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Clinical predictors and relationship between early and late atrial tachyarrhythmias after pulmonary vein antrum isolation
Clinical predictors and relationship between early and late atrial tachyarrhythmias after pulmonary vein antrum isolation Sakis Themistoclakis, MD,* Robert A. Schweikert, MD,† Walid I. Saliba, MD,† Aldo Bonso, MD,* Antonio Rossillo, MD,* Giovanni Bader, MD,* Oussama Wazni, MD,† David J. Burkhardt, MD,† Antonio Raviele, MD,* Andrea Natale, MD, FHRS‡ *From Cardiovascular Department, Umberto I Hospital, Mestre-Venice, Italy, †Section of Cardiac Pacing and Electrophysiology, Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, and ‡Stanford University, Palo Alto, California. BACKGROUND Several studies have reported early (EAT) and late (LAT) atrial tachyarrhythmias following atrial fibrillation (AF) ablation, but the factors associated with them and their clinical significance are not well known. OBJECTIVE The purpose of this study was to investigate the predictors and the relationship between EAT and LAT after AF ablation. METHODS A total of 1298 patients with paroxysmal (54%), persistent (18%), or permanent (28%) AF underwent intracardiac echocardiography-guided pulmonary vein antrum isolation and were followed for 41 ⫾ 10 months. EAT and LAT were defined as an episode of AF or atrial flutter/tachycardia lasting longer than 1 minute that occurred within the first 3 months of ablation and after 3 months postablation, respectively. RESULTS After a single ablation procedure, EAT developed in 514 (40%) patients and LAT in 292 (22%) patients. At a multivariable analysis, longer AF duration (odds ratio [OR] 1.03), history of hypertension (OR 1.32), left atrial enlargement (OR 1.55), perma-
Introduction Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with a prevalence between 0.9% and 2.5% in the general population and an increasing incidence with age.1,2 The clinical significance and financial impact of AF management create a need for effective treatment. Antiarrhythmic drugs for prevention of AF recurrences frequently are ineffective and often are associated with adverse and toxic effects that may nullify the possible benefit of sinus rhythm maintenance. In the last 10 years, left atrial catheter ablation aimed at pulmonary vein (PV) isolation and/or elimination of the arrhythmic substrate has been proposed as a definitive cure for this arrhythmia.3 Some investigators have examined the incidence of AF after ablation and found that early arrhythmic recurrences (i.e., within the first 2
nent AF (OR 1.72), and lack of superior vena cava isolation (OR 1.60) were significantly associated with EAT. Independent predictors of LAT were longer AF duration (OR 1.03), history of hypertension (OR 1.65), persistent (OR 2.17) or permanent AF (OR 2.28), and occurrence of EAT (OR 30.62). The risk of LAT was inversely related to the time to first EAT occurrence (OR 20, 54, and 1,052 in first, second, and third month, respectively). Notably, 49% of patients with EAT did not experience LAT. CONCLUSION EAT strongly predict LAT. However, EAT did not automatically mean ablation failure. Delaying redo procedure may be appropriate during the first 2 months after ablation. Longer AF duration, hypertension, and nonparoxysmal AF are independent predictors of EAT and LAT. KEYWORDS Atrial fibrillation; Catheter ablation; Left atrial flutter; Pulmonary vein; Recurrences (Heart Rhythm 2008;5:679 – 685) © 2008 Heart Rhythm Society. All rights reserved.
weeks to 3 months after the procedure) are common, occurring in as many as 50% of patients.4 –9 However, these recurrences often disappear after the initial period and do not necessarily indicate failure of the procedure over time. It is important to realize that these data derive from small series of patients with relatively short-term follow-up. Furthermore, the factors predictive of both early (EAT) and late atrial tachyarrhythmias (LAT) and their clinical relevance have not been thoroughly investigated. The aim of the present study was to identify the clinical variables associated with EAT and LAT and to assess the relationship between these arrhythmias in a very large cohort of patients undergoing PV antrum isolation.
Methods Patient population
Address reprint requests and correspondence: Dr. Antonio Raviele, Cardiovascular Department, Umberto I Hospital, 30174 Mestre-Venice, Italy. E-mail address: [email protected]. (Received September 12, 2007; accepted January 19, 2008.)
Consecutive patients referred to Cleveland Clinic Foundation, Cleveland, Ohio, USA, or Umberto I Hospital, MestreVenice, Italy, for treatment of AF by PV antrum isolation between September 2001 and June 2005 were included in
1547-5271/$ -see front matter © 2008 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2008.01.031
680 the study. On referral, all patient data were prospectively recorded in a computerized database. All patients selected for PV antrum isolation had a history of symptomatic, drug-resistant paroxysmal, persistent, or permanent AF. Before the ablation procedure, all patients gave written informed consent. The study was approved by the institutional ethics committee, and patient data were collected in accordance with institutional ethics guidelines. Amiodarone was discontinued more than 4 months before the procedure; other antiarrhythmic drugs were discontinued at least five half-lives before ablation. Prior to ablation, patients underwent standard examinations and oral anticoagulation therapy.10,11 In order to have a homogeneous patient population, only subjects who had undergone a single AF ablation procedure were included in the study.
PV antrum isolation All patients underwent PV antrum isolation using the intracardiac echocardiography-guided technique, as previously described.12–14 In brief, after double transseptal puncture performed under intracardiac echocardiographic guidance, a circular mapping catheter (Lasso, Biosense Webster, Diamond Bar, CA, USA) and an 8-mm radiofrequency ablation catheter (Celsius DS, Biosense Webster) were advanced into the left atrium. A 10Fr 64-element phased-array ultrasound imaging catheter (AcuNav, Acuson Inc., Mountain View, CA, USA) was used to identify the antra of PVs and to guide sequential placement of the circular mapping catheter along the complete circumference of each PV antrum. Radiofrequency ablation was performed whenever PV potentials were recorded with the circular mapping catheter around the PV antra, with the power titrated based on microbubble formation detected by intracardiac echocardiography.12,13 The end-point of ablation was complete electrical disconnection of all PV antra from the left atrium. Superior vena cava (SVC) isolation also was performed. Postablation challenge with high-dose isoproterenol (up to 20 g/min) was used to disclose non-PV antrum/SVC foci.14
Postablation follow-up All patients were monitored in the hospital overnight and usually were discharged the day after the procedure. Oral anticoagulation with warfarin was restarted in all patients on the evening of the ablation procedure and continued for at least 3 to 6 months. Usually, patients with persistent or permanent AF were placed on antiarrhythmic drug therapy for the first 2 months after PV antrum isolation to prevent early arrhythmic recurrences and to favor reverse electrical and structural atrial remodeling. In contrast, patients with paroxysmal AF were left untreated unless they developed early arrhythmic recurrences after ablation. Typically, a class IC agent, sotalol or dofetilide were given; amiodarone was never given. Antiarrhythmic drugs were discontinued 2 months after ablation in all patients in sinus rhythm. Patients were examined in the outpatient clinic 1, 3, 6, 9, and 12 months after ablation and every 6 months thereafter. An ECG and 48-hour Holter recording were obtained routinely
Heart Rhythm, Vol 5, No 5, May 2008 in all patients within 1 month after the procedure and at each follow-up examination. Patients were supplied with a transtelephonic rhythm transmitter for 5 months after PV antrum isolation. They were asked to transmit their rhythm every time they had symptoms compatible with arrhythmias, and one to three times per day even if they were asymptomatic. Interrogation of implanted devices was used (when available) to confirm arrhythmia recurrence. Patients were advised to report any recurrence of symptoms to the clinic, at which point 48-hour Holter monitoring was performed. Documentation of arrhythmic episodes was based on ECG and/or Holter data, rhythm transmitter, and implanted device recordings. Patient compliance with the monitoring protocol was 98% in the first 3 months and 92% thereafter. All patients had a minimum follow-up of 1 year. Early atrial tachyarrhythmias (EAT) were defined as recurrences of AF or episodes of new-onset left atrial flutter/tachycardia lasting longer than 1 minute that occurred during the first 3 months after ablation. Late atrial tachyarrhythmias (LAT) were defined as such arrhythmias that occurred more than 3 months after ablation. None of the patients who experienced EAT were considered for a second procedure before 6 to 12 months after the initial ablation because of difficulties in planning the redo procedure sooner. AF was classified as paroxysmal, persistent, or permanent in accordance with ACC/AHA/ESC 2006 guidelines.15
Statistical analysis Data are given as mean ⫾ SD for continuous variables and as percentage values for categorical variables unless otherwise indicated. Comparison of continuous variables between two groups was made by independent-samples Student’s t-test. Categorical variables were compared by Chisquare analysis. Two-tailed P ⬍.05 was considered significant. Multivariable logistic regression analysis was performed to determine the independent predictors of EAT and LAT. The variables selected for testing in multivariable analysis were those with P ⬍.10 in the univariate model. A significant risk was obtained if the 95% confidence interval (CI) exceeded 1 and P ⬍.05. Statistical analyses were performed using Stata statistical software (Release 9, StataCorp, College Station, TX, USA).
