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

Pulmonary vein isolation for atrial fibrillation: forever young.

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