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Comparison of RadiofrequencyCatheter Ablation of Drivers andCircumferential Pulmonary VeinIsolation in Atrial Fibrillation
A Noninferiority Randomized Multicenter RADAR-AF Trial
Felipe Atienza, MD, PHD,* Jesús Almendral, MD, PHD,y José Miguel Ormaetxe, MD, PHD,z Ángel Moya, MD,xJesús Daniel Martínez-Alday, MD, PHD,k Antonio Hernández-Madrid, MD, PHD,{ Eduardo Castellanos, MD,#Fernando Arribas, MD, PHD,** Miguel Ángel Arias, MD, PHD,# Luis Tercedor, MD,yy Rafael Peinado, MD, PHD,zzMaria Fe Arcocha, MD,z Mercedes Ortiz, PHD,y Nieves Martínez-Alzamora, PHD,xx Ángel Arenal, MD, PHD,*Francisco Fernández-Avilés, MD, PHD,* José Jalife, MD,kk for the RADAR-AF Investigators

ABSTRACT

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BACKGROUND Empiric circumferential pulmonary vein isolation (CPVI) has become the therapy of choice for drug-

refractory atrial fibrillation (AF). Although results are suboptimal, it is unknown whether mechanistically-based strategies

targeting AF drivers are superior.

OBJECTIVES This study sought to determine the efficacy and safety of localized high-frequency source ablation (HFSA)

compared with CPVI in patients with drug-refractory AF.

METHODS This prospective, multicenter, single-blinded study of 232 patients (age 53 � 10 years, 186 males) ran-

domized those with paroxysmal AF (n ¼ 115) to CPVI or HFSA-only (noninferiority design) and those with persistent AF

(n ¼ 117) to CPVI or a combined ablation approach (CPVI þ HFSA, superiority design). The primary endpoint was freedom

from AF at 6 months post-first ablation procedure. Secondary endpoints included freedom from atrial tachyarrhythmias

(AT) at 6 and 12 months, periprocedural complications, overall adverse events, and quality of life.

RESULTS In paroxysmal AF, HFSA failed to achieve noninferiority at 6 months after a single procedure but, after redo

procedures, was noninferior to CPVI at 12months for freedom fromAF and AF/AT. Serious adverse events were significantly

reduced in the HFSA group versus CPVI patients (p¼ 0.02). In persistent AF, there were no significant differences between

treatment groups for primary and secondary endpoints, but CPVI þ HFSA trended toward more serious adverse events.

CONCLUSIONS In paroxysmal AF, HFSA failed to achieve noninferiority at 6 months but was noninferior to CPVI at

1 year in achieving freedom of AF/AT and a lower incidence of severe adverse events. In persistent AF, CPVI þ HFSA

offered no incremental value. (Radiofrequency Ablation of Drivers of Atrial Fibrillation [RADAR-AF]; NCT00674401)

(J Am Coll Cardiol 2014;64:2455–67) © 2014 by the American College of Cardiology Foundation.

m the *Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio

rañón, Madrid, Spain; yHospital Universitario Montepríncipe, Madrid, Spain; zHospital de Basurto, Bilbao, Spain; xHospital Vall

ebron, Barcelona, Spain; kClinica San Sebastian, Bilbao, Spain; {Hospital Ramón y Cajal, Madrid, Spain; #Hospital Virgen de la

lud, Toledo, Spain; **Hospital Doce de Octubre, Madrid, Spain; yyHospital Virgen de las Nieves, Granada, Spain; zzHospital La

z, Madrid, Spain; xxUniversidad Politécnica de Valencia, Valencia, Spain; and the kkUniversity of Michigan, Ann Arbor,

chigan. This study was funded by the Centro Nacional de Investigaciones Cardiovasculares and by an unrestricted research

nt from St. Jude Medical. Dr. Atienza has received research grants from St. Jude Medical; and is on the advisory board of

dtronic, Inc. Dr. Jalife is on the scientific advisory board of Topera, Inc. All other authors have reported that they have no

ationships relevant to the contents of this paper to disclose.

ten to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

u can also listen to this issue’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

nuscript received July 16, 2014; revised manuscript received August 31, 2014, accepted September 5, 2014.

http://clinicaltrials.gov/ct2/show/NCT00674401

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http://dx.doi.org/10.1016/j.jacc.2014.09.053

ABBR EV I A T I ON S

AND ACRONYMS

AAD = antiarrhythmic drug

AF = atrial fibrillation

AT = atrial tachyarrhythmia

CPVI = circumferential

pulmonary vein isolation

DF = dominant frequency

HF = high frequency

HFS = high-frequency sources

HFSA = high-frequency

source ablation

LA = left atrium

PV = pulmonary vein

RF = radiofrequency

SAE = serious adverse eve

Atienza et al. J A C C V O L . 6 4 , N O . 2 3 , 2 0 1 4

Catheter Ablation of AF Drivers D E C E M B E R 1 6 , 2 0 1 4 : 2 4 5 5 – 6 7

2456

C urrently-available antiarrhythmicdrugs (AADs) used to treat atrialfibrillation (AF) have limited effi-

cacy and are frequently associated withadverse long-term effects (1). The demon-stration that AF triggers are most commonlylocated in the pulmonary veins (PVs) led todevelopment of radiofrequency (RF)-basedablative strategies aimed at creating circum-ferential lesions around the PV ostia (1,2).Empiric circumferential pulmonary veinisolation (CPVI) is effective in w70% to 80%of patients with paroxysmal AF and is thetherapy of choice for drug-refractory AF (1).However, the procedure includes risks, andresults remain suboptimal due to PV recon-nection and non-PV sources that maintain

AF (1). Moreover, the CPVI success rate in the moreprevalent persistent AF is significantly lower thanwith paroxysmal AF, and substrate-based ablationstrategies have been proposed (1,3).

nt(s)

SEE PAGE 2468

Advanced signal analysis methods have demon-strated that AF is maintained by high-frequencysources (HFS), often located at the PV-left atrial(LA) junction and less frequently at other sites inboth atria (4–8). Therefore, several studies havesuggested that instead of empirically targeting thePVs, AF may be eliminated by directly ablatingAF-driving sources or “rotors” that exhibit high-frequency, periodic activity (4–8). However, theclinical outcomes of this mechanistically-basedstrategy remain unknown.

