A Randomized Assessment of the Incremental Role of Ablation of Complex Fractionated Atrial Electrograms After Antral Pulmonary Vein Isolation for Long-Lasting Persistent Atrial Fibrillation

Study subjects

There were 119 consecutive patients who consented to participate in this study to eliminate their long-lasting persistent AF. There were 96 men and 23 women, and their mean age was 60 ± 9 years (range 33 to 80 years). The mean left atrial size and left ventricular ejection fraction were 46 ± 6 mm and 0.53 ± 0.10, respectively. Atrial fibrillation had been persistent for 5 ± 5 years before ablation. The clinical characteristics of patients in each group are shown in Table 1.Patients who had undergone a prior ablation procedure for AF were excluded from this study.

Electrophysiologic study

All patients provided informed written consent. An electrophysiologic study was performed in the fasting state. All antiarrhythmic drugs except amiodarone were discontinued at least 4 to 5 half-lives before the study. Amiodarone was discontinued ≥8 weeks earlier. All vascular access was obtained through a femoral vein. A quadripolar catheter positioned in the coronary sinus was used for recording electrograms and atrial pacing. After transseptal puncture, systemic anticoagulation was achieved with intravenous heparin to maintain an activated clotting time of 325 to 350 s. All PVs were mapped with a decapolar ring catheter (Lasso, Biosense Webster, Diamond Bar, California). An open-irrigation, 3.5-mm-tip deflectable tip catheter (Thermocool, Biosense Webster) was used for mapping and ablation. Bipolar electrograms were recorded at a bandpass of 30 to 500 Hz (EPMedSystems, West Berlin, New Jersey).

An electroanatomical mapping system (Carto, Biosense Webster) was used to reconstruct the 3-dimensional geometry of the left atrium and PVs. To avoid inadvertent collateral injury, the esophagus was visualized by barium swallow (5). After the barium swallow, conscious sedation was achieved with midazolam and fentanyl.

Radiofrequency energy was delivered at a maximum power output of 35 W at a flow rate of 30 ml/min and a maximum temperature of 45°C. The power was reduced to 20 to 25 W at a flow rate of 17 ml/min, during applications of energy near the PV ostia, in the posterior left atrium, or in the coronary sinus. The end point of each individual application at a given site was voltage abatement or up to 40 s of application with adequate tissue contact and power delivery.

Study protocol

The study protocol was approved by the Institutional Review Board. All patients presented in AF. First, all patients underwent APVI to target CFAEs within the antrum of the PVs, with an end point of complete electrical isolation of all PVs (Fig. 1).This study defined CFAEs as electrograms with a cycle length ≤120 ms or shorter than the AF cycle length in the coronary sinus, or electrograms that were fractionated or displayed continuous electrical activity (Fig. 2)(3).

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Figure 1

Antral PV Isolation

Shown are left lateral (A)and posteroanterior (B)projections of a 3-dimensional electroanatomic depiction of the left atrium (LA). Red tagsindicate ablation sites. LI = left inferior; LS = left superior; PV = pulmonary vein; RI = right inferior; RS = right superior.

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Figure 2

Examples of CFAEs

Examples of complex fractionated atrial electrograms (CFAEs). Abl = distal bipole of the ablation catheter; CS = distal bipole of the coronary sinus catheter.

APVI was completed in all patients and complete PV isolation was achieved whether or not AF terminated during the procedure. Because termination of AF by catheter ablation has been associated with a more favorable clinical outcome in patients with paroxysmal and persistent AF (3,6,7), patients with termination of AF during APVI did not undergo additional ablation of CFAEs (Group A). Patients who still had AF after APVI were randomly assigned to undergo no further ablation (Group B) or to undergo additional ablation of CFAEs in the left atrium and coronary sinus up to 2 additional hours of procedure duration or until AF terminated, whichever came first (Group C) (Fig. 3).

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Figure 3

Ablation of CFAEs

Shown are right anterior oblique (A)and posteroanterior (B)projections of a 3-dimensional electroanatomic depiction of the LA. Red tagsindicate ablation sites. Abbreviations as in Figures 1 and 2.

