JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 23, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2014.09.053
Comparison of Radiofrequency Catheter Ablation of Drivers and Circumferential Pulmonary Vein Isolation 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,x Jesús 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,zz Maria 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 BACKGROUND Empiric circumferential pulmonary vein isolation (CPVI) has become the therapy of choice for drugrefractory 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) randomized 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 12 months for freedom from AF and AF/AT. Serious adverse events were significantly reduced in the HFSA group versus CPVI patients (p ¼ 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.
From the *Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; yHospital Universitario Montepríncipe, Madrid, Spain; zHospital de Basurto, Bilbao, Spain; xHospital Vall d’Hebron, Barcelona, Spain; kClinica San Sebastian, Bilbao, Spain; {Hospital Ramón y Cajal, Madrid, Spain; #Hospital Virgen de la Salud, Toledo, Spain; **Hospital Doce de Octubre, Madrid, Spain; yyHospital Virgen de las Nieves, Granada, Spain; zzHospital La Paz, Madrid, Spain; xxUniversidad Politécnica de Valencia, Valencia, Spain; and the kkUniversity of Michigan, Ann Arbor, Michigan. This study was funded by the Centro Nacional de Investigaciones Cardiovasculares and by an unrestricted research grant from St. Jude Medical. Dr. Atienza has received research grants from St. Jude Medical; and is on the advisory board of Medtronic, Inc. Dr. Jalife is on the scientific advisory board of Topera, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 16, 2014; revised manuscript received August 31, 2014, accepted September 5, 2014.
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JACC VOL. 64, NO. 23, 2014
Catheter Ablation of AF Drivers
DECEMBER 16, 2014:2455–67
C
ABBREVIATIONS AND ACRONYMS AAD = antiarrhythmic drug AF = atrial fibrillation AT = atrial tachyarrhythmia CPVI = circumferential pulmonary vein isolation
DF = dominant frequency HF = high frequency
urrently-available
antiarrhythmic
committee of the participating centers. All patients
drugs (AADs) used to treat atrial
provided written informed consent.
fibrillation (AF) have limited effi-
STUDY POPULATION. All patients from the outpa-
cacy and are frequently associated with
tient clinics with indication for AF ablation were
adverse long-term effects (1). The demon-
screened for eligibility. Inclusion criteria included
stration that AF triggers are most commonly
symptomatic paroxysmal AF, refractory/intolerant
located in the pulmonary veins (PVs) led to
to at least 1 AAD documented within 12 months
development of radiofrequency (RF)-based
of randomization, anticoagulation >4 weeks prior
ablative strategies aimed at creating circum-
to inclusion, or a transesophageal echocardiogram
ferential lesions around the PV ostia (1,2).
excluding intracardiac thrombus. Persistent AF was
HFS = high-frequency sources
Empiric
HFSA = high-frequency
isolation (CPVI) is effective in w70% to 80%
with patients anticoagulated for >4 weeks prior to
of patients with paroxysmal AF and is the
ablation and willing to give informed consent.
therapy of choice for drug-refractory AF (1).
PV = pulmonary vein
Patients were excluded if they had prior AF ablation;
However, the procedure includes risks, and
inadequate anticoagulation levels; LA thrombus,
RF = radiofrequency
results remain suboptimal due to PV recon-
tumors, or cardiac abnormalities precluding the pro-
SAE = serious adverse event(s)
nection and non-PV sources that maintain
cedure; contraindications to systemic anticoagula-
AF (1). Moreover, the CPVI success rate in the more
tion; AF secondary to reversible causes; left atrial size
prevalent persistent AF is significantly lower than
>55 mm; pregnancy; thyroid disease; other investi-
with paroxysmal AF, and substrate-based ablation
gational study involvement; and implanted device.
source ablation
LA = left atrium
circumferential
pulmonary
vein
strategies have been proposed (1,3). SEE PAGE 2468
Advanced signal analysis methods have demonstrated that AF is maintained by high-frequency sources (HFS), often located at the PV-left atrial (LA) junction and less frequently at other sites in both atria (4–8). Therefore, several studies have suggested that instead of empirically targeting the PVs, AF may be eliminated by directly ablating AF-driving sources or “rotors” that exhibit highfrequency, periodic activity (4–8). However, the clinical
outcomes
of
this
mechanistically-based
strategy remain unknown.
