International Journal of Cardiology 176 (2014) 891–895
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Conventional radiofrequency catheter ablation compared to multi-electrode ablation for atrial fibrillation Pim Gal, Alissa E.S.M. Aarntzen, Jaap Jan J. Smit, Ahmet Adiyaman, Anand R. Ramdat Misier, Peter Paul H.M. Delnoy, Arif Elvan ⁎ Department of Cardiology, Isala Klinieken, Zwolle, The Netherlands
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Article history: Received 29 April 2014 Received in revised form 8 July 2014 Accepted 5 August 2014 Available online 13 August 2014 Keywords: Atrial fibrillation Pulmonary vein isolation Radiofrequency catheter ablation Point by point ablation Multi-electrode ablation Long-term follow-up
a b s t r a c t Background: Limited data is available on long-term atrial fibrillation (AF) free survival after multi-electrode catheter pulmonary vein isolation (PVI). The aim of this study was to compare point-by-point PVI to multielectrode PVI in terms of procedural characteristics and long-term AF free survival. Methods and results: 460 consecutive patients were randomly allocated: 230 patients underwent conventional, point-by-point ablation with a radiofrequency ablation catheter (cPVI group) and 230 patients underwent multi-electrode, phased radiofrequency ablation (MER group). Median follow-up was 43 months. Mean age was 56 years, 82% of patients had paroxysmal AF. Baseline characteristics did not differ among catheter groups. Acute electrical PVI was achieved in 99.7% of pulmonary veins, with no differences among catheter groups. Procedure time and ablation time were significantly shorter in the MER group. There were significantly less complications in the MER group (4.8% vs. 1.3%, P = 0.025). After a mean of 1.5 procedures, AF free survival without the use of antiarrhythmic drugs was 74% at 1 year and 46% at 5 years follow-up and did not differ among catheter groups (cPVI group 45%, MER group 48%, P = 0.777). In multivariate analysis, BMI, AF duration and CHADSVASc score were predictors of AF free survival. Conclusion: Multi-electrode ablation was superior in procedure duration and ablation time, with less complications. However, both conventional point-by-point PVI and multi-electrode PVI achieved a high acute PVI success rate and showed a comparable long-term AF free survival. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary vein isolation (PVI) is an effective treatment for atrial fibrillation (AF), although it is hampered by relative frequent recurrences of AF [1–3]. Multiple ablation systems have been developed in an attempt to increase AF free survival, although previous studies did not show a significant difference among PVI techniques [4–10]. However, there is little comparative data on real world, long-term AF free survival after multi-electrode ablation. The aim of this study was to compare conventional, electro-anatomic irrigated tip radiofrequency (RF) point-by-point ablation to duty-cycled multi-electrode RF ablation in
a large patient population with a long-term follow-up in terms of procedural characteristics and AF free survival. 2. Methods 2.1. Patient population 460 consecutive patients with symptomatic AF who were accepted for primo PVI were included in this study. Patients were randomly allocated to one of 2 ablation techniques: conventional RF point-by-point ablation (cPVI group) and multi-electrode, duty-cycled, phased RF ablation (MER group). Data were collected in a prospective hospital database. All patients consented to their data being registered and used for publication as did the Board of Hospital Administrators. 2.2. Preablation protocol
Abbreviations: AADs, anti-arrhythmic drugs; AF, atrial fibrillation; BMI, body mass index; cPVI, conventional, point-by-point pulmonary vein isolation; CT, computed tomography; ECG, electrocardiogram; INR, international normalized ratio; LLPV, left lower pulmonary vein; LUPV, left upper pulmonary vein; MER, multi-electrode catheter pulmonary vein isolation; min, minutes; PSLAX, parasternal long axis echocardiographic view; PV, pulmonary vein; PVI, pulmonary vein isolation; RF, radiofrequency; RLPV, right lower pulmonary vein; RUPV, right upper pulmonary vein; SD, standard deviation; TIA, transient ischemic attack. ⁎ Correspondence author at: Isala Klinieken, Dept of Cardiology, Dr. Van Heesweg 2, 8025 AB Zwolle, The Netherlands. Tel.: +31 38 4242374; fax: +31 38 4243222. E-mail address: [email protected] (A. Elvan).
http://dx.doi.org/10.1016/j.ijcard.2014.08.034 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
All patients underwent a CT scan, to asses left atrial and pulmonary vein anatomy. Patients were admitted 24 h before the ablation procedure. During hospitalization, cardiac rhythm in all patients was continuously monitored. Transthoracic echocardiography was performed routinely 1 day before ablation to determine right and left ventricular function, valvular abnormalities, and left and right atrial dimensions. Transesophageal echocardiography was performed directly pre-ablation to assess interatrial septum and to rule out intracardiac thrombus. Routine blood tests were performed, including electrolytes and cardiac enzymes. Patients who used oral anticoagulants were ‘bridged’ using low molecular weight heparins up to 3 days prior to the ablation procedure, in accordance with local guidelines.
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2.3. Ablation protocol
2.9. Statistical analyses
All ablation procedures were performed under general anesthesia supervised by a cardiovascular anesthesiologist. After placement of a 6F quadripolar catheter in the coronary sinus, two transseptal punctures were performed in patients undergoing cPVI and a single transseptal puncture was performed in patients undergoing MER ablation. In all patients, transseptal puncture was performed using a Brockenbrough needle under fluoroscopic and pressure guidance. After the first transseptal puncture, 10,000 IU of unfractionated heparin was administered. An 8.5F sheath (SL-1, St. Jude Medical, Minnetonka, MN, USA) was used for PV angiography. During either ablation procedure, all sheaths were continuously flushed with saline containing 2500 IU heparin per 500 ml saline. An activated clotting time between 300 and 350 s was targeted. Additional heparin was administered when needed. The activated clotting time was checked during the procedure at regular intervals of 30 min.
