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Left Atrial Appendage Isolation Using Percutaneous (Endocardial/Epicardial) Devices: Pre-clinical and Clinical Experience Jorge Romero M.D, Andrea Natale M.D, FACC, FHRS, FESCM.D, FACC, FHRS, FESC, Krysthel Engstrom M.D, Luigi Di Biase M.DPh.D., FACC, FHRS www.elsevier.com/locate/tcm

PII: DOI: Reference:

S1050-1738(15)00154-1 http://dx.doi.org/10.1016/j.tcm.2015.05.009 TCM6180

To appear in: trends in cardiovascular medicine

Cite this article as: Jorge Romero M.D, Andrea Natale M.D, FACC, FHRS, FESCM.D, FACC, FHRS, FESC, Krysthel Engstrom M.D, Luigi Di Biase M.DPh.D., FACC, FHRS, Left Atrial Appendage Isolation Using Percutaneous (Endocardial/Epicardial) Devices: Pre-clinical and Clinical Experience, trends in cardiovascular medicine, http://dx.doi.org/10.1016/j.tcm.2015.05.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Left Atrial Appendage Isolation Using Percutaneous (Endocardial/Epicardial) Devices: Pre-clinical and Clinical Experience Jorge Romero, M.D1,2, Andrea Natale3,4,6,7,8,9, M.D, FACC, FHRS, FESC, Krysthel Engstrom, M.D2, and Luigi Di Biase1,3,4,5, M.D-PhD, FACC, FHRS 1

Montefiore Medical Center, Albert Einstein College of Medicine. Bronx, NY, USA Ronald Reagan UCLA Medical Center, David Geffen School of Medicine at UCLA. Los Angeles, CA, USA 3 Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, Texas, USA. 4 Department of Biomedical Engineering, University of Texas, Austin, Texas, USA. 5 Department of Cardiology, University of Foggia, Foggia, Italy. 6 Division of Cardiology, Stanford University, Palo Alto, California, USA. 7 Case Western Reserve University, Cleveland, Ohio, USA 8 Scripps Clinic, San Diego, California, USA 9 Dell Medical School, Austin, Texas, USA 2

Address for correspondence Luigi Di Biase, MD, PhD, FACC, FHRS Section Head Electrophysiology Director of Arrhythmia Services Associate Professor of Medicine, Department of Medicine (Cardiology) Montefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, 111 East 210th Street Bronx, NY 10467 Email: [email protected]

Disclosures: Dr. Di Biase is a consultant for Biosense Webster, Boston Scientific, St Jude Medical and Stereotaxis. Dr Di Biase received speaker honoraria/travel from Medtronic, Atricure, 1

EPiEP and Biotronik. Dr. Natale received speaker honorariums from Boston Scientific, Biosense Webster, St. Jude Medical, Biotronik and Medtronic, Dr Natale is a consultant for Biosense Webster St Jude Medical and Janssen. Dr Romero has no disclosures.

Abstract Atrial fibrillation (AF) is the most common arrhythmia in the elderly population and it is associated with a 4- to 5-fold increased risk of thromboembolic events. It was not until the mid 1950s that the left atrial appendage (LAA) was identified as the main location of thrombus formation particularly in patients with non-valvular AF. In this review, we explain at some extent its embryology, anatomy and physiology as well as the clinical and pre-clinical trials published to date testing the safety and efficacy of most LAA closure devices. Among those devices, the most studied include the PLAATO system (ev3 Endovascular, Plymouth, MN), the Amplatzer cardiac plug (St Jude, Golden Valley, MN) (St. Jude Medical, Minneapolis, MN), the WATCHMAN device (Boston Scientific, Plymouth, MN) (Atritech Inc., Plymouth, MN), and the LARIAT device (SentreHEART, Palo Alto, CA). Similarly, newer LAA closure devices currently under investigation such The Transcatheter Patch (Custom Medical Devices, Athens, Greece), AEGIS and the Coherex WaveCrest (Salt Lake City, UT) will also be discussed. Future perspectives and the need for well-designed prospective studies between devices and new oral anticoagulant drugs are also proposed.

Keywords: atrial fibrillation, percutaneous LAA Closure Devices, stroke prevention,left atrial appendage; stroke; anticoagulation

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In the aging population, atrial fibrillation (AF) is considered the most common rhythm disturbance. The prevalence of AF in the United States ranged from 2.7 to 6.1 million in 2010, and the trend suggests this will likely rise between 5.6 and 12 million by 2050 (1,2). AF is associated with a 4 to 5-fold increased risk of thromboembolic events, and according to the Framingham study, the percentage of strokes due to AF increases noticeably from 1.5% at the age of 50 to 23.5% at the age of 80 (3). Furthermore, the adjusted stroke rates based on CHADS2 score ranges from 1.9% to 18.2% per year (4). Previously deemed an insignificant and non-functional anatomical structure, the left atrial appendage (LAA) was identified as the site of thrombus formation in the mid-1950s (5). Understanding the anatomy and physiology of the LAA became the interest of many investigators, as well as testing different imaging modalities and techniques to assess its dimensions, blood flow patterns, and presence of thrombus. More importantly, different devices have been designed with the intention of permanently occluding this structure as it is estimated that approximately 47% of thrombi in valvular AF and 91% in nonvalvular AF are formed in the appendage (6). In this review, we briefly outlined prior AF treatments used to prevent cardioembolic strokes and discussed in detail the results of preclinical and clinical trials of the main LAA closure devices (Table 1).