defined as continuous AF sustained beyond 7 days,
STUDY
DESIGN. Randomization
was
performed
according to AF type using a web-based system and was balanced at each site. Paroxysmal AF patients were randomly assigned 1:1 to CPVI or HFSA. Persistent AF patients were randomly assigned 1:1 to CPVI or a combined ablation approach (CPVI þ HFSA). Because of the nature of the intervention, physicians performing the ablation procedure were not blinded to treatment group assignment. FOLLOW-UP. Patients were followed by physicians
blinded to the assigned treatment arm at 3, 6, and 12 months from the first ablation procedure, and 12-lead electrocardiogram, 48-h Holter recordings, and qual-
RADAR-AF (Radiofrequency Ablation of Drivers of
ity of life (QOL) questionnaires were obtained at each
Atrial Fibrillation) was a multicenter, single-blinded,
follow-up visit. Holter analysis was blinded with
randomized clinical trial designed to compare the
respect to randomization and treatment. All adverse
efficacy and safety of the standard ablation strategy
events were reviewed and adjudicated by an inde-
(CPVI) with a strategy of localized high-frequency
pendent data safety monitoring committee.
source ablation (HFSA) alone in paroxysmal AF
ABLATION PROCEDURE AND STRATEGIES. Electro-
or combined with CPVI in persistent AF (9). We
physiological study common to all patients. AADs
hypothesized that: 1) in paroxysmal AF patients, the
were stopped >5 half-lives prior to the procedure,
efficacy of selective HFSA would be similar to
except for amiodarone. In patients arriving in sinus
empirical CPVI but with fewer complications; and
rhythm (SR), AF was induced following a standard-
2) in persistent AF patients, a combination of CPVI
ized protocol (8). If AF was not sustained for >5 min,
plus HFSA would increase efficacy without increasing
the patient was excluded from study. Once in AF, the
complications.
patient was randomized. Three-dimensional geometry of the atria was reconstructed using the Ensite
METHODS
NavX System version 8.0 (St. Jude Medical, Minne-
An extended version of the Methods section is
a 3.5-mm irrigated-tip ablation catheter (Therapy
provided in the Online Appendix; a description of the
Cool Path, St. Jude Medical, St. Paul, Minnesota).
ablation strategies utilized is detailed in the following
C P V I s t r a t e g y . In patients assigned to CPVI, the PVs
text. The study protocol was approved by the ethics
were isolated using circumferential lesions around
apolis, Minnesota) (8). RF energy was delivered using
JACC VOL. 64, NO. 23, 2014
Atienza et al.
DECEMBER 16, 2014:2455–67
Catheter Ablation of AF Drivers
the PV antrum with confirmation of entrance block using a multipolar circular catheter (Figure 1A). An
2457
F I G U R E 1 Study Ablation Strategies
additional roof line was allowed, but conduction block across the line was not formally required. Organized atrial tachyarrhythmias (ATs) or flutter occurring after CPVI could be mapped and ablated at the discretion of the investigator. If the patient was in AF at the procedure’s end, he/she could be cardioverted, and remapping was performed to confirm PV isolation. Termination and/or noninducibility of AF were not procedural endpoints. H F S A s t r a t e g y . A high-density dominant frequency (DF) LA map was created by sequentially moving the ablation and/or circular mapping catheter throughout the entire left atrium. Sites with high-frequency (HF) atrial electrograms were identified by an automated algorithm designed to calculate the DF and depict local atrial activation frequency on the 3-dimensional LA shell (Figure 1B) (8). HFS were targeted until ablation endpoints were reached: 1) elimination of all HFS or conversion to SR; and 2) noninducibility of AF postablation. If AF did not terminate after LA HFSA, DF maps from the right atrium (RA) and coronary sinus (CS) were obtained and HFS were targeted at the operator’s discretion. A maximum of 3 to 4 HFS per
(A) Circumferential pulmonary vein isolation (CPVI) as seen from the left atrial (LA) pos-
chamber were targeted for ablation (4 sites in LA and 3
terior view. Red dots indicate ablation lesions. (B) High-frequency source ablation (HFSA)
sites in RA and CS). Ablation of HF sites located at a PV
as seen in this LA dominant frequency (DF) map, posterior view, showing an HFS located at
antrum was performed by creating a circumferential set of lesions around the ostium of the responsible vein until PV isolation was obtained (Figure 1B) (7,9). HF
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).
sites located elsewhere in the atria were targeted for ablation until local potentials were completely abated
assigned in the first procedure, except for the
through creation of a coin-like circumferential set of
HFSA-only arm, where the investigator could perform
lesions. Organized ATs occurring after elimination of
either CPVI or HFSA.
