Abstract 1 INTRODUCTION ORIGINAL ARTICLE

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1 Received: 5 October 2017 Revised: 2 November 2017 Accepted: 6 November 2017 DOI: /jce ORIGINAL ARTICLE Feasibility of percutaneous left atrial appendage closure using a novel LAmbre occluder in patients with atrial fibrillation: Initial results from a prospective cohort registry study Shaojie Chen MD, PhD Boris Schmidt MD, FHRS Stefano Bordignon MD Fabrizio Bologna MD Takahiko Nagase MD Nikolaos Tsianakas MD Laura Perrotta MD K. R. Julian Chun MD Cardioangiologisches Centrum Bethanien Frankfurt Am Main, Medizinische Klinik III, Markuskrankenhaus, Frankfurt Am Main, Germany Correspondence Shaojie Chen, MD, PhD and K. R. Julian Chun, MD, Cardioangiologisches Centrum Bethanien, Medizinische Klinik III, Markuskrankenhaus, Wilhelm-Epstein Straße 4, Frankfurt am Main, Germany. drsjchen@126.com; J.chun@ccb.de Disclosures: None. Abstract Background: The LAmbre TM occluder is a novel device for percutaneous left atrial appendage closure (LAAC). The presented study aimed to report the initial experience in implantation of the novel LAmbre for LAAC in patients with nonvalvular AF. Methods: We conducted a prospective, observational, cohort registry study to evaluate the feasibility of percutaneous LAAC using the LAmbre system. Results: Thirty patients (15 female, mean age 77.6 ± 8.9 years) who had high risks of stroke and contraindications for oral anticoagulation were prospectively enrolled in this registry study. The mean CHA2DS2-VaSc was 3.9 ± 1.5, and the mean HAS-BLED score was 4.1 ± 1.0. Twenty (66.7%) patients had chicken-wing LAA morphology. The implant success rate was 100%. The mean fluoroscopic time and procedure time were 3.5 ± 1.9 and 29.0 ± 10.1 minutes, respectively. No significant procedure-related complications were observed during in-hospital and acute clinical follow-up. Conclusion: In this preliminary study, the LAmbre occluder showed an excellent implant success rate, favorable implant property, and very low incidence of complications. Larger sample, randomized studies are further warranted. KEYWORDS atrial fibrillation, cardiac catheter, LAA occluder, LAmbre, left atrial appendage, left atrial appendage occlusion, stroke 1 INTRODUCTION Atrial fibrillation (AF) is the most common cardiac arrhythmia. Around 20 30% of strokes are attributable to AF, and more may be associated with undiagnosed subclinical AF. 1 Oral anticoagulation therapy using vitamin K antagonists or novel oral anticoagulants has been shown to significantly reduce the rate of stroke in patients with AF. 1 Despite the efficacy of the pharmacotherapy, complex drug interactions, poor patients compliance, risk of major bleeding particularly in patients with impaired liver, or renal functions limit their clinical administration in selected patient groups. 2 Thus, a nonpharmacological approach to prevention of stroke in patients with AF seems rational. Previous research showed that up to 90% of left atrial thrombi were located in the left atrial appendage (LAA) among patients with nonvalvular AF. 3 Prior large randomized trials have shown promising results that percutaneous transcatheter occlusion of the atrial appendage by LAA occluder device was noninferior to conventional warfarin therapy in patients with nonvalvular AF in terms of efficacy. 4,5 However, a higher rate of adverse safety events in the LAA device group should be noted. Although the implant success rate is becoming increasingly higher and complication events are decreased in recent years, there are still anatomically and technically complicated cases where novel devices J Cardiovasc Electrophysiol. 2017;1 7. wileyonlinelibrary.com/journal/jce c 2017 Wiley Periodicals, Inc. 1

2 2 CHEN ET AL. FIGURE 1 LAmbre device design and angiography guided implantation [Color figure can be viewed at wileyonlinelibrary.com] with a better design could facilitate the procedure and thus may potentially improve the clinical outcome. The LAmbre LAA occluder (Lifetech Scientific [Shenzhen] Co., Ltd., Shenzhen, China) has been recently recognized with the Conformité Européenne (CE) mark. Its novel designs included: (1) slim delivery system, (2) double stabilization system design, and (3) flexible waist and size adaptive cover. In this study, we report the initial periprocedural data of a prospective cohort patients indicated to LAA closure (LAAC) using the novel LAmbre LAA occluder device. 