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LAA Anatomy and Physiology The LAA originates in the primordial embryonic left atrium (LA), where it acquires the trabecular appearance (i.e., pectinate muscles), and ultimately, the smooth left atrium (LA) progresses from an outgrowth of the pulmonary veins (Figure 1). The LAA is a highly mobile and dynamic structure. Distinct patterns of contraction and relaxation either in sinus rhythm or in AF have been described (7). Analysis by transesophageal echocardiogram (TEE), cardiac computed tomography (CCT) and cardiac magnetic resonance imaging (CMRI) images illustrate that it is a long-angled structure and varies widely in shape and dimension (including orifice size) (8,9). In approximately 50% of the population, the LAA is composed of two lobes, and in one third of the population is composed of three (10). The four most common clinically used terms to describe the different LAA morphologies are chicken wing (48%), cactus (30%), windsock (19%) and cauliflower (3%) (Figure 2). It has been demonstrated that LAA morphology correlates with the risk of stroke in patients with AF, chicken wing morphology being the one that is less associated with cerebrovascular accidents (CVA) (i.e., 4% vs. 10-18%) (11). Diverse studies have revealed that atrial and brain natriuretic peptides are produced and secreted in the LAA, hence its role in volume homeostasis. This may have clinical implications immediately after LAA closure devices are implanted, particularly in subjects with dilated cardiomyopathy who might develop acute heart failure exacerbation given the significant decline of these peptides in blood stream (12-14).

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Oral Anticoagulation (AC) Despite being underutilized due to risk of bleeding, falls, difficulty with INR monitoring, non-compliance, drug and dietary interaction, renal impairment and advanced age, the number of warfarin sodium (Coumadin®) prescriptions for AF have considerably increased over time (15). However, it is estimated that up to 30% of patients who would benefit from this therapy based on CHADS2 score are not on AC (16). Average annual frequencies of fatal, major, and minor chronic AC-related bleeding are approximately 0.6%, 3.0%, and 9.6%, respectively. These are five-fold greater compared to those not on warfarin therapy (17). Although we currently have access to new selective oral anticoagulants such as direct thrombin inhibitors (i.e., dabigatran) and direct factor Xa inhibitors (e.g., rivaroxaban, apixaban and edoxaban), most of the aforementioned contraindications for chronic AC still remain.

Surgical Therapy In select patients, surgical LAA occlusion is an alternative treatment option to prevent embolic strokes. In 1949, Madden achieved the first LAA excision in two patients with AF and rheumatic mitral disease. Thereafter, a randomized trial, the LAA occlusion study (LAAOS), was conducted in 77 patients to evaluate the safety and efficacy of occlusion at the time of elective coronary bypass graft surgery using sutures and staples. Occlusion was achieved in only 66% of the patients and the use of staples had the highest efficacy assessed. Staples had 72% efficacy and sutures only 45% (18). A meta-analysis of clinical trials demonstrated that most studies reported merely 55-66% successful occlusion rate using a variety of methods including stapling, ligation and amputation, 5

hence revealing a significant limitation of the surgical approach. A proposed reason for this might be inability to achieve acceptable rates of complete occlusion on TEE during the procedure (19). A prospective study in 2008 evaluated the success of several surgical LAA closure techniques by TEE. In general, there was a high rate of failure (60%), with LAA excision being the most effective technique with a 73% successful rate out of the successful LLA closures Success rate for suture and stapler exclusion was 23% and 0%, respectively (20). In 2010, the Food and Drug Administration (FDA) approved the AtriClip for stroke prevention in patients with AF undergoing open-heart surgery. Yet, data on this device are scarce. Percutaneous LAA Closure Devices The first promising study in humans took place approximately a decade ago when closure devices were implanted percutaneously with a loop snare via thoracoscopy (21). Subsequently, several devices were proposed and tested for efficacy and safety. Among those devices, the most studied include the PLAATO system (ev3 Endovascular, Plymouth, MN), the Amplatzer cardiac plug (St Jude, Golden Valley, MN) (St. Jude Medical, Minneapolis, MN), the WATCHMAN device (Boston Scientific, Plymouth, MN) (Atritech Inc., Plymouth, MN), and the LARIAT device (SentreHEART, Palo Alto, CA). Numerous small-scale observational studies and a few randomized controlled trials have demonstrated feasibility of this approach, and will be discussed in detail in this review.

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PLAATO System In 2002, the Percutaneous Left Atrial Appendage Occlusion (PLAATO) endovascular device (ev3 endovascular, Plymouth, MN) was created (22). This device consists of a self-expanding nitinol cage covered with polyteranofluoroethylene (ePTFE) and three rows of anchors that secures itself within the LAA ostium. The PLAATO device diameters range from 15 to 32 mm and it is selected approximately 20-40% larger than the LAA ostium diameter (Figure 3). The ePTFE membrane is echo-reflective due to microscopically trapped air in its structure allowing device visualization with TEE or intracardiac echocardiogram (ICE) during deployment. Once the device expands into the LAA, contrast is injected both distally and proximally to assess position and presence of leakage. If sealing is not adequate, the device is collapsed, repositioned, and re-expanded, or completely retrieved if rendered undersized. The first experience with PLAATO was in a canine model. The device was implanted in 25 dogs that were eventually euthanized in order to grossly and histologically examine their LAA. The LAA resulted occluded in all cases with neither thrombi associated with the implantation or embolic infarcts in brain or kidney (23). These preliminary results stimulated other investigators to test this device on humans and also to develop other similar models. The same year the system was created, the feasibility and safety of the PLAATO system was evaluated in 15 patients with chronic AF at high risk for stroke who were poor candidates for long-term AC. The LAA was successfully occluded in all of the patients. In four patients, however, the implant had to be removed and exchanged for a greater size. There were no reports of strokes, device embolization or LAA perforation. In one of these subjects, the first procedure was complicated by 7

hemopericardium. At 1-month follow-up, fluoroscopy and TEE revealed continued stable implant position with smooth atrial facing surface and no evidence of thrombus (22). A following study involving the same patients demonstrated that the PLAATO devices remained stable with minimal residual flow and had no effect on the anatomic and hemodynamic properties of the mitral valve and left upper pulmonary vein (24).