Results Patient characteristics The study enrolled 1,298 patients (1,088 at Cleveland Clinic Foundation and 210 at Umberto I Hospital). The baseline characteristics of these patients are summarized in Table 1. AF was paroxysmal in 699 (54%) patients, persistent in 230 (18%), and permanent in 369 (28%). Hypertension was present in 33% of cases and structural heart disease in 32% of cases. Left atrial diameter was ⬎4 cm in 891 (69%) patients. Mean left ventricular ejection fraction was ⬍40% in 115 (9%) patients.
Themistoclakis et al Table 1
Post-AF Ablation Arrhythmias
Baseline patient characteristics
No. of patients Age (years) Gender [n (%)] Male Female AF type [n (%)] Paroxysmal Persistent Permanent AF duration (years) Hypertension Structural heart disease [n (%)] Valvular heart disease Ischemic heart disease Dilated cardiomyopathy Hypertrophic cardiomyopathy Other Left atrial size (cm) Left ventricular ejection fraction (%)
1,298 56.1 ⫾ 10.9 1,016 (78) 282 (22) 699 (54) 230 (18) 369 (28) 6.6 ⫾ 5.8 426 (33) 415 (32) 164 (13) 134 (11) 69 (5) 30 (2) 18 (1) 4.4 ⫾ 0.7 54 ⫾ 8
Continuous variables are given as mean ⫾ SD. AF ⫽ atrial fibrillation.
PV antrum isolation All four PV antra were successfully isolated in all patients. Additional SVC isolation was successfully achieved in 1,018 (78%) patients. In the remaining 280 (22%) patients, SVC isolation was not performed due to the lack of SVC potentials or because of phrenic nerve capture during highvoltage pacing. Non-PV antrum/SVC foci were identified in 98 (7.5%) patients and were successfully ablated in all cases. All patients with AF at the time of the procedure were in sinus rhythm at the end of the procedure as a result of ablation or after electrical cardioversion.
Postablation EAT After the ablation procedure, 514 (40%) patients had EAT. Recurrences of AF and episodes of new-onset left atrial flutter/tachycardia were recorded in 461 (36%) and 53 (4%) patients, respectively. EAT were symptomatic in 493 (96%) patients and asymptomatic in 21 (4%). The first episode of EAT occurred in the majority of patients (417 [81%]) within the first month following ablation, particularly within the first week (259 [50%] patients). After 1 month, the incidence progressively decreased to 10% in the second month (51 patients) and 9% in the third month (46 patients; Figure 1). AF recurrences were observed in 80% (370/461), 10% (46/461), and 10% (45/461) of patients during the first, second, and third month, respectively. Similarly, episodes of new-onset left atrial flutter/ tachycardia occurred in 89% (47/53), 9% (5/53), and 2% (1/53) of patients during the first, second, and third month, respectively. No significant differences with regard to the incidence and timing of EAT were observed between patients enrolled in the two centers. Univariate analysis revealed that the following clinical variables were related to EAT: older age, longer duration of AF, history of hypertension, left atrial enlargement, history of persistent/permanent AF, and absence of SVC isolation
681 (Table 2). In multivariable analysis, only longer duration of AF (odds ratio [OR] 1.03), history of hypertension (OR 1.32), left atrial enlargement (OR 1.55), history of permanent AF (OR 1.72), and absence of SVC isolation (OR 1.60) remained independent predictors of EAT (Table 3).
Postablation LAT During a mean follow-up of 41 ⫾ 10 months (range 21– 63 months), 292 (22%) patients experienced LAT, whereas 1,006 (78%) patients maintained sinus rhythm without antiarrhythmic drugs after a single ablation procedure. Symptomatic and asymptomatic LAT were observed in 288 (98.6%) and 4 (1.4%) patients, respectively. Mean time to first LAT was 181 ⫾ 141 days (range 90 –720 days). Recurrences of AF and episodes of new-onset left atrial flutter/ tachycardia were observed in 252 (19%) and 40 (3%) patients, respectively. LAT occurred in 264 (51%) of 514 patients with EAT and in 28 (3.6%) of 784 patients without (P ⬍.0001). Both recurrence of AF and episodes of new-onset left atrial flutter/tachycardia were observed more frequently in patients with EAT. In particular, recurrences of AF occurred in 228 (44%) patients with EAT and in 24 (3.1%) patients without EAT. Similarly, episodes of new-onset left atrial flutter/ tachycardia occurred in 36 (7%) patients with EAT and in 4 (0.5%) patients without EAT. LAT occurred more frequently in patients who experienced the first EAT in the third month than in those who experienced the first EAT in the second or first month (98% vs 69% and 44%, respectively; Figure 2). No significant differences were observed between patients enrolled in the two centers. Univariate analysis revealed that the following clinical variables were related to LAT: longer duration of AF, presence of structural heart disease, history of hypertension, left atrial enlargement, history of persistent/permanent AF, occurrence of EAT, time to first EAT episode, and lack of SVC isolation (Table 4). In multivariable analysis, occurrence of EAT was found to be the strongest independent predictor of LAT (OR 30.62; Table 5). Risk of LAT was inversely related to time
Figure 1 (EAT).
Time to the first episode of early atrial tachyarrhythmia
682 Table 2
Heart Rhythm, Vol 5, No 5, May 2008 Clinical variables related to early atrial tachyarrhythmias by univariate analysis
Variable Age (years) Gender [n (%)] Female Male AF type [n (%)] Paroxysmal Persistent Permanent AF duration (years) Left atrial diameter ⬎4 cm [n (%)] Left ventricular ejection fraction ⱕ40% [n (%)] Hypertension [n (%)] Structural heart disease [n (%)] SVC isolation [n (%)] Non-PV antrum/SVC foci [n (%)]
EAT (514 patients)
No EAT (784 patients)
Unadjusted OR (95% CI)
P value
56.9 ⫾ 10.7
55.5 ⫾ 10.9
1.01 (1–1.02)
.029
105 (21) 409 (79)
177 (23) 607 (77)
Reference 1.14 (0.85–1.49)
.359
237 (46) 95 (18) 182 (36) 7.2 ⫾ 6.4 389 (76) 45 (9) 196 (38) 171 (33) 352 (35) 35 (7)
462 (59) 135 (17) 187 (24) 6.1 ⫾ 5.3 502 (64) 70 (9) 230 (29) 244 (31) 162 (58) 63 (8)
Reference 1.37 (1.01–1.86) 1.89 (1.46–2.45) 1.03 (1.01–1.05) 1.74 (1.36–2.25) 0.97 (0.65–1.43) 1.49 (1.17–1.88) 1.09 (0.86–1.39) 0.43 (0.32–0.58) 0.83 (0.54–1.28)
.043 ⬍.001 .003 ⬍.001 .888 .001 .435 ⬍.001 .413
Continuous variables are given as mean ⫾ SD. AF ⫽ atrial fibrillation; CI ⫽ confidence interval; EAT ⫽ early atrial tachyarrhythmias; OR ⫽ odds ratio; PV ⫽ pulmonary vein; SVC ⫽ superior vena cava.
to first EAT episode: the earlier the first EAT episode, the lower the risk of LAT (OR 20 in the first month vs 54 in the second month and 1,052 in the third month; Table 4). A longer duration of AF (OR 1.03), history of hypertension (OR 1.65), and history of persistent (OR 2.17) or permanent AF (OR 2.28) were other independent predictors of LAT (Table 5).
