Percutaneous closure of left atrial appendage for stroke prevention

cor et vasa 58 (2016) e250–e260

Available online at www.sciencedirect.com

ScienceDirect journal homepage: http://www.elsevier.com/locate/crvasa

Review article – Special issue: Acute Ischemic Stroke

Percutaneous closure of left atrial appendage for stroke prevention Petr Neužil a,b,*, Tomáš Mráz a,b, Jan Petrů a,b, Pavel Hála a,b, Martin Mates a,b, Petr Kmoníček a,b, Milena Prokopová a,b, Vivek Y. Reddy a,b a b

Cardiology Department, Na Homolce Hospital, Prague, Czech Republic Mount Sinai Medical Center, New York, United States

article info

abstract

Article history:

Transcatheter left atrial appendage closure (LAAC) is an alternative therapy for stroke

Received 5 December 2015

prevention in atrial fibrillation (AF) patients. There are increasing data supporting this

Received in revised form

‘‘local’’ prevention of thromboembolism in the patients with high-risk CHA2DS2-VASc score.

17 February 2016

LAAC might be a very important alternative in patients with limitations/contraindication to

Accepted 18 February 2016

the anticoagulation therapy. Two main randomized clinical trials data indicated the utility

Available online 17 March 2016

and safety of Watchman LAAC device for stroke prevention in patients with AF as a non-

Keywords:

mechanical occluders (prospective, multicentric studies), clear profit of these devices could

Atrial fibrillation

be limited by: (a) residual tamponade rate of 1–3%; (b) lack of complete 100% closure in one-

inferior treatment strategy. Despite overall effectiveness showed for all currently used

Thromboembolism

third of patients. To improve the outcome, the new generations of these devices are

Stroke

designed to present: (i) a less traumatic implanting procedure; (ii) better placement and

Left atrial appendage occlusion

coverage of the LAA orifice. The present article summarizes the rationale, clinical data, devices, implantation techniques and follow-up drug regimens. In conclusion, we need more data and more studies to prove the LAAC principle specifically in the new era of direct oral anticoagulation therapy. # 2016 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . Left atrial appendage exclusion . . . . PLAATO occluder . . . . . . . . . . . . . . . WATCHMAN occluder. . . . . . . . . . . . ACP – AMULET occluder . . . . . . . . . . LARIAT ENDO-EPI exclusion system New systems for LAA occlusion . . . .

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* Corresponding author at: Department of Cardiology, Na Homolce Hospital, Prague, Roentgenova 2, 150 30 Praha 5, Czech Republic. Tel.: +420 2 5727 2211; fax: +420 2 5727 2302. E-mail address: [email protected] (P. Neužil). http://dx.doi.org/10.1016/j.crvasa.2016.02.007 0010-8650/# 2016 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.

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Conclusion . . . . . . . . . Authors' contribution . Conflict of interest . . . Ethical statement . . . . Funding body . . . . . . . References . . . . . . . . . .

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Introduction Atrial fibrillation (AF) is the most common arrhythmia in the elderly population. The prevalence of AF in the general population is around 0.9, but in the age of 65 years, it reaches 5.9%. The average age of the patients with documented AF is 75 years. For example, in the US, the projected number of subjects with AF is expected to rise to between 5.6 and 12 million in 2050 from 2.7 to 6.1 million in 2010 [1,2]. The Framingham study proved that AF is associated with a four- to five-fold increased risk of thromboembolic events and that the percentage of strokes secondary to AF increases dramatically from 1.5% at 50 years of age to 23.5% at 80 years of age [3]. Furthermore, the adjusted stroke rate based on the CHADS2 index score ranges from 1.9% to 18.2%. Recently, EHRA guidelines recommend the CHA2DS2VASc score over the original CHADS2 score to assess stroke risk in patients with AF. Among the patients aged 65–95 years old with non-valvular atrial fibrillation, very few (<7%) will be classified as low risk according to the CHA2DS2-VASc score. Left atrial appendage (LAA) was originally considered as an innocent and non-functional anatomic cardiac structure, and only two decades ago, it was identified as the location of thrombus formation [4]. Moreover, it is documented by several studies that approximately 92% of thrombi in non-valvular AF are localized in the LAA; in the four major transesophageal echocardiography (TEE) studies, detection of the thrombus in LAA was even greater – 98% [5]. In the last 15 years, the LAA came to be the structure of interest for many investigators who have investigated this structure from different perspectives. We need to understand better its anatomy and physiology, as well as recommend different imaging modalities and techniques to assess its shape, size, and blood flow patterns (the Doppler signal velocity), detect echocontrast formation or exclude presence of thrombus. To eliminate the risk of devastating thromboembolic event (stroke/ TIA), different devices or approaches for LAA exclusion were developed in order to stop entry, keep permanent occlusion and, even more, reach electrical isolation. The LAA is a highly complex and dynamic structure with very effective contraction and relaxation specifically during sinus rhythm. This contraction capability decreases during AF [6]. The main advantage of recent development in imaging technology transesophageal echocardiography – TEE, computed tomography (CT), and magnetic resonance imaging (MRI) included is detailed visualization of LAA structure that markedly varies in shape and size (volumes, length, width, and orifice size) [7]. Majority of LAA morphologies are composed of two sometimes up to three lobes [8]. Several LAA morphologies have been described but the four most common represent different clinical outcome as recently described Di Biase [9]. He and co-authors have documented LAA morphology as the independent risk factor for stroke/TIA in