The Feasibility Trials were two prospective studies, which evaluated the efficacy of PLAATO system in a much larger sample of patients (n = 111) with a mean age of 71, chronic non-valvular AF, at least one risk factor for stroke and contraindication for AC. Almost all (97%) patients had complete LAA occlusion after device deployment. The complications were the following: two patients experienced stroke, one patient required cardiovascular surgery and consequently suffered in-hospital neurological death in the first 30 days, and three patients required pericardiocentesis due to hemopericardium. At a mean follow up of 9.8 months, two patients (1.8%) experienced ischemic stroke. TEE at one and six-months follow-up demonstrated that the device was in stable position with no thrombus on their surfaces in these two cases. This trial showed a relative risk reduction of stroke rate of 65% on the basis of the CHADS2 score (2.5) of the studied population (2.2% with PLAATO vs. 6.3% expected by CHADS). These results suggested that occlusion devices could be an alternative therapy for patients with AF with contraindication for long-term AC (25). Follow-up 5 years after the last patient was enrolled revealed a total of 7 deaths, 5 major strokes and 3 minor strokes. The annual stroke/transient ischemic attack (TIA) rate was 3.8% with the device, and it is important to note that based on the CHADS score of this study population, the expected rate was

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6.6% (42% reduction with PLAATO) (26). Lastly, results from the European PLAATO trial, which enrolled an even larger sample of patients (n=180) with persistent AF and AC contraindication revealed successful LAA occlusion in 90% of the patients. Two died within 24 hours of the procedure and six cardiac tamponades occurred (3.3%), with two cases requiring pericardiocentesis. In one patient (0.6%), the chosen device was small and embolized into the aorta after its release; nonetheless, it was snared and replaced without further complications. In a follow-up of 129 documented patient-years, the stroke rate was 2.3% per year vs. the expected 6.6% incidence per year of stroke according to CHADS2. Unfortunately, the trial was stopped prematurely due to financial glitches (27).

Amplatzer Cardiac Plug Device The Amplatzer Septal Occluder originally used for patent foramen ovale or atrial septal defect closure was redesigned into The Amplatzer Cardiac Plug (ACP) (St Jude, Golden Valley, MN), with the purpose to occlude the LAA only a year after the PLAATO system was introduced into clinical practice. Investigators stated that this device would not require general anesthesia or echocardiography guidance, and it could be readily deployed. The first generation ACP is a nitinol wire mesh and polyester patch selfexpanding device consisting of a lobe and a disk connected by a central waist. The lobe has diameters ranging from 16 to 30 mm (Figure 4). The device is selected typically 1020% larger than the narrowest diameter of the LAA body and is delivered under fluoroscopic guidance over a 10-F or 13-F sheath via transseptal puncture. It is anchored in the LAA approximately 1 cm behind its ostium, and the disk unfolds to cover the 9

entrance of the appendage (Figure 4). This first clinical study involving ACP enrolled 16 patients with paroxysmal and persistent AF. 85% of the procedures were performed with local anesthesia. Complete LAA occlusion was achieved in all cases, yet one device embolized requiring cardiac surgery (28). There were no strokes or other complications at 4-month follow-up. In 2011, results from the initial European experience, which included 136 patients with paroxysmal/permanent AF unable to take AC, were retrospectively analyzed to assess the efficacy and safety of the device within the first 24 hours. A total of 10 (7%) major complications were reported, including 3 (2.2%) acute ischemic strokes and two device embolizations, both of which were recaptured successfully. Five patients developed hemopericardium. Clinically significant pericardial effusion requiring pericardiocentesis occurred in five patients, one of those was caused by pulmonary artery puncture with the trans-septal needle. The first prospective study using ACP was performed in Switzerland in 2012. Eighty-six patients with AF and contraindication to AC were included. All the implants were fluoroscopically guided and the LAA was completely occluded in 97% of the cases. There

were

four

major

complications:

one

cardiac

tamponade

requiring

pericardiocentesis, two transient ischemic attacks, and one device embolization, which required percutaneous retrieval. One in-hospital death unrelated to the procedure occurred after six days. After 25.9 patient-years follow-up there were neither strokes nor late device embolizations. Six patients exhibited thrombus formation on the device, which resolved after three months of AC (29).

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The initial safety and feasibility Asia-Pacific experience rendered encouraging results for the ACP. Twenty patients were enrolled and followed up for one year. The LAA was successfully occluded in 95% of the cases. One procedure was abandoned because of catheter-related thrombus formation. Follow-up TEE demonstrated that all the LAA orifices were sealed without device-related thrombus. Neither stroke nor death occurred at a mean follow-up of 12.7 months (30). A year later, Lopez-Minguez published another study of 35 consecutive patients in whom the device was implanted under general anesthesia. After the first 5 patients, 3dimensional imaging was incorporated in the procedure in order to avoid device embolization seen in prior studies. There were no cardiac complications during the implantation or hospital stay, however, one vascular complication (arteriovenous fistula) occurred. TEE monitoring was performed at 24 hours, 1, 3, 6, and 12 months and 5 thrombi were found, which resolved with AC. After 21-month follow-up one patient suffered a TIA without neurological sequalae (31). Long-term results from prospective studies in Canada and Switzerland were recently published. The Canadian experience included 52 patients with non-valvular AF and contraindication for AC (CHADS2 score of 3). Most patients received short-term dualantiplatelet therapy after the procedure and single antiplatelet therapy subsequently. The procedure was successful in 98.1% of the cases and the main complications were device embolizations (1.9%) and pericardial effusions (1.9%), with no cases of periprocedural stroke. The stroke rate was 1.9% at a mean follow-up of 20 months. The presence of mild peri-device leak was observed in 16.2% of patients at 6-months by TEE (32). Similarly, 10-year experience in Switzerland (n = 152), in which all procedures were performed

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under local anesthesia without TEE guidance, revealed that procedural complications occurred in 9.8%, being neurologic events (n= 3) and device embolization (n= 7) the most common. Embolization occurred more frequently in the non-dedicated Amplatzer devices as compared to the ACP group (5 patients vs. 2 patients). Neurologic events occurred in two patients (1.3%), peripheral embolism in one patient, and major bleeding in four patients at an average of 32 months. Patients were discharged on acetylsalicylic acid and clopidogrel for several months (33).

