Ablation for Atrial Fibrillation Combined With Left Atrial Appendage Closure

JACC: CLINICAL ELECTROPHYSIOLOGY

VOL. 1, NO. 6, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 2405-500X/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacep.2015.07.009

Ablation for Atrial Fibrillation Combined With Left Atrial Appendage Closure Arash Alipour, MD, PHD,* Martin J. Swaans, MD, PHD,* Vincent F. van Dijk, MD,* Jippe C. Balt, MD, PHD,* Martijn C. Post, MD, PHD,* Mike A.R. Bosschaert, MD,* Benno J. Rensing, MD, PHD,* Vivek Y. Reddy, MD,y Lucas V.A. Boersma, MD, PHD*

ABSTRACT OBJECTIVES The study sought to determine long-term clinical effects of combining catheter ablation (CA) and left atrial appendage (LAA) occlusion (LAAO) in a single procedure. BACKGROUND CA relieves symptoms in atrial fibrillation (AF), but freedom from AF is not assured. Thus, oral anticoagulation (OAC) remains necessary in high stroke risk patients. LAAO has proved a viable alternative for preventing thromboembolic complications. METHODS Symptomatic patients with drug-refractory AF (CHADS2 $1) and indications for LAAO were included. Transesophageal echocardiography was performed to assess LAA size/anatomy/thrombus. After CA, LAAO was performed using the Watchman device (Atritech, Inc., Plymouth, Minnesota, Minnesota). At 3 months, OAC was switched to aspirin/clopidogrel if LAAO criteria were met. RESULTS From September 2009 to October 2013, 62 patients (22 female, 64  8 years of age, CHADS2 2.5) underwent combined procedures. Indications for LAAO included history of stroke despite OAC (29.0%), contraindications for OAC (24.2%), high stroke risk (24.2%), and miscellaneous reasons (22.6%). LAAO resulted in complete acute closure in all, with a median number of 1 device. After a median follow-up of 38 (range: 25 to 45) months, 95% of the patients met the criteria for successful sealing and 78% could discontinue OAC, while recurrence of AF was documented in 42%. During long-term follow-up, 3 ischemic strokes were observed with an annual stroke risk of 1.7%, which is lower than the expected annual risk of 6.5%. CONCLUSIONS LAAO combined with CA for AF can be performed successfully and safely in a single procedure, with a lower than expected stroke rate. Further studies are necessary to determine which patients benefit most from the combined therapy. (J Am Coll Cardiol EP 2015;1:486–95) © 2015 by the American College of Cardiology Foundation.

A

trial fibrillation (AF) is the most common

Fibrillation Follow-up Investigation of Rhythm Man-

arrhythmia with tremendous expenditure

agement) (5) trials have shown that neither rate or

of health resources (1–3). Various antiar-

rhythm control by AAD can eliminate AF or prevent

rhythmic drugs (AAD) are used, often accompanied

adverse events. Catheter ablation (CA) is more

by side effects while rarely resulting in complete

effective than AAD to reduce the burden of AF (6).

freedom of AF. The RACE (Rate Control versus

However, the actual freedom of AF is lower than

Electrical Cardioversion) (4) and AFFIRM (Atrial

initial studies suggested, especially in patients with

Listen to this manuscript’s audio summary by JACC: Clinical Electrophysiology

From the *Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands; and the yHelmsley Electrophysiology

Editor-in-Chief

Center, Mount Sinai School of Medicine, New York, New York. The procedures were financed by a research funding grant to the St.

Dr. David J. Wilber.

Antonius Hospital, up to a maximum of 30 procedures per year. Dr. Swaans has served as a proctor for Abbott Vascular and Boston Scientific; a consultant for Boston Scientific; and a lecturer for Philips Healthcare. Drs. Rensing and Boersma have served as consultants for Boston Scientific; and the fees have been directed to the Research & Development Department of Cardiology. Dr. Reddy has received research grant support from and has served as a consultant for Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received February 20, 2015; revised manuscript received July 8, 2015, accepted July 16, 2015.

Alipour et al.

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 6, 2015 DECEMBER 2015:486–95

(longstanding) persistent AF with remodeled and

Research Funding grant by the St. Antonius

ABBREVIATIONS

enlarged atria (6).

Hospital, up to a maximum of 30 procedures

AND ACRONYMS

Stroke is the most devastating complication of AF,

per year.

accounting for 15% to 20% of all strokes (7). According

The indication for ablation was docu-

to guidelines, oral anticoagulation (OAC) is indicated

mented symptomatic and recurrent parox-

to prevent thromboembolic events in patients with

ysmal

high stroke risk based on CHADS 2 or CHA2DS2-VASc

despite at least 1 AAD and cardioversion in

scores (1). Vitamin K antagonists have several disad-

accordance with international guidelines.

vantages including (major) bleedings, intolerance,

The indications for concomitant LAAO were

noncompliance, and a narrow therapeutic range

an increased risk of stroke (CHADS 2 score $1),

(8–10). The novel factor IIa and Xa inhibitors (novel

with a (relative) contraindication for and/or

oral anticoagulations [NOACs]) have advantages over

failure of OAC. The risks of stroke and

vitamin K antagonists, but may still lead to bleeding,

bleeding were determined according to the

and also have limitations such as the absence of

CHADS2 and the HAS-BLED scores. To assess

antidotes in case of bleeding, limited long-term data,

LAA anatomy, and exclude LAA thrombus

limited

and significant structural cardiac abnormal-

cardiovascular

487

Left Atrial Appendage Closure and Ablation for AF

outcome

data,

and

high

medication cost (11–14).

