INVASIVE ELECTROPHYSIOLOGYAND PACING (J SINGH, SECTION EDITOR)

Cather-Based Approaches to Stroke Preventionin Atrial Fibrillation

Sunil Kapur & Moussa Mansour

Published online: 21 September 2013# Springer Science+Business Media New York 2013

Abstract The left atrial appendage (LAA) is a prominentsource of cardioembolic stroke in patients with nonvalvularatrial fibrillation (AF). While systemic anticoagulation is thecommon therapeutic choice, these medications carry manycontraindications and possible complications. Epicardial andendovascular techniques for occlusion of LAA have beenexplored and early clinical data is accumulating. In the comingyears, this data will help guide the management of AF patientsat risk of bleeding as well as potentially become first-linetherapy to reduce the risk of thromboembolic stroke. Thepurpose of this article is to review current endovascular andepicardial catheter based LAA occlusion devices and theclinical data supporting their use.

Keywords Atrial fibrillation . Left atrial appendage .

Anticoagulation . PLAATO .Watchman . PROTECT-AF .

PREVAIL .Amplatzer . LARIAT . Cather-based approaches .

Stroke prevention

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhyth-mia, currently affecting over 3 million Americans [1]. Clini-cally, the management of AF revolves around (a) alleviation ofsymptoms related to an accelerated atrial/ventricular rate and(b) prevention of systemic embolism. Over the past decade,

there has been significant evolution in the management of thesymptoms of AF via both pharmacologic and non-pharmacologic advances. Likewise, the prevention of systemicembolism has seen significant progression with the recent devel-opment of novel oral anti-coagulants. However, approximately50 % of patients with AF are maintained without systemicanticoagulation and even many of those patients spend only aportion of the time within a target international normalized ration(INR) range. These facts underlie the problems that accompanysystemic anticoagulation. It is for this reason that non-pharmacologic prevention of embolism has gained significanttraction. Among patients with nonvalvular AF, the majority ofthrombi are located within the left atrial appendage (LAA). Assuch, non-pharmacologic therapy has centered around occlusion,obliteration or removal of the LAA.

Left Atrial Appendage Fundamentals

The LAA is a remnant of the original embryonic left atriumformed during the thirdweek of gestation. The LAA empties intothe left atrium through an orifice located between the left upperpulmonary vein and the left ventricle. Epicardially, it is locatedon the lateral wall of the heart close to the circumflex artery andthe great cardiac vein. On the endocardial surface, it is within1 cm of the mitral valve (MV) annulus [2]. Its unique anatomyallows predisposition to in-situ thrombus formation. Clinicalstudies using various imaging modalities such as TEE andmagnetic resonance angiography demonstrate significant hetero-geneity in LAA morphology [3–5]. These anatomic factorscomplicate mechanical occlusion of the appendage. While sev-eral purported physiologic roles of the LAAhave been described,pathophysiologic descriptions of the LAA is a source of embo-lism in AF date back to the 1940s [6]. Review of human data hassuggested that at least 90 % of LA thrombi are found within the

This article is part of the Topical Collection on Invasive Electrophysiologyand Pacing

S. Kapur :M. MansourBrigham and Women’s Hospital, Boston, MA, USA

S. Kapur :M. Mansour (*)Massachusetts General Hospital, 55 Fruit Street, GRB-109, Boston,MA 02114, USAe-mail: mmansour@partners.org

Curr Cardiol Rep (2013) 15:419DOI 10.1007/s11886-013-0419-6

LAA [7]. As such, the concept of LAAmodification as amethodto reduce thrombo-embolism has arisen.

A variety of surgical techniques have been described to closethe LAA, with various degrees of efficacy. These are reviewedelsewhere [8]. In the 1990s, interest was increased with theinclusion of atrial appendage removal at the time of MAZE [9].The data for surgical LAA exclusion consist primarily of retro-spective case series and case reports, although an ongoing trial islooking to further elucidate the risks and benefits (LAAOSII;http://clinicaltrials.gov/NCT00908700). In recent years, there hasbeen a significant push to develop minimally invasive orthoracoscopic devices. Concurrently, interest in the LAA hasbeen driven by the development in percutaneous occlusiondevices. These are divided into two fundamental deliverytechniques -- endocardial and epicardial approaches.