Patients were appointed by the type of procedure (cPVI vs. MER). Data are mentioned as means ± SD, median with interquartile range or percentage where appropriate. Statistical significance between means were calculated by the Student's t-test (unpaired) for continuous variables and Chi-square test for categorical variables in the analysis of baseline characteristics, acute PVI results, procedural characteristics and complications. A log-rank test was used to compare AF free survival among catheter groups. Uni- and multivariate Cox proportional hazard models were used to determine predictors of AF free survival. A P-value of ≤ 0.050 was regarded significant. Statistical analysis was performed using IBM Statistics version 20.0 (IBM SPSS Statistics for Windows, 2011: Armonk, New York, USA).
2.4. Conventional point-by-point ablation
3.1. Patient population
A multipolar steerable circular catheter for circumferential pulmonary vein (PV) mapping (Lasso™, Biosense Webster Inc., Diamond Bar, CA, USA) and a saline irrigated RF ablation catheter with a 3.5 mm tip electrode (Thermocool™, Biosense Webster Inc., Diamond Bar, CA, USA) were inserted through the above mentioned sheaths into the left atrium. A left atrial electro-anatomical map was created using 3D software (Carto™, Biosense Webster Inc., Diamond Bar, CA, USA). Templates of PV signals were recorded, pacing from the coronary sinus catheter or pacing from the mapping catheter positioned in the left atrial appendage was used whenever deemed necessary to distinguish electrical PV potentials from other electrical activity. After entering the PV, the circular catheter was positioned as close as possible to the PV ostium. PVI was performed by delivering RF energy in a point-by-point fashion to the PV antrum creating contiguous circular ablation lesions. RF energy was applied in a temperature-control mode with a temperature setting of 43 °C. RF energy was applied at 30 W with a flow rate of 15 ml/min or at 40 W with a flow rate of 30 ml/min, depending on the site of ablation. The endpoint of the ablation procedure was PV isolation, as documented by entrance and exit block or dissociation of PV potentials. No adenosine testing was performed.
3. Results
460 consecutive patients were included in this study, with a mean age of 56.3 (±10.0) years, with 230 patients undergoing cPVI and 230 patients undergoing MER ablation. Baseline characteristics did not differ significantly among catheter groups. Baseline characteristics are displayed in Table 1. 3.2. Acute PVI Acute PVI was achieved in 1834 out of 1840 (99.7%) PVs, and all 4 PVs could be isolated in 454 out of 460 patients (98.7%). Table 2 describes the acute PVI results. There were no significant differences in acute PVI success among catheter groups. 3.3. Procedural characteristics
2.5. Multi-electrode catheter ablation The multi-electrode pulmonary vein RF ablation catheter (PVAC™, Medtronic, Minneapolis, MN, USA) is a mapping and ablation catheter with a 25 mm diameter circular electrode array. This catheter has a bidirectional steering mechanism and an over-thewire design. The details of this device have been described previously [11]. The multielectrode RF system (MER) was introduced into the left atrium via the SL-1 sheath. Using a 0.032 in. guidewire placed in the PV, the catheter was positioned at the antrum of each PV to record local electrical activity at the veno-atrial junction prior to RF energy application, creating PV templates. RF energy was applied using the RF generator (Medtronic Genius, Minneapolis, MN, USA) with a target temperature setting of 60 °C, RF energy setting of 4:1 or 2:1 ratio between bipolar and unipolar energy, and 60 s RF application duration. Multiple applications of RF were delivered using the available energy settings until isolation of each pulmonary vein was achieved. After ablations were performed at all veno-atrial junctions, the MER was used to remap all PV ostia. If the PVs appeared to be incompletely isolated, additional RF applications were delivered using the MER until the PV isolation was achieved. No adenosine testing was performed.
2.6. Post-ablation management Patients were hospitalized for at least 24 h and monitored telemetrically. Oral anticoagulants were resumed immediately after the procedure, with a target INR of 2.5–3.5, in accordance with local guidelines. Low molecular weight heparin was administered in a patient-weight dependent dose until INR was adequate. Complications were defined according to European AF guidelines [12]. No cerebral imaging was performed routinely to assess asymptomatic cerebral lesions.
2.7. Follow-up A blanking period of 3 months was defined after PVI. Patients visited the outpatient clinic at 3, 6 and 12 months after PVI, including 24-hour Holter ECG. Follow-up after the 12 month outpatient clinic visit was performed by the referring physician. Patients were immediately referred to the emergency room in the case of symptoms. Furthermore, patients were contacted telephonically at the end of the study period when they were discharged from follow-up and were inquired about any AF symptoms and the use of anti-arrhythmic drugs (AADs).
2.8. Study endpoints The primary endpoint of our study was AF free survival, defined as patients without AF/atrial flutter/ atrial tachycardia recurrence after a blanking period of 3 months. AF recurrence was defined as an ECG showing the characteristics of AF, or on a 30 second telemetry strip, in accordance with European AF ablation guidelines [12].
The mean procedure duration was significantly longer in the cPVI group compared to the MER group (177.7 ± 48.7 vs. 133.9 ± 38.8 min, P b 0.001). Ablation time was significantly longer in the cPVI group compared to the MER group (45.3 ± 30.3 vs. 32.6 ± 12.0 min, P = 0.008). Procedural characteristics are displayed in Table 3. There were more complications in the cPVI group compared to the MER group (4.8% vs. 1.3%, P = 0.030), mainly caused by a significantly higher number of femoral vascular access complications in the cPVI group Table 1 Baseline characteristics.
