Impact of type of atrial fibrillation and repeat catheter ablation on long-term freedom from atrial fibrillation: Results from a multicenter study

Article Outline

• Abstract
• Introduction
• Methods
  • Patient characteristics
  • Electrophysiologic study and catheter ablation
  • Follow-up
  • Statistical analysis
• Results
  • Paroxysmal atrial fibrillation
  • Nonparoxysmal (persistent and long-standing persistent) atrial fibrillation
  • Cox regression analysis
  • Primary recurrence
  • Secondary recurrence
• Complications
• Discussion
  • Study limitations
• Conclusion
• References
• Copyright

Background/Objective

The purpose of this prospective multicenter study was to compare results of catheter ablation in patients with paroxysmal atrial fibrillation (PAF) and those with nonparoxysmal atrial fibrillation (NPAF). The impact and the role of repeat catheter ablation were assessed in patients with recurrence.

Methods/Results

One thousand four hundred four patients underwent catheter ablation for atrial fibrillation (AF) performed by 12 operators at four institutions using a single technique guided by intracardiac echocardiography. Of these patients, 728 had PAF and 676 had NPAF. Among the NPAF patients, 293 had persistent AF and 383 had long-standing persistent AF. Patients with NPAF had a higher incidence of hypertension and/or structural heart disease (64.8% vs 48.5%, P = .003) and a lower mean left ventricular ejection fraction (53.3% ± 8.7% vs 55.7 ± 6.5%, P <.001). All patients underwent antral isolation of all four pulmonary veins and the superior vena cava. At mean follow-up of 57 ± 17 months, 565 of 728 patients with PAF and 454 of 676 patients with NPAF (77.6% vs 67.2%, P <.001) had freedom from AF after a single ablation procedure. For arrhythmia recurrences, 74.2% (121/163) patients with PAF and 74.8% (166/222) with NPAF underwent repeat ablation, after which 92.4% patients with PAF and 84.0% patients with NPAF remained free from AF.

Conclusion

Pulmonary vein antrum isolation guided by intracardiac echocardiography results in significant freedom from AF, even when performed by multiple operators in different centers. At least moderate efficacy can be achieved in patients with NPAF, although the success rate is lower than in patients with PAF. Considerably higher success can be achieved in both groups with repeat ablation.

Keywords: Atrial fibrillation, Catheter ablation, Nonparoxysmal, long-standing persistent atrial fibrillation

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Introduction 

Catheter ablation of atrial fibrillation (AF) has been a challenge for interventional electrophysiologists. The approach to management of AF changed significantly after Haissaguerre et al¹ demonstrated the importance of triggers of AF from the thoracic pulmonary veins. Earlier attempts focused on ablating these triggers distally in the pulmonary veins (PVs). This was followed by suboptimal results and a higher incidence of PV stenosis and necessitated ablation more proximally along the vestibular space of the PVs called the PV antrum.², ³

Intracardiac echocardiography helps in guiding catheter ablation for AF.⁴, ⁵ Intracardiac echocardiography has helped us to improve outcomes and decrease complications from the procedure. As a result, we have been able to offer catheter ablation to a more complex group of patients with AF, including patients with older age,⁵ structural heart disease,⁷ left ventricular dysfunction,⁷ or prosthetic valves. However, catheter ablation remains a technically complex procedure, and the results have not always been reproducible.

We report the results of catheter ablation for AF performed using a single approach by multiple operators in patients with paroxysmal atrial fibrillation (PAF) or nonparoxysmal atrial fibrillation (NPAF), with emphasis on the impact of repeat catheter ablation in patients with recurrence after a single ablation. To the best of our knowledge, this is one of the largest series of patients with NPAF, especially persistent and long-standing persistent AF.

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Methods 

Patient characteristics 

The study included 1,404 consecutive patients who underwent catheter ablation for AF at four centers. All patients had symptomatic, drug-resistant AF. Patients were excluded from the study if they were <18 years old or >85 years old or if they had a contraindication to oral anticoagulation.

Patients were enrolled as follows: 953 patients from Cleveland Clinic (Cleveland, OH, USA) from December 2000 to June 2004; 102 patients from Sutter Pacific Heart Center (San Francisco, CA, USA) from June 2001 to December 2002; 89 patients from Southlake Regional Health Center (Newmarket, Ontario, Canada) from March 2004 to March 2006; and 260 patients from Umberto I Hospital (Mestre-Venice, Italy) from September 2002 to June 2006. From the start date to the stopping date, all patients undergoing AF ablation at each individual center were included in the study. Some of the patients from the Cleveland Clinic have been included in previous publications from this group.⁶, ⁸

Patients were classified as having paroxysmal, persistent, or long-standing persistent AF per ACC/AHA/ESC guidelines⁹ and the HRS/EHRA/ECAS Consensus Statement.¹⁰ Patients were divided into three groups: PAF (N = 728), persistent AF (N = 293), and long-standing persistent AF (N = 383). Of the 1,404 patients, 676 (48.1%) had NPAF.

