Canadian Journal of Cardiology

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(2015) 1e12

Systematic Review/Meta-analysis

Ablation of Complex Fractionated Atrial Electrograms for Atrial Fibrillation Rhythm Control: A Systematic Review and Meta-analysis Opeyemi Fadahunsi, MBBS, MPH,a Taiwo Talabi, MD, MPH,b Abiola Olowoyeye, MD, MPH,c Anthony Iluyomade, MD,d Oluwaseun Shogbesan, MD, MPH,a and Anthony Donato, MD, MHPEa,e a

Department of Medicine, Reading Health System, West Reading, Pennsylvania, USA b c

d e

Moffitt Cancer Center, Tampa, Florida, USA

Children’s Hospital Los Angeles, Los Angeles, California, USA St John’s Episcopal Hospital, Far Rockaway, New York, USA

Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, USA

ABSTRACT

  RESUM E

Background: Pulmonary vein isolation (PVI) has become an increasingly important therapy in the management of atrial fibrillation (AF), however, the best procedural techniques to ensure success have not been determined. We assessed the incremental benefit of complex fractionated atrial electrograms (CFAEs) ablation for AF rhythm control. Methods: PubMed, Embase, CENTRAL, and Clinicaltrials.gov databases were searched up until May 7, 2015. Included were randomized controlled trials that compared PVI with PVI and CFAEs ablation (PVIþ) with a minimum of 3 months’ follow-up. Statistical analysis was performed with Review Manager version 5.3 (Cochrane Collaboration, Oxford, United Kingdom). Categorical and continuous outcomes were reported as summary risk differences and mean differences (MDs), respectively. P < 0.05 was considered statistically significant for all analyses.

Introduction : L’isolation des veines pulmonaires (IVP) est devenue un traitement de plus en plus important dans la prise en charge de la fibrillation auriculaire (FA). Cependant, les meilleures techniques ussite n’ont pas e  te  de termine es. d’intervention pour favoriser la re value  l’avantage supple mentaire de l’ablation de la FA à Nous avons e lectrogrammes auriculaires complexes fractionne s (EACF) l’aide des e pour la maîtrise du rythme. thodes : Nous avions examine  les banques de donne es PubMed, Me Embase, CENTRAL et Clinicaltrials.gov jusqu’au 7 mai 2015. Nous y  des essais cliniques ale atoires comportant un suivi avions trouve  l’IVP à l’ablation EACF minimal de 3 mois qui avaient compare e à l’IVP (IVPþ). L’analyse statistique e tait re alise e à l’aide de combine la version 5.3 du Review Manager (Collaboration Cochrane, Oxford, sultats cate goriques et continus e taient rapporte s Royaume-Uni). Les re

Since the first description by Michel Haïssaguerre et al. in 1998,1 catheter ablation has now become a cornerstone for rhythm control in patients with atrial fibrillation (AF). Multiple randomized controlled trials (RCTs) have shown that catheter ablation is superior to antiarrhythmic agents for rhythm control.2,3 The most recent guidelines on management of AF from major societies, including the European Society of Cardiology (2012; class IIa recommendation, level

of evidence B),4 Canadian Cardiovascular Society (2014; conditional recommendation, moderate-quality evidence),5 and American Heart Association/American College of Cardiology/Heart Rhythm Society (2014; class IIa recommendation, level of evidence B)6 now recommend catheter ablation as a reasonable first option over antiarrhythmic agents for rhythm control in certain patients with recurrent symptomatic paroxysmal AF. With this expansion in indication for catheter ablation for AF, there will be an increased focus on the optimization of these procedures. Pulmonary vein isolation (PVI), often described as a ‘triggerbased’ approach, is the most commonly described technique for AF ablation. Ablation is focused on the fibrillary waves that originate around the entry of the pulmonary veins into the left atrium.1 Success of this procedure (defined as freedom from atrial tachyarrhythmias) is between 40% and 75%, leaving a

Received for publication May 24, 2015. Accepted July 10, 2015. Corresponding author: Dr Opeyemi Fadahunsi, Department of Medicine, Reading Health System, Sixth Ave and Spruce St, West Reading, PA 19611. Tel.: þ1-484-628-8255; fax: þ1-484-628-9003. E-mail: [email protected] See page 11 for disclosure information.

http://dx.doi.org/10.1016/j.cjca.2015.07.008 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

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Canadian Journal of Cardiology Volume - 2015

Results: Ten randomized controlled trials randomized patients to PVIþ (n ¼ 635) and PVI (n ¼ 427) with follow-up ranging from 3 to 23 months. There was no significant difference in freedom from atrial tachyarrhythmias without antiarrhythmic agents after a single ablation between PVIþ and PVI (313 of 635 vs 230 of 427; risk difference, 0.01 [95% confidence interval (CI)0.08 to 0.10]; P ¼ 0.78; I2 ¼ 52%). Findings were not different for any prespecified subgroup analyses, including paroxysmal vs nonparoxysmal AF, automated vs manual detection of CFAEs, and left atrial vs biatrial ablation. PVIþ led to significantly increased procedure time (MD, 49.81 minutes [95% CI 42.86-56.76]; P < 0.001), fluoroscopy time (MD, 11.55 minutes [95% CI 8.02-15.07]; P < 0.001), and radiofrequency energy application time (MD, 19.16 minutes [95% CI 6.61-31.70]; P ¼ 0.003) compared with PVI. Conclusions: Ablation of CFAEs in addition to PVI did not increase freedom from atrial tachyarrhythmias but procedural times were increased.