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patients with AF. In this very first study, patients with chicken wing morphology were less likely to have a thromboembolic event than other three morphologies. Incidence of described morphologies: chicken wing (48%), cactus (30%), windsock (19%), and cauliflower (3%) (Fig. 1). LAA neurohumoral activity has been shown as important parameter in volume homeostasis; atrial natriuretic factor and inclusive brain natriuretic peptide are produced and secreted in significant amounts. This might have clinical implications when LAA exclusion is indicated in patients with dilated cardiomyopathy [10].

Left atrial appendage exclusion Oral anticoagulation Warfarin (Coumadin) domination has significantly decreased the incidence of thromboembolic

Fig. 1 – Four dominant LAA morphologies which may represent different levels of risk for stroke in patients with atrial fibrillation.

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events and this effect was described in several studies [11,12]. Prevention of cardioembolic strokes in patients suffering AF is durable and is prominent over the years. But at the same time, relatively high number of publications has reported underutilization of oral anticoagulation with warfarin therapy. The risk of bleeding (e.g., intracranial hemorrhage and gastrointestinal bleeding), difficulty to get stable INR level, non-compliance, drug and diet interaction, and advanced age caused that only 50–60% of the patients indicated for long-term anticoagulation based on the CHADS2 or CHA2DS2-VASc score reported effective medication [13]. Currently, new (or direct) oral anticoagulants, such as the direct thrombin inhibitors (i.e., dabigatran) and factor Xa inhibitors (e.g., rivaroxaban, apixaban and edoxaban), with their very selective effect in the coagulation cascade are available, but significant number of contraindications for long-term anticoagulation therapy remains. In 1949, Madden performed the first LAA excision in two patients with AF and rheumatic mitral disease. The LAA occlusion study (LAAOS) published in 2005 was the first randomized trial that evaluated safety and efficacy of the LAA occlusion at the time of elective bypass graft surgery. LAAOS included 77 patients with high risk of stroke in whom LAA occlusion was attempted using sutures and staples. Occlusion was achieved in only 66% of the patients and the use of staples had the highest efficacy. The efficacy was assessed with TEE at 8 weeks after the procedure, where staples had 72% efficacy and sutures only 45% [14]. In 2000, Katz reported TEE single-center study with 50 patients when incomplete closure after surgical LAA suture was found in 18 patients; it represents 36% of all patients. This incomplete closure with LA-LAA residual communication increased risk of thromboembolism [15]. Recently, another prospective TEE study confirmed incomplete exclusion as the main limitation of the surgical approach with 40% of the cases (successful LAA closure occurred more frequently with excision (73%) than suture exclusion (23%) and stapler exclusion (0%)) [16]. Metaanalysis of clinical trials demonstrated the limitation of the surgical approach given the fact that most studies reported 55–66% successful occlusion rate only. Technique of closure is very important parameter with variety of methods including stapling, ligation and amputation [17]. Fifteen years ago, the first in man study was reported with closure device being implanted completely percutaneously via transseptal puncture when metal basket was implanted

inside LAA to get complete occlusion of LAA cavity [18]. It was PLAATO occluder (ev3 Endovascular, Plymouth, MN) that was the very first LAAC system. Later, other devices or approaches for percutaneous closure appeared like the WATCHMAN device (Boston Scientific, Plymouth, MN), the Amplatzer Cardiac Plug and Amulet (St. Jude, Golden Valley, MN), and the LARIAT device (SentreHEART, Palo Alto, USA). The last CE approved device is WaveCrest occluder (Biosense-Weebster, CA) (Fig. 2). Only the Watchman device and the Lariat device are FDA approved for US market. This review will focus on the potential benefits and obstacles of LAA closure systems (Figs. 2–5).

