JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 23, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.09.054
EDITORIAL COMMENT
Pulmonary Vein Isolation for Atrial Fibrillation Forever Young* Pasquale Santangeli, MD, Francis E. Marchlinski, MD
T
he efficacy of pulmonary vein isolation (PVI)
although confusion in this sense may easily arise
as a treatment for drug-refractory atrial
when facing data from published studies (Figure 1).
fibrillation (AF) has been established through
The results of the randomized RADAR-AF (Radio-
more than 15 years of clinical studies, which have
frequency Ablation of Drivers of Atrial Fibrillation)
shown consistent, reproducible results worldwide.
trial published in this issue of the Journal should be
The PVI technique has evolved to include antral isola-
viewed in this context (3). The RADAR-AF trial tested
tion to enhance safety and efficacy. However, the suc-
the hypothesis that localized high-frequency source
cess rate with current PVI techniques remains
ablation (HFSA) is noninferior to conventional antral
suboptimal, with single-procedure efficacy ranging
PVI in patients with paroxysmal AF and that a hybrid
between 50% and 75% (1).
strategy of PVI plus HFSA is superior to PVI alone in
Patients with persistent AF experience the worst
patients with persistent AF. High-frequency sources
outcomes, leading to the hypothesis that additional
(HFS) have been implicated in the maintenance of
ablation beyond the pulmonary veins (PVs) may be
human AF, and HFSA has achieved arrhythmia con-
required to improve success in these patients. Addi-
trol in patients with drug-refractory AF in uncon-
tional targets have focused on putative mechanisms
trolled case series (5). However, no prior clinical
responsible for AF maintenance, such as empirical
study compared HFSA with conventional PVI as a
linear ablation (1) or ablation of AF focal sources
treatment strategy for drug-refractory AF.
or rotors identified using various computational mapping techniques (2,3). This hypothesis, although
SEE PAGE 2455
sound from a mechanistic perspective related to AF maintenance, is flawed by the fact that none of the
The primary endpoint of the RADAR-AF trial was
studies comparing PVI alone with other non-PV
freedom from AF off of antiarrhythmic drugs at
ablation
ever
6 months. Secondary endpoints included freedom
achieved the desired goal of durable PVI: PV recon-
strategies
from AF at 1 year and procedural safety outcomes. In
nection rules in patients experiencing post-ablation
brief, the study failed to meet the primary endpoint;
arrhythmia recurrence (4). In the presence of PV
indeed, PVI only was superior to HFSA only at
reconnection, AF recurrences should neither be used
6-month follow-up in patients with paroxysmal AF
to claim ineffectiveness of PVI nor used to support
and was equivalent to PVI plus HFSA in patients with
the
persistent AF. The study, however, did show that
necessity
of
(with
or
additional
without
extra-PV
PVI)
ablation,
HFSA-only ablation reached the secondary endpoint of noninferiority at 1 year compared with PVI alone in *Editorials published in the Journal of the American College of Cardiology
patients with paroxysmal AF (79% vs. 81%) and
reflect the views of the authors and do not necessarily represent the
trended toward higher procedure-related complica-
views of JACC or the American College of Cardiology. From the Electrophysiology Section, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Both
tions with PVI (14% vs. 5%). To what extent can the findings of RADAR-AF be
authors have reported that they have no relationships relevant to the
generalized to the reader’s patients? The main re-
contents of this paper to disclose.
sults appear valid; the trial was well conducted and
Santangeli and Marchlinski
JACC VOL. 64, NO. 23, 2014 DECEMBER 16, 2014:2468–70
adequately powered to address its primary endpoint. However, caution is necessary when interpreting the
F I G U R E 1 Example: PV Reconnection Confounding Effect in PVI
secondary endpoints, for which the study was not
All Pts Undergoing AF Ablation (n = 200)
specifically designed and likely not powered. For instance, the higher rate of complications occurring
AF recurrence at 1 year AF-free survival Yes No 60 140 70%
in the PVI arm of the paroxysmal AF group (14%), which
was
driven
by
2469
Pulmonary Vein Isolation for AF
4
pericardial
effusions,
appeared substantially higher than that occurring with the same procedure in patients with persistent
Pts With Permanent PVI (n = 102)
Pts With PV Reconnection (n = 98)
AF recurrence at 1 year AF-free survival Yes No 2 100 98%
AF recurrence at 1 year AF-free survival Yes No 58 40 41%
AF (3%). Without sufficient power, it is hard to evaluate the effect of chance in the reported complications. Overall, the main findings of the RADAR-AF trial provide additional evidence supporting the current recommendations for using PVI across the spectrum of patients with AF (1). Importantly, PV reconnection
In this “hypothetical” trial of 200 patients (pts) undergoing pulmonary vein isolation (PVI), 70% reported survival free from recurrent atrial fibrillation (AF) at 1 year. AF recurrences over follow-up were largely driven by patients with pulmonary vein (PV) reconnection.
was confirmed as the leading mechanism of AF
This does not imply that PVI per se is not effective as a treatment strategy for AF or that
recurrence in both study groups. Even in patients
additional non-PV ablation is necessary, because the success rate in the subgroup with
who underwent HFSA only, PV isolation was used to
permanent PVI is nearly perfect (98%).
