Key Points
Question
Does adding posterior wall isolation (PWI) to pulmonary vein isolation (PVI) improve success in patients with persistent atrial fibrillation (AF) undergoing first-time catheter ablation?
Findings
In this randomized clinical trial that included 338 patients with persistent AF, there was no significant difference in 12-month freedom from recurrent atrial arrhythmia after a single procedure and without antiarrhythmic medication among those with PVI and PWI compared with PVI alone (52.4% vs 53.6%, respectively; hazard ratio, 0.99).
Meaning
Among patients with persistent AF undergoing first-time catheter ablation, the addition of PWI to PVI did not improve freedom from atrial arrhythmias compared with PVI alone.
Abstract
Importance
Pulmonary vein isolation (PVI) alone is less effective in patients with persistent atrial fibrillation (AF) compared with paroxysmal AF. The left atrial posterior wall may contribute to maintenance of persistent AF, and posterior wall isolation (PWI) is a common PVI adjunct. However, PWI has not been subjected to randomized comparison.
Objective
To compare PVI with PWI vs PVI alone in patients with persistent AF undergoing first-time catheter ablation.
Design, Setting, and Participants
Investigator initiated, multicenter, randomized clinical trial involving 11 centers in 3 countries (Australia, Canada, UK). Symptomatic patients with persistent AF were randomized 1:1 to either PVI with PWI or PVI alone. Patients were enrolled July 2018-March 2021, with 1-year follow-up completed March 2022.
Interventions
The PVI with PWI group (n = 170) underwent wide antral pulmonary vein isolation followed by posterior wall isolation involving linear ablation at the roof and floor to achieve electrical isolation. The PVI-alone group (n = 168) underwent wide antral pulmonary vein isolation alone.
Main Outcomes and Measures
Primary end point was freedom from any documented atrial arrhythmia of more than 30 seconds without antiarrhythmic medication at 12 months, after a single ablation procedure. The 23 secondary outcomes included freedom from atrial arrhythmia with/without antiarrhythmic medication after multiple procedures, freedom from symptomatic AF with/without antiarrhythmic medication after multiple procedures, AF burden between study groups at 12 months, procedural outcomes, and complications.
Results
Among 338 patients randomized (median age, 65.6 [IQR, 13.1] years; 76.9% men), 330 (97.6%) completed the study. After 12 months, 89 patients (52.4%) assigned to PVI with PWI were free from recurrent atrial arrhythmia without antiarrhythmic medication after a single procedure, compared with 90 (53.6%) assigned to PVI alone (between-group difference, –1.2%; hazard ratio [HR], 0.99 [95% CI, 0.73-1.36]; P = .98). Of the secondary end points, 9 showed no significant difference, including freedom from atrial arrhythmia with/without antiarrhythmic medication after multiple procedures (58.2% for PVI with PWI vs 60.1% for PVI alone; HR, 1.10 [95% CI, 0.79-1.55]; P = .57), freedom from symptomatic AF with/without antiarrhythmic medication after multiple procedures (68.2% vs 72%; HR, 1.20 [95% CI, 0.80-1.78]; P = .36) or AF burden (0% [IQR, 0%-2.3%] vs 0% [IQR, 0%-2.8%], P = .47). Mean procedural times (142 [SD, 69] vs 121 [SD, 57] minutes, P < .001) and ablation times (34 [SD, 21] vs 28 [SD, 12] minutes, P < .001) were significantly shorter for PVI alone. There were 6 complications for PVI with PWI and 4 for PVI alone.
Conclusions and Relevance
In patients undergoing first-time catheter ablation for persistent AF, the addition of PWI to PVI alone did not significantly improve freedom from atrial arrhythmia at 12 months compared with PVI alone. These findings do not support the empirical inclusion of PWI for ablation of persistent AF.
Trial Registration
anzctr.org.au Identifier: ACTRN12616001436460
This randomized clinical trial compares pulmonary vein isolation (PVI) vs PVI with posterior wall isolation for achieving freedom from atrial arrhythmia in adult patients with persistent atrial fibrillation undergoing first-time catheter ablation in Australia, the UK, and Canada.
