JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 21, 2017 ª 2017 PUBLISHED BY ELSEVIER ON BEHALF OF THE

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1 ª 2017 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN /$ STRUCTURAL: ATRIAL INTERVENTION FOCUS Percutaneous Left Atrial Appendage Closure With the LAmbre Device for Stroke Prevention in Atrial Fibrillation A Prospective, Multicenter Clinical Study He Huang, MD, a,b,c Yu Liu, MD, a,b,c Yawei Xu, MD, d Zulu Wang, MD, e Yigang Li, MD, f Kejiang Cao, MD, g Shu Zhang, MD, h Yanzong Yang, MD, i Xinchun Yang, MD, j Dejia Huang, MD, k Bo Yu, MD, l Xi Su, MD, m Liqun Wu, MD, n Congxin Huang, MD a,b,c ABSTRACT OBJECTIVES The authors sought to assess the clinical outcomes of left atrial appendage (LAA) closure with the LAmbre closure system in patients with nonvalvular atrial fibrillation (NVAF). BACKGROUND Over 90% of thrombi are located in the LAA in NVAF patients. METHODS A prospective, multicenter study was conducted in 153 NVAF patients with CHADS 2 score $1. RESULTS The LAA was successfully occluded in 152 patients. Serious complications occurred in 5 patients. During the 12-month follow-up, ischemic stroke occurred in 2 patients, 1 patient had incomplete LAA sealing, and there was no device embolization. CONCLUSIONS LAA closure with the LAmbre device shows encouraging results for stroke prevention. (J Am Coll Cardiol Intv 2017;10: ) 2017 Published by Elsevier on behalf of the American College of Cardiology Foundation. Atrial fibrillation (AF) is the most common sustained arrhythmia observed in clinical practice and is a major cause of morbidity and mortality due to cardioembolic stroke, which is responsible for 15% to 20% of all ischemic strokes (1). The incidence of ischemic stroke among patients with nonvalvular AF (NVAF) is approximately 5% per year, a 5.6-fold increase when compared with an From the a Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People s Republic of China; b Cardiovascular Research Institute of Wuhan University, Wuhan, People s Republic of China; c Hubei Key Laboratory of Cardiology, Wuhan, People s Republic of China; d Department of Cardiology, Shanghai Tenth People s Hospital, Tongji University School of Medicine, Shanghai, People s Republic of China; e Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, People s Republic of China; f Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People s Republic of China; g Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People s Republic of China; h State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People s Republic of China; i Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, People s Republic of China; j Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, People s Republic of China; k Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People s Republic of China; l Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People s Republic of China; m Department of Cardiology, Wuhan Asian Heart Hospital, Wuhan, People s Republic of China; and the n Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People s Republic of China. This work was supported by grants from the National Natural Science Foundation of China (No and No ), and the Science and Technology Support Program of Hubei Province (No. 2013BCB013). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The first two authors contributed equally to this work. Manuscript received March 14, 2017; revised manuscript received June 8, 2017, accepted June 29, 2017.

2 NOVEMBER 13, 2017: age-matched population in sinus rhythm (2). There is a great deal of published reports on stroke prevention demonstrating that oral anticoagulation with warfarin is the current most common and effective therapy topreventstrokeassociatedwithaf(3 5). Unfortunately, this treatment is generally underused due to its several limitations, including the narrow therapeutic window, the drug and food interactions, the need for repeated monitoring, and the poor patient tolerance. SEE PAGE 2195 Autopsy and echocardiography studies have shown that more than 90% of atrial thrombi in patients with NVAF locate in the left atrial appendage (LAA) (6,7). Therefore, percutaneous LAA closure has been developed as an alternative strategy to warfarin for stroke prophylaxis in AF patients. Many studies demonstrated the effectiveness of percutaneous LAA closure in stroke prevention in patients with AF (8 16). The PROTECT-AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) study showed that percutaneous LAA closure with WATCHMAN device (Boston Scientific, Natick, Massachusetts) was superior to warfarin in patients with NVAF for the prevention of stroke, systemic embolization, cardiovascular death, and all-cause mortality after 3.8 years of follow-up (13). In addition, another LAA-occluding device, the Amplatzer Cardiac Plug (St. Jude Medical, Saint Paul, Minnesota), has shown favorable efficacy for the prevention of AF-related thromboembolism (16). LAmbre (Lifetech Scientific, Shenzhen, China) is a new, self-expanding LAA occluder, specifically designed for LAA closure. Preliminary study suggested the percutaneous LAA closure with LAmbre device is feasible with a high success rate in canines (17). However, there are no data available on the clinical safety and efficacy of this device. This prospective, multicenter clinical study reported the initial experience of LAmbre implantation for NVAF patients in China. METHODS STUDY POPULATION. This was an open-label, nonrandomized pilot trial designed to assess the safety, feasibility, and efficacy of deploying the LAmbre LAA occlusion device. One hundred fifty-three consecutive patients who underwent percutaneouslaaclosurewiththelambredeviceat 