Although post-procedural AC is not required for the ACP, there were cases of thrombus formation around the device in each study. Plich et al, performed serial TEEs before discharge and after 3, 6, and 12 months, and found an incidence of 17% of thrombus formation on the devices despite dual anti-platelet therapy. A CHADS2 score greater than 4.3, CHA2DS2-VASc score grater than 6.8, pre-interventional platelet count higher than 282.5 nL and ejection fraction less than 40% were all independent risk factors for thrombus formation. These results emphasized the need for close and serial TEE followup and the importance of post-procedural AC in patients at higher risk of thrombus formation (34). Recently, a second generation of the ACP was designed: the ACP 2 Amulet (St. Jude Medical, Saint Paul, MN, USA). This device allows closure of larger LAA as well as improves stability and decreases the risk of embolization. The Amulet is a self-expanding device that has a longer distal lobe and a larger diameter of the proximal disc and waist than the ACP 1. The device is implanted in a similar fashion than its predecessor and has the advantage of being repositionable. Compared to the ACP, the Amulet has more hooks

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(10 vs. 6 pairs) that are stiffer with diameters between 16 to 34 mm (35). (Figure 4). This device is not currently available in the United States.

WATCHMAN device The WATCHMAN device (Atritech, Inc., MA, Plymouth) is a self-expanding nitinol frame with fixation anchors and a permeable polyester cover, available in five sizes (21, 24, 27, 30 and 33 mm) (Figure 5). The device should be approximately 10-20% bigger than the LAA for appropriate fit. After trans-septal access is obtained, a pigtail catheter is advanced into the LAA under TEE and fluoroscopic guidance, and the sheath is then advanced over the pigtail into the LAA. The pigtail catheter’s purpose is to decrease the chance of LAA perforation. This device requires AC for at least 45 days postimplantation. The first global experience with the first generation WATCHMAN was a prospective study that included 66 patients with permanent or paroxysmal non-valvular AF who were eligible for warfarin therapy, with a mean follow-up of 740 days. At 45 days, 93% of the devices exhibited successful sealing of the LAA. Two patients experienced device embolization, both successfully retrieved percutaneously; two cardiac tamponades; two TIAs; one air embolism, and one delivery wire fracture occurred (first generation device), which required surgical intervention. Four patients developed a flat thrombus layer on the device at 6 months that resolved with additional AC. Strokes did not occur during followup despite >90% of patients having discontinued AC. Fixation barbs were modified with the second-generation device to prevent device embolization (36). The PROTECT AF (WATCHMAN® Left Atrial Appendage System for Embolic 13

PROTECTion in Patients with Atrial Fibrillation) study was the first multicenter randomized controlled trial comparing LAA closure device vs. Coumadin. It evaluated the efficacy and safety of this device in 707 patients with non-valvular AF eligible for AC. This study was designed in a non-inferiority manner. Patients were randomized in a 2:1 ratio to percutaneous closure of the LAA (n= 463) or to AC (n= 244) and followed up for 18 months. WATCHMAN was successfully deployed in 91% of patients. At the 45day mark follow-up, warfarin was discontinued in 86% of patients who received the device and 92% of patients by 6 months. At 45 days and 6 months follow-up in the device group, warfarin was discontinued in 86% and 92% of the patients respectively. The primary endpoint for efficacy was a composite of stroke, cardiovascular death, and systemic embolism, and the primary endpoint for safety included major bleeding, pericardial effusion, and device embolization. The primary efficacy event rate was 3.0 per 100 patient-years in the intervention group and 4.9 per 100 patient-years in the control group

(RR 0.62, 95% CI 0.35-1.25). At 1,065 patient-years follow-up the

probability of non-inferiority of the intervention was more than 99.9%. Primary safety events were statistically more frequent in the intervention group than in the control group (7.4 vs. 4.4 per 100 patient-years, RR 1.69, CI 1.01-3.19). There were 5 (1.1%) procedure-related ischemic strokes, 3 (0.6%) device embolizations and 22 (3.5%) pericardial effusions. Despite these results, the Food and Drug Administration (FDA) insisted on second randomized controlled trial due to high initial rate of early pericardial effusions and procedure-related strokes (37). The Continued Access Protocol (CAP) Registry was designed to allow continued access to the WATCHMAN device data from a subset of the PROTECT AF study and to gain

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further safety and efficacy data on the device from a non-randomized registry of patients undergoing WATCHMAN implantation. The safety end points included bleeding and procedure-related events (pericardial effusion, stroke and device embolization). There was a significant decrease in the rate of procedure or device-related safety events within 7 days of implantation in comparison to the initial PROTECT AF study (7.7% vs. 3.3%, P= 0.007). Similarly, the rate of complications was significantly lower between the first and second halves of PROTECT AF and even lower in the subjects included in CAP (10.0%, 5.5%, and 3.7%, respectively). Similarly, the rate of serious pericardial effusion within 7 days of implantation was lower in the CAP Registry vs. PROTECT AF (5.0% vs. 2.2%, P=0.019). There were no reports of procedure-related strokes. Consequently, it was assumed that as operator experience increased, so did safety, yet this hypothesis was not corroborated in the PREVAIL study, in which there were no differences between new and experienced operators (38). Results of the 2.3-year follow-up PROTECT AF trial revealed that after 1588 patientyears of follow-up (mean 2.3±1.1 years) the primary efficacy event rates were 3.0% in the WATCHMAN group and 4.3% in the warfarin group (percent per 100 patient-years) (RR, 0.71; 95% CI 0.44-1.30). This met the criteria for non-inferiority (probability of non-inferiority >0.999). Moreover, although not statistically significant, there were more primary safety events in the WATCHMAN group (5.5% per year) than in the control group (3.6% per year) (RR, 1.53; 95% CI, 0.95-2.70) (39). Newer data from the PROTECT AF trial at a mean follow up of 3.8 years was published in 2014. Non-inferiority was repeatedly demonstrated and for the first time, superiority for the primary efficacy endpoint (i.e., composite of stroke, cardiovascular death and 15

