required. PV isolation had to be checked at the end of anatomical circumferential ablation after spontaneous restoration of normal sinus rhythm or after electrical cardioversion. A circular decapolar mapping catheter (LASSO®, Biosense Webster Inc., Diamond Bar, California) was used to check PV isolation. Each PV ostium was considered completely isolated when: 1) PV potentials disappeared or were disconnected (entry block); and 2) pacing from at least 3 points inside the encircled PV with a stimulus of 10 mA of amplitude and 2 ms of duration allowed local capture without left atrium capture (exit block). PV isolation after circumferential ablation was not mandatory. Patients with conduction along the cavo-tricuspid isthmus underwent inferior vena cava–tricuspid annulus isthmus ablation after completion of the left atrium ablation, in the same session.
Continuous measurements were expressed as mean ± SD (range), and were compared by means of Student's t-test with equal or unequal variances. The normality of distribution of continuous variables was assessed by visual inspection of the histograms. Discrete variables were analyzed by Fisher's exact test using the Monte Carlo estimation of the exact p-value when appropriate. Among patients with successful ablation the actuarial probability of freedom from AF after ablation was calculated with the method of Kaplan and Meier. Differences between the curves were tested for significance by the log-rank statistic. A p value b 0.05 was considered statistically significant. Logistic regression analysis was conducted to study the effects of baseline characteristics, medical history, medication history, left atrial diameter, status of procedure success and study sites on the success of the endpoint. Univariate logistic regression models were conducted for each of the potential predictors. A p-value b0.20 was used for the purpose of screening covariates. Forward, backward and Stepwise selection algorithms were used for selecting the covariates into the multivariate logistic regression model. Only covariates with a p-value b0.05 remained in the final model. Odds ratio and 95% confidence limit were calculated. Analysis was performed by means of SAS 9.2.
2.3. Follow-up
4. Results
A blanking period of 2 months was scheduled in order to allow the consolidation of radiofrequency lesions and resolution of any pericarditis secondary to the RFA. Before the end of the blanking period, one electrical cardioversion was allowed to restore sinus rhythm in the event of persistent AF, and one transcatheter ablation in the event of intolerable recurrent atrial flutter/tachycardia. Patients were followed for a maximum of 24 months after the blanking period with outpatient visits and ECG recordings at 2, 5, 8, 11, 14, 17, 20, 23 and 26 months and 24-hour Holter monitor recordings at 2, 5, 8, 14, 20, and 26 months. In order to exclude asymptomatic AT recurrences, each patient was provided with a personal device that had the capability of recording a single-lead ECG during an event and also transmitting
Demographic data of the 82 study patients are presented in Table 1. The majority (80.5%) of our patients were male. Most of them suffered from structural heart disease (mainly hypertensive cardiopathy, 57.5%). 4.1. Catheter ablation PV ablation was electrophysiologically successful in 38/82 (46.3%) patients. There were 77 subjects (77/82, 93.9%) where left atrial linear
Fig. 1. Diagram of the accountability of subjects.
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Table 1 Demographic data.
Table 2 Summary of covariates. Study group (n = 82)
Age, years (mean ± SD) Male gender Diabetes mellitusa Hypertensive cardiopathya Other structural heart diseasesa Previous antiarrhythmic class I drug trieda Previous antiarrhythmic class II drug trieda Previous antiarrhythmic class III drug trieda Baseline left atrial dimension, mm (mean ± SD)b Duration of AF history, years (mean ± SD)c a b c
57.2 ± 9.1 66 (80.5%) 4 (5.0%) 46 (57.5%) 2 (2.5%) 45 (54.9%) 8 (9.8%) 27 (32.9%) 44.3 ± 5.2 2.4 ± 2.5
Data available for 80 patients. Data available for 76 patients. Data available for 72 patients.