or

(longstanding)

persistent

AF,

ities, transesophageal echocardiography (TEE)

The left atrial appendage (LAA) may be the source

was carried out in all patients within 1 week

of thrombi in >90% of patients with nonvalvular AF

of the procedure. All data were collected

(15). Randomized clinical trials have shown that

prospectively by means of a web-based

percutaneous mechanical occlusion of the left atrial

database.

appendage (LAAO) can be an effective alternative to OAC (16–18). In the 2012 ESC guidelines, LAAO has received a Class IIb recommendation in high stroke risk patients that are contraindicated for long-term use of OAC (1). The combination therapy of AF ablation with LAAO would avoid the added risk of multiple procedures, while providing a permanent reduction in stroke risk, and abolishing the need for OAC. Specifically in patients with contraindications for OAC, LAAO has proven safe and successful (19). Previously, our group has published short-term data showing that combining CA and LAAO is feasible and safe (20). In this prospective registry study, we now show procedural data for a larger group of patients, with longterm follow-up data on bleeding, stroke, and the need for OAC.

AAD = antiarrhythmic drugs AF = atrial fibrillation CA = catheter ablation INR = international normalized ratio

LAA = left atrial appendage LAAO = left atrial appendage occlusion

NOAC = novel oral anticoagulation

OAC = oral anticoagulation PV = pulmonary vein PVAC = pulmonary vein ablation catheter

ROW = Rendu-Osler-Weber TEE = transesophageal echocardiography

ABLATION PROCEDURE. All procedures were per-

formed in patients under general anesthesia, preferably under continued OAC use, aiming at therapeutic international normalized ratio (INR) levels of 2 to 3. AAD were continued. Ablation

was

performed

with

the

Phased

radiofrequency catheter system (Medtronic/Ablation Frontiers, Inc., Carlsbad, California) as described before in detail by our group (20–23). The filter settings of the EP system (Bard, Inc., Lowell, Massachusetts) for the phased radiofrequency catheters were set from 100 to 500 kHz for the pulmonary vein (PV) ablation catheter (PVAC), with signal amplification at 5,000. PV isolation was performed with PVAC, while in patients with longstanding persistent AF complex-fractionated atrial electrogram ablation was performed with the multiarray catheters, multiarray septal catheter (septum), and

METHODS

multiarray ablation catheter (LA roof, free wall, mitral isthmus, mitral annulus, and posterior wall)

PATIENT SELECTION. The study was designed as an

(23). Electrodes 1 and 10 of the PVAC were discon-

open-label, nonrandomized, prospective registry.

nected as these may induce silent cerebral ischemias

From September 2009 to September 2013, patients

by interaction.

who were eligible for both CA and LAAO were

A 7-F sheath was introduced through the right

included. All patients were seen by an electrophysi-

femoral vein. A quadripolar catheter was introduced

ologist in the outpatient clinic to evaluate eligibility.

into the coronary sinus for pacing purposes. A

They signed a written consent form. The hospital’s

standard transseptal puncture was performed with a

ethics committee approved the study. All procedures

radiofrequency Brockenbrough needle (Baylis Medi-

were done in accordance with the hospital’s ethics

cal Company Inc., Montreal, Quebec, Canada) with a

standards and the Helsinki Declaration of 1975

12.5-F outer diameter/9.5-F inner diameter steerable

(revised in 2008). As LAAO is not reimbursed in the

sheath (Channel, Bard, Lowell, Massachusetts). After

Netherlands, the procedures were financed by a

transseptal puncture, angiography was performed

488

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Left Atrial Appendage Closure and Ablation for AF

via the sheath to delineate the PVs and LAA. A single

TEE) was chosen, to have sufficient compression for

heparin IV bolus of 10,000 IU was administered

stable positioning. The device deploys by retracting

through the sheath to accompany the first hour of

the access sheath. Before releasing it from the de-

ablation with a repeated bolus of 5,000 IU after each

livery catheter, several release criteria had to be ful-

additional half-hour. After successful transseptal

filled, including proper LAA position, no or minimal

puncture the PVAC was used for antrum ablation in

(<5 mm) residual lateral flow past the device, and a

all PVs. In all PVs, the guidewire was consecutively

tug test for stability. If all these device release criteria

positioned in different side branches to allow the

were confirmed, the device was released and its po-

ablation catheter to enter the antrum from different

sition reconfirmed by angiography and TEE. Patients

angles. The applications were made as proximal as

were discharged the following day after a chest x-ray

possible, trying to reach away from the ostium to-

to verify the Watchman position in the heart. Vitamin

ward the antrum as far as possible. The right

K antagonists were either continued or started as

middle vein was cannulated separately, regardless

standard of care after CA and LAAO with INR between

of whether this was a separate vein or a side-branch.

2 and 3, if necessary with bridging low-molecular-

In patients with a left common antrum, ablation

weight heparin until INR was >2.0. In patients with

was performed as proximal as possible while still

an absolute contraindication for OAC, low-molecular-

achieving sufficient contact for adequate tissue

weight heparin was given for at least 3 weeks, as this

temperature.