PLAATO occluder The feasibility trials (two prospective, multicenter trials) assessed the efficacy of the PLAATO system in a much larger sample of patients (n = 111) with a mean age of 71 and chronic non-valvular AF with a contraindication for AC and at least one risk factor for stroke. Almost all the patients had a complete LAA occlusion after the device deployment (97%). Two patients experienced stroke and one patient needed cardiovascular surgery and experienced in-hospital neurological death in the first 30 days after procedure. Three other patients required pericardiocentesis due to a hemopericardium. Two patients (1.8%) experienced an ischemic stroke during a mean follow-up of 9.8 months. TEE performed at the 1- and 6-month follow-up on these two patients demonstrated that the device was in a stable position with no thrombus on the surfaces. This trial demonstrated a relative risk reduction of stroke rate of 65% on the basis of the CHADS2 score (2.5) of the studied population (PLAATO 2.2% versus expected by CHADS 6.3%). These promising results suggested that occlusion devices might really become an alternative therapy for patients with AF and a contraindication for long-term anticoagulation [19]. There was even a larger European PLAATO trial, which enrolled 180 patients with persistent AF, and contraindication for AC revealed a successful LAA occlusion in 162 patients (90%). Two patients died within 24 h of the procedure (1%) and six cardiac tamponades were observed (3.3%), with two cases requiring pericardiocentesis. In one patient, the chosen device was too small and embolized into the aorta after its release (0.6%). It was snared and replaced without further complications. In a follow-up time of 129

Fig. 2 – Implantable occluders: PLAATO was implanted first in man in 2002, but due to financial issue, production was stopped in 2005. Watchman, ACP and WaveCrest got CE mark; Watchman is the only one who got FDA approval in 2015.

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Fig. 3 – Endoepicardial system to exclude LAA by snare introduced over LAA. Bottom 3D echocardiography endoscopic view – LAA before and after closure.

Fig. 4 – Innovated Watchman – Watchman Flex (Boston-Scientific Inc.) and ACP – Amulet (St. Jude Medical Inc.).

documented patient-years, three strokes occurred (2.3% per year). The expected incidence of stroke according to the CHADS2 score was 6.6% per year. This trial was stopped prematurely due to financial problems despite very promising preliminary clinical results [20].

WATCHMAN occluder The next system, WATCHMAN device (Atritech, Inc., Boston Scientific, Plymouth, MA), was introduced later. This is a

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Fig. 5 – CT 3D reconstruction image of the left atrium before and after Watchman implantation (A, B); CT image of PLAATO one year after implantation with discrete leak into the LAA (C); transesophageal echocardiography after Watchman implantation with color Doppler small leak visualization (D).

self-expanding nitinol frame with fixation anchors and a permeable polyester cover. There are five sizes (21, 24, 27, 30, and 33 mm). This device requires anticoagulation for at least 45 days post-implantation, and after verification a leak less than 3 mm dual antiplatelet therapy is initiated. The first experience of the WATCHMAN device was a prospective study that included 66 patients with permanent or paroxysmal nonvalvular AF who were eligible for warfarin therapy. Occlusion level was very effective with 93% of devices reaching successful sealing of LAA. Two patients experienced device embolization, both successfully retrieved percutaneously. Four patients from this feasibility trial developed a thrombus sitting on the device (<6 months after implant), which resolved with restart of anticoagulation therapy. No strokes occurred during follow-up despite >90% of patients discontinuing the anticoagulation therapy [21]. The PROTECT AF (WATCHMAN® Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation) study was initiated based on these encourage data as the first multicenter randomized control trial comparing LAA closure device (WATCHMAN) versus Warfarin with primary endpoint to evaluate efficacy and safety (Fig. 6) and designed as a noninferiority trial. The study included 707 patients with nonvalvular AF eligible for long-term anticoagulation and patients were randomized in a 2:1 ratio to percutaneous closure of the LAA (n = 463) or to AC treatment (n = 244) and followed up for 18 months. A WATCHMAN device was successfully deployed in 91% of patients in whom implantation was attempted. At the 45-day follow-up, warfarin was discontinued in 86% of patients who received the device, and 92% of patients met the

criteria by 6 months, mainly because of a reduction in peridevice leaks. 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% CrI 0.35–1.25). At 1065 patient-years of follow-up, the probability of non-inferiority of the intervention was more than 99.9%. Primary safety events were more frequent in the intervention group than in the control group

Fig. 6 – PROTECT-AF: Kaplan–Meier curve of long-term follow-up with significantly less events in Watchman group.

