The following are 20 key points to remember from the review about cardiovascular therapies targeting left atrial appendage (LAA), including rationale, evidence, optimal patient selection, and common challenges encountered with mechanical LAA exclusion.¹ The review included a description of LAA anatomy, current surgical and percutaneous LAA exclusion techniques, and challenges with optimal patient selection along with encountered complications:

1. LAA is the most common site of thrombus formation due to atrial fibrillation (AF). Currently, the treatment of choice for patients with AF with a CHA₂DS₂-VASc score ≥2 is oral anticoagulation with warfarin or direct oral anticoagulants (DOACs). However, there is a significant patient population with contraindications or noncompliance to that treatment. Recently, several treatment strategies evolved around LAA occlusion as a solution to this problem. LAA occlusion has four important roles: Preventing stroke and systemic thromboembolism, decreasing arrhythmia burden, influencing atrial remodeling (improving left atrial reservoir and conduit function), and influencing systemic homeostasis (downregulating renin-angiotensin-aldosterone system and adrenergic input).
2. LAA is considered a vestigial structure in our body. We currently have a poor understanding of the exact role of LAA in the human heart, which can be summarized into three categories: neurohormonal through the release of atrial natriuretic peptide and natriuresis, reservoir acting as a decompression structure in the left atrium when pressure is elevated, and electrical function.
3. Several factors contribute to the role of LAA as the most common site of atrial thrombus in AF patients, such as shape of LAA, ostium of the neck, and extent of trabeculations. There are four types of LAA morphologies, and they are listed in order of tendency of stroke or transient ischemic attack: cauliflower, windsock, cactus, and chicken wing.
4. LAA exclusion can be done using a surgical or percutaneous technique. The surgical procedure can be performed by a suture (epicardial, endocardial, or amputation and epicardial) or a device (AtriClip [AtriCure, Inc.; Mason, OH], ENDOLOOP [Ethicon US, LLC; Blue Ash, OH], LigaSure [(Medtronic; Dublin, Ireland)], TigerPaw [Maquet, Inc.; Rastatt, Germany] or stapler). The percutaneous technique includes epicardial (Sierra [Aegis Surgical, Ltd.; Durham, NC]), endocardial (WATCHMAN [Boston Scientific; Marlborough, MA], Amplatzer Cardiac Plug and Amplatzer Amulet [Abbott Vascular; Santa Clara, CA], PLAATO [ev3 endovascular; Plymouth, MN], and other investigational devices), and hybrid (LARIAT [SentreHEART, Inc.; Redwood City, CA]).
5. The Society of Thoracic Surgeons 2017 Clinical Practice Guidelines for the Surgical Treatment of Atrial Fibrillation recommended Class IIA recommendation for surgical LAA closure,² whereas previous recommendations by the American College of Cardiology and American Heart Association and the European Society of Cardiology gave Class IIB recommendation for routine LAA exclusion in patients undergoing cardiac surgery. Despite the absence of randomized clinical trials (RCTs) that compare the surgical techniques, observational studies have shown that among the suture techniques, LAA amputation followed by epicardial suture closure was the most effective strategy. Concerning the surgical device techniques, the only available current device is the AtriClip LAA exclusion system, which has shown promising results with >98% closure at 3-months follow-up with minimal risk of bleeding. The device was recently approved by the US Food and Drug Administration (FDA) for LAA ligation. Despite the absence of recommendation regarding prophylactic LAA closure during a surgical procedure, studies (ATLAS [AtriClip® Left Atrial Appendage Exclusion Concomitant to Structural Heart Procedures] and LAOOS III [Left Atrial Appendage Occlusion Study III]) are underway to evaluate whether high-risk patients would benefit from prophylactic closure of LAA along with another cardiac procedure.
6. The PLAATO device is the first percutaneous LAA occlusion device and was withdrawn from market in 2006 for business reasons.
7. The WATCHMAN nitinol cage percutaneous LAA closure device has been studied in many trials. Most of the studies were from patients eligible for oral anticoagulation and not from patients in whom oral anticoagulation was contraindicated. The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) study showed that nitinol cage percutaneous LAA closure was noninferior to warfarin for cardiovascular mortality, all-cause mortality, and systemic thromboembolism. However, the nitinol cage group had higher rate of adverse effects mostly related to the procedure (major bleeding, pericardial effusion, and stroke). The PREVAIL (Evaluation of the WATCHMAN Left Atrial Appendage (LAA) Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trial was performed to answer some of the safety issues with percutaneous nitinol cage procedure. Results showed that the nitinol cage percutaneous LAA closure did not achieve the first pre-specified criteria for noninferiority and achieved only the second non-inferiority criterion. Despite that, the FDA approved the nitinol cage percutaneous LAA closure device in 2015.
8. One of the major drawbacks of the PROTECT AF and PREVAIL trials is the post-procedural use of warfarin, which is an important factor in patients with contraindications to oral anticoagulation. However, two world registries and the ASAP (ASA Plavix Feasibility Study With WATCHMAN Left Atrial Appendage Closure Technology) trial have demonstrated the safety of post-nitinol cage percutaneous LAA closure device management with DAPT (aspirin and clopidogrel).
9. There are currently two generations of the self-expanding nitinol plug for LAA closure, but there are no RCTs that compare the devices with oral anticoagulants. Data from observational studies with the first-generation self-expanding nitinol plug showed a decrease in stroke rates and less major bleeding. The two devices received the Conformité Européene mark but are not FDA approved yet.
10. Endo-epicardial suture delivery (LARIAT system) is another percutaneous LAA occlusion technique. Data from observational studies show a high success rate with LAA exclusion. Currently, the LARIAT system is approved by the FDA for soft-tissue apposition but not for stroke prevention.
11. The LAA plays an important role acting as a non-pulmonary vein trigger in the initiation and maintenance of AF (especially persistent). Even though the percutaneous endo-epicardial suture delivery system, LAA exclusion system, and surgical excision do electrically isolate the LAA, they have complications (especially catheter ablation with increased risk of thromboembolism, cardiac tamponade, and electromechanical dissociation with the need of a possible surgery). There are no data to support the role of endocardial LAA exclusion using the nitinol cage percutaneous LAA closure device or the self-expanding nitinol plug in electrical isolation of the LAA.
12. The impact of endocardial and epicardial LAA exclusion on systemic homeostasis and neurohormonal modulation has been poorly studied. However, results showed significant decrease in blood pressure post epicardial exclusion along with an ultimate down-regulation of the renin-angiotensin-aldosterone system due to the interplay of several factors.
13. Despite being first line for stroke prevention in AF, a lot of patients have contraindications to anticoagulation with warfarin or DOAC due to several reasons. No RCTs on the nitinol cage percutaneous LAA closure were conducted in noneligible patients to anticoagulants. However, the ASAP trial and EWOLUTION (Registry on WATCHMAN Outcomes in Real-Life Utilization) support the benefit of LAA closure in this specific population. Ongoing trials are exploring if endocardial LAA closure is noninferior to DOAC.
14. There are limited data concerning the benefit of LAA closure in dialysis patients because most studies have excluded them. Further studies are needed to elucidate whether LAA exclusion is beneficial in dialysis patients who require anticoagulation.
15. Currently, there are no data to support LAA exclusion in patients with high HAS-BLED or CHA₂DS₂-VASc scores.
16. Only observational studies have shown the role of LAA exclusion in reducing arrhythmia burden; therefore, RCTs (such as the ongoing aMAZE [aMAZE Study: LAA Ligation Adjunctive to PVI for Persistent or Longstanding Persistent Atrial Fibrillation]) are needed to explore the benefit of LAA closure.
17. Several factors should be taken into consideration when deciding the appropriate LAA closure device/technique for each patient. These include device availability in a given country, operator experience, patient characteristics (prior surgical history, ability to tolerate short-term oral anticoagulation), requirement of cardiac surgery, and need for arrhythmia management. Furthermore, pre-procedural imaging such as cardiac computed tomography or TEE is important to define LAA anatomy aiding in procedural planning.
18. Theoretically, concomitant LAA closure in patients undergoing AF ablation might be helpful. It has been previously studied and reported feasible and safe. However, the issue of procedure reimbursement will limit the combination of multiple procedures in one setting. Moreover, performing AF ablation after LAA closure remains one of the challenges associated with the procedure.
19. The greatest challenge associated with percutaneous LAA closure is post-procedural antithrombotic therapy and associated bleeding. Incidence of post-procedural device-related thrombus ranges between 3 and 7.2%. If a thrombus is found on post-procedural TEE, then oral anticoagulation for 3-6 months with follow-up TEE is recommended. The second most common complications are post-procedural leaks occurring, with incidence ranging between 0 and 63% depending on the type of LAA device and the frequency and modality of monitoring. It has been reported with both endocardial and endo-epicardial closure but not LAA exclusion system closure. However, the consequences of those leaks are still not clear, so continued TEE surveillance and temporary initiation of anticoagulation are recommended.
20. Despite being a rare complication, device embolization stays a potential challenge associated with endocardial LAA devices (nitinol cage percutaneous LAA closure device and transcatheter self-expanding nitinol plugs), with a reported incidence <4%. Current recommendations are to obtain pre-procedural imaging by both TEE and computed tomography. Follow-up TEEs are recommended at 45 days, 6 months, and 12 months to document LAA closure (defined as complete seal or efficient seal with a leak ≤5 mm).

