RETRACTED: Impact of Rotor Ablation in Nonparoxysmal Atrial Fibrillation Patients Results From the Randomized OASIS Trial [J Am Coll Cardiol 2016;68:274–82]

Accepted Manuscript Impact of Rotor Ablation in Non-Paroxysmal AF Patients: Results from a Randomized Trial (OASIS) Sanghamitra Mohanty, MD, Carola Gianni, MD, Prasant Mohanty, MBBS, MPH, Philipp Halbfass, MD, Tamara Metz, BSN RN, Chintan Trivedi, MD, MPH, Thomas Deneke, MD, Gery Tomassoni, MD, Rong Bai, MD, Amin Al-Ahmad, MD, Shane Bailey, MD, John David Burkhardt, MD, G Joseph Gallinghouse, MD, Rodney Horton, MD, Patrick M. Hranitzky, MD, Javier E. Sanchez, MD, Luigi Di Biase, MD, PHD, Andrea Natale, MD PII:

S0735-1097(16)32827-3

DOI:

10.1016/j.jacc.2016.04.015

Reference:

JAC 22521

To appear in:

Journal of the American College of Cardiology

Received Date: 5 April 2016 Revised Date:

17 April 2016

Accepted Date: 18 April 2016

Please cite this article as: Mohanty S, Gianni C, Mohanty P, Halbfass P, Metz T, Trivedi C, Deneke T, Tomassoni G, Bai R, Al-Ahmad A, Bailey S, Burkhardt JD, Gallinghouse GJ, Horton R, Hranitzky PM, Sanchez JE, Di Biase L, Natale A, Impact of Rotor Ablation in Non-Paroxysmal AF Patients: Results from a Randomized Trial (OASIS), Journal of the American College of Cardiology (2016), doi: 10.1016/ j.jacc.2016.04.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Impact of Rotor Ablation in Non-Paroxysmal AF Patients: Results from a Randomized Trial (OASIS)

RI PT

Sanghamitra Mohantya, MD, Carola Giannia, MD, Prasant Mohantya, MBBS, MPH, Philipp Halbfassb, MD, Tamara Metza, BSN RN, Chintan Trivedia, MD, MPH, Thomas Denekeb, MD, Gery Tomassonic, MD, Rong Baia,d, MD, Amin Al-Ahmada, MD, Shane Baileya, MD, John David Burkhardta, MD, G Joseph Gallinghousea, MD, Rodney Hortona, MD, Patrick M Hranitzkya, MD, Javier E Sancheza, MD, Luigi Di Biasea,b, MD, PHD, Andrea Natalea, e-i, MD

M AN U

SC

Affiliations: a Texas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, Texas b Cardiovascular Center Bad Neustadt, Germany c Lexington Cardiology at Central Baptist, Lexington, Kentucky d Beijing Anzhen Hospital, Capital Medical University, Beijing, China e Electrophysiology and Arrhythmia Services, California Pacific Medical Center, San Francisco, California f Interventional Electrophysiology, Scripps Clinic, La Jolla, California g Metro Health Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio h Division of Cardiology, Stanford University, Stanford, California i Dell Medical School, University of Texas, Austin, Texas

EP

TE D

Disclosures: Dr. Di Biase is a consultant for Biosense Webster, Boston Scientific Stereotaxis and St Jude Medical. Dr Di Biase received speaker honoraria/travel from Medtronic, Atricure, EPiEP and Biotronik. Dr. Natale received speaker honorariums from Boston Scientific, Biosense Webster, St. Jude Medical, Biotronik and Medtronic, Dr Natale is a consultant for Biosense Webster St Jude Medical and Janssen. Dr Burkhardt is a consultant for Biosense-Webster and Stereotaxis. All the remaining authors have no disclosures.

AC C

Address for correspondence: Andrea Natale, MD Texas Cardiac Arrhythmia Institute St. David’s Medical Center 3000 N. IH-35, Suite 720 Austin, Texas 78705 Telephone + 1 (512) 544-8186 Fax + 1 (512) 544-8184 E-mail: [email protected]

1

ACCEPTED MANUSCRIPT

TE D

M AN U

SC

RI PT

Abstract Introduction: Few studies have reported focal impulse and rotor modulation (FIRM)-guided ablation to be superior to PV isolation (PVAI) in persistent (PeAF) and long-standing persistent atrial fibrillation (LSPAF) patients, but none of these trials were randomized. Objectives: We compared the efficacy of FIRM ablation with or without PVAI vs PVAI plus non-PV trigger ablation in PeAF and LSPAF patients. Methods: Non-paroxysmal AF patients undergoing first ablation were randomized (1:1:1) to FIRM only (group 1), FIRM+ PVAI (group 2) or PVAI+ posterior wall (PW) +non-PV trigger ablation (group 3). Freedom from atrial tachycardia (AT)/AF was the primary endpoint. Secondary endpoint included acute procedural success, defined as AF termination or ≥10% slowing or organization into AT. Results: Total of 113 patients were enrolled at 3 centers; 29 in group 1 and 42 in group 2 and 3 each. Enrollment in group 1 was terminated early for futility. Focal drivers or rotors were detected in all group 1 and 2 patients with a mean of 4±1.2 and 4.2± 1.7 per patient in respective groups. Procedure time was 222±49, 233± 48 and 131± 51 minutes in groups 1, 2 and 3 (p<0.001); it was significantly shorter in group 3 compared to groups 1 and 2 (p<0.001). In group 1 and 2, acute success after rotor only ablation was achieved in 12 (41%) and 11 (26%) patients respectively. After 12±7 month follow-up, 4 (14%), 22 (52.4%) and 32 (76%) patients in groups 1, 2 and 3 were AF/AT-free off anti-arrhythmic drugs (log-rank p<0.0001). Group 3 patients experienced higher success compared to group 1 (p<0.001) and group 2(p= 0.02). Conclusion: This is the first randomized study that compared three ablation strategies in nonparoxysmal AF patients and reported a very poor outcome with rotor-only ablation. Moreover, PVAI plus rotor ablation had significantly longer procedure time and lower efficacy than PVAI + PW + non-PV trigger-ablation. Key Words: FIRM-guided ablation, PVAI, non-paroxysmal AF, rotors, non-PV triggers