HF sites could be mapped and ablated at the investigator’s discretion. If AF persisted despite elimination of all HF sites from the LA, RA, and CS, the AF could be cardioverted and the procedure terminated. C o m b i n e d s t r a t e g y : C P V I D H F S A . A high-density DF LA map was obtained and then CPVI was performed. If the patient remained in AF, HFS were targeted for ablation, according to the previously described protocol, until ablation endpoints were reached: 1) elimination of HFS; and 2) PV isolation (Figure 1C). If AF did not terminate after LA HFSA, RA and CS DF maps were obtained and HFS was targeted (at operator discretion). If AF persisted despite elim-
STUDY
OUTCOMES. The
primary
endpoint
was
freedom from AF at 6 months post-first ablation procedure off of AADs. Secondary endpoints included freedom from AF/AT at 6 and 12 months off/on AADs; need for redo procedures; incidence of periprocedural complications and overall adverse events; fluoroscopy time and procedure duration; and QOL at baseline and at 3, 6, and 12 months assessed using the specific AF-QOL questionnaire (10). Recurrent AF/AT was defined as AF/AT of at least 30 s duration documented by electrocardiogram or device recording system >2 months following catheter ablation (1).
ination of all HFS from the LA, RA, and CS, AF could
SAFETY OUTCOMES. Adverse events were classified
be cardioverted and the procedure terminated.
according to their seriousness and whether they were
R e d o p r o c e d u r e s . A 2-month blanking period was
procedure related (Online Appendix) (1).
observed, after which AADs were discontinued. Redo
STATISTICAL
procedures due to recurrent AF were not allowed
in paroxysmal AF was that HFSA would be noninferior
within the first 6 months; they were performed 6 to
and
7.5 months post-ablation using the same strategy
noninferiority was achieved in the primary analysis,
METHODS. The
associated
with
lower
primary hypothesis risk
than
CPVI.
If
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Atienza et al.
JACC VOL. 64, NO. 23, 2014
Catheter Ablation of AF Drivers
DECEMBER 16, 2014:2455–67
a closed testing procedure was conducted for superiority. also
Secondary were
tested
efficacy for
and
safety
superiority.
RESULTS
endpoints analyses
We enrolled 232 patients (115 [49%] paroxysmal AF
were intention-to-treat. Statistical significance was
All
and 117 [51%] persistent AF) between May 2009 and
considered 1-sided for paroxysmal and 2-sided for
May 2012, with last follow-up in May 2013. The
persistent AF and was declared if the p value
2 groups were well-matched with respect to baseline
was 5 min 129 Other 114 Refused participation 232 Patients randomized
Paroxysmal AF 115 patients 56 Patients HFSA strategy 1 Patient excluded protocol violation 55 Patients analyzed at 6 months
59 Patients CPVI strategy
Persistent AF 117 patients 59 Patients HFSA+CPVI combined strategy
58 Patients CPVI strategy
59 Patients analyzed at 6 months
58 Patients analyzed at 6 months
1 Patient lost to follow up 58 Patients analyzed at 6 months
1 Patient withdrawn consent
1 Patient withdrawn consent 54 Patients analyzed at 1 year
58 Patients analyzed at 1 year
58 Patients analyzed at 1 year
1 Patient withdrawn consent 57 Patients analyzed at 1 year
Patient distribution according to eligibility, atrial fibrillation (AF) type, ablation strategy assignment, and follow-up duration. Abbreviations as in Figure 1.
3.79 0.5 veins were isolated compared with
RF duration (Table 2) (see Online Appendix for further
2.22 1.1 in the HFSA group (p < 0.001). Delivered
details).