lesions were placed. In these 77 subjects, 28 of them (28/77, 36.4%) had bidirectional block across the line confirmed. Mean procedural time resulted of 180.5 ± 74.1 min; mean fluoroscopy time of 34.5 ± 25.1 min; and mean duration of RF ablation applications of 48.2 ± 18.5 min. 4.2. Follow-up Mean follow-up duration was 24.7 ± 4.2 months (range 9–26). A total of 7554 TTM ECG recordings were collected during the study. The mean interval between TTM ECG recordings was 5.6 ± 3.7 days (range 1–95). After the blanking period, 69/82 (84.1%) patients presented with at least one episode of documented AT. Persistent ATs were observed in 28/69 (40.1%) patients, while in 41/69 (59.9%) patients a paroxysmal arrhythmia was the first observation. Atrial flutter/tachycardia was the AT observed in 5/69 (7.2%) patients. Nine out of 69 patients (13.0%) with documented ATs were completely asymptomatic. During the follow-up 17 subjects (17/82, 20.7%) underwent more than 1 procedure: 15 subjects (15/82, 18.3%) had 2 procedures while 2 subjects (2/82, 2.4%) had 3 procedures. Finally, a mean of 1.2 ± 0.5 procedures per patient was performed during the study. Including redo procedures, 24/82 (29.3%) patients were free from any documented atrial tachyarrhythmias without AAD. With the reintroduction of AAD and/or repetition of catheter ablation, 62/82 (75.6%) patients were in sinus rhythm at the end of follow-up.
Covariate
Gender Male Female Hypertensive cardiopathy Yes No Diabetes mellitus Yes No Other structural heart diseases Yes No Previous class I AAD Yes No Previous class II AAD Yes No Previous class III AAD Yes No Electrophysiologically successful ablation Yes No Age, years (mean ± SD) Baseline LA diameter, mm (mean ± SD) Duration of AF history, years (mean ± SD)
Freedom from AT Yes
No
13 (19.7%) 0 (0.0%)
53 (80.3%) 16 (100.0%)
5 (10.9%) 7 (20.6%)
41 (89.1%) 27 (79.4%)
1 (25.0%) 11 (14.5%)
3 (75.0%) 65 (85.5%)
0 (0.0%) 12 (15.4%)
2 (100.0%) 66 (84.6%)
8 (17.8%) 4 (11.4%)
37 (82.2%) 31 (88,6%)
1 (12.5%) 11 (15.3%)
7 (87.5%) 61 (84.7%)
3 (11.1%) 9 (17.0%)
24 (88.9%) 44 (83.0%)
10 (26.3%) 3 (6.8%) 52.8 ± 11.9 45.9 ± 2.4 1.3 ± 0.7
28 (73.7%) 41 (93.2%) 58.3 ± 8.1 44.5 ± 5.5 2.6 ± 2.7
p-Value
.0624
.3428
.4851
1.0000
0.5360
1.0000
.7418
.0309
.1443 .1023 .0044
AAD: antiarrhythmic drugs; LA = left atrial; AF = atrial fibrillation.
During the 24 months of follow-up, the rate of sinus rhythm maintenance resulted significantly higher in patients with electrophysiologically successful ablation than in patients without electrophysiologically successful ablation (Log Rank p = .04; Fig. 2). 5. Discussion 5.1. Main findings Main findings of this study are: 1) mid-term outcome of a single procedure of catheter ablation without the adjunction of AAD is poor in patients with persistent AF; 2) in this study population, acute demonstration of bidirectional electrical disconnection of PV increases the success rate of circumferential ablation; and 3) most of the patients experienced a paroxysmal AF recurrence after catheter ablation.
4.3. Adverse events
5.2. Previous studies
One (1.2%) procedure-related adverse event was reported: one cardiac tamponade during ablation of the right superior PV which required percutaneous drainage. Three iatrogenic left atrial flutters were observed, which were treated with a repeat ablation during the blanking period. A probable device-related event (dyspnea during a hypertensive crisis) was observed in one patient (1.2%).