Discussion Incidence, predictors, and clinical implications of EAT Previous studies have examined the incidence of EAT, defined as the recurrence of AF or the development of new-onset left atrial flutter/tachycardia occurring within 2 weeks to 3 months after ablation.4 –9 According to these studies, the incidence of EAT ranges between 35% and 46%.4 –9 In the present study, we found a similar percentage Table 3 Clinical variables related to early atrial tachyarrhythmias by multivariable analysis Variables Age (per year) AF type Paroxysmal* Persistent Permanent AF duration (per year) Left atrial diameter ⱕ4 cm* ⬎4 cm Hypertension No* Yes Superior vena cava isolation No* Yes
Odds ratio
Standard error
1.00
0.006
.528
0.98–1.01
1 1.25 1.72 1.03
0.219 0.261 0.011
.207 ⬍.001 .005
0.89–1.76 1.28–2.32 1.01–1.05
1 1.55
0.228
.003
1.16–2.07
1 1.32
0.184
.046
1.01–1.74
1 0.40
0.066
⬍.001
0.29–0.55
AF ⫽ atrial fibrillation. *Baseline category.
P value
(40%). EAT in our patients occurred more frequently within the first month after ablation, and the incidence progressively decreased during the second and third month. In the literature, early recurrences of AF are much more common (95%) than new-onset left atrial flutter/tachycardia.7 This also was the case in our study (90%). Possible predictors of EAT have been investigated only in a limited number of patients exclusively with paroxysmal and persistent AF, with controversial results. In their experience with 110 patients, Oral et al4 did not find any parameter associated with EAT. In contrast, in studies of populations ranging from 50 to 207 patients, other investigators have reported several variables to be independent predictors of EAT: presence of multiple AF foci,6 persistent AF,5 presence of structural heart disease,7 left atrial enlargement,5,8 left atrial electrical abnormalities,5 and lack of successful ablation of all targeted PVs.7 In the present study, which involved a very large cohort of 1,298 patients with paroxysmal, persistent, and permanent AF, a longer
95% confidence interval
Figure 2 Incidence of late atrial tachyarrhythmias (LAT) in accordance with the time of occurrence of early atrial tachyarrhythmias (EAT). The incidence was lower in patients in whom the occurrence of EAT was earlier.
Themistoclakis et al Table 4
Post-AF Ablation Arrhythmias
683
Clinical variables related to late atrial tachyarrhythmias by univariate analysis
Variable Age (years) Gender [n (%)] Female Male EAT [n (%)] Time to first EAT [n (%)] No EAT ⱕ30 days 31–60 days 61–90 days AF type [n (%)] Paroxysmal Persistent Permanent AF duration (years) Left atrial diameter ⬎4 cm [n (%)] Left ventricular ejection fraction ⱕ40% [n (%)] Hypertension [n (%)] Structural heart disease [n (%)] SVC isolation [n (%)] Non-PV antrum/SVC foci [n (%)]
LAT (292 patients)
No LAT (1,006 patients)
56.5 ⫾ 11.1
56 ⫾ 10.8
65 (22) 227 (78) 264 (90) 28 184 35 45
(10) (63) (12) (15)
107 (37) 65 (22) 120 (41) 7.9 ⫾ 6.7 237 (81) 30 (10) 131 (45) 109 (37) 196 (19) 18 (6)
Unadjusted OR (95% CI)
P value
1.00 (0.99–1.01)
.554
217 (22) 789 (78) 250 (25)
Reference 0.96 (0.70–1.31) 29 (19.2–44.2)
.812 ⬍.001
756 233 16 1
Reference 20 (13.7–30.8) 54 (26.8–109.4) 1,052 (140–7,877)
⬍.001 ⬍.001 ⬍.001
Reference 2.21 (1.55–3.16) 2.68 (1.98–3.61) 1.04 (1.02–1.06) 2.31 (1.67–3.19) 1.22 (0.78–1.89) 1.93 (1.48–2.52) 1.36 (1.03–1.78) 0.53 (0.39–0.72) 0.75 (0.45–1.28)
⬍.001 ⬍.001 ⬍.001 ⬍.001 .373 ⬍.001 .026 ⬍.001 .300
(75) (23) (2) (0)
592 (59) 165 (16) 249 (25) 6.2 ⫾ 5.5 654 (65) 85 (8) 295 (29) 306 (30) 822 (81) 80 (8)
Continuous variables are given as mean ⫾ SD. AF ⫽ atrial fibrillation; CI ⫽ confidence interval; EAT ⫽ early atrial tachyarrhythmias; LAT ⫽ late atrial tachyarrhythmias; OR ⫽ odds ratio; PV ⫽ pulmonary vein; SVC ⫽ superior vena cava.
duration of arrhythmia, history of hypertension, left atrial enlargement, history of permanent AF, and lack of SVC isolation were found to be independent predictors of EAT after a single ablation procedure. According to our data, the risk of EAT increases by approximately 3% per year of AF duration before the ablation. The risk is 32% greater for patients with hypertension and 55% greater for patients with left atrial diameter ⬎4 cm. The risk is 47% higher in patients with permanent AF compared to those with persistent AF and 72% higher than in those with paroxysmal AF. These EAT-associated variables probably reflect negative Table 5
electrical and anatomic atrial remodeling and may explain the higher propensity to develop EAT. In our series, the risk of EAT was 60% lower in patients with successful isolation of SVC compared to patients in whom SVC isolation was not achieved. This is in agreement with previous studies that identified the SVC as the major source of non-PV triggers and found that SVC isolation, as adjunctive strategy to PV antrum isolation, could improve the outcome of AF ablation.16,17 Further randomized trials are needed to prove that routine SVC isolation is useful in every AF ablation procedure.
Clinical variables related to late atrial tachyarrhythmias by multivariable analysis
Variable EAT No* Yes AF type Paroxysmal* Persistent Permanent AF duration (per year) Left atrial diameter ⱕ4 cm* ⬎4 cm Hypertension No* Yes Structural heart disease No* Yes Superior vena cava isolation No* Yes
Odds ratio
Standard error
P value
95% confidence interval
1 30.62
7.830
⬍.001
18.55–50.54
1 2.17 2.28 1.03
0.539 0.482 0.015
.002 ⬍.001 .029
1.33–3.53 1.51–3.46 1.00–1.06
1 1.39
0.310
.142
0.90–2.15
1 1.65
0.312
.009
1.14–2.39
1 1.09
0.225
.675
0.74–1.65
1 0.77
0.163
.209
0.51–1.16
AF ⫽ atrial fibrillation; EAT ⫽ early atrial tachyarrhythmias. *Baseline category.