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(7.4 per 100 patient-years versus 4.4 per 100 patient-years; RR 1.69, 1.01–3.19). There were five (1.1%) procedure-related ischemic strokes, three (0.6%) device embolizations, and 22 pericardial effusions (3.5%). The study was compromised by higher initial rate of pericardial effusions and procedurerelated strokes [22,23]. Consequently, the Continued Access Registry (CAP) and the PREVAIL trial were designed to confirm the efficacy of the WATCHMAN device and to provide more data about safety. In fact, the rate of complications was significantly lower between the first and second halves of PROTECT AF, and even lower in patients who participated in CAP (10.0%, 5.5%, and 3.7%, respectively). The rate of serious pericardial effusion within 7 days of implantation was 2.2%, which was 50% of the safety events in PROTECT AF, and was lower in the CAP Registry (5.0% versus 2.2%, respectively; p = 0.019). No procedure-related strokes have occurred [23]. Later, the results of the 2.3-year follow-up of the PROTECT AF trial were published. After 1588 patient-years 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% per year), which met the criteria for non-inferiority (probability of non-inferiority >0.999). 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) [24]. The mean follow-up was 45 months, and non-inferiority (>0.999) for the primary efficacy endpoint (composite of stroke, cardiovascular death and systemic embolism) was repeatedly demonstrated (WATCHMAN 2.3% (1.7–3.2), warfarin 3.8% (2.5–4.9)). Interestingly, for the first time, the primary safety endpoint was similar to the warfarin group (3.6% versus 3.1% HR 1.17 [0.78–1.95]). As expected, the WATCHMAN group revealed a significantly lower rate of hemorrhagic strokes (0.2 versus 1.1, RR: 0.15 [0.09–0.49]). Furthermore, total mortality was also significantly lower in the device group, with a 34 relative risk reduction HR 0.66 (95% CI 0.45–0.98). Data from PROTECT-AF indicate that residual peridevice flow into the LAA after percutaneous closure with the WATCHMAN LAA closure device was very common. However, those were not associated with an increased risk of thromboembolism even including moderate (1–3 mm) or severe (>3 mm) ones. The authors are aware that given the low event rate in this sub-study, this conclusion must be interpreted with caution [25,26]. Food and Drug Administration (FDA), due to high initial rate of pericardial effusions and procedure-related strokes in PROTECT-AF trial, ask for extension of data, and so the PREVAIL trial (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device in Patients with Atrial Fibrillation). A total of 407 patients with a mean CHADS2 score of 2.6 were randomized in a 2:1 fashion to device versus warfarin. The first co-primary endpoint was the occurrence of death, ischemic stroke, systemic embolism, and procedure- or device-related complications requiring major cardiovascular or endovascular intervention in the first 7 days. 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 co-primary endpoint was a composite of stroke, systemic embolism, and cardiovascular or unexplained death at 18 months of follow-up. Unfortunately, this trial did not meet this endpoint. The observed adverse event rate for both the

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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 greater than the pre-specified criterion of 1.75 (95% CI) to demonstrate non-inferiority. This might in part be explained given the fact that the stroke rate in the PREVAIL control group was lower than in any other published studies using AC (1.6–2.2%) [27,28]. Despite there being at least one-third of new operators not involved in PROTECT-AF trial, a significant increase in implant success rate (95.1%) compared with PROTECT AF (90.9%) was noted, with no difference in the success rate between new and experienced implanters ( p = 0.282). To clear the need for temporary anticoagulation therapy after WATCHMAN device implantation, 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 oral AC was conducted. This was a multicenter, prospective, non-randomized study with 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, and the mean follow-up was 14 months. Serious procedure- or devicerelated safety events occurred in 13 out of 150 patients (8.7%). All-cause stroke or systemic embolism occurred in four patients (2.3% per year): ischemic stroke in three patients (1.7% per year) and hemorrhagic stroke in one patient (0.6% per year). This ischemic stroke rate was less than that expected (7.3% per year) based on the CHADS2 and CHA2DS2-VASc scores of the studied patients [29]. These data support that the WATCHMAN device can be safely performed without post-procedural anticoagulation. In the last part of year 2015, new generation of WATCHMAN-FLEX was introduced. This device is much shorter comparing WATCHMAN first gen and also the distal parts of nitinol is oblique, i.e. very atraumatic. This device could be fully recaptured several times. In March 2015, Watchman received FDA approval for US market.