The

guidewire

was

consecutively

period constitutes the highest risk period (26). In

positioned in the upper and lower PV to allow

these patients aspirin, clopidogrel, or both were also

complete circumferential ablation of the common

started.

antrum. The endpoint with PVAC ablation (PV isolation)

FOLLOW-UP. Patients were seen by their treating

was confirmed by the absence of local potentials

electrophysiologist in the outpatient clinic 90 days

with PVAC mapping inside each vein combined with

after the procedure. Before this visit, TEE imaging

pacing maneuvers from the CS, and/or the PV to

was performed at approximately 60 days to evaluate

distinguish local potentials from far field potentials

LAAO, thrombus formation, device position, and re-

(20–22). The endpoint for multiarray septal catheter ablation was elimination of all septal complex

sidual flow. Sealing was considered successful when there was either no flow (complete), or the presence

within

of a remaining jet <5 mm (24,25). Patients using OAC

reach of the array in a 360  circle. For the multi-

were then switched to aspirin indefinitely. In the OAC

array catheter ablation this was elimination of LA

contraindicated group, aspirin was also continued

roof, free wall, mitral annulus, and posterior wall

indefinitely while clopidogrel (75 mg daily) was pre-

(23). CFAEs were defined visually as local contin-

scribed for 6 months unless contraindicated. If

uous deflections with multiple components crossing

criteria for successful sealing were not met, TEE was

the baseline.

repeated at 3 to 6 months. A yearly follow-up was

fractionated

atrial

electrograms

(CFAEs)

done by examining the electronic hospital charts, LAAO. Watchman (Atritech, Inc., Plymouth, Minne-

and/or contacting the treating cardiologist, and/or

sota,

contacting the patients to provide information on

Minnesota/Boston

Scientific,

Marlborough,

Massachusetts) implantation was carried out imme-

their evolution.

diately subsequent to the ablation procedure under

Long-term rhythm follow-up was left at the

2D or 3D TEE guidance. Details of the Watchman de-

discretion of the referring cardiologist or treating

vice and procedure have been described elsewhere

electrophysiologist as needed. In all patients, a 12-

(20,24,25). The initial 12.5-F sheath was replaced by a

lead electrocardiogram was routinely obtained at

14-F transseptal access sheath (Atritech, Inc.), which

the 3 months outpatient clinic appointment and

was positioned in the LAA. With a pigtail catheter,

Holters were performed in the first year after the in-

additional angiograms were made to determine size

dex procedure. Adverse event monitoring focused on

and shape of the LAA. This access sheath serves a

bleeding complications, and stroke or systemic em-

conduit for the delivery catheter, which contains the

bolism. Ischemic stroke was defined as the sudden

device, a self-expanding nitinol frame with fixation

onset of a focal neurological deficit in the distribution

barbs and a permeable polyester fabric cover. There

of a single brain artery with symptoms and/or signs

are 5 device sizes (21, 24, 27, 30, and 33 mm) to

persisting $24 h, or when #24 h if accompanied by

accommodate varying LAA anatomy and size. A de-

the evidence of tissue loss without hemorrhage based

vice size 10% to 20% larger than the largest diameter

on computed tomography or magnetic resonance

of the LAA body (as measured by angiography and

brain imaging (27).

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STATISTICS. Descriptive

Left Atrial Appendage Closure and Ablation for AF

to

3.0), respectively. A total of 77.4% of patients had a

report patient characteristics. Continuous variables

statistics

were

used

history of stroke or transient ischemic attack. Anti-

with normal distribution were reported as mean  SD.

coagulation therapy with OAC or NOAC was used in

Median (25th to 75th percentiles) were used when

80.6% of patients, while 5 patients used only aspirin

normal distribution was absent. Percentages were

due to major bleeding in their history. Seven patients

used to report categorical variables. All statistical

used a combination of aspirin and P2Y 12 inhibitors

analyses were performed in SPSS software (version

(Figure 1).

22.0, SPSS Inc., Chicago, Illinois).

The indication to perform LAAO was stroke under OAC with proper INR in 18 patients. Fifteen patients had a contraindication for OAC (13 bleedings under

RESULTS

OAC, 1 at risk of falling, and 1 with unstable INR

BASELINE CHARACTERISTICS. A total of 62 patients

(22 female, 64  8 years of age) underwent CA combined with LAAO in a single procedure. The baseline characteristics are described in Table 1. The majority of patients had a history of paroxysmal AF. The median CHADS2, CHA2DS2-VASc, and HAS-BLED scores were 2.5 (2.0 to 3.0), 3.0 (2.75 to 4.00), and 2.0 (2.0 to

values). The third group (n ¼ 15) was eligible for OAC but was offered LAAO due to high CHADS2 score and all with a history of stroke with a CHADS2 score $2, while in another 14 patients miscellaneous practical reasons from either the physician or patient led to LAAO. These included loss of job in case of OAC use/ INR control issues (n ¼ 4: 1 police officer, 1 pilot, 1 businessman who was abroad often, and 1 patient had inadequate variable INR values), and refusal to use OAC (n ¼ 9), while 1 patient wanted to make a journey

T A B L E 1 Baseline Characteristics in 62 Patients With the

around the world.