References

1. Turagam MK, Velagapudi P, Kar S, et al. Cardiovascular Therapies Targeting Left Atrial Appendage. J Am Coll Cardiol 2018;72:448-63.
2. Badhwar V, Rankin JS, Damiano RJ Jr, et al. The Society of Thoracic Surgeons 2017 Clinical Practice Guidelines for the Surgical Treatment of Atrial Fibrillation Ann Thorac Surg 2017;103:329-41.

Keywords: Adrenergic Agents, Alloys, American Heart Association, Amputation, Anticoagulants, Aspirin, Atrial Appendage, Atrial Fibrillation, Atrial Natriuretic Factor, Atrial Remodeling, Blood Pressure, Cactaceae, Cardiac Tamponade, Catheter Ablation, Down-Regulation, Echocardiography, Transesophageal, Feasibility Studies, Fibrinolytic Agents, Follow-Up Studies, Homeostasis, Ischemic Attack, Transient, Natriuresis, Organothiophosphorus Compounds, Patient Selection, Pericardial Effusion, Registries, Renal Dialysis, Renin-Angiotensin System, Stroke, Surgeons, Suture Techniques, Sutures, Thromboembolism, Thrombosis, Ticlopidine, Tomography, United States Food and Drug Administration, Warfarin, Arrhythmias, Cardiac

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