RADAR-AF (Radiofrequency Ablation of Drivers ofAtrial Fibrillation) was a multicenter, single-blinded,randomized clinical trial designed to compare theefficacy and safety of the standard ablation strategy(CPVI) with a strategy of localized high-frequencysource ablation (HFSA) alone in paroxysmal AFor combined with CPVI in persistent AF (9). Wehypothesized that: 1) in paroxysmal AF patients, theefficacy of selective HFSA would be similar toempirical CPVI but with fewer complications; and2) in persistent AF patients, a combination of CPVIplus HFSA would increase efficacy without increasingcomplications.

METHODS

An extended version of the Methods section isprovided in the Online Appendix; a description of theablation strategies utilized is detailed in the followingtext. The study protocol was approved by the ethics

committee of the participating centers. All patientsprovided written informed consent.

STUDY POPULATION. All patients from the outpa-tient clinics with indication for AF ablation werescreened for eligibility. Inclusion criteria includedsymptomatic paroxysmal AF, refractory/intolerantto at least 1 AAD documented within 12 monthsof randomization, anticoagulation >4 weeks priorto inclusion, or a transesophageal echocardiogramexcluding intracardiac thrombus. Persistent AF wasdefined as continuous AF sustained beyond 7 days,with patients anticoagulated for >4 weeks prior toablation and willing to give informed consent.Patients were excluded if they had prior AF ablation;inadequate anticoagulation levels; LA thrombus,tumors, or cardiac abnormalities precluding the pro-cedure; contraindications to systemic anticoagula-tion; AF secondary to reversible causes; left atrial size>55 mm; pregnancy; thyroid disease; other investi-gational study involvement; and implanted device.

STUDY DESIGN. Randomization was performedaccording to AF type using a web-based system andwas balanced at each site. Paroxysmal AF patientswere randomly assigned 1:1 to CPVI or HFSA. Persis-tent AF patients were randomly assigned 1:1 to CPVIor a combined ablation approach (CPVI þ HFSA).Because of the nature of the intervention, physiciansperforming the ablation procedure were not blindedto treatment group assignment.

FOLLOW-UP. Patients were followed by physiciansblinded to the assigned treatment arm at 3, 6, and 12months from the first ablation procedure, and 12-leadelectrocardiogram, 48-h Holter recordings, and qual-ity of life (QOL) questionnaires were obtained at eachfollow-up visit. Holter analysis was blinded withrespect to randomization and treatment. All adverseevents were reviewed and adjudicated by an inde-pendent data safety monitoring committee.

ABLATION PROCEDURE AND STRATEGIES. Electro-physiological study common to all patients. AADswere stopped >5 half-lives prior to the procedure,except for amiodarone. In patients arriving in sinusrhythm (SR), AF was induced following a standard-ized protocol (8). If AF was not sustained for >5 min,the patient was excluded from study. Once in AF, thepatient was randomized. Three-dimensional geome-try of the atria was reconstructed using the EnsiteNavX System version 8.0 (St. Jude Medical, Minne-apolis, Minnesota) (8). RF energy was delivered usinga 3.5-mm irrigated-tip ablation catheter (TherapyCool Path, St. Jude Medical, St. Paul, Minnesota).CPVI st rategy . In patients assigned to CPVI, the PVswere isolated using circumferential lesions around

FIGURE 1 Study Ablation Strategies

(A) Circumferential pulmonary vein isolation (CPVI) as seen from the left atrial (LA) pos-

terior view. Red dots indicate ablation lesions. (B) High-frequency source ablation (HFSA)

as seen in this LA dominant frequency (DF) map, posterior view, showing an HFS located at

the antrum of the right inferior pulmonary vein. Yellow dots indicate ablation lesions.

(C) CPVI þ HFSA is illustrated in LA and right atrial DF maps, anterior (right) and posterior

(left) view, showing CPVI and HFSA lesions (white dots).

J A C C V O L . 6 4 , N O . 2 3 , 2 0 1 4 Atienza et al.D E C E M B E R 1 6 , 2 0 1 4 : 2 4 5 5 – 6 7 Catheter Ablation of AF Drivers

2457

the PV antrum with confirmation of entrance blockusing a multipolar circular catheter (Figure 1A). Anadditional roof line was allowed, but conductionblock across the line was not formally required.Organized atrial tachyarrhythmias (ATs) or flutteroccurring after CPVI could be mapped and ablated atthe discretion of the investigator. If the patient wasin AF at the procedure’s end, he/she could becardioverted, and remapping was performed to con-firm PV isolation. Termination and/or noninducibilityof AF were not procedural endpoints.HFSA strategy . A high-density dominant frequency(DF) LA map was created by sequentially moving theablation and/or circular mapping catheter throughoutthe entire left atrium. Sites with high-frequency (HF)atrial electrograms were identified by an automatedalgorithm designed to calculate the DF and depict localatrial activation frequency on the 3-dimensional LAshell (Figure 1B) (8). HFS were targeted until ablationendpoints were reached: 1) elimination of all HFS orconversion to SR; and 2) noninducibility of AF post-ablation. If AF did not terminate after LA HFSA,DFmaps from the right atrium (RA) and coronary sinus(CS) were obtained and HFS were targeted at the op-erator’s discretion. A maximum of 3 to 4 HFS perchamber were targeted for ablation (4 sites in LA and 3sites in RA and CS). Ablation of HF sites located at a PVantrum was performed by creating a circumferentialset of lesions around the ostiumof the responsible veinuntil PV isolation was obtained (Figure 1B) (7,9). HFsites located elsewhere in the atria were targeted forablation until local potentials were completely abatedthrough creation of a coin-like circumferential set oflesions. Organized ATs occurring after elimination ofHF sites could be mapped and ablated at the in-vestigator’s discretion. If AF persisted despite elimi-nation of all HF sites from the LA, RA, and CS, the AFcould be cardioverted and the procedure terminated.Combined strategy : CPVI D HFSA. A high-densityDF LA map was obtained and then CPVI was per-formed. If the patient remained in AF, HFS weretargeted for ablation, according to the previouslydescribed protocol, until ablation endpoints werereached: 1) elimination of HFS; and 2) PV isolation(Figure 1C). If AF did not terminate after LA HFSA, RAand CS DF maps were obtained and HFS was targeted(at operator discretion). If AF persisted despite elim-ination of all HFS from the LA, RA, and CS, AF couldbe cardioverted and the procedure terminated.Redo procedures . A 2-month blanking period wasobserved, after which AADs were discontinued. Redoprocedures due to recurrent AF were not allowedwithin the first 6 months; they were performed 6 to7.5 months post-ablation using the same strategy