In patients who remained in AF, sinus rhythm was restored by pharmacological cardioversion with ibutilide or transthoracic cardioversion.

Post-ablation management and follow-up

All patients were discharged home the next day taking warfarin and low molecular weight heparin until the international normalized ratio was >2.0. The same drug regimen was continued for 8 to 12 weeks after ablation in patients who were receiving an antiarrhythmic drug before the procedure.

The first outpatient clinic visit was at 3 months after the ablation procedure. The patients then were seen every 3 to 6 months. Patients were also asked to call a clinical coordinator if they experienced symptoms suggestive of an arrhythmia. The patients were provided with a 30-day autotriggered event monitor 6 months after ablation. A repeat ablation procedure was offered to all patients with recurrent atrial arrhythmias. During repeat ablation, APVI was confirmed and repeated in all patients if there was recovery of conduction. At the discretion of the operator, CFAEs were also targeted until AF terminated or all CFAEs were eliminated, regardless of the initial randomization group.

Warfarin was discontinued in patients who were confirmed to be in sinus rhythm beyond 6 months after the final ablation procedure as long as there was no history of thromboembolic events or another indication to continue anticoagulant therapy (8).

Statistical analysis

Continuous variables are expressed as mean ± 1 SD and were compared by Student ttest or by analysis of variance. The Tukey test was performed for post hoc analyses. Categorical variables were compared by chi-square analysis or with the Fisher exact test as appropriate. A p value <0.05 indicated statistical significance.

To detect a 25% difference in clinical outcome at a power of 0.80 and 1-tailed alpha of 0.05, 46 patients in each group would be necessary. Therefore, 50 patients were randomly assigned to Groups B and C. The primary end point of the study was freedom from symptomatic and asymptomatic AF and other atrial tachyarrhythmias in the absence of antiarrhythmic drug therapy after a single ablation procedure. Any episode of atrial tachyarrhythmia ≥30 s in duration beyond 12 weeks after ablation was considered to be a recurrence.

APVI and subsequent randomization

All PVs were completely isolated in all patients during APVI. The mean duration of radiofrequency energy application was 54 ± 19 min. The mean fluoroscopy and procedure times were 59 ± 23 min and 254 ± 47 min, respectively.

Among the 119 patients, AF terminated in 19 (16%, Group A): to sinus rhythm in 16 and to atrial tachycardia/flutter in 3. The remaining 100 patients with AF after APVI were randomized to no further ablation (Group B, n = 50) or to ablation of CFAEs (Group C, n = 50). The clinical and echocardiographic characteristics of patients among the 3 groups were similar except for the left atrial size. Patients in Group A had a smaller left atrial diameter than patients in Groups B and C (Table 1).

Ablation of CFAEs (Group C)

The sites of CFAEs targeted in the left atrium and coronary sinus are shown in Table 2.Ablation was performed within the coronary sinus in 24 of 50 (48%) patients. The mean duration of radiofrequency energy application to eliminate CFAEs was 33 ± 22 min. The mean additional fluoroscopy and procedure durations for ablation of CFAEs were 20 ± 14 min and 75 ± 77 min, respectively.

Atrial fibrillation terminated in 9 of 50 patients (18%) in Group C during ablation of CFAEs: to sinus rhythm in 5 and to atrial tachycardia/flutter in 4. Due to the length of the procedure, sinus rhythm was restored by ibutilide (n = 1) or transthoracic cardioversion (n = 3) in patients who had atrial flutter. In the remaining 41 patients, sinus rhythm was restored by ibutilide infusion (n = 11) or by transthoracic cardioversion (n = 30).

Maintenance of sinus rhythm after a single ablation procedure

At a mean follow-up of 10 ± 3 months after a single ablation procedure, 19 of 50 patients (38%) in Group B and 18 of 50 patients (36%) in Group C were in sinus rhythm in the absence of antiarrhythmic drug therapy (p = 0.84). Among the 31 of 50 patients in Group B who had recurrent atrial arrhythmias, 23 (46%) had persistent AF, 6 (12%) had paroxysmal AF, and 2 (4%) had atrial flutter. Among the 32 of 50 patients in Group C who had recurrent atrial arrhythmias, 24 (48%) had persistent AF, 2 (4%) had paroxysmal AF, and 6 (12%) had atrial flutter (p = 0.14 for atrial flutter) during a mean follow-up of 10 ± 3 months.