Introduction
Atrial fibrillation (AF) is the most common sustained arrhythmia, with increasing prevalence in the context of an aging population and metabolic syndrome.1,2 AF is associated with significant morbidity and mortality, including cardiac failure and stroke.3 An early rhythm control strategy that may include catheter ablation was associated with a significant reduction in stroke and in cardiovascular and overall mortality compared with rate control in a 2020 study.4 Catheter ablation had consistently shown superiority to drug therapy in the restoration and maintenance of sinus rhythm.1,3
The cornerstone of AF ablation is pulmonary vein isolation (PVI), which was less effective in persistent AF compared with paroxysmal AF.1,5 Meta-analyses had reported a single procedure success for catheter ablation for persistent AF ranging from 43% to 67%.6 In an attempt to improve outcomes, adjunctive strategies targeting non–pulmonary vein triggers and atrial substrate modification had been pursued.7,8 However, when subjected to large randomized clinical trials (RCTs), additional ablation had failed to demonstrate superiority beyond PVI alone.7,8,9
The posterior wall of the left atrium is embryologically related to the pulmonary veins and houses the septopulmonary bundle, which had been proposed to play a role in the maintenance of persistent AF.10,11,12 As such, posterior wall isolation (PWI) had evolved and become popularized, with nonrandomized studies showing promising results.11,12,13,14 However, successful PWI can be challenging, given epicardial connections and the close proximity of the esophagus with an attendant risk of inadvertent injury. The CAPLA (Catheter Ablation for Persistent Atrial Fibrillation: A Multicenter Randomized Trial of Pulmonary Vein Isolation vs PVI With Posterior Left Atrial Wall Isolation) randomized study aimed to determine whether the addition of PWI to PVI improves outcomes in patients undergoing first-time catheter ablation for persistent AF.
Methods
Trial Design
The primary hypothesis is that PWI in addition to PVI in patients with persistent AF will decrease AF recurrence compared with PVI alone. The study was granted ethics approval by the Alfred Hospital Human Ethics and Research Committee (Melbourne, Australia). All participants provided written informed consent. The trial design has been published.15 The protocol and statistical analysis plan are included in Supplement 1.
Study Participants
Patients were recruited from 11 experienced centers in 3 countries (Australia, Canada, UK). Patients were eligible if they were 18 years or older, had symptomatic persistent AF refractory to at least 1 antiarrhythmic medication, and were undergoing a first-time ablation procedure for persistent AF. Persistent AF was defined as a sustained episode lasting between 7 days and 3 years. The main exclusion criteria include (1) paroxysmal AF, (2) long-standing persistent AF lasting more than 3 years, and (3) hypertrophic cardiomyopathy. Detailed inclusion and exclusion criteria are reported in eTable 1 in Supplement 2.
Randomization
Patients were randomly assigned in a 1:1 ratio to PVI with PWI or PVI alone. Randomization allocation was computer generated and stratified by study site. The participants were blinded to the randomization group, but the electrophysiologists performing the ablation could not be.
Study Procedures
Antiarrhythmic medication was discontinued approximately 5 half-lives before the procedure. Uninterrupted oral anticoagulation was encouraged. Radiofrequency ablation of AF was performed under general anesthesia with intraprocedural transesophageal echocardiography to exclude left atrial appendage thrombus and guide transseptal access. Esophageal temperature monitoring was used in all cases. Endocardial 3D mapping with multipolar mapping catheters was performed using CARTO (Biosense Webster) or Ensite Precision/Velocity (Abbott Medical) mapping systems. Irrigated contact force–sensing ablation catheters were used in all procedures,16 with minimum target contact force greater than 5 g. Recommended ablation targets were an Ablation Index of 500 to 550 anteriorly and 350 to 400 posteriorly for the CARTO system and a Lesion Index of 5 to 6 anteriorly and 3.5 to 4 posteriorly for the Ensite system. PVI involved wide antral circumferential ablation around the pulmonary veins, with the end point of electrical isolation. In patients randomized to PWI a floor line joining the most inferior margins of the inferior pulmonary veins, and a roof line connecting the superior-most aspect of the superior pulmonary veins, was deployed following PVI (Figure 1). The floor line is deployed first, as block is readily apparent through a delay and change in activation on the multipolar mapping catheter placed on the posterior wall during pacing from the proximal electrodes of the coronary sinus catheter. If PWI was not achieved with linear ablation, mapping and targeting of the earliest electrograms within the “box” (area on the posterior wall encircled by the posterior PVI lines bilaterally, the roof ablation line and the floor ablation line) was completed (eFigure 1 in Supplement 2). PVI and PWI were confirmed through the identification of entrance and exit block, and either the presence of spontaneous potentials or the complete absence of local electrograms with no capture at high-output pacing.
Figure 1. Pulmonary Vein Isolation With and Without Posterior Wall Isolation.
A, Pulmonary vein isolation (PVI) with posterior wall isolation achieved by adding a roof ablation line connecting the superior aspects of the pulmonary veins and floor ablation line connecting the inferior aspects of the pulmonary veins. B, Wide antral circumferential ablation around the pulmonary veins bilaterally to achieve PVI.
