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Clinical Electrophysiology

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Dr. David J. Wilber.

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Incidence of Atrial FibrillationAfter Atrial Flutter Ablation

Waddah Maskoun, MD,a,b Maria Isabel Pino, MD,c Karam Ayoub, MD,c Oscar L. Llanos, MD,c Ahmed Almomani, MD,a

Ramez Nairooz, MD,a Abdul Hakeem, MD,a,b John Miller, MDd

ABSTRACT

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OBJECTIVES This study was conceived to perform a comprehensive systematic review and meta-analysis of the

available evidence to compute the incidence of atrial fibrillation (AF) after successful atrial flutter (AFL) catheter ablation,

defined by targeting for bidirectional block, using different types of follow-up modalities and durations.

BACKGROUND Cavotricuspid-isthmus dependent AFL is usually initiated by short bursts of AF. The incidence of AF

after AFL ablation is variable. We evaluated the variation in the reported incidence of AF depending on the type and

duration of follow-up, and AF incidence in patients with prior AF versus no prior AF.

METHODS A systematic review and meta-analysis of published studies between January 1996 and April 2015 and ab-

stracts in the last 2 years describing patients who underwent AFL ablation and the subsequent incidence of AF was

performed.

RESULTS Forty-eight studies were included (n ¼ 8,257, ablation success rate: 96%, 79% male). Incidence of new-onset

AF correlated with follow-up duration (29% for a weighted mean follow-up duration of 30 months). New-onset AF

incidence with <2 years follow-up was 12.4% among group 1 (electrocardiogram and symptoms-driven evaluation,

n ¼ 759), 19% for group 2 (outpatient Holter monitoring for 1 day to 7 days/year, n ¼ 315), and 45% for group 3

(>7 days/year Holter monitoring or by implanted cardiac devices, n ¼ 178). Mean follow-up duration was 15.3 months,

18.5 months, and 16.3 months, respectively. In patients with and without prior AF, the incidence for AF after AFL ablation

was 35.3% during mean follow-up duration of 29.7 months. In studies with <2 years follow-up duration, AF incidence

was 54% in patients with prior AF versus 13.9% without prior AF (odds ratio: 7.43, 95% confidence interval: 4.96 to 11.11;

p < 0.00001). In studies with >2 years follow-up duration, AF incidence was 51.3% in patients with prior AF versus

26.2% without prior AF (odds ratio: 2.93, 95% confidence interval: 2.42 to 3.56; p < 0.00001).

CONCLUSIONS The incidence of AF after AFL ablation is high especially in patients with prior AF when compared to

those without prior AF. The detection of AF in patients without prior AF significantly increases with more frequent

monitoring and/or longer follow-up duration. (J Am Coll Cardiol EP 2016;2:682–90) © 2016 by the American College of

Cardiology Foundation.

A trial fibrillation (AF) is the most commoncardiac arrhythmia, and its association withsystemic thromboembolism is well estab-

lished (1,2). Right atrial cavotricuspid isthmus (CTI)dependent atrial flutter (AFL) and AF are frequentlyseen in the same patient in clinical practice. This

m the aDivision of Cardiology, University of Arkansas for Medical Scien

ntral Arkansas Veterans Healthcare System, Little Rock, Arkansas; cDepartm

dical Sciences, Little Rock, Arkansas; and the dDivision of Cardiology, In

iana. Dr. Miller has received fellow training grants from Medtronic, Bos

ria from Medtronic, Boston Scientific, Biosense-Webster, St. Jude Medica

mpensation) for Topera. All other authors have reported that they have no

close.

nuscript received January 29, 2016; revised manuscript received March 8

association generally reflects a similar arrhythmo-genic substrate. AFL is almost always initiated by var-iable length bursts of AF (3,4).

Because of the well-defined anatomic substrate ofAFL and the disappointing efficacy of antiarrhythmicdrug therapy in treating AFL, catheter ablation of the

ces, Little Rock, Arkansas; bDivision of Cardiology,

ent of Internal Medicine, University of Arkansas for

diana University School of Medicine, Indianapolis,

ton Scientific, and Biosense-Webster; speaking hon-

l, and Biotronik; and is a scientific advisor (without

relationships relevant to the contents of this paper to

, 2016, accepted March 31, 2016.