684 Published data indicate that many patients who suffer EAT (31%–57%) do not continue to have atrial tachyarrhythmias at short-term and medium-term follow-up.4 –9 Therefore, these arrhythmias, although associated with a significantly higher incidence of LAT, cannot be regarded as failure of the ablation procedure. Our results are in agreement with these literature data. We found that half of our 514 patients with EAT had no arrhythmic recurrences in long-term follow-up (41 months) without antiarrhythmic drugs. However, our data also indicate that EAT are associated with a 31-fold higher risk of developing LAT; therefore, they have an unfavorable prognostic significance. This is especially true for EAT that occur in the second and third months after ablation. Consequently, unlike the investigators who did not take EAT into account and who regarded the period immediately after ablation as a blanking period, we believe that these arrhythmias should be recorded and held in due consideration. Patients who develop EAT should be followed up much more closely over time than those who do not. Moreover, suspending anticoagulant therapy in these patients is more problematic; therefore, this step is inadvisable, at least for a period that is sufficiently long (6 –12 months) to allow ascertainment of the absence of LAT. In our study, time to the first EAT episode was inversely related to risk of LAT. The risk was lower when EAT developed in the first month (OR 20) and increased progressively in the second month (OR 54) and the third month (OR 1,052). This probably is due to the fact that the mechanism responsible for EAT is different according to the time interval elapsed from the ablation procedure. In the first few days, the cause of EAT likely is a transient and potentially reversible phenomenon, particularly postablation atrial inflammation18 and/or incomplete healing of lesion sets.19 In the subsequent days and months, the most frequent mechanism is the development of gaps in the initial ablation lesion leading to resumption of electrical conduction in previously isolated veins.20 –22 In the present study, according to the recommendations of the 2007 expert consensus statement,10,11 we considered the first 3 months after ablation to be the blanking period. However, these recommendations are based on the personal experience of the Task Force members and literature reports on small series of patients. Our report is the first large population study that provides consistent data on the most appropriate duration of the blanking period. In our study, the observation that almost all patients with EAT occurring during the third month experienced LAT strongly suggests that the blanking period should be limited to the first 2 months. It also is clear from our data that no arrhythmia disappearance should be expected without antiarrhythmic drugs beyond the second month after the initial procedure. Thus, although scheduling an additional session usually is not justified when EAT develop in the first 2 months after the initial ablation, a redo
Heart Rhythm, Vol 5, No 5, May 2008 procedure seems to be appropriate when the arrhythmias occur after this period.
Incidence and predictors of postablation LAT Long-term success rates of AF ablation reportedly range from 45% to 95%.10 Previous attempts to identify possible predictors of LAT have yielded discrepant conclusions. Lee et al6 examined different clinical variables in relation to the procedural outcome in patients with paroxysmal AF and found that only the presence of early recurrences of AF predicted late recurrences, a result similar to that of Berkowitsch et al.9 However, in a study conducted on a smaller patient population, the same authors did not find any predictor of LAT.23 Vasamreddy et al24 identified the presence of persistent AF, permanent AF, and age older than 50 years prior to ablation as independent predictors of AF recurrences after ablation. In contrast, Callans et al20 observed that the procedure was more likely to be successful in older patients and that variables such as a history of persistent AF, left atrial dilation, obesity, and mitral regurgitation did not affect the clinical outcome. However, Burruezo et al25 identified left atrial dilation and presence of hypertension as strong preprocedural predictors. Moreover, Pappone et al26 found that only left atrial enlargement and encircling of a PV ostial area ⬍15% of the left atrial surface independently predict LAT. In our study, among the different variables, presence of EAT emerged as the strongest independent risk factor for failure of the ablation procedure. Based on our results, having an EAT, especially after the first month, is associated with high risk of LAT (51%). Conversely, the absence of EAT is associated with a significantly lower risk of LAT (3.6%). Other independent predictors of LAT in our series were longer duration of AF, history of hypertension, and history of persistent or permanent AF. According to our data, the risk of LAT increases by 3% per year of AF duration before ablation. The risk is twice as high in patients with persistent and permanent AF as in those with paroxysmal AF and is 65% higher in patients with history of hypertension. These data confirm that anatomic and electrical atrial remodeling probably plays an important role in determining LAT occurrence. According to this hypothesis, it could be reasonable to perform the ablation procedure at an earlier stage, before the arrhythmia becomes long-standing or evolves from paroxysmal to persistent or permanent.
Study limitations All patients were treated by the same ablation technique; therefore, we cannot exclude the possibility that using different techniques might yield different results. Nevertheless, the data reported in the literature seem to indicate that the ablation technique used does not influence the incidence of EAT, which is reported to be similar among the focal (39%),6 segmental (35%– 41%),4,6,8 circumferential (46%),7 and antral (40%) approaches. However, considering the differences in long-term results reported in the literature, it is possible that the ablation technique has an influence on LAT. In patients with long-
Themistoclakis et al
Post-AF Ablation Arrhythmias
lasting AF, the adjunctive creation of linear lesions or the ablation of fragmented potentials may improve the success of the procedure.10,11,27,28 However, this strategy is controversial.10,21,22 In particular, the addition of linear lesions has been reported to be associated with a high incidence of atypical atrial flutter: up to 24% vs the 4% observed in the present study.10,22 Transtelephonic monitoring was performed systematically for only 5 months after ablation. Therefore, we cannot rule out the possibility that patients may have asymptomatic LAT beyond this period. However, periodic clinical and ECG examinations and Holter monitoring did not document asymptomatic recurrence. Moreover, prolonging such scrupulous transtelephonic monitoring further would not be feasible in clinical practice, nor would it be readily accepted by patients. Finally, it appears that late recurrences 1 year after ablation are rare.10,11,26,29
Conclusion The results of this study confirm that EAT are very frequent and demonstrate that such arrhythmias have an unfavorable prognostic significance in that they are strong predictors of LAT. This is especially true for EAT that occur in the second and third months after ablation. However, because nearly half of patients with EAT will not develop LAT, a conservative strategy is warranted during the first months postablation. Both EAT and LAT are significantly associated with longer duration of AF, history of hypertension, and permanent AF. In addition, left atrial enlargement predicts EAT. These data suggest that anatomic and electrical atrial remodeling may play an important role in favoring postablation arrhythmias. Studies are needed to determine whether the incidence of these arrhythmias may be reduced by performing the ablation procedure earlier, before AF becomes long-standing or evolves from paroxysmal to persistent or permanent.
Acknowledgments We thank Ms. Michelle Williams-Andrews, Dr. Mohamed Kanj, from the Cleveland Clinic Foundation, Dr. Andrea Corrado, and Dr. Michela Madalosso from Umberto I Hospital for contributions in data collection. We also thank Dr. Jennifer E. Cummings and Dr. Mauricio Arruda from the Cleveland Clinic Foundation for reading the manuscript and making several helpful suggestions.
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28.
29.