Oral anticoagulation was mandated for a minimum of 3 months after ablation. Antiarrhythmic medication use was allowed during the 3-month blanking period after ablation, although this was discouraged beyond 3 months. Repeat ablation procedures were allowed in participants with recurrent atrial arrhythmias who required antiarrhythmic medication beyond 3 months. Patients in the PVI-alone group were permitted to cross over and undergo PWI only in the presence of enduring PVI; otherwise, pulmonary vein reisolation was performed.
All participants were followed up for a minimum of 12 months after ablation, with clinical or telehealth reviews at 6 weeks and 3, 6, 9, and 12 months after ablation. Arrhythmia recurrence was assessed using preexisting implantable cardiac devices, implantable loop recorders, or twice-daily electrocardiographic (ECG) monitoring with the KardiaMobile device (AliveCor). In patients nonadherent to ECG monitoring, 24-hour Holter monitoring was performed at 3, 6, 9, and 12 months. All arrhythmia recurrences were adjudicated by a central monitoring committee blinded to patient treatment allocation.
Study End Points
The primary study end point was freedom from any documented atrial arrhythmia (AF, atrial tachycardia, or atrial flutter) of more than 30 seconds, excluding the initial 3-month blanking period, at a minimum of 12 months’ follow-up after a single ablation procedure without antiarrhythmic medication. Continuation of antiarrhythmic medication beyond 3 months, or a repeat ablation procedure at any time, were considered treatment failures for the primary outcome analysis. Patients lost to follow-up were censored at the last known date of follow-up.
There were 23 prespecified secondary end points, with the following reported in this manuscript: procedural outcomes; freedom from atrial arrhythmia, with or without antiarrhythmic medication, after multiple procedures; freedom from atrial flutter/tachycardia, with or without antiarrhythmic medication, after multiple procedures; freedom from symptomatic AF, with or without antiarrhythmic medication, after multiple procedures; freedom from symptomatic atrial arrhythmia, with or without antiarrhythmic medication, after multiple procedures; periprocedural complications; number of repeat procedures; posterior wall isolation outcomes; targeted end point ablation vs targeted end point with ablation of additional atrial arrhythmias and subsequent outcomes; and AF burden outcomes at 12 months. Details of all secondary outcomes are provided in Supplement 2.
All serious adverse events were adjudicated by an independent data and safety monitoring board.
Statistical Analysis
Sample size calculation was based on prior studies which reported a single-procedure success rate of 60% with PVI alone.8 An incremental benefit of 15% from adding PWI was assumed based on findings from an observational study by O’Neill et al,14 which reported a 75% success rate from PWI. Based on this, 152 participants were needed in each group to reject the null hypothesis that the success rates for experimental and control participants were equal, with a power of 80% and type I error probability (2-sided) of .05. To account for a possible 10% participant dropout, 169 participants in each group were needed, resulting in a total sample size of 338.
All arrhythmia outcome analyses were performed on patients who underwent an ablation procedure and were followed up for longer than the initial 3-month blanking period, based on their randomization group. Analyses of safety outcomes were carried out in all patients who underwent an ablation procedure. The primary outcome and time to event secondary outcomes were analyzed using Kaplan-Meier survival curves. Treatment groups were compared with the log-rank test with 1 degree of freedom. Hazard ratios (HRs) and CIs for time to event outcomes were estimated using univariate Cox proportional hazards modeling. The proportional hazards assumption was assessed by visual inspection of the log plot and through formal test of interaction. Patients lost to follow-up after 6 months were censored at last known date of follow-up.
Post hoc subgroup analyses were conducted for the following variables: younger than 65 years vs 65 years or older, male vs female, persistent AF vs long-standing persistent AF (long-standing persistent AF defined as continuous AF with duration of >1 year), New York Heart Association class I vs II or greater, CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) score 2 or less vs greater than 2, body mass index less than 27 vs 27 or greater (calculated as weight in kilograms divided by square of height in meters), and the presence vs absence of congestive cardiac failure, sleep apnea, alcohol excess (>8 standard drinks/week), and hypertension. Subgroup analyses were performed using Cox regression modeling, with interaction within subgroups assessed with a randomization × subgroup interaction term. Sensitivity analyses were conducted for the following groups: patients who had successful PWI and patients who had frequent ECG monitoring used for rhythm monitoring.
For those who developed AF after ablation, AF duration was calculated from the day of AF recurrence onset to the date of AF reversion (either spontaneously/with antiarrhythmic medication/direct current cardioversion/repeat ablation) or to the end of the 12-month follow-up, whichever occurred first. The AF burden was expressed as a percentage by dividing the AF duration over the 1-year follow-up period.