Age (years) Gender men (%) BMI (kg/m2) LA size in PSLAX (mm) CHA2DS2VASc score 0 1 2 3 4 5–7 Co-morbidity (%) Hypertension Diabetes mellitus Previous TIA/stroke Structural heart disease Type AF: paroxysmal Failed AADs (range) Class I Class III AF duration (years)
Total group n = 460
cPVI n = 230
MER n = 230
P
56.3 (±10.0) 347 (75.4%) 27.6 (±4.2) 41.0 (±4.8)
56.1 (±9.8) 173 (75.2%) 27.4 (±4.0) 40.6 (±4.9)
56.6 (±10.3) 174 (76.0%) 27.9 (±4.3) 41.7 (±4.7)
0.610* 0.914† 0.307* 0.190*
178 (38.7%) 160 (34.8%) 75 (16.3%) 36 (7.8%) 2 (0.4%) 1 (0.2%)
95 (41.3%) 77 (33.5%) 32 (13.9%) 18 (7.8%) 1 (0.4%) 0
83 (36.2%) 83 (36.2%) 43 (18.8%) 18 (7.9%) 1 (0.4%) 1 (0.4%)
0.613†
161 (35.0%) 30 (6.5%) 25 (5.4%) 53 (11.5%) 375 (81.5%) 1.58 (0–4) 282 (61.3%) 329 (71.5%) 8.3 (±5.1)
71 (30.9%) 17 (7.4%) 9 (3.9%) 30 (13.0%) 184 (80.0%) 1.53 (0–4) 139 (60.4%) 161 (70.0%) 8.6 (±5.2)
90 (39.3%) 13 (5.7%) 16 (7.0%) 23 (10.0%) 193 (83.9%) 1.62 (0–4) 143 (62.4%) 168 (73.4%) 7.9 (±5.0)
0.063† 0.450† 0.150† 0.307† 0.256† 0.321† 0.533† 0.765† 0.154*
Data are presented as absolute numbers or means ± their SD or absolute numbers with percentages where appropriate. P-value between cPVI and MER group; *: Student's t-test; †: χ2-test. cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter pulmonary vein isolation; BMI: body mass index; LA: left atrium; PSLAX: parasternal long axis echocardiographic view; TIA: transient ischemic attack; AF: atrial fibrillation; AAD: anti-arrhythmic drugs.
P. Gal et al. / International Journal of Cardiology 176 (2014) 891–895 Table 2 Acute pulmonary vein isolation success.
LUPV LLPV RUPV RLPV Total
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Table 4 Complications.
cPVI (n = 230)
MER (n = 230)
P
228 (99.1%) 229 (99.6%) 230 (100%) 229 (99.6%) 916 (99.6%)
230 (100%) 230 (100%) 229 (99.6%) 229 (99.6%) 918 (99.8%)
0.157 0.318 0.320 0.998 0.664
Data are presented as absolute numbers with their respective percentages. P-value between cPVI and MER group (χ2-test). cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter pulmonary vein isolation; LUPV: left upper pulmonary vein; LLPV: left lower pulmonary vein; RUPV: right upper pulmonary vein; RLPV: right lower pulmonary vein.
(2.2% vs. 0%, P = 0.025). Moreover, female patients were more likely to develop complications (6.2% vs. 2.0%, P = 0.025), mainly attributable to a significantly higher number of pneumonias (3.5% vs. 0.3%, P = 0.004) and atrial perforations (1.8% vs 0%, P = 0.013). All complications were temporary, except for 1 patient with a retinal infarction in the MER group. Table 4 displays the characteristics of the complications.
Femoral vascular access Pneumonia Atrial perforation Retinal infarction Transient global amnesia Stroke/TIA Total
cPVI group (n = 230)
MER group (n = 230)
P
5 (2.2%) 4 (1.7%) 2 (0.9%) 0 (0%) 0 (0%) 0 (0%) 11 (4.8%)
0 (0%) 1 (0.4%) 0 (0%) 1 (0.4%) 1 (0.4%) 0 (0%) 3 (1.3%)
0.025 0.177 0.156 0.317 0.317 – 0.030
Data are presented as absolute numbers with their respective percentages. P-value between cPVI and MER group (χ2-test). cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter pulmonary vein isolation; TIA: transient ischemic attack.
catheter ablation. The main findings of this study are 1) both ablation techniques show a comparable, high acute PVI success rate, 2), both techniques are safe, although there were significantly less femoral vascular access complications in the MER group and 3) long-term AF free survival did not differ significantly among catheter groups. 4.1. Procedural characteristics
3.4. AF free survival Median follow-up was 43.2 (q1–q3: 30.6–59.0) months. There were 3 patients without documented AF recurrence who were still using AADs of classes I and III during follow-up. Patients underwent an average of 1.46 (±0.63) PVI procedures. In the cPVI group, after a mean of 1.48 (± 0.60) PVI procedures, the AF free survival without the use of AADs was 76.0% at 1 year, 67.8% at 2 years, 62.1% at 3 years, 50.6% at 4 years and 45.5% at 5 years. In the MER group, after a mean of 1.43 (± 0.65) PVI attempts, the AF free survival without the use of AADs was 72.7% at 1 year, 63.7% at 2 years, 57.1% at 3 years, 52.8% at 4 years and 47.7% at 5 years. There was no significant difference in AF free survival among catheter groups (log-rank test, P = 0.777). Fig. 1 displays the AF free survival of both catheter groups. In univariate analysis, a higher BMI, history of hypertension, history of diabetes mellitus and a higher CHADSVASc score were significantly associated with a reduced AF free survival. Interestingly, a longer history of AF was associated with a higher AF free survival. Compared to the 25% of patients with the longest AF duration, patients with the 25% shortest AF duration appear to have a higher BMI (28.0 vs. 27.2 kg/m2), a history of hypertension (40% vs. 28%) and diabetes (8% vs. 4%) more often, a higher mean CHADSVASc score (0.97 vs. 0.85), more frequently persistent AF (19% vs. 11%) and the mean number of repeat PVI procedures was lower (0.45 vs. 0.55). In multivariate analysis, BMI, AF duration and CHADSVASc score were significantly associated with AF free survival. A history of hypertension or diabetes mellitus was not associated with AF free survival in multivariate analysis. Uni- and multivariate analyses are displayed in Table 5. 4. Discussion This study reports the real-world data on procedural characteristics and long-term AF free survival of 460 patients, comparing PVI using conventional point-by-point RF catheter ablation to multi-electrode RF Table 3 Ablation characteristics.