2 METHOD 2.1 Patients Between October 2016 and August 2017, consecutive patients with nonvalvular AF (without significant mitral stenosis or artificial heart valves or valve repair) who were scheduled for percutaneous LAAC with the LAmbre device were prospectively included in the study at the Cardioangiologische Centrum Bethanien (CCB), Frankfurt, Germany. All patients were enrolled in the institutional registry database (Number: LAAO-LAmbre-CCB). The inclusion criteria were: 18 years and older, both sexes, paroxysmal, persistent or permanent nonvalvular AF, high risk for stroke (CHADS2 score 2), contraindication to long-term oral anticoagulation therapy, e.g., patients with bleeding events after anticoagulation therapy, or intolerance or refusal to take warfarin; we also included patients who demonstrated isolated noncontractile LAA after multiple AF ablation procedures. The exclusion criteria were: (1) patients who had rheumatic, significant degenerative, or congenital valvular heart diseases, artificial heart valve replacement operation; (2) acute myocardial infarction or unstable angina, decompensated heart failure (New York Heart Association functional class III IV), or heart transplantation; (3) stroke or

3 CHEN ET AL. 3 FIGURE 2 LAmbre TEE guided device implantation [Color figure can be viewed at wileyonlinelibrary.com] transient ischemic attack (TIA) within 30 days; (4) patients with atrial septal occluder; (5) clinical conditions not allowing transesophageal echocardiography (TEE) and sedation; (5) poor peripheral vessel access not allowing device delivery; (6) echocardiography exclusion criteria: left ventricular ejection fraction (LVEF) 30%; presence of LAA thrombus; significant mitral valve stenosis (the area of mitral valve 2cm 2 ); significant and unexplained pericardial effusion ( 4cm 2 ). All clinical, periprocedural, echocardiographic, and outcome variables were prospectively collected. The study conduction complied with the Declaration of Helsinki and was approved by the institution. Informed consent was obtained from the included patients before the procedure. 2.2 The LAmbre device The LAmbre (Lifetech Scientific [Shenzhen] Co., Ltd.) is a CE recognized LAA closure device. As shown in Figure 1, it is self-expanded and consists of: (1) 8- to 10-Fr delivery sheath (delivery system), (2) hook-embedded umbrella, and (3) size selective cover. The umbrella has eight small distal hooks engaging into LAA walls and eight U- shaped ends trapping in LAA trabeculations (double stabilization system design). The umbrella and the cover are connected with a short central waist that acts as an articulating, compliant connection between both, allowing the cover to self-orient to the atrium wall. The LAmbre LAA occluder is constructed from a nitinol mesh and polyester membranes. The proximal cover is filled with sewn-in polyethylene terephthalate fabric. There are different cover sizes which could be selected for the same umbrella size. 6 General size information of the LAmbre device including Umbrella-Cover-Delivery system is presented in Supplementary File 1 (referred to: lifetechmed). 2.3 Device implantation The method for the device implantation was published previously. 7,8 In brief, all procedures were performed by experienced operators. Patients were under deep sedation by using boluses of midazolam and a continuous infusion of propofol (1%). A TEE was used to rule out intracardiac and LAA thrombus. After a single transseptal puncture, the transseptal sheath was exchanged with LAmbre delivery sheath and it was continuously flushed with heparinized saline (20 ml/h). (After selective LAA angiogram, the LAA was directly cannulated using a semireleased umbrella creating a ball-shaped figure or the 10F delivery sheath was exchanged over the wire in the LAA orifice.) Activated clotting time was adjusted to > 250 seconds during the procedure. The size of the device was chosen based on angiographic and TEE measurements. The degree of device oversizing was based on the anatomy of the LAA, manufacturer's recommendation, and the experience of the operator. Successful device position was defined as no or minimal contrast leak ( 3 mm) into LAA by angiography as well as TEE. Figures 1 and 2 showed the angiography- and TEE-guided implantation process of the device. Major complications were defined as periprocedural death, cardiac temponade, stroke, embolism, pericardial effusion, and major bleeding. Minor complications were defined as minor bleeding or vascular complications without the need for further intervention or transfusion or prolonged hospitalization.