Continuous variables were summarized with means and standard deviations unless the distribution was skewed, in which case medians and IQRs were reported. Categorical variables were summarized as frequencies and percentages. Differences in variables between groups, such as the atrial arrhythmia burden, were analyzed using χ2/Fisher exact test for categorical data, and the t test or Mann-Whitney U test for normally distributed and skewed continuous data, respectively.
P < .05 (2-sided) was considered statistically significant. Statistical analyses were performed using SPSS version 27 (IBM). Because of the potential for type I error due to multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory.
Results
Patients
A total of 338 patients were enrolled into the study between July 2018 and March 2021. Baseline characteristics were balanced between groups (Table 1). In the PVI-alone group 1 patient did not receive any ablation. The 12-month follow-up was completed by 330 of 337 patients (97.9%). Three patients in the PVI with PWI group and 2 in the PVI-alone group were lost to follow-up after 6 months. There were 2 non–procedural-related deaths (Figure 2).
Table 1. Cohort Characteristics.
| Characteristic | No. (%) | |
|---|---|---|
| PVI + PWI (n = 170) | PVI alone (n = 168) | |
| Demographics | ||
| Age, median (IQR), y | 65.7 (58.7-71.1) | 65.5 (57.8-71.7) |
| Men | 131 (77.1) | 128 (76.2) |
| Women | 39 (22.9) | 40 (23.8) |
| BMI, median (IQR)a | 29.1 (26.3-32.8) | 28.6 (26.0-33.1) |
| Longest median continuous duration of AF, median (IQR), mo | 5 (2-8) | 5 (2-8) |
| CHA2DS2-VASc score, median (IQR)b | 2 (1-3) | 2 (1-3) |
| No. of cardioversions before ablation, median (IQR) | 2 (1-2) | 2 (1-2) |
| Comorbidities | ||
| Obesity (BMI >27a) | 110 (64.7) | 110 (65.5) |
| Hypertension | 85 (50.0) | 74 (44.0) |
| Congestive cardiac failurec | 45 (26.5) | 53 (31.5) |
| Ischemic heart disease | 18 (10.6) | 23 (13.7) |
| Type 2 diabetes | 17 (10.0) | 18 (10.7) |
| Stroke | 11 (6.5) | 7 (4.2) |
| No. of failed antiarrhythmic medications | ||
| 0 | 14 (8.2) | 17 (10.1) |
| 1 | 117 (68.8) | 117 (69.6) |
| 2 | 37 (21.8) | 31 (18.5) |
| >2 | 2 (1.2) | 2 (1.8) |
| Antiarrhythmic medication use at trial enrollment | ||
| Flecainide | 29 (17.1) | 19 (11.3) |
| Sotalol | 45 (26.5) | 34 (20.2) |
| Amiodarone | 51 (30.0) | 56 (33.3) |
| Echocardiographic parameters | ||
| Left atrium diameter, cmd | 4.6 (0.6) | 4.4 (0.7) |
| LAVI, mL/m2e | 49.5 (15.5) | 45.2 (13.5) |
| Right atrial area, median (IQR), cm2f | 23 (19-26) | 22 (19-26) |
| E:e’ ratio, median (IQR)g | 9 (7.6-12.0) | 9 (7.5-12.7) |
| LVEF, median (IQR), %h | 56 (45-60) | 55 (45-60) |
| AF or atrial arrhythmia at start of procedure | 108 (63.5) | 98 (58.3) |
| Rhythm monitoring after ablation | ||
| ILR or ICED | 27 (15.9) | 26 (15.6) |
| Frequent ECG monitoring | 119 (70.0) | 118 (70.7) |
| 24-h Holter monitor | 24 (14.1) | 23 (13.7) |
Abbreviations: AF, atrial fibrillation; BMI, body mass index; CHA2DS2-VASc, congestive heart failure, hypertension, age ≥75 years (doubled), diabetes, stroke/transient ischemic attack/thromboembolism (doubled), vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque), age 65-75 years, sex category (female); ICED, implantable cardiac electronic device; ILR, implantable loop recorder; LAVI, left atrial indexed volume; LVEF, left ventricular ejection fraction; PVI, pulmonary vein isolation; PWI, posterior wall isolation.
Calculated as weight in kilograms divided by square of height in meters.
Score is used to estimate stroke risk in patients with nonrheumatic atrial fibrillation. Score ranges from 0 to 9. Scores 2 or greater are associated with elevated stroke risk, and oral anticoagulation is recommended for stroke prevention.
Defined as ejection fraction less than 50%.
Normal values, less than 4.1 cm for men; less than 3.9 cm for women.
Normal value, 34 mL/m2 or less.