Since the initial description of PVs as triggers of AF [2], our hope was that PV isolation by means of catheter ablation could cure all types of AF. Unfortunately, over time, we have learned that when we face “long standing” persistent AF, PV isolation alone may not be enough [8,9]. Other strategies were added to PV isolation in order to increase the success rate in these patients, including creation of linear lines along the left atrial roof or the mitral isthmus [8,16,17], elimination of those areas of the left atrium displaying continuous electrical activity, complex fractionated activity, locally short cycle length, temporal gradient between the distal and the proximal dipoles of the ablation catheter, centrifugal activation [17–20], and complete isolation of the posterior left atrium [21,22]. Nevertheless, PV isolation remains the cornerstone of AF treatment in all these strategies [1] despite the fact that, according to some reports, PV isolation did not seem necessary for ablation treatment of persistent or “long standing” AF [10–13]. The controversy over the role of PV isolation in persistent AF patients was fomented in the recent past by the results of Pratola et al. [12]. In contrast with previous publications in
4.4. Predictors of successful follow-up Several demographic and clinical procedural variables were analyzed to determine whether they were correlated with the absence of documented AT relapse during the follow-up (Table 2). Results of univariate logistic regression analysis are presented in Table 3. Only an electrophysiologically successful ablation correlated with the absence of documented AT relapse (26.3% with electrophysiologically successful ablation vs 6.8% without electrophysiologically successful ablation, p = .0309). The data were confirmed at the multivariate logistic regression analysis (OR 5.32, 95% CL 1.02–27.72; p = .0472).
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Table 3 Univariate and multivariate logistic regression analyses of potential predictors for freedom from any documented atrial tachyarrhythmias. Variable
Age Gender Hypertension Diabetes mellitus Structural heart disease Previous class I AAD Previous class II AAD Previous class III AAD Procedural success Baseline LA dimension Duration of AF history
Univariate logistic regression
Multivariate logistic regression
p-Value
OR (95% CL)
p-Value
OR (95% CL)
.0653 .9625 .2356 .5721 .9808 .4334 .8350 .4899 .0240 .3125 .1538
0.94 (0.89–1.00) –a 0.47 (0.14–1.64) 1.97 (0.19–20.69) –a 1.68 (0.46–6.10) 0.79 (0.09–7.09) 0.61 (0.15–2.47) 4.88 (1.23–19.33) 0.94 (0.83–1.06) 0.60 (0.30–1.21)
.3174
0.97, CL 95% 0.91–1.03
.0472
5.32, 95% CL 1.02–27.72
.0826
0.83, 95% CL 0.67–1.03
AAD: antiarrhythmic drugs; LA = left atrial; AF = atrial fibrillation. a The maximum likelihood estimation is not available due to the sparseness of the data (zero cell).
which recovered PV conduction after the initial procedure was a dominant finding in patients with recurrent AT [23–25], Pratola concluded that in persistent AF patients, sinus rhythm could persist after ablation despite the recovery of PV conduction [12]. Our results may resolve this controversy as they suggest that acute demonstration of bidirectional electrical disconnection of PV increases the efficacy of circumferential PV ablation in persistent AF patients. To the best of our knowledge our study finding is unique on this issue for three reasons: 1) the study population consisted entirely of persistent AF patients; 2) the length of follow-up was very long (mean 24.7 ± 4.2 months); and 3) collection of over 7500 TTM ECG recordings in order to identify asymptomatic AT relapse. This differs from previously published studies in which paroxysmal AF patients were well represented, asymptomatic AF recurrences after ablation were not collected, and follow-up was shorter [6,10,26].
5.3. Other predictors of successful persistent AF ablation In previous studies onmid-term follow-up of persistent AF ablation, left atrial size and duration of AF history result significantly correlated with a bad outcome [27–29]. In the present study duration of AF history results significantly correlated with AT recurrences during the followup at the univariate analysis, but not at the multivariate analysis. Left atrial size did not appear to correlate with the mid-term outcome even at the univariate analysis. This could be the result of the strict exclusion criteria we adopted at enrollment: patients with AF as the sole rhythm for N 6 months, or with a left atrial diameter N50 mm were excluded from the study [14].