Informed consent was obtained from all patients prior to the procedure. Antiarrhythmic drugs were discontinued for at least five half-lives prior to the procedure, and amiodarone was stopped at least 5 months prior to the procedure. The patients continued to receive anticoagulation until 2 days prior to the procedure. The first 350 patients underwent transesophageal echocardiography prior to the procedure. Subsequently the need for transesophageal echocardiography was limited to patients presenting in AF/atrial flutter, those with left ventricular dysfunction, or patients with a prior history of a thromboembolic event.

Electrophysiologic study and catheter ablation 

Four venous accesses were obtained in each patient. The two venous accesses from the right groin were used for transseptal catheterization to guide the mapping and ablation catheter in the left atrium (LA). A 20-mm, decapolar circular mapping catheter with a deflectable loop was used for mapping (Lasso, Biosense-Webster, Baldwin Park, CA, USA), and an 8-mm tip catheter (Celsius, Biosense-Webster) or a 4-mm internal cooled tip catheter (EP Technologies, Sunnyvale, CA, USA) was used for ablation. A single left femoral 11Fr venous access was used to guide a 10Fr 64-element phased-array ultrasound imaging catheter (AcuNav, Acuson, Mountain View, CA, USA) in the right atrium. Intracardiac echocardiography was used to guide transseptal puncture, identify the PV antrum, guide placement of the circular mapping catheter, monitor tissue heating to guide delivery of radiofrequency energy, and look for complications such as effusion, thrombi, or char formation.³ A single venous access in the right internal jugular vein was used to place a 14- to 20-pole catheter in the coronary sinus. The distal 7–10 poles were positioned in the coronary sinus along the mitral annulus and the proximal 7–10 poles along the crista terminalis.

Double transseptal access was obtained via two separate puncture sites in the interatrial septum. Patients were anticoagulated using intravenous heparin with a bolus of 10,000 to 15,000 units just prior to the transseptal puncture and then infusion of 1,000 units per hour. The infusion was adjusted to maintain an activated coagulation time >350 seconds. The transseptal sheaths were also infused with heparinized saline during the procedure. The circular mapping catheter was used to map the PV antrum.

Radiofrequency catheter ablation was performed targeting contiguous sites that showed the earliest activation of PV potentials. Radiofrequency energy was applied at these sites to achieve complete abolition of all PV potentials along the antrum and entrance block into the PVs.

Radiofrequency energy was delivered using a step-up protocol as previously described by our group⁴, ⁶ and was guided by monitoring microbubbles on intracardiac echocardiography. All patients enrolled from the Southlake Regional Health Center and the Umberto I Hospital underwent ablation with the 8-mm-tip ablation catheter (Celsius, Biosense-Webster). All repeat ablations at these two centers were also performed with the 8-mm-tip ablation catheter. In the other two centers, catheter ablation also was guided by monitoring microbubbles on intracardiac echocardiography. A total of 41 patients from Sutter Pacific Heart Center and 595 patients from the Cleveland Clinic underwent ablation with the 8-mm-tip ablation catheter. The initial 61 patients from San Francisco and the initial 358 patients from Cleveland Clinic underwent ablation using the 4-mm internal cooled-tip catheter (EP Technologies, Sunnyvale, CA, USA). Among the repeat catheter ablations, the 8-mm-tip ablation catheter was used in all patients, except for seven patients in whom the 3.5-mm-tip external irrigated-tip ablation catheter (Biosense-Webster) was used.

The protocol with the internal cooled-tip catheter has been described previously.⁴, ⁶ With the 8-mm-tip catheter, the target temperature was kept constant at 55°C, and the power was titrated upward in 5-W increments from 30 to 70 W while monitoring for microbubble formation. Using this approach, the antra of all four PVs were isolated. The target end point was complete loss of potentials along the PV antrum rather than just a decrease in the amplitude of the electrical signals and entrance block in the PVs. The superior vena cava (SVC) was also isolated circumferentially except if phrenic nerve stimulation was demonstrated by high-output pacing.¹¹

In patients with NPAF, ablation in the LA was extended to the entire posterior wall down to the coronary sinus and along the left side of the septum toward the mitral annulus. In addition, non-PV triggers were targeted in all patients (PAF and NPAF) when identified during the procedure.