assigned in the first procedure, except for theHFSA-only arm, where the investigator could performeither CPVI or HFSA.

STUDY OUTCOMES. The primary endpoint wasfreedom from AF at 6 months post-first ablationprocedure off of AADs. Secondary endpoints includedfreedom from AF/AT at 6 and 12 months off/on AADs;need for redo procedures; incidence of periproceduralcomplications and overall adverse events; fluoros-copy time and procedure duration; and QOL at base-line and at 3, 6, and 12 months assessed using thespecific AF-QOL questionnaire (10). Recurrent AF/ATwas defined as AF/AT of at least 30 s duration docu-mented by electrocardiogram or device recordingsystem >2 months following catheter ablation (1).

SAFETY OUTCOMES. Adverse events were classifiedaccording to their seriousness and whether they wereprocedure related (Online Appendix) (1).

STATISTICAL METHODS. The primary hypothesisin paroxysmal AF was that HFSA would be noninferiorand associated with lower risk than CPVI. Ifnoninferiority was achieved in the primary analysis,



2458

a closed testing procedure was conducted for superi-ority. Secondary efficacy and safety endpointsalso were tested for superiority. All analyseswere intention-to-treat. Statistical significance wasconsidered 1-sided for paroxysmal and 2-sided forpersistent AF and was declared if the p valuewas <0.05. Comparison of time to event was per-formed using Kaplan-Meier analysis and the log-ranktest. Continuous baseline variables were comparedusing the Student t test or Mann-Whitney test ac-cording to the variables statistical distribution. Cate-gorical variables were compared using Fisher exacttest. Repeated measures analysis of variance was usedto examine the effect of treatment strategy by time onQOL for each group. All statistical analyses were per-formed using SPSS version 17.0 (IBM, Armonk, NewYork) and Comprehensive Meta-Analysis version 2.2(Biostat Inc., Englewood, New Jersey).

TABLE 1 Baseline Characteristics of Patients

Paroxysmal AF (n ¼ 113)

CPVI(n ¼ 58)

HFSA(n ¼ 55)

Male 49 (84) 40 (73)

Age, yrs 53 � 10 54 � 12

BMI, kg/m2 27.5 � 4.2 28 � 3.1

Medical history

Hypertension 17 (29) 24 (44)

Dyslipidemia 16 (27) 22 (40)

Diabetes 2 (3) 3 (5)

Alcohol 2 (3) 3 (5)

Tobacco 26 (45) 21 (38)

Previous stroke/TIA 2 (3) 0

Structural heart disease 7 (12) 12 (22)

Valvular disease 4 (7) 4 (7)

AF diagnosis, yrs 4.13 (1.45-8.77) 3.66 (1.1-9.4)

LVEF, % 60 (60–65) 60 (60–65)

LA diameter, mm 40 � 5 40 � 6

NYHA functional class

I 52 (90) 51 (93)

II 6 (10) 4 (7)

III

CHADS2 score*

0 36 (62) 29 (53)

1 19 (33) 22 (40)

$2 3 (5) 4 (7)

Prior AAD use

1 33 (57) 40 (73)

2 21 (36) 10 (18)

3 4 (7) 4 (7)

4 0 (0) 1 (1.8)

Values are n (%), mean � SD, or median (interquartile range). *CHADS2 score awards2 points for stroke.

AAD ¼ antiarrhythmic drug; AF ¼ atrial fibrillation; BMI ¼ body mass index; CHADS2transient ischemic attack; CPVI ¼ circumferential pulmonary vein isolation; HFSA ¼ high-NYHA ¼ New York Heart Association; TIA ¼ transient ischemic attack.

RESULTS

We enrolled 232 patients (115 [49%] paroxysmal AFand 117 [51%] persistent AF) between May 2009 andMay 2012, with last follow-up in May 2013. The2 groups were well-matched with respect to baselineclinical characteristics (Table 1). Mean age was 54 �10 years, and 20% of the patients were women. Onepatient was excluded due to protocol violation, 1 waslost to follow-up, and 3 withdrew consent after6-month follow-up (Figure 2).ABLATION PROCEDURE. In paroxysmal AF patientsassigned to HFSA, after 31 � 16 min, DF mappingidentified a median of 3 HFS (interquartile range[IQR]: 2 to 4 HFS) per patient (Table 2, Figure 3).Overall, a median of 2.87 HFS (IQR: 2 to 3 HFS) wereablated; 18 sites were not ablated due to anatomicalrestrictions or safety concerns. In CPVI patients,