ACP – AMULET occluder Shortly after the PLAATO system was introduced into clinical practice, the Amplatzer Cardiac Patch (ACP) (St Jude, Golden Valley, MN), which was originally used for atrial septal defect closure, was tried to seal the LAA too. The ACP occluder is a self-expanding device made of nitinol wire mesh and a polyester patch and consists of two main parts: a lobe and a disk connected by a central waist. The lobe has diameters from 16 to 30 mm. The device is delivered over two sizes sheaths (10 F or 13 F). It is anchored in the LAA approximately 1 cm behind the ostium, and then the disk unfolds to cover the entrance of the LAA. This first clinical study enrolled 16 patients with paroxysmal and persistent AF. During a 4-month follow-up, there were no strokes or other complications. Complete LAA occlusion was achieved in all cases, but there was one device embolization that required cardiac surgery [30]. It was paused in development until 2011 when initial European experience was released. This was a retrospective analysis of 136 patients with paroxysmal/permanent AF not

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able to take anticoagulation, which assessed the efficacy and safety of this device in the first 24 h after procedure. A total of 10 major complications were reported (7%). These included three acute ischemic strokes (2.2%) and two device embolizations, both of which were successfully percutaneously recaptured. Moreover, five patients developed hemopericardium. The first prospective study using the ACP 1 was performed in Switzerland in 2012. Eighty-six consecutive patients were included with AF and contraindication to AC. All the implants were guided with fluoroscopy and LAA was completely occluded in 97% of the cases. There were four major complications: one patient developed cardiac tamponade requiring pericardiocentesis; two TIAs; and one device embolization with percutaneous retrieval. There was one inhospital death after 6 days, unrelated to the procedure. After 25.9 patient-years of follow-up (mean 4 months), there were neither strokes nor late device embolizations. Six patients showed evidence of thrombus formation on the device, which resolved after 3 months of anticoagulation was started [31]. Later, López-Mínguez et al. [32] published another study with 35 consecutive patients in whom the device was implanted under general anesthesia. After the first five patients, threedimensional imaging was incorporated in order to avoid device embolization seen in prior studies. The results of the implantation and the follow-up were analyzed over a 1-year period. There were no cardiac complications during the implantation or hospital stay. There was one vascular complication (arteriovenous fistula). TEE monitoring was performed at 24 h, 1, 3, 6, and 12 months and they found five thrombi, which were resolved with heparin. In the followup period of 21 months, one had TIA without further consequences [32]. Similarly, this was observed in the 10-year experience in Switzerland with 152 patients in which all procedures were performed under local anesthesia without TEE guidance. Patients were discharged on acetylsalicylic acid and clopidogrel for a couple of months. Short-term safety endpoints (procedural complications) occurred in 15 (9.8%) patients: neurologic events (n = 3) and device embolization (n = 7) were the most common ones. Device embolization occurred more frequently in the non-dedicated Amplatzer devices than the ACP group (5 patients versus 2 patients). Mean intermediate-term follow-up of the study population was 32 months. Neurologic events occurred in two (1.3%), peripheral embolism in one, and major bleeding in four patients [33]. Although the ACP 1 does not require immediate postprocedure anticoagulation, there have been some cases in every single study of thrombus formation around the device. Plicht et al. [34] performed serial TEE before discharge and after 3, 6, and 12 months, and found an incidence of 17% of thrombus formation on the Amplatzer device despite dual antiplatelet therapy. A CHADS2 score was greater than 4.3, and CHA2DS2-VASc score was greater than 6.8. Left ventricle ejection fraction was also less than 40%. These results emphasize the need for close and serial TEE follow-up, and suggest the use of post-procedural anticoagulation. In terms of improving this thromboembolic risk of ACP 1st generation, the ACP AMULET (St. Jude Medical, Saint Paul, MN) as a secondgeneration Amplatzer device was invented. The AMULET device is implanted in a similar fashion to ACP 1 but compared to ACP 1 the AMULET has more hooks (10 pairs versus 6 pairs),

which are stiffer, and it has diameters from 16 to 34 mm. It is recommended to select a device about 3–6 mm larger than the LAA orifice [35].