4 4 CHEN ET AL. TABLE 1 Baseline characteristics of the included patients TABLE 2 Periprocedural data Patients' characteristics Sample size, n 30 Female, n (%) 15 (50.0%) Age (y) 77.6 ± 8.9 Height (cm) ± 9.9 Weight (kg) 76.9 ± 14.9 BMI (kg/m 2 ) 26.5 ± 3.9 Paroxysmal AF, n (%) 14 (46.7%) Nonparoxysmal AF, n (%) 16 (53.3%) Heart failure, n (%) 4 (13.3%) Hypertension, n (%) 22 (73.3%) Age > 75, n (%) 20 (66.7%) Diabetes, n (%) 9 (30%) Previous stroke/tia, n (%) 4 (13.3%) Vascular diseases, n (%) 5 (16.7%) Coronary artery disease, n (%) 15 (50%) Liver/renal dysfunction, n (%) 15 (50) Labile INR, n (%) 2 (6.7%) Drugs predisposing to bleed 30 (100%) Bleeding events, n (%) 21 (70%) *GI bleeding, n (%) 12 (57.1%) *Non-GI bleeding, n (%) 9 (42.9%) CHADS-VASc score 3.9 ± 1.5 HAS-BLED score 4.1 ± 1.0 Anticoagulation pre-procedure 30 (100%) Apixaban, n (%) 11 (36.7%) Rivaroxaban, n (%) 6 (20%) Warfarin, n (%) 13 (43.3%) BMI = body mass index; GI = gastrointestinal. *Drugs predisposing to bleed: anticoagulant. For the first 6 months after procedure, patients are scheduled to be treated with dual antiplatelet inhibition using 300 mg aspirin (ASA) and 75 mg clopidogrel once daily, followed by the ASA therapy. Follow-up was performed by conventional clinical visits. Six weeks to 6 months after the procedure patients underwent follow-up TEE to evaluate the LAA stability and sealing and to rule out the presence of pericardial effusion or embolization. 2.4 Statistical analysis The results are described as mean ± standard deviation (SD) for normally distributed data or median and interquartile ranges were used when appropriate. Statistical analyses were performed using the SPSS software version 17.0 (Chicago, IL, USA). 3 RESULTS As shown in Table 1, during the study period, 30 patients (15 female, mean age 77.6 ± 8.9 years) underwent percutaneous LAA occlusion Patients undergoing implantation, n 30 Presenting sinus rhythm during procedure, n (%) 22 (73.3%) LAA size (mm) 21.2 ± 4.4 Device size (mm) 25.9 ± 5.4 Oversize (mm) 4.7 ± 1.8 Chicken-wing LAA, n (%) 20 (66.7%) Reposition, mean ± SD 0.7 ± 1.1 Reposition = 0, n (%) 16 (53.3%) Reposition > 2, n (%) 1 (3.3%) Success, n (%) 30 (100%) Fluoroscopy time (min) 3.5 ± 1.9 Procedure time (min) 29.0 ± 10.1 Complications Periprocedural death, n (%) 0 Stroke, n (%) 0 Thrombosis, n (%) 0 Air embolism, n (%) 0 Cardiac temponade, n (%) 0 Pericardial effusion, n (%) 0 Major bleeding of access site, n (%) 0 Postprocedure dual antiplatelet, n (%) 25 (83.3%) Dual antiplatelet at discharge, n (%) 29 (96.7%) Remain on anticoagulation, n (%) 1 (3.3%) Follow-up TEE after 6 weeks to 6 months, n (%) 25 (83.3%) Device dislodgment, n (%) 0 Thrombosis in LA, n (%) 0 Residual flow > 5 mm, n (%) 0 Pericardial effusion, n (%) 0 using the LAmbre occluder. All patients had nonvalvular AF (14 paroxysmal and 16 nonparoxysmal AF). The mean CHA2DS2-VaSc score was 3.9± 1.5. Fifteen (50%) patients had coronary heart disease, 15 (50%) patients had impaired liver or renal function, and 21 (70%) patients had clinical bleeding events, including 12 (57.1%) patients who had gastrointestinal (GI) bleeding. The mean HAS-BLED score was 4.1 ± 1.0. During procedure, no patient required general anesthesia. As shown in Table 2, the LAmbre device was successfully implanted in all 30 (100%) patients. Twenty patients (66.7%) had chicken-wing LAA morphology including 1 patient who had twice failed procedures previously using Watchman and Amulet devices implantation because of very challenging LAA morphology. Figure 3 shows the implantation of LAmbre device in a challenging LAA anatomy case. Overall, as shown in Table 2, the mean LAA size was 21.2 ± 4.4 mm, the mean device size was 25.9 ± 5.4 mm. The mean oversize was 4.7 ± 1.8 mm, the median LAA device oversizing of LAA was 5 mm (range 3 6 mm). The mean fluoroscopic time and procedure time were 3.5 ± 1.9 and 29.0 ± 10.1 minutes. Sixteen patients (53.3%) underwent direct device implantation without additional device reposition. No significant procedure-related complications were observed during inhospital observation.