12 hospitals in China between March 2014 and January 2015 were prospectively studied. All patients had a diagnosis of NVAF, over 18 years of age, scored at least 1 point according to the congestive heart failure, hypertension, age $75 years, diabetes mellitus, and prior stroke or transient ABBREVIATIONS AND ACRONYMS ischemic attack (CHADS 2 ) score, and were not suitable for long-term anticoagulation AF = atrial fibrillation with warfarin (presence of a ce- CHADS 2 = congestive heart failure, hypertension, rebrovascular or gastrointestinal bleeding age 75 years, diabetes history, increased bleeding tendency, poor compliance, or warfarin allergy). All patients received transthoracic and transesophageal mellitus, and prior stroke or transient ischemic attack CHA2DS2-VASc = congestive heart failure, hypertension, age echocardiography (TEE) before the LAmbre implantation procedure. Patients found to have thrombus formation in the left atrium, a 75 years (doubled), diabetes mellitus prior stroke or transient ischemic attack (doubled). vascular disease, left ventricular ejection fraction <30%, or a LAA orifice diameter #12 mm were excluded age 65 to 74 years, and sex category (female) from the study. Other exclusion criteria LAA = left atrial appendage included symptomatic carotid disease, acute NVAF = nonvalvular atrial myocardial infarction or unstable angina, fibrillation New York Heart Association functional class IV, prior stroke or transient ischemic attack TEE = transesophageal echocardiography within 30 days, acute infective endocarditis, hemorrhagic disease, pregnancy, life expectancy <2 years, presence of a prosthetic valve, or presence of an atrial septal repair or closure history. Informed consent was obtained from all studied patients, and the study was approved by the institutional review board. DEVICE IMPLANTATION. The LAmbre LAA closure system comprises an implant and a delivery system, and is designed for device implantation via the transseptal route into the LAA. The LAmbre implant is a self-expanding, nitinol-based device consisting of an umbrella and a cover connected by a short central waist. The distal umbrella comprises 8 claws with individual stabilizing hooks with a polyethylene terephthalate membrane on the distal face. The proximal cover is filled with sewn-in polyethylene terephthalate fabric (Figure 1).TheLAmbreimplant is available in 15 diameter sizes referring to the umbrella, that is, 16 to 36 mm. The delivery system consists of a double-curve configuration delivery sheath (8-F to 10-F in size) and a delivery cable, allowing for contrast injection and device positioning. The implantation was performed under general anesthesia by the femoral vein approach under fluoroscopic, angiographic, and continuous TEE guidance. After transseptal puncture, intravenous heparin was immediately administered to patients to achieve activated clotting time of at least 250 s. The delivery sheath was then placed in the proximal part of LAA. The diameters of the orifice and length of LAA are measured from LAA angiography in right anterior oblique cranial projection. The size of the implant would be 4 to 8 mm larger than the measured LAA orifice, based on the clinical judgment of the

3 2190 JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 21, 2017 NOVEMBER 13, 2017: F I G U R E 1 The LAmbre Implant surrounding structures (Figure 2). A gentle tug test is performed to ensure device stability. If the implant location or stability is deemed unsatisfactory, the implant would be completely retrieved and redeployed unless proper device position is achieved. FOLLOW-UP. All patients were prescribed aspirin 100 mg per day indefinitely, and clopidogrel 75 mg per day for 3 months after the procedure. TTE was performed at day 1 post-implantation to exclude device embolization and pericardial effusion. Clinical follow-up was arranged at 1, 3, 6, and 12 months after LAmbre device implantation to assess the clinical outcomes. TEE was scheduled at 3 and 12 months to assess device position, peridevice LAA flow, and device-related thrombus. MAJOR ADVERSE EVENTS. Major adverse events were defined as death, stroke, systemic embolism, The LAmbre is a self-expanding nitinol-based device consisting device embolization, pericardial bleeding requiring of a fabric-enriched cover and an umbrella connected with a an intervention (cardiac tamponade), or other major short central waist. bleeding requiring invasive treatment or blood transfusion. physician. The distal umbrella was released into the LAA by stepwise pushing out the device from the delivery sheath. Subsequently, the sheath was withdrawn to expose the proximal cover, allowing it to expand in the left atrium and seal the LAA ostium. STATISTICAL ANALYSIS. The occurrence of events is expressed as absolute numbers and percentage. Continuous variables are summarized by mean SD, and minimum and maximum values. RESULTS Once the implant was placed in the LAA, angiography and echocardiography were performed to check de- BASELINE CHARACTERISTICS. There were 153 patients vice positioning, LAA sealing and impingement on treated at 12 centers in China who met all inclusion F I G U R E 2 Well-Positioned LAmbre Device in the LAA (Left upper panel) LAA angiography before closure. (Right upper panel) LAA angiography after closure. (Left lower panel) TEE examination before LAA closure. (Middle and right lower panels) TEE examination after LAA closure. Angiographic and TEE examinations suggest that the LAmbre device completely occluded the LAA, and there is no significant peridevice leak. The arrows indicate the location of LAA ostium. LAA ¼ left atrial appendage; TEE ¼ transesophageal echocardiography.