Persistent AF (n ¼ 117)

p ValueCPVI

(n ¼ 58)CPVI þ HFSA

(n ¼ 59) p Value

0.168 47 (81) 48 (81) 0.965

0.693 54 � 10 55 � 9 0.568

0.439 28.7 � 3.7 29.1 � 3.4 0.50

0.123 20 (34) 29 (49) 0.108

0.171 20 (34) 15 (25) 0.285

0.674 5 (9) 8 (14) 0.395

0.674 2 (3) 4 (7) 0.414

0.567 22 (38) 26 (44) 0.50

NA 4 (7) 4 (7) 0.98

0.211 22 (38) 17 (29) 0.296

1.00 10 (17) 4 (7) 0.081

0.745 1.32 (0.50-4.87) 1.5 (0.58-3.75) 0.719

0.801 60 (54.8–60.0) 60 (55–62) 0.657

0.791 45 � 7 45 � 6 0.922

0.743 0.113

50 (86) 42 (71)

8 (14) 16 (27)

0 1 (2)

0.595 0.149

33 (57) 23 (39)

18 (31) 25 (42)

7 (12) 11 (19)

0.139 0.379

32 (55) 34 (58)

22 (38) 24 (41)

4 (7) 1 (2)

1 point for congestive heart failure, hypertension, age $75 years, and diabetes, and

¼ congestive heart failure, hypertension, age $75 years, diabetes mellitus, stroke/frequency source ablation; LA ¼ left atrium; LVEF ¼ left ventricular ejection fraction;

FIGURE 2 Patient Inclusion Flow Chart

58 Patients analyzedat 1 year


58 Patientsanalyzedat 1 year


1 Patient excludedprotocol violation

1 Patient lostto follow up

1 Patient withdrawn

consent

1 Patient withdrawn

consent

1 Patient withdrawn

consent

56 PatientsHFSA strategy

59 PatientsCPVI strategy

232 Patientsrandomized

823 Patientsassessed for

eligibility

Paroxysmal AF115 patients

Persistent AF117 patients

58 PatientsCPVI strategy

59 PatientsHFSA+CPVI

combined strategy

591 Excluded:477 Did not meet inclusion criteria:

182 Previous AF ablation116 Included in other protocols

or ablation technologies33 Thyroid dysfunction17 Non-inducible AF >5 min

129 Other114 Refused participation

55 Patientsanalyzed at 6

months


months


months


months

Patient distribution according to eligibility, atrial fibrillation (AF) type, ablation strategy assignment, and follow-up duration. Abbreviations as

in Figure 1.


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3.79 � 0.5 veins were isolated compared with2.22 � 1.1 in the HFSA group (p < 0.001). DeliveredRF time was significantly shorter in patients under-going HFSA versus CPVI (p < 0.01). A significantlyhigher percentage of patients undergoing HFSAconverted to SR during ablation (45% vs. 28%;p < 0.05).

In persistent AF patients assigned to CPVI þ HFSA,after 28 � 17 min, DF mapping identified a medianof 3 HFS (IQR: 2 to 5 HFS) per patient (Figure 3),3.88 � 0.45 veins were isolated, and a median of 3 HFS(IQR: 2 to 4.25 HFS) were ablated; 26 HFS were notablated. In persistent AF patients assigned to CPVI,3.93 � 0.45 veins were isolated. Compared with theCPVI group, the CPVI þ HFSA group had significantlylonger procedure duration and a trend toward longer

RF duration (Table 2) (see Online Appendix for furtherdetails).EFFICACY OUTCOMES. In paroxysmal AF, freedomfrom AF without AADs at 6 months (primaryendpoint) was seen in 83% of CPVI versus 73% ofHFSA patients (risk difference [RD]: �0.1; lowerlimit 1-sided 95% confidence interval [CI]: �0.228;p ¼ 0.228 for noninferiority; p ¼ 0.901 for superiority)(Figure 4). Freedom from AF/AT at 6 months also wassimilar (69% of CPVI vs. 65% of HFSA patients;RD: �0.035; lower limit 1-sided 95% CI: �0.18;p ¼ 0.08 for noninferiority; p ¼ 0.654 for superiority).After a single procedure, time to first AF recurrenceand time to first AF/AT recurrence were not signifi-cantly different between groups (Figure 5). At 1 year,freedom from AF was seen in 79% of CPVI and 81% of

TABLE 2 Procedural Characteristics

Paroxysmal AF Persistent AF

CPVI(n ¼ 58)

HFSA(n ¼ 55) p Value

CPVI(n ¼ 58)

CPVI þ HFSA(n ¼ 59) p Value

Induced AF 46 (81) 49 (89) 0.26 11 (19) 11 (19) 0.61

Mean AF cycle length, ms 172 � 35 176 � 33 0.55 171 � 33 169 � 33 0.79

DF mapping time, min NA 31 � 16 NA NA 28 � 17 NA

RF time, min 36 (24.7–47.1) 29 (20–39) 0.01 37 (29.7–50.0) 43 (31–53) 0.10

Fluoroscopy time, min 60 (45.8–79.3) 59 (40–81) 0.66 66 (47–78.3) 67 (50–83) 0.43

Total procedure time, min 215 � 66 228 � 65 0.31 202 � 58 239 � 61 0.001

HFS NA 3 (2–4) NA NA 3 (2–5) NA

Ablated HFS NA 2.87 (2–3) NA NA 3 (2.00–4.25) NA

Total number nonablated HFS NA 18 NA NA 26 NA

Isolated pulmonary veins 3.79 � 0.50 2.22 � 1.10 <0.001 3.93 � 0.45 3.88 � 0.45 0.56

Patients with additional ablation lines 3 0 NA 11 22 0.03

Patients converting to SR during ablation 16 (28) 25 (45) <0.05 3 (5) 7 (12) 0.19

Patients converting to AT during ablation 6 (10) 7 (13) 0.69 12 (21) 20 (34) 0.11

Patients with redo procedures 17 (29) 13 (24) 0.5 13 (22) 16 (27) 0.56

Ablated HFS during redo procedure NA 3 (1.75–3.00) NA NA 3 (1.5–5.0) NA

Isolated pulmonary veins during redo procedure 3.59 � 1.00 2.46 � 0.96 0.004 2.92 � 1.40 3.31 � 0.79 0.36

Values are n (%), mean � SD, or median (interquartile range).