AC C

EP

Abbreviations: PVAI: Pulmonary vein antrum isolation; PeAF: Persistent AF; LSPAF: Longstanding persistent AF; FIRM: focal impulse and rotor modulation; LAA: left atrial appendage; AAD: antiarrhythmic drugs

2

ACCEPTED MANUSCRIPT

Introduction The low efficacy of medical therapy in maintaining sinus rhythm along with the plethora of side-effects of those drugs have prompted the search for new techniques and technologies to

RI PT

optimize the catheter ablation procedure for the treatment of atrial fibrillation (AF) (1).

Pulmonary vein antrum isolation (PVAI) is still the cornerstone for AF ablation in paroxysmal AF patients with reported success rate as high as 80% (2). However in persistent (PeAF) and

SC

long-standing persistent AF (LSPAF), the success rate is much lower even with repeat

procedures (3). The main reason behind this poor outcome is the lack of information on the

M AN U

optimal ablation technique and the best targets to achieve freedom from arrhythmia (4). The PeAF and LSPAF are chronic state of the disease with progressive atrial fibrosis and evolving pulmonary and non-pulmonary vein (non-PV) triggers (2). It is still unclear whether substrate ablation alone or the elimination of triggers of AF or a combination of both, is the ideal ablation

TE D

approach in this subset of AF population (4). The uncertainty has been compounded by the findings from the recently completed STAR-AF II trial which failed to observe any reduction in the rate of recurrent AF when additional linear ablation or ablation of complex fractionated

EP

electrograms (CFAEs) were performed along with PVI in PeAF patients (5). Of the many newly emerging approaches to modify AF-sustaining substrate, one promising strategy is the FIRM-

AC C

guided ablation that targets electrical rotors and focal sources that are believed to be responsible for perpetuation of AF (6). If rotors/ focal sources are mechanisms that sustain AF, then it stands to reason that the ablation of these rotors should be associated with improved clinical outcomes (7). Some trials have reported improved success rate with rotor ablation alone or in combination with PVAI versus PVAI alone, but the results could be biased as none of these studies were randomized (7-9). Therefore, we designed this prospective study, OASIS, to compare the

3

ACCEPTED MANUSCRIPT

efficacy of FIRM ablation with or without PVAI vs PVAI plus non-PV trigger ablation in PeAF and LSPAF patients. Methods

RI PT

Trial Design

Outcome of Different Ablation Strategies In Persistent and Long-Standing Persistent Atrial Fibrillation (OASIS) was a non-blinded randomized trial comparing effectiveness of three

SC

ablation approaches for the treatment of AF. Consenting eligible subjects were randomly

assigned (1:1:1) to undergo FIRM guided ablation (group 1), FIRM+ PVAI ablation (group 2) or

M AN U

ablation with PVAI, PW, and non-PV triggers (Group 3) (Figure 1). The study protocol was approved by the Institutional Review Boards of the respective institutions. The trial was conducted in accordance with Declaration of Helsinki. The trial was registered at ClinicalTrials.gov (Identifier: NCT02533843).

TE D

Study Population

All patients presenting at the 3 participating centers (Texas Cardiac Arrhythmia Institute, Austin, Texas, USA; Lexington Cardiology at Central Baptist, Lexington, KY, USA and

EP

Cardiovascular Center Bad Neustadt, Germany) with non-paroxysmal AF undergoing catheter ablation were screened. Patients were included in the study if they were ≥18 years of age, have

AC C

persistent or long-standing persistent AF, undergoing first ablation procedure, and willing to provide written informed consent. Exclusion criteria included reversible causes of atrial arrhythmia (such as hyperthyroidism, pneumonia, pulmonary embolism, sarcoidosis and excessive alcohol consumption), prior ablation procedures and pregnancy. Randomization

4

ACCEPTED MANUSCRIPT

A central computerized randomization scheme was generated using block randomization, and sets of randomly selected blocks were provided to the investigating sites. To maintain allocation

subject’s eligibility is verified and is ready to be randomized. Endpoint:

RI PT

concealment, the site administrators were instructed not to reveal the arm assignment until the

Single procedure freedom from any recurrent AF/atrial flutter (AFL)/atrial tachycardia (AT) off

SC

AADs was the primary endpoint. Recurrence was defined as atrial arrhythmia (AF, AFL or AT) of > 30 second duration off antiarrhythmic drugs (AAD) at follow-up. Any episodes that

M AN U

occurred during the first 60 days (blanking period) after the procedure were not considered as recurrence. Secondary endpoints included acute procedural success and peri-procedural complications. Acute procedural success was defined as AF termination or ≥10% slowing or organization into AT.