Percutaneous LAA Endocardial Occlusion

Three devices have been investigated: the Percutaneous LAATranscatheter Occlusion or PLAATO System (eV3, Plym-outh, MN), the Amplatzer Cardiac Plug (St. Jude Medical,Minneapolis, MN), and the Watchman (Boston Scientific,Maple Grove, MN) device. All are delivered percutaneouslythrough transseptal access to the left atrium (LA).

PLAATO

In 2001 the Percutaneous LAA Transcatheter Occlusion(PLAATO) was the first device of its kind used in humans.As of the time of writing, the PLAATO device has beenevaluated in research studies but has not received Food andDrug Administration (FDA) approval. Trans-esophagealechocardiogram (TEE) or intracardiac echocardiographicguidance is commonplace.

The PLAATO System is a self-expandable nitinol cagewith a polytetrafluoroethylene membrane. The purpose ofthe membrane is both to occlude the orifice of the LAA andto allow tissue incorporation into the device. Small anchorsalong the struts and passing through the occlusive membraneassist with device anchoring and encourage healing response.The device is delivered through a custom 14Fr transseptalsheath curved to point at the LAA.

Although it is no longer available, data from early experi-ence with this first-in-class device are instructive. Preliminarysuccess in canine models was demonstrated in the late 1990s.The first human implantation of the PLAATO device wasdescribed in 15 patients with persistent AF and contraindica-tions to oral anticoagulant therapy published in 2002 [10]. Itsinitial thorough evaluation involved an international multicen-ter registry of 111 patients with contraindication to oralanticoagulation [11]. In this cohort, device implantation was97% successful, and LAA occlusion was documented in 98%

of patients at the 6-month follow-up TEE. There were sevenmajor adverse events, including one death and two strokes, ata mean follow-up of 9.8 months. Overall, the stroke rate of2.2 % per year compared with the estimated annual stroke rateof 6.3 % for this population represented a 65 % relativereduction in stroke.

Later trials with the device showed similar success. AEuropean study reported on 180 patients with nonrheumaticatrial fibrillation and a contraindication to warfarin and whowere treated with the device [12•]. Placement was successfulin 90 % of patients. Two patients died within 24 hours of theprocedure (1.1 %), and six patients had cardiac tamponade(3.3 %), with two requiring surgical drainage. During afollow-up of 129 patient-years, there were three strokes, fora rate of 2.3 % per year.

The 5-year North American results consisted of 64 AFpatients who were similarly at high risk of stroke (meancongestive heart failure, hypertension, age, diabetes mellitus,prior stroke or transient ischemic attack [CHADS2] score=2.6) and were not oral anticoagulation candidates [13]. Deviceimplantation success was 100 %, with 98 % success by corelaboratory TEE. In comparison with historical controls, withan expected 6.6 % stroke rate, the PLAATO device in this trialshowed a 3.8 % stroke rate, or a 42 % relative risk reduction.

To date, the PLAATO experience showed that in anonrandomized cohort, device implantation is feasible, and com-paredwith the stroke risk estimated using the CHADS2 score, cutthe stroke rate by 40 % to 65 % in higher risk AF patients.

WATCHMAN

A year after the PLAATO design was first implanted, theWATCHMANLAA closure device was implanted in humans.

The WATCHMAN LAA system is a self-expanding nickeltitanium (nitinol) device. It has a polyester covering andfixation barbs for attachment to the endocardium (Fig. 1a).Like PLAATO, implantation is performed percutaneouslythrough a catheter delivery system, utilizing venous accessand transseptal puncture. Following implantation, patients areanticoagulated with warfarin or alternate agents for approxi-mately 45 days as the fabric of the Watchman is blood per-meable and requires warfarin until TEE demonstrates sealingof the LAA. After this period, patients are maintained onantiplatelet agents indefinitely.

The most notable randomized clinical trial with any LAAocclusion device is the Watchman Left Atrial AppendageSystem for Embolic Protection in Patients with Atrial Fibril-lation (PROTECT-AF) trial [14]. The population was at lowerrisk than the PLAATO studies with a mean CHADS2 meanscore of 2.17. The study randomized 707 patients withnonvalvular AF from 59 sites worldwide 2:1 to the WATCH-MAN device to determine device noninferiority for efficacy.