Normal value, 18 cm2 or less.
An estimate of left ventricular filling pressure, which is a marker of left ventricular diastolic function (or left ventricular “relaxation”). Normal average value: less than 10.
A measure of global left ventricular function obtained by measuring the difference between end diastolic and end systolic left ventricular volumes. Normal values: greater than 52% in men or greater than 54% in women.
Figure 2. Recruitment, Randomization, and Patient Flow in the CAPLA Trial.
AF indicates atrial fibrillation; CAPLA, Catheter Ablation for Persistent Atrial Fibrillation: A Multicentre Randomized Trial of Pulmonary Vein Isolation vs PVI With Posterior Left Atrial Wall Isolation; PVI, pulmonary vein isolation; PWI, posterior wall isolation.
Procedural Characteristics
At the time of ablation, 206 patients (60.9%) were in AF/atrial tachycardia/atrial flutter, which included 108 (63.5%) in the PVI with PWI group and 98 (58.3%) in the PVI-alone group. Fourteen patients (8.2%) in the PVI with PWI group and 11 (6.5%) in the PVI-alone group had failed attempts at cardioversion at the beginning of procedure for AF (P = .33). All patients in the study achieved successful PVI. High-power short-duration ablation (defined as ablation power ≥40 W on the posterior left atrial wall), was used in 50 patients (29.4%) in the PVI with PWI group and 46 (27.4%) in the PVI-alone group (P = .72).
Primary Outcome
At 12 months, freedom from recurrent atrial arrhythmia after 1 ablation procedure, without the use of antiarrhythmic medication, was present in 89 of 170 patients (52.4%) assigned to PVI with PWI, compared with 90 of 168 (53.6%) assigned to PVI alone (between-group difference, –1.2%; hazard ratio [HR], 0.99 [95% CI, 0.73-1.36]; P = .98) (Table 2 and Figure 3).
Table 2. Major Efficacy Outcomes.
| No. (%) | P value | |||
|---|---|---|---|---|
| PVI + PWI (n = 170) | PVI alone (n = 168) | Absolute difference | ||
| Primary outcome | ||||
| Freedom from any documented atrial arrhythmia, after a single ablation procedure, without antiarrhythmic medications | 89 (52.4) | 90 (53.6) | −1 (−1.2) | .98 |
| Secondary outcomes | ||||
| Freedom from any documented atrial arrhythmia episodes >30 s at 12 mo after 1 or 2 ablation procedures with or without antiarrhythmic medications | 99 (58.2) | 101 (60.1) | −2 (−1.9) | .57 |
| Freedom from documented atrial flutter or atrial tachycardia episodes >30 s at 12 mo after 1 or 2 ablation procedures with or without antiarrhythmic medications | 142 (84.5) | 148 (87.1) | −6 (−2.6) | .31 |
| Freedom from symptomatic AF episodes >30 s at 12 mo after 1 or 2 ablation procedures with or without antiarrhythmic medications | 116 (68.2) | 121 (72.0) | −5 (−3.8) | .36 |
| Freedom from symptomatic atrial arrhythmia episodes >30 s at 12 mo after 1 or 2 ablation procedures with or without antiarrhythmic medications | 114 (67.0) | 119 (70.8) | −5 (−3.8) | .45 |
Abbreviations: AF, atrial fibrillation; PVI, pulmonary vein isolation; PWI, posterior wall isolation.
Figure 3. Any Atrial Arrhythmia Recurrence, Without Antiarrhythmic Medication, After a Single Ablation Procedure.
There was no significant difference in any atrial arrhythmia recurrence, after 90 days’ blanking period, without antiarrhythmic medication from a single procedure, between PVI alone vs PVI with PWI. Median observation time was 275 days in both groups.
Secondary Outcomes
Mean procedural times (142 [SD, 69] minutes for the PVI with PWI group vs 121 [SD, 57] minutes for the PVI-alone group; mean difference, 21 minutes [95% CI, 20.9 to 23.0]; P < .001) and radiofrequency ablation times (34 [SD, 21] minutes vs 28 [SD, 12] minutes; mean difference, 6 minutes [95% CI, 7.0 to 8.5]; P < .001) were significantly shorter for PVI alone, whereas mean fluoroscopy times were not significantly different (11.5 [SD, 6.8] minutes vs 10.5 [SD, 7.2] minutes; mean difference, 1 minute [95% CI, 0.4 to 0.5]; P = .35) (eFigure 2 in Supplement 2).