recurrence after pulmonary vein isolation for atrial fibrillation. Am J Cardiol 2003;91:83– 85. Lee SH, Tai CT, Hsieh MH, et al. Predictors of early and late recurrence of atrial fibrillation after catheter ablation of paroxysmal atrial fibrillation. J Interv Card Electrophysiol 2004;10:221–226. Bertaglia E, Stabile G, Senatore G, et al. Predictive value of early atrial tachyarrhythmia recurrence after circumferential anatomical pulmonary vein ablation. Pacing Clin Electrophysiol 2005;28:366 –371. Jiang H, Lu Z, Lei H, et al. Predictors of early recurrence and delayed cure after segmental pulmonary vein isolation for paroxysmal atrial fibrillation without structural heart disease. J Interv Card Electrophysiol 2006;15:157–163. Berkowitsch A, Greiss H, Vukajlovic D, et al. Usefulness of atrial fibrillation burden as a predictor for success of pulmonary vein isolation. Pacing Clin Electrophysiol 2005;28:1292–1301. Natale A, Raviele A, Arentz T, et al. Venice Chart international consensus document on atrial fibrillation ablation. J Cardiovasc Electrophysiol 2007;18: 560 –580. Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. Heart Rhythm 2007;4: 816 – 861. Verma A, Marrouche NF, Natale A. Pulmonary vein antrum isolation: Intracardiac echocardiography-guided technique. J Cardiovasc Electrophysiol 2004;15: 1335–1340. Marrouche NF, Martin DO, Wazni O, et al. Phased-array intracardiac echocardiography monitoring during pulmonary vein isolation in patients with atrial fibrillation. Impact on outcome and complications. Circulation 2003;107:2710 – 2716. Kanj M, Wazni O, Natale A. Pulmonary vein antrum isolation. Heart Rhythm 2007;4:S73–S79. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation 2006;114:700 –752. Lin WS, Tai CT, Hsieh MH, et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation 2003;107:3176 – 3183. Arruda M, Mlcochova H, Prasad SK, et al. Electrical isolation of superior vena cava: an adjunctive strategy to pulmonary vein antrum isolation improving the outcome of AF ablation. J Cardiovasc Electrophysiol 2007;18:1261–1266. Grubman E, Pavri BB, Lyle S, et al. Histopathologic effects of radiofrequency catheter ablation in previously infarcted human myocardium. J Cardiovasc Electrophysiol 1999;10:336 –342. Fenelon G, Brugada P. Delayed effects of radiofrequency energy: mechanisms and clinical implications. Pacing Clin Electrophysiol 1996;19:484 – 489. Callans DJ, Gerstenfeld EP, Dixit S, et al. Efficacy of repeated pulmonary vein isolation procedures in patients with recurrent atrial fibrillation. J Cardiovasc Electrophysiol 2004;15:1050 –1055. Verma A, Kilicaslan F, Pisano E, et al. Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation 2005;112:627– 635. Raviele A, Themistoclakis S, Rossillo A, et al. Iatrogenic postatrial fibrillation ablation left atrial tachycardia/flutter: how to prevent and treat it? J Cardiovasc Electrophysiol 2005;16:298 –301. Hsieh MH, Tai CT, Lee SH, et al. The different mechanisms between late and very late recurrences of atrial fibrillation in patients undergoing a repeated catheter ablation. J Cardiovasc Electrophysiol 2006;17:231–235. Vasamreddy CR, Lickfett L, Jayam VK, et al. Predictors of recurrence following catheter ablation of atrial fibrillation using an irrigated-tip ablation catheter. J Cardiovasc Electrophysiol 2004;15:692– 697. Berruezo A, Tamborero D, Mont L, et al. Pre-procedural predictors of atrial fibrillation recurrence after circumferential pulmonary vein ablation. Eur Heart J 2007;28:836 – 841. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation. Outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003;42: 185–197. Haissaguerre M, Hocini M, Sanders P, et al. Catheter ablation of long-lasting persistent atrial fibrillation: clinical outcome and mechanisms of subsequent arrhythmias. J Cardiovasc Electrophysiol 2005;16:1138 –1147. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044 –2053. Hsieh MH, Tai CT, Tsai CF, et al. Clinical outcome of very late recurrence of atrial fibrillation after catheter ablation of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2003;14:598 – 601.
Introduction Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with a prevalence between 0.9% and 2.5% in the general population and an increasing incidence with age.1,2 The clinical significance and financial impact of AF management create a need for effective treatment. Antiarrhythmic drugs for prevention of AF recurrences frequently are ineffective and often are associated with adverse and toxic effects that may nullify the possible benefit of sinus rhythm maintenance. In the last 10 years, left atrial catheter ablation aimed at pulmonary vein (PV) isolation and/or elimination of the arrhythmic substrate has been proposed as a definitive cure for this arrhythmia.3 Some investigators have examined the incidence of AF after ablation and found that early arrhythmic recurrences (i.e., within the first 2
nent AF (OR 1.72), and lack of superior vena cava isolation (OR 1.60) were significantly associated with EAT. Independent predictors of LAT were longer AF duration (OR 1.03), history of hypertension (OR 1.65), persistent (OR 2.17) or permanent AF (OR 2.28), and occurrence of EAT (OR 30.62). The risk of LAT was inversely related to the time to first EAT occurrence (OR 20, 54, and 1,052 in first, second, and third month, respectively). Notably, 49% of patients with EAT did not experience LAT. CONCLUSION EAT strongly predict LAT. However, EAT did not automatically mean ablation failure. Delaying redo procedure may be appropriate during the first 2 months after ablation. Longer AF duration, hypertension, and nonparoxysmal AF are independent predictors of EAT and LAT. KEYWORDS Atrial fibrillation; Catheter ablation; Left atrial flutter; Pulmonary vein; Recurrences (Heart Rhythm 2008;5:679 – 685) © 2008 Heart Rhythm Society. All rights reserved.
weeks to 3 months after the procedure) are common, occurring in as many as 50% of patients.4 –9 However, these recurrences often disappear after the initial period and do not necessarily indicate failure of the procedure over time. It is important to realize that these data derive from small series of patients with relatively short-term follow-up. Furthermore, the factors predictive of both early (EAT) and late atrial tachyarrhythmias (LAT) and their clinical relevance have not been thoroughly investigated. The aim of the present study was to identify the clinical variables associated with EAT and LAT and to assess the relationship between these arrhythmias in a very large cohort of patients undergoing PV antrum isolation.
Methods Patient population
Address reprint requests and correspondence: Dr. Antonio Raviele, Cardiovascular Department, Umberto I Hospital, 30174 Mestre-Venice, Italy. E-mail address: [email protected]. (Received September 12, 2007; accepted January 19, 2008.)
Consecutive patients referred to Cleveland Clinic Foundation, Cleveland, Ohio, USA, or Umberto I Hospital, MestreVenice, Italy, for treatment of AF by PV antrum isolation between September 2001 and June 2005 were included in
1547-5271/$ -see front matter © 2008 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2008.01.031
680 the study. On referral, all patient data were prospectively recorded in a computerized database. All patients selected for PV antrum isolation had a history of symptomatic, drug-resistant paroxysmal, persistent, or permanent AF. Before the ablation procedure, all patients gave written informed consent. The study was approved by the institutional ethics committee, and patient data were collected in accordance with institutional ethics guidelines. Amiodarone was discontinued more than 4 months before the procedure; other antiarrhythmic drugs were discontinued at least five half-lives before ablation. Prior to ablation, patients underwent standard examinations and oral anticoagulation therapy.10,11 In order to have a homogeneous patient population, only subjects who had undergone a single AF ablation procedure were included in the study.