LARIAT ENDO-EPI exclusion system The LARIAT (SentreHEART, Palo Alto, CA) device consists of three components: (i) a balloon catheter (EndoCATH 15 mm); (ii) magnet-tipped guidewires (FindrWIRZ 0.025–0.035 in.); and (iii) an epicardially delivered 12 F suture delivery device (LARIAT). The LARIAT system device requires both endocardial and epicardial approaches to exclude the LAA. Four steps are required: (i) pericardial and transseptal access; (ii) placement of the endocardial magnet-tipped guidewire in the apex of the LAA with balloon identification of the LAA os; (iii) connection of the epicardial and endocardial magnet-tipped guidewires for stabilization of the LAA; and (iv) snare capture of the LAA with closure confirmation and release of the pre-tied suture for LAA ligation [36]. The endoluminal balloon inflated in the LAA markedly when the suture is being delivered significantly decreases the possibility of an incomplete isolation of this structure from the LA. Since the LAA is closed from outside with a single ligature, there is no permanent intracardiac foreign body left behind and no risk of device embolization or risk of infection. Contrast cardiac CT scan is routinely obtained in AF patients being considered for LARIAT to ensure that the size and orientation of the appendage is amenable to ligation. In brief, contraindications to this approach include LAA width greater than 40 mm, a superiorly oriented LAA behind the left pulmonary artery, and a history of conditions that would result in pericardial adhesions (e.g., history of pericarditis, open-heart surgery, thoracic radiation, prior epicardial ablation, etc.). 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 LAAs in the 26 dogs included in this study were completely isolated, and follow-up echocardiography demonstrated no flow between the LA and LAA [37]. This study demonstrated that LARIAT was safe, effective, and without the risk of device migration or embolization, thrombus formation, and cardiac tamponade. Bartus et al. [36] published the first and largest clinical experience using the LARIAT device in Poland in 2013. This study screened a total of 119 patients (CHADS2: 1.9), but 16 (13.4%) patients were excluded based on LAA size >40 mm (n = 8) and a superior–posterior orientation of the LAA apex, generally behind the pulmonary artery (n = 8). A total of 81 of 85 (95%) patients had complete closure right after the suture was tightened. Three patients had a ≤2-mm residual LAA leak and one had a ≤3-mm jet by TEE color Doppler evaluation. There were no complications secondary to device deployment. However, as expected, there were two pericardial access-related complications and one due to transseptal puncture. 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. Two patients developed severe acute pericarditis and one patient was found to have late pericardial effusion. There were also two unexplained sudden deaths and

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Fig. 7 – New line of mechanical transcatheter occluders.

two late strokes thought to be non-embolic. At 1 month, all the patients who had complete occlusion immediately after the procedure revealed no communication between the left atrium and the LAA. A year later, 65 patients underwent TEE examination with a 98% complete LAA closure. In general, the prior studies reported that the LARIAT device can be readily deployed with low rates of adverse events, most of which are complications attributable to obtaining epicardial access (i.e., left hepatic lobe puncture, epigastric vessels laceration, and RV perforation). Similarly, LAA tear and post-procedure pericarditis are well-known complications. Although the major benefit of the LARIAT device when compared with the other endovascular devices, particularly the WATCHMAN device, is that there is no need of anticoagulation after successful complete isolation of the LAA, our Homolka single-center experience and other authors have showed early (1 month) and late (2–4 months) partial reopenings with bidirectional flow between the LAA and the LA [38,39]. Han and colleagues [40] enrolled 68 patients who underwent LAA ligation with the LARIAT device. They 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 from the LAA after the closure of the snare demonstrated complete isolation of the appendage with no capture of LA in 90% of those individuals. These changes might be consistent with LAA ischemic necrosis. Whether or not LAA ligation might indeed play an important role in decreasing the AF burden remains to be elucidated. This device is FDA approved in the United States.