TE D

Definitions

Electrical rotors: Sustained clockwise or counter clockwise activation around a core (6, 8). Focal impulses: Centrifugal activation from an origin (8).

EP

Non-PV triggers: Ectopic triggers originating from sites other than pulmonary veins such as interatrial septum, superior vena cava, left atrial appendage (LAA), crista terminalis and

AC C

coronary sinus (CS). Both sustained (>30 seconds) as well as non-sustained triggers including repetitive short- lasting bursts of arrhythmia (<30 sec) or premature atrial contractions (PAC) (≥10 beats/minute) with earliest activation from non-PV sites were targeted for ablation (10). Acute procedural success: AF termination or ≥10% slowing or organization into atrial tachycardia (AT) (Online Figure 1 A-D) Ablation Procedure

5

ACCEPTED MANUSCRIPT

Our mapping and ablation procedures have been described in detail in our earlier publications (6,11,12). Briefly, anti-arrhythmic drugs (AAD), excepting amiodarone, were discontinued 3-5 days before the procedure; amiodarone was stopped at least 4-6 months prior to

RI PT

the ablation. All patients underwent ablation under general anesthesia and uninterrupted anticoagulation with warfarin or novel oral anti-coagulants (NOACs). PVAI was always preceded by rotor ablation in group 2.

SC

FIRM-mapping (6, 8, 12)

Ablation commenced with FIRM mapping in group 1 and 2 patients. A 3-dimensional

M AN U

map of the atria was constructed using an electroanatomic mapping system (CARTO, Biosense Webster, Diamond Bar, CA, USA or EnSite NavX, St.Jude Medical, St.Paul, MN, USA) before advancing the 64-pole basket mapping catheter (FIRMap, Abbott, Chicago, IL) in the right atrium first and left atrium next (). FIRM mapping was performed during AF. Unipolar

TE D

electrograms were recorded for 1 minute and exported to a dedicated proprietary mapping system (RhythmView, Abbott, Chicago, IL, USA). RF energy was delivered with a 3.5-mm irrigated-tip ablation catheter with the acute endpoint of AF source elimination as confirmed

EP

with FIRM remapping. Rotors and focal impulses were considered AF sources only if they lay in reproducible spatial regions with source precision. If AF persisted despite elimination of all

AC C

rotors or converted into AT, the patient was cardioverted. PVAI, posterior wall (PW) and non-PV trigger ablation (11, 12) PVAI and electrical isolation of the left atrial posterior wall were performed using 3.5-

mm irrigated-tip catheter guided by circular mapping catheter, intra-cardiac echocardiography (ICE) and a 3-D mapping system. Radiofrequency (RF) energy was delivered with a maximum temperature setting of 420C and a power of up to 45W. An esophageal probe was utilized in all

6

ACCEPTED MANUSCRIPT

patients to monitor esophageal luminal temperature during ablation in areas in close proximity to the esophagus, such as the left atrial posterior wall. When ablating the posterior wall, the power was decreased to 35W. Complete abolition of all PV potentials rather than decrease in the

RI PT

amplitudes was the end point and confirmed by entrance block. If ablation was unsuccessful in terminating the arrhythmia, cardioversion was performed to restore sinus rhythm.

After stable sinus rhythm was achieved either during ablation or after cardioversion,

SC

isoproterenol 20- 30µg/min for 15–20min was given to disclose any non-PV triggers and to look for acute pulmonary vein reconnection. Mapping was done using the circular mapping catheter

M AN U

during isoproterenol challenge to identify the site of origin of significant ectopic activity by comparing the activation sequence of the sinus beat with that of the ectopic beat. Additional RF energy was used to ablate the non-PV foci, both sustained and non-sustained. Patients were discharged after an overnight stay on their previously ineffective AADs, with the exception of

Follow-up

TE D

amiodarone, which was never restarted during the 2-month blanking period.

Follow-up was performed at 1, 3, 6 and 12 months with office visits, cardiology

EP

evaluation, 12-lead electrocardiogram (ECG), and 7 day holter monitoring at 3, 6 and 12 months. Additionally, patients were given event-recorders for the first 5 months following the procedure

AC C

and were asked to transmit their rhythm every time they had symptoms compatible with arrhythmias and at least 3 times a week even if asymptomatic. Oral anticoagulant therapy was continued up to 6 months following the procedure, after

which it was discontinued in all patients that remained arrhythmia-free. If the patients underwent LAA isolation, a TEE was performed at 6 months to assess the contractility and flow velocity of the LAA and in case of inadequate flow-velocity, patients were kept on anticoagulants (13).

7

ACCEPTED MANUSCRIPT

Sample Size In the absence of historical data on FIRM-guided ablation procedure in non-paroxysmal population, we were not able to perform a formal power analysis. Instead, we planned to

RI PT

continue approaching consecutive patients until we have enrolled 42 patients in each group. The justification for this sample size was based on feasibility of enrolling enough participants within a reasonable time frame.