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The control group was maintained on warfarin therapy and theWATCHMAN group received warfarin for 45 days. Efficacywas assessed by a primary composite end point of stroke,cardiovascular death, and systemic embolism. Implant successwas 91 %. If the TEE at 45 days showed minimal flow in theLAA and no thrombus or clinical end points, then warfarinwas discontinued with aspirin/clopidogrel to 6 months,followed by aspirin alone. At 45 days, 86 % of the Watchmanpatients were able to stop warfarin. Core laboratory echocar-diography documented successful closure in 92 % by6 months. In theWatchman group, there was a 38% reductionin primary efficacy, 29 % in stroke, and 38 % in deathcompared with the warfarin control group. Meanwhile, therewas a 77% increase in primary safety events in the Watchmangroup. The primary end point for safety was serious adverseevents, which included major bleeding, pericardial effusion,and device embolization. However, procedural complicationsoccurred in a relatively high percentage: 49 of 453 (10.6 %) ofthe device cohort. The control group had a 6.6 % (16 of 244)adverse event rate, which consisted of major bleeding (4.3 %)and hemorrhagic stroke (2.5 %). The PROTECT-AF studysuccessfully demonstrated the noninferiority of the Watchmandevice compared with standard therapy with warfarin.

As with most procedures, with experience come betterresults. In a recent analysis comparing the PROTECT AFTrial with the subsequent Continued Access Protocol (CAP)Registry [15], the reported data found that procedure-related

and device-related adverse events were greater in the first halfof PROTECTAF than in the second half. In early 2013, datawas presented for the 4 year follow up of the study. Theprimary efficacy event rate per 100 patient-years was lowerwith the Watchman device compared with controls (2.3 % vs.3.8%), demonstrating a 40% relative risk reduction (RR 0.60;95 % CI 0.41-1.05). In addition, in an intention-to-treat anal-ysis, patients who received the novel device were at reducedrisk compared with warfarin-treated patients for both all-causemortality (3.2 % vs. 4.8 %; HR 0.66; 95 % CI 0.45-0.98; P=0.0379) and cardiovascular mortality (1.0 % vs. 2.4 %; HR0.40; 95 % CI 0.23-0.82; P=0.0045). While not fully pub-lished, this data suggests the WATCHMAN device may actu-ally demonstrate superior outcomes as compared to the previ-ously published non-inferiority [16].

The WATCHMAN device was considered for FDA ap-proval in 2009 based on the results of the PROTECT-AFrandomized controlled trial. While the FDA advisory panelfor this topic voted in favor of approval, the FDA did not grantfinal approval after concluding that further studies of efficacyand safety were necessary.

Currently, the PREVAIL study (Prospective RandomizedEVAluation of theWatchman LAAClosure Device in Patientswith Atrial Fibrillation Version Long TermWarfarin Therapy)is underway to seek FDA approval in the United States. ThePREVAIL trial enrolled 407 patients from 41 US centers whowere randomized 2:1 to the device or control (warfarin).

Fig. 1 a The WATCHMANdevice. b Fluoroscopic stillduring the deployment of thelariat device. Seen are theechocardiogram probe (*),temporary balloon in the left atrialappendage (**), two magnet-tipped guidewires [oneendocardial (#), one epicardial($)] and a closure snare device(%)

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Device patients were given 45 days of warfarin therapy. Thetrial included new centers and operators to document thatenhancements to the training program are effective. The studyhas not been published in its entirety.

Amplatzer Occlusion Device

The Amplatzer septal occluder (ASO, AGA Medical/St. JudeMedical, St. Paul, MN) has been in use for almost 15 years,with extensive success in patent foramen ovale and atrialseptal defect closure and is FDA-approved for this indication.

The first human clinical application in LAA occlusion wasin 2002. In a series of 16 patients, LAA occlusion was suc-cessful in 15, with one instance of device embolization requir-ing surgical intervention [17]. Subsequently, the AmplatzerCardiac Plug (ACP, AGAMedical) was developed specifical-ly for LAA occlusion. It has a similar platform as theAmplatzer septal occluder and consists of a self-expandingflexible nitinol mesh with a distal lobe with retaining hooks, aproximal disk, and a central polyester patch. The mechanismof the lobe and disk for sealing the LAA orifice has beingtermed the pacifier principle.

In the initial European experience, the device was success-fully implanted in 96 % of patients [18•]. Asia-Pacific expe-rience was similar [19]. The ACP received the ConformitéEuropéene (CE) mark in 2008. Implantations with the devicehave been done in more than 1200 patients worldwide. TheAmplatzer device has not yet received FDA-approval forLAA closure device. A randomized clinical study comparingthe efficacy of the ACP device vs. warfarin was just started inthe United States.

Epicardial LAA Occlusion

Two devices in various stages of development involve atranscatheter transpericardial technique. The LARIAT SutureDelivery Device (SentreHEART Inc, Palo Alto, CA) and theAegis electrocardiogram-guided LAA Capture and LigationSystem.

LARIAT

The LARIAT Suture Delivery Device (SentreHEART Inc,Palo Alto, CA) uses a combination of transseptal placementof a temporary balloon in the LAA, two magnet-tippedguidewires inserted into the LAA and the pericardial space,and a closure snare device (Fig. 1b). A 40-mm pre-tied radi-opaque suture loop ligates the LAA. Because of the need forpericardial access, patients with a history of coronary arterybypass surgery or pericarditis who may have adhesions in thisspace are not suitable candidates for the LARIAT procedure.

Unlike endocardial, the LARIAT procedure does not requirethe use of immediate postprocedural anticoagulation therapywith warfarin. Because of the unavoidable irritation of thepericardium associated with the pericardial access used in theLARIAT procedure, most patients develop pericarditis afterthe procedure.

This device demonstrated successful LAA closure in acanine model with 100 % successful deployment in a seriesof 37 [20]. Limited early data showed the feasibility of theprocedure in 13 human patients [21]. In 2011, a total of 13patients undergoing either mitral valve surgery (n=2) or elec-trophysiological study and radiofrequency catheter ablationfor AF (n=11) underwent ligation of the LAAwith the Lariatsnare device. Both mitral valve replacement (MVR) patientshad complete closure of the LAA determined by visual in-spection; 10 of 11 patients having ablation underwent a suc-cessful closed-chest LAA ligation procedure with TEE andcontrast fluoroscopy verification of closure of the LAA. Bothmitral valve replacement (MVR) patients had complete clo-sure of the LAA determined by visual inspection; 10 of 11patients having ablation underwent a successful closed-chestLAA ligation procedure with TEE and contrast fluoroscopyverification of closure of the LAA.

Subsequent data from a larger series confirmed the largelypositive results [22••]. Eighty-five (96 %) of 89 patientsunderwent successful LAA ligation. Eighty-one of 85 patientshad complete closure immediately. Three of 85 patients had a ≤2-mm residual LAA leak and one of 85 patients had a ≤3-mm jetby TEE color Doppler evaluation. There were no complicationsdue to the device. There were 3 access-related complications(during pericardial access, n=2; and transseptal catheterization,n=1), all treated conservatively without any patient requiringsurgery. Adverse events included severe pericarditis post-operatively (n=2), late pericardial effusion (n=1), unexplainedsudden death more than 6 months after the procedure (n=2), andlate strokes thought to be non-embolic also occurring more than6 months after the procedure (n=2). At 1 month (81 of 85) and3 months (77 of 81) post-ligation, 95 % of the patients hadcomplete LAA closure by TEE. Of the patients undergoing 1-year TEE (n=65), there was 98 % complete LAA closure,including the patients with previous leaks.

The LARIAT is approved in Europe and was approved bythe Food and Drug Administration in 2009.

Aegis System

The Aegis system is an epicardial electrocardiogram-guidedLAA capture and ligation System. It permits LAA closure inthe closed pericardial space with a single sheath puncture. Ithas two components: an appendage grasper and a ligator. Thegrasper has an articulating jaw with specially mounted elec-trodes to permit navigation and identification of position andtissue captured by means of electrical signals. An atrial

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electrogram recorded between the two jaws identifies thetissue captured as atrial myocardium, thus distinguishing theLAA from epicardial fat and ventricular tissue. Additionalrecordings between each jaw and the shaft, and bipolar re-cordings along the shaft permit identification of the grasper’sposition relative to electrically active cardiac tissue. Once thesystem is positioned near the LAA, injection of contrast atclose proximity is performed to outline the LAA to facilitateand confirm its capture. Capture is further confirmed by TEE.The second component is a ligator/ hollow suture which ispreloaded with a 0.012 inch support wire to provide mechan-ical support and for fluoroscopic visualization. Once the loopis in position it is cinched down, occluding the LAA, afterwhich the wire is removed leaving only the suture behind. Theloop can be repeatedly opened and closed until capture isachieved. An initial suture can also be used as a guide formore proximal sutures. Its viability has been shown in a dogmodel [23]. Further studies have shown improving results onan intermediate basis [24]. Human data is not available to date.

Thorascopic Devices

Beyond the two aforementioned devices, other systems using athorascopic approach are currently in development. First, theEpitek (Minneapolis, MN) Anchorage Closure System uses asubxiphoid approach combined with an endoscope and an LAAforceps-like grasper. Access is obtained by an access needle andsubsequent sequential dilation from 6Fr to 30Fr in 2Fr incre-ments. The appendage is grasped, and a snare advanced over itwith a pre-tied suture and to ligate the LAA. A thoracoscope:with a 75° field of view, has standard endoscope connections.The Medtronic Cardioblate is thoracoscopic, handheld system.Access is achieved through an 11.5 mm port in the left thorax. Anitinol wire is used to expand a radiopaque silicone band to 36×

25 mm to occlude the atrial appendage. A polyester fabric coverallows for tissue ingrowth and epicardial encapsulation of theband. The device is used in canine experiments for both right andleft atrial appendage closure [25, 26]. A clinical trial wasterminated.

Conclusions

Pharmacologic therapies to prevent stroke in AF have numerouslimitations, prompting the development of device-based thera-pies. Because of its complex anatomy and diminished blood flowduring AF, the left atrial appendage (LAA) has been a commonsite of left atrial thrombi and presumed source of thromboembo-lism. Systemic anticoagulation to treat what may be largely alocalized phenomenon is associated with significant complica-tions. These challenges have led to interest in mechanical exclu-sion of the LAA as a means of preventing thromboembolism inAF. In this paper and summarized in Table 1, we reviewed thecurrent state of percutaneous left atrial exclusion for strokeprevention in AF, and the strengths and limitations of each ofthese strategies. The nonsurgical approaches to excluding theLAA from the central circulation can be divided into two broadcategories: transseptal endovascular devices and percutaneousepicardial devices. Early data from both categories is promising.The availability of several approaches will allow physician se-lection of the optimal approach for a given patient based onclinical, physiological, and anatomical considerations. LAA ex-clusion stands to become an increasingly attractive option forpatients with nonvalvular AF.

Compliance with Ethics Guidelines

Conflict of Interest Sunil Kapur declares that he has no conflict ofinterest.

Table 1 Summary of the available devices with route of delivery, advantages, and disadvantages

DEVIC PLAATO AMPLATZER WATCHMAN LARIAT

Material Expandable nitinolcage with a PTFEmembance

Nitinol device withpolyester covering

Nitinol mesh withretaining hooks,a proximal disk,and a central polyesterpatch

Epicardial closure snare

Device location Device location Endocardial Endocardial Epicardial

Access 14Fr transseptal sheath Transseptal Transseptal Transeptal + Pericardial

Notes First device of its kindused in humans

Requires anticoagulationperi- implantation

Randomized clinicaltrial recently initiated

Requires anticoagulationperi- implantation

Requires anticoagulationperi- implantation

PROTECT-AF andPREVAILTrial

Difficult with pericardialscarring i.e. patientswith prior cardiacsurgery

No peri-implantationanticoagulation required

Approval Not FDA-approved FDA-approved for septalclosure; not for LAAocclusion

Not FDA-approved FDA-approved

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Moussa Mansour has been a consultant for Biosense Webster and St.Jude Medical; has received grant support from Biosense Webster, MC10,Boston Scientific; and has received travel/accommodations expensescovered or reimbursed from St. Jude Medical.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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