AT ¼ atrial tachyarrhythmias; DF ¼ dominant frequency; RF ¼ radiofrequency; SR ¼ sinus rhythm; other abbreviations as in Table 1.



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HFSA patients (RD: 0.022; lower limit 1-sided 95%CI: �0.102; p ¼ 0.008 for noninferiority; p ¼ 0.385 forsuperiority), and freedom from AF/AT was seen in72% of CPVI vs. 76% of HFSA patients (RD: 0.054;lower limit 1-sided 95% CI: �0.08; p ¼ 0.004 for

FIGURE 3 Schematic Diagram of HFS Distribution in the Atria

MV TV

LAA RAA

N=5

N=40

N=10

N=29

N=29

N=9

N=28

N=3

N=5

N=2

N=3

N=3N=2

CS

IVC

RIPVLIPV

RSPVLSPV

SVC

Paroxysmal AF

N=2

Posterior view of the atria showing HFS distribution in patients with par

clustered at the pulmonary vein antrum and the left atrial posterior wall

persistent AF patients, including the LA body, the septum, and the right a

appendage; LSPV ¼ left superior pulmonary vein; LIPV ¼ left inferior pu

RSPV ¼ right superior pulmonary vein; RIPV ¼ right inferior pulmonary

noninferiority; p ¼ 0.255 for superiority). After redoprocedures, time to first AF or AF/AT recurrence wasnot significantly different between groups (Figure 5).

In persistent AF, freedom from AF without AADsat 6 months was seen in 60% of CPVI versus 61% of

MV TV

LAA RAA

N=8

N=5N=3

N=7N=2

N=17

N=24

N=19 N=23N=25

N=23

N=26N=15N=7

N=3

CS

IVC

RIPVLIPV

RSPVLSPV

SVC

Persistent AF

oxysmal (left) and persistent (right) AF. HFS are predominantly

in paroxysmal AF, whereas a more widespread distribution is found in

trium. CS ¼ coronary sinus; IVC ¼ inferior vena cava; LAA ¼ left atrial

lmonary vein; MV ¼ mitral valve; RAA ¼ right atrial appendage;

vein; SVC ¼ superior vena cava; TV ¼ tricuspid valve.

FIGURE 4 Comparisons of Efficacy and Safety Endpoints

Freedom from AF 6 monthsFreedom from AF/AT 6 monthsFreedom from AF 1 yearFreedom from AF/AT 1 yearPeriprocedural AESerious AE

Freedom from AF 6 monthsFreedom from AF/AT 6 monthsFreedom from AF 1 yearFreedom from AF/AT 1 yearPeriprocedural AESerious AE

0.9010.6540.3850.2550.0680.017

0.2280.0800.0080.004

0.028-0.228-0.180-0.102-0.080-0.173-0.263

0.1100.1450.1880.007-0.038

0.078-0.100-0.0350.0220.054-0.083-0.150

0.0880.0750.0820.0550.068

Riskdifference

Standarderror

Lowerlimit

Upperlimit

p Value fornoninferiority

p Value forsuperiority

Riskdifference

Standarderror

Lowerlimit

Upperlimit

p Value forsuperiority

Risk Difference

Risk Difference

Freedom from AF/AT noninferior

0.9410.6280.6440.6460.1450.050

0.1840.1340.2120.2150.1580.268

-0.170-0.223-0.131-0.133-0.023-0.000

0.0900.0910.0880.0890.0460.068

0.007-0.0440.0410.0410.0670.134

-0.50 -0.25 0.00 0.25 0.50CPVI+HFSA vs. CPVI

-0.50 -0.25 0.00 0.25 0.50HFSA vs. CPVI

Efficacy and safety endpoints

Efficacy and safety endpoints

Persistent Atrial Fibrillation

Paroxysmal Atrial Fibrillation

Forest plots compare CPVI versus HFSA only in paroxysmal AF and CPVI versus CPVI þ HFSA in persistent AF. AE ¼ adverse events; AT ¼ atrial tachycardia; other

abbreviations as in Figures 1 and 2.


2461

CPVI þ HFSA patients (RD: 0.007; 95% CI: �0.17 to0.184; p ¼ 0.941). Similarly, freedom from AF/AT at6 months was seen in 60% of CPVI versus 56% ofCPVI þ HFSA patients (RD: �0.044; 95% CI: �0.223to 0.134; p ¼ 0.628). After a single procedure, timeto first AF recurrence and first AF/AT recurrencewere not significantly different between groups(Figure 6). At 1 year, freedom from AF was seenin 65% of CPVI and 69% of CPVI þ HFSA patients(RD: 0.041; 95% CI: �0.131 to 0.212; p ¼ 0.644),whereas freedom from AF/AT was seen in 63%CPVI versus 67% CPVI þ HFSA patients (RD: 0.041;95% CI: �0.133 to 0.215; p ¼ 0.646). After redoprocedures, time to first AF or first AF/AT recur-rence did not differ significantly between groups(Figure 6).

SAFETY OUTCOMES. In paroxysmal AF patients,procedure-related adverse events occurred in 8 (14%)patients in the CPVI versus 3 (5%) patients in theHFSA group (RD: �0.083; upper limit 1-sided 95% CI:0.007; p ¼ 0.068 for superiority) (Table 3, Figure 4),

whereas overall serious adverse events (SAE)occurred in 5 (9%) patients in the HFSA and 14 (24%)in the CPVI group (RD: -0.15; upper limit 1-sided95% CI: �0.038; p ¼ 0.017 for superiority). In persis-tent AF patients, procedure-related adverse eventsoccurred in 2 (3%) patients in the CPVI and 6 (10%)in the CPVI þ HFSA group (RD: 0.067; 95% CI: �0.023to 0.158; p ¼ 0.145), whereas overall SAEs occurredin 6 (10%) patients in the CPVI versus 14 (24%)in the CPVI þ HFSA group (RD: 0.134; 95% CI: 0 to0.268; p ¼ 0.05).