At the time of the repeat procedure, in addition to ablation of sites showing recovery of conduction from PVs and other sites, challenge with isoproterenol infusion with doses up to 20 μg/min was performed to identify triggers outside the previously ablated regions (ablated regions included PV antrum, SVC–right atrium junction, and left side of septum). In addition, any recurrence of an organized atrial arrhythmia, such as atrial flutter or atrial tachycardia, in any patient was additionally mapped and ablated using three-dimensional mapping.

Follow-up 

After the procedure, anticoagulation was resumed the same night, and patients were discharged home the next day. Patients with long-standing persistent AF, left ventricular dysfunction, or a history of thromboembolism received overlapping anticoagulation with enoxaparin for 3 days after the procedure. The remaining patients received a double dose of Coumadin on the night of the ablation, followed by the routine preprocedural dose from the next day. Patients underwent 48-hour Holter monitoring after discharge and at 3, 6, 9, and 12 months after the procedure. In addition, patients were given an event recorder for the first 5 months to record any symptomatic events and random recordings two to three times per week to monitor for any asymptomatic episodes of AF/flutter. Follow-up was scheduled at 3 and 6 months in the clinic and at 9 and 12 months by telephone call.

All patients also underwent three-dimensional computed tomographic (CT) scan at 3 months to look for any evidence of PV stenosis. CT scan was repeated at 6 and 12 months for patients who had any evidence of narrowing. Patients were considered for angioplasty/stenting if they had any evidence of symptomatic or severe PV stenosis.

The first 8 weeks after ablation was considered a blanking period, so for the purpose of analysis any recurrences of AF/flutter during this period were ignored. Recurrence was considered of significance only if patients continued to have AF/flutter beyond the first 8 weeks after the ablation. These patients were given the option either to initiate antiarrhythmic drugs or to consider repeat catheter ablation. The repeat ablation was performed using the same approach. Recurrence after the secondary procedure was also noted to be of significance only if it persisted beyond 8 weeks of the procedure. Anticoagulation was stopped 6 months after the procedure in patients who showed sinus rhythm and was continued in case of procedural failure.

Statistical analysis 

Continuous data are given as mean ± SD and as counts and percent if categorical. Student's t-test, one-way analysis of variance, Chi-square test, and Fisher exact test were used to compare differences across AF types. Where required, post hoc analysis was performed using Tukey-Kramer multiple comparison method. Multivariate Cox regression was used to identify significant predictors of AF recurrence while controlling for clinically relevant covariates. All potential confounders were entered into the model based on known or expected clinical relevance, regardless of their statistical significance. The controlling variables used in the model are age, gender, preprocedural left ventricular ejection fraction (LVEF), LA size, duration of AF, hypertension, structural heart disease, and type of AF. For the purpose of analysis, age and duration of AF were dichotomized at median, and LVEF and LA size were categorized into ≤55% and >55% and <40 mm and ≥40 mm, respectively. Tests were run to examine the presence of significant interactions and to identify possible multi-colinearity of the covariates. The hazard ratio (HR) and 95% confidence interval (CI) of AF recurrence were computed. Recurrence-free survival over time was calculated by Kaplan-Meier method. All tests were two-sided, and P <.05 was considered significant. Analyses were performed using SPSS 9.0 (SPSS, Inc., Chicago, IL, USA) and SAS 9.2 (SAS Institute, Inc., Cary, NC, USA).

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Results 

A total of 1,404 consecutive patients were included in the study. Of these patients, 1,066 (75.9%) were male. The cohort had a mean age of 55.8 ± 11 years. Of the 1,404 patients, 728 (51.9%) had PAF and 676 (48.1%) had NPAF. Of the 676 patients with NPAF, 293 (20.9% of the total population) had persistent AF and 383 (27.3% of the total population) had long-standing persistent AF. Baseline characteristics of the entire population are summarized in Table 1.