Combined Procedure of AF Ablation and Watchman LAAO

Age, yrs

64  8

Sex

PROCEDURAL AND IN-HOSPITAL RESULTS CHARACTERISTICS. Ablation by PVAC was performed in

Male

40 (64.5)

44 patients, while additional CFAE ablation by the

Female

22 (35.5)

multiarray septal catheter and multiarray ablation catheters was carried out in the remaining 18 patients

Type of AF Paroxysmal

39 (62.9)

with longstanding persistent AF. The mean total

Persistent

16 (25.8)

procedure time was 99  24 min including a mean

7 (11.3)

39  11 min for LAAO. At the end of the procedure,

Long-standing persistent CHADS2 CHA2DS2-VASc History of transient ischemic attack/stroke HAS-BLED score

2.5 (2–3) 3.0 (2.75–4.00)

8 patients had accepted minimal residual flow

48 (77.4)

(flow #5 mm), while in all other cases complete LAAO

2.0 (2.0–3.0)

was documented on TEE. There were no major, and only 5 minor periprocedural complications: 1 patient

Anticoagulation (N)OAC

50 (80.6)

developed a small tongue hematoma (likely due to

Other

12 (19.4)

either intubation or TEE probe manipulation), and

Antiarrhythmic drugs*

4 patients developed a small groin hematoma man-

Class I

19

Class II

26

Class III

27

Class IV

2

Class V

5

Indication

aged conservatively. All patients were discharged the next day after X-ray confirmation of the Watchman positioned in the LAA (Table 2). SHORT-TERM 90 DAYS AND LONG-TERM FOLLOWUP AFTER THE PROCEDURE. TEE data 60 days after

Stroke with VKA

18 (29.0)

Contraindication for VKA

15 (24.2)

High stroke risk

15 (24.2)

patients (50% complete sealing and 45% minimal re-

Miscellaneous reasons

14 (22.6)

sidual flow of <5 mm). Flow >5 mm was observed in 2

the procedure overall successful LAAO 59 (95%)

patients, with asymptomatic device embolization in 1

LAA LAA width, mm

19.9  3.4

patient observed after 2 months. Additional imaging

LAA length, mm

28.6  5.4

showed that the device had embolized to the

19 (30.6)

abdominal aorta, allowing it to be successfully

Multilobular

Values are mean  SD, n (%), or median (25th to 75th percentile). *According to the Vaughan-Williams classification. AF ¼ atrial fibrillation; (N)OAC ¼ (novel) oral anticoagulation; LAA ¼ left atrial appendage; VKA ¼ vitamin K antagonist.

retrieved by an uneventful percutaneous femoral technique. After a median follow-up of 38 (25 to 45) months, 36 (58.1%) patients (23, 11, and 2 patients with

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Left Atrial Appendage Closure and Ablation for AF

F I G U R E 1 Flowchart of Changes in Anticoagulation Therapy Throughout the Study

Flowchart of the use of aspirin (ASA), the combination of ASA and P2Y12 inhibitor (P2Y12-), oral anticoagulation (OAC), and novel oral anticoagulation (NOAC) in 62 patients undergoing the combined procedure before the procedure, at 3 months, and at the end of follow-up time. VKA ¼ vitamin K antagonist.

paroxysmal, persistent, and longstanding persistent

Two patients died: 1 due to pneumonia with septic

AF, respectively) had neither documented AF re-

shock (while on aspirin) and the other due to exten-

currences nor symptoms suggestive for AF (Table 3).

sive multiorgan hemorrhage resulting from Rendu-

A redo ablation was performed in 9 patients while 5

Osler-Weber (ROW) disease, despite not using any

patients underwent a (mini)-MAZE surgical proce-

form of anticoagulation.

dure. The latter patients had persistent or long-

Three major bleedings were recorded in the follow-

standing persistent AF and severely enlarged left

up period. The first patient (using aspirin) suffered

atrium. These reasons including other important

major bowel bleeding caused by a carcinoma. The

factors as informed patient choice, application of

second (using no anticoagulation or antiplatelet drug)

ESC guidelines, and results of the FAST (Atrial

suffered major bowel bleeding due to ROW disease.

Fibrillation Catheter Ablation versus Surgical Abla-

The third patient (using aspirin) had major recurrent

tion Treatment) trial (28) led to a surgical procedure

lung bleeding due to pathological bronchiectasis,

rather than a percutaneous one.

which had been the indication for LAAO instead of

During follow-up, 11 of the 62 patients (18%) either

OAC in the first place.

remained on, or restarted the use of, (N)OAC due to recurrent AF as determined by their treating physi-

STROKE DURING FOLLOW-UP. During follow-up, 2

cian. In 50 patients who were on (N)OAC before the

patients had an episode of possible neurological

procedure, 39 were switched to aspirin. Another 9

symptoms that were nonwitnessed, without neuro-

patients used a combination of aspirin and a P2Y 12

logical disabilities during physical exam nor signs of

inhibitor due to myocardial infarction, or did not use

neurological damage on computed tomography/

any anticoagulation at all (Table 3).

magnetic resonance (Table 4).

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Left Atrial Appendage Closure and Ablation for AF

T A B L E 2 Procedural Characteristics in 62 Patients With the

Combined Procedure of AF Ablation and Watchman LAA Occlusion

Three ischemic strokes were observed during the median and mean follow-up periods of 38 and 35 months, respectively, all confirmed by a neurologist.

Procedure PVAC

44 (71.0)

PVAC/MASC/MAAC

18 (29.0)

During follow-up, none of these strokes were accompanied by lasting disabilities and full recovery occurred. Interestingly, in 2 patients, the strokes

Device Number

1 (1–2)

occurred still in the first 4 months after the proce-

Size, mm

24 (24–27)

dure, 1 of them (with ROW disease) while still even on

Size

OAC with an appropriate INR. The third stroke

21

12 (19.4)

24

32 (51.6)

27

16 (25.8)