REDO PROCEDURES. In paroxysmal AF patients,there was no significant difference in the proportionsof patients undergoing redo procedures (Table 2). Inpatients assigned to CPVI (n ¼ 17), all but 1 patient had3.59 � 1.0 reconnected veins that were re-isolated,and 3 patients underwent additional linear ablationin the LA. In patients assigned to HFSA (n ¼ 13), CPVIwas performed in 2 due to operator preference and in 1due to the absence of HFS in the atria; in theremaining, a median of 3 HFS (IQR: 1.75 to 3 HFS)

FIGURE 5 Survival Curves for Paroxysmal AF Patients

1.0

0.8

0.6

0.4

0.2

0.0

.00

58 57 4840 39

43 403755 53

3.00 6.00 9.00 12.00Months after Ablation

CPVIHFSA

Free

dom

from

AF

afte

r 1 P

roce

dure

p=0.724

ABLATION PROCEDURECPVIHFSA

1.0

0.8

0.6

0.4

0.2

0.0

.00

58 57 4036 34

37 343255 51


CPVIHFSA

Free

dom

from

AF/

AT a

fter

1 Pr

oced

ure

p=0.828


1.0

0.8

0.6

0.4

0.2

0.0

.00

58 57 5252 49

47 424255 54


CPVIHFSA

Free

dom

from

AF/

AT a

fter

Red

o Pr

oced

ures

p=0.566


1.0

0.8

0.6

0.4

0.2

0.0

.00

58 57 5653 51

50 464455 55


CPVIHFSA

Free

dom

from

AF

afte

r Red

o Pr

oced

ures

p=0.862


Paroxysmal Atrial Fibrillation

Kaplan-Meier curves of time to first AF and time to first AF/AT recurrence after a single procedure (left) and after redo procedures (right) in paroxysmal AF patients

undergoing CPVI versus HFSA. Abbreviations as in Figures 1, 2, and 4.



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were identified and ablated with 2.46 � 0.96 veinsconcomitantly isolated. All PVs harboring HFS ablatedat the redo procedure had been previously isolatedduring the index procedure, whereas the rest of theveins were spared.

In persistent AF patients, there also was no sig-nificant difference in the proportion of patients

undergoing redo procedures (Table 2). Of the patientsassigned to CPVI (n ¼ 13), 11 had 2.92 � 1.4 recon-nected veins that were re-isolated, 7 underwentadditional linear ablation, and 1 underwent addi-tional HFSA. In patients assigned to CPVI þ HFSA(n ¼ 16), 3.31 � 0.79 veins were reconnected andre-isolated. Five patients did not undergo DF

FIGURE 6 Survival Curves for Persistent AF Patients

1.0

0.8

0.6

0.4

0.2

0.0

.00

58 55 3436 36

28 213059 52


CPVICPVI+HFSA

Free

dom

from

AF

afte

r 1 P

roce

dure

p=0.282

ABLATION PROCEDURECPVICPVI+HFSA

1.0

0.8

0.6

0.4

0.2

0.0

.00

58 55 3433 33

28 212759 52


CPVICPVI+HFSA

Free

dom

from

AF/

AT a

fter

1 Pr

oced

ure

p=0.575


1.0

0.8

0.6

0.4

0.2

0.0

.00

58 57 5150 50

45 363959 57


CPVICPVI+HFSA

Free

dom

from

AF/

AT a

fter

Red

o Pr

oced

ures

p=0.806


CPVICPVI+HFSA

1.0

0.8

0.6

0.4

0.2

0.0

.00

58 57 5150 50

45 374059 57


CPVICPVI+HFSA

Free

dom

from

AF

afte

r Red

o Pr

oced

ures

p=0.792

ABLATION PROCEDURE

Persistent Atrial Fibrillation

Kaplan-Meier curves of time to first AF and time to first AF/AT recurrence after a single procedure (left) and after redo procedures (right) in persistent AF patients

undergoing CPVI versus CPVI þ HFSA. Abbreviations as in Figures 1, 2, and 4.


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mapping due to operator preference (n ¼ 3), technicalfailure (n ¼ 1), and SR conversion during CPVI andnoninducibility (n ¼ 1); in the remaining patients, amedian of 3 (IQR: 1.5 to 5) HFS were identified andablated.QOL OUTCOMES. Baseline QOL measures weresimilar between treatment groups in both AF types.

There was a progressive improvement in physical,mental, and sexual QOL scores at 6 and 12 monthsafter ablation in both treatment groups and AF types(Table 4). However, QOL comparisons betweentreatment groups in both AF types at 6 and 12 monthspost-ablation were not significantly different (OnlineAppendix).

TABLE 3 Serious Adverse Events

Paroxysmal AF Persistent AF

CPVI HFSA CPVI CPVI þ HFSA

Procedural adverse events

Pericarditis/chest pain 1 1

Tamponade 2 1 2

Pericardial effusion conservatively treated 2

Vascular complications 1 1 1 1

Pleural effusion 1

Pneumonia <1 month after ablation 1 2

PV stenosis 1

Urinary tract infection 1

Adverse events >1 month after the procedure

Hypotension/HF after cardioversion for AF 1 1 1

AF/AT/flutter requiring hospitalization/ablation 5 1 1 5

Syncope 1

Thyroid dysfunction 1

Bleeding after surgery 1 1

Chest pain 1 1

Stroke after switching acenocumarol for dabigatran 1

Traumatism with hospital admission* 1 1 1

Pharmacologic AV block† 1

Events reported as serious adverse events during the study follow-up; some patients had more than 1 seriousadverse event. *Traumatisms due to accidents or causal falls not related to cardiac events. †Pharmacologic AVblock 2 months after the procedure due to beta-blocker treatment that resolved after discontinuation.

AV ¼ atrioventricular; HF ¼ heart failure; other abbreviations as in Tables 1 and 2.