RF time was significantly shorter in patients under-
EFFICACY OUTCOMES. In paroxysmal AF, freedom
going HFSA versus CPVI (p < 0.01). A significantly
from AF without AADs at 6 months (primary
higher percentage of patients undergoing HFSA
endpoint) was seen in 83% of CPVI versus 73% of
converted to SR during ablation (45% vs. 28%;
HFSA patients (risk difference [RD]: 0.1; lower
p < 0.05). In persistent AF patients assigned to CPVI þ HFSA,
limit 1-sided 95% confidence interval [CI]: 0.228; p ¼ 0.228 for noninferiority; p ¼ 0.901 for superiority)
after 28 17 min, DF mapping identified a median
(Figure 4). Freedom from AF/AT at 6 months also was
of 3 HFS (IQR: 2 to 5 HFS) per patient (Figure 3),
similar (69% of CPVI vs. 65% of HFSA patients;
3.88 0.45 veins were isolated, and a median of 3 HFS
RD: 0.035; lower limit 1-sided 95% CI: 0.18;
(IQR: 2 to 4.25 HFS) were ablated; 26 HFS were not
p ¼ 0.08 for noninferiority; p ¼ 0.654 for superiority).
ablated. In persistent AF patients assigned to CPVI,
After a single procedure, time to first AF recurrence
3.93 0.45 veins were isolated. Compared with the
and time to first AF/AT recurrence were not signifi-
CPVI group, the CPVI þ HFSA group had significantly
cantly different between groups (Figure 5). At 1 year,
longer procedure duration and a trend toward longer
freedom from AF was seen in 79% of CPVI and 81% of
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Atienza et al.
JACC VOL. 64, NO. 23, 2014
Catheter Ablation of AF Drivers
DECEMBER 16, 2014:2455–67
T A B L E 2 Procedural Characteristics
Paroxysmal AF
Induced AF Mean AF cycle length, ms
Persistent AF
p Value
CPVI (n ¼ 58)
CPVI þ HFSA (n ¼ 59)
49 (89)
0.26
11 (19)
11 (19)
0.61
176 33
0.55
171 33
169 33
0.79
CPVI (n ¼ 58)
HFSA (n ¼ 55)
46 (81) 172 35
p Value
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
215 66
228 65
0.31
202 58
239 61
0.001
DF mapping time, min
Total procedure time, min 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 Isolated pulmonary veins Patients with additional ablation lines
NA
18
NA
NA
26
NA
3.79 0.50
2.22 1.10
VOL. 64, NO. 23, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2014.09.053
Comparison of Radiofrequency Catheter Ablation of Drivers and Circumferential Pulmonary Vein Isolation 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,x Jesús 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,zz Maria 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 BACKGROUND Empiric circumferential pulmonary vein isolation (CPVI) has become the therapy of choice for drugrefractory 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) randomized 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 12 months for freedom from AF and AF/AT. Serious adverse events were significantly reduced in the HFSA group versus CPVI patients (p ¼ 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.
From the *Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; yHospital Universitario Montepríncipe, Madrid, Spain; zHospital de Basurto, Bilbao, Spain; xHospital Vall d’Hebron, Barcelona, Spain; kClinica San Sebastian, Bilbao, Spain; {Hospital Ramón y Cajal, Madrid, Spain; #Hospital Virgen de la Salud, Toledo, Spain; **Hospital Doce de Octubre, Madrid, Spain; yyHospital Virgen de las Nieves, Granada, Spain; zzHospital La Paz, Madrid, Spain; xxUniversidad Politécnica de Valencia, Valencia, Spain; and the kkUniversity of Michigan, Ann Arbor, Michigan. This study was funded by the Centro Nacional de Investigaciones Cardiovasculares and by an unrestricted research grant from St. Jude Medical. Dr. Atienza has received research grants from St. Jude Medical; and is on the advisory board of Medtronic, Inc. Dr. Jalife is on the scientific advisory board of Topera, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 16, 2014; revised manuscript received August 31, 2014, accepted September 5, 2014.
2456
Atienza et al.