30

1 (1.6)

small residual flow <5 mm in the other 2 patients, all

33

1 (1.6)

without evidence of thrombus on the device. In 1 pa-

Total procedure time, min

98.6  24.0

tient with a history of myocardial infarction resulting

LAA closure time, min

38.7  20.3

in dyskinesia of the left ventricle apex, a new LV

Total fluoroscopy time, min

17.3  10.5

apical thrombus was observed on MRI, which could

Complications 0

Air embolism

0

Minor bleeding

dure. TEE showed complete LAA sealing in 1, and

be related to the stroke. Neurological analysis showed

Pericardial effusion Major bleeding

occurred much later—almost 3 years after the proce-

0 5 (8.1)

that all 3 patients had plaque formation in the carotid arteries, with >50% stenosis in both carotids in 1 patient. Interestingly, 2 of the 3 patients had a compelling contraindication for OAC due to a history

TEE Successful implantation

62 (100)

of significant and recurrent bleeding, 1 as a result of

No residual flow

54 (90)

ROW disease. In 2 of the 3 patients, ECG monitoring

Minimal residual flow Hospitalization, days

8 (12.9)

documented recurrence of AF, while the last patient

2 (2–2)

was asymptomatic and had no AF documented even on continuous rhythm monitoring by an implantable

Values are n (%), median (25th to 75th percentile), or mean  SD. MAAC ¼ multiarray ablation catheter; MASC ¼ multiarray septal catheter; PVAC ¼ pulmonary vein ablation catheter; TEE ¼ transesophageal echocardiography; other abbreviations as in Table 1.

loop recorder. There were no hemorrhagic strokes. The real time annual stroke risk for the group was 1.7%, compared to a CHADS2-based expected annual risk of 6.5% (if

T A B L E 3 Follow-Up Characteristics After a Median Follow-Up Period

of 38 (25 to 45) Months in 62 Patients With the Combined Procedure

Complete occlusion

31 (50.0)

Minimal residual flow (<5 mm jet)

28 (45.2)

DISCUSSION

2 (3.2)

Device embolization

1 (1.6)

Thrombus on device

0 (0)

Freedom from AF

strokes observed than expected if no anticoagulation would be used.

Follow-up TEE

Device malposition (>5 mm jet)

untreated by OAC). This translates into 74% fewer

36 (58.1)

To our knowledge, this is the first prospective study of combined LAAO and radiofrequency ablation of AF with a median follow-up of more than

Paroxysmal

23 (37.1)

Persistent

11 (17.7)

3 years in patients with high stroke risk and/or

2 (3.3)

contraindication(s)

Redo ablation

9 (14.5)

adequate LAA sealing was achieved in 95% of pa-

Surgical (mini)-Maze

5 (8.1)

tients, 58% of patients had neither documented AF

Long-standing persistent

Anticoagulation

for

OAC.

During

follow-up,

recurrence nor symptoms, while 78% of patients

D(OAC)

11 (17.8)

Aspirin

42 (67.7)

Other*

9 (14.5)

Complications during follow-up

could discontinue OAC therapy. The results show that the strategy of ablation and LAAO combined in a single procedure can be performed safely and

Death

2 (3.2)

successfully, with a long-term annual rate of stroke

Stroke

3 (4.8)

that

Major bleeding

3 (4.8)

CHADS2 score.

Values are n (%). *Among these patients 6 used a combination of aspirin/P2Y12 inhibitor due to myocardial infarction and the rest was not on anticoagulation. Abbreviations as in Tables 1 and 2.

was

74%

lower

than

expected

based

on

EFFICACY OF AF ABLATION. The efficacy of a single

ablation procedure ranges from 50% to 60% in general at 1 year (6,22,23,29), to 47% for long-term

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Left Atrial Appendage Closure and Ablation for AF

T A B L E 4 Characteristics of the Stroke Patients

Patient #

CHADS2

Sealing of the Device

History of Bleeding

AF Recurrence

Time After Procedure (months)

Anticoagulation at the Time of Stroke

Stroke Type

Plaque in the Carotid

1

2

<5 mm

yes

yes

2

OAC

iCVA

Yes

2

1

Complete

yes

yes

4

aspirin

iCVA

Yes

3

1

<5 mm

no

no

32

aspirin

iCVA

>50%

AF ¼ atrial fibrillation; iCVA ¼ ischemic cerebrovascular accident; OAC ¼ oral anticoagulation.

freedom from paroxysmal AF (30). Weerasooriya et al.

accidents. However, procedural safety may be an

(31) have shown that success rate decreases dramati-

issue as a recent systemic review showed a signifi-

cally toward 29% after 5 years in patients with mixed

cant amount of serious adverse events consisting of

types of AF. Although Holter monitoring was not

cardiac tamponade and bleeding needing urgent

systematically performed, 58% of patients became

surgery, and even 1 death (36).

asymptomatic and had no AF documented on any type of recording during the complete follow-up

EFFICACY AND SAFETY OF STROKE PREVENTION

period. Such a long-term efficacy is in line with the

IN THE COMBINED APPROACH. After the median

literature, especially given that 37% of our patients

follow-up of 38 months, 3 ischemic strokes were

had nonparoxysmal AF with significant comorbidity.

found, translating into an annualized stroke rate

If anything, in our population the true AF recurrence

of 1.7%. When compared to the expected CHADS2

would be underestimated, which only strengthens

calculated annual risk of 6.5% and taking into

the case for indefinite stroke prevention in high-risk

consideration that most patients were able to dis-

patients even after ablation. Finally, there is in-

continue (N)OAC therapy, these real-life data suggest

creasing appreciation that while ablation certainly

that the combined procedure may significantly

has a dramatic favorable effect on patient symptoms,

reduce the rate of both stroke and bleeding. How-

freedom from recurrent AF does not assure freedom

ever, in line with long-term follow-up data of

from cardioembolic events. Despite maintaining si-

PROTECT-AF (The Watchman Left Atrial Appendage

nus rhythm, there remains a high stroke risk in pa-

System for Embolic Protection in Patients With AF)

tients with extensive atrial scar related to both/either

and PREVAIL (Prospective randomized evaluation of

pre-existing disease progression and/or ablation-

the Watchman Left Atrial Appendage Closure device

related damage (32).