Table 1. Baseline and procedural characteristics

SN	Variable	Paroxysmal AF (1)	NPAF (2)	P value (1 vs 2)	Persistent AF (3)	Long-standing persistent AF (4)	P value (1 vs 3 vs 4)
1	No. of patients	728	676	—	293	383	—
2	Age (years)	54.5±11.8	57.2±10.2	<.001	57.1±10.2	57.3±10.2	<.001
3	Male/female	528/200	538/138	—	222/71	316/67	—
	Males (%)	72.5%	79.5%	.002	75.8%	82.5%	<.001
4	Duration (years)	6.4±5.6	6.4±5.3	.889	5.9±5.3	6.8±5.3	.152
5	Left atrial size (cm)	4.15±0.61	4.55±0.59	<.001	4.37±0.61	4.69±0.54	<.001
6	Left ventricular ejection fraction (%)	55.7±6.5	53.3±8.7	<.001	55.6±7.5	51.7±9.1	<.001
7	Hypertension/structural heart disease	353(48.5%)	438(64.8%)	.003	163(55.6%)	275(71.8%)	<.001
8	No. of antiarrhythmic drugs	2.89±1.4	3.10±2.4	.082	2.63±1.2	3.28±2.8	.111
9	Fluoroscopy time (min)	79.6±24.8	82.3±24.7	.074	84.7±26.3	81.2±23.8	.164
10	Procedural time (h)	3.79±1.3	3.90±1.2	.213	3.99±1.3	3.85±1.2	.003
11	Radiofrequency time (min)	39±7	54±13	<.001	48±11	59±13	<.001
12	Non-PVA/SVC foci	21(2.9%)	97(14.3%)	<.001	24(8.2%)	73(19.1%)	<.001
13	Follow-up duration (months)	59±16	53±17	<.001	51±19	57±16	<.001

AF = atrial fibrillation; non-PVA/SVC foci = foci outside the conventional ablated areas, which include the pulmonary vein antrum, the superior vena cava, and the left side of the septum; NPAF = nonparoxysmal atrial fibrillation; SN = serial number.

Among the total cohort, 385 (27.3%) of 1,404 patients had recurrence after the primary procedure, resulting in freedom from AF in 1,019 (72.6%) of 1,404 patients. Of the 385 patients with arrhythmia recurrence, 334 (86.8%) had AF, 72 (18.7%) had LA flutter, 25 (6.5%) had typical atrial flutter, and 17 (4.4%) had an atrial tachycardia.

A total of 287 (74.5%) of 385 patients underwent a redo procedure. Of these patients, 247 underwent a second procedure. Another 34 patients underwent a third ablation, and six patients underwent a fourth ablation. After repeat ablation, freedom from AF could be achieved in a total of 1,241 (88.4%) of 1,404 patients.

Paroxysmal atrial fibrillation 

The PAF cohort included 728 patients (72.5% male, mean age 54.5 ± 11.8 years; Table 1). All patients underwent antrum isolation of all four PVs and the SVC. Mean duration of the procedure was 3.79 ± 1.3 hours, and mean fluoroscopy time was 79.6 ± 24.8 minutes of single-plane pulse fluoroscopy. Mean radiofrequency duration was 39 ± 7 minutes. In this group, non-PV foci were observed in 21 (2.9%) of 728 patients.

Of the 728 patients who underwent ablation, a total of 163 (22.4%) patients continued to have AF or atrial flutter beyond the first 8 weeks of ablation In 155 patients, this occurred within 12 months from ablation procedure and in five patients between months 13 and 24 after ablation. The remaining three patients had recurrence 24 months after the procedure. Hence, after the first procedure, 77.6% of the patients were free from arrhythmia without the need for any further antiarrhythmic drugs. This was considered the primary freedom from AF after a single procedure. A repeat procedure was offered to all 163 patients who failed, but only 121 (74.2%) underwent a repeat catheter ablation.

Recovery of conduction across the PV–LA junction was noted in all patients undergoing a repeat ablation, and 13 (10.7%) of 121 patients continued to have atrial arrhythmias even beyond the 8 weeks after repeat ablation. Hence, from the primary cohort of 728 patients, after a mean follow-up of 59 ± 16 months, 55 (7.6%) patients continued to have AF/flutter. This total number included the 42 of 163 primary recurrence patients who did not undergo a repeat catheter ablation for various reasons. This resulted in an overall freedom from AF in 92.4% patients.

Nonparoxysmal (persistent and long-standing persistent) atrial fibrillation 

A total of 676 of 1,404 patients had NPAF. This included 293 patients with persistent AF and 383 patients with long-standing persistent AF. The baseline characteristics of this population are given in Table 1. Compared to the PAF group, the NPAF group had more male patients, was significantly older, and had more patients with a history of hypertension and structural heart disease. The average duration of AF was not significantly different between the two groups. Mean LA size was progressively larger, and preprocedural LVEF was increasingly smaller across the three AF types: PAF, persistent, and long-standing persistent AF (the difference was significant in post hoc test).

As can be seen from Table 1, all these differences were more prominent in patients with long-standing persistent AF than in patients with persistent AF, suggesting a gradient of change in patients from paroxysmal to persistent to long-standing persistent AF.