Procedure duration (min) Ablation time (min) Fluoroscopy time (min)
cPVI group (n = 230)
MER group (n = 230)
P
177.7 (±48.7) 45.3 (±30.3) 29.7 (±12.3)
133.9 (±38.8) 32.6 (±12.0) 31.9 (±12.3)
b0.001 b0.001 0.064
Data are presented as means ± their SD. P-value between cPVI and MER group, Student's t-test. cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter pulmonary vein isolation.
Both catheter systems show a high acute PVI success rate. Procedure time and ablation time were significantly shorter in the MER group, in accordance with previous reports [4,5]. There was a trend to a shorter fluoroscopy time in the cPVI group, potentially due to the 3D electroanatomic mapping system [13]. 4.2. Complications Conventional point-by-point ablation necessitates an additional venous puncture compared to MER ablation, which may have caused the lower vascular complication rate in the MER group. Furthermore, inexperienced EP fellows performed venous punctures, which may have also increased the complication rate. The current study is in line with previous studies that showed gender differences in complications [14]. MER ablation has been associated with an increased prevalence of micro-embolisms after ablation compared to other PVI techniques [15–18]. In this study, there was one retinal infarction in the MER group, presumably due to an embolism, and one transient global amnesia, of which the etiology is unknown. Of note, a recent study by Verma et al. [19] showed several procedural changes, among which turning off the 1st or 10th electrode, reduced the number of asymptomatic cerebral micro-embolisms to 1.7%, comparable to other PVI techniques. 4.3. AF free survival The AF free survival in this study was not significantly different among catheter groups, which is in line with previous studies [4]. Although both PVI techniques show a high acute PVI success rate, patients developed AF recurrences during the entire follow-up, in line with previous reports [20,21]. The 5-year AF free survival is approximately 50% for both catheter groups, and presumably, progression of the AF substrate is an important factor in the development of late AF recurrences. In multivariate analysis, BMI, AF duration and CHADSVASc score were significantly associated with AF free survival. BMI, [22] hypertension and diabetes [23] have been associated with AF free survival in previous reports. A recent study reported no association between AF duration and AF free survival after PVI [24]. We hypothesize that patient selection bias may, at least in part, explain the association between AF duration and AF free survival after PVI. Patients with a long history of paroxysmal AF but with structurally normal hearts usually have a good prognosis after ablation. In the current study, patients with a long history of AF with a beneficial AF status may have been accepted for PVI and thus included in the study, whereas patients with a long history of AF with an unfavorable AF status (higher BMI, history of
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Fig. 1. Atrial fibrillation free survival after pulmonary vein isolation. The AF free survival of all patients with a mean of 1.46 (±0.62) PVI attempts during the entire follow-up is displayed. There is no significant difference in AF free survival among catheter groups (log-rank test, P = 0.777). AF: atrial fibrillation; cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter ablation. P-value among catheter groups.
hypertension, diabetes, persistent AF) were not accepted for PVI and thus not included in the study. There is a clear clinical need to identify predictors of long-term AF free survival and develop ablation techniques to modify the substrate for AF and increase long-term AF free survival.
asymptomatic cerebral lesions. It is known that ECG and Holter monitoring provides limited information on the AF burden of patients. AF free survival might be lower because patients did not undergo cardiac rhythm monitoring with loop recorders during follow-up.
6. Conclusion
4.4. Future perspectives As mentioned, MER ablation is being used less frequently in current clinical practice due to its association with asymptomatic cerebral emboli. A novel ablation catheter with a multi-electrode circular design (PVAC Gold™, Medtronic Inc, Minneapolis, MN), which uses gold electrodes instead of platinum electrodes, potentially increases safety with the same efficacy as the conventional PVAC with platinum electrodes. The present study shows that multi-electrode catheter systems are potentially beneficial over other catheter systems in terms of procedural characteristics, although large, randomized studies are necessary to provide firm clinical evidence. 5. Limitations With regard to interpreting our data, the following limitations should be considered. This is an observational study, with patients being allocated to the different ablation catheter procedures, although baseline characteristics did not differ significantly among catheter groups. Patients did not undergo routine brain imaging to assess
Both conventional point-by-point pulmonary vein isolation and multi-electrode catheter ablation achieved a high acute PVI success rate and both are safe techniques, although there were significantly less femoral vascular access complications in the MER group. Both catheter systems show a comparable long-term AF free survival. Future research should be aimed at identifying predictors of long-term AF free survival and increasing long-term AF free survival after catheter ablation.
Author contributions Concept/design: P Gal, A Elvan Data collection: P Gal, AESM Aarntzen Data analysis/interpretation: P Gal, A Elvan Drafting article: P Gal, A Elvan, A Adiyaman Statistics: P Gal Critical revision of article: all authors Approval of article: all authors
Table 5 Univariate and multivariate analysis. Univariate analysis
P-value
Hazard ratio
95% CI
Multivariate analysis
P-value
Hazard ratio
95% CI
Female gender Age BMI Persistent AF AF duration Used AADs LA dimension in PSLAX Structural heart disease Hypertension Diabetes mellitus CHA2DS2VASc score Previous TIA/stroke MER ablation*
0.249 0.105 0.018 0.757 0.020 0.476 0.985 0.132 0.007 0.021 0.002 0.726 0.063
1.180 1.010 1.039 0.949 0.963 0.956 1.000 0.703 1.420 1.769 1.218 0.913 1.271
0.891–1.563 0.998–1.021 1.007–1.072 0.683–1.319 0.933–0.994 0.843–1.083 0.953–1.049 0.445–1.111 1.098–1.836 1.091–2.867 1.076–1.378 0.550–1.517 0.987–1.638
BMI AF duration CHA2DS2VASc score
0.010 0.019 0.026
1.045 0.963 1.164
1.011–1.081 0.933–0.994 1.019–1.331
Univariate and multivariate analysis of the association between patient and PV characteristics and AF free survival after PVI. *: as compared to RF ablation. BMI: body mass index; AF: atrial fibrillation; AAD: anti-arrhythmic drugs; LA: left atrium; PSLAX: parasternal long axis echocardiographic view; TIA: transient ischemic attack; MER: multielectrode catheter pulmonary vein isolation.