AB BR E V I A T I O N S

AND ACRONYM S

AF = atrial fibrillation

AFL = atrial flutter

CI = confidence interval

CTI = cavotricuspid isthmus

ECG = electrocardiogram

OR = odds ratio

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683

CTI is a common procedure. Catheter ablation of theCTI is successful in the long-term for approximately91% of patients with AFL if bidirectional CTI blockwas achieved, and 76% if bidirectional block was notachieved (5,6). Bidirectional block is considered thestandard for successful AFL ablation in currentpractice. However, long-term freedom from atrialarrhythmias after CTI AFL ablation may be compro-mised by the occurrence of AF. The reported inci-dence rate of AF after AFL ablation is variable (3).Some have suggested that AF could possibly beinitiated by AFL itself (3); whereas others have shownthat successful ablation of lone AFL might notimprove the natural history of AF progression bycomparing patients with lone AFL who did and didnot have ablation (7).

We performed a comprehensive systematic reviewand meta-analysis of the available evidence tocompute the true incidence of AF after successful AFLcatheter ablation, defined by targeting for bidirec-tional block, using different types of follow-upmodalities and durations.

METHODS

DATA SOURCES AND SEARCH STRATEGY. Wesearched online databases including PubMed,Cochrane CENTRAL, EMBASE, Web of Science, andCINAHL databases for English language studies pub-lished between January 1996 (when bidirectionalblock started to become the standard for successfulAFL ablation) and April 2015 describing patients whounderwent typical AFL catheter ablation with andwithout prior AF. We used the following keywords:“atrial fibrillation,” “atrial flutter,” “ablation,” “bidi-rectional block,” and “recurrence.” Three reviewers(W.M., M.P., and O.L.) identified studies that met thefollowing inclusion criteria: 1) clinical studies pub-lished in the English language; 2) either full-lengtharticle or conference abstract (only from the last 2years); 3) adult patients who underwent typical AFLablation only (no pulmonary vein isolation) and tar-geting for bidirectional block; 4) length of follow-upwas at least 30 days; 5) the presence or absence ofAF before AFL ablation was well documented; and 6)reporting occurrence of AF lasting >30 s (if theduration was mentioned in the study) after AFLablation.

Studies were excluded if they met any of thefollowing criteria: 1) if patients other than typicalAFL were included; 2) if bidirectional block was notthe target for successful ablation; 3) if follow-upduration was not documented; 4) if all the patients

in the study had AF; or 5) if there wereduplicate published data. In addition, wemanually searched clinical trial databases,reviews, meta-analyses, and reference listsof all retrieved reports for potential relevantstudies not found in our initial electronicdatabase search.

STUDY SELECTION, ENDPOINTS, AND

DEFINITIONS. We used the MOOSE (Meta-

analysis of Observational Studies in Epidemiology)checklist to select studies for this review (8). We alsofollowed the PRISMA (Preferred Reporting Items forSystematic reviews and Meta-Analyses) guidelines forreporting systematic reviews and meta-analyses(9,10). Objective assessment of the trials was per-formed using the method specified in the CochraneHandbook of Systematic Reviews and the Newcastle–Ottawa scale for case control studies (11,12). Primaryoutcome of interest was incidence of AF after AFLablation detected by electrocardiogram (ECG), Holtermonitor, loop recorder, or implantable recorder. Weperformed meta-analysis for the incidence of AF afterAFL ablation in patients with and without prior AF,we also evaluated AF incidence in patients who hadAFL ablation and no prior AF based on duration offollow-up and who were followed up by ECGs, clinicvisits, symptom-driven evaluation, and routine Hol-ter monitoring for #7 days per year. We also evalu-ated AF rates in studies with <2 years follow-up basedon type of follow-up by categorizing them into 3groups: group 1 included ECG, clinical follow-up, andsymptom-driven evaluation; group 2 additionallyincluded scheduled 24-hour outpatient Holter moni-toring for #7 days per year regardless of symptoms;and group 3 included scheduled >7 days outpatientHolter monitoring per year or patients with implantedcardiac devices. We also evaluated possible risk fac-tors of AF development after AFL ablation in patientswith no prior AF.