systemic embolism). Interestingly, for the first time the primary safety endpoint was similar to the warfarin group. As expected, the Watchman group revealed a significantly lower rate of hemorrhagic strokes. Furthermore, total mortality was also significantly lower in the device group with a 34% relative risk reduction (40). Shockingly, a PROTECT AF sub-study disclosed that 32% of the patients had at least some degree of peri-device leak at 12 months suggesting that residual peri-device flow into the LAA after closure with the Watchman was very common. However, even moderate (1-3mm) or severe (>3mm) leak was not associated with increased risk of thromboembolism. Given the low event rate in this sub-study these results must be interpreted with caution (41,42). The PREVAIL trial (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device in Patients with Atrial Fibrillation), one of the most anticipated trials on the safety of WATCHMAN device, was designed in order to validate the initial results of the PROTECT AF trial. A total of 407 patients with a mean CHADS2 score of 2.6 were randomized in a 2:1 fashion to device vs. warfarin. The first co-primary endpoint was 7day occurrence of death, ischemic stroke, systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention. The observed adverse event rate was 2.2% (6/269) resulting in an observed upper bound of 2.618%, which is less than the pre-specified criterion of 2.67% (95% CI). The second coprimary endpoint was a composite of stroke, systemic embolism, and cardiovascular or unexplained death at 18 months. Unfortunately, the trial did not meet this endpoint. The observed adverse event rate for both the WATCHMAN group and the warfarin group was 0.064, resulting in a RR of 1.07 with an observed upper bound of 1.88, slightly 16

greater than the pre-specified criterion of 1.75 (95% CI). This might partially be explained by the fact that the stroke rate in the PREVAIL control group was 0.7%, which is significantly lower than in any other published studies using AC (1.6-2.2%) (43-45). Moreover, only a small percentage of patients were actually followed up to 18 months in both study arms. A significant increase in implant success rate (95.1%) compared to PROTECT AF (90.9%) was noted, with no difference in success rate between new and experienced implanters (p= 0.282). The PREVAIL study has finally formally been published (46). The fact that the WATCHMAN device requires short to intermediate term AC is of paramount importance given the fact that the main indication for LAA closure devices is contraindication to chronic oral AC. This motivated the conduction of the ASAP study (the ASA Plavix Feasibility Study With WATCHMAN Left Atrial Appendage Closure Technology) for patients at high risk for stroke but with contraindications to AC. This multicenter, prospective, non-randomized study included 150 patients with non-valvular AF (mean CHADS2 score was 2.8 and CHA2DS2-VASc 4.4) who received dual antiplatelet therapy (i.e., continuous ASA and Plavix for 6 months) instead of oral AC for 45 days. The primary efficacy endpoint was a composite of ischemic stroke, hemorrhagic stroke, systemic embolism, and cardiovascular or unexplained death with a mean followup of 14 months. Serious procedure or device related safety events occurred in 13 out of 150 patients (8.7%), all-cause stroke or systemic embolism occurred in four (2.3% per year), ischemic stroke in three (1.7% per year) and hemorrhagic stroke in one (0.6% per year). This ischemic stroke rate in these patients was less than the expected based on the

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CHADS2 and CHA2DS2-VASc scores (7.3% per year) (47). These data support that the Watchman device can be safely performed without post-procedural AC. In March 2015, the FDA concluded that the benefits associated with Boston Scientific's WATCHMAN device outweighed its risks and has finally approved it as an option for high-risk patients (CHADS-VASc of 2 or higher) with non-valvular AF who are seeking an alternative to long-term AC therapy.

LARIAT system The LARIAT (SentreHEART, Palo Alto, CA) device consists of a balloon catheter (EndoCATH 15 mm), magnet tipped guidewires (FindrWIRZ 0.025-0.035 inch), and epicardially delivered 12-F suture device (LARIAT) (Figure 6). To isolate he LAA, this system requires both endocardial and epicardial approaches. Four steps are required; 1) pericardial and transseptal access, 2) placement of the endocardial magnet-tipped guidewire in the apex of the LAA with balloon identification of the LAA os, 3) connection of the epicardial and endocardial magnet-tipped guidewires for stabilization of the LAA, and 4) snare capture of the LAA with closure confirmation and release of the pre-tied suture for LAA ligation (Figure 7) (48). The endoluminal balloon inflated in the LAA when the suture is being delivered is thought to significantly decrease the possibility of an incomplete isolation. Since the LAA is closed from the outside with a single ligature, there is no permanent intracardiac foreign body and no risk of device embolization or infection. Contraindications to this approach include LAA width greater than 40 mm, a superiorly 18

oriented LAA behind the left pulmonary artery and a history of conditions that would result in pericardial adhesions (i.e., history of pericarditis, open-heart surgery, thoracic radiation, prior epicardial ablation, etc). Contrast- enhanced CT scan is routinely obtained in patients being considered for LARIAT to ensure that the size and orientation of the appendage is amenable for ligation. The first pre-clinical experience with this device was carried out in a canine model, in which the investigators evaluated the safety and effectiveness of the LARIAT device. All the LAA in 26 dogs included in this study were completely isolated and follow up echocardiography confirmed no flow between the LA and LAA (49). This demonstrated that LARIAT was safe and effective, without the previously complications of the other devices. Subsequently in Poland in 2013, Bartus published the first and largest clinical experience using the LARIAT. The study screened a total of 119 patients (CHADS2 1.9) and excluded 16 subjects (13.4%) based on LAA size > 40mm (n= 8) and a superiorposterior orientation of the LAA apex (n= 8). Three cases were cancelled due to pericardial adhesions, which precluded pericardial access. A total of 81 (95%) patients had complete closure after the suture was delivered. Three patients had a ≤ 2 mm residual LAA leak and one had a ≤ 3 mm jet by TEE color Doppler. There were no complications secondary to device deployment; however, there were 2 pericardial access-related and one transseptal puncture-related complication. One patient had a right ventricular (RV) puncture, which was dilated over the guidewire with hemopericardium requiring drainage. The second one was a laceration of a superficial epigastric vessel. A third complication occurred during the transseptal catheterization, resulting in perforation and hemopericardium. There were two unexplained sudden deaths and two late strokes 19

believed to be non-embolic. At one month all the patients who had complete occlusion immediately after procedure had no communication between LA and LAA. Sixty-five patients underwent TEE a year later with a 98% complete LAA closure. This prospective observational study demonstrated that this new approach is a feasible alternative to AC with excellent success rate and low risk of complications (50). A smaller US retrospective study was published thereafter. This included 21 patients with AF, CHADS2 score ≥2 and contraindications to AC. Patients who received the LARIAT device had a 95% successful rate for complete LAA exclusion that was preserved at 3 months. One-year follow-up revealed no evidence of stroke. Two patients developed hemopericardium due to RV perforation, one patient required open-heart surgery and the other required several pericardiocentesis. Three patients developed pericarditis less than one month after the procedure, one of which required drainage (51). In our experience, colchicine seems to be the most effective treatment for patients who develop pericarditis and this is partially supported by the results from the randomized, double blind CROP-2 trial (52). Two more recent multicenter studies were published this year. The first report by Miller et al included 41 consecutive patients with a mean CHADS2 score of 3.0, a mean HASBLED score of 4.4 and accumulated 24.6 person-years of follow up. It showed a similar acute success in LAA closure (93%). Interestingly, a TEE or CTA performed by 3.3 months demonstrated LAA leakage in 24% of patients. One patient had a TIA (2%), and 8 developed pericardial effusions requiring pericardiocentesis (20%). Unfortunately, four procedures on this report were complicated by perforation of the LAA (9%). Of these, 2 patients required open surgical correction (53). A much larger multicenter study (Results From the U.S. Transcatheter LAA Ligation Consortium) published by Price et al