Mean procedural time for ablation in this group was 3.9 ± 1.2 hours, and mean fluoroscopy time was 82.3 ± 24.7 minutes of single-plane pulse fluoroscopy. Mean radiofrequency time was significantly higher for NPAF patients than for PAF patients (54 ± 13 minutes vs 39 ± 7 minutes, P <.001). Mean radiofrequency delivery time for patients with persistent AF was 48 ± 11 minutes and for those with long-standing persistent AF was 59 ± 13 minutes.

Non-PV triggers were identified in 97 (14.3%) of 676 patients with NPAF. The presence of non-PV foci were significantly higher in patients with long-standing persistent AF than in patients with persistent AF or PAF (19.1%, 8.2%, and 2.9% respectively, P <.001).

After the primary procedure, 222 of the 676 patients (32.8%) with NPAF had recurrence of AF/atrial flutter beyond the first 8 weeks of ablation (184 patients had recurrences within 12 months, 21 patients between 13 and 24 months, and 17 patients beyond 24 months from the ablation procedure). The resultant primary freedom from AF after catheter ablation in patients with NPAF was 67.2%. This was significantly lower than the success in patients with PAF (P <.001; Figure 1). Of the 222 patients of NPAF with recurrence, 166 (74.8%) patients underwent a repeat catheter ablation. In these patients, the PVs were remapped, and the areas with recovery of conduction or with incomplete isolation were ablated using a strategy similar to the one performed during the primary procedure. At follow-up, 52 (31.3%) of 166 patients with NPAF who underwent repeat ablation developed recurrence of AF or atrial flutter that persisted beyond 8 weeks of ablation (46 developed recurrences within 12 months, 4 patients within 24 months, and 2 patients beyond 24 months of follow-up).

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• Figure 1. 

  Primary and secondary freedom from atrial fibrillation (AF) recurrence in patients with paroxysmal, persistent, and long-standing persistent AF. P value shown compares all the groups.

Thus, 108 of 676 patients with NPAF (which includes 56/222 patients with recurrences who did not undergo a repeat ablation) continued to have atrial arrhythmias even after repeat ablation. Hence, at a mean follow-up of 53 ± 17 months, 84% of patients with NPAF were free from atrial arrhythmias without the need for any antiarrhythmic drugs (Table 2).

Table 2. Freedom from AF after initial and repeat catheter ablations

SN	Variable	Paroxysmal AF (1)	NPAF (2)	P value (1 vs 2)	Persistent AF (3)	Long-standing persistent AF (4)	P value (1 vs 3 vs 4)
1	Primary recurrence	163/728	222/676	—	71/293	151/383	—
2	Primary freedom from AF	77.6%	67.2%	<.001	75.8%	60.6%	<.001
3	Redo ablation done	121(74.2%)	166(74.8%)	.904	51(71.8%)	115(76.2%)	.782
4	Recurrence after redo (secondary)	13/121	52/166	—	15/51	37/115	—
5	Total recurrence (secondary)⁎	55/728	108/676	—	35/293	73/383	—
6	Secondary freedom from AF	92.4%	84.0%	<.001	88.1%	80.9%	<.001

AF = atrial fibrillation; NPAF = nonparoxysmal atrial fibrillation; SN = serial number.

The secondary freedom from AF even after repeat ablation was significantly lower in patients with NPAF than in those with PAF (P <.001). However, there was a significant clinical improvement in the absolute numbers, as an additional 114 (16.9%) of 76 patients achieved freedom from AF as a result of the repeat ablation (84.0% NPAF vs 92.4% PAF, P <.001; Table 2).

When patients with NPAF were further subdivided into persistent and long-standing persistent AF, Tukey-Kramer multiple comparison analysis showed that the primary freedom from AF in patients with long-standing persistent AF was lower than both PAF and persistent AF groups (60.6% vs 77.6% and 60.6% vs 75.8%, respectively, P <.05 for both the comparisons; Figure 1). No significant difference in primary freedom was observed between patients with PAF and persistent AF (77.6% vs 75.8%).

The total or secondary freedom from AF (Table 2) was 92.4% in patients with PAF, 88.1% in persistent AF, and 80.9% in long-standing persistent AF, respectively. Although the overall rate of freedom from AF continued to be lower in patients with NPAF (P <.001; Figure 1), it is important to note that all groups showed a significant increase in the absolute percentage rise of success with a repeat procedure (PAF 14.8%, persistent AF 12.3%, long-standing persistent AF 20.3%).