JACC VOL. 64, NO. 23, 2014
Catheter Ablation of AF Drivers
DECEMBER 16, 2014:2455–67
C
ABBREVIATIONS AND ACRONYMS AAD = antiarrhythmic drug AF = atrial fibrillation AT = atrial tachyarrhythmia CPVI = circumferential pulmonary vein isolation
DF = dominant frequency HF = high frequency
urrently-available
antiarrhythmic
committee of the participating centers. All patients
drugs (AADs) used to treat atrial
provided written informed consent.
fibrillation (AF) have limited effi-
STUDY POPULATION. All patients from the outpa-
cacy and are frequently associated with
tient clinics with indication for AF ablation were
adverse long-term effects (1). The demon-
screened for eligibility. Inclusion criteria included
stration that AF triggers are most commonly
symptomatic paroxysmal AF, refractory/intolerant
located in the pulmonary veins (PVs) led to
to at least 1 AAD documented within 12 months
development of radiofrequency (RF)-based
of randomization, anticoagulation >4 weeks prior
ablative strategies aimed at creating circum-
to inclusion, or a transesophageal echocardiogram
ferential lesions around the PV ostia (1,2).
excluding intracardiac thrombus. Persistent AF was
HFS = high-frequency sources
Empiric
HFSA = high-frequency
isolation (CPVI) is effective in w70% to 80%
with patients anticoagulated for >4 weeks prior to
of patients with paroxysmal AF and is the
ablation and willing to give informed consent.
therapy of choice for drug-refractory AF (1).
PV = pulmonary vein
Patients were excluded if they had prior AF ablation;
However, the procedure includes risks, and
inadequate anticoagulation levels; LA thrombus,
RF = radiofrequency
results remain suboptimal due to PV recon-
tumors, or cardiac abnormalities precluding the pro-
SAE = serious adverse event(s)
nection and non-PV sources that maintain
cedure; contraindications to systemic anticoagula-
AF (1). Moreover, the CPVI success rate in the more
tion; AF secondary to reversible causes; left atrial size
prevalent persistent AF is significantly lower than
>55 mm; pregnancy; thyroid disease; other investi-
with paroxysmal AF, and substrate-based ablation
gational study involvement; and implanted device.
source ablation
LA = left atrium
circumferential
pulmonary
vein
strategies have been proposed (1,3). SEE PAGE 2468
Advanced signal analysis methods have demonstrated that AF is maintained by high-frequency sources (HFS), often located at the PV-left atrial (LA) junction and less frequently at other sites in both atria (4–8). Therefore, several studies have suggested that instead of empirically targeting the PVs, AF may be eliminated by directly ablating AF-driving sources or “rotors” that exhibit highfrequency, periodic activity (4–8). However, the clinical
outcomes
of
this
mechanistically-based
strategy remain unknown.
defined as continuous AF sustained beyond 7 days,
STUDY
DESIGN. Randomization
was
performed
according to AF type using a web-based system and was balanced at each site. Paroxysmal AF patients were randomly assigned 1:1 to CPVI or HFSA. Persistent AF patients were randomly assigned 1:1 to CPVI or a combined ablation approach (CPVI þ HFSA). Because of the nature of the intervention, physicians performing the ablation procedure were not blinded to treatment group assignment. FOLLOW-UP. Patients were followed by physicians
blinded to the assigned treatment arm at 3, 6, and 12 months from the first ablation procedure, and 12-lead electrocardiogram, 48-h Holter recordings, and qual-
RADAR-AF (Radiofrequency Ablation of Drivers of
ity of life (QOL) questionnaires were obtained at each
Atrial Fibrillation) was a multicenter, single-blinded,
follow-up visit. Holter analysis was blinded with
randomized clinical trial designed to compare the
respect to randomization and treatment. All adverse
efficacy and safety of the standard ablation strategy
events were reviewed and adjudicated by an inde-
(CPVI) with a strategy of localized high-frequency
pendent data safety monitoring committee.
source ablation (HFSA) alone in paroxysmal AF
ABLATION PROCEDURE AND STRATEGIES. Electro-
or combined with CPVI in persistent AF (9). We
physiological study common to all patients. AADs
hypothesized that: 1) in paroxysmal AF patients, the
were stopped >5 half-lives prior to the procedure,
efficacy of selective HFSA would be similar to
except for amiodarone. In patients arriving in sinus
empirical CPVI but with fewer complications; and
rhythm (SR), AF was induced following a standard-
2) in persistent AF patients, a combination of CPVI
ized protocol (8). If AF was not sustained for >5 min,
plus HFSA would increase efficacy without increasing
the patient was excluded from study. Once in AF, the
complications.
patient was randomized. Three-dimensional geometry of the atria was reconstructed using the Ensite
METHODS
NavX System version 8.0 (St. Jude Medical, Minne-
An extended version of the Methods section is
a 3.5-mm irrigated-tip ablation catheter (Therapy
provided in the Online Appendix; a description of the
Cool Path, St. Jude Medical, St. Paul, Minnesota).
ablation strategies utilized is detailed in the following
C P V I s t r a t e g y . In patients assigned to CPVI, the PVs
text. The study protocol was approved by the ethics
were isolated using circumferential lesions around
apolis, Minnesota) (8). RF energy was delivered using
JACC VOL. 64, NO. 23, 2014
Atienza et al.