20

revealed similar safety concerns. Device success, defined as suture deployment was achieved in 94%, but there was a high complication rate. Major complications, defined as death, myocardial infarction, stroke or cardiac surgery, were observed in 9.7% of the patients. Most frequent complications were major bleedings (9.1%), which mostly required blood transfusion, and significant pericardial effusion (10.4%). LAA laceration or perforation was seen in 4 patients. Follow-up was available in 134 patients at a median of 112 days. Death, myocardial infarction, or stroke occurred in 4 patients (2.9%). Among 63 patients with acute closure and transesophageal echocardiography follow-up, there were 3 thrombi (4.8%) and a markedly high incidence of residual leak (20%) (54). Consequently, randomized control trials using the LARIAT device in order to evaluate efficacy and more importantly safety, optimal post-procedure medical therapy, and the effect of operator experience on procedural safety are eagerly awaited. Although the major benefit of the LARIAT device when compared with other endovascular devices, particularly the WATCHMAN device, is that AC is not required LAA’s successful complete isolation, our group and others have shown early (1 month) and late (2-4 months) partial re-openings with bidirectional flow between the LAA and the LA. This obviously has relevant clinical implications and we consider that AC should be continued for at least 1-3 months after device placement in order to confirm complete occlusion and avoid strokes if no absolute contraindications are present (55,56). The GoreVR HelexVR Septal Occluder (W. L. Gore and Associates, Newark, Delaware) might be used to address and close these gaps given that spontaneous resolution is unlikely (57). ACP and a repeat LARIAT procedure might also be used with great success for this purpose (58). Surprisingly, even with complete LAA occlusion, thrombus

21

formation at the stump of the ligated LAA has been seen. Thrombus at the site of closure may represent thrombus extension from an appendage that has slightly opened after the procedure. Another appealing theory is that by pulling of the balloon-tipped catheter and endocardial magnet-tipped wire through a very narrow LAA neck the endothelium is traumatized creating a pro-thrombotic environment (59). However, between 3 to 5% of thrombi after successful closure has been observed by centers that discontinue AC immediately after the procedure. On the contrary, this finding has not been reported by centers that before discontinuing AC confirm successful complete closure at the 1-month follow-up TEE (60,61). The arrhythmogenic role of the LAA is well known and at least 30% of patients with persistent AF have triggers in this area (62). LAA catheter ablation improved AF ablation success rate. Nevertheless, it might cause electromechanical dissociation with the potential for thrombus formation. Preclinical models and surgical studies postulated that the LAA could be potentially electrically isolated by surgical epicardial clipping occlusion. One group demonstrated complete electrical isolation of the LAA in 10 AF patients who underwent off-pump coronary artery bypass surgery with bilateral pulmonary vein isolation and LAA clip occlusion. Before and after the clip was placed, pacing maneuvers were performed to assess electrical exit and entry blocks from the LAA (63). Han and colleges studied 68 patients who underwent LAA ligation with the LARIAT and demonstrated a significant decrease in LAA unipolar and bipolar voltages before and after the snare was tightened. Ninety four percent of these patients had a reduction in LAA voltage with a third of these having complete elimination of LAA voltage. Pacing

22

from the LAA after closure of the snare demonstrated complete isolation of the appendage with no capture of LA in 90 % of the patients (64). This may be consistent with LAA ischemic necrosis. Whether or not LAA ligation might play an important role in decreasing the AF burden remains to be clarified. The LARIAT device is 510 (k) FDA approved in the United States for soft tissue approximation and/or ligation with a pre-tied polyester suture. New LAA closure devices LAmbre: This self-expanding nitinol-based device comprising a hook-embedded umbrella with a large cover (4-6mm) connected by a short central waist and filled with sewn-in polyethylene terephthalate comes in different sizes ranging from 16 to 36 mm (Figure 8). The size of the LAA is measured by angiogram and the device should be 4-8 mm larger. The delivery system is placed on the proximal part of the LAA and the umbrella device is deployed by pushing out the device from the delivery sheath to the desired landing zone, opening the umbrella and grasping onto the LAA walls by the hooks. The sheath is removed to expose the disc and expansion in the atrium. This new device has two main advantages: small delivery system and the ability to reposition during implantation (65). AEGIS: permits LAA closure via epicardial approach and has two parts: the appendage grabber and the ligator. The grabber has an articulating jaw with mounted electrodes, allowing identification and position of the LAA by means of electrical signals. When positioning near the LAA, injection of contrast is achieved to outline the LAA, and ICE or TEE evaluates proper capture. The ligator is a preloaded hollow suture that can be 23

opened and closed repeatedly until proper closure is achieved. This system has been tested only in animals. The Transcatheter Patch (Custom Medical Devices, Athens, Greece): is a soft, frameless, bioabsorbable balloon-deliverable device similar to other LAA occluders but with the difference that it is fixed within the LAA with surgical adhesives, which reduces the risk of LAA perforation. The supporting balloon is made of latex and the patch of polyurethane foam. This device was studied in 20 patients showing successful placement in 17 cases (66). Coherex WaveCrest (Salt Lake City, UT) occlusion system: is one of the latest developments in closure devices. It is umbrella-shaped and is deployed similarly to other endovascular devices. It has more anchors than any other device to avoid embolization and the material that faces the LA minimizes thrombus formation allowing rapid endothelization (Figure 9 A-B). This device was initially tested in animals with satisfactory results and last year the results from WaveCrest I Trial were reported. Acute procedural success was achieved in 93% of patients (68/73) and complete LAA closure at 45 days in 92% (67/73). Two pericardial effusions developed, however, there were no procedural stroke, device embolization or device-associated thrombus.