SC

A relatively high recurrence among the FIRM only subjects (group 1) triggered an

unplanned interim assessment by the internal safety committee. The committee recommended

M AN U

terminating the arm for futility, and continuing with the planned enrollment for other two groups. Statistical analysis

The primary analysis was conducted for the intent-to-treat (ITT) population, which consisted of all randomized patients undergoing ablation procedure. Primary endpoint was tested

TE D

using survival analysis method, and the null hypothesis was tested using log-rank test, multiplecomparison adjustment of survival curves was performed using Tukey-Kramer method. Subjects who were recurrence-free at the end of follow-up were censored.AF-free time was defined as

EP

time from procedure date to censor date. Survival curves were constructed using Kaplan-Meier method. Unadjusted and multivariable adjusted Cox regression models were used for assessing

AC C

independent predictors of AF-free survival. Sex and AF type were entered into the model as covariates Incidence of procedural complications was compared between cohorts using Fisher’s exact test. Patient demographic and clinical characteristics were reported using descriptive statistics. Continuous data are described as mean ± standard deviation and as counts and percent if categorical. Analysis of variance (ANOVA) and chi-square tests were used to compare groups. Tukey-Kramer method was used for ANOVA post-hoc pairwise comparison. Procedure time and

8

ACCEPTED MANUSCRIPT

radiofrequency time were compared between groups 2 and 3 by using independent-samples ttest. All tests were two-sided and a P-value of <0.05 was considered statistically significant.

RI PT

Analyses were performed using SAS software version 9.2 (SAS Institute Inc., Cary, NC, USA). Results Study Population

SC

A total of 378 patients were screened during the study period and 113 were enrolled at the 3 centers; 29 in group 1 and 42 in group 2 and 3 each. Enrollment in group 1 was terminated

M AN U

early for futility after enrollment of the 29 patients. Study design and patient disposition is presented in a flow diagram (Figure 1). Groups were well balanced on baseline and clinical characteristics (Table 1). In summary, LSPAF 31%, 29%, 31%; LA diameter 4.73±0.75, 4.84±0.74, 4.67±0.69; LVEF 54±10, 55.4±9.9, 55±10 in group 1, 2 and 3 respectively.

TE D

Electrical Rotors

Focal drivers or rotors were detected in all group 1 and 2 patients with a mean of 4.0±1.2 and 4.2± 1.7 rotors per patient in respective groups (p=0.55). A total of 116 AF rotors (61% LA

EP

and 39 % RA) and 117 (68% LA and 33% RA) lying in widespread locations were detected in groups 1 and 2 respectively. Distribution of AF rotors in the two groups is summarized in Table

AC C

2 and Figure 2.

Non-PV triggers

During the isoproterenol challenge non-PV triggers were detected in all patients in group

3. The foci were most commonly mapped to the coronary sinus (73.8%), left atrial appendage (38.1%), LA septum (50.0%), superior vena cava (28.6%), and mitral valve annulus (4.8%). The sources were ablated.

9

ACCEPTED MANUSCRIPT

Procedure time was 222±49, 233± 48 and 131± 51 minutes in groups 1, 2 and 3 (p<0.001); it was significantly shorter in group 3 compared to groups 1 and 2 (p<0.001). Compared to group 2, group 3 patients had significantly longer radiofrequency time (42.3 ±14.1

RI PT

and 54.1 ±21.4 minutes respectively, p=0.003). Procedural parameters are summarized in Table 2. After rotor ablation, acute success was achieved in 12 (41%) and 11 (26%) in group 1 and 2 respectively.

SC

Freedom from Arrhythmia Recurrence

After 12±7 month follow-up, 4 of 29 (14%) in group 1, 22 (52.4%) in group 2 and 32

M AN U

(76%) patients in group 3 were AF/AT-free without AADs (log-rank p<0.0001). Patients in group 3 experienced significantly higher success compared to group 1 (p<0.001) and group 2 (p=0.02) (log-rank p adjusted for multiple pair-wise testing). Sensitivity analysis of primary endpoint was performed after stratifying by AF type. In persistent AF patients the success rate

TE D

was 53% (16/30) and 72% (21/29) in group 2 and 3 respectively (log-rank p=0.13). In the LSP AF cohort, 6 of 12 (50.0%) patients in group 2 and 11 of 13 (84.6%) in group 3 were recurrence free (log-rank p=0.06).

EP

Predictor of Recurrence

We assessed the prognostic role of the ablation approach by fitting a Cox model. Group 1

AC C

was excluded from this analysis. These findings revealed that compared to group 3 (PVAI, PW, and non-PV trigger ablation), group 2 (FIRM+ PVAI ablation) was associated with significantly higher risk of recurrence. Unadjusted hazard ratio was 2.37 (95% CI 1.1 to 5.07), p=0.025. After adjusting for sex and AF type the in multivariable model the hazard ratio was 2.36 (95% CI 1.11 to 5.09), p=0.027. Complications

10

ACCEPTED MANUSCRIPT

No procedure-related adverse events occurred in any of the patients in group 1. Two patients (1 in group 2 and 1 in group 3) had minor groin hematoma and 1 patient in group 2 had a small pericardial effusion that was conservatively managed with fresh-frozen plasma and

RI PT

protamine. No major adverse events such as stroke, pulmonary stenosis, esophageal injury or major bleeding events were reported. Discussion

SC

To the best of our knowledge, this is the first randomized trial that compared the efficacy of FIRM ablation with or without PVAI vs PVAI plus posterior wall plus non-PV trigger

M AN U

ablation in PeAF and LSPAF patients. Our main findings were the following; 1) Acute procedural success after targeting the FIRM-identified rotors was achieved in a small number of patients; 41% and 26% in group 1 and 2 respectively, 2) Rotor-only ablation had very poor outcome in terms of arrhythmia recurrence for which that arm was terminated prematurely and 3)

TE D

PVAI plus rotor ablation had significantly longer procedure time and lower efficacy than PVAI + PW + non-PV trigger-ablation.