in patients with atrial fibrillation versus long-term

Another LAAO device mainly used in the United

warfarin therapy) (16,17), neither OAC nor LAAO can

States is the LARIAT device (SentreHEART, Inc.,

completely eradicate strokes. The most recent pub-

Redwood City, California). It relies on elimination of

lished 4-year PROTECT-AF data showed significantly

the LAA by an epicardial string around the neck of

lower event rates in the Watchman group versus

the appendage. This does not only close the LAA

warfarin group, though the outcome was mainly

cavity, but may also lead to elimination of electrical

driven by fewer hemorrhagic strokes and cardiovas-

activity. This may be beneficial in patients where the

cular deaths while the stroke rate did not differ (18).

LAA is a source for ectopic triggers or part of the AF

In our heterogeneous study population with signifi-

substrate. Indeed, Di Biase et al. (33) have shown

cant comorbidities and mean age of 68 years,

that in a selected patient group with recurrent AF

embolic strokes could also have developed from

after an initial ablation, 27% showed foci arising

noncardiac origins such as atheromatous plaque in

from the LAA. Recent data have shown that com-

the thoracic aorta or carotid arteries (37,38). Carotid

plete LAAO by LARIAT device resulted in a reduction

artery echocardiography indeed showed plaque for-

of AF burden specifically in patients with proven

mation or stenosis >50% in the 3 patients that

LAA ectopy (34). Whether other LAA devices results

developed

in a similar devitalization and antiarrhythmic effects

However, the observed annual stroke rate of 1.7%

has not been published so far. There is only 1 study

was still higher than desired after combining an

comparing the Watchman device to LARIAT (35). The

ablation meant to cure AF, and adding LAAO to

LARIAT device showed a lower rate of residual leaks

prevent stroke. In the 3 patients with stroke, no

at 1-year follow-up, but no significant clinical impact

common explanatory denominator was apparent and

was observed, especially not for cerebrovascular

their CHADS 2 score was even fairly low. AF was

stroke

during

the

follow-up

period.

Alipour et al.

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 6, 2015 DECEMBER 2015:486–95

Left Atrial Appendage Closure and Ablation for AF

documented in the 2 patients with stroke within 4

implantable loop recorder to establish freedom from

months of the procedure, while continuous rhythm

AF. With our strategy we were able to show that at

monitoring with implantable loop recorder showed

least 42% of patients had recurrence of AF. This may

no AF recurrence in the patient with stroke after

underestimate the absolute recurrence of AF, spe-

3 years. In 2 patients, sealing was incomplete but

cifically in asymptomatic patients who were even

still acceptable with <5 mm. Although prior retro-

unwilling to undergo further testing. With the pra-

spective analysis of the PROTECT-AF trial did not

gmatic strategy we describe the need for the long-

establish a relation between minimal residual flow

term intense rhythm follow-up actually becomes

and thromboembolism (39), this cannot be com-

less relevant as patients are protected by their

pletely ruled out.

Watchman LAAO. Larger (randomized) trials are

The acute safety profile of the combined procedure was very good, with only 5 minor and no major pro-

needed with more stringent criteria and dedicated arrhythmia detection.

cedural complications. The few procedural compli-

Finally, we cannot rule out asymptomatic cerebral

cations observed were not device related but resulted

emboli. In early publications (40,41) in small regis-

mostly from femoral access. Using a fixed team of

tries it was observed that PVAC ablation was

skilled implanters with optimal echocardiographic

accompanied by a substantially higher rate of asy-

imaging facilitates a good safety record. The benefit

mptomatic cerebral emboli up to 40%. By performing

of experience is supported by even shorter procedural

an elaborate root cause analysis in an animal model,

times compared to our previously published data

Haines et al. (42) observed several possible mecha-

(20). The fact that 95% of implants showed acute

nisms for asymptomatic cerebral emboli including

successful LAAO, is also in line with the data pub-

air introduction from the transseptal sheath, and

lished in the PROTECT-AF and PREVAIL trials (16,17).

overlap of electrodes 1 and 10 of the array, leading to

During the follow-up period, 3 device implants did

overheating and coagulum formation. In response,

not result in sufficient LAA sealing. Two patients had

several changes were made to procedure workflow,

a malposition of the Watchman with >5 mm residual

the generator, and the PVAC array. The ERACE

flow, and OAC therapy was therefore maintained.

(Evaluation of Reduction of Asymptomatic Cerebral

In 1 patient (the third implant in our center in 2010),

Embolism) trial (43) showed that with adequate INR

asymptomatic device embolization to the abdominal

>2.0 and activated clotting time >350 s, underwater

aorta occurred, with uneventful retrieval from the

loading of the PVAC to avoid microbubbles, dis-

groin.

connecting either pair 1 or pair 5 of the array to avoid overlap, and using the new GENius CONTACT-

STUDY LIMITATIONS. The population in the study is

IQ

heterogeneous, including patients with failed OAC,

resulted in a decrease of asymptomatic cerebral

and with bleeding and/or strict contraindication to

emboli rate to 1.7%, which is on the low end of re-

OAC, but also high stroke risk patients who were

ported asymptomatic cerebral emboli rates of other

included for miscellaneous and/or practical reasons

techniques.

generator

(Medtronic,

Carlsbad,

California),

despite eligibility for OAC. This makes the history of these patients highly variable, as well as their ability to use any form of anticoagulation after LAAO.