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DISCUSSION

This prospective randomized study demonstratesthat in paroxysmal AF patients, an ablation strategytargeting HFS until AF termination did not reachnoninferiority compared with CPVI after a singleprocedure to achieve freedom of AF at 6 months.However, after redo ablation procedures, HFSA wasnoninferior to empiric CPVI at 12 months to achievefreedom from AF and AT. Importantly, patients un-dergoing HFSA had a significantly lower incidence ofSAEs. In contrast, in persistent AF patients, addingHFSA to CPVI offered no incremental value andshowed a trend toward more complications comparedwith CPVI.

THE ROLE OF HFS IN AF MAINTENANCE. Techniquesaimed at empirically isolating the PVs yield successrates that barely surpass the 60% to 70% midtermefficacy rate reported with multiple procedures andAADs, and yet they increase risks and cost (1,3).Consequently, interest has grown in mechanistically-based ablation strategies that might be more effectiveand safe. Experimental studies have demonstratedthat AF is maintained by HFS (rotors or drivers)anchored at the posterior LA wall and the junctionwith the PVs (11). Studies by Haïssaguerre et al. (2)

demonstrated that rapidly-firing ectopic foci in thePVs were capable of initiating and even maintainingAF and could be eliminated with RF ablation. Suchfindings paved the way for the currently used CPVIablation technique, aimed at electrically isolating thePVs from the atrium (1). However, in persistent AF,CPVI is less effective, and more extensive ablativetechniques have been proposed (1,3,12–15), which in-crease not only the procedure time and fluoroscopicexposure, but also the risk of complications (15). Forall of these reasons, a search for alternative mappingand ablation strategies is urgently needed.

BENCH-TO-BEDSIDE TRANSLATIONAL RESEARCH. In aseries of forward translational studies, we have usedspectral analysis techniques developed and validatedin the animal laboratory to identify and ablate HFS inAF patients (4,6–9,11). Those studies showed thatreal-time spectral mapping of AF was safe andenabled identification and effective elimination ofHFS, leading to favorable long-term SR maintenancerates. Based on such findings, we hypothesized thatin paroxysmal AF, more selective ablation of sitesresponsible for AF maintenance would be as effectiveas CPVI while decreasing complication risks (CentralIllustration) (9). Although we failed to demonstratenoninferiority for the primary endpoint at 6 months,this result reflects only single procedure efficacy.Nevertheless, there was a trend toward statisticalsignificance in the secondary endpoint of freedomfrom AF/AT at 6 months (p ¼ 0.08 for noninferiority).At 1 year, HFSA provided similar efficacy rates interms of freedom from AF and AF/AT compared withCPVI, despite shorter delivered RF time and fewerisolated veins. Noninferiority could only be reachedafter redo procedures, with reconnection of previ-ously ablated PVs harboring HFS the dominantrecurrence mechanism in this group. Moreover, long-term complications were significantly reduced in theHFSA-only group.

The results concur with other studies using elec-trophysiological instead of purely anatomic end-points. In a randomized single-center study, Dixit et al.(16) demonstrated that isolation of arrhythmogenicveins was as efficacious as empiric isolation of all veinsin achieving long-term AF control, with all seriousprocedural events occurring in the empiric isolationarm. Using a different approach, Oral et al. (17) showedthat rendering AF noninducible by additional LAablation after CPVI was associated with better clinicalefficacy, but it increased the incidence of LA flutter.Narayan et al. (18) used a novel computationally-basedmapping approach to reveal AF rotors in the left orright atrium, then selectively ablated them with

TABLE 4 Quality of Life Assessment With Change From Baseline to 6 and 12 Months

AF-QOL QuestionnaireMean Change

Baseline vs. 6 MonthsMean DifferenceBetween Groups p Value*

Mean ChangeBaseline vs. 12 Months

Mean DifferenceBetween Groups p Value*

Paroxysmal AF

CPVI HFSA CPVI HFSA

Physical scores 20.6 � 4.3 17.4 � 3.8 3.2 � 5.7 0.578 26.4 � 4.9 22.7 � 4.3 3.71 � 5.5 0.569

Mental scores 21.1 � 4.7 15.1 � 3.5 5.9 � 5.7 0.3 30.6 � 5.1 21 � 3.9 8.6 � 6.4 0.137

Sexual scores 8.7 � 4.7 11.6 � 5.3 �2.9 � 7.2 0.687 23.7 � 5.4 15.5 � 5.6 8.2 � 8.1 0.315

Persistent AF

CPVI CPVI þ HFSA CPVI CPVI þ HFSA

Physical scores 20.5 � 4.5 15.1 � 4.2 5.4 � 6.2 0.387 31.2 � 3.4 25.2 � 3.9 6 � 5.2 0.251

Mental scores 14.9 � 3.9 9.1 � 3 6 � 5 0.237 24 � 3.5 16 � 4 8 � 5.3 0.135

Sexual scores 4 � 5.2 10.1 � 5.8 �6.1 � 7.8 0.436 17 � 4.8 12.1 � 5.5 4.9 � 7. 3 0.506

Values are mean � SE. *Student t test for paired data.

CENTRAL ILLUSTRATION Ablation Strategies Compared in PatientsWith Paroxysmal Atrial Fibrillation

Empiric circumferential pulmonary vein isolation was compared with high-frequency

source ablation. The dominant frequency map (left) enabled detection of the highest

frequency (purple) source (rotor) located at the left inferior pulmonary vein (1) with

fibrillatory conduction to the right atrium (2) that activated at the lowest rate (red to

white), as shown in boxes 1 and 2, where local bipolar recordings and the corresponding

power spectrum are depicted.


2465

favorable long-term results. More recently, thePRECISE-AF trial demonstrated that AF source abla-tion alone can eliminate paroxysmal AF without theneed to ablate the PVs (19). However, these single-center experiences have not been reproduced in large(n>100) randomizedmulticenter trials. Ours is thefirstmechanistically-based randomized AF ablation trialthat derives from translation of basic science knowl-edge into AF therapy (20).