tant respectivement la synthèse des risques attribuables à comme e s et les diffe rences moyennes (DM). P < 0,05 e tait des facteurs donne re  statistiquement significatif pour toutes les analyses. conside sultats : Dans le cadre de 10 essais cliniques ale atoires qui comRe  te  re partis de portaient un suivi allant de 3 à 23 mois, les patients ont e atoire à l’IVPþ (n ¼ 635) et à l’IVP (n ¼ 427). Aucune manière ale rence significative n’a e  te  observe e dans l’absence de diffe tachyarythmie auriculaire sans antiarythmiques après une seule ablation entre l’IVPþ et l’IVP (313 de 635 vs 230 de 427; risque , 0,01 [intervalle de confiance (IC) à attribuable à un facteur donne sultats n’ont pas e  te  95 %, 0,08 à 0,10]; P ¼ 0,78; I2 ¼ 52 %). Les re rents dans toutes les analyses en sous-groupes pre spe cifie es, y diffe tection compris la FA paroxystique vs la FA non paroxystique, la de e vs manuelle des EACF, et l’ablation auriculaire gauche vs automatise  des dure es biauriculaire. L’IVPþ comparativement à l’IVP a entraîne d’intervention (DM, 49,81 minutes [IC à 95 %, 42,86-56,76]; P < 0,001), de fluoroscopie (DM, 11,55 minutes [IC à 95 %, 8,02nergie à radiofre quence 15,07]; P < 0,001) et d’application de l’e (DM, 19,16 minutes [IC à 95 %, 6,61-31,70]; P ¼ 0,003) significativement plus longues. e à l’IVP n’a pas augmente  Conclusions : L’ablation EACF combine  les dure es l’absence de tachyarythmie auriculaire, mais avait prolonge d’interventions.

substantial minority of patients with arrhythmia recurrence.7-9 This led to the addition of other ablation techniques (often characterized as ‘substrate-based’), such as linear ablation and the more popular ablation of complex fractionated atrial electrograms (CFAEs). CFAEs are areas within the atria that contain abnormal electrograms that are thought to degenerate into AF and can also maintain this abnormal rhythm.10 RCTs on these procedures have shown mixed results, with some showing modest improvement, and others have not.11,12 Because the CFAEs theory was the most widely studied, we sought to systematically review the evidence for its benefit. Since the last systematic review of RCTs on this topic,13 there have been 3 new RCTs published, suggesting that the body of evidence in this field has become more robust.14-16 Specific objectives were to: (1) assess the benefit of the combination of ablation of CFAEs with PVI in the management of AF; and (2) assess subgroups of automated vs manual detection of CFAEs and left atrial vs biatrial ablation of CFAEs.

criteria; discrepancies were adjudicated by a third reviewer (T.T.). Inclusion criteria included: (1) ablation performed for AF rhythm control; (2) RCTs that compared any form of PVI with the same procedure with the combination of CFAEs ablation (henceforth referred to as PVIþ)ddifferent PVI methods were allowed for inclusion as long as the same method was used for the control and intervention arms; (3) assessed freedom from atrial tachyarrhythmias as an outcome; and (4) follow-up of at least 3 months’ duration.

Methods A systematic review of the literature was performed according to the guidelines developed by the Cochrane Collaboration.17 Electronic databases of PubMed, Embase, CENTRAL, and Clinicaltrials.gov were searched. The search was performed from inception of catheter ablation for AF (January 1, 1998) until May 7, 2015. The search terms included “atrial fibrillation” AND “catheter ablation” AND “electrograms.” Studies were limited to RCTs, English language articles, and studies on humans. References from studies identified from the databases were also hand-searched for potential studies. Study selection Two reviewers (O.S. and O.F.) independently evaluated the titles, abstracts, and full articles. For an article to be included, both reviewers had to agree that it met the inclusion

Quality of studies Risk of bias in included studies was assessed independently by 2 authors (A.O. and A.I.) according to the method developed by the Cochrane Collaboration.17 Disagreements in bias assessments were resolved through consensus or by a third reviewer (O.F.). The following 6 domains were assessed: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting, and others. Because physicians who performed the ablation could not be blinded to the intervention, emphasis for this domain was placed on blinding of participants and outcome assessors. For each domain, bias could be low (plausible bias unlikely to seriously alter results), unclear (information not provided in study), and high (plausible bias that seriously weakens confidence in results). Outcomes The primary outcome assessed was freedom from atrial tachyarrhythmias without use of antiarrhythmic agents after a single ablation. Atrial tachyarrhythmias could include AF, atrial flutter, or other forms of atrial tachycardia. Secondary outcomes were freedom from atrial tachyarrhythmias with or without use of antiarrhythmic agents after multiple ablations, freedom from AF without use of antiarrhythmic agents after a single ablation, procedure time, fluoroscopy time, and