5 CHEN ET AL. 5 FIGURE 3 LAmbre in a challenging anatomy Mean TEE follow-up was 52 ± 16 day after the procedure. Twentyfive of the 30 patients (83.3%) underwent TEE follow-up after procedure. Of them, 16 (64%) patients had no leak jet, 5 (20%) patients had leak jet 2 mm, 3 (12%) patients had leak jet 3 mm, and 1 (4%) patient had leak jet 4 mm. All patients fulfilled adequate sealing and good stability of the device by TEE follow-up. Twenty-five (83.3%) out of 30 patients completed 6 weeks to 6 months TEE follow-up; no complications (device dislodgement, LA thrombosis, pericardia effusion) were found. The antiplatelet and anticoagulation therapy after LAAO procedure is summarized in Table 2. Postprocedure dual-antiplatelet therapy was administered right after the implant in 25 (83.3%) patients, and another 4 patients received their dual-antiplatelet therapy at discharge (1 2 days later) considering the bleeding risk right after the procedure and TEE; another one patient had LAA isolation before LAAO and thus remained on anticoagulation therapy. 4 DISCUSSION These initial results show the feasibility and safety property of the LAmbre occluder for catheter-based LAA occlusion among patients with AF who had high risk of stroke and contraindications for oral anticoagulants. In review of the existing data, several devices have been proposed to achieve durable LAA closure using a percutaneous catheter approach, and the Watchman device (Boston Scientific) is the most investigated LAA occluder. The Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients with Atrial Fibrillation (PROTECT-AF) trial was the first large randomized trial to test the Watchman device. 4 Seven hundred and seven patients with nonvalvular AF were enrolled and randomized to long-term warfarin or device therapy. During a mean follow-up of 18 months, the primary efficacy (composite endpoint of stroke,

6 6 CHEN ET AL. systemic embolism, and cardiovascular death) event rate was not significantly different in both groups. The PROTECT-AF study demonstrated the noninferiority of the Watchman device as compared with standard therapy with warfarin. Furthermore, the long-term follow-up data of the PROTECT-AF trial published in 2014 demonstrated that during a mean follow-up of 3.8 years the device group was associated with less combined endpoint of stroke, systemic embolism, and cardiovascular and all-cause death compared with warfarin. These favorable outcomes of the device were driven largely by lower rates of hemorrhagic stroke as well as hemorrhagic stroke-related deaths. 5 Despite the promising results of the LAAC device therapy, its complication rate should be noted. In the PROTECT-AF study, the device implantation success rate was 91%, and the device group was accompanied with a higher risk of procedure complications such as pericardial effusion and procedural stroke. Primary safety adverse events occurred more frequently in the device group than in the control group (7.4 vs. 4.4 per 100 patient-years; RR 1.69). The complications associated with LAAC device implantation were typically observed early in the periprocedural period. 4 In the Prospective Randomized Evaluation of the Watchman LAA Closure Device in Patients with Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL) study, the device implantation success rate was increased to 95%, and safety events (composited of acute occurrence of death, ischemic stroke, systemic embolism, and procedure-related complications requiring intervention) were decreased to 2.2% of the patients. 9 However, there are still anatomically and technically complicated cases where novel devices with a better design could facilitate the procedure and thus may improve the clinical outcomes. Although the presented study is an initial clinical experience, the preliminary data show excellent results in terms of implantation success and safety properties. By the definition (minimal leak 3 mm), the implantation success was achieved in all enrolled patients including 66.7% patients with complicated chicken-wing LAA anatomy. More than half of the patients were successfully implanted the device without reposition. The average fluoroscopic time was 3.5 minutes and most procedures were completed within 30 minutes. There were no periprocedural complications with respect to adverse events such as death, stroke, embolism, myocardial infarction, cardiac temponade, pericardial