4 NOVEMBER 13, 2017: and exclusion criteria and were enrolled in the study. Mean patient age was 69 years (range 42 to 86 years), and56%weremale.ahistoryofparoxysmalafwas noted in 25 of 153 (16%) patients, persistent AF in 85 of 153 (56%) patients, and permanent AF in 43 of 152 (28%) patients. The most common risk factor for stroke was hypertension (73%), and 65% of patients previously had an ischemic stroke/transient ischemic attack. The average CHADS 2 score was 2.5, representing a 6.4% annual risk for stroke (Figure 3) (18,19). The mean congestive heart failure, hypertension, age$75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled)-. vascular disease, age 65 to 74 years, and sex category (female) (CHA 2 DS 2 -VASc)scorewas4.0.Onthebasis of the CHA 2 DS 2 -VASc score, the expected annual risk for thromboembolism was 5.2% (20). Table 1 showed the baseline characteristics of the study participants. IMPLANTATION PROCEDURE. The LAA was successfully occluded by the LAmbre device in 152 patients (99.4%). In 87% of the successful cases, device implantation was managed with the first device selected, and in 9% or 3%, a second or third device, respectively, was needed. The implant was completely retrieved and redeployed in 43% patients. The average angiographic maximal LAA diameter was 24 mm, and the mean LAA landing zone diameter was 23 mm (Table 2). The distribution of successfully deployed devices is shown in Figure 4. The mean procedure duration was 66 min, and the average contrast volume was 84 ml. COMPLICATIONS. There were serious complications in 5 (3.3%) of the patients (Table 3). Clinically serious pericardial effusion (defined as the need for pericardiocentesis or surgical intervention) was documented in 3 patients. Two of these patients were treated with pericardiocentesis, and 1 underwent surgical LAA excision. One patient experienced an ischemic stroke probably because of embolism of cardiac thrombus. Her condition improved with conservative treatment. A major bleeding event was observed in 1 patient. She was transfused with 2 U of packed red blood cells. No acute device embolization was observed before discharge. Minor complications were hematoma at puncture site of femoral vein in 2, femoral arteriovenous fistula in 1, and pseudoaneurysm in 1 of the cases. There were no procedurerelated deaths. FOLLOW-UP RESULTS. During the 12-month clinical follow-up period, ischemic stroke occurred in 2 patients. Both patients had a prior history of stroke. FIGURE 3 Expected Annual Rate of StrokeBasedonCHADS 2 Score Gage et al (yellow squares) (19); Gage et al (red diamonds) (18). The average CHADS 2 score of the study population was 2.5, representing a 6.4% annual risk for stroke. CHADS2 ¼ congestive heart failure, hypertension, age $75 years, diabetes mellitus, and prior stroke or transient ischemic attack. TABLE 1 Baseline Patient Characteristics (N ¼ 153) Clinical Age, yrs Men 87 (56.2) Congestive heart failure 15 (9.8) Hypertension 111 (72.6) Age $65 yrs 108 (70.6) Age $75 yrs 46 (30.1) Diabetes mellitus 19 (12.4) Previous history of TIA/stroke 99 (64.7) Coronary artery disease 38 (24.8) Atrial fibrillation pattern Paroxysmal AF 25 (16.3) Persistent AF 85 (55.6) Permanent AF 43 (28.1) CHADS 2 score (20.9) 2 43 (28.1) 3 48 (31.4) 4 24 (15.7) 5 5 (3.3) 6 1 (0.7) CHA 2 DS 2 -VASc score (6.5) 2 20 (13.1) 3 32 (20.9) 4 38 (24.8) 5 25 (16.3) 6 15 (9.8) 7 9 (5.9) 8 4 (2.6) Values are mean SD or n (%). AF ¼ atrial fibrillation; TIA ¼ transient ischemic attack.