There was no significant difference between the groups with regard to freedom from any atrial arrhythmia, with or without antiarrhythmic medication, after multiple ablation procedures (HR, 1.10 [95% CI, 0.79-1.55]; P = .57), freedom from atrial flutter/tachycardia, with or without antiarrhythmic medication, after multiple procedures (HR, 1.39 [95% CI, 0.73-2.66]; P = .31); freedom from symptomatic AF, with or without antiarrhythmic medication, after multiple procedures (HR, 1.20 [95% CI, 0.80-1.78]; P = .36); and freedom from symptomatic atrial arrhythmia, with or without antiarrhythmic medication, after multiple procedures (HR, 1.17 [95% CI, 0.79-1.73]; P = .45) (Table 2; eFigures 3-6 in Supplement 2). Recurrences of AF in the PVI with PWI group were paroxysmal in 49 patients (62.8%) and persistent in 29 (37.2%), and in the PVI-alone group were paroxysmal in 48 (61.5%) and persistent in 30 (38.5%).
Repeat ablation within 12 months of follow-up was performed in 16 patients (9.4%) in the PVI with PWI group and in 16 (9.5%) in the PVI-alone group (eTable 2 in Supplement 2). In the PVI with PWI group, pulmonary vein reconnection, posterior wall reconnection, or both was present in 11 of 16 patients (68.8%), including 11 with posterior wall reconnection. Isolation of pulmonary vein and posterior wall was restored in all. In the presence of enduring PVI and PWI, additional ablation included a combination of mitral isthmus (n = 4), cavotricuspid isthmus (n = 3), superior vena cava isolation (n = 1), and targeting complex fractionated electrograms (n = 1). In the PVI-alone group, pulmonary vein reconnection was present in 12 of 16 patients (75%) and 4 of 16 (25%) underwent PWI in the presence of enduring PVI.
PWI details are reported in eTable 2 in Supplement 2. PWI success was achieved in 86.5% of patients, with 50.3% requiring focal ablation within the posterior wall box to achieve electrical isolation or silence. Of the 23 cases in which PWI was unsuccessful, ablation was limited by rapid temperature elevations greater than 38 °C in 17 patients (73.9%), with median temperature of 39.3 °C (IQR, 38.8-39.9 °C). Ablation targeting epicardial connections within the posterior wall box was performed in 18 of 23 patients (78.2%).
Targeted end point ablation, in which ablation was performed as per randomization allocation only, was compared with targeted end point ablation with additional ablation during the index procedure (including cavotricuspid isthmus line/focal atrial tachycardia/atrioventricular nodal reentry tachycardia ablation), with no significant difference in atrial arrhythmia outcome at 12 months (HR, 1.28 [95% CI, 0.89-1.84], P = .18) (eFigure 7 in Supplement 2).
Median atrial arrhythmia burden was 0% (IQR, 0%-2.3%) in the PVI with PWI group and 0% (IQR, 0%-2.8%) in the PVI-alone group at 12 months of follow-up (P = .47) (eFigure 8 in Supplement 2).
Post Hoc Outcomes
Post hoc subgroup analyses were consistent with the primary outcome, with results presented in eFigure 9 in Supplement 2. There was no significant difference in event occurrence between groups in patients with long-standing persistent AF (15/30 for PVI with PWI vs 19/27 for PVI alone; HR, 0.54 [95% CI, 0.28-1.07]; P = .07), in those who underwent successful posterior wall isolation (67/147 for PVI with PWI vs 78/168 for PVI alone; HR, 0.93 [95% CI, 0.67-1.30]; P = .68), and in those who had frequent intermittent ECG monitoring (57/119 for PVI with PWI vs 56/118 for PVI alone; HR, 0.94 [95% CI, 0.65-1.36]; P = .74). Post hoc analysis also showed that the primary outcome was unaffected by study site.
Adverse Events
There were 6 complications in the PVI with PWI group and 4 in the PVI-alone group (eTable 3 in Supplement 2). Complications in the PVI-alone group were pericarditis requiring readmission (n = 1), phrenic nerve injury (n = 1), and cardiac failure (n = 2); in the PVI with PWI group the complications were femoral hematoma (n = 1), arterial injury (n = 1), pericardial tamponade (n = 1), cardiac failure (n = 2), and pneumonia (n = 2). There was zero procedural mortality, with no cerebrovascular events or esophageal fistula.
Discussion
In patients undergoing first-time catheter ablation for persistent AF, the empirical addition of PWI to PVI alone did not significantly improve freedom from atrial arrhythmia at 12 months compared with PVI alone. Secondary arrhythmia recurrence outcomes with or without antiarrhythmic medication after multiple procedures were not significantly different between the 2 ablation approaches. Adding PWI to PVI resulted in longer procedural and radiofrequency ablation times, without a demonstrable increase in complication rates.