We observed a significantly longer procedure time with rotor ablation with or without

EP

PVAI in our study population which was in agreement with some earlier trials (7, 14) and in disparity with others (15). This discrepancy can be due to detection of more rotors than that

AC C

reported by the CONFIRM study (mean of 4 vs 2 per patient) that most likely made the procedure time longer (15).

Despite lengthier procedure time, we failed to accomplish the high acute success with

rotor ablation as reported by earlier studies (15-17); one possible explanation for which is the difference in the study population. In all of the abovementioned trials, the population was comprised of subjects with paroxysmal and persistent AF whereas our study included only non-

11

ACCEPTED MANUSCRIPT

paroxysmal AF (PeAF and LSPAF) patients and it is well known that acute termination is not an easy task to accomplish in this subset of AF population (18). In accordance with our finding, two recently published single-center experiences, have reported similarly low acute procedural

RI PT

success in non-paroxysmal population (7, 19). Other feasible reasons might be the small sample size, non-randomized study design with possible bias in patient selection and the learning-curve effect (6).

SC

In our study, acute success was achieved in higher number of patients in group 1

compared to group 2. However, no conclusions can be drawn from this observation as the groups

M AN U

were unbalanced in terms of number of patients included in the analysis. At 12±7 month followup, only 14% of our patients that underwent rotor-only ablation (group 1) remained arrhythmiafree off-AAD. Because of this poor outcome, this arm was deemed futile and discontinued prematurely to avoid exposing the patients to inappropriate risks. Our success rate was

TE D

surprisingly lower compared to the reported results by Miller et al (71.4%) and the CONFIRM trial (70.6%), which can be again due to the difference in the selected population (9, 15). It is also possible that ablation limited to only rotors is not sufficient to maintain sinus rhythm in non-

EP

paroxysmal AF and additional ablations are required. This was evidenced by the procedure outcome in group 2 and 3 of our study patients, where additional ablations led to a better success

AC C

rate compared to group 1; after 12±7 month follow-up, the single-procedure success rate offAAD was 4 (14%), 22 (52.4%) and 32 (76%) in groups 1, 2 and 3 respectively (p<0.0001). Although the arrhythmia-free survival following PVAI + rotor ablation (group 2) in our population was lower than that of previous studies (Miller et al: 80.5% and CONFIRM: 82.4%), it was comparable with the findings of Tomassoni et al (single procedure off-AAD success rate 58% in PeAF and 25% in LSPAF) (9, 15, 19).

12

ACCEPTED MANUSCRIPT

Our results demonstrated the extensive approach of PVAI + left atrial posterior wall (LAPW) + ablation of non-PV triggers to be the most effective ablation strategy in the nonparoxysmal AF population. Several factors may have concertedly contributed to the observed

RI PT

high success rate of this ablation approach such as isolation of LAPW and ablation of non-PV triggers detected by isoproterenol challenge.

The common embryologic origin of the PVs and the LAPW provides the anatomic basis

SC

that suggests the role of LAPW as an arrhythmogenic substrate in the origin and maintenance of AF and consequently isolation of the LAPW has been shown to increase the short- and mid-term

M AN U

success rate of PVAI in non-paroxysmal AF patients (20-23). With the persistence of AF, both the frequency and number of non-PV triggers increase and several studies have shown the benefits of ablation of those extra-PV foci in providing effective and durable arrhythmia-free survival (2, 24-27).

TE D

We observed the best outcome with substrate ablation including non-PV triggers combined with PVAI in non-paroxysmal AF patients which reaffirmed the current guideline recommendation that patients with persistent AF undergoing catheter ablation should receive

EP

additional substrate ablation to improve outcome (28). However, in the recently published STAR AF II trial, no reduction in recurrence was observed with additional substrate ablation such as

AC C

linear ablations or ablation of complex fractionated electrograms (CFAEs) (5). The discrepancy can be best explained by quoting the STAR AF II investigators, “Perhaps neither complex electrograms nor lines are the correct supplemental targets for ablation”. Several earlier randomized trials have reported no additional advantages of linear ablation approach over PVI alone in AF/AT patients although the lines required significantly more ablation time, radiation dose and longer procedure duration (29-31). Similarly, CFAE ablation has been reported to

13

ACCEPTED MANUSCRIPT

confer no long-term incremental benefit when performed in addition to PV antral isolation (32, 33). Last but not the least; although more extensive ablation was performed in group 3, it took

RI PT

less procedure and fluoroscopic time than the other two strategies while offering comparable safety and better efficacy. Limitations

SC

We acknowledge few limitations in this trial; 1) AF recurrence could have been

underestimated as the patients were not constantly monitored and we could have also missed

M AN U

some asymptomatic events. However, patients included in this study were symptomatic and were able to distinguish their AF symptoms. Also, in an earlier study conducted by our group, we did not observe significant differences in the captured arrhythmia events between the implantable loop recorder and conventional monitoring (34), 2) a lengthier follow-up would have provided a

TE D

better comparison of the long-term outcome of PVAI +rotors ablation versus PVAI + LAPW +non-PV triggers ablation, but historically, the success rate of the latter ablation approach has been similar after ≥2 years follow-up (27), 3) the relatively small sample size. However, we

Conclusion

EP

could still detect a true effect that was statistically significant.