5.4. Mid-term outcome of persistent AF ablation Clinical outcome of our patients appears poor, because only 15.6% remained free of any AT recurrence during the 24 months of followup. This result is in contrast with a previous randomized study on circumferential ablation of chronic AF patients, where 74% of patients maintained sinus rhythm 12 months after ablation [26]. However, in Oral and Pappone's paper patients were followed for only 12 months, and many patients repeated ablation during the study or were on antiarrhythmic drugs. Most recently, in a randomized comparison between catheter ablation and surgical ablation in patients who had already failed one catheter ablation procedure or had a mild enlarged left atrium, only 36.0% of persistent AF patients maintained sinus rhythm without AAD 12 months after the second catheter ablation [30]. The poor outcome of our study has several explanations. 1) Most of our patients (about 60%) presented with paroxysmal AF as their recurrent AT: being the presence of a trigger the principal reason of this kind of relapse, if in all our patients electrophysiological PV isolation was achieved, most of these recurrences could be avoided. Moreover, paroxysmal recurrences could have been unrecognized in previous studies without an intensive follow-up as in our study. 2) Creation of linear lesions along the roof and the mitral isthmus might increase the success rate of persistent AF ablation when completeness of lines is assessed [31]. On the contrary, bidirectional block across the line was confirmed only in one third of our patients. 3) In clinical practice, most persistent AF patients could benefit from continuation of AADs, as was documented in the CACAF Study [32]. 4) Repeat ablation could increase outcome of these patients too. In fact, at 24-month follow-up 75.6% of our patients were in sinus rhythm at final visit. Importantly, during repeated procedures ablation strategies in addition to PV isolation are often required [33]. 6. Limitations With extensive use of TTM we could detect AT in 9 completely asymptomatic patients. However, we cannot exclude the possibility that other asymptomatic AT relapses could have been undetected. Despite a low percentage of documented PV electrical isolation, during the follow-up we observed a rate of organized tachyarrhythmias (7.2%) not superior to those reported in Literature [34]. The small numbers did not allow us to find a correlation between assessment of PV isolation and occurrence of atrial flutter/tachycardia. 7. Conclusions
Fig. 2. Kaplan–Meier estimates of the time to atrial fibrillation occurrence in the patients with electrophysiologically successful ablation (red line) and without electrophysiologically successful ablation (blue line).
In conclusion, our data further support the assessment of PV isolation also in persistent AF patients.
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Appendix A Chairman: Emanuele Bertaglia, MD. Steering Committee: Emanuele Bertaglia, MD (Chairman); Gaetano Senatore, MD; Giuseppe Stabile, MD. Safety Monitoring Committee: Hein Heidbuchel, MD; Stephan Willems, MD; Harry Crijns, MD. Participating centers (listed in alphabetical order): Camposampiero—Italy (R. Verlato, P. Baccillieri, P. Turrini); Ciriè—Italy (G. Senatore, G. Donnici, M. Fazzari); Cotignola— Italy (P. Turco, B. El Jamal); Ferrara—Italy (C. Pratola, E. Baldo, R. Ferrari, P. Notarstefano); Florence—Italy (A. Colella, L. Padeletti); London Heart Hospital—UK (M. Lowe); London St. Mary's Hospital—UK (N. Peters, W. Davies, V. Markides, P. Kanagaratnam); Maddaloni—Italy (G. Stabile, A. De Simone); Mirano—Italy (E. Bertaglia, P. Pascotto, F. Zerbo, F. Zoppo); Oulu—Finland (P. Raatikainen); Rome—Italy (F. Lamberti, R. Nardo); Trento—Italy (M. Del Greco, M. Disertori); Treviso—Italy (R. Mantovan, V. Calzolari, P. Stritoni).
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