Fadahunsi et al. Ablation of CFAEs for AF Rhythm Control

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radiofrequency (RF) energy ablation time. Data on safety end points reported in the studies were collected and reported. Outcomes and safety end points were chosen based on recommendations from the 2012 Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society expert consensus statement on catheter and surgical ablation of AF.18 Statistical analysis One author (O.F.) independently abstracted data from all studies and these were verified for completeness and accuracy by a second author (A.O.). Subgroup analyses were prespecified for the following: (1) paroxysmal vs nonparoxysmal AF; (2) manual vs automated detection of CFAEs; and (3) ablation of left atrium vs both atria. Statistical analysis was performed using Review Manager version 5.3 (Cochrane Collaboration, Oxford, United Kingdom). For categorical outcomes, summary risk differences (RDs) and 95% confidence intervals (CIs) were estimated using the MantelHaenszel statistical method and a random effects model. RD is the difference between the event risk in the control group (PVI) and the treatment group (PVIþ). RD was chosen as the summary effect estimate because of its relevance and ease of interpretation for clinicians. For continuous outcomes, summary mean differences and 95% CIs were estimated using the inverse variance statistical method and a random effects model. c2 statistics was used to test for subgroup differences. The I2 statistic was calculated to evaluate the degree of heterogeneity among the trials as described by Higgins and Thompson.19 A P value of < 0.05 was considered statistically significant for all analyses. When heterogeneity was found, a sensitivity analysis sequentially excluding studies with different methodology was performed to identify any effect on the summary estimate. Furthermore, the risk ratio was estimated for the primary outcome to assess for any change in our initial findings. A funnel plot was used to visually assess publication bias. Results Characteristics of included studies and patients After an initial database search and exclusion of duplicates, we identified 117 unique articles for abstract screening. Of these, 25 full text eligible articles were reviewed. Fifteen studies were excluded and the reasons for exclusion are as noted in Figure 1. Ten studies met inclusion criteria for systematic and meta-analysis.11,12,14-16,20-24 Baseline characteristics of included studies are noted in Table 1. There were 5 studies on patients with paroxysmal AF,11,15,20,21,23 4 studies of nonparoxysmal AF,14,16,22,24 and 1 study of both types of AF.12 The treatment group intervention was ablation of CFAEs in addition to the control group intervention in all studies. The intervention in the control group in all studies was PVI (antral or circumferential). Five studies detected CFAEs using automation,12,14-16,20 and the other 5 studies did it manually,11,21-24 using the method defined by Nademanee et al.10 Ablation of CFAEs was restricted to the left atrium in 4 studies,14,20,23,24 and the other 6 studies ablated both atria.11,12,15,16,21,22

Figure 1. Flow diagram showing process of study selection.

Table 2 shows the baseline characteristics of patients in included studies. A total of 1062 patients were randomly assigned to PVIþ (n ¼ 635) and PVI (n ¼ 427). Quality of included studies and publication bias Risk of bias assessment is as shown in Supplemental Figures S1 and S2. Most of the included studies had low to unclear risk of bias. Visual inspection of the funnel plot did not reveal publication bias (Supplemental Fig. S3). Outcomes The primary outcome was freedom from atrial tachyarrhythmias without use of antiarrhythmic agents after a single ablation. After a single PVIþ ablation procedure, 313 of 635 patients were free from atrial tachyarrhythmias at follow-up compared with 230 of 427 patients for the PVI group as shown in Figure 2. This difference was not statistically significant (RD, 0.01; 95% CI, 0.08 to 0.10; P ¼ 0.78). There was evidence of moderate heterogeneity (I2 ¼ 52%; P ¼ 0.03). Subgroup analysis To examine the effect of additional ablation of CFAEs, we performed the following prespecified subgroup analyses. Paroxysmal vs nonparoxysmal AF. Subgroup analysis was performed for these 2 types of AF (see Fig. 3). One study was excluded because the patient population included paroxysmal and nonparoxysmal AF.12 There was no additional benefit for ablation of CFAEs in patients with paroxysmal AF (144 of 207 vs 126 of 181; RD, 0.01; 95% CI, 0.10 to 0.08; P ¼ 0.90) or nonparoxysmal AF (144 of 394 vs 90 of 214; RD, 0.02; 95% CI, 0.18 to 0.13; P ¼ 0.76). There was no significant interaction between study treatment and type of AF (P ¼ 0.84). Automated vs manual detection of CFAEs. Five of the 10 studies (published from 2010 onward) used automated

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Table 1. Characteristics of included randomized controlled studies

Follow-up (months)* 22.6  6.4

CFAE ablation sites LA, CS

Blanking out period (months) 3

AAD discontinuation after ablation (months) 3

Primary end point definition Freedom from ATA > 30 seconds at median of 22.6 months follow-up

Control CPVAI

PVI and CFAE

PVI

Manual

LA, RA, CS

24-Hour HM at 1 month, 7-day HM at 3 months, symptoms of ATA

1

0

PVAI and CFAE

PVAI

Manual

LA, RA, CS

Event recorder for 5 months with 4 recordings per week; 48-hour HM at 3, 6, 12, and 15 months

2

2

12

PVI and ablation of non-PV triggers and CFAE

PVI and ablation of non-PV triggers

Automated

LA

1.5

6

Non-PaAF

16

PVAI and CFAE

PVAI

Manual

LA, RA, CS

2

2

Freedom from AF and/or AT > 1 minute without AAD after a single procedure

PaAF

12

PVI and CFAE

PVI

Automated

LA, RA, CS

30-Day TTM (automated and patient-triggered) at 6 weeks, 6 months, 1 year, and during symptoms of arrhythmias Event recorder with 4 recordings per week when asymptomatic and symptomatic for the first 6 months; 48-hour HM at 3, 6, 9, 12, and 15 months 24-Hour HM before visit every 1-3 months; additional tele-ECG recordings when symptomatic

0.3

3

Recurrence of ATA > 30 seconds at 12 months

Study/setting Chen et al.20 Single-centre

AF type PaAF

Deisenhofer et al.11 Single-centre

PaAF

3

Di Biase et al.21 Multicentre

PaAF

13.7  2.2

Dixit et al.14 Single Centre

Non-PaAF

Elayi et al.22 Multicentre

Nuhrich et al.15 Single centre

End point determination ECG and 24-hour HM at 3 days, 1, 3, 6, and 12 months, and with symptoms

Freedom from ATA > 30 seconds with a 7-day HM in combination with freedom from symptomatic AF and/or AT 3 months after ablation Freedom from ATA with or without AADs that lasted > 1 minute at the 1 year followup Freedom from ATA without AAD at 1 year after a single ablation procedure

Inclusion criteria Age 18-80 years; 2 ECG documented AF episodes  7 days apart within the past 6 months; symptomatic AF refractory to  1 class I or III AAD Age 18-80 years; symptomatic paroxysmal AF with episodes lasting up to 7 days and with  4 AF episodes per month; failed therapy with  1 class I or III AAD History  1 year of paroxysmal AF; refractory to  2 AADs; and presented to the EP laboratory in spontaneous AF  30 Years; patients with drug-refractory AF who underwent their first ablation procedure for persistent or longlasting persistent AF Longstanding history of AF;  2 failed AADs; AF was permanent for > 1 year (1 cardioversion failed to restore SR for > 1 week with AAD during this period Failed AAD; AF sustained after PVI for > 10 minutes without reinducing Continued

Canadian Journal of Cardiology Volume - 2015

Intervention CPVAI and CFE

Electrogram detection Automated

Study/setting Oral et al.23 Single-centre

AF type PaAF

Follow-up (months)* 6

Oral et al.24 Single-centre

Non-PaAF

10  3

Verma et al.12 Multicentre

PaAF and non-PaAF

Verma et al.16 Multicentre

Non-PaAF

Electrogram detection Manual

CFAE ablation sites LA

Intervention LACA with ablation lines in posterior LA and MI with CFAE

Control LACA with ablation lines in posterior LA and MI

APVI and CFAE

APVI

Manual

LA, CS

12

PVI and CFE

PVI

Automated

LA, RA, CS

18

PVI and CFE

PVI

Automated

LA, RA, CS

End point determination NP contacted patients every 4 weeks and patients called NP whenever they had symptoms, in which case an event recorder was used Patients called with symptoms. Autotriggered event monitor for 6 months 12-Lead ECG and 48hour HM at 3, 6, and 12 months. External loop recorders (>2 weeks) and/or TTM to confirm rhythms for patient-reported symptoms Visit, ECG and 24hour HM at 3, 6, 9, 12, and 18 months; weekly TTM transmissions for 18 months and with symptoms

Blanking out period (months) 1.5

AAD discontinuation after ablation (months) 3

Primary end point definition Freedom from AF without AADs after single procedure

Inclusion criteria Symptomatic drugresistant paroxysmal AF in whom LACA had failed or in whom AF > 1 minute was inducible

NR

3

Freedom from ATA without AADs after single procedure

Patients with long-lasting persistent AF who remained in AF after APVI

3

2

Drug-refractory, highburden paroxysmal (episodes > 6 hours, > 4 hours in 6 months) or persistent AF

3

Continued as needed

Freedom from AF recurrence > 30 seconds from months 3 to 12 after ablation after 1 or 2 procedures with and without AAD Freedom from documented AF episode > 30 seconds after 1 procedure with or without AAD

Fadahunsi et al. Ablation of CFAEs for AF Rhythm Control

Table 1. Continued.

Symptomatic persistent AF (a sustained episode > 7 days and < 3 years) refractory to at least 1 AAD and to receive first-time ablation

AAD, antiarrhythmic drugs; AF, atrial fibrillation; APVI, antral pulmonary vein isolation; AT, atrial tachycardia; ATA, atrial tachyarrhythmias; CFAE, complex fractionated atrial electrogram; CFE, complex fractionated electrogram; CPVAI, circumferential pulmonary vein antral isolation; CS, coronary sinus; ECG, electrocardiogram; EP, electrophysiology; HM, Holter monitoring; LA, left atrium; LACA, left atrial radiofrequency circumferential ablation; MI, mitral isthmus; NP, nurse practitioner; NR, not reported; PaAF, paroxysmal atrial fibrillation; PV, pulmonary vein; PVAI, pulmonary vein antral isolation; PVI, pulmonary vein isolation; RA, right atrium; SR, sinus rhythm; TTM, transtelephonic monitoring. * Follow-up time refers to the total time until the primary outcome of this meta-analysis was reached.

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3.6 5 6 0.8* 6.4 1 6 6 6 6 3.9 4 5 3.3 2.5 NR 4 4 9.4 5.0 11.2 10 7.5 9 11.5 2 9 8 10 9 56.4 55 58.4 60 59.2 63 56 62 59 60 58 50 34 51 49 35 30 50 34 263

AF, atrial fibrillation; LA, left atria; LVEF, left ventricular ejection fraction; NR, not reported; PVI, pulmonary vein isolation; PVIþ, pulmonary vein isolation and ablation of complex fractionated atrial electrograms. * Left atria size provided in cm2.

PVI

66.2  4.1 NR 55  8 56  9 52  NR 67  1 59  4 53  12 62  7 55  11

PVIþ

         

4.2 6 6 0.7* 6.6 1 7 6 5 6 PVI

         

34.7 43 43 4.8 45.1 40 43 47 43 44

PVIþ

34.2 44 44 4.9 46.2 40 44 46 41 44          

3.5 3 5.7 5.4 3.5 NR 5 5 6.6 6.3

PVI

         

4.4 4 5.3 4.7 5.5 3 7 6 6.4 4.3 PVIþ

71 69 83 87 69 61 80 82 75 78 67 82 88 90 65 63 87 82 74 81

4.3 4 5.3 3.6 6.3 4 6 5 7.6 4.2

PVI PVIþ

         

13.2 10 8.1 8 10.3 2 11 10 11 10

PVI

          35 48 35 55 48 33 30 50 32 67

52.2 58 57 59 58.1 59 55 58 55 58

PVIþ PVI PVIþ Study

Chen et al.20 Deisenhofer et al.11 Di Biase et al.21 Dixit et al.14 Elayi et al.22 Nuhrich et al.15 Oral et al.23 Oral et al.24 Verma et al.12 Verma et al.16

LA diameter  SD, mm Duration of AF  SD, years Male sex, % Age  SD, years Patients, n

Table 2. Baseline characteristics of patients in included randomized controlled studies

64.5  3.3 NR 54.6  6 56  14 55  NR 68  1 58  7 54  9 59  12 57  10

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LVEF  SD, %

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detection of CFAEs (see Fig. 4).12,14-16,20 For the automated subgroup, there was no incremental benefit to ablation of CFAEs (183 of 422 vs 115 of 216; RD, 0.03; 95% CI, 0.17 to 0.11; P ¼ 0.67). Similarly, for the manual subgroup, no benefit was found for the combination of CFAE with PVI (130 of 213 vs 115 of 211; RD, 0.06; 95% CI, 0.03 to 0.15; P ¼ 0.19). There was no significant interaction between study treatment and method of CFAEs detection (P ¼ 0.29). Left atrial vs biatrial ablation. Six of the 10 studies carried out ablation in both atria,11,12,15,16,21,22 and the other studies ablated CFAE sites found only in the left atrium (see Fig. 5).14,20,23,24 There was no significant difference for both subgroup analyses: both atria (222 of 446 vs 142 of 257; RD, 0.06; 95% CI, 0.06 to 0.18; P ¼ 0.31) and left atrium only (91 of 189 vs 88 of 170; RD, 0.07; 95% CI, 0.18 to 0.05; P ¼ 0.25). There was no significant interaction between study treatment and site of ablation (P ¼ 0.12). Secondary outcomes: freedom from atrial tachyarrhythmias with or without use of antiarrhythmic agents after multiple ablations. Six studies including 730 patients reported on this outcome and randomized patients to PVIþ (n ¼ 460) and PVI (n ¼ 270).11,12,15,16,22,24 There was also no significant difference between PVIþ compared with PVI (RD, 0.05; 95% CI, 0.07 to 0.16; P ¼ 0.43; I2 ¼ 64%; see Supplemental Fig. S4). Freedom from AF without use of antiarrhythmic agents after a single ablation. Six studies including 692 patients reported on this outcome.12,15,16,20,23,24 There was also no significant difference between PVIþ compared with PVI (RD, 0.08; 95% CI, 0.03 to 0.19; P ¼ 0.15; I2 ¼ 53%; see Supplemental Fig. S5). Procedural outcomes. Seven studies had data on procedural duration (see Fig. 6).11,12,14-16,20,22 As expected, PVIþ increased mean procedural times compared with PVI (mean difference, 49.81 minutes; 95% CI, 42.86-56.76; P < 0.001). Eight studies reported on fluoroscopy times.11,12,14-16,20-22 Additional CFAE ablation increased mean fluoroscopy time by 11.55 minutes (95% CI, 8.02-15.07; P < 0.001). Four studies reported on RF energy application time.11,12,15,21 Additional CFAE ablation increased RF energy application time by a mean of 19.16 minutes (95% CI, 6.61-31.70; P ¼ 0.003). Safety end points Safety end points were inconsistently reported in the included studies. Therefore, we could not pool results in a meta-analysis. Three of the studies made no mention of complications in their report.15,21,23 There were few complications overall, however, the most commonly reported complications were vascular complications or bleeding (11 cases), pulmonary vein stenosis (5 cases), pericardial effusion (5 cases), cardiac perforation with tamponade (4 cases), and cerebrovascular events (4 cases). One death due to esophageal fistula was reported.

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Figure 2. Freedom from atrial tachyarrhythmias without antiarrhythmic agents after single ablation: overall. CI, confidence interval; M-H, MantelHaenszel; PVI, pulmonary vein isolation; PVIþ, pulmonary vein isolation and ablation of complex fractionated atrial electrograms.

Sensitivity analysis and heterogeneity There was moderate heterogeneity for the primary outcome analyzed (I2 ¼ 52%; P ¼ 0.03). We repeated analysis of the primary outcome using risk ratio as the effect estimate. This did not alter our findings or the magnitude of heterogeneity (see Supplemental Fig. S6). Sequential exclusion of each study did not alter the primary findings. Both Dixit et al. (ablation of nonpulmonary vein triggers according to institution protocol)14 and Oral et al. (ablation of lines in left atrium and mitral isthmus)23 used additional procedures beyond PVI or ablation of CFAEs. Because both procedures were performed in the intervention and control groups, we included them in the meta-analysis because we believed we could still assess the incremental benefit of ablation of CFAEs. When these 2 studies were excluded, our primary outcome remained unchanged. Restriction of meta-analysis to studies that involved first-time ablation did not alter our primary findings or affect heterogeneity.12,15,16,20-22 Included studies varied in their patient selection criteria. Four studies performed randomization after initial PVI, thus ensuring that the

final cohort included in their comparison were those who truly had spontaneous or inducible AF after PVI.15,20,23,24 Thus, every patient in the PVIþ group had PVI and ablation of CFAEs. Meta-analysis of our primary outcome including these 4 studies did not alter the original findings. However, the magnitude of heterogeneity was reduced (I2 ¼ 0%; P ¼ 0.66).

Discussion Main findings In this meta-analysis of 10 studies, we compared ablation of CFAEs with PVI vs isolated PVI and found no difference in the freedom from atrial tachyarrhythmias without use of antiarrhythmic agents after a single procedure at follow-up times ranging from 3 to 23 months. Similarly, there was no difference in the freedom from atrial tachyarrhythmias with or without use of antiarrhythmic agents after multiple ablations or freedom from AF without use of antiarrhythmic agents

Figure 3. Freedom from atrial tachyarrhythmias without antiarrhythmic agents after single ablation: according to type of atrial fibrillation. CI, confidence interval; M-H, Mantel-Haenszel; PVI, pulmonary vein isolation; PVIþ, pulmonary vein isolation and ablation of complex fractionated atrial electrograms.

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Figure 4. Freedom from atrial tachyarrhythmias without antiarrhythmic agents after single ablation: according to method of CFAE detection. CI, confidence interval; M-H, Mantel-Haenszel; PVI, pulmonary vein isolation; PVIþ, pulmonary vein isolation and ablation of complex fractionated atrial electrograms.

after a single ablation. We did not find any additional benefit of ablation of CFAEs in any of the subgroups examined, including paroxysmal vs persistent AF, automated vs manual detection of CFAEs, and left atrial vs biatrial ablation. PVIþ was associated with significantly increased procedural, fluoroscopy, and RF energy application times. See a summary of findings in Table 3. Comparison with published studies including metaanalyses Our finding that 54% of patients who underwent isolated PVI were free from atrial tachyarrhythmias is within the range

reported in the literature of 40%-75%.7-9 There was no incremental benefit for the combination of CFAEs ablation, as was also noted in 2 previously published systematic reviews.25,26 However, our findings did differ somewhat from those of other systematic reviews.13,27-29 Our study differed from Kong et al.,13 which was also a review of RCTs, in 2 major ways. First, we were able to add 4 new additional RCTs in our meta-analysis.14-16,20 Second, we differed in the approach used to abstract data from Elayi et al.,22 who randomly assigned patients to 3 groups: circumferential pulmonary vein ablation (group 1), pulmonary vein antrum isolation (PVAI; group 2), and ablation of CFAEs followed by PVAI (group 3). Kong et al. combined groups 1 and 2 to form

Figure 5. Freedom from atrial tachyarrhythmias without antiarrhythmic agents after single ablation: according to site of ablation. CI, confidence interval; M-H, Mantel-Haenszel; PVI, pulmonary vein isolation; PVIþ, pulmonary vein isolation and ablation of complex fractionated atrial electrograms.

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Figure 6. (A) Procedure time; (B) fluoroscopy time; and (C) radiofrequency (RF) energy application time. CI, confidence interval; IV, inverse variance; PVI, pulmonary vein isolation; PVIþ, pulmonary vein isolation and ablation of complex fractionated atrial electrograms.

their control group.13 However, we decided to use group 2 (PVAI) as our control group because the intervention group (group 3) also used PVAI, thus allowing us to assess the incremental benefit of ablation of CFAEs. Determining the incremental benefit of CFAEs was difficult to ascertain in the study by Kong et al. because the differences between groups might be as a result of the varying efficacies of circumferential pulmonary vein ablation and PVAI. The disparity in the primary end point success rate of isolated PVI in paroxysmal (70%) and nonparoxysmal (42%) AF is consistent with literature.7-9 Nonparoxysmal AF, which includes persistent AF and long-standing persistent AF (defined as persistent AF > 1 year),18 has consistently shown lower success rates after catheter ablation compared with paroxysmal AF. It has been suggested that with established arrhythmias, there are additional changes in the underlying atrial substrate that perpetuate AF as a consequence of the electrical and structural remodelling of the atria.30 Until 2010, most studies on ablation of CFAEs identified atrial electrograms through visual inspection, which can be subjective.31 Since 2010, when automated software became available, newer studies have used this capability. This is the first systematic review to our knowledge to assess subgroup analysis of automated vs manual detection of CFAEs. We did not find any significant difference to suggest a benefit for additional CFAEs ablation for either subgroup. There is not enough evidence to dismiss automated detection of CFAEs as

an improvement over manual detection, however, because these were secondary end points of our study and the trials did not directly compare them head to head. Hocini et al. studied 148 patients with persistent AF and noted that the right atrium is the primary AF driver in 20% of cases.32 Hence, we hypothesized that there would be a higher success rate in studies that used biatrial ablation compared with studies of solitary left atrial ablation. However, we did not find any difference in our subgroup analysis of groups addressing the right atrium. Our findings might be limited by the observation of moderate heterogeneity in this subgroup analysis. Strengths and limitations This study represents the largest pooled analysis of RCTs on this subject to our knowledge. We report herein on prespecified subgroup analyses not available in earlier systematic reviews and meta-analyses. In addition, we performed an exhaustive sensitivity analysis that did not alter our primary findings. Despite these strengths, there are limitations to this study. Published experience with ablation of CFAEs is currently modest, even when data are pooled; our sample size could have missed a small overall benefit of ablation. As with all summary data meta-analyses, lack of access to individual patient-level data limited our ability to investigate the effects of patient-level characteristics on our outcomes. The mean left ventricular ejection fraction for patients in the individual

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Canadian Journal of Cardiology Volume - 2015

Table 3. Summary of findings: ablation of CFAEs and PVI compared with PVI for atrial fibrillation rhythm control Outcomes Categorical outcomes Freedom from atrial tachyarrhythmias without antiarrhythmic agents after single ablation: overall AF type Nonparoxysmal AF Paroxysmal AF CFAE detection Automated Manual detection CFAE ablation site Both atria Left atrium Freedom from atrial tachyarrhythmias with or without antiarrhythmic agents after multiple ablations Freedom from atrial fibrillation without antiarrhythmic agents after single ablation Continuous outcomes Mean procedure time Mean fluoroscopy time Mean RF energy application time

RD/MD (95% CI)

RR (95% CI)

P value*

Number of participants (studies)

1.02 (0.87 to 1.18)

0.78

1062 (10)

PVIþ (n/N)

PVI (n/N)

313/635

230/427

0.01 (0.08 to 0.10)

144/394 144/207

90/214 126/181

0.02 (0.18 to 0.13) 0.01 (0.10 to 0.08)

0.93 (0.63-1.37) 0.99 (0.87-1.12)

183/422 130/213

115/216 115/211

0.03 (0.17 to 0.11) 0.06 (0.03 to 0.15)

0.93 (0.71-1.21) 1.08 (0.94-1.25)

222/446 91/189 291/460

142/257 88/170 183/270

0.06 (0.06 to 0.18) 0.07 (0.18 to 0.05) 0.05 (0.07 to 0.16)

246/451

138/241

0.08 (0.03 to 0.19)

NA NA NA

NA NA NA

49.81 (42.86-56.76) 11.55 (8.02-15.07) 19.16 (6.61-31.70)

1.09 (0.90-1.32) 0.89 (0.70-1.13) 1.06 (0.90-1.24)

0.84þ 0.76 0.90 0.29þ 0.67 0.19 0.12þ 0.31 0.25 0.43

703 (6) 359 (4) 730 (6)

1.12 (0.95-1.31)

0.15

692 (6)

12 months16,20,22 did not alter the results of the primary outcome. Second, ablation procedure specifics differed according to the protocols used in the different studies. Importantly, this procedure is demanding and technical, and there could have been differences in operator skill and experience between and within studies that we were unable to measure that might explain differences in outcome. Third, the method of arrhythmia identification at follow-up ranged from loop

recorder for weeks to Holter monitoring for 24 hours; differential measurement of outcomes might have influenced these results. Fourth, populations included in each study were quite different. In some studies, patients with sustained or inducible AF after PVI were randomized to placebo (ie, PVI) or CFAE ablation (ie, PVIþ).15,20,23,24 This implies that everyone randomized to the PVIþ group would receive the ablation of CFAEs. In contrast, other studies randomized patients before PVI ablation to PVI or PVIþ.11,12,14,16,21,22 Thus, not all patients randomized to the PVIþ group would receive CFAEs ablation because ablation of CFAEs would only happen if there was sustained or inducible AF, which might be absent after PVI. Therefore, the true effect of PVIþ might be underestimated in these latter studies. Fifth, AF is a heterogeneous disease. Studies on persistent AF were lumped together with long-standing persistent AF, which might require different substrate modifications. Clinical implications and future research The recent updates from the European (2012), Canadian (2014), and American (2014) guidelines for the management of patients with AF are likely to increase the continued uptake of catheter ablation for AF.4-6 These guidelines do not specify the type of ablation procedure other than it has to be performed by an experienced electrophysiologist. Ablation of CFAEs has been studied extensively with modest to no improvement. We found no benefit in this systematic review and meta-analysis. However, additional CFAEs ablation significantly increased procedural, fluoroscopy, and RF energy application times. Safety end points were not reported in

Fadahunsi et al. Ablation of CFAEs for AF Rhythm Control

detail in included studies which limits any comment on the adverse events profile of additional CFAEs ablation. Linear ablation is an alternative substrate modification approach that involves the creation of linear lesions most commonly in the left atrial roof and mitral isthmus. This approach has not been promising as recently demonstrated by the Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF) II trial.16 Some other studies have investigated the benefit of a stepwise approach that combines multiple ablation strategies including PVI, CFAEs ablation, and linear ablation.33 Outcomes after single procedures are not promising, but success rates after repeat ablation procedures are encouraging. Recently, exploration of other substrate modifier techniques that individualize patient-tailored ablation procedures has commenced. Narayan et al. proposed ablation of focal sources or ‘rotor’ and findings from nonrandomized prospective studies are promising.34 Haïssaguerre et al., using noninvasive signal processing, have proposed driver domains to be the substrate for persistent AF.35 Similarly, Kottkamp et al. described patient-specific ablation strategies that included electroanatomic voltage mapping and box isolation of fibrotic areas and noninvasive methods for localizing atrial fibrosis using delayed enhancement magnetic resonance imaging.36 Conclusions Additional ablation of CFAEs with PVI did not improve the maintenance of sinus rhythm after single or multiple ablation procedures. This was associated with increased procedural, fluoroscopy, and RF energy application times. Further multicentre randomized studies are needed that recruit a large homogenous population with longer follow-up and detailed reporting of safety end points to provide additional evidence on the role of ablation of CFAEs in AF rhythm control. Acknowledgements The authors deeply appreciate Valerie Schaeffer, Reading Hospital Library Assistant, for her help in retrieving some of the articles. We are indebted to Megan McCreary for her attention to details in the reviewing of many iterations of the report. Disclosures The authors have no conflicts of interest to disclose. References 1. Haïssaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659-66. 2. Mont L, Bisbal F, Hernandez-Madrid A, et al. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study). Eur Heart J 2014;35: 501-7. 3. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. JAMA 2014;311:692-700.

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4. Camm AJ, Lip GY, De CR, et al. 2012 Focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47. 5. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1-76. 6. Verma A, Cairns JA, Mitchell LB, et al. 2014 Focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation. Can J Cardiol 2014;30:1114-30. 7. Bertaglia E, Tondo C, De SA, et al. Does catheter ablation cure atrial fibrillation? Single-procedure outcome of drug-refractory atrial fibrillation ablation: a 6-year multicentre experience. Europace 2010;12:181-7. 8. Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006;354:934-41. 9. Tilz RR, Rillig A, Thum AM, et al. Catheter ablation of long-standing persistent atrial fibrillation: 5-year outcomes of the Hamburg Sequential Ablation Strategy. J Am Coll Cardiol 2012;60:1921-9. 10. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044-53. 11. Deisenhofer I, Estner H, Reents T, et al. Does electrogram guided substrate ablation add to the success of pulmonary vein isolation in patients with paroxysmal atrial fibrillation? A prospective, randomized study. J Cardiovasc Electrophysiol 2009;20:514-21. 12. Verma A, Mantovan R, Macle L, et al. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial. Eur Heart J 2010;31:1344-56. 13. Kong MH, Piccini JP, Bahnson TD. Efficacy of adjunctive ablation of complex fractionated atrial electrograms and pulmonary vein isolation for the treatment of atrial fibrillation: a meta-analysis of randomized controlled trials. Europace 2011;13:193-204. 14. Dixit S, Marchlinski FE, Lin D, et al. Randomized ablation strategies for the treatment of persistent atrial fibrillation: RASTA study. Circ Arrhythm Electrophysiol 2012;5:287-94. 15. Nuhrich JM, Steven D, Berner I, et al. Impact of biatrial defragmentation in patients with paroxysmal atrial fibrillation: results from a randomized prospective study. Heart Rhythm 2014;11:1536-42. 16. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812-22. 17. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. 2011. The Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org. Accessed June 6, 2014. 18. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart

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28. Li WJ, Bai YY, Zhang HY, et al. Additional ablation of complex fractionated atrial electrograms after pulmonary vein isolation in patients with atrial fibrillation: a meta-analysis. Circ Arrhythm Electrophysiol 2011;4:143-8.

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29. Wu SH, Jiang WF, Gu J, et al. Benefits and risks of additional ablation of complex fractionated atrial electrograms for patients with atrial fibrillation: a systematic review and meta-analysis. Int J Cardiol 2013;169:35-43.

20. Chen M, Yang B, Chen H, et al. Randomized comparison between pulmonary vein antral isolation versus complex fractionated electrogram ablation for paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:973-81. 21. Di Biase L, Elayi CS, Fahmy TS, et al. Atrial fibrillation ablation strategies for paroxysmal patients: randomized comparison between different techniques. Circ Arrhythm Electrophysiol 2009;2:113-9. 22. Elayi CS, Verma A, Di BL, et al. Ablation for longstanding permanent atrial fibrillation: results from a randomized study comparing three different strategies. Heart Rhythm 2008;5:1658-64. 23. Oral H, Chugh A, Lemola K, et al. Noninducibility of atrial fibrillation as an end point of left atrial circumferential ablation for paroxysmal atrial fibrillation: a randomized study. Circulation 2004;110:2797-801. 24. Oral H, Chugh A, Yoshida K, et al. 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. J Am Coll Cardiol 2009;53:782-9. 25. Assasi N, Xie F, Blackhouse G, et al. Comparative effectiveness of catheter ablation strategies for rhythm control in patients with atrial fibrillation: a meta-analysis. J Interv Card Electrophysiol 2012;35:259-75. 26. Wynn GJ, DAS M, Bonnett LJ, et al. Efficacy of catheter ablation for persistent atrial fibrillation: a systematic review and meta-analysis of evidence from randomized and nonrandomized controlled trials. Circ Arrhythm Electrophysiol 2014;7:841-52. 27. Hayward RM, Upadhyay GA, Mela T, et al. Pulmonary vein isolation with complex fractionated atrial electrogram ablation for paroxysmal and nonparoxysmal atrial fibrillation: a meta-analysis. Heart Rhythm 2011;8: 994-1000.

30. Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol 2008;1:62-73. 31. El HM, Houben R, Berte B, et al. Bipolar electrograms characteristics at the left atrial-pulmonary vein junction: toward a new algorithm for automated verification of pulmonary vein isolation. Heart Rhythm 2015;12:21-31. 32. Hocini M, Nault I, Wright M, et al. Disparate evolution of right and left atrial rate during ablation of long-lasting persistent atrial fibrillation. J Am Coll Cardiol 2010;55:1007-16. 33. Scherr D, Khairy P, Miyazaki S, et al. Five-year outcome of catheter ablation of persistent atrial fibrillation using termination of atrial fibrillation as a procedural endpoint. Circ Arrhythm Electrophysiol 2015;8:18-24. 34. Narayan SM, Baykaner T, Clopton P, et al. Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared with trigger ablation alone: extended follow-up of the CONFIRM trial (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation). J Am Coll Cardiol 2014;63:1761-8. 35. Haïssaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130:530-8. 36. Kottkamp H, Bender R, Berg J. Catheter ablation of atrial fibrillation: how to modify the substrate? J Am Coll Cardiol 2015;65:196-206.

Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2015.09.002.

Ablation of Complex Fractionated Atrial Electrograms for Atrial Fibrillation Rhythm Control: A Systematic Review and Meta-analysis.

Pulmonary vein isolation (PVI) has become an increasingly important therapy in the management of atrial fibrillation (AF), however, the best procedura...
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