PV antrum isolation All patients underwent PV antrum isolation using the intracardiac echocardiography-guided technique, as previously described.12–14 In brief, after double transseptal puncture performed under intracardiac echocardiographic guidance, a circular mapping catheter (Lasso, Biosense Webster, Diamond Bar, CA, USA) and an 8-mm radiofrequency ablation catheter (Celsius DS, Biosense Webster) were advanced into the left atrium. A 10Fr 64-element phased-array ultrasound imaging catheter (AcuNav, Acuson Inc., Mountain View, CA, USA) was used to identify the antra of PVs and to guide sequential placement of the circular mapping catheter along the complete circumference of each PV antrum. Radiofrequency ablation was performed whenever PV potentials were recorded with the circular mapping catheter around the PV antra, with the power titrated based on microbubble formation detected by intracardiac echocardiography.12,13 The end-point of ablation was complete electrical disconnection of all PV antra from the left atrium. Superior vena cava (SVC) isolation also was performed. Postablation challenge with high-dose isoproterenol (up to 20 g/min) was used to disclose non-PV antrum/SVC foci.14
Postablation follow-up All patients were monitored in the hospital overnight and usually were discharged the day after the procedure. Oral anticoagulation with warfarin was restarted in all patients on the evening of the ablation procedure and continued for at least 3 to 6 months. Usually, patients with persistent or permanent AF were placed on antiarrhythmic drug therapy for the first 2 months after PV antrum isolation to prevent early arrhythmic recurrences and to favor reverse electrical and structural atrial remodeling. In contrast, patients with paroxysmal AF were left untreated unless they developed early arrhythmic recurrences after ablation. Typically, a class IC agent, sotalol or dofetilide were given; amiodarone was never given. Antiarrhythmic drugs were discontinued 2 months after ablation in all patients in sinus rhythm. Patients were examined in the outpatient clinic 1, 3, 6, 9, and 12 months after ablation and every 6 months thereafter. An ECG and 48-hour Holter recording were obtained routinely
Heart Rhythm, Vol 5, No 5, May 2008 in all patients within 1 month after the procedure and at each follow-up examination. Patients were supplied with a transtelephonic rhythm transmitter for 5 months after PV antrum isolation. They were asked to transmit their rhythm every time they had symptoms compatible with arrhythmias, and one to three times per day even if they were asymptomatic. Interrogation of implanted devices was used (when available) to confirm arrhythmia recurrence. Patients were advised to report any recurrence of symptoms to the clinic, at which point 48-hour Holter monitoring was performed. Documentation of arrhythmic episodes was based on ECG and/or Holter data, rhythm transmitter, and implanted device recordings. Patient compliance with the monitoring protocol was 98% in the first 3 months and 92% thereafter. All patients had a minimum follow-up of 1 year. Early atrial tachyarrhythmias (EAT) were defined as recurrences of AF or episodes of new-onset left atrial flutter/tachycardia lasting longer than 1 minute that occurred during the first 3 months after ablation. Late atrial tachyarrhythmias (LAT) were defined as such arrhythmias that occurred more than 3 months after ablation. None of the patients who experienced EAT were considered for a second procedure before 6 to 12 months after the initial ablation because of difficulties in planning the redo procedure sooner. AF was classified as paroxysmal, persistent, or permanent in accordance with ACC/AHA/ESC 2006 guidelines.15
Statistical analysis Data are given as mean ⫾ SD for continuous variables and as percentage values for categorical variables unless otherwise indicated. Comparison of continuous variables between two groups was made by independent-samples Student’s t-test. Categorical variables were compared by Chisquare analysis. Two-tailed P ⬍.05 was considered significant. Multivariable logistic regression analysis was performed to determine the independent predictors of EAT and LAT. The variables selected for testing in multivariable analysis were those with P ⬍.10 in the univariate model. A significant risk was obtained if the 95% confidence interval (CI) exceeded 1 and P ⬍.05. Statistical analyses were performed using Stata statistical software (Release 9, StataCorp, College Station, TX, USA).
Results Patient characteristics The study enrolled 1,298 patients (1,088 at Cleveland Clinic Foundation and 210 at Umberto I Hospital). The baseline characteristics of these patients are summarized in Table 1. AF was paroxysmal in 699 (54%) patients, persistent in 230 (18%), and permanent in 369 (28%). Hypertension was present in 33% of cases and structural heart disease in 32% of cases. Left atrial diameter was ⬎4 cm in 891 (69%) patients. Mean left ventricular ejection fraction was ⬍40% in 115 (9%) patients.
Themistoclakis et al Table 1
Post-AF Ablation Arrhythmias
Baseline patient characteristics
No. of patients Age (years) Gender [n (%)] Male Female AF type [n (%)] Paroxysmal Persistent Permanent AF duration (years) Hypertension Structural heart disease [n (%)] Valvular heart disease Ischemic heart disease Dilated cardiomyopathy Hypertrophic cardiomyopathy Other Left atrial size (cm) Left ventricular ejection fraction (%)
1,298 56.1 ⫾ 10.9 1,016 (78) 282 (22) 699 (54) 230 (18) 369 (28) 6.6 ⫾ 5.8 426 (33) 415 (32) 164 (13) 134 (11) 69 (5) 30 (2) 18 (1) 4.4 ⫾ 0.7 54 ⫾ 8
Continuous variables are given as mean ⫾ SD. AF ⫽ atrial fibrillation.
PV antrum isolation All four PV antra were successfully isolated in all patients. Additional SVC isolation was successfully achieved in 1,018 (78%) patients. In the remaining 280 (22%) patients, SVC isolation was not performed due to the lack of SVC potentials or because of phrenic nerve capture during highvoltage pacing. Non-PV antrum/SVC foci were identified in 98 (7.5%) patients and were successfully ablated in all cases. All patients with AF at the time of the procedure were in sinus rhythm at the end of the procedure as a result of ablation or after electrical cardioversion.
Postablation EAT After the ablation procedure, 514 (40%) patients had EAT. Recurrences of AF and episodes of new-onset left atrial flutter/tachycardia were recorded in 461 (36%) and 53 (4%) patients, respectively. EAT were symptomatic in 493 (96%) patients and asymptomatic in 21 (4%). The first episode of EAT occurred in the majority of patients (417 [81%]) within the first month following ablation, particularly within the first week (259 [50%] patients). After 1 month, the incidence progressively decreased to 10% in the second month (51 patients) and 9% in the third month (46 patients; Figure 1). AF recurrences were observed in 80% (370/461), 10% (46/461), and 10% (45/461) of patients during the first, second, and third month, respectively. Similarly, episodes of new-onset left atrial flutter/ tachycardia occurred in 89% (47/53), 9% (5/53), and 2% (1/53) of patients during the first, second, and third month, respectively. No significant differences with regard to the incidence and timing of EAT were observed between patients enrolled in the two centers. Univariate analysis revealed that the following clinical variables were related to EAT: older age, longer duration of AF, history of hypertension, left atrial enlargement, history of persistent/permanent AF, and absence of SVC isolation
681 (Table 2). In multivariable analysis, only longer duration of AF (odds ratio [OR] 1.03), history of hypertension (OR 1.32), left atrial enlargement (OR 1.55), history of permanent AF (OR 1.72), and absence of SVC isolation (OR 1.60) remained independent predictors of EAT (Table 3).
Postablation LAT During a mean follow-up of 41 ⫾ 10 months (range 21– 63 months), 292 (22%) patients experienced LAT, whereas 1,006 (78%) patients maintained sinus rhythm without antiarrhythmic drugs after a single ablation procedure. Symptomatic and asymptomatic LAT were observed in 288 (98.6%) and 4 (1.4%) patients, respectively. Mean time to first LAT was 181 ⫾ 141 days (range 90 –720 days). Recurrences of AF and episodes of new-onset left atrial flutter/ tachycardia were observed in 252 (19%) and 40 (3%) patients, respectively. LAT occurred in 264 (51%) of 514 patients with EAT and in 28 (3.6%) of 784 patients without (P ⬍.0001). Both recurrence of AF and episodes of new-onset left atrial flutter/tachycardia were observed more frequently in patients with EAT. In particular, recurrences of AF occurred in 228 (44%) patients with EAT and in 24 (3.1%) patients without EAT. Similarly, episodes of new-onset left atrial flutter/ tachycardia occurred in 36 (7%) patients with EAT and in 4 (0.5%) patients without EAT. LAT occurred more frequently in patients who experienced the first EAT in the third month than in those who experienced the first EAT in the second or first month (98% vs 69% and 44%, respectively; Figure 2). No significant differences were observed between patients enrolled in the two centers. Univariate analysis revealed that the following clinical variables were related to LAT: longer duration of AF, presence of structural heart disease, history of hypertension, left atrial enlargement, history of persistent/permanent AF, occurrence of EAT, time to first EAT episode, and lack of SVC isolation (Table 4). In multivariable analysis, occurrence of EAT was found to be the strongest independent predictor of LAT (OR 30.62; Table 5). Risk of LAT was inversely related to time
Figure 1 (EAT).