In persistent AF, we found a more evenly-spaceddistribution of HFS (Figures 1 and 3) (4,7), with effi-cacy of CPVI þ HFSA similar to CPVI but with a trendtoward higher complication rates. Several factorsmight account for these disappointing results: 1) arelevant number of HFS were spared from ablationdue to safety concerns, precluding elimination ofcritical DF sites maintaining AF (Online Appendix);2) atrial fibrosis increases AF complexity in persistentpatients, precluding accurate DF measurement; and/or 3) the mechanisms underlying the maintenance ofAF in these patients might be undetectable using DF.

Substrate modification strategies have been com-bined with CPVI to try to enhance procedural efficacyin patients with persistent AF (12–15). Like our trial,other randomized studies found that additional sub-strate modification beyond PVI did not improveefficacy in patients with persistent AF (13,14). Incontrast, efficacy increased with CPVI followed byautomatic complex fractionated electrogram ablation(12) and rotor/focal sources ablation followed by CPVI(18). These conflicting data suggest that additionalextensive substrate modification beyond PVI, specif-ically DF ablation, does not consistently improveprocedure efficacy. Hence, further research is neededto enable detection and elimination of extrapulmo-nary vein sources of AF maintenance in this patientpopulation.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE 1: The

PVs are the most common location of triggers for AF,

and CPVI has become the therapy of choice for drug-

refractory AF. However, procedural risks and subop-

timal results due to non-PV sources that maintain AF

are important limitations. Whether the ablation of

non-PV triggers, complex fractionated electrograms,

rotors, or focal sources (localized HFSA), alone or in

combination with CPVI is associated with greater

procedural success or long-term complications

compared with CPVI alone has not been established.

COMPETENCY IN MEDICAL KNOWLEDGE 2:

In patients with paroxysmal AF, HFSA proved to be

noninferior to CPVI in achieving freedom from atrial

tachyarrhythmias at 1 year after the procedures and

was associated with a lower incidence of severe

adverse events. In persistent AF, however, procedures

combining CPVI with HFSA did not provide incre-

mental value and were associated with a trend to

increase complications risk.

TRANSLATIONAL OUTLOOK: Further advances in

arrhythmia mapping and signal analysis technologies

that increase the accuracy and completeness of abla-

tion of sources driving AF could influence the relative

efficacy and safety of the CPVI and HFSA strategies.



2466

Our periprocedural complication rate of 8% iscomparable to previous studies, large administrativedatabases, and registries (12,21). Our long-term SAErate (16.9%) was slightly higher than recent random-ized studies in paroxysmal (14.2%) and persistent AF(15.9%) patients (22,23), but lower than the EuropeanAtrial Fibrillation Ablation Pilot registry that alsoincluded post-ablation AT/flutter as a proceduralcomplication (26.5%) (24). Our results suggest that inparoxysmal AF, a more limited mechanistically-basedablation strategy is safer than empirically isolatingthe PVs. In contrast, in persistent AF, extensive atrialablation techniques including atrial lines, fraction-ated electrogram ablation, or HFSA added to CPVI, areassociated with an increased rate of complications(15,16). Therefore, the present study calls into ques-tion the generalized use of ablation strategies aimedat creating extensive lesions in the atria of patientswith persistent AF.

STUDY LIMITATIONS. DF mapping and detailed re-view of measured DFs was required to eliminatespurious measurements, which increased proceduretime. Also, sequential data point acquisition mayraise concerns regarding DF spatiotemporal stability.Due to safety concerns, several HFS were spared fromablation, and prior evidence suggests a betteroutcome would have been expected after ablation ofall HFS (7). Finally, more extensive electrocardiogrammonitoring may have detected additional episodes ofAF, but this may affect both treatment arms.

CONCLUSIONS

In paroxysmal AF, HFSA failed to achieve non-inferiority at 6 months after a single procedure butwas as efficacious as CPVI in achieving freedom of AF/AT at 1 year, with a lower incidence of SAEs. Inpersistent AF, CPVI þ HFSA offered no incrementalvalue, with a trend toward increased complications.These results may offer a novel mechanistic treat-ment paradigm for paroxysmal AF.

ACKNOWLEDGMENTS The authors wish to thank allof the RADAR-AF trial investigators (see the OnlineAppendix for a complete list) and Omer Berenfeld,PhD, for thoughtful discussions.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Felipe Atienza, Hospital General Universitario GregorioMarañón, Cardiology Department, C/ Dr Esquerdo, 46,28007 Madrid, Spain. E-mail: [email protected].

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2. Haïssaguerre M, Jais P, Shah DC, et al. Sponta-neous initiation of atrial fibrillation by ectopicbeats originating in the pulmonary veins. N Engl JMed 1998;339:659–66.

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14. Dixit S, Marchlinski FE, Lin D, et al. Random-ized ablation strategies for the treatment ofpersistent atrial fibrillation: RASTA study. CircArrhythm Electrophysiol 2012;5:287–94.

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19. Narayan AM, Krummen D, Donsky A, Swarup V,Tomassoni G, Miller J. Treatment of paroxysmalatrial fibrillation by targeted elimination of stablerotors and focal sources without pulmonary veinisolation: The PRECISE Trial (abstr). Heart Rhythm2013;10:LB01–5.

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22. Cosedis Nielsen J, Johannessen A,Raatikainen P, et al. Radiofrequency ablation asinitial therapy in paroxysmal atrial fibrillation.N Engl J Med 2012;367:1587–95.

23. Boersma LV, Castella M, van Boven W, et al.Atrial fibrillation catheter ablation versus surgicalablation treatment (FAST): a 2-center randomizedclinical trial. Circulation 2012;125:23–30.

24. Arbelo E, Brugada J, Hindricks G, et al. TheAtrial Fibrillation Ablation Pilot Study: a EuropeanSurvey on Methodology and results of catheterablation for atrial fibrillation conducted by theEuropean Heart Rhythm Association. Eur Heart J2014;35:1466–78.

KEY WORDS dominant frequency mapping,high-frequency source ablation

APPENDIX For an extended Methodssection and a full list of the RADAR-AF trialinvestigators, please see the online versionof this article.












































































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