CONCLUSIONS

Some patients underwent repeated CA or surgical ablation with LAA removal. This makes it chal-

LAAO combined with ablation for AF can be per-

lenging to estimate the expected stroke risk in this

formed successfully and safely in a single procedure.

population. Although the study population has

Long-term follow-up shows a lower than expected

doubled compared to our first feasibility study (21),

stroke rate compared to the expected baseline

the number of patients remains limited. However,

CHADS2 score. However, this stroke rate is higher

the relatively long follow-up time makes the data

than desirable after combined therapy to prevent

solid to interpret on key events. Our prospective

stroke at both ends. Further studies are needed to

study is purely observational without a conven-

illuminate the patient phenotype, which benefits the

tional control group. For patients with a contra-

most from the combined therapy.

indication for OAC, such control data are not readily available; such a trial seems ethically prob-

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

lematic. As this was a practical observational trial

Arash Alipour, Department of Cardiology, St. Antonius

aiming at proof of principle, there was no system-

Hospital, P.O. Box 2500, 3430 EM Nieuwegein, the

atic long-term rhythm follow-up with Holter or

Netherlands. E-mail: [email protected].

493

494

Alipour et al.

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 6, 2015 DECEMBER 2015:486–95

Left Atrial Appendage Closure and Ablation for AF

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: The

thromboembolic risk is effectively reduced without having

2 competencies describing best the implications of the

to continue (N)OAC, which is especially important in those

study for current practice are patient care and medical

at high risk of (recurrent) bleeding. In the randomized

knowledge. Patient care comprises that the best suitable

clinical trials PROTECT-AF and PREVAIL trials, Watchman

and effective care is the out-of-the-box combined therapy

LAAO showed a complication risk of 5% to 20%. Ablation

for the individual patients with severe comorbidity and

of AF also carries a significant risk of complications of 5%

with symptomatic drug-refractory AF at high risk of

to 10%. Many of these risks are similar, such as groin

bleeding. Sufficient medical knowledge of both therapies

bleeding, tamponade, and stroke, simply due to the fact

would eventually promote health for the specific AF pa-

that these procedures require access to the left atrium. It

tient with severe comorbidity.

is therefore only logical that combining these procedures limits the inherent risks and patient discomfort of 2

TRANSLATIONAL OUTLOOK: Besides reducing

separate procedures. Whether this is cost-effective de-

discomfort, the long-term success rate was at least

pends on reimbursement policies in each country, actual

reasonable with 58% of patients with no documented AF

reduction in stroke, and long-term freedom of AF after

recurrence nor symptoms after 38 months of follow-up.

ablation. The latter has been found to be lower than ex-

Overall, high-risk patients need to remain on OAC even

pected in studies with long-term rhythm monitoring.

after ablation in line with the Consensus statement by the

Translating our clinical study into care of individual pa-

Heart Rhythm Society/European Heart Rhythm Associa-

tients with symptomatic drug-refractory AF and high risk

tion/European Cardiac Arrhythmia Society, as we cannot

of bleeding means that oral anticoagulation can be

prove that AF is 100% cured, and even long-term recur-

stopped, regardless of the long-term outcome of ablation

rence may occur. By adding LAAO in these patients, their

for AF.

REFERENCES 1. Camm AJ, Lip GY, De Caterina R, et al., ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC guidelines for

6. Haegeli LM, Calkins H. Catheter ablation of atrial fibrillation: an update. Eur Heart J 2014;35: 2454–9.

the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation—developed with the special contribution of the European Heart Rhythm Association. Europace 2012;14:1385–413.

7. De Backer O, Arnous S, Ihlemann N, et al. Percutaneous left atrial appendage occlusion for stroke prevention in atrial fibrillation: an update. Open Heart 2014;1:e000020.

2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370–5. 3. Stewart S, Hart CL, Hole DJ, McMurray JJ. Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study. Heart 2001;86:516–21. 4. Van Gelder IC, Hagens VE, Bosker HA, et al. Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347: 1834–40. 5. Wyse DG, Waldo AL, DiMarco JP, et al., Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33.

8. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger pts with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. Circulation 2011;123:2363–72. 9. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly pts with atrial fibrillation. Circulation 2007;115: 2689–96. 10. Sudlow M, Thomson R, Thwaites B, Rodgers H, Kenny RA. Prevalence of atrial fibrillation and eligibility for anticoagulants in the community. Lancet 1998;352:1167–71.

Dabigatran versus warfarin in pts with atrial fibrillation. N Engl J Med 2009;361:1139–51. 13. Patel MR, Mahaffey KW, Garg J, et al., ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–91. 14. Granger CB, Alexander JH, McMurray JJ, et al., ARISTOTLE Committees and Investigators. Apixaban versus warfarin in pts with atrial fibrillation. N Engl J Med 2011;365:981–92. 15. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical pts with atrial fibrillation. Ann Thorac Surg 1996;61: 755–9. 16. Reddy VY, Doshi SK, Sievert H, et al., PROTECT AF Investigators. Percutaneous left atrial appendage closure for stroke prophylaxis in pts with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Pts with Atrial Fibrillation) Trial. Circulation 2013;127:720–9. 17. Holmes DR Jr., Kar S, Price MJ, et al. Pro-

11. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;376:975–83.

spective randomized evaluation of the Watchman Left Atrial Appendage Closure device in pts with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014;64: 1–12.