Time to the first episode of early atrial tachyarrhythmia
682 Table 2
Heart Rhythm, Vol 5, No 5, May 2008 Clinical variables related to early atrial tachyarrhythmias by univariate analysis
Variable Age (years) Gender [n (%)] Female Male AF type [n (%)] Paroxysmal Persistent Permanent AF duration (years) Left atrial diameter ⬎4 cm [n (%)] Left ventricular ejection fraction ⱕ40% [n (%)] Hypertension [n (%)] Structural heart disease [n (%)] SVC isolation [n (%)] Non-PV antrum/SVC foci [n (%)]
EAT (514 patients)
No EAT (784 patients)
Unadjusted OR (95% CI)
P value
56.9 ⫾ 10.7
55.5 ⫾ 10.9
1.01 (1–1.02)
.029
105 (21) 409 (79)
177 (23) 607 (77)
Reference 1.14 (0.85–1.49)
.359
237 (46) 95 (18) 182 (36) 7.2 ⫾ 6.4 389 (76) 45 (9) 196 (38) 171 (33) 352 (35) 35 (7)
462 (59) 135 (17) 187 (24) 6.1 ⫾ 5.3 502 (64) 70 (9) 230 (29) 244 (31) 162 (58) 63 (8)
Reference 1.37 (1.01–1.86) 1.89 (1.46–2.45) 1.03 (1.01–1.05) 1.74 (1.36–2.25) 0.97 (0.65–1.43) 1.49 (1.17–1.88) 1.09 (0.86–1.39) 0.43 (0.32–0.58) 0.83 (0.54–1.28)
.043 ⬍.001 .003 ⬍.001 .888 .001 .435 ⬍.001 .413
Continuous variables are given as mean ⫾ SD. AF ⫽ atrial fibrillation; CI ⫽ confidence interval; EAT ⫽ early atrial tachyarrhythmias; OR ⫽ odds ratio; PV ⫽ pulmonary vein; SVC ⫽ superior vena cava.
to first EAT episode: the earlier the first EAT episode, the lower the risk of LAT (OR 20 in the first month vs 54 in the second month and 1,052 in the third month; Table 4). A longer duration of AF (OR 1.03), history of hypertension (OR 1.65), and history of persistent (OR 2.17) or permanent AF (OR 2.28) were other independent predictors of LAT (Table 5).
Discussion Incidence, predictors, and clinical implications of EAT Previous studies have examined the incidence of EAT, defined as the recurrence of AF or the development of new-onset left atrial flutter/tachycardia occurring within 2 weeks to 3 months after ablation.4 –9 According to these studies, the incidence of EAT ranges between 35% and 46%.4 –9 In the present study, we found a similar percentage Table 3 Clinical variables related to early atrial tachyarrhythmias by multivariable analysis Variables Age (per year) AF type Paroxysmal* Persistent Permanent AF duration (per year) Left atrial diameter ⱕ4 cm* ⬎4 cm Hypertension No* Yes Superior vena cava isolation No* Yes
Odds ratio
Standard error
1.00
0.006
.528
0.98–1.01
1 1.25 1.72 1.03
0.219 0.261 0.011
.207 ⬍.001 .005
0.89–1.76 1.28–2.32 1.01–1.05
1 1.55
0.228
.003
1.16–2.07
1 1.32
0.184
.046
1.01–1.74
1 0.40
0.066
⬍.001
0.29–0.55
AF ⫽ atrial fibrillation. *Baseline category.
P value
(40%). EAT in our patients occurred more frequently within the first month after ablation, and the incidence progressively decreased during the second and third month. In the literature, early recurrences of AF are much more common (95%) than new-onset left atrial flutter/tachycardia.7 This also was the case in our study (90%). Possible predictors of EAT have been investigated only in a limited number of patients exclusively with paroxysmal and persistent AF, with controversial results. In their experience with 110 patients, Oral et al4 did not find any parameter associated with EAT. In contrast, in studies of populations ranging from 50 to 207 patients, other investigators have reported several variables to be independent predictors of EAT: presence of multiple AF foci,6 persistent AF,5 presence of structural heart disease,7 left atrial enlargement,5,8 left atrial electrical abnormalities,5 and lack of successful ablation of all targeted PVs.7 In the present study, which involved a very large cohort of 1,298 patients with paroxysmal, persistent, and permanent AF, a longer
95% confidence interval
Figure 2 Incidence of late atrial tachyarrhythmias (LAT) in accordance with the time of occurrence of early atrial tachyarrhythmias (EAT). The incidence was lower in patients in whom the occurrence of EAT was earlier.
Themistoclakis et al Table 4
Post-AF Ablation Arrhythmias
683
Clinical variables related to late atrial tachyarrhythmias by univariate analysis
Variable Age (years) Gender [n (%)] Female Male EAT [n (%)] Time to first EAT [n (%)] No EAT ⱕ30 days 31–60 days 61–90 days AF type [n (%)] Paroxysmal Persistent Permanent AF duration (years) Left atrial diameter ⬎4 cm [n (%)] Left ventricular ejection fraction ⱕ40% [n (%)] Hypertension [n (%)] Structural heart disease [n (%)] SVC isolation [n (%)] Non-PV antrum/SVC foci [n (%)]
LAT (292 patients)
No LAT (1,006 patients)
56.5 ⫾ 11.1
56 ⫾ 10.8
65 (22) 227 (78) 264 (90) 28 184 35 45
(10) (63) (12) (15)
107 (37) 65 (22) 120 (41) 7.9 ⫾ 6.7 237 (81) 30 (10) 131 (45) 109 (37) 196 (19) 18 (6)
Unadjusted OR (95% CI)
P value
1.00 (0.99–1.01)
.554
217 (22) 789 (78) 250 (25)
Reference 0.96 (0.70–1.31) 29 (19.2–44.2)
.812 ⬍.001
756 233 16 1
Reference 20 (13.7–30.8) 54 (26.8–109.4) 1,052 (140–7,877)
⬍.001 ⬍.001 ⬍.001
Reference 2.21 (1.55–3.16) 2.68 (1.98–3.61) 1.04 (1.02–1.06) 2.31 (1.67–3.19) 1.22 (0.78–1.89) 1.93 (1.48–2.52) 1.36 (1.03–1.78) 0.53 (0.39–0.72) 0.75 (0.45–1.28)
⬍.001 ⬍.001 ⬍.001 ⬍.001 .373 ⬍.001 .026 ⬍.001 .300
(75) (23) (2) (0)
592 (59) 165 (16) 249 (25) 6.2 ⫾ 5.5 654 (65) 85 (8) 295 (29) 306 (30) 822 (81) 80 (8)
Continuous variables are given as mean ⫾ SD. AF ⫽ atrial fibrillation; CI ⫽ confidence interval; EAT ⫽ early atrial tachyarrhythmias; LAT ⫽ late atrial tachyarrhythmias; OR ⫽ odds ratio; PV ⫽ pulmonary vein; SVC ⫽ superior vena cava.
duration of arrhythmia, history of hypertension, left atrial enlargement, history of permanent AF, and lack of SVC isolation were found to be independent predictors of EAT after a single ablation procedure. According to our data, the risk of EAT increases by approximately 3% per year of AF duration before the ablation. The risk is 32% greater for patients with hypertension and 55% greater for patients with left atrial diameter ⬎4 cm. The risk is 47% higher in patients with permanent AF compared to those with persistent AF and 72% higher than in those with paroxysmal AF. These EAT-associated variables probably reflect negative Table 5
electrical and anatomic atrial remodeling and may explain the higher propensity to develop EAT. In our series, the risk of EAT was 60% lower in patients with successful isolation of SVC compared to patients in whom SVC isolation was not achieved. This is in agreement with previous studies that identified the SVC as the major source of non-PV triggers and found that SVC isolation, as adjunctive strategy to PV antrum isolation, could improve the outcome of AF ablation.16,17 Further randomized trials are needed to prove that routine SVC isolation is useful in every AF ablation procedure.