P. Gal et al. / International Journal of Cardiology 176 (2014) 891–895
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Conventional radiofrequency catheter ablation compared to multi-electrode ablation for atrial fibrillation Pim Gal, Alissa E.S.M. Aarntzen, Jaap Jan J. Smit, Ahmet Adiyaman, Anand R. Ramdat Misier, Peter Paul H.M. Delnoy, Arif Elvan ⁎ Department of Cardiology, Isala Klinieken, Zwolle, The Netherlands
a r t i c l e
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Article history: Received 29 April 2014 Received in revised form 8 July 2014 Accepted 5 August 2014 Available online 13 August 2014 Keywords: Atrial fibrillation Pulmonary vein isolation Radiofrequency catheter ablation Point by point ablation Multi-electrode ablation Long-term follow-up
a b s t r a c t Background: Limited data is available on long-term atrial fibrillation (AF) free survival after multi-electrode catheter pulmonary vein isolation (PVI). The aim of this study was to compare point-by-point PVI to multielectrode PVI in terms of procedural characteristics and long-term AF free survival. Methods and results: 460 consecutive patients were randomly allocated: 230 patients underwent conventional, point-by-point ablation with a radiofrequency ablation catheter (cPVI group) and 230 patients underwent multi-electrode, phased radiofrequency ablation (MER group). Median follow-up was 43 months. Mean age was 56 years, 82% of patients had paroxysmal AF. Baseline characteristics did not differ among catheter groups. Acute electrical PVI was achieved in 99.7% of pulmonary veins, with no differences among catheter groups. Procedure time and ablation time were significantly shorter in the MER group. There were significantly less complications in the MER group (4.8% vs. 1.3%, P = 0.025). After a mean of 1.5 procedures, AF free survival without the use of antiarrhythmic drugs was 74% at 1 year and 46% at 5 years follow-up and did not differ among catheter groups (cPVI group 45%, MER group 48%, P = 0.777). In multivariate analysis, BMI, AF duration and CHADSVASc score were predictors of AF free survival. Conclusion: Multi-electrode ablation was superior in procedure duration and ablation time, with less complications. However, both conventional point-by-point PVI and multi-electrode PVI achieved a high acute PVI success rate and showed a comparable long-term AF free survival. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary vein isolation (PVI) is an effective treatment for atrial fibrillation (AF), although it is hampered by relative frequent recurrences of AF [1–3]. Multiple ablation systems have been developed in an attempt to increase AF free survival, although previous studies did not show a significant difference among PVI techniques [4–10]. However, there is little comparative data on real world, long-term AF free survival after multi-electrode ablation. The aim of this study was to compare conventional, electro-anatomic irrigated tip radiofrequency (RF) point-by-point ablation to duty-cycled multi-electrode RF ablation in
a large patient population with a long-term follow-up in terms of procedural characteristics and AF free survival. 2. Methods 2.1. Patient population 460 consecutive patients with symptomatic AF who were accepted for primo PVI were included in this study. Patients were randomly allocated to one of 2 ablation techniques: conventional RF point-by-point ablation (cPVI group) and multi-electrode, duty-cycled, phased RF ablation (MER group). Data were collected in a prospective hospital database. All patients consented to their data being registered and used for publication as did the Board of Hospital Administrators. 2.2. Preablation protocol
Abbreviations: AADs, anti-arrhythmic drugs; AF, atrial fibrillation; BMI, body mass index; cPVI, conventional, point-by-point pulmonary vein isolation; CT, computed tomography; ECG, electrocardiogram; INR, international normalized ratio; LLPV, left lower pulmonary vein; LUPV, left upper pulmonary vein; MER, multi-electrode catheter pulmonary vein isolation; min, minutes; PSLAX, parasternal long axis echocardiographic view; PV, pulmonary vein; PVI, pulmonary vein isolation; RF, radiofrequency; RLPV, right lower pulmonary vein; RUPV, right upper pulmonary vein; SD, standard deviation; TIA, transient ischemic attack. ⁎ Correspondence author at: Isala Klinieken, Dept of Cardiology, Dr. Van Heesweg 2, 8025 AB Zwolle, The Netherlands. Tel.: +31 38 4242374; fax: +31 38 4243222. E-mail address: [email protected] (A. Elvan).
http://dx.doi.org/10.1016/j.ijcard.2014.08.034 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
All patients underwent a CT scan, to asses left atrial and pulmonary vein anatomy. Patients were admitted 24 h before the ablation procedure. During hospitalization, cardiac rhythm in all patients was continuously monitored. Transthoracic echocardiography was performed routinely 1 day before ablation to determine right and left ventricular function, valvular abnormalities, and left and right atrial dimensions. Transesophageal echocardiography was performed directly pre-ablation to assess interatrial septum and to rule out intracardiac thrombus. Routine blood tests were performed, including electrolytes and cardiac enzymes. Patients who used oral anticoagulants were ‘bridged’ using low molecular weight heparins up to 3 days prior to the ablation procedure, in accordance with local guidelines.
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2.3. Ablation protocol
2.9. Statistical analyses
All ablation procedures were performed under general anesthesia supervised by a cardiovascular anesthesiologist. After placement of a 6F quadripolar catheter in the coronary sinus, two transseptal punctures were performed in patients undergoing cPVI and a single transseptal puncture was performed in patients undergoing MER ablation. In all patients, transseptal puncture was performed using a Brockenbrough needle under fluoroscopic and pressure guidance. After the first transseptal puncture, 10,000 IU of unfractionated heparin was administered. An 8.5F sheath (SL-1, St. Jude Medical, Minnetonka, MN, USA) was used for PV angiography. During either ablation procedure, all sheaths were continuously flushed with saline containing 2500 IU heparin per 500 ml saline. An activated clotting time between 300 and 350 s was targeted. Additional heparin was administered when needed. The activated clotting time was checked during the procedure at regular intervals of 30 min.