AC C

This is the first randomized study that compared three ablation strategies in non-

paroxysmal AF patients and reported a very poor outcome with rotor-only ablation. Furthermore, acute procedural success was achieved in very few after the ablation of rotors. Additionally, rotor ablation combined with pulmonary vein isolation had significantly longer procedure time and lower efficacy than the ablation strategy including isolation of left atrial posterior wall and non-

14

ACCEPTED MANUSCRIPT

pulmonary vein triggers along with PV isolation in patients with persistent or long-standing

AC C

EP

TE D

M AN U

SC

RI PT

persistent atrial fibrillation.

15

ACCEPTED MANUSCRIPT

References 1. Burkhardt JD, Di Biase L, Natale A. Long-Standing Persistent Atrial Fibrillation: The Metastatic Cancer of Electrophysiology. J Am Coll Cardiol 2012; 60 (19):1930-1931

RI PT

2. Lappe JM, Cutler MJ, Day JD et al. Ablation for Persistent Atrial Fibrillation-Is There a Role for More Than PVI? Curr Treat Options Cardiovasc Med. 2016;18(3):15

3. Brooks AG, Stiles MK, Laborderie J et al. Outcomes of long-standing persistent atrial

SC

fibrillation ablation: a systematic review. Heart Rhythm. 2010;7(6):835-46.

4. Di Biase L, Santangeli P, Burkhardt JD et al. Which is the best approach for ablation of

M AN U

long-standing persistent atrial fibrillation? Pacing Clin Electrophysiol. 2013 ;36(10): 1198-201.

5. Verma A, Jiang CY, Betts TR et al. STAR AF II Investigators. Approaches to catheter ablation for persistent atrial fibrillation

TE D

6. Gianni C, Mohanty S, Di Biase L et al. Acute and early outcomes of focal impulse and rotor modulation (FIRM)-guided rotors-only ablation in patients with non-paroxysmal atrial fibrillation. Heart Rhythm. 2016;13(4):830-5.

EP

7. Sommer P, Kircher S, Rolf S et al. Successful Repeat Catheter Ablation of Recurrent Longstanding Persistent Atrial Fibrillation With Rotor Elimination as the Procedural

AC C

Endpoint: A Case Series. J Cardiovasc Electrophysiol. 2016;27(3):274-80.

8. Narayan SM, Baykaner T, Clopton P et al. Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared with trigger ablation alone: extended

follow-up of the CONFIRM trial (Conventional Ablation for Atrial Fibrillation With or

Without Focal Impulse and Rotor Modulation). J Am Coll Cardiol. 2014;63(17):1761-8

16

ACCEPTED MANUSCRIPT

9. Miller JM, Kowal RC, Swarup V et al. Initial independent outcomes from focal impulse and rotor modulation ablation for atrial fibrillation: multicenter FIRM registry. J Cardiovasc Electrophysiol. 2014;25(9):921-9.

RI PT

10. Gokoglan Y, Mohanty S, Gunes MF et al. Pulmonary Vein Antrum Isolation In Patients With Paroxysmal Atrial Fibrillation: More Than A Decade Of Follow-Up. Circ Arrhythm Electrophysiol. In press.

fibrillation? Curr Opin Cardiol. 2013;28(1):26-35

SC

11. Di Biase L, Santangeli P, Natale A. How to ablate long-standing persistent atrial

M AN U

12. Zhao Y, Di Biase L, Trivedi C et al. Importance of non-pulmonary vein triggers ablation to achieve long-term freedom from paroxysmal atrial fibrillation in patients with low ejection fraction. Heart Rhythm. 2016;13(1):141-9

13. Di Biase L, Burkhardt JD, Mohanty P et al. Left atrial appendage: an under-recognized

TE D

trigger site of atrial fibrillation. Circulation. 2010;122(2):109-18. 14. Lin YJ, Lo MT, Lin C et al. Prevalence, Characteristics, Mapping, and Catheter Ablation of Potential Rotors in Non-paroxysmal Atrial Fibrillation. Circ Arrhythm Electrophysiol.

EP

2013; 6(5):851-8.

15. Narayan SM, Krummen DE, Shivkumar K et al. Treatment of atrial fibrillation by the

AC C

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(7):628-36.

16. Narayan SM, Krummen DE, Donsky A et al. Precise rotor elimination without concomitant pulmonary vein isolation for the successful elimination of paroxysmal atrial fibrillation. HeartRhythm2013;10:1414.

17

ACCEPTED MANUSCRIPT

17. Shivkumar K, Ellenbogen KA, Hummel JD et al. Acute termination of human atrial fibrillation by identification and catheter ablation of localized rotors and sources: first

Cardiovasc Electrophysiol. 2012;23(12):1277-85.