Cox regression analysis 

Our current study primarily assessed the impact of the type of AF on the outcomes of catheter ablation using the circular mapping technique under the guidance of intracardiac echocardiography. Within the various groups, there tends to be a difference in relation to the baseline characteristics of the patients. This is largely a nature of the disease and will be hard to eliminate completely.

However, to assess the impact of demographic attributes and potential risk factors on the success of catheter ablation, Cox regression analysis was performed. The multivariate model was used to adjust for potential confounders (see Statistical analysis for detail). The event-free survival analysis separately estimated the relative risk of recurrence after first and redo procedures for PAF and NPAF patients.

Primary recurrence 

After mean follow-up of 59 ± 16 months for patients with PAF, the event-free survival after single procedure demonstrated significant association with LA size (HR 1.33, CI 1.01–1.76, P = .043). No other variables used in the model (described in Statistical analysis) were predictive of failure (Figure 2A). Among NPAF patients, those with shorter duration of AF had significantly higher chances for success (HR 1.74, CI 1.12–2.48, P = .003). After subdividing NPAF into persistent and long-standing persistent AF, hypertension was a definite predictor of recurrences in patients with persistent AF (HR 2.55, CI 1.02–6.43, P = .044).

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• Figure 2. 

  Multivariate Cox model of freedom from atrial fibrillation (AF) after the first ablation procedure. Plot shows hazard ratio and 95% confidence interval. HTN = hypertension; LA = left atrial; LVEF = left ventricular ejection fraction; NPAF = nonparoxysmal atrial fibrillation; PAF = paroxysmal atrial fibrillation; STR HD = structural heart disease.

When PAF and NPAF populations were combined, the type of AF and preprocedural LA size were strong predictors of recurrences after a single procedure. NPAF patients had significantly higher risk of recurrence (HR 1.53, CI 1.15–2.03, P <.001) than did those with PAF. Similarly, patients with larger LA size exhibited greater chance of recurrence (HR 1.30, CI 1.01-167, p = 0.032). The plots showing the odds ratio with 95% CIs are presented in Figures 2 and Table 3.

Table 3. Multivariate Cox regression analysis of recurrence of AF after first ablation (primary recurrence) of the entire population

Age and duration of AF are dichotomized at median.

AF = atrial fibrillation; NPAF = nonparoxysmal atrial fibrillation; PAF = paroxysmal atrial fibrillation.

Multivariate analysis to examine the presence of significant trend in AF recurrence among the individual centers was performed. After controlling for potential confounders, we did not find any statistically significant difference in the risk of AF recurrence across the participating centers. For the primary recurrence, the p value for linear trend was 0.150 in the PAF population and 0.729 for NPAF.

Secondary recurrence 

Female gender was a significant predictor of secondary recurrence in both PAF and NPAF groups (HR 9.10, CI 1.63-9.72, P = 0.012 for PAF; HR 2.77, CI 1.01-7.57, P = 0.043 NPAF). When patients with NPAF were stratified into persistent and long-standing persistent AF groups, female gender (HR 2.60, CI 1.1-8.96, P = 0.04) and hypertension (HR 2.45, CI 1.05-5.40, P = 0.04) were the primary predictors of failure among patients with persistent AF. In the PAF, NPAF combined population, female gender, hypertension, and type of AF (having NPAF) emerged as significant predictors of failure. The HR for secondary recurrence is presented in Figure 3 and Table 4.

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• Figure 3. 

  Multivariate Cox model of secondary freedom from atrial fibrillation (AF) after redo ablation(s). Plot shows hazard ratio and 95% confidence interval. HTN = hypertension; LA = left atrial; LVEF = left ventricular ejection fraction; NPAF = nonparoxysmal atrial fibrillation; PAF = paroxysmal atrial fibrillation; STR HD = structural heart disease.

Table 4. Multivariate Cox regression analysis of recurrence of AF after redo ablation(s) (secondary recurrence) of the entire population

Age and duration of AF are dichotomized at median.

AF = atrial fibrillation; NPAF = nonparoxysmal atrial fibrillation; PAF = paroxysmal atrial fibrillation.

Interestingly, age (as seen by our previous experience⁶), and LVEF did not seem to have any effect on either primary or secondary freedom from AF. Larger LA size appeared to have a strong negative impact on success of primary ablation in PAF, NPAF combined population. However, the effect was lost when the NPAF populations were separately analyzed. When comparing the risk of recurrence across participating centers in PAF and NPAF combined population, we did not find any significant trend (P value for linear trend = 0.729).