DECEMBER 16, 2014:2455–67
Catheter Ablation of AF Drivers
the PV antrum with confirmation of entrance block using a multipolar circular catheter (Figure 1A). An
2457
F I G U R E 1 Study Ablation Strategies
additional roof line was allowed, but conduction block across the line was not formally required. Organized atrial tachyarrhythmias (ATs) or flutter occurring after CPVI could be mapped and ablated at the discretion of the investigator. If the patient was in AF at the procedure’s end, he/she could be cardioverted, and remapping was performed to confirm PV isolation. Termination and/or noninducibility of AF were not procedural endpoints. H F S A s t r a t e g y . A high-density dominant frequency (DF) LA map was created by sequentially moving the ablation and/or circular mapping catheter throughout the entire left atrium. Sites with high-frequency (HF) atrial electrograms were identified by an automated algorithm designed to calculate the DF and depict local atrial activation frequency on the 3-dimensional LA shell (Figure 1B) (8). HFS were targeted until ablation endpoints were reached: 1) elimination of all HFS or conversion to SR; and 2) noninducibility of AF postablation. If AF did not terminate after LA HFSA, DF maps from the right atrium (RA) and coronary sinus (CS) were obtained and HFS were targeted at the operator’s discretion. A maximum of 3 to 4 HFS per
(A) Circumferential pulmonary vein isolation (CPVI) as seen from the left atrial (LA) pos-
chamber were targeted for ablation (4 sites in LA and 3
terior view. Red dots indicate ablation lesions. (B) High-frequency source ablation (HFSA)
sites in RA and CS). Ablation of HF sites located at a PV
as seen in this LA dominant frequency (DF) map, posterior view, showing an HFS located at
antrum was performed by creating a circumferential set of lesions around the ostium of the responsible vein until PV isolation was obtained (Figure 1B) (7,9). HF
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).
sites located elsewhere in the atria were targeted for ablation until local potentials were completely abated
assigned in the first procedure, except for the
through creation of a coin-like circumferential set of
HFSA-only arm, where the investigator could perform
lesions. Organized ATs occurring after elimination of
either CPVI or HFSA.
HF sites could be mapped and ablated at the investigator’s discretion. If AF persisted despite elimination of all HF sites from the LA, RA, and CS, the AF could be cardioverted and the procedure terminated. C o m b i n e d s t r a t e g y : C P V I D H F S A . A high-density DF LA map was obtained and then CPVI was performed. If the patient remained in AF, HFS were targeted for ablation, according to the previously described protocol, until ablation endpoints were reached: 1) elimination of HFS; and 2) PV isolation (Figure 1C). If AF did not terminate after LA HFSA, RA and CS DF maps were obtained and HFS was targeted (at operator discretion). If AF persisted despite elim-
STUDY
OUTCOMES. The
primary
endpoint
was
freedom from AF at 6 months post-first ablation procedure off of AADs. Secondary endpoints included freedom from AF/AT at 6 and 12 months off/on AADs; need for redo procedures; incidence of periprocedural complications and overall adverse events; fluoroscopy time and procedure duration; and QOL at baseline and at 3, 6, and 12 months assessed using the specific AF-QOL questionnaire (10). Recurrent AF/AT was defined as AF/AT of at least 30 s duration documented by electrocardiogram or device recording system >2 months following catheter ablation (1).
ination of all HFS from the LA, RA, and CS, AF could
SAFETY OUTCOMES. Adverse events were classified
be cardioverted and the procedure terminated.
according to their seriousness and whether they were
R e d o p r o c e d u r e s . A 2-month blanking period was
procedure related (Online Appendix) (1).
observed, after which AADs were discontinued. Redo
STATISTICAL
procedures due to recurrent AF were not allowed
in paroxysmal AF was that HFSA would be noninferior
within the first 6 months; they were performed 6 to
and
7.5 months post-ablation using the same strategy
noninferiority was achieved in the primary analysis,
METHODS. The
associated
with
lower
primary hypothesis risk
than
CPVI.