New systems for LAA occlusion 1. The LAMBRE is a self-expanding nitinol-based device comprising a hook-embedded umbrella with a cover connected to a short central waist. The cover is larger than the umbrella, approximately 4–6 mm, and filled with sewn in polyethylene terephthalate fabric. This new device has two main advantages: a small delivery system and the ability to reposition during implantation [41] (Fig. 7). 2. The AEGIS permits LAA closure by an epicardial approach and it has two parts: (i) appendage grabber and (ii) ligator. The first component (Grabber) has an articulating jaw with

mounted electrodes, allowing identification and positioning of the LAA by means of electrical signals. When positioning near the LAA, injection of contrast is achieved to outline the LAA and prove proper capture by ICE or TEE. The ligator is a preloaded hollow suture that can be opened and closed repeatedly until proper closure has been achieved. This system has been tested in animals. 3. The Transcatheter Patch (Custom Medical Devices, Athens, Greece) is a soft, frameless, bioabsorbable balloon-deliverable device delivered similarly to other LAA occluders, but the difference is that it is fixed within the LAA with surgical adhesive, which reduces the risk of LAA perforation. The supporting balloon is made of latex and the patch from polyurethane foam. It was studied in 20 patients, showing successful placement in 17 cases [42]. 4. The Coherex WaveCrest (Salt Lake City, USA, BiosenseWebster, CA, USA) LAA occlusion system is a one of the latest developments in closure devices. This device has an umbrella shape, and it 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 and allows rapid endothelization. It was initially tested in animals with satisfactory results, and the results from the WaveCrest I trial were presented last year. Acute procedural success and acute closure were obtained in 93% of patients (68/73), and complete LAA closure at 45 days in 92% of cases (67/73) of the enrolled patients (92%). Two pericardial effusions and no procedural stroke, device embolization or device associated thrombus were observed. There is now CE marked the second-generation device which is better anchored. The most prominent advantage of this device is very proximal LAA ostial implantation. WaveCrest II is the CE certificated device which is now part of Bisense Webster (Diamond Bar, USA) products.

Conclusion The 2012 focused update of the ESC Guideline for the Management of AF state that a percutaneous LAA closure device may be considered in patients with high stroke risk and contraindications for long-term anticoagulation (class IIb and

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level of evidence B) [43]. Conversely, AHA/ACC/HRS guidelines for the Management of Patients With Atrial Fibrillation from 2014 make no recommendations about these devices!!!! [44]. Percutaneous LAA exclusion techniques or occlusion devices represent without any doubt a very straightforward therapeutic option to minimize the stroke/TIA/systemic embolization risk in patients with non-valvular AF. The main indication for these devices has been contraindications for oral anticoagulation; some authors have suggested to use them as an alternative for long-term oral anticoagulation in order to avoid the risk of major and fatal hemorrhagic events, which makes them even more appealing. Furthermore, percutaneous LAA occlusion devices have proved to be cost-effective compared with warfarin [45]. Nevertheless, the European and American guidelines for the management of these patients are still not clear considering mechanical occlusion of LAA as a part of so called ‘‘local’’ anticoagulation therapy. This is in part because most of the studies have had small samples and short-term follow-up, some of them with conflicting data. The only randomized data are still with WATCHMAN device only which clearly shows us with increasing time since implantation procedure increase also the benefit from this device. This time-related benefit needs to be also considered not only as an aspect of effectiveness but also in terms of cost benefit! Occlusion of the LAA is also likely to be evaluated as a part of catheter ablation therapy to reach mechanical and electrical isolation of LAA [40]. Additionally, it has been 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, which are not treated with AC, and which have a marked impact in learning capacity and memory loss when compared with nonAF patients [46]. More importantly, most of the studies using devices have not included control groups, and a few have used warfarin as a comparison. The advent of new era of direct anticoagulation therapy (NOAC) must increase the need to run the comparative studies between occluders of LAA and NOACs. An indirect analysis presented from the PROTECT AF trial and RELY showed that the WATCHMAN would not have reached the non-inferiority endpoint if Pradaxa had been the control group. It would be interesting to analyze and compare the data from the Aristotle study given the fact that Apixaban is the only oral anticoagulant that 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 showed a significant reduction in bleeding risk and total mortality [47]. This could be answered by the prospective randomized trial PRAGUE-17 study (NCT02426944) which compared Apixaban with both CE marked occluders (WATCHMAN Flex and AMULET) [48]. This prospective head-to-head comparison among devices and the use of NOACs is needed to discover which device is best and if indeed they are as good as NOACs in this patient population.

Authors' contribution All authors significantly contributed to write this overview paper.

Conflict of interest Research grant for PROTECT AF trial (NCT00129545).

Ethical statement Authors state that the research was conducted according to ethical standards.

Funding body None.

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