Patients were appointed by the type of procedure (cPVI vs. MER). Data are mentioned as means ± SD, median with interquartile range or percentage where appropriate. Statistical significance between means were calculated by the Student's t-test (unpaired) for continuous variables and Chi-square test for categorical variables in the analysis of baseline characteristics, acute PVI results, procedural characteristics and complications. A log-rank test was used to compare AF free survival among catheter groups. Uni- and multivariate Cox proportional hazard models were used to determine predictors of AF free survival. A P-value of ≤ 0.050 was regarded significant. Statistical analysis was performed using IBM Statistics version 20.0 (IBM SPSS Statistics for Windows, 2011: Armonk, New York, USA).
2.4. Conventional point-by-point ablation
3.1. Patient population
A multipolar steerable circular catheter for circumferential pulmonary vein (PV) mapping (Lasso™, Biosense Webster Inc., Diamond Bar, CA, USA) and a saline irrigated RF ablation catheter with a 3.5 mm tip electrode (Thermocool™, Biosense Webster Inc., Diamond Bar, CA, USA) were inserted through the above mentioned sheaths into the left atrium. A left atrial electro-anatomical map was created using 3D software (Carto™, Biosense Webster Inc., Diamond Bar, CA, USA). Templates of PV signals were recorded, pacing from the coronary sinus catheter or pacing from the mapping catheter positioned in the left atrial appendage was used whenever deemed necessary to distinguish electrical PV potentials from other electrical activity. After entering the PV, the circular catheter was positioned as close as possible to the PV ostium. PVI was performed by delivering RF energy in a point-by-point fashion to the PV antrum creating contiguous circular ablation lesions. RF energy was applied in a temperature-control mode with a temperature setting of 43 °C. RF energy was applied at 30 W with a flow rate of 15 ml/min or at 40 W with a flow rate of 30 ml/min, depending on the site of ablation. The endpoint of the ablation procedure was PV isolation, as documented by entrance and exit block or dissociation of PV potentials. No adenosine testing was performed.
3. Results
460 consecutive patients were included in this study, with a mean age of 56.3 (±10.0) years, with 230 patients undergoing cPVI and 230 patients undergoing MER ablation. Baseline characteristics did not differ significantly among catheter groups. Baseline characteristics are displayed in Table 1. 3.2. Acute PVI Acute PVI was achieved in 1834 out of 1840 (99.7%) PVs, and all 4 PVs could be isolated in 454 out of 460 patients (98.7%). Table 2 describes the acute PVI results. There were no significant differences in acute PVI success among catheter groups. 3.3. Procedural characteristics
2.5. Multi-electrode catheter ablation The multi-electrode pulmonary vein RF ablation catheter (PVAC™, Medtronic, Minneapolis, MN, USA) is a mapping and ablation catheter with a 25 mm diameter circular electrode array. This catheter has a bidirectional steering mechanism and an over-thewire design. The details of this device have been described previously [11]. The multielectrode RF system (MER) was introduced into the left atrium via the SL-1 sheath. Using a 0.032 in. guidewire placed in the PV, the catheter was positioned at the antrum of each PV to record local electrical activity at the veno-atrial junction prior to RF energy application, creating PV templates. RF energy was applied using the RF generator (Medtronic Genius, Minneapolis, MN, USA) with a target temperature setting of 60 °C, RF energy setting of 4:1 or 2:1 ratio between bipolar and unipolar energy, and 60 s RF application duration. Multiple applications of RF were delivered using the available energy settings until isolation of each pulmonary vein was achieved. After ablations were performed at all veno-atrial junctions, the MER was used to remap all PV ostia. If the PVs appeared to be incompletely isolated, additional RF applications were delivered using the MER until the PV isolation was achieved. No adenosine testing was performed.
2.6. Post-ablation management Patients were hospitalized for at least 24 h and monitored telemetrically. Oral anticoagulants were resumed immediately after the procedure, with a target INR of 2.5–3.5, in accordance with local guidelines. Low molecular weight heparin was administered in a patient-weight dependent dose until INR was adequate. Complications were defined according to European AF guidelines [12]. No cerebral imaging was performed routinely to assess asymptomatic cerebral lesions.
2.7. Follow-up A blanking period of 3 months was defined after PVI. Patients visited the outpatient clinic at 3, 6 and 12 months after PVI, including 24-hour Holter ECG. Follow-up after the 12 month outpatient clinic visit was performed by the referring physician. Patients were immediately referred to the emergency room in the case of symptoms. Furthermore, patients were contacted telephonically at the end of the study period when they were discharged from follow-up and were inquired about any AF symptoms and the use of anti-arrhythmic drugs (AADs).
2.8. Study endpoints The primary endpoint of our study was AF free survival, defined as patients without AF/atrial flutter/ atrial tachycardia recurrence after a blanking period of 3 months. AF recurrence was defined as an ECG showing the characteristics of AF, or on a 30 second telemetry strip, in accordance with European AF ablation guidelines [12].
The mean procedure duration was significantly longer in the cPVI group compared to the MER group (177.7 ± 48.7 vs. 133.9 ± 38.8 min, P b 0.001). Ablation time was significantly longer in the cPVI group compared to the MER group (45.3 ± 30.3 vs. 32.6 ± 12.0 min, P = 0.008). Procedural characteristics are displayed in Table 3. There were more complications in the cPVI group compared to the MER group (4.8% vs. 1.3%, P = 0.030), mainly caused by a significantly higher number of femoral vascular access complications in the cPVI group Table 1 Baseline characteristics.