The Kaplan-Meier survival analysis exhibited a significant difference in recurrence across AF types after a single ablation. At the end of the follow-up period, 565 (78%) patients with PAF, 222 (76%) patients with persistent AF, and 232 (61%) patients with long-standing persistent AF were free from AF/atrial tachycardia (P <.001). The success rates after redo ablation were 108 (89%), 36 (71%), and 78 (68%) for PAF, persistent AF, and long-standing persistent AF, respectively (P <.001). When comparing NPAF (114 [69%]) with PAF (108 [89%]), the difference was significant (P <.001). Kaplan-Meier plots are shown in Figure 4, Figure 5.

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• Figure 4. 

  Kaplan-Meier survival estimates for freedom from atrial fibrillation/atrial tachycardia (AF/AT) recurrence after a single ablation. LS = long-standing; PAF = paroxysmal atrial fibrillation.

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• Figure 5. 

  Kaplan-Meier survival estimates for freedom from atrial fibrillation/atrial tachycardia (AF/AT) recurrence after more than one ablation procedure. LS = long-standing; PAF = paroxysmal atrial fibrillation.

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Complications 

Forty-six (3.28%) patients had complications during the study. The distribution of these complications in each group is given in Table 5. This included 5 (0.36%) patients with tamponade, 6 (0.43%) with thromboembolic events including transient ischemic attack or stroke, and 18 (1.28%) with severe PV stenosis. One patient had a nonhemorrhagic stroke and underwent an angioplasty. He subsequently had hemorrhagic conversion requiring hemicraniectomy. He later developed acute deep venous thrombosis, which was followed 2 weeks later by a fatal pulmonary embolism.

Table 5. Complications after catheter ablation for atrial fibrillation

SN	Variable	Paroxysmal AF (1)	NPAF (2)	P value (1 vs 2)	Persistent AF (3)	Long-standing persistent AF (4)	P value (1 vs 3 vs 4)
1	Total complications	25(3.4%)	21(3.1%)	.731	7(2.4%)	14(3.7%)	.612
2	Transient ischemic attack/stroke	3(0.4%)	2(0.3%)	1	1(0.3%)	1(0.3%)	.746
3	Severe pulmonary vein stenosis	10(1.4%)	8(1.2%)	.816	4(1.4%)	4(1.1%)	.904
4	Tamponade	4(0.6%)	2(0.3%)	.688	0(0%)	2(0.5%)	.646
5	Other	8(1.1%)	9(1.3%)	.808	2(0.7%)	7(1.8%)	.439

AF = atrial fibrillation; NPAF = nonparoxysmal atrial fibrillation; SN = serial number.

A total of 17 (1.21%) patients had other complications, which included partial or complete diaphragmatic paralysis (n = 5), transient altered mental status (n = 2), optic neuritis (n = 1), major vascular bleed (n = 3), retroperitoneal bleeding (n = 1), hemothorax (n = 1), deep venous thrombosis (n = 1), femoral arteriovenous fistula (n = 1), coronary embolism (n = 1), and lasso entrapment in the mitral valve (n = 1).

Of the total cohort of 1,404 patients, 44 (3.1%) had moderate (51%–70%) PV stenosis. On repeat CT scan of these 44 patients, 2 had some worsening but continued to have <70% stenosis, and 4 showed worsening of stenosis to >70% (severe). Another 122 (8.7%) of the 1,404 patients had mild (31%–50%) stenosis. Only 5 of these 122 patients showed progression of the stenosis to a moderate degree (51%–70%), but none of the patients in this group showed any progression to severe stenosis. The other 117 of 122 patients with mild PV stenosis had either regression of the disease or stable lesions.

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Discussion 

AF is a challenging arrhythmia to treat. Although catheter-based strategies have evolved, there is no universal acceptance of a single approach. In addition, the results of many of these strategies have not been replicated. The present study showed that PV antrum isolation with intracardiac echocardiographic guidance using the circular mapping technique performed at different centers by multiple operators can achieve cure in a large percentage of patients with different forms of the disease. Both three-dimensional CT scan and magnetic resonance imaging along with intracardiac echocardiography have recognized that the PV–LA junction extends beyond the tubular portion of the PV and might include a large portion, if not all, of the LA posterior wall.², ¹², ¹³, ¹⁴ This area is considered the PV antrum and has been ablated.

The present study evaluated the impact of the type of AF on the efficacy and outcome of the procedure. In general, one may recognize that the patients referred and taken for ablation may be a select group of younger and more symptomatic patients and represent only a portion of patients with the disease, which tends to increase in incidence with age. However, only limited data are available on the efficacy of catheter ablation in patients with long-standing persistent AF and almost no data are available on its efficacy in long-standing persistent AF.