RI PT

multicenter experience of focal impulse and rotor modulation (FIRM) ablation. J

18. Chugh A. Catheter ablation of persistent atrial fibrillation: how much is enough? Circ Arrhythm Electrophysiol. 2015;8(1):2-4.

SC

19. Tomassoni G, Duggal S, Muir M, Hutchins L et al. Long-term Follow-up of FIRMguided Ablation of Atrial Fibrillation: A Single-center Experience. The Journal of

M AN U

Innovations in Cardiac Rhythm Management, 2015; 6: 2145–2151

20. Bai R, Di Biase L, Mohanty P et al. Proven isolation of the pulmonary vein antrum with or without left atrial posterior wall isolation in patients with persistent atrial fibrillation. Heart Rhythm. 2016; 13(1):132-40.

TE D

21. Damiano RJ Jr, Schwartz FH, Bailey MS et al. The Cox maze IV procedure: predictors of late recurrence. J Thorac Cardiovasc Surg. 2011;141(1):113-21 22. Saad E, Slater C. Complete Isolation Of The Left Atrial Posterior Wall (Box Lesion) To

EP

Treat Longstanding Persistent Atrial Fibrillation. JAfib, 2014-15; 7(4): 6-9 23. Sanders P, Hocini M, Jaïs P et al. Complete isolation of the pulmonary veins and

AC C

posterior left atrium in chronic atrial fibrillation. Long-term clinical outcome. Eur Heart J. 2007;28(15):1862-71

24. Natale A, Di Biase L, Mohanty P et al. Importance Of Ablation Of Non-sustained Triggers Disclosed By High Dose Of Isoproterenol After Extended Pulmonary Vein Antral Isolation. Abstract, HRS 2010

18

ACCEPTED MANUSCRIPT

25. Mohanty S, Santangeli P, Mohanty P et al. Catheter ablation of asymptomatic longstanding persistent atrial fibrillation: impact on quality of life, exercise performance,

2014;25(10):1057-64

RI PT

arrhythmia perception, and arrhythmia-free survival. J Cardiovasc Electrophysiol.

26. Miyazaki S, Kuwahara T, Kobori A et al. Long-term clinical outcome of extensive

pulmonary vein isolation-based catheter ablation therapy in patients with paroxysmal and

SC

persistent atrial fibrillation. Heart. 2011;97(8):668-73

27. Mohanty S, Di Biase L, Mohanty P et al. Effect of periprocedural amiodarone on

M AN U

procedure outcome in patients with longstanding persistent atrial fibrillation undergoing extended pulmonary vein antrum isolation: results from a randomized study (SPECULATE). Heart Rhythm. 2015;12(3):477-83

28. 7. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus

TE D

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: a report of the Heart Rhythm Society (HRS) Task

EP

Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the

AC C

European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS),

and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the

19

ACCEPTED MANUSCRIPT

Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012; 9(4): 632.e21-696.e21. 29. Arbelo E, Guiu E, Bisbal F, Ramos P, Borras R, Andeu D, Tolosana JM, Berruezo A,

RI PT

Brugada J, Mont L. Benefit of Left Atrial Roof Linear Ablation in Paroxysmal Atrial Fibrillation: A Prospective, Randomized Study. J Am Heart Assoc. 2014;3:e000877. 30. Estner HL, Hessling G, Biegler R, et al. Complex fractionated atrial electrogram or linear

Pacing Clin Electrophysiol. 2011;34(8):939-48.

SC

ablation in patients with persistent atrial fibrillation--a prospective randomized study.

M AN U

31. Wynn GJ, Panikker S, Morgan M, et al. Biatrial linear ablation in sustained nonpermanent AF: Results of the substrate modification with ablation and antiarrhythmic drugs in nonpermanent atrial fibrillation (SMAN-PAF) trial. Heart Rhythm. 2016;13(2):399-406

TE D

32. Wong KC, Paisey JR, Sopher M, et al. No Benefit of Complex Fractionated Atrial Electrogram Ablation in Addition to Circumferential Pulmonary Vein Ablation and Linear Ablation: Benefit of Complex Ablation Study. Circ Arrhythm Electrophysiol.

EP

2015;8(6):1316-24

33. Vogler J, Willems S, Sultan A, et al. Pulmonary Vein Isolation Versus Defragmentation:

AC C

The CHASE-AF Clinical Trial. J Am Coll Cardiol. 2015;66(24):2743-52

34. Mohanty S, Natale A, Mohanty P et al. Pulmonary Vein Isolation to Reduce Future Risk of Atrial Fibrillation in Patients Undergoing Typical Flutter Ablation: Results from a Randomized Pilot Study (REDUCE AF). Heart Rhythm. 2015;12(9):1963-71

20

ACCEPTED MANUSCRIPT

Figure Legends: Figure 1: Flow diagram showing patient distribution according to eligibility, assignment to ablation strategy, and follow-up.

RI PT

Figure 2: Distribution of the rotors in the left and the right atrium. LAA, area around the left atrial appendage; LIAS, left interatrial septum; LW, lateral wall; MVA, area around the mitral valve annulus; TVA, area around the tricuspid valve annulus; PV, pulmonary veins; PW,

SC

posterior wall; RIAS, right interatrial septum

Figure 3: Kaplan-Meier curve comparing freedom from recurrence across the study

M AN U

groups. After 12±7 month follow-up, 4 (14%), 22 (52.4%) and 32 (76%) patients in groups 1, 2 and 3 were AF/AT-free off AADs (log-rank p<0.0001). Any episodes that occurred during the

AC C

EP

TE D

first 60 days (blanking period) after the procedure were not considered as recurrence.

