In this brief review, we discuss the rationale for left atrial appendage (LAA) occlusion and supportive data on outcomes following LAA closure.

Atrial fibrillation (AF) is the most common significant cardiac arrhythmia, affecting more than 33 million individuals worldwide.¹ The incidence is increasing in frequency as the population ages and as screening programs document asymptomatic AF. This is an extremely important arrhythmia and implicated as the second most common etiology for stroke. Although oral anticoagulation is beneficial in lowering the risk of stroke, 1 in 10 patients have a contraindication to warfarin therapy.² Furthermore, 1 in 5 patients in randomized clinical trials for prevention of stroke discontinued novel oral anticoagulants during follow-up, leaving these individuals unprotected. Among patients who do tolerate either warfarin or novel oral anticoagulants, major or recurrent bleeding, intracranial bleeds, and the like often lead to interruption of anticoagulation. Nearly 40% of patients at risk of stroke thus do not receive any anticoagulation due to contraindication, bleeding, or patient/physician preferences.³ Previous studies have reported that >90% of cardiac emboli in nonvalvular atrial fibrillation (NVAF) originate in the LAA.⁴ LAA occlusion has thus emerged as an alternative for stroke prevention in such patients with an elevated stroke risk (based on CHADS₂ or more commonly CHA₂DS₂-VASc score) who have appropriate rational for avoiding oral anticoagulation.

The WATCHMAN Device (Boston Scientific; Natick, MA) is the most extensively studied and the only Food and Drug Administration (FDA) approved percutaneous LAA closure device available in the United States. It consists of a semi-spherical nitinol frame with a polyethylene terephthalate membrane coating to block thrombus embolization and 10 fixation barbs that anchor the device into the LAA. The device is deployed transseptally using a dedicated 14 Fr sheath and a 12 Fr delivery catheter, usually under transesophageal echocardiography and fluoroscopic guidance, but it can also be placed using intracardiac echocardiography. The pivotal PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) trial randomized 707 patients with NVAF and an additional risk factor for stroke to dose-adjusted warfarin or LAA closure with WATCHMAN in a 2:1 fashion.⁵ The primary end-point of stroke, systemic embolism, and cardiovascular or unexplained death occurred in 3% in the WATCHMAN group versus 4.9% (percent per 100 patient years) in the warfarin group (risk ratio [RR] 0.62; 95% confidence interval [CI], 0.35-1.25). Hemorrhagic strokes were lower with the WATCHMAN device. There was also a reduction in the composite end-point of disabling stroke or death in the WATCHMAN arm (RR 0.41; 95% CI, 0.22-0.82). However, there was an increase in primary safety events in the WATCHMAN arm (RR 1.69; 95% CI, 1.01-3.19), including serious pericardial effusion in 5% of these patients. Because of concerns about the up-front potential safety hazard, additional data was required for FDA approval.

In the follow-up PREVAIL (Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trial, 407 patients (with a relatively higher CHADS₂ score of 2.6 compared with PROTECT-AF) were similarly randomized in a 2:1 fashion to WATCHMAN and warfarin. The first primary end-point of stroke, systemic embolism, or unexplained death did not meet the pre-specified non-inferiority margin. However, the second co-primary end-point of stroke or systemic embolism >7 days post-randomization met its statistical non-inferiority margin.⁶ Procedural complications decreased to 4.2% compared with 8.7% in PROTECT AF (p = 0.004). Patient-level meta-analysis of the PROTECT, PREVAIL, and continued access registry data has further shown lower hemorrhagic stroke (0.15 vs. 0.96 events per 100 patient years of follow-up), cardiovascular/unexplained death (1.1 vs. 2.3 events per 100 patient years, p = 0.006), and non-procedural bleeding (6 vs. 11.3 events per 100 patient years, hazard ratio 0.51, p = 0.006) with the WATCHMAN Device compared with warfarin.⁷

The patients need to be on warfarin for at least 45 days post-WATCHMAN. This regimen was chosen to allow for device endothelialization. Patients can then be switched to clopidogrel and aspirin (for another 4.5 months and then aspirin 325 mg indefinitely thereafter) if the residual leak on transesophageal echocardiography at 45 days is <5 mm. A recently published retrospective multicenter study found the use of novel oral anticoagulants in the post-WATCHMAN period to be associated with similar rates of bleeding events (0.5 vs. 0.9%, p = 0.6) and composite of device-related thrombosis or thromboembolism (1.4 vs. 0.9%, p = 1) compared with uninterrupted warfarin.⁸ There are no randomized data to compare the efficacy of the WATCHMAN Device in patients who cannot tolerate even short-term anticoagulation. However, in the ASAP (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology) trial, the rate of all-cause stroke or systemic embolism (2.3% per year) in patients with the Watchman Device was >60% lower than expected in a population with a mean CHADS₂ score of 2.8 treated with antiplatelet therapy.⁹ A dedicated randomized clinical trial (ASAP TOO [Assessment of the WATCHMAN™ Device in Patients Unsuitable for Oral Anticoagulation]) of patients with NVAF at increased risk of stroke but who are not candidates for any anticoagulation has been initiated, randomizing patients to either Watchman and aspirin/clopidogrel or conservative medical therapy alone with aspirin and/or clopidogrel.