eliminate HFS at most index procedures and, in those with AF recurrences, all of the PVs harboring AFtriggering HFS at repeat procedures had been iso-
PVs (7). Also, no information was provided on
lated at the index procedure. These findings further
whether any effort was made to elicit acute PV
support the notion that achieving permanent PVI
reconnection at the time of the index procedure with
should be the main goal of catheter-based approaches
intravenous adenosine or high-dose isoproterenol.
to treat AF, but it remains a big challenge. In this
The latter could have increased the chance to elicit
regard, generalization of the RADAR-AF results is
and appropriately target latent non-PV triggers for AF
still questionable, due to the variability in ablation
that seem clinically relevant in an important sub-
techniques and approaches, which can affect PVI
group of patients. Previous studies suggest that non-
durability and, therefore, procedure efficacy. For
PV locations with HFS are consistent with common
example, for several years we have been implement-
AF trigger sites, and empirical ablation of such sites
ing strategies to enhance catheter stability to increase
may have explained some of the benefit of HFSA.
the effectiveness of ablation lesions, decrease the
Finally, the discretionary use of linear roof abla-
chance of chronic PV reconnection, and ultimately
tion might have diluted PVI effectiveness, as no
improve the success rate (6). These strategies include
conclusive data support the benefit of any left atrial
general anesthesia with jet ventilation to minimize
linear ablation (especially in paroxysmal AF); in
respiratory movement, steerable sheaths, periproce-
fact, evidence suggests that linear ablation may
dural monitoring of tissue-catheter contact and lesion
be proarrhythmic, particularly if performed without
formation with intracardiac echocardiography, and
confirming block. Given the good outcome with PVI
the use of adenosine to confirm early persistence of
in both paroxysmal and persistent AF patients in
PVI. None of these tools was used in the RADAR-AF
the
trial, and their absence might have undervalued
modifications would only further support the pri-
an even greater benefit of PVI when analyzing
macy and outcome of antral PVI and non-PV trigger
arrhythmia-free survival at longer follow-up (1 year).
ablation.
RADAR-AF
trial,
these
additional
technical
There are a few other considerations regarding the
In conclusion, the results of the RADAR-AF trial
protocol of this important study worth highlighting.
should be considered as more evidence favoring
The procedural endpoint adopted for PVI in the
antral PVI in patients with either paroxysmal or
RADAR-AF study was entry block, and additional roof
persistent AF. Future research efforts should be
linear ablation (without mandatory achievement of
directed toward the attainment and noninvasive
conduction block) was performed but at the discre-
confirmation of durable PVI. By achieving this goal,
tion of the operator. In our experience, demonstra-
we can unequivocally identify the smaller group of
tion of exit block in addition to entry block is
patients who truly do not respond to effective PVI
clinically relevant, as unidirectional entry block (with
only and may require different ablation approaches
exit conduction) can be observed in up to 20% of
and/or targets, including HFSA.
2470
Santangeli and Marchlinski
JACC VOL. 64, NO. 23, 2014 DECEMBER 16, 2014:2468–70
Pulmonary Vein Isolation for AF
In 1974, after 8 years away from the stage, during which time he had become a father, Bob Dylan
consistently important when performing AF ablation procedures.
released his 14th studio album, Planet Waves. The album featured 2 versions of a song dedicated to his
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
son, where he wished him to stay “Forever Young”
Francis E. Marchlinski, Hospital of the University of
(8). More than 15 years after its introduction, PVI
Pennsylvania, 9 Founders Pavilion–Cardiology, 3400
has stood the test of time and, in the words of
Spruce Street, Philadelphia, Pennsylvania 19104.
Bob Dylan, will likely stay “forever young” and
E-mail:
[email protected].
REFERENCES 1. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/ EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm 2012;9:632–96, e21. 2. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628–36. 3. Atienza F, Almendral J, Ormaetxe JM, et al. Comparison of radiofrequency catheter ablation of
drivers and circumferential pulmonary vein isolation in atrial fibrillation: a noninferiority randomized multicenter RADAR-AF trial. J Am Coll Cardiol 2014; 64:2455–67.
6. Hutchinson MD, Garcia FC, Mandel JE, et al. Efforts to enhance catheter stability improve atrial fibrillation ablation outcome. Heart Rhythm 2013; 10:347–53.
4. Callans DJ, Gerstenfeld EP, Dixit S, et al. Efficacy of repeat pulmonary vein isolation procedures in patients with recurrent atrial fibrillation. J Cardiovasc Electrophysiol 2004;15:1050–5.
7. Gerstenfeld EP, Dixit S, Callans D, et al. Utility
5. Atienza F, Almendral J, Jalife J, et al. Real-time dominant frequency mapping and ablation of dominant frequency sites in atrial fibrillation with left-to-right frequency gradients predicts longterm maintenance of sinus rhythm. Heart Rhythm 2009;6:33–40.
of exit block for identifying electrical isolation of the pulmonary veins. J Cardiovasc Electrophysiol 2002;13:971–9. 8. Dylan B. Forever Young. On: Planet Waves. Los Angeles, CA: Asylum Records, 1974.
KEY WORDS atrial fibrillation, catheter ablation, pulmonary vein isolation