Atrial fibrillation (AF) is a common sustained cardiac arrhythmia of profound clinical significance and increasing prevalence. The number of individuals in the United States affected by AF is expected to increase to greater than 10 million by the year 2050.1 Although there are numerous important clinical consequences of AF, the most significant in terms of morbidity and mortality is thromboembolic stroke.
Studies have implicated AF as the cause of approximately one-quarter of all strokes in patients older than 80 years of age.2 Research has also demonstrated anticoagulation therapy to reduce the risk of AF-associated stroke by 64%.2 Accordingly, patients with AF and at significant risk for stroke are typically placed on prophylactic anticoagulation therapy, with warfarin being the most studied treatment.3 However, as anticoagulation therapy increases the risk of bleeding, many patients with AF are poor candidates for warfarin use.4 Further complicating anticoagulation therapy with warfarin is the fact that many patients have poor tolerance for this medication, and it has a narrow therapeutic use. Some studies have estimated that only 50% to 60% of all patients receiving treatment with warfarin are in the therapeutic international normalized ratio (INR) range of 2.0 to 3.0.5,6 As a result of these issues, only approximately 50% of patients who are eligible for long-term warfarin therapy are treated with it.6
A number of novel non-vitamin K antagonist oral anticoagulant medications (NOACs) are currently in various stages of clinical testing for use in patients with AF.7-9 For the most part, these agents have demonstrated efficacy in the prevention of embolic stroke; however, they are generally more expensive, still cause increased bleeding risk, and with the exception of dabigatran, currently have no approved reversal agents.7-10
Other treatment strategies for AF include membrane-active antiarrhythmic drugs (eg, amiodarone, sotalol, propafenone), as well as catheter ablation. However, although these modalities may provide symptomatic relief for individuals with AF, neither method has been shown to be reliable in preventing thromboembolic events. Long-term anticoagulation therapy is nevertheless still recommended for these patients.11,12 Given the above-mentioned issues, alternative methods have been developed to help prevent thromboembolic stroke in patients with AF.
Left Atrial Appendage Closure
Of particular note, research has shown that the left atrial appendage (LAA), a small “sac-like” structure in the wall of the left atrium, is the source of thrombi in more than 90% of patients with nonvalvular AF.13 It has been postulated that the LAA has a particular propensity for clot formation due to increased blood stasis, as well as to extensive trabeculations present in that portion of this atrial pouch.14
In one study that utilized transesophageal echocardiographic (TEE) imaging prior to electrical cardioversion in a group of patients with AF, approximately 15% of patients not on anticoagulation therapy displayed evidence of left atrial thrombus after being in AF for longer than 48 hours. The LAA was the site for 33 of the 34 clots identified in the study.15 Thus, it appears that the LAA is by far the most significant source of cardiac thromboembolism in patients with nonvalvular AF. As a result, a number of percutaneous catheter-based devices have been developed in order to close off the LAA from the systemic circulation. In effect, the prophylactic exclusion of this atrial region with a high propensity for thrombus formation serves to protect against thromboembolic stroke.
At present, the 3 main devices and techniques of clinical significance for LAA occlusion are the WATCHMANTM LAA closure device (Boston Scientific), the LARIAT® suture delivery device (SentreHEART), and the AMPLATZERTM Cardiac Plug (St. Jude Medical).
WATCHMAN and LARIAT Systems
The WATCHMAN LAA closure device is a self-expanding nitinol structure with fixation barbs, as well as a permeable polyester fabric cover. This device is implanted via a percutaneous catheter-based delivery system, using a trans-septal approach under TEE guidance to seal off the ostium of the LAA and consequently exclude this region from the systemic circulation.16 In contrast, the LARIAT suture delivery device uses a percutaneous and epicardial suture ligation approach; that is, the introduction of a preformed suture mounted on a delivery snare to lasso the LAA.17 Specifically, this procedure involves: (a) transseptal/endocardial and pericardial access to the LAA, (b) delivery of endocardial magnet-tipped guidewires in the apex and associated pericardiac region of the LAA, (c) connection of the epicardial and endocardial magnet-tipped guidewires to stabilize the LAA, and (d) snare capture of the LAA with subsequent release of the pre-tied suture for ligation.18 The AMPLATZER Cardiac Plug is a self-expandable device comprising a distal lobe to anchor the body of the LAA and a proximal disk connected by an articulating waist, which works to seal off the ostium of the LAA.19
The WATCHMAN device has been extensively studied in a number of trials.20-22 In 2009, the PROTECT AF trial (“Percutaneous Closure of the Left Atrial Appendage vs Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation: A Randomised Noninferiority Trial”) was published.21 This multicenter, noninferiority, randomized control trial compared the WATCHMAN device to warfarin therapy in adult patients with nonvalvular AF. Efficacy was assessed via a primary composite end point of stroke, systemic embolism, and cardiovascular death. Ultimately, this study established noninferiority of the WATCHMAN device compared with warfarin therapy alone for all primary end points. At 1065 patient-years follow-up, the primary efficacy event rate was calculated to be 3.0 per 100 patient-years in the WATCHMAN group vs 4.9 per 100 patient-years in the warfarin group, thus demonstrating an approximately 40% relative risk reduction in the WATCHMAN group vs the warfarin group.21 Furthermore, compared with the warfarin group, the WATCHMAN group experienced an approximately 85% relative reduction in hemorrhagic stroke, a 60% relative reduction in cardiovascular mortality, and a 34% relative reduction in all-cause mortality.20,21
Subsequent to the publication of the PROTECT AF trial, the US Food and Drug Administration (FDA) identified a number of issues affecting the overall validity of this study; specifically, with regard to patient selection criteria (ie, inclusion of patients with CHADS2 scores of 1), periprocedural complications, and the reportedly confounding use of clopidogrel following device implantation.16,20 Thus, a confirmatory randomized trial—the PREVAIL (Prospective Randomized Evaluation of the Watchman LAA Closure Device in Patients with Atrial Fibrillation vs Long Term Warfarin Therapy) trial—was performed to address these issues; the results were published in 2014.16 This study, which again compared LAA closure via the WATCHMAN device with warfarin therapy alone, addressed the aforementioned concerns by modifying inclusion criteria, engaging new cardiac electrophysiologists, and discontinuing clopidogrel 7 days prior to percutaneous implantation of the device. At the conclusion of the trial, the 18-month event rate of the first co-primary composite end point (again prespecified as a composite of stroke, systemic embolism, and cardiovascular death) was 0.064 in the WATCHMAN group vs 0.063 in the warfarin group; thus, technically not achieving noninferiority criteria. However, noninferiority was achieved for the 18