Age (years) Gender men (%) BMI (kg/m2) LA size in PSLAX (mm) CHA2DS2VASc score 0 1 2 3 4 5–7 Co-morbidity (%) Hypertension Diabetes mellitus Previous TIA/stroke Structural heart disease Type AF: paroxysmal Failed AADs (range) Class I Class III AF duration (years)
Total group n = 460
cPVI n = 230
MER n = 230
P
56.3 (±10.0) 347 (75.4%) 27.6 (±4.2) 41.0 (±4.8)
56.1 (±9.8) 173 (75.2%) 27.4 (±4.0) 40.6 (±4.9)
56.6 (±10.3) 174 (76.0%) 27.9 (±4.3) 41.7 (±4.7)
0.610* 0.914† 0.307* 0.190*
178 (38.7%) 160 (34.8%) 75 (16.3%) 36 (7.8%) 2 (0.4%) 1 (0.2%)
95 (41.3%) 77 (33.5%) 32 (13.9%) 18 (7.8%) 1 (0.4%) 0
83 (36.2%) 83 (36.2%) 43 (18.8%) 18 (7.9%) 1 (0.4%) 1 (0.4%)
0.613†
161 (35.0%) 30 (6.5%) 25 (5.4%) 53 (11.5%) 375 (81.5%) 1.58 (0–4) 282 (61.3%) 329 (71.5%) 8.3 (±5.1)
71 (30.9%) 17 (7.4%) 9 (3.9%) 30 (13.0%) 184 (80.0%) 1.53 (0–4) 139 (60.4%) 161 (70.0%) 8.6 (±5.2)
90 (39.3%) 13 (5.7%) 16 (7.0%) 23 (10.0%) 193 (83.9%) 1.62 (0–4) 143 (62.4%) 168 (73.4%) 7.9 (±5.0)
0.063† 0.450† 0.150† 0.307† 0.256† 0.321† 0.533† 0.765† 0.154*
Data are presented as absolute numbers or means ± their SD or absolute numbers with percentages where appropriate. P-value between cPVI and MER group; *: Student's t-test; †: χ2-test. cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter pulmonary vein isolation; BMI: body mass index; LA: left atrium; PSLAX: parasternal long axis echocardiographic view; TIA: transient ischemic attack; AF: atrial fibrillation; AAD: anti-arrhythmic drugs.
P. Gal et al. / International Journal of Cardiology 176 (2014) 891–895 Table 2 Acute pulmonary vein isolation success.
LUPV LLPV RUPV RLPV Total
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Table 4 Complications.
cPVI (n = 230)
MER (n = 230)
P
228 (99.1%) 229 (99.6%) 230 (100%) 229 (99.6%) 916 (99.6%)
230 (100%) 230 (100%) 229 (99.6%) 229 (99.6%) 918 (99.8%)
0.157 0.318 0.320 0.998 0.664
Data are presented as absolute numbers with their respective percentages. P-value between cPVI and MER group (χ2-test). cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter pulmonary vein isolation; LUPV: left upper pulmonary vein; LLPV: left lower pulmonary vein; RUPV: right upper pulmonary vein; RLPV: right lower pulmonary vein.
(2.2% vs. 0%, P = 0.025). Moreover, female patients were more likely to develop complications (6.2% vs. 2.0%, P = 0.025), mainly attributable to a significantly higher number of pneumonias (3.5% vs. 0.3%, P = 0.004) and atrial perforations (1.8% vs 0%, P = 0.013). All complications were temporary, except for 1 patient with a retinal infarction in the MER group. Table 4 displays the characteristics of the complications.
Femoral vascular access Pneumonia Atrial perforation Retinal infarction Transient global amnesia Stroke/TIA Total
cPVI group (n = 230)
MER group (n = 230)
P
5 (2.2%) 4 (1.7%) 2 (0.9%) 0 (0%) 0 (0%) 0 (0%) 11 (4.8%)
0 (0%) 1 (0.4%) 0 (0%) 1 (0.4%) 1 (0.4%) 0 (0%) 3 (1.3%)
0.025 0.177 0.156 0.317 0.317 – 0.030
Data are presented as absolute numbers with their respective percentages. P-value between cPVI and MER group (χ2-test). cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter pulmonary vein isolation; TIA: transient ischemic attack.
catheter ablation. The main findings of this study are 1) both ablation techniques show a comparable, high acute PVI success rate, 2), both techniques are safe, although there were significantly less femoral vascular access complications in the MER group and 3) long-term AF free survival did not differ significantly among catheter groups. 4.1. Procedural characteristics
3.4. AF free survival Median follow-up was 43.2 (q1–q3: 30.6–59.0) months. There were 3 patients without documented AF recurrence who were still using AADs of classes I and III during follow-up. Patients underwent an average of 1.46 (±0.63) PVI procedures. In the cPVI group, after a mean of 1.48 (± 0.60) PVI procedures, the AF free survival without the use of AADs was 76.0% at 1 year, 67.8% at 2 years, 62.1% at 3 years, 50.6% at 4 years and 45.5% at 5 years. In the MER group, after a mean of 1.43 (± 0.65) PVI attempts, the AF free survival without the use of AADs was 72.7% at 1 year, 63.7% at 2 years, 57.1% at 3 years, 52.8% at 4 years and 47.7% at 5 years. There was no significant difference in AF free survival among catheter groups (log-rank test, P = 0.777). Fig. 1 displays the AF free survival of both catheter groups. In univariate analysis, a higher BMI, history of hypertension, history of diabetes mellitus and a higher CHADSVASc score were significantly associated with a reduced AF free survival. Interestingly, a longer history of AF was associated with a higher AF free survival. Compared to the 25% of patients with the longest AF duration, patients with the 25% shortest AF duration appear to have a higher BMI (28.0 vs. 27.2 kg/m2), a history of hypertension (40% vs. 28%) and diabetes (8% vs. 4%) more often, a higher mean CHADSVASc score (0.97 vs. 0.85), more frequently persistent AF (19% vs. 11%) and the mean number of repeat PVI procedures was lower (0.45 vs. 0.55). In multivariate analysis, BMI, AF duration and CHADSVASc score were significantly associated with AF free survival. A history of hypertension or diabetes mellitus was not associated with AF free survival in multivariate analysis. Uni- and multivariate analyses are displayed in Table 5. 4. Discussion This study reports the real-world data on procedural characteristics and long-term AF free survival of 460 patients, comparing PVI using conventional point-by-point RF catheter ablation to multi-electrode RF Table 3 Ablation characteristics.
Procedure duration (min) Ablation time (min) Fluoroscopy time (min)
cPVI group (n = 230)
MER group (n = 230)
P
177.7 (±48.7) 45.3 (±30.3) 29.7 (±12.3)
133.9 (±38.8) 32.6 (±12.0) 31.9 (±12.3)
b0.001 b0.001 0.064
Data are presented as means ± their SD. P-value between cPVI and MER group, Student's t-test. cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter pulmonary vein isolation.