STATISTICAL ANALYSIS. Outcomes are reported asodds ratio (OR) and their respective 95% confidenceintervals (CIs) for each study and for the meta-analysis of all studies. We assessed heterogeneityusing the Cochran Q test and the Higgins I2 test.A Cochran’s Q p value <0.10 and I2 >50% wereconsidered to demonstrate heterogeneity in thismeta-analysis. Random effects model described byDer-Simonian and Laird was used for the main anal-ysis (13). Statistical analysis was performed withReview Manager (RevMan, Cochrane Collaboration,version 5.2). Results were considered statisticallysignificant at p < 0.05. A p value for interaction was

Maskoun et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 2 , N O . 6 , 2 0 1 6

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examined among subgroups and considered signifi-cant if 0.10 or less.

RESULTS

Forty-eight studies with 8,257 patients undergoingAFL ablation met the predefined selection criteria(Figure 1). The average weighted age was 62.7 � 12.4years, and 78.7% were male (Table 1). Several studies

FIGURE 1 Study Selection

Flowchart depicts the selection of studies for inclusion in the meta-ana

studies without translation, non-human studies, guidelines, pediatric stu

did not include patients with failed AFL ablationsand some studies excluded those (n ¼ 100) from thefollow-up but included them in the patients’ char-acteristics. Bidirectional CTI block was achieved in96% of the followed patients. Patients with recurrentAFL had repeat AFL ablation in the vast majority ofthe studies. Forty-six studies used radiofrequencyablation and 2 studies used cryoablation (14,15).Only 60 patients had AF ablation in addition to

lysis. *Other: Meta-analyses, systematic reviews, foreign language

dies.

TABLE 1 Baseline Characteristics in Included Studies

No. ofStudies n or n/N (%) Mean � SD

Age (yrs) 47 8,215 62.7 � 12. 4

Males 47 6,475/8,215 (78.8%) —

Hypertension 30 2,413/5,853 (41.2%) —

Diabetes mellitus 20 818/5,057 (16.2%) —

Heart failure 22 1,165/4,377 (26.6%) —

Antiarrhythmic drugs 21 1,284/2,407 (53.3%) —

Structural/valvular heart disease 31 2,274/4,937 (46%) —

EF (%) 27 4,773 52 � 14.3

LA diameter (mm) 25 3,895 42 � 7.2

Follow-up (months) 48 8,157 29.7 � 26.5

EF ¼ ejection fraction; LA ¼ left atrium.

TABLE 2 Demographics of AFL Patients With and Without Prior AF in

the 35 Studies

No. ofStudies n or n/N (%) Mean � SD or %

Age (yrs) 34 6,577 62.9 � 16

Males 34 5,133/6,577 (78%) 78%

Hypertension 19 1,892/4,924 (38.4%) 38.4%

Diabetes mellitus 12 657/4,238 (15.5%) 15.5%

Heart failure 16 936/3,458 (27.1%) 27.1%

Antiarrhythmic drugs 14 1,065/1,898 (56.1%) 56.1%

Structural/valvular heart disease 25 2,081/4,195 (49.6%) 49.6%

EF 18 3,637 52 � 14.8

LA diameter (mm) 16 2,790 41.8 � 6.9

Follow-up (months) 35 6,519 29.7 � 28.3

AF ¼ atrial fibrillation; AFL ¼ atrial flutter; other abbreviations as in Table 1.

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AFL ablation for a history of AF (5). The papers werebased on 28 prospective observational studies(14–41), 5 randomized trials (42–46), and 14 retro-spective studies (5,7,47–58). Only 1 abstract (a retro-spective study [59]) was included. Most papersdescribed prior AF as paroxysmal or persistent.Excluding prior AF, when described in the studies,was done by reviewing prior ECGs, Holter monitor,and prior medical records. Most papers used parox-ysmal, persistent, or permanent for the definition ofthe AF occurrence after AFL ablation. Most papersused >30 s of AF duration on Holter monitor orimplanted cardiac devices when they listed theduration.

AF INCIDENCE RATE BASED ON HISTORY OF AF AND

DURATION OF FOLLOW-UP. Thirty-five studies re-ported AF incidence after AFL ablation in patientswith prior AF (n ¼ 2,743; 42%) versus no prior AF(n ¼ 3,776; 58%). Mean age was 62.9 � 16 years and78% were male (Table 2). None of these 35 studies hadintense monitoring after AFL ablation (i.e., >7 daysroutine scheduled outpatient Holter monitor regard-less of symptoms). Meta-analysis for AF rate after AFLablation is shown in Figure 2.