Guidelines The 2012-focused update of the ESC guidelines for the management of AF recommend that percutaneous LAA closure device may be considered in patients with high risk of stroke (CHADS-VASc score of 2 or higher) and contraindications for long-term AC (Class: II b and level of evidence: B) (67). Of note, the recently published 2014 24

AHA/ACC/HRS guidelines for the management of patients with atrial fibrillation make no recommendations regarding the use of these devices (68). Future Perspective Percutaneous LAA occlusion devices represent a very provocative therapeutic option to reduce the stroke burden in patients with non-valvular AF. Furthermore, percutaneous LAA occlusion devices have proven to be cost-effective compared to warfarin (69). The advantage and possibly main indication for their use is in patients having absolute contraindications for AC and now even in patients who prefer to avoid long-term AC. Nevertheless, the European and American guidelines for the management of these patients still remain guarded, due partly to the small sample size in the studies and shortterm follow up. Additionally, it is well established that LAA devices do not fully prevent the risk of cardioembolic stroke probably because thrombi can form in locations other than the LAA even in non-valvular AF patients (5%). CT studies have demonstrated a significant number of subclinical small strokes in AF patients who are not treated with AC, which has a marked impact in learning capacity and memory loss when compared to non-AF patients (70,71). An indirect analysis presented at the American College of Cardiology (ACC) Scientific Sessions 2010 from the PROTECT AF and RELY trials suggested that WATCHMAN would have not reached the non-inferiority endpoint if dabigatran had been the control group. It would be interesting to analyze and compare the data from the ARISTOTLE study given the fact that apixaban similar to dabigatran not only demonstrated to be non-inferior, but superior to warfarin in reducing the risk of stroke and systemic embolism in patients with AF. Moreover, apixaban is associated with a significant reduction in bleeding risks and total mortality (45). Finally, prospective 25

head-to-head comparisons among devices and using the new oral agents for AC are needed to establish what the best device is and if indeed they are as good as AC in this patient population.

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Figures and legends Figure 1. Left atrial appendage (LAA) anatomy. Classical chicken wing morphology. Note its relationship with the left atrium (LA), left superior pulmonary vein (LSPV) and left ventricle. * = Heavy trabeculations (pectinate muscles).

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Figure 2. LAA morphologies. The four most common LAA morphologies are depicted on the left by CCT and on the right by CMRI. a) Cactus morphology is composed of a dominant central lobe with secondary lobes extending from the central lobe in both superior and inferior directions. b) Windsock morphology has one dominant lobe of sufficient length as the primary structure. Variations of this LAA type arise with the location and number of secondary or even tertiary lobes arising from the dominant lobe. c) Cauliflower morphology presents with a limited overall length with more complex internal characteristics. Variations of this LAA type have a more irregular shape of the LAA ostium (oval vs. round) and a variable number of lobes with lack of a dominant lobe. d) Chicken wing morphology presents an obvious bend in the proximal or middle part of the dominant lobe, or folding back of the LAA anatomy on itself at some distance from the perceived appendage ostium. This type of LAA may have secondary lobes or twigs. (Courtesy of Dr Luigi Di Biase)

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Figure 3. PLAATO system. The device is constructed of a nitinol frame and an implant occlusion membrane consisting of a laminated ePTFE. Note the small anchors along the frame passing through the occlusive membrane, which assist with device anchoring and stability.

Figure 4. Amplatzer Cardiac Plug. ACP 1 (left) and the new generation ACP 2 (right). The device is composed of a lobe and a disk connected by a central waist, which occludes the left atrial appendage ostium like a pacifier. Note how the lobe is anchored 1 -2 cm distal of the LAA orifice, whereas the disc totally covers the ostium of the LAA.

34

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Figure 5. WATCHMAN device. Nitinol cage with a polytetrafluoroethylene membrane. Paruchute-shaped device that incorporates a row of fixation barbs.

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Figure 6. LARIAT device. See endocardial and epicardial magnet tipped guidewires in the LAA, which creates a monorail that allows the suture loop to be positioned at the base of the appendage.

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Figure 7. Fluoroscopic view of LARIAT device. RAO projection depicting both endocardial (small) and epicardial (large) magnets (a). Note the connection between magnets and the open LARIAT device approximating the LAA (b). Finally, the LARIAT device has been tightened and deployed epicardially around the ostium of the LAA (c). (same patient)

38

39

Figure 8. LAMBRE

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Figure 9. A: WaveCrest LAA closure device

B: Reproduction of the device placed into LAA

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Tables and Legends Table 1. Pre-clinical and clinical studies evaluating safety and efficacy of the LAA closure devices.

Study

Design

Device

Control

Population

Follow-up

Results

Complications

Sievert 2002

Prospective

PLAATO n = 15

None

Persistent AF AC contraindicated

1 month

LAA Occluded 100% Stroke/TIA 0%

Hemopericardium (1)

Ostermayer 2005 (Feasibility Trial)

Prospective (multicenter trial)

PLAATO n = 111

None

Non valvular chronic AF AC contraindicated + 1 risk of stroke CHADS2 2.5

9.8 months

LAA Occluded 97% Acute stroke 1.8%

Neurological death (1) Cardiovascular surgery (1) Hemopericardium with periocardiocentesis (3) Acute stroke (2)

Block 2009

Prospective (multicenter trial)

PLAATO n = 64

None

Permanent or paroxysmal AF High-risk (CHADS of 2 or more) AC contraindicated

60 months

Stroke 3.8%

Neurological death (1) Cardiovascular surgery (1) Hemopericardium with periocardiocentesis (3) Acute stroke (2)

Bayard 2010 (European PLAATO Study)

Prospective

PLAATO n = 180

None

Non valvular chronic AF AC contraindicated + 1 risk of stroke CHADS2 3

2 months

LAA Occluded 90% Stroke 2.3%

Death 24 hours (2) Hemopericardium (6) Perocardiocentesis (2) Device embolization (1)