At a mean follow-up of 10 ± 3 months after a single ablation procedure, among the 19 patients in Group A in whom AF terminated during APVI, 15 (79%) were in sinus rhythm without antiarrhythmic drug therapy and 4 (21%) had recurrent AF.

Among the 100 randomized patients, there were no predictors of sinus rhythm after a single ablation procedure. Among all 119 study patients, sinus rhythm was maintained in the absence of antiarrhythmic drug therapy in 18 of 28 patients (64%) in whom AF terminated during ablation and in 34 of 91 patients (37%) in whom AF persisted after ablation (p = 0.01). There were no other predictors of sinus rhythm after a single ablation procedure.

Repeat ablation procedures

In 119 patients, 157 procedures were performed. A second ablation procedure was performed in 1 of 19 patients (5%) in Group A, 18 of 50 patients (36%) in Group B, and 17 of 50 patients (34%) in Group C at a mean of 7 ± 2 months after the first procedure (p = 0.83 for Group B vs. C). The second procedure was performed for recurrent AF in 32 patients (1 in Group A, 17 in Group B, and 14 in Group C) and atrial flutter in 4 patients (1 in Group B and 3 in Group C). A third ablation procedure was performed in 1 patient in Group A for recurrent AF and 1 patient in Group C for recurrent atrial flutter 5 and 7 months after the second procedure.

During the repeat ablation procedures, CFAEs were identified near ≥1 PVs in all patients and were ablated by ostial and/or antral applications of radiofrequency energy. There was recovery of conduction to ≥1 PVs in all patients. APVI was confirmed in all patients. Additional ablation of CFAEs was performed at the discretion of the operator. Including the repeat ablation procedures in the 100 randomized patients, 40 patients were treated by APVI alone, and 60 patients had additional ablation of CFAEs after APVI during the first, repeat, or both procedures.

Clinical outcome after repeat procedures

At a mean of 9 ± 4 months after the last ablation procedure, 15 of 19 patients (79%) in Group A, 34 of 50 patients (68%) in Group B, and 30 of 50 patients (60%) in Group C were in sinus rhythm without antiarrhythmic drug therapy (p = 0.40 for Group B vs. C).

Among the 19 patients in Group A, 4 (21%) remained in AF. Among the 16 patients in Group B who had recurrent atrial arrhythmias, 9 (18%) had persistent AF, 5 (10%) had paroxysmal AF, and 2 (4%) had atrial flutter. Among the 20 patients in Group C who had recurrent atrial arrhythmias, 12 (24%) had persistent AF, 2 (4%) had paroxysmal AF, and 6 (12%) had atrial flutter.

After 9 ± 4 months after the final procedure, among the 100 randomized patients, 27 of 40 patients (68%) who only underwent APVI and 36 of 60 patients (60%) who also had ablation of CFAEs after APVI during the first, repeat, or both procedures, were in sinus rhythm in the absence of antiarrhythmic drug therapy (p = 0.45). Among the 40 patients who only had APVI, 8 (20%) had persistent AF, 5 (12%) had paroxysmal AF, and none had recurrent atrial flutter; whereas among the 60 patients who also had ablation of CFAEs, 14 (23%) had persistent AF, 2 (3%) had paroxysmal AF, and 8 (13%) had atrial flutter (p = 0.02 for atrial flutter).

Complications

After 157 ablation procedures in 119 patients, 2 patients developed transient pericarditis and 1 patient had a small pericardial effusion without tamponade. There were 2 vascular complications, including a self-limited extraperitoneal bleed and a femoral arteriovenous fistula.

Main findings

This study demonstrates that up to 2 h of additional ablation of CFAEs outside of the antral regions in patients who remained in AF after APVI did not improve the clinical efficacy of APVI. Regardless of whether or not CFAEs were also targeted, APVI resulted in maintenance of sinus rhythm in the absence of antiarrhythmic drug therapy in ∼70% of patients with long-lasting persistent AF after 1 to 2 ablation procedures.