21

ACCEPTED MANUSCRIPT

Group I (n=29)

Group II (n=42)

Group III (n=42)

p-value

62.4 ± 10.3

65.1 ± 10.2

67.6 ± 8.5

0.08

20 (69.0)

30(71.4)

LSPAF (long-standing persistent)

9 (31.0)

12(28.6)

Male gender

23 (79.3)

28 (66.7)

29 (69.1)

0.49

RI PT

Body Mass Index (kg/m2)

31.1 ± 4.4

32.8 ± 7.1

32.9 ± 7.6

0.51

Left Atrial Diameter (mm)

4.73 ± 0.75

4.84 ± 0.74

4.67 ± 0.69

0.62

Left ventricular Ejection Fraction (%)

54.5 ± 9.9

55.4 ± 9.9

55.4 ± 9.5

0.93

Hypertension

25 (86.2)

31 (73.8)

27 (64.3)

0.12

Diabetes

4 (13.8)

6 (14.3)

8 (19.1)

0.78

Obstructive Sleep Apnea

7 (24.1)

7 (16.7)

9 (21.4)

0.73

Congestive Heart Failure

6 (20.7)

8 (19.1)

6 (14.3)

0.75

TE D

Table 1: Baseline demographic and clinical characteristics

2 (4.8)

2 (4.8)

1.00

Age (years)

2 (6.9)

AC C

EP

Stroke/Transient Ischemic Attack

29(69.1)

22

0.97

13 (31.0)

M AN U

Persistent

SC

AF Type

ACCEPTED MANUSCRIPT

Table 2: Procedural Characteristics of the study population (N=113) Group II (n=42)

Group III (n=42)

p-value

222 ± 49

233 ± 48

131 ± 51

<0.001

49.2 ± 16.8

33.0 ± 21.1

29.0 ±15.8

<0.001

Radiofrequency Time (min)

35 ± 16

42.3 ± 14.1

54.1 ± 21.4

<0.001

Direct Current Cardioversion

29 (100.0)

38 (90.5)

31 (73.8)

0.004

116

177

NA

----

Number of RA Rotors

45 (38.8)

59 (33.3)

Number of LA Rotors

71 (61.2)

118 (66.7)

Rotors per patient

4.0 ± 1.2

4.21 ± 1.7

1.55 ± 0.95 2.45 ± 1.06

1.41 ± 1.01 2.81 ± 1.19

0 (0.0)

0 (0.0)

Fluoro Time (min)

M AN U

Number of Rotors

SC

Procedural Time (min)

RI PT

Group I (n=29)

RA Rotors per patient LA Rotors per patient

AC C

EP

TE D

Complications

23

NA

0.34

NA

0.55

NA

0.54

NA

0.19

1 (2.4)

0.63

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

Impact of rotor ablation in non-paroxysmal AF patients: Results from a randomized trial (OASIS)

RI PT

Sanghamitra Mohanty1, MD MS FHRS, Carola Gianni1, MD, Prasant Mohanty1, MBBS MPH, Philipp Halbfass2, MD, Tamara Metz1, BSN RN, Chintan Trivedi1, MD MPH, Thomas Deneke2, MD, Gery Tomassoni3, MD, Rong Bai1,4, MD FHRS, Amin Al-Ahmad 1, MD, Shane Bailey1, MD, John David Burkhardt1, MD, G Joseph Gallinghouse1, MD, Rodney Horton1, MD, Patrick M Hranitzky1, MD, Javier E Sanchez1, MD, Luigi Di Biase1,2, MD PHD FHRS Andrea Natale1, 5-9, MD, FACC FHRS FESC

SC

Online Figure Legends

Online Figure 1A: Example of atrial fibrillation slowing or organizing to AFL with rotor

M AN U

ablation (CR, crista terminalis; CS, coronary sinus). 2a and 2b: slowing of AF before and after rotor ablation; 2c and 2d: organization of AF to AFL during rotor ablation. Despite acute procedural success, both of these patients experienced recurrence and underwent repeat ablation. Online Figure 1B: Example of atrial fibrillation slowing or organizing to AFL with rotor ablation (CR, crista terminalis; CS, coronary sinus). 2a and 2b: slowing of AF before and

TE D

after rotor ablation; 2c and 2d: organization of AF to AFL during rotor ablation. Despite acute procedural success, both of these patients experienced recurrence and underwent repeat ablation.

EP

Online Figure 1C: Example of atrial fibrillation slowing or organizing to AFL with rotor ablation (CR, crista terminalis; CS, coronary sinus). 2a and 2b: slowing of AF before and

AC C

after rotor ablation; 2c and 2d: organization of AF to AFL during rotor ablation. Despite acute procedural success, both of these patients experienced recurrence and underwent repeat ablation. Online Figure 1D: Example of atrial fibrillation slowing or organizing to AFL with rotor ablation (CR, crista terminalis; CS, coronary sinus). 2a and 2b: slowing of AF before and after rotor ablation; 2c and 2d: organization of AF to AFL during rotor ablation. Despite acute procedural success, both of these patients experienced recurrence and underwent repeat ablation.

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT