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Left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation Expert Rev. Cardiovasc. Ther. Early online, 1–8 (2015)

Duong Le1, Remo Morelli1, Nitish Badhwar2 and Randall J Lee*2 1 St Mary’s Hospital, San Francisco, CA, USA 2 Department of Medicine and Cardiovascular Research Center, University of California, San Francisco, Box 1354, San Francisco, CA 94143, USA *Author for correspondence: Tel.: +1 415 476 5706 Fax: +1 415 476 6260 [email protected]

The most severe consequence of atrial fibrillation (AF) is a cardioembolic stroke. The incidence of cardioembolic stroke increases significantly in patients with AF. Although warfarin has been the mainstay of the prevention of cardioembolic stroke, there are several limitations to the use of warfarin that hinder its effectiveness. This article provides the historical development of devices that exclude the left atrial appendage, their effectiveness and potential patient selection, as an alternative to warfarin and the novel oral anticoagulation therapy for the prevention of cardioembolic stroke in patients with AF. KEYWORDS: atrial fibrillation . cardioembolic stroke . LARIAT . left atrial appendage . occlusion devices

Atrial fibrillation (AF) is the most common arrhythmia worldwide and accounts for 15–20% of all strokes in the US [1,2]. It is estimated that 2.3 million US adults have AF and is projected to increase to 5.6 million by 2050 [1]. The most feared complication of AF is thromboembolic stroke arising from the left atrial appendage (LAA) [3]. Thromboembolic stroke is associated with substantial morbidity and a twofold increase in all-cause mortality, highlighting its significance [1,4]. Oral anticoagulation (OAC) treatment provides the most effective strategy to prevent stroke and thromboembolism in high-risk AF patients. Randomized clinical trials have demonstrated that OAC substantially reduces, but does not eliminate, the risk of cerebral complications in AF patients [5]. However, OAC therapy with warfarin is associated with both major and minor hemorrhagic complications [6]. Poor compliance, maintaining a therapeutic window, and bleeding complications have severely limited its use [7]. Novel oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, apixaban and edoxaban have been US FDA approved for stroke prevention in patients with non-valvular AF but have also been associated with a substantial bleeding risk and a discontinuation due to side effects [8–12].


For these reasons, mechanical approaches using surgical or percutaneous methods have been developed as an alternative to patients intolerant to OAC for stroke prevention. Rationale

It is widely accepted that thrombus formation in the LAA is the result of stagnant blood flow. Autopsy, transesophageal echocardiography and direct inspection of the LAA demonstrates that approximately 90% of atrial thrombi formation were located in the atrial appendage in patients with non-valvular AF [13]. Attempts to surgically amputate the LAA during intracardiac surgery have resulted in incomplete closure, leading a potential nidus for thrombus formation and the risk for a thromboembolic event [14]. The limitations of surgery and intolerance to OAC have prompted the need for other approaches. Evolution of percutaneous techniques in LAA exclusion

LAA exclusion associated with mitral valve surgery has been performed since the late 1940s [15,16] and is recommended in the American College of Cardiology/American Heart Association guidelines for mitral valve surgery to reduce the stroke risk [17,18]. LAA exclusion

 2015 Informa UK Ltd

ISSN 1477-9072


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Le, Morelli, Badhwar & Lee

is also an integral component of the Cox-Maze procedure for the prevention of stroke and treatment of AF [19]. The LAA is felt to be “our most lethal human attachment” and its removal is advocated during any open-heart procedure [20]. The PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) device was conceived in 1998 and developed based on the principle that if the LAA could be excluded by a simple, minimally invasive technique, it would provide an alternative strategy to surgery for preventing stroke in patients with nonrheumatic AF [21]. Preclinical trials demonstrated the safety to deliver and occlude the LAA with the PLAATO device (Appriva Medical, Palo Alto, CA/EV3 Inc., Plymouth, Minnesota) with resultant complete endothelialization of the atrial surface of the implant [21]. This led to the first human implantation of the prototypical LAA occlusion device in 2001 with initial promising results of successful PLAATO implantation into the LAA [22]. The initial multi-center observational study in 111 patients with contraindication to OAC therapy reported a successful implantation rate of 97% (110 of 111 patients) [23]. There were four severe adverse events requiring surgery, two stroke and three transient ischemic attacks, with a stroke rate of 2.2%, but a total embolic event rate of 5.5%. The promise of the PLAATO device for occluding the LAA has led to a plethora of both endocardial and epicardial devices targeted for excluding the LAA to prevent stroke. Endocardial devices are considered easier to deploy, while epicardial approaches do not leave any foreign body in the LAA. Ultimately, use of any device will be dependent on safety, efficacy of LAA closure and effect on stroke, systemic embolism and death. Watchman clinical history

The Watchman device (Boston Scientific Corp., Maple Grove, Minnesota) is the only LAA occlusion device with randomized, multi-center studies investigating safety, stroke, systemic embolism and death. The initial PROTECT AF trial was a 700 patient prospective, randomized safety and efficacy trial that was a non-inferiority trial comparing the Watchman device to warfarin in patients with nonvalvular AF and at least one risk factor for stroke [24]. The PROTECT AF study demonstrated non-inferiority to warfarin in all cause of stroke, with the main benefit being a decrease in hemorrhagic stroke. Although short-term efficacy of the Watchman device was shown to be non-inferior to warfarin, there were concerns from the initial US FDA meeting on 23 April 2009 that resulted in a “not approval” letter [25]. FDA concerns included: number of acute safety events, need for longer-term follow-up, the selection of low stroke risk patients (CHADS 1 score) and many patients were treated with chronic clopidogrel and/or remained on warfarin longer than 45 days after device implantation [26]. At the request of the FDA, the sponsor developed the Prevail study to address the limitations of PROTECT AF study. The PREVAIL study was a Bayesian trial design taking into consideration data from PROTECT AF with the focus on safety and efficacy of LAA occlusion for stroke prevention in patients with doi: 10.1586/14779072.2015.1057123

non-valvular AF compared to long-term warfarin therapy [27]. The Prevail study primary endpoints included: Primary efficacy composite of stroke, systemic embolism and cardiovascular/ unexplained death; Early safety composite of all-cause death, ischemic stroke, serious adverse event or device/procedure related events requiring open cardiovascular surgery or major endovascular intervention and Late ischemic efficacy composite of ischemic stroke or systemic embolism, excluding the first 7 days post randomization [27]. Concurrently, the FDA allowed sites that participated in the PROTECT AF study to continue to collect long-term follow-up on safety and efficacy from the Protect AF study and treat additional patients under a registry, the Continuous Access Registry (CAP) [28]. The PREVAIL study failed to meet the pre-specified noninferiority criteria for its primary efficacy due to the duration of the trial and the low event rate in the control group [27]. The PREVAIL study did achieve its safety endpoint and its secondary primary endpoint was met for rate difference, but not for risk ratio [26]. During the second FDA panel meeting, results of the PROTECT AF study, CAP registry, PREVAIL study and PROTECT AF long-term follow-up were presented. The panel weighed the combined data of the WATCHMAN studies that included the non-inferiority of the WATCHMAN device (PROTECT-AF), improved safety results [28], improved success and procedural safety confirmed with new and experienced operators (PREVAIL study) and WATCHMAN superiority to warfarin for primary efficacy, CV death and all-cause mortality at 4 years [29]. The FDA panel voted 13-1 for device approval regarding safety and efficacy and that the benefits of the WATCHMAN device outweigh the risks in patients who meet the study criteria. Additionally, a cost-utility analysis demonstrated that the Watchman device is more cost–effective than warfarin for the prevention of cardioembolic stroke associated with nonvalvular AF [30]. The cost–effectiveness analysis combined with the long-term mortality benefit seen with the Watchman device provided enthusiasm for the Watchman device as an alternative to warfarin for the prevention of cardioembolic stroke in patients with nonvalvular AF. However, during the PMA review, additional long-term PREVIAL data were presented to the FDA by the sponsor. Additional ischemic strokes occurred after 1 year in the post-WATCHMAN group. The PREVAIL trial no longer met the non-inferiority to warfarin specifications, indicating that the WATCHMAN device was inferior to warfarin in preventing ischemic stroke in patients with nonvavular AF. The FDA required a third panel review. In the October 2014 panel review, the sponsor presented not only the updated negative findings of the PREVIAL study, but also the totality of the data of all the WATCHMAN studies. The panel was asked to consider the positive non-inferiority and improved mortality data of the PROTECT AF study and safety data from the CAP registry and PREVAIL trial. The panel voted 12 in favor to 0 against that the WATCHMAN LAA closure device is safe; 6 in favor to 7 against that it is not effective and 6 in favor to 5 against, with 1 abstention, that its benefits outweigh its risks [25]. On 13 March 2015, the WATCHMAN Expert Rev. Cardiovasc. Ther.

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LAA occlusion for stroke prevention in patients with AF

device received PMA approval. This WATCHMAN device is indicated to reduce the risk of thromboembolism from the LAA in patients with non-valvular AF who: Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy, Are deemed by their physicians to be suitable for warfarin, Have an appropriate rationale to seek a nonpharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin. The WATCHMAN device is contraindicated in patients unable to take warfarin, aspirin or clopidogrel. AMPLATZER Cardiac Plug

The AMPLATZER Cardiac Plug (ACP) (St. Jude Medical, Minneapolis, Minnesota) is a self-expanding device made from nitinol mesh and polyester patch with two disk connected by a waist adapted from the septal occluder used for atrial septal defects and patent foramen ovale closure to occlude the LAA in a “pacifier principle” [31]. The initial European experience studied 143 patients who underwent ACP device implantation [32]. In 137 of 143 patients, LAA occlusion was attempted and 132 (96%) were successful. Serious complications include 10 (7%) patients (ischemic stroke, device embolization, significant pericardial effusions) [32]. Minor complications included insignificant pericardial effusions, transient myocardial ischemia and loss of the implant in the venous system [32]. In the largest multicenter trial non-randomized retrospective observational study, Tzikas et al. evaluated 1047 high-risk AF patients (CHA2DS2-VASc score 4.5 ± 1.6, HAS-BLED score 3.1 ± 1.2) from 22 European centers [32]. Procedural success was achieved in 97.3% with follow-up completed in 98.2% (1001/ 1019) of successful implanted patients (average 13 months, total 1349 patient-years) [33]. There were 52 (4.97%) periprocedural major adverse events including procedure-related deaths (0.76%), strokes (0.86%) and cardiac tamponade 31/1349 patient-years) and a 61% risk reduction in annual rate of major bleeding (2.1%, 28/1349 patient-years) [33]. All-cause mortality at 1 year was 4.2% and no deaths were present at follow-up as device related [33]. On follow-up, aspirin monotherapy increased from 31 to 64%, warfarin monotherapy decreased from 16 to 1.6% and the average duration of dual antiplatelet therapy was 3.8 months [33]. Although bleeding events were greater in patients who underwent combined LAA occlusion and in those who were on more aggressive antithrombotic therapy, stroke risk reduction was higher in patients with greater than 1-year followup [33]. The study concluded that LAA occlusion with the ACP device showed favorable outcome from AF-related thromboembolism; however, the benefits, long-term outcomes and duration of OAC post-implantation still remain unclear. The Amplatzer plug does not currently have FDA approval. However, it and other LAA occlusion devices with CE mark in Europe as the Wave Crest (Coherix), LAMBRE (Lifetech), Occlutech (Occlutech) will potentially be evaluated in a device to WATCHMAN non-inferiority study for FDA approval in the future.


Patient selection: who is a good candidate for LAA exclusion?

In the US, the FDA labeling seems to be a very broad indication for the Watchman device as an alternative to warfarin. These patients are a minority among patients receiving LAA occlusion in the countries where such devices are approved without restrictions. Medical reasoning would suggest that patients who are not amenable to OAC therapy would be the candidates that should be offered the device as recommended in the European guidelines for LAA exclusion [34]. LAA occlusion devices should not be universally thought as a substitute for OAC therapy. The WATCHMAN studies were compared to warfarin. However, the development of the newer anticoagulants (NOAC) have shown either equivalence or superiority in preventing cardioembolic events compared to warfarin with less bleeding risks, especially intracerebral hemorrhagic strokes [8–11]. A meta-analysis of the NOACs from the RE-LY, ROCKET AF, ARISTOTLE and ENGAGE AF–TIMI 48 trials demonstrated a significant reduction in the composite of stroke or systemic embolic events by 19% compared with warfarin and a 14% non-significant reduction in major bleeding, a reflection of decreased intracranial hemorrhage [35]. Therefore, the benefits seen with the WATCHMAN as compared to warfarin might not be present if compared to NOACs. Patients with contraindications to OAC therapy have little to no options for the prevention of cardioembolic stroke. The contraindications to OAC population of patients have been excluded from the WATCHMAN studies and NOAC trials. In the AVERROES trial that compared apixiban to aspirin in warfarin-intolerant AF patients at risk for cardioembolic stroke, apixiban was superior to aspirin in preventing cardioembolic stroke with a significantly lower incidence of bleeding [36]. However, the AVERROES trial also excluded patients with serious bleeding events in the previous 6 months, high risk of bleeding and documented intracranial hemorrhagic tendencies. Epicardial LAA exclusion devices have been advocated for patients with contraindication to OAC therapy due to the lack of needing transition warfarin therapy recommended with the WATCHMAN device. Minimal surgical approaches using the Atriclip (AtriCure, Cincinnati, OH) or Tiger Paw (LAAx, Indianapolis, IN) devices and the LARIAT (SentreHEART, Redwood City, CA) suture delivery device are currently available in the US. LAA ligation with the LARIAT device

The LARIAT device obtained FDA 510K approval in 2006 for delivery of a suture or knot to approximate and/or ligate soft tissue structures with updates in 2009 and 2014 [37–39]. The FDA approval was a general tool kit use approval that did not indicate a specific tissue type. The LARIAT procedure used the LARIAT device to develop an adaptation of the open-heart procedure for ligating the LAA via a percutaneous approach [40–42]. The LARIAT device for exclusion of the LAA consists of three components: a 15 mm compliant occlusion balloon catheter (EndoCATH), 0.025¢¢ and 0.035¢¢ magnet-tipped guide wires doi: 10.1586/14779072.2015.1057123

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Le, Morelli, Badhwar & Lee

(FindrWRZ) and a 12F suture delivery device (LARIAT) [43]. The procedure involves four basic steps: pericardial and transseptal access, placement of the endocardial magnet-tipped guidewire in the apex of the LAA with balloon identification of the LAA os connection of the epicardial and endocardial magnet-tipped guidewires for stabilization of the LAA and snare capture of the LAA with closure confirmation and release of the pre-tied suture for LAA ligation [43]. The initial observational study assessing safety and closure demonstrated greater than 96% complete LAA closure with acceptable low access complications and periprocedural adverse events [43]. Subsequent small single-center studies have corroborated the initial findings [44,45], but others have noted higher leak rates and adverse event rates [46,47]. In a recent study characterizing and comparing leaks between the LARIAT device and Watchman device, there was 13% leaks with the LARIAT device and 25% leaks with the Watchman device. The Watchman leak is an eccentric leak while the LARIAT leak is a concentric leak that is amenable to closure with closure devices [48]. Leaks were not associated with embolic events which corroborate data from the Protect AF study [49]. The differences in the early experiences with the LARIAT device highlight the need for proper training. The use of micropuncture needle for pericardial access and post-LAA ligation with cholchicine should help with pericardial access-related and inflammatory-related adverse events [50]. Prospective randomized trials with the LARIAT device and ultimately a registry to follow patients after their procedure are needed to confirm efficacy and safety. The LARIAT procedure is a more complex procedure compared to LAA device implants due to the need for both a “dry” pericardial access and transseptal catherization. Proper patient selection and specific training should mitigate procedural adverse events [50]. The advantage of not leaving a foreign material within the left atrium needs to be balanced with the sequelae of the inflammatory response associated with a necrotizing LAA in the pericardium [43,51]. In our experience at UCSF, prior to the use of post-LAA ligation colchicine, 3 of the initial 12 patients undergoing LAA ligation developed either a serosanguinous pericardial effusion (n = 1) or left-sided serous pleural effusion (n = 2), highlighting the potential dramatic consequences of the inflammatory response to LAA ligation. Since the implementation of cholchicine, we have not experienced further episodes of pleural effusions or pericardial effusions (n = 66). The use of cholchicine decreases the inflammation related effects of cholchicine, but does not eliminate these events [50]. The LARIAT procedure has been considered for patients only with contraindication to OAC therapy and not as an OAC alternative [50]. A recent multi-center observational study in patients with AF at risk for cardioembolic strokes that had contraindications to OAC therapy underwent LAA ligation with the LARIAT device and did not receive any OAC therapy after LAA ligation [SIEVERT H, RASEKH A, BARTUS K,










doi: 10.1586/14779072.2015.1057123

The study objectives

focused on safety and long-term outcomes of stroke and death. The study consisted of 139 patients with a mean CHAD score of 2.4 ± 1.2 who were followed for an average of 2.9 ± 1.1 years (400 patient-years of follow-up). Stroke and systemic embolism were noted in four patients for an event rate of 1% (an 80% reduction in stroke with a CHADs 2.4 score). There were seven deaths (event rate of 2.8%), but only one patient who had a post-procedure pulmonary embolism was attributed to the procedure. These event rates are similar to those seen in both the Aristotle and AVVEROES trials with apixiban [10,35,36]. Additionally, the results are comparable to event rates noted with LAA implants that did not receive OAC therapy after LAA occlusion [33,52]. While the results with the LARIAT device in patients with AF who have a contraindication to warfarin with risk of cardioembolic events are encouraging, a prospective stroke study is needed and is currently being developed for an FDA-approved trial. Similar trials or registry data are needed with the WATCHMAN and Amplatzer plug LAA occlusion devices that have been shown in observational studies to potentially have a benefit in preventing stroke and embolic events [33,52]. With the development of new LAA occlusion devices and increased use of NOACs, stroke prevention in patients with nonvavular AF is in evolution. Although the initial data on LAA exclusion devices are promising, long-term follow-up is required to assess the potential of late thrombus formation, migration and erosion. As the devices become more available, additional evaluation of safety and outcomes are needed in the general clinical practice. Comparative advantages and disadvantages of currently available endocardial and epicardial LAA closure devices are presented in TABLE 1. Potential consequences of LAA exclusion

Exclusion of the LAA is an attractive alternative to OAC therapy, especially in patients with intolerances or contraindication to OAC therapy. However, the LAA has important roles as a reservoir in maintaining cardiac output and an endocrine organ in the release of atrial natriuretic peptide and possibly brain natriuretic peptide [53]. Atrial natriuretic peptide and brain natriuretic peptide are peptide hormones that have natriuretic, diuretic and vasodilatory properties [54,55]. LAA exclusion may alter the normal physiological functions of the LAA by disrupting mechanical function and the release of natriuretic peptides in response to volume expansion that may promote heart failure and electrolyte abnormalities [56–58]. Additionally, LAA necrosis and fibrosis associated with LAA ligation may lead to degranulation and release of natriuretic peptides resulting in hyponatremia and hypotension [59]. These potential consequences of LAA exclusion warrant post-procedural management of fluid volume and electrolyte imbalances. Other potential challenges and problems for LAA closure include thrombus formation, leaks and late embolic events. LAA implant devices are associated with 4–4.5% thrombus formation [24,33,52] while the LARIAT is associated with a 1–2% thrombus formation [43], [SIEVERT H, RASEKH A, BARTUS K, ET AL. LAA LIGATION IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS AT HIGH RISK FOR EMBOLIC EVENTS WITH

Expert Rev. Cardiovasc. Ther.

LAA occlusion for stroke prevention in patients with AF


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Table 1. Comparative advantages and disadvantages of currently available endocardial and epicardial LAA closure devices. LAA Implants


Deployment of device





Transseptal and pericardial access

Foreign body


No †

Patient Contraindications

Patients need to take transition OAC therapy

Cardiac surgery Pectus excavatum

LAA Anatomical Contraindications

Shallow landing zone LAA os 33 mm‡ LAA os 34 mm§

Tip of LAA behind the pulmonary artery Maximum width of LAA body >45 mm

Potential late complications

Thrombus formation Migration Erosion

Thrombus formation Inflammatory responses resulting in prolonged pericarditis, pericardial effusion or pleural effusion

Potential Antiarrhythmic Effect

May prohibit pulmonary vein isolation if device encroaches lateral ridge (Coumadin ridge)

Leads to electrical isolation

Applies only to the Watchman device in the USA. ACP plug. Watchman. LAA: Left atrial appendage. ‡ §



Further studies are needed to determine the most effective post-LAA occlusion regiment for anti-thrombotic and/or OAC therapy. All devices are associated with leaks. Although it has been suggested that leaks

Left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation.

The most severe consequence of atrial fibrillation (AF) is a cardioembolic stroke. The incidence of cardioembolic stroke increases significantly in pa...
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