5 2192 JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 21, 2017 NOVEMBER 13, 2017: TABLE 2 Procedural Details (N ¼ 152) LAA length, mm LAA orifice diameter, mm LAA landing zone diameter, mm Success at first attempt 87 (57.2) Number of LAA occluder retrieve and re-deployment Success at first device selected 133 (87.5) Success at second device selected 14 (9.2) Success at third device selected 5 (3.3) LAA leak 23 (15.3) Residual flow <1 mm 2 (1.3) Residual flow 1 3 mm 20 (13.3) Residual flow >3 mm 1 (0.7) Procedure time (min) Values are mean SD, %, or n (%). LAA ¼ left atrial appendage. Hemorrhagic stroke occurred in 1 patient. TEE revealed no pulmonary venous obstruction or delayed device embolization. Thrombus formation on the atrial surface of the device was documented in 2 patients during surveillance TEEs at a follow-up of 3 months. Both patients had no neurological symptoms and were conservatively managed, and 1 patient was noncompliant with anticoagulation treatment starting early after device implantation. One patient suddenly died of unknown cause at day 7 postdischarge. The death was deemed unrelated to the LAA closure device. One hundred twenty-one patients came for 12-month TEE follow-up. Ninetynine percent (120 of 121) of the LAA were completely sealed with absence of flow or with minimal flow around the device (jet of <3 mm).table 4 summarizes the clinical outcomes during follow-up. FIGURE 4 The Size Distribution of Successfully Implanted Occluders The size refers to the diameter of the umbrella and the cover, respectively. A total of 15 sizes were used, including 10 regular sizes (cover 4 to 6 mm larger) and 5 specific sizes (cover 12 to 14 mm larger). TABLE 3 Procedure-Related Complications (N ¼ 153) Major complications 5 (3.3) Cardiac effusion requiring intervention 3 (2.0) Stroke 1 (0.7) Major bleeding 1 (0.7) Minor complications 4 (2.6) Femoral hematoma 2 (1.3) Arteriovenous fistula 1 (0.7) Pseudoaneurysm 1 (0.7) Values are n (%). DISCUSSION This is the first study to our knowledge to report the clinical outcomes among patients with NVAF having the new LAmbre LAA occluder device implanted. We have shown that LAA closure with the LAmbre device is feasible and has a high short-term procedural success rate. Moreover, follow-up results suggest that the LAmbre device could be associated with encouraging clinical outcomes in the prevention of stroke. The structure of the LAmbre device is different compared with the WATCHMAN and the Amplatzer Cardiac Plug devices. The WATCHMAN device is a relatively long, mesh-like umbrella device and therefore not suitable for patients with shallow LAA or multiple-lobe LAA. However, with the continuous improvements in implant techniques, the implant procedure success reached 98.5% in the EWOLUTION (Registry on Watchman Outcomes in Real-Life Utilization) registry (21). The Amplatzer Cardiac Plug device consists of a distal lobe and proximal disk connected by an articulating waist. The multicenter experience with the Amplatzer Cardiac Plug reported a favorable procedural success (97.3%) (16). The LAmbre device is a short device to be placed within 2 cm of the LAA ostium and is delivered by a relatively small sheath (8-F to 10-F). The implant can be intentionally recaptured, completely retrieved, and then redeployed. More importantly, the LAmbre device has more sizes and is more suitable for special morphological LAA. In this study, we achieved 99.4% short-term procedural success, and there was no problem encountered during recapture and repositioning. Significant pericardial effusion (defined as the need for percutaneous or surgical interventions) is a severe complication that plagued the LAA closure procedure. In the PROTECT AF trial, this complication was related to the experience of the operator because it occurred in 7.1% of the first 3 patients at each site and in 4.4% of subsequent patients (22). The initial

6 NOVEMBER 13, 2017: TABLE 4 Clinical Outcomes During Follow-Up Adverse events (n ¼ 152) Death 1 (0.7) Ischemic stroke 2 (1.3) Hemorrhagic stroke 1 (0.7) Thrombus formation on the device 2 (1.3) LAA sealing by TEE examination (n ¼ 121) No residual flow 102 (84.3) Residual flow <1 mm 0 Residual flow 1 3 mm 18 (14.9) Residual flow >3 mm 1 (0.8) Values are n (%). LAA ¼ left atrial appendage; TEE ¼ transesophageal echocardiography. European Amplatzer Cardiac Plug series (N ¼ 143) reported 3.6% of serious pericardial effusion after Amplatzer Cardiac Plug implants (23). A major difference between the LAmbre and the WATCHMAN devices or the Amplatzer Cardiac Plug device is the deployment sequence. During deployment of the LAmbre device, the delivery