12. Connolly SJ, Ezekowitz MD, Yusuf S, et al., RE-LY Steering Committee and Investigators.

TECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs

18. Reddy VY, Sievert H, Halperin J, et al., PRO-

Alipour et al.

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 6, 2015 DECEMBER 2015:486–95

warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014;312:1988–98.

Left Atrial Appendage Closure and Ablation for AF

27. Gangireddy SR, Halperin JL, Fuster V, Reddy VY. Percutaneous left atrial appendage closure for stroke prevention in patients with atrial fibrillation: an assessment of net clinical benefit.

19. Reddy VY, Möbius-Winkler S, Miller MA, et al. Left atrial appendage closure with the Watchman device in pts with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix

28. Boersma LV, Castella M, van Boven W, et al.

Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61:2551–6.

Atrial fibrillation catheter ablation versus surgical ablation treatment (FAST): a 2-center randomized clinical trial. Circulation 2012;125:23–30.

20. Swaans MJ, Post MC, Rensing BJ, Boersma LV. Ablation for atrial fibrillation in combination with left atrial appendage closure: first results of a feasibility study. J Am Heart Assoc 2012;1: e002212.

29. Brooks AG, Stiles MK, Laborderie J, et al. Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 2010;7:835–46.

21. Mulder AA, Balt JC, Wijffels MC, Wever EF, Boersma LV. Safety of pulmonary vein isolation and left atrial complex fractionated atrial electrograms ablation for atrial fibrillation with phased radiofrequency energy and multi-electrode catheters. Europace 2012;14:1433–40. 22. Boersma LV, Wijffels MC, Oral H, Wever EF, Morady F. Pulmonary vein isolation by duty-cycled bipolar and unipolar radiofrequency energy with a multielec-trode ablation catheter. Heart Rhythm 2008;5:1635–42. 23. Mulder AA, Wijffels MC, Wever EF, Boersma LV. Pulmonary vein isolation and left atrial complex-fractionated atrial electrograms ablation for persistent atrial fibrillation with phased radio frequency energy and multielectrode catheters: efficacy and safety during 12 months follow-up. Europace 2011;12:1695–702. 24. Fountain RB, Holmes DR, Chandrasekaran K, et al. The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Pts with Atrial Fibrillation) trial. Am Heart J 2006;151: 956–61.

Eur Heart J 2012;33:2700–8.

analytic review of the FDA MAUDE database. JAMA Intern Med 2015;175:1104–9. 37. Onalan O, Crystal E. Left atrial appendage exclusion for stroke prevention in pts with nonrheumatic atrial fibrillation. Stroke 2007;38:624–30. 38. Whitlock RP, Healey JS, Connolly SJ. Left atrial appendage occlusion does not eliminate the need for warfarin. Circulation 2009;120:1927–32. 39. Viles-Gonzalez JF, Kar S, Douglas P, et al. The

30. Ouyang F, Tilz R, Chun J, et al. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation 2010;122:2368–77. 31. Weerasooriya R, Khairy P, Litalien J, et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol 2011;57:160–6. 32. Buber J, Luria D, Sternik L, et al. Left atrial contractile function following a successful modified Maze procedure at surgery and the risk for subsequent thromboembolic stroke. J Am Coll Cardiol 2011;58:1614–21. 33. Di Biase L, Burkhardt JD, Mohanty P, et al. Left atrial appendage: an underrecognized trigger site of atrial fibrillation. Circulation 2010;122:109–18. 34. Afzal MR, Kanmanthareddy A, Earnest M, et al. Impact of left atrial appendage exclusion using an epicardial ligation system (LARIAT) on atrial fibrillation burden in patients with cardiac implantable electronic devices. Heart Rhythm 2015; 12:52–9.

clinical impact of incomplete left atrial appendage closure with the Watchman Device in pts with atrial fibrillation: a PROTECT AF Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Pts With Atrial Fibrillation) substudy. J Am Coll Cardiol 2012;59:923–9. 40. Herrera Siklódy C, Deneke T, Hocini M, et al. Incidence of asymptomatic intracranial embolic events after pulmonary vein isolation: comparison of different atrial fibrillation ablation technologies in a multicenter study. J Am Coll Cardiol 2011;58: 681–8. 41. Gaita F, Leclercq JF, Schumacher B, et al. Incidence of silent cerebral thromboembolic lesions after atrial fibrillation ablation may change according to technology used: comparison of irrigated radiofrequency, multipolar nonirrigated catheter and cryoballoon. J Cardiovasc Electrophysiol 2011;22:961–8. 42. Haines DE, Stewart MT, Dahlberg S, et al. Microembolism and catheter ablation I: a comparison of irrigated radiofrequency and multielectrodephased radiofrequency catheter ablation of pulmonary vein ostia. Circ Arrhythm Electrophysiol 2013;6:16–22.

25. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in pts with atrial fibrillation: a randomised non-

35. Pillarisetti J, Reddy YM, Gunda S, et al. Endocardial (Watchman) vs epicardial (Lariat) left atrial appendage exclusion devices: understanding the differences in the location and type of leaks and their clinical implications. Heart Rhythm 2015;

43. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electro-

inferiority trial. Lancet 2009;374:534–42.

12:1501–7.

physiol 2013;6:835–42.

26. Oral H, Chugh A, Ozaydin M, et al. Risk of

36. Chatterjee S, Herrmann HC, Wilensky RL, et al.

thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006;114:759–65.

Safety and procedural success of left atrial appendage exclusion with the Lariat device: a systematic review of published reports and

KEY WORDS atrial fibrillation, left atrial appendage closure, stroke

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