The overall incidence of AF after ablation was35.3% during mean weighted follow-up duration of29.7 months. AF incidence after AFL ablation was23.2% in patients with no prior AF and 52.1% in thosewith prior AF (OR: 4.05; 95% CI: 3.24 to 5.07;p < 0.00001). Subgroup analysis based on duration offollow-up showed a significant variation of thisprobability (p < 0.0001) between the group with <2years follow-up compared to >2 years follow-up. Thedifference was due to an increase of AF incidence ratein patients with no prior AF (Figure 3). In studieswith <2 years follow up, AF weighted average inci-dence after AFL ablation was 54% in patients withprior AF and 13.9% in those with no prior AF (OR:7.43; 95% CI: 4.96 to 11.11; p < 0.00001). In studieswith >2 years follow-up, post-ablation AF developedin 51.3% of those with prior AF and in 26.2% of thosewith no prior AF (OR: 2.93; 95% CI: 2.42 to 3.56;p < 0.00001).

AF INCIDENCE RATE AFTER AFL ABLATION WITH

NO PRIOR AF BASED ON DURATION OF FOLLOW-UP

AND TYPE OF FOLLOW-UP. The correlation betweenthe AF incidence rates and duration of follow-upafter AFL ablation in patients with no priorAF was evaluated in 44 studies (n ¼ 5,185) asshown in the bubble regression plot (Figure 4). Fourstudies (31,42,44,46) and 54 patients in anotherstudy (57) were excluded because monitoring was

more than the routine 7 days outpatient Holtermonitor per year. The incidence of new-onsetAF was 28.8% at a weighted mean follow-up of30.4 months.

The incidence rate of AF after AFL ablation inpatients with no prior AF and <2 years follow-up wassignificantly different among the 3 groups based ontype of follow-up (Figure 5). The incidence rate was12.4% in group 1 (n ¼ 759) (15,16,21,23,27–29,34–37,39,45,54,58), 19% in group 2 (n ¼ 315) (19,33,41,43,52), and 45% in group 3 (n ¼ 178, 66 of themhad implanted loop recorder) (31,42,44,46). Meanfollow-up duration was 15.3 months, 18.5 months,and 16.3 months, respectively.

Eight studies provided patient characteristics forthose with no history of AF who developed AF andthose who did not develop AF after AFL ablation(Table 3). Structural heart disease and larger left atrialdiameter were more common in the patients whodeveloped AF.

FIGURE 2 Meta-Analysis

Meta-analysis of the atrial fibrillation (AF) incidence rate after atrial flutter (AFL) ablation in patients with history of (H/o) AF versus no prior AF

and the effects of the duration of the follow-up was evaluated by sub-group analysis for studies with <2 years of follow-up versus >2 years of

follow-up (studies reported as first author and year of publication). CI ¼ confidence interval; M-H ¼ Metropolis-Hastings algorithm.

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DISCUSSION

The main finding of the study is that the AF inci-dence rate after successful AFL ablation (bidirec-tional CTI block) in patients with no prior AF is veryhigh. This should be taken into consideration whenmanaging patients with AFL. A prior meta-analysisby Perez et al. (6) on the outcome of AFL ablationhad 2 limitations: the short follow-up duration for

most studies and no intensive monitoring done. Weonly included studies with bidirectional CTI blockto minimize the possibility that the AF duringfollow-up was initiated by recurrent AFL (3). TheAFL incidence rate was higher in patients who hadAFL ablation and bidirectional block was notachieved (6). We added 21 new studies that werepublished since prior meta-analysis (62.5% of thetotal patients in our study were new patients).

FIGURE 4 Bubble Regression Plot

The bubble regression plot for the AF incidence rates after AFL ablation in patients with no

prior AF. Abbreviations as in Figure 2.

FIGURE 3 AF Incidence Rate

AF incidence rate after AFL ablation in patients with and without prior history of (Hx) AF

and the effect of the duration of follow-up. Abbreviations as in Figure 2.

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Our study is the first to perform a forest plot andcalculate Mantel-Hanzel OR for comparison of AFoccurrence after AFL ablation targeting bidirectionalblock in those with and those without history of AFand subdivided studies according to time of follow-up. To our knowledge, this is the first meta-analysisto clearly demonstrate the impact of the follow-upduration and the type of monitoring during follow-up on the incidence of AF after AFL ablation withconfirmed bidirectional block. We clearly showedthat this resulted in significant variation of the AFoccurrence rate among the studies. The higherincidence rate of AF after AFL ablation with longerfollow-up could have been due to the onset of newAF, the increase of frequency or duration of the AFepisodes, or any combination.

Current guidelines recommend anticoagulation todecrease the risk of stroke with no difference be-tween AFL and AF patients (60). However, theguidelines do not clearly address the anticoagulationplan or type of arrhythmia monitoring after success-ful AFL ablation in patients with no documentedprior AF. The ASSERT (Asymptomatic Atrial Fibrilla-tion and Stroke Evaluation in Pacemaker Patients andthe Atrial Fibrillation Reduction Atrial Pacing Trial)showed that subclinical atrial tachyarrhythmiasdetected on pacemakers and implanted defibrillatorswere associated with a 2.5-fold increased risk forischemic stroke in patients without a history of AF(61). Stroke events in patients with AFL could be dueto coexisting AF (62). Stroke rates were higher inpatients who developed AF after AFL ablation (55,56).Clementy et al. (5) showed that stroke rate after AFLablation was similar among the patients who hadprior AF and no prior AF after AFL ablation. Ourstudy findings demonstrate that the patients’CHADS2VASc score after successful AFL ablation andno prior AF should be used to determine whether thepatient should be placed on long-term anti-coagulation. Our recommendations are based on thevery high incidence of AF after AFL ablation. In somestudies with long-term follow-up, the AF incidencerates were very high (62% and 82%) (32,50) after AFLablation in patients with no prior AF. The data in ourstudy was not sufficient to analyze the risk of strokeevents after AFL ablation in patients with andwithout prior AF.

Voight et al. (57) showed that AF detection ratewas higher after AFL ablation in patients with noprior AF who had cardiac implantable electronic de-vices. Our meta-analysis results are consistent withthis and suggest that if monitoring for documentedAF is indicated before starting anticoagulation, forpatients with high HAS-BLED (Hypertension,

Abnormal renal and liver function, Stroke, Bleeding,Labile INRs, Elderly, Drugs or alcohol) scores forinstance (63), then intense monitoring with animplanted loop recorder might need to be consid-ered. This is because of the significant difference inthe detection rate of AF with different types andduration of monitoring. Patients with a large leftatrium or those who have structural/valvular heartdisease might have increased incidence of AF after

FIGURE 5 AF Incidence Rate

AF incidence rate after AFL ablation (in patients with no prior AF) and <2 years follow-up

with different type of monitoring. (A) Shows symptom driven versus routine monitoring.

(B) Shows routine monitoring versus intensive monitoring. OR ¼ odds ratio; other

abbreviations as in Figure 2.

TABLE 3 DemographVersus Those Who Di

Age (yrs)

Males

Hypertension

Diabetes mellitus

Heart failure

Antiarrhythmic drugs

Structural/valvularheart disease

EF (%)

LA diameter (mm)

Values are mean � SD or n

CI ¼ confidence interval

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AFL ablation, which might be helpful with regard tothe anticoagulation decision in patients with, forexample, high HAS-BLED scores.

Another important point in our study is that pa-tients with prior AF should have AF ablation at thetime of AFL ablation as a standard of care due to thehigh incidence rate of AF rate (52% without intensemonitoring in our study) after AFL ablation. Studiesshowed that early AF ablation improved the proce-dure success rates (64,65). Exceptions for this

ic Comparison of Patients Who Developed AF After AFL Ablationd Not (Among Those With No Prior AF)

No AF AfterAFL Ablation

AF After AFLAblation p Value OR (95% CI)

65.5 � 11.6 65.9 � 10.5 0.55 —

608/712 (85.4%) 510/610 (83.6%) 0.96 —

488/734 (66.5%) 486/623 (78.0%) 0.05 0.74 (0.54 to 1.00)

161/515 (31.3%) 52/198 (26.3%) 0.44 —

133/614 (21.7%) 82/259 (31.7%) 0.09 —

94/577 (16.3%) 54/216 (25.0%) 0.06 —

133/680 (19.6%) 181/556 (32.6%) 0.008 0.64 (0.47 to 0.89)

51.1 � 13.3 50.2 � 10.7 0.88 —

41.7 � 7.6 44.1 � 7.4 0.02 �2.63 (�4.90 to �0.37)

/N (%), unless otherwise indicated.