catheter is positioned at the very proximal portion of the LAA, and the umbrella is released to the landing zone by gently pushing forward en bloc. LAA perforation is less likely to occur by avoiding both deep location of the delivery sheath and device manipulation at the distal LAA. In our series, serious pericardial effusion occurred only in 3 patients (2.0%). Device embolization is a rare, but tough, complication of the LAA closure procedure. Although our small series reported that no device embolization occurred, device embolization occurred in 3 patients (0.6%) in the PROTECT AF trial: 1 was noted during the procedure and 2 were discovered by TEE on day 45 (9). The initial European experience of LAA closure with the Amplatzer Cardiac Plug also reported 2 cases of device embolization (1.5%) (23). Three possible mechanisms may contribute to improve the stability of the LAmbre device. First, claws and hooks of the distal umbrella facilitate the anchoring to the LAA wall. Second, an oversized umbrella provides a stenting effect against the LAA wall. Last, the pectinate muscles located at the mid-to-distal portion of LAA may trap the individual claws of the umbrella. The expected annual risk of stroke based on the CHADS 2 score and CHA 2 DS 2 -VASc score in this study cohort was calculated to be 6.4% and 5.2%, respectively (18 20). However, the observed ischemic stroke rate was only 1.3%, representing significantly fewer events than expected. Although this result does not provide sufficient power to demonstrate equivalence or superiority to anticoagulation, the results appear generally comparable to those reported for the PLAATO system, the WATCHMAN system, and the Amplatzer Cardiac Plug system, which have also been demonstrated to have a lower event rate of stroke compared with the expected stroke rate predicted by the CHADS 2 score or CHA 2 DS 2 -VASc score (8,10,16). Two patients had thrombus seen on the device at 3-month follow-up, 1 of which was noncompliant with anticoagulation treatment starting early after device implantation. Therefore, adequate antithrombotic therapy with aspirin and clopidogrel is important to prevent thrombus formation before the endothelialization process finished. However, given the known occurrence of later thrombus formation on the atrial surface of the device, even after complete endothelialization of the device (24,25), the optimal therapeutic regimen or therapeutic time needs to be further investigated. STUDY LIMITATIONS. The present study included NVAF patients with a CHADS 2 score of 1 or greater; from these, 10 (6.5%) were moderate stroke risk (CHA 2 DS 2 -VASc score ¼ 1) (Table 1). However, current guidelines would recommend aspirin or antithrombotic therapy in this risk cohort. In addition, there was no control group, and the use of CHADS 2 and CHA 2 DS 2 -VASc scores for comparisons is methodologically imperfect. A recent systematic review showed that substantial variation exists across cohort studies and randomized controlled trials in overall stroke rates and rates corresponding to CHA 2 DS 2 - VASc point scores (26). Finally, this is a small sample study with a medium-term follow-up, and therefore, it is not sufficient to conclude the long-term efficacy and safety of the LAmbre device in stroke prevention in AF patients. Thus, prospective, multicenter, randomized, controlled (LAmbre vs. oral anticoagulant agents) clinical trials are needed to further confirm the efficacy and safety of LAmbre device in NVAF patients with high risk of stroke. CONCLUSIONS LAA closure with the LAmbre device shows encouraging results for stroke prevention in patients with NVAF. Further large-scale trials are needed to confirm the long-term safety and efficacy of this novel device. ADDRESS FOR CORRESPONDENCE: Dr. Congxin Huang, Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, No.238 Jiefang Road, Wuhan , People s Republic of China. huangcongxin@vip.163.com.

7 2194 JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 21, 2017 NOVEMBER 13, 2017: PERSPECTIVES WHAT IS KNOWN? Preliminary study suggested the percutaneous LAA closure with the LAmbre device is feasible. WHAT IS NEXT? Prospective, multicenter, randomized, controlled clinical trials are needed to further confirm the long-term efficacy and safety of the LAmbre device. WHAT IS NEW? This prospective, multicenter, clinical study showed a low ischemic stroke rate with a small number of complications. REFERENCES 1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001; 285: Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22: Go AS, Hylek EM, Chang Y, et al. 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