effusion, and access site complications. There were no complications found with echocardiography on discharge and acute clinical observation. Twenty-five out of 30 patients completed TEE follow-up; no complications (device dislodgement, thrombosis, pericardial effusion) were observed. These results could be explained by the increasing experience of the operators in LAA closure. Furthermore, we have to acknowledge the favorable design of the LAmbre device. This new device is highly adaptable to different LAA morphologies, and it can be quite useful in difficult anatomies (as shown in Figure 3). The combination of distal hooks and the U-shaped ends (double stabilization system), the option of different cover sizes for the same umbrella size, and the central flexible waist design could help to achieve complete sealing and good device stabilization particularly in complex cases. The LAmbre designed with a smaller (8- to 10-Fr) delivery sheath (compared with Fr for Watchman) is also a distinguishing feature of the device, and this may contribute to a reduced risk of vessel access complications. The major limitation of this study is the single-center, observational nature and the sample size of the study was small. However, as a feasibility and safety assessment study for a novel LAAC device, this is by far to our knowledge the largest cohort reporting the periprocedural and short-term clinical results of the LAmbre device. The data showed excellent results of the device implantation, and the fact that all the procedures were performed by experienced operators in a high volume heart center should be taken into account. The presented study only focused on the periprocedure and acute outcomes after the device implantation, although, based on our previous study, the risk of occurrence procedure-related safety events in long-term follow-up was quite low. 6,7 Nonetheless, larger sample size, multicenter, comparative, randomized studies with long-term follow-up are warranted. 5 CONCLUSION This prospective, observational, cohort study presents excellent periprocedural and short-term clinical outcome data on catheterbased LAAC using the novel LAmbre LAA occluder for stroke prevention in patients with nonvalvular AF who had contraindications of oral anticoagulation therapy. Further randomized studies with long-term follow-up are warranted. ACKNOWLEDGMENT We thank all the participants in this study. We thank all the CCB (Cardioangiologisches Centrum Bethanien Frankfurt) Team members for their clinical and scientific contribution. We appreciate the technical support from Lifetech Scientific. Dr. Shaojie Chen receives the Fellowship Awards from European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC). ORCID Shaojie Chen MD, PhD REFERENCES 1. Kirchhof P, Benussi S, Kotecha D, et al ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37: Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15: Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg. 1996;61: Holmes DR, Reddy VY, Turi ZG, et al. PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy

7 CHEN ET AL. 7 for prevention of stroke in patients with atrial fibrillation: A randomised non-inferiority trial. Lancet. 2009;374: Reddy VY, Sievert H, Halperin J, et al. PROTECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: A randomized clinical trial. JAMA. 2014;312: Lam YY, Yan BP, Doshi SK, et al. Preclinical evaluation of a new left atrial appendage occluder (Lifetech LAmbre TM device) in a canine model. Int J Cardiol. 2013;168: Chun KR, Bordignon S, Urban V, et al. Left atrial appendage closure followed by 6 weeks of antithrombotic therapy: A prospective single-center experience. Heart Rhythm. 2013;10: Schmidt B, Bordignon S, Fuernkranz A, Perrotta L, Scherer D, Chun KR. Decennial analysis of interventional left atrial appendage closure. J Cardiovasc Electrophysiol. 2015;26: Holmes DR, Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: The PREVAIL trial. J Am Coll Cardiol. 2014;64:1 12. SUPPORTING INFORMATION Additional Supporting Information may be found online in the supporting information tab for this article. How to cite this article: Chen S, Schmidt B, Bordignon S, et al. Feasibility of percutaneous left atrial appendage closure using a novel LAmbre occluder in patients with atrial fibrillation: Initial results from a prospective cohort registry study. J Cardiovasc Electrophysiol. 2017;00:1 7.