; OR ¼ odds ratio; other abbreviations as in Tables 1 and 2.

concomitant ablation will be: high-risk patients, ifcontraindication for AF ablation was present, if AFLablation was mainly performed because of difficultyof rate control during AFL only but not AF, or if thepatient has a preference to undergo AFL ablation onlyand to begin or continue antiarrhythmic medicationsfor the AF.

Some randomized studies have shown a decreasein the AF incidence rate or burden after AF ablationat time of the AFL ablation in patients with no priorAF (42,44,46). More studies are needed at thispoint.

STUDY LIMITATIONS. Studies were mixed betweenprospective, retrospective, and randomized controlstudies. There is also the possibility of a reportingbias and the usual limitations of meta-analysisstudies (66,67). The majority of the patients weremale. Sixty patients had pulmonary vein isolation inaddition to AFL ablation for prior AF (5). However,this is a small number among the whole and will notaffect our results. In addition, we performed analysisafter excluding this study and it did not affect theforest plot results.

The lack of prior AF in the included studies may beincorrect because AF can be asymptomatic or it mayoccur when the patients were not monitored. But thisreflects our current practice.

In the intensive monitoring group (group 3), wecombined the implanted cardiac devices data, whichare more comprehensive, with other monitoringtechniques. However, the AF incidence rate wasabout the same in the implant loop recorder patients(47%) and the other monitoring technique patients(44.6%).

Left atrial size has been suggested as a risk factorfor AF development after AFL ablation (50,53). How-ever, most studies defined dilated left atrium with a4-cm diameter as a cut off for males rather than theleft atrium volume index which is the current stan-dard in American Society of Echocardiography (ASE)guidelines. Furthermore, the left atrium volume in-dex definition for normal and dilated left atriumchanged in the most recent ASE guidelines (from 28 to34 ml/m2 for upper normal) (68,69).

New possible risk factors for AF development af-ter AFL ablation, such as advanced interatrial blockand the HATCH score (based on hypertension,age $75 years, transient ischemic attack or stroke,chronic obstructive pulmonary disease, and heartfailure) was not evaluated in our study and might behelpful in predicting AF but need further evaluation(22,49).

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: The incidence of

AF after AFL ablation in patients with no prior AF is very high,

which supports continuing anticoagulation after AFL ablation

until further stroke data is available.

TRANSLATIONAL OUTLOOK: Further studies are needed

on the concomitant AF ablation at the time of AFL ablation

in patients with no prior AF. These studies need to compare

procedure complication rates, future hospital admissions for

AF, and future use of antiarrhythmic medications and/or

AF ablation. Further studies are also needed to address

the risk of stroke after AFL ablation in patients with no

prior AF.

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CONCLUSIONS

The incidence of AF after AFL ablation is high. Theduration and type of follow-up have a significantimpact on the difference between studies in detectingAF after AFL ablation. Our study results indicate thatsuccessful AFL ablation should not change the long-term anticoagulation plan after the procedure, andCHADS2VASc score should be used to determineanticoagulation due to the high AF incidence rateafter AFL ablation. Concomitant AF ablation shouldbe performed at the time of AFL ablation in patientswith prior documented AF, with few exceptions, andmore studies are needed in patients with no prior AFat this point.

ACKNOWLEDGMENTS The authors thank Dr.Brembilla-Perrot at Nancy University Hospital,Nancy, France, for providing more information abouttheir study which we used in our meta-analysis (20).

REPRINT REQUESTS AND CORRESPONDENCE:

Dr. Waddah Maskoun, Division of Cardiology,

Department of Internal Medicine, Central ArkansasVeterans Healthcare System, University of Arkansasfor Medical Sciences, 4300 West 7th Street, LittleRock, Arkansas 72205. E-mail: wmaskoun@uams.edu.

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KEY WORDS ablation, atrial fibrillation,atrial flutter, Holter monitor, implant looprecorder