If
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JACC VOL. 64, NO. 23, 2014
Catheter Ablation of AF Drivers
DECEMBER 16, 2014:2455–67
a closed testing procedure was conducted for superiority. also
Secondary were
tested
efficacy for
and
safety
superiority.
RESULTS
endpoints analyses
We enrolled 232 patients (115 [49%] paroxysmal AF
were intention-to-treat. Statistical significance was
All
and 117 [51%] persistent AF) between May 2009 and
considered 1-sided for paroxysmal and 2-sided for
May 2012, with last follow-up in May 2013. The
persistent AF and was declared if the p value
2 groups were well-matched with respect to baseline
was 5 min 129 Other 114 Refused participation 232 Patients randomized
Paroxysmal AF 115 patients 56 Patients HFSA strategy 1 Patient excluded protocol violation 55 Patients analyzed at 6 months
59 Patients CPVI strategy
Persistent AF 117 patients 59 Patients HFSA+CPVI combined strategy
58 Patients CPVI strategy
59 Patients analyzed at 6 months
58 Patients analyzed at 6 months
1 Patient lost to follow up 58 Patients analyzed at 6 months
1 Patient withdrawn consent
1 Patient withdrawn consent 54 Patients analyzed at 1 year
58 Patients analyzed at 1 year
58 Patients analyzed at 1 year
1 Patient withdrawn consent 57 Patients analyzed at 1 year
Patient distribution according to eligibility, atrial fibrillation (AF) type, ablation strategy assignment, and follow-up duration. Abbreviations as in Figure 1.
3.79 0.5 veins were isolated compared with
RF duration (Table 2) (see Online Appendix for further
2.22 1.1 in the HFSA group (p < 0.001). Delivered
details).
RF time was significantly shorter in patients under-
EFFICACY OUTCOMES. In paroxysmal AF, freedom
going HFSA versus CPVI (p < 0.01). A significantly
from AF without AADs at 6 months (primary
higher percentage of patients undergoing HFSA
endpoint) was seen in 83% of CPVI versus 73% of
converted to SR during ablation (45% vs. 28%;
HFSA patients (risk difference [RD]: 0.1; lower
p < 0.05). In persistent AF patients assigned to CPVI þ HFSA,
limit 1-sided 95% confidence interval [CI]: 0.228; p ¼ 0.228 for noninferiority; p ¼ 0.901 for superiority)
after 28 17 min, DF mapping identified a median
(Figure 4). Freedom from AF/AT at 6 months also was
of 3 HFS (IQR: 2 to 5 HFS) per patient (Figure 3),
similar (69% of CPVI vs. 65% of HFSA patients;
3.88 0.45 veins were isolated, and a median of 3 HFS
RD: 0.035; lower limit 1-sided 95% CI: 0.18;
(IQR: 2 to 4.25 HFS) were ablated; 26 HFS were not
p ¼ 0.08 for noninferiority; p ¼ 0.654 for superiority).
ablated. In persistent AF patients assigned to CPVI,
After a single procedure, time to first AF recurrence
3.93 0.45 veins were isolated. Compared with the
and time to first AF/AT recurrence were not signifi-
CPVI group, the CPVI þ HFSA group had significantly
cantly different between groups (Figure 5). At 1 year,
longer procedure duration and a trend toward longer
freedom from AF was seen in 79% of CPVI and 81% of
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Catheter Ablation of AF Drivers
DECEMBER 16, 2014:2455–67
T A B L E 2 Procedural Characteristics
Paroxysmal AF
Induced AF Mean AF cycle length, ms
Persistent AF
p Value
CPVI (n ¼ 58)
CPVI þ HFSA (n ¼ 59)
49 (89)
0.26
11 (19)
11 (19)
0.61
176 33
0.55
171 33
169 33
0.79
CPVI (n ¼ 58)
HFSA (n ¼ 55)
46 (81) 172 35
p Value
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
215 66
228 65
0.31
202 58
239 61
0.001
DF mapping time, min
Total procedure time, min 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 Isolated pulmonary veins Patients with additional ablation lines
NA
18
NA
NA
26
NA
3.79 0.50
2.22 1.10