In the search for adjunctive strategies to improve ablation outcomes in patients with persistent AF beyond those achieved with PVI alone,8,9,12,17,18 the results of this study represent a further disappointment. There are plausible mechanisms by which the posterior wall of the left atrium may play a role in the initiation and maintenance of AF, and consequently it has become a common target for ablation beyond the pulmonary veins. It has a common embryologic origin to the pulmonary veins and houses the septopulmonary bundle, which may be a site of conduction slowing and wave-front collision.19,20 Postulated benefits of PWI include autonomic ganglia modification, inclusion of rotors or regions of fibrosis or complex fractionated activity, atrial debulking, and reinforcement of PVI.21 Indeed small nonrandomized studies exploring PWI had shown promising results.11,12,13 A subgroup analysis from the AATAC randomized trial reported freedom from AF in 79% (95% CI, 68%-86%) of the PVI with PWI group, compared with 36% (95% CI, 17%-56%) of the PVI-alone group.22
Two recent RCTs using cryoballoon ablation had reported positive results from additional PWI; however, these studies were limited by small sample size and by the requirement for radiofrequency ablation to complete PWI.23,24 A meta-analysis reported a significantly lower risk of atrial arrhythmia recurrence (risk ratio, 0.74 [95% CI, 0.62-0.90]; P < .001) and AF (risk ratio, 0.67 [95% CI, 0.50-0.91]; P = .01) with adjunctive PWI in patients with persistent AF but not in patients with paroxysmal AF. Adding PWI to PVI required longer ablation and procedural times but equivalent fluoroscopy times, which was also seen in this study.25
The POBI-AF study, a smaller multicenter RCT involving patients with persistent AF randomized to PVI alone or PVI with posterior wall box isolation,18 reported no significant difference in AF recurrence. AF surveillance was based on Holter monitoring, a combination of force-sensing and non–force-sensing catheters were used, bidirectional block at the floor line was not mandated, and an anterior mitral line was deployed in 83% of patients. The CONVERGE trial compared a hybrid surgical epicardial/endocardial catheter approach of PVI with PWI compared with catheter-based radiofrequency PVI. There was a significant reduction in recurrent arrhythmias with the hybrid surgical approach; however, serious adverse events were reported in 7.8% of patients vs 0% with catheter-based PVI alone.26 The CONVERGE trial reported freedom from atrial arrhythmia in 53% of patients in the hybrid surgical group, comparable to the outcome reported in the present study. The present study, a large randomized study using contemporary radiofrequency ablation technology, had not indicated any benefit of empirical PWI in addition to PVI alone.
In a quest to improve procedural outcomes, electrophysiologists are tempted to pursue more extensive ablation; however, this can be proarrhythmic if atrial tissue is incompletely ablated or bidirectional block is not achieved.8 Longer procedure times may increase the risk of complications.7 In the DECAAF-II trial there was a significant increase in the incidence of complications in the magnetic resonance imaging–guided atrial fibrosis ablation group, without an attendant significant improvement in success.7 A previous meta-analysis had reported a success rate of 66.7% (95% CI, 60.8%-72.2%) with PVI alone in patients with persistent AF,6 whereas in the present study 53.9% of patients in the PVI-alone group remained arrhythmia-free at 12 months. This was consistent with the PVI-alone findings from the DECAAF-II trial.7 In the present study daily or continuous rhythm monitoring was more rigorous than intermittent Holter monitors predominantly used in earlier AF ablation trials.25
The present study did not support the empirical deployment of PWI for first-time AF ablation. However, further studies are needed to identify patient subgroups who may benefit. One may speculate that PWI may be considered in patients with recurrent AF in the presence of enduring PVI,10 low posterior wall voltage,11,27,28 or longer-standing persistent AF. However the DECAAF-II trial reported no significant improvement in outcomes with magnetic resonance imaging–guided atrial fibrosis ablation compared with PVI alone.7
While the primary outcome for the present study was reported based on the currently accepted standard of 30 seconds of arrhythmia recurrence,1 atrial arrhythmia/AF burden was also included because it is increasingly considered a more clinically meaningful end point.29 The CABANA trial showed significant reduction in AF burden in the catheter ablation group compared with the medical therapy group, which is associated with a significant improvement in quality-of-life outcomes. In the present study the median AF burden at 12 months was 0%, in keeping with AF ablation as an effective rhythm control strategy. The appropriate end point for reporting the primary outcome of AF ablation trials remains contentious.