Some of the other percutaneous devices include an AMPLATZER cardiac plug or the AMPLATZER Amulet device (St. Jude Medical; Saint Paul, MN) and the WaveCrest device (Coherex Medical; Salt Lake City, UT), both of which are available in Europe. The AMPLATZER cardiac plug consists of a self-expanding nitinol frame with a distal lobe connected to a proximal disc by an articulated waist and 6-10 pairs of stabilizing wires around the distal perimeter. The largest available literature on this device (n = 1,047) demonstrated an annual stroke risk of 2.3% (59% lower than expected based on patient risk scores).¹⁰ A newer iteration of this device (AMPLATZER Amulet device) is reported to have a lower rate of periprocedural leaks with no risk of dislodgment. WaveCrest consists of a nitinol frame and expanded polytetrafluoroethylene cover and is a relatively short device designed for proximal deployment. Results from ongoing randomized trials for both these devices are awaited.

The LARIAT Suture Delivery Device (SentreHEART, Inc.; Redwood City, CA) and in-trial Aegis device (Aegis Medical Innovations, Inc.; Vancouver, Canada) offer an alternative epicardial approach to LAA occlusion especially in patients who cannot tolerate any anticoagulation or do not have suitable LAA anatomy for endocardial occlusion. In the largest published series for LARIAT (n = 712), procedural success was achieved in 95.5%.^11,12 Procedural safety concerns remain with LARIAT due to possible LAA perforation and tamponade requiring urgent cardiac surgery. The Aegis device has thus far been studied only in canine models.

Both open and minimally invasive thoracoscopic techniques have been employed for surgical LAA occlusion, although earlier data were limited, and incomplete closure was a concern. Newer devices such as the epicardial Atriclip system (AtriCure, Inc.; Mason, OH) could offer superior rates of effective occlusion. The current European Society of Cardiology and American Heart Association/American College of Cardiology guidelines suggest that surgical excision of the LAA may be considered in patients undergoing cardiac surgery or thoracoscopic atrial fibrillation surgery (Grade IIB).¹³

Some of the barriers to the widespread utilization of LAA occlusion include technical skills, risk of complications, lack of direct comparative data against novel oral anticoagulants, and price/reimbursement issues. Operator experience with the WATCHMAN Device is improving, and the complication rate has been low even with new operators in the real-world post-FDA-approval experience.¹⁴ More comparative data will be available on LAA occlusions versus novel oral anticoagulants as results from ongoing trials become available.¹⁵ Furthermore, multiple studies have previously demonstrated the cost-effectiveness of LAA occlusion for NVAF¹⁶ even more so than novel oral anticoagulants.¹⁷ In conclusion, LAA occlusion offers a well-established procedure for NVAF patients who are not candidates for long-term anticoagulation.

References

1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014;129:837-47.
2. O'Brien EC, Holmes DN, Ansell JE, Allen LA, Hylek E, Kowey PR, et al. Physician practices regarding contraindications to oral anticoagulation in atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Am Heart J 2014;167:601-9.e1.
3. Kakkar AK, Mueller I, Bassand JP, et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry. PLoS One 2013;8:e63479.
4. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755-9.
5. Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013;127:720-9.
6. 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.
7. Holmes DR Jr, Doshi SK, Kar S, et al. Left Atrial Appendage Closure as an Alternative to Warfarin for Stroke Prevention in Atrial Fibrillation: A Patient-Level Meta-Analysis. J Am Coll Cardiol 2015;65:2614-23.
8. Enomoto Y, Gadiyaram VK, Gianni C, et al. Use of non-warfarin oral anticoagulants instead of warfarin during left atrial appendage closure with the Watchman device. Heart Rhythm 2017;14:19-24.
9. Reddy VY, Mobius-Winkler S, Miller MA, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61:2551-6.
10. Tzikas A, Shakir S, Gafoor S, et al. Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention 2016;11:1170-9.
11. Lakkireddy D, Afzal MR, Lee RJ, et al. Short and long-term outcomes of percutaneous left atrial appendage suture ligation: Results from a US multicenter evaluation. Heart Rhythm 2016;13:1030-6.
12. Price MJ, Gibson DN, Yakubov SJ, et al. Early safety and efficacy of percutaneous left atrial appendage suture ligation: results from the U.S. transcatheter LAA ligation consortium. J Am Coll Cardiol 2014;64:565-72.
13. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071-104.
14. Reddy VY, Gibson DN, Kar S, et al. Post-Approval U.S. Experience With Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation. J Am Coll Cardiol 2017;69:253-61.
15. Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation (PRAGUE-17) (ClinicalTrials.gov website). 2016. Accessed 12/15/16. Available at: https://clinicaltrials.gov/ct2/show/NCT02426944.
16. Reddy VY, Akehurst RL, Armstrong SO, et al. Cost effectiveness of left atrial appendage closure with the Watchman device for atrial fibrillation patients with absolute contraindications to warfarin. Europace 2016;18:979-86.
17. Reddy VY, Akehurst RL, Armstrong SO, Amorosi SL, Beard SM, Holmes DR Jr. Time to Cost-Effectiveness Following Stroke Reduction Strategies in AF: Warfarin Versus NOACs Versus LAA Closure. J Am Coll Cardiol 2015;66:2728-39.

Keywords: Anticoagulants, Aspirin, Atrial Appendage, Atrial Fibrillation, Echocardiography, Transesophageal, Pericardial Effusion, Polyethylene Terephthalates, Polytetrafluoroethylene, Risk Factors, Stroke, Thromboembolism, Thrombosis, Ticlopidine, Warfarin, Angiography, Heart Atria

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