Clinical variables related to late atrial tachyarrhythmias by multivariable analysis
Variable EAT No* Yes AF type Paroxysmal* Persistent Permanent AF duration (per year) Left atrial diameter ⱕ4 cm* ⬎4 cm Hypertension No* Yes Structural heart disease No* Yes Superior vena cava isolation No* Yes
Odds ratio
Standard error
P value
95% confidence interval
1 30.62
7.830
⬍.001
18.55–50.54
1 2.17 2.28 1.03
0.539 0.482 0.015
.002 ⬍.001 .029
1.33–3.53 1.51–3.46 1.00–1.06
1 1.39
0.310
.142
0.90–2.15
1 1.65
0.312
.009
1.14–2.39
1 1.09
0.225
.675
0.74–1.65
1 0.77
0.163
.209
0.51–1.16
AF ⫽ atrial fibrillation; EAT ⫽ early atrial tachyarrhythmias. *Baseline category.
684 Published data indicate that many patients who suffer EAT (31%–57%) do not continue to have atrial tachyarrhythmias at short-term and medium-term follow-up.4 –9 Therefore, these arrhythmias, although associated with a significantly higher incidence of LAT, cannot be regarded as failure of the ablation procedure. Our results are in agreement with these literature data. We found that half of our 514 patients with EAT had no arrhythmic recurrences in long-term follow-up (41 months) without antiarrhythmic drugs. However, our data also indicate that EAT are associated with a 31-fold higher risk of developing LAT; therefore, they have an unfavorable prognostic significance. This is especially true for EAT that occur in the second and third months after ablation. Consequently, unlike the investigators who did not take EAT into account and who regarded the period immediately after ablation as a blanking period, we believe that these arrhythmias should be recorded and held in due consideration. Patients who develop EAT should be followed up much more closely over time than those who do not. Moreover, suspending anticoagulant therapy in these patients is more problematic; therefore, this step is inadvisable, at least for a period that is sufficiently long (6 –12 months) to allow ascertainment of the absence of LAT. In our study, time to the first EAT episode was inversely related to risk of LAT. The risk was lower when EAT developed in the first month (OR 20) and increased progressively in the second month (OR 54) and the third month (OR 1,052). This probably is due to the fact that the mechanism responsible for EAT is different according to the time interval elapsed from the ablation procedure. In the first few days, the cause of EAT likely is a transient and potentially reversible phenomenon, particularly postablation atrial inflammation18 and/or incomplete healing of lesion sets.19 In the subsequent days and months, the most frequent mechanism is the development of gaps in the initial ablation lesion leading to resumption of electrical conduction in previously isolated veins.20 –22 In the present study, according to the recommendations of the 2007 expert consensus statement,10,11 we considered the first 3 months after ablation to be the blanking period. However, these recommendations are based on the personal experience of the Task Force members and literature reports on small series of patients. Our report is the first large population study that provides consistent data on the most appropriate duration of the blanking period. In our study, the observation that almost all patients with EAT occurring during the third month experienced LAT strongly suggests that the blanking period should be limited to the first 2 months. It also is clear from our data that no arrhythmia disappearance should be expected without antiarrhythmic drugs beyond the second month after the initial procedure. Thus, although scheduling an additional session usually is not justified when EAT develop in the first 2 months after the initial ablation, a redo
Heart Rhythm, Vol 5, No 5, May 2008 procedure seems to be appropriate when the arrhythmias occur after this period.
Incidence and predictors of postablation LAT Long-term success rates of AF ablation reportedly range from 45% to 95%.10 Previous attempts to identify possible predictors of LAT have yielded discrepant conclusions. Lee et al6 examined different clinical variables in relation to the procedural outcome in patients with paroxysmal AF and found that only the presence of early recurrences of AF predicted late recurrences, a result similar to that of Berkowitsch et al.9 However, in a study conducted on a smaller patient population, the same authors did not find any predictor of LAT.23 Vasamreddy et al24 identified the presence of persistent AF, permanent AF, and age older than 50 years prior to ablation as independent predictors of AF recurrences after ablation. In contrast, Callans et al20 observed that the procedure was more likely to be successful in older patients and that variables such as a history of persistent AF, left atrial dilation, obesity, and mitral regurgitation did not affect the clinical outcome. However, Burruezo et al25 identified left atrial dilation and presence of hypertension as strong preprocedural predictors. Moreover, Pappone et al26 found that only left atrial enlargement and encircling of a PV ostial area ⬍15% of the left atrial surface independently predict LAT. In our study, among the different variables, presence of EAT emerged as the strongest independent risk factor for failure of the ablation procedure. Based on our results, having an EAT, especially after the first month, is associated with high risk of LAT (51%). Conversely, the absence of EAT is associated with a significantly lower risk of LAT (3.6%). Other independent predictors of LAT in our series were longer duration of AF, history of hypertension, and history of persistent or permanent AF. According to our data, the risk of LAT increases by 3% per year of AF duration before ablation. The risk is twice as high in patients with persistent and permanent AF as in those with paroxysmal AF and is 65% higher in patients with history of hypertension. These data confirm that anatomic and electrical atrial remodeling probably plays an important role in determining LAT occurrence. According to this hypothesis, it could be reasonable to perform the ablation procedure at an earlier stage, before the arrhythmia becomes long-standing or evolves from paroxysmal to persistent or permanent.
Study limitations All patients were treated by the same ablation technique; therefore, we cannot exclude the possibility that using different techniques might yield different results. Nevertheless, the data reported in the literature seem to indicate that the ablation technique used does not influence the incidence of EAT, which is reported to be similar among the focal (39%),6 segmental (35%– 41%),4,6,8 circumferential (46%),7 and antral (40%) approaches. However, considering the differences in long-term results reported in the literature, it is possible that the ablation technique has an influence on LAT. In patients with long-
Themistoclakis et al
Post-AF Ablation Arrhythmias
lasting AF, the adjunctive creation of linear lesions or the ablation of fragmented potentials may improve the success of the procedure.10,11,27,28 However, this strategy is controversial.10,21,22 In particular, the addition of linear lesions has been reported to be associated with a high incidence of atypical atrial flutter: up to 24% vs the 4% observed in the present study.10,22 Transtelephonic monitoring was performed systematically for only 5 months after ablation. Therefore, we cannot rule out the possibility that patients may have asymptomatic LAT beyond this period. However, periodic clinical and ECG examinations and Holter monitoring did not document asymptomatic recurrence. Moreover, prolonging such scrupulous transtelephonic monitoring further would not be feasible in clinical practice, nor would it be readily accepted by patients. Finally, it appears that late recurrences 1 year after ablation are rare.10,11,26,29
Conclusion The results of this study confirm that EAT are very frequent and demonstrate that such arrhythmias have an unfavorable prognostic significance in that they are strong predictors of LAT. This is especially true for EAT that occur in the second and third months after ablation. However, because nearly half of patients with EAT will not develop LAT, a conservative strategy is warranted during the first months postablation. Both EAT and LAT are significantly associated with longer duration of AF, history of hypertension, and permanent AF. In addition, left atrial enlargement predicts EAT. These data suggest that anatomic and electrical atrial remodeling may play an important role in favoring postablation arrhythmias. Studies are needed to determine whether the incidence of these arrhythmias may be reduced by performing the ablation procedure earlier, before AF becomes long-standing or evolves from paroxysmal to persistent or permanent.
Acknowledgments We thank Ms. Michelle Williams-Andrews, Dr. Mohamed Kanj, from the Cleveland Clinic Foundation, Dr. Andrea Corrado, and Dr. Michela Madalosso from Umberto I Hospital for contributions in data collection. We also thank Dr. Jennifer E. Cummings and Dr. Mauricio Arruda from the Cleveland Clinic Foundation for reading the manuscript and making several helpful suggestions.
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