Limitations
This study has several limitations. First, a heterogenous approach to rhythm monitoring after ablation was used, although more than 85% of the cohort had close monitoring with implantable cardiac devices or single-lead twice-daily ECG transmissions. Ideally all participants would have had implantable devices for surveillance, but the cost to this investigator-initiated RCT was prohibitive. Second, operators could not be blinded to randomization; however, they were not involved in the interpretation of the study end point. Third, AF burden before ablation was not reported because the intensity and duration of rhythm monitoring prior to study enrollment was not standardized across all participants. Newer techniques to isolate the posterior wall using pulsed-field ablation are evolving but have not been subjected to randomized studies.30
Conclusions
In patients undergoing first-time catheter ablation for persistent atrial fibrillation, the addition of posterior wall isolation to pulmonary vein isolation did not significantly improve freedom from atrial arrhythmia at 12 months compared with pulmonary vein isolation alone. These findings do not support the empirical inclusion of posterior wall isolation for ablation of persistent atrial fibrillation.
CAPLA Study Protocol and Statistical Analysis Plan
eFigure 1. Posterior Wall Isolation With Ablation Lesions Within Box
eFigure 2. Fluoroscopy, Procedural and RF Ablation Times Between PVI + PWI vs PVI-Alone Groups
eFigure 3. Kaplan-Meier Curve of Freedom From Documented Any Atrial Arrhythmia Episodes >30 Seconds at 12 Months After 1 or 2 Ablation Procedures, With or Without Antiarrhythmic Medications
eFigure 4. Kaplan-Meier Curve of Freedom From Documented Atrial Flutter or Atrial Tachycardia Episodes >30 Seconds at 12 Months After 1 or 2 Ablation Procedures, With or Without Antiarrhythmic Medications
eFigure 5. Kaplan-Meier Curve of Freedom From Symptomatic AF Episodes >30 Seconds at 12 Months After 1 or 2 Ablation Procedures, With or Without Antiarrhythmic Medications
eFigure 6. Kaplan-Meier Curve of Freedom From Symptomatic Atrial Arrhythmia Episodes >30 Seconds at 12 Months After 1 or 2 Ablation Procedures, With or Without Antiarrhythmic Medications
eFigure 7. Kaplan-Meier Curve of Freedom From Documented Any Atrial Arrhythmia Episodes >30 Seconds at 12 Months, Between Targeted End Point Ablation Vs Targeted End Point With Additional Arrhythmia Ablation, After 1 Procedure Without Antarrhythmic Medication
eFigure 8. Atrial Fibrillation Burden in PVI-Alone Group vs PVI + PWI Group at 12 Months of Follow-up
eFigure 9. Post hoc Subgroup Analysis
eTable 1. Detailed Inclusion and Exclusion Criteria
eTable 2. Procedural Outcomes
eTable 3. Serious Adverse Events
eTable 4. Characteristics of Long Standing Persistent AF Subgroup
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
CAPLA Study Protocol and Statistical Analysis Plan
eFigure 1. Posterior Wall Isolation With Ablation Lesions Within Box
eFigure 2. Fluoroscopy, Procedural and RF Ablation Times Between PVI + PWI vs PVI-Alone Groups
eFigure 3. Kaplan-Meier Curve of Freedom From Documented Any Atrial Arrhythmia Episodes >30 Seconds at 12 Months After 1 or 2 Ablation Procedures, With or Without Antiarrhythmic Medications
eFigure 4. Kaplan-Meier Curve of Freedom From Documented Atrial Flutter or Atrial Tachycardia Episodes >30 Seconds at 12 Months After 1 or 2 Ablation Procedures, With or Without Antiarrhythmic Medications
eFigure 5. Kaplan-Meier Curve of Freedom From Symptomatic AF Episodes >30 Seconds at 12 Months After 1 or 2 Ablation Procedures, With or Without Antiarrhythmic Medications
eFigure 6. Kaplan-Meier Curve of Freedom From Symptomatic Atrial Arrhythmia Episodes >30 Seconds at 12 Months After 1 or 2 Ablation Procedures, With or Without Antiarrhythmic Medications
eFigure 7. Kaplan-Meier Curve of Freedom From Documented Any Atrial Arrhythmia Episodes >30 Seconds at 12 Months, Between Targeted End Point Ablation Vs Targeted End Point With Additional Arrhythmia Ablation, After 1 Procedure Without Antarrhythmic Medication
eFigure 8. Atrial Fibrillation Burden in PVI-Alone Group vs PVI + PWI Group at 12 Months of Follow-up
eFigure 9. Post hoc Subgroup Analysis
eTable 1. Detailed Inclusion and Exclusion Criteria
eTable 2. Procedural Outcomes
eTable 3. Serious Adverse Events
eTable 4. Characteristics of Long Standing Persistent AF Subgroup
Data Sharing Statement