Both catheter systems show a high acute PVI success rate. Procedure time and ablation time were significantly shorter in the MER group, in accordance with previous reports [4,5]. There was a trend to a shorter fluoroscopy time in the cPVI group, potentially due to the 3D electroanatomic mapping system [13]. 4.2. Complications Conventional point-by-point ablation necessitates an additional venous puncture compared to MER ablation, which may have caused the lower vascular complication rate in the MER group. Furthermore, inexperienced EP fellows performed venous punctures, which may have also increased the complication rate. The current study is in line with previous studies that showed gender differences in complications [14]. MER ablation has been associated with an increased prevalence of micro-embolisms after ablation compared to other PVI techniques [15–18]. In this study, there was one retinal infarction in the MER group, presumably due to an embolism, and one transient global amnesia, of which the etiology is unknown. Of note, a recent study by Verma et al. [19] showed several procedural changes, among which turning off the 1st or 10th electrode, reduced the number of asymptomatic cerebral micro-embolisms to 1.7%, comparable to other PVI techniques. 4.3. AF free survival The AF free survival in this study was not significantly different among catheter groups, which is in line with previous studies [4]. Although both PVI techniques show a high acute PVI success rate, patients developed AF recurrences during the entire follow-up, in line with previous reports [20,21]. The 5-year AF free survival is approximately 50% for both catheter groups, and presumably, progression of the AF substrate is an important factor in the development of late AF recurrences. In multivariate analysis, BMI, AF duration and CHADSVASc score were significantly associated with AF free survival. BMI, [22] hypertension and diabetes [23] have been associated with AF free survival in previous reports. A recent study reported no association between AF duration and AF free survival after PVI [24]. We hypothesize that patient selection bias may, at least in part, explain the association between AF duration and AF free survival after PVI. Patients with a long history of paroxysmal AF but with structurally normal hearts usually have a good prognosis after ablation. In the current study, patients with a long history of AF with a beneficial AF status may have been accepted for PVI and thus included in the study, whereas patients with a long history of AF with an unfavorable AF status (higher BMI, history of
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Fig. 1. Atrial fibrillation free survival after pulmonary vein isolation. The AF free survival of all patients with a mean of 1.46 (±0.62) PVI attempts during the entire follow-up is displayed. There is no significant difference in AF free survival among catheter groups (log-rank test, P = 0.777). AF: atrial fibrillation; cPVI: conventional point-by-point pulmonary vein isolation; MER: multi-electrode catheter ablation. P-value among catheter groups.
hypertension, diabetes, persistent AF) were not accepted for PVI and thus not included in the study. There is a clear clinical need to identify predictors of long-term AF free survival and develop ablation techniques to modify the substrate for AF and increase long-term AF free survival.
asymptomatic cerebral lesions. It is known that ECG and Holter monitoring provides limited information on the AF burden of patients. AF free survival might be lower because patients did not undergo cardiac rhythm monitoring with loop recorders during follow-up.
6. Conclusion
4.4. Future perspectives As mentioned, MER ablation is being used less frequently in current clinical practice due to its association with asymptomatic cerebral emboli. A novel ablation catheter with a multi-electrode circular design (PVAC Gold™, Medtronic Inc, Minneapolis, MN), which uses gold electrodes instead of platinum electrodes, potentially increases safety with the same efficacy as the conventional PVAC with platinum electrodes. The present study shows that multi-electrode catheter systems are potentially beneficial over other catheter systems in terms of procedural characteristics, although large, randomized studies are necessary to provide firm clinical evidence. 5. Limitations With regard to interpreting our data, the following limitations should be considered. This is an observational study, with patients being allocated to the different ablation catheter procedures, although baseline characteristics did not differ significantly among catheter groups. Patients did not undergo routine brain imaging to assess
Both conventional point-by-point pulmonary vein isolation and multi-electrode catheter ablation achieved a high acute PVI success rate and both are safe techniques, although there were significantly less femoral vascular access complications in the MER group. Both catheter systems show a comparable long-term AF free survival. Future research should be aimed at identifying predictors of long-term AF free survival and increasing long-term AF free survival after catheter ablation.
Author contributions Concept/design: P Gal, A Elvan Data collection: P Gal, AESM Aarntzen Data analysis/interpretation: P Gal, A Elvan Drafting article: P Gal, A Elvan, A Adiyaman Statistics: P Gal Critical revision of article: all authors Approval of article: all authors
Table 5 Univariate and multivariate analysis. Univariate analysis
P-value
Hazard ratio
95% CI
Multivariate analysis
P-value
Hazard ratio
95% CI
Female gender Age BMI Persistent AF AF duration Used AADs LA dimension in PSLAX Structural heart disease Hypertension Diabetes mellitus CHA2DS2VASc score Previous TIA/stroke MER ablation*
0.249 0.105 0.018 0.757 0.020 0.476 0.985 0.132 0.007 0.021 0.002 0.726 0.063
1.180 1.010 1.039 0.949 0.963 0.956 1.000 0.703 1.420 1.769 1.218 0.913 1.271
0.891–1.563 0.998–1.021 1.007–1.072 0.683–1.319 0.933–0.994 0.843–1.083 0.953–1.049 0.445–1.111 1.098–1.836 1.091–2.867 1.076–1.378 0.550–1.517 0.987–1.638
BMI AF duration CHA2DS2VASc score
0.010 0.019 0.026
1.045 0.963 1.164
1.011–1.081 0.933–0.994 1.019–1.331
Univariate and multivariate analysis of the association between patient and PV characteristics and AF free survival after PVI. *: as compared to RF ablation. BMI: body mass index; AF: atrial fibrillation; AAD: anti-arrhythmic drugs; LA: left atrium; PSLAX: parasternal long axis echocardiographic view; TIA: transient ischemic attack; MER: multielectrode catheter pulmonary vein isolation.
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