APVI

The mechanisms by which APVI exerts its beneficial effects may include: 1) elimination of PV tachycardias that initiate (9) and perpetuate AF (7,10); 2) exclusion of PV antrum, which has similar histoembryologic properties and arrhythmogenic activity to that of the PVs (11); 3) elimination of anchor points of high-frequency sources such as rotors (12–14); 4) ablation of ganglionated plexi and/or “AF nests” in the proximity of the PV antra (15–19); and 5) debulking of the left atrium by 25% to 30% so that a circuit can no longer accommodate a wavelength within the effective refractory period and conduction velocity of the left atrium (20,21).

Although termination of AF is infrequent during APVI, a majority of patients remain in sinus rhythm after 1 to 2 attempts at APVI. APVI may eliminate triggers/initiators or primary drivers of AF and may modulate the inducibility and sustainability of AF by altering autonomic innervation. Residual drivers beyond the PV antra may not be able to self-initiate or sustain after APVI (22). Because recovery of PV conduction is a common observation and may be equally likely in patients with and without recurrences (23,24) and because the number of completely isolated PVs does not necessarily predict clinical outcome (25), the efficacy of APVI clearly depends on more than elimination of PV arrhythmogenicity.

Because APVI has a modest clinical efficacy of ∼70% for persistent AF, it is clear that APVI does not eliminate all potential drivers of AF. On the other hand, ablation of CFAEs without completely isolating all PVs has been reported to terminate AF in some patients and eliminate AF in a majority of patients with paroxysmal and persistent AF (2,3,26). Termination of AF indicates effective elimination of most, if not all, drivers of AF and is associated with a more favorable outcome, as was the case in this study (7,27–29). Therefore, targeting CFAEs after APVI may be beneficial by eliminating drivers of AF not typically eliminated by APVI.

Targeting CFAEs to eliminate residual drivers of AF

Based on the commonly used criteria of electrogram fractionation, continuous electrical activity, or short cycle length, CFAEs are ubiquitous in the atria and coronary sinus, suggesting limited specificity (30). Prior studies suggested that CFAEs may indicate sites of slow conduction, collision, anchor points for reentrant circuits (31), wavebreak and fibrillatory conduction at the periphery of a rotor or an anatomical barrier such as the septopulmonary bundle (32,33), or sites of autonomic innervation (34). High-frequency electrograms have been suggested to indicate sites close to a rotor. However, in a prior study (30), <3% of all atrial sites demonstrated electrograms with a cycle length <120 ms, a widely used criterion for CFAEs. CFAEs may also represent passive depolarization due to anisotropy and summation of electrograms from overlapping layers of myocardium (35,36).

Atrial fibrillation terminated in ∼35% of patients during initial APVI in 16% and during additional ablation of CFAEs in 18% of the patients in this study. This conversion rate is lower than reported in 2 other studies (2,28). In a study by Nademanee et al. (2), 63% of 64 patients with chronic AF had termination of AF. In a study by Haïssaguerre et al. (28), which used a stepwise approach, AF terminated in 87% of 60 patients. In the first study (2), CFAEs in the right atrium were also targeted. However a prior study (29) demonstrated that additional ablation of CFAEs in the right atrium increased the conversion rate by only 3%. In the study of stepwise ablation (28), linear ablation along the roof and mitral isthmus had to be performed in >50% of patients to terminate AF and the end point of ablation was termination of AF using a variety of ablation strategies. However, in the present study, linear ablation was not performed, and the purpose of the study was to assess only the incremental value of CFAE ablation after APVI.

Study limitations

CFAEs were identified in the time domain by visual inspection. However, similar criteria have been widely accepted and used in prior studies (2). Furthermore, a recent study (37) that used automated electrographic analysis reported rates of termination and freedom from AF similar to those observed in this study.

A second limitation is that during repeat procedures CFAEs were targeted at the discretion of the operator without a randomization scheme. However, the clinical characteristics of both groups of patients were similar. Furthermore, the primary end point of the study was clinical efficacy after a single ablation procedure.

A third consideration is that CFAEs in the right atrium were not targeted in this study. However, a prior study (29) demonstrated that routine ablation of CFAEs in the right atrium was not incremental to left atrial ablation.