Not surprisingly, the results from the present study show that patients with NPAF seem to have a higher incidence of associated diseases such as hypertension and structural heart disease. They also are likely to have reduced mean LVEF and larger mean LA dimensions. It was possible to achieve fairly encouraging results with primary freedom from AF of 60.6% in patients with long-standing persistent AF and 75.8% in patients with persistent AF. These results show higher success rates than those reported by Oral et al¹⁵ in their earlier experience, likely because their procedure was limited to segmental ostial isolation and no attempts were made to target foci outside the PV. In this respect, it is important to recognize that antrum isolation includes the posterior wall of the LA and extends anterior to the right PVs.

Although the success rate in our study was acceptable after the first ablation, it was significantly lower in patients with NPAF (Table 2 and Figure 1). Whether this reflects the need for ablation strategies designed to modify the substrate remains unclear. However, the increased success rate with a repeat procedure following a similar approach would argue against this hypothesis. On the other hand, it is important to note that in patients with NPAF, ablation was extended to the entire posterior wall down to the coronary sinus and along the LA septum and down to the mitral annulus. In addition, the SVC was isolated in all patients. Moreover, non-PV triggers were noted in 2.9% of patients with PAF, 8.2% of patients with persistent AF, and 19.1% of patients with long-standing persistent AF.

The overall freedom from atrial arrhythmias after a repeat ablation was 92.4% in PAF patients and 84.0% in NPAF patients. This group, when further subdivided, showed success rates of 88.1% in persistent AF and 80.9% in long-standing persistent AF. These results continued to show a significant difference when compared to results of patients with PAF (P <.001; Table 2), but the clinical impact of a repeat procedure was very noticeable. This suggests that a high degree of success in terms of freedom from AF can be achieved in both patients with PAF and those with NPAF. However, a fair proportion of these patients may require a redo ablation to achieve these results.

In our experience, significant recovery of conduction around the PV antrum is usually seen in patients with recurrence of AF.¹⁶ This finding suggests that before considering a more extensive ablation strategy in a repeat procedure, one must at least verify that the primary end point of the first procedure has been persistently achieved. Ouyang et al¹⁷ reported approximately 95% cure rates in a small series of 40 patients with persistent AF after two procedures with the double-lasso technique. They also showed recovery of conduction is the dominant finding during the repeat ablation.¹⁷, ¹⁸ With this approach, the end point is similar to that in our procedure, but a smaller area is ablated and isolated. In addition, the length of follow-up was shorter in the series reported by Ouyang et al.¹⁷, ¹⁸ Whether a larger amount of atrial tissue must be ablated in patients with NPAF appears likely but requires further investigation. Of interest, foci outside the PV antrum appeared more frequent in patients with long-standing persistent AF. Sanders et at¹⁹ reported on the feasibility of complete exclusion/isolation of the PVs and the posterior LA in patients having chronic AF, with a long-term success rate of 63% at 2-year follow-up. However, their study included only 27 patients.

Only limited data are available on the efficacy of catheter ablation in patients with NPAF, especially long-standing persistent AF. To the best of our knowledge, this is the largest multicenter group of patients who have been compared using the same ablative strategy for both the initial and the repeat procedures. In addition, this is the first report on the results of a large series of patients with long-standing persistent AF.

Importantly, as previously reported by our group²⁰ and by Dixit et al,²¹ the ablation catheter used does not affect results.

Study limitations 

An important limitation of a study on outcome after AF catheter ablation such as this is our limited ability to detect arrhythmia relapses, especially asymptomatic episodes. Success rate is therefore related to the intensity of monitoring during follow-up. Furthermore, long-term follow-up was performed by the referring doctor and confirmed only with phone calls and not with medical evaluations. Although we recognize this as a limitation, we would like to emphasize that the monitoring was quite extensive. In addition, we encouraged patients to visit their local cardiologists in conjunction with experienced AF nurses who monitored the patients via phone calls, making it less likely that important information was not captured.

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Conclusion 

There is increasing evidence that catheter ablation in patients with AF is an effective treatment strategy. This prospective multicenter study analyzed the efficacy of catheter ablation performed by different operators in patients with NPAF and compared it to the results in patients with PAF. The results show that isolation of the PV antrum and the SVC using intracardiac echocardiography and circular mapping can achieve encouraging cure rates in both patients with PAF and those with NPAF, even when the procedure is performed at different centers by different operators. Although the success rate is higher in patients with PAF, repeat catheter ablation is a useful strategy to enhance freedom from AF and should be taken into consideration when planning ablation in patients with AF.

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