Meier 2003

Retrospective

ACP n = 16

None

Paroxysmal and persistent AF AC contraindicated

4 months

LAA Occluded 100% Stroke/TIA 0%

Device embolization (1)

Park 2011 (European Experience)

Retrospective

ACP n = 136

None

Paroxysmal and persistent AF AC contraindicated

24 hours

LAA Occluded 96% Stroke 2.2%

Device embolization (2) Hemopericardium (5)

Guerios 2012

Prospective

ACP n = 86

None

Non valvular persistent and paroxysmal AF AC contraindicated CHADS2 2.6

4 months

LAA Occluded 97% Stroke 0%

Hemopericardium (1) Thoracentesis (1) Device embolization (1) TIA (2)

Lopez-Minguez 2013

Prospective

ACP n = 35

None

Non valvular AF AC contraindicated CHADS2 2.4

21 months

LAA Occluded 97% Stroke 0% TIA 1%

Arteriovenous Fistula (1)

Lam 2012 (Asia-Pacific Experience)

Prospective

ACP n = 20

None

Non valvular AF AC contraindicated CHADS2 2.3

12 months

LAA Occluded 95% Stroke 0%

Coronary artery air embolization (1)

Urena 2013 (Canada Experience)

Prospective

ACP n = 52

None

Non valvular AF AC contraindicated CHADS2 3

20 months

LAA Occluded 98% Stroke 1.9%

Device embolizationM(1.9%) Pericardial Effusion (1.9%)

Nietlispach 2013 (Switzerland Experience)

Retrospective (Analysis of prospectively collected data)

Amplatzer I n = 152

None

Non valvular AF AC contraindicated CHADS2 3.4

32 months

Stroke 1.3%

Device embolization (7) Cardiac tamponade (4.1) Acute stroke (3)

42

Sick 2007 (Initial Worldwide Experience)

Prospective

WATCHMAN n = 66

None

Chronic persistent AF Able to take AC CHADS2 1.8

61 +/- 28 months

LAA Occluded 93% Stroke 0%

Device embolization (2) Cardiac tamponade (2) Air embolism (1) TIA (2)

Holmes 2009 (PROTECT AF)

Prospective RCT 2:1 Ratio

WATCHMAN Intervention group = 463 Control group = 244

Warfarin

Non valvular AF Able to take AC CHADS2 2.2

18 months 1065 patients/year

Stroke 2.3% Cardiovascular death 0.7% Systemic embolism 0.3%

Major bleeding, (16) Pericardial effusion (22) Device embolization (3)

Reddy 2011 (PROTECT AF vs. CAP Registry)

Prospective

WATCHMAN CAP N= 460

PROTEC T AF N= 542

Non valvular AF Able to take AC CHADS2 ≥ 2

Median 2.5 years

N/A

Clinically significant pericardial effusion (10) Stroke (0) Major Bleeding (3)

Reddy 2013 (ASAP)

Prospective Nonrandomized

WATCHMAN N= 150

None

Non valvular AF CHADS2 ≥ 1 AC contraindicated

14.4 ± 8.6 months

Death (5%) Ischemic stroke (1.7%) Hemorrhagic stroke (0.6%)

Device embolization (2) Pericardial effusion with tamponade (2) Ischemic stroke (1)

Holmes 2014 (PREVAIL)

Prospective RCT 2:1 Ratio

WATCHMAN Intervention group = 269 Control group = 138

Warfarin

Non valvular AF Able to take AC CHADS2 ≥ 2

18 months

Ischemic Stroke 1.9% Hemorrhagic stroke 0.4% Cardiovascular death 2.6% Systemic embolism 0.4%

Device embolization (2) Pericardial effusion with tamponade (1) Major bleeding (1)

Price 2014

Retrospective (Multicenter)

LARIAT N= 154

None

Non valvular AF Median CHADS2 = 3

112 days

Device success 92% Residual leak 7% LAA thrombus 5% Death, MI or stroke 2.9% -Stroke (2) -Death (3)

Major bleeding (14) Significant pericardial effusions (16)- 4 due to LAA perf/laceration Tamponade (7) Pleural effusion (4) RV perforation during pericardial access (2) LAA perforation during pericardial access (1)

Miller 2014

Retrospective (Multicenter)

LARIAT N = 41

None

Persistent, paroxysmal or permanent AF and relative contraindication to AC CHADS2 3 +/- 1.3

7.2 months ±7.2

Acute Success 93% LAA Leak 24% Stroke or TIA 2% Death 0%

Major bleeding (2) LAA perforation (4) Pericardial effusion requiring pericardiocentesis (9) Pericarditis (7) Pleural effusion (6)- required thoracentesis

Bartus 2013

Prospective

LARIAT n = 89

None

Non valvular AF AC contraindicated and poor candidate for AC CHADS2 1.9

12 months

LAA Occluded 96% Embolic Stroke 0% Lacunar Stroke due to HTN 0.01% Hemorrhagic Stroke 0.01%

Pericardial effusion due to right ventricular puncture (dilated over guide wire) (1) Epigastric vessel laceration (1) Perforation and hemopericardium during transseptal access (1) Pericarditis (2) Late pericardial effusion (1)

Massumi 2013

Retrospective

LARIAT n = 21

None

Paroxysmal and persistent AF AC contraindicated CHADS2 3.2

12 months

LAA Occluded 100% Stroke 0%

Right ventricule perforation requiring surgery (1) Pericardiocentesis (1)

Lam 2013

Pre-clinical Prospective Nonrandomised

LAmbre N = 89 (Canines)

None

N/A

6 months

Major organ infarct on autopsy 0%

Device related thrombus (1) Pericardial effusion clinically significant (1)

43

Toumanides 2011

Prospective

Transcatheter Patch N= 20

None

Idiopathic AF CHADS2 >3

12 months

LAA Occluded 85%

Stroke (0) Bleeding (0) Device thombus (1)

Starck 2012

Prospective

AtriClip N= 10

None

Paroxysmal AF

Periprocedure

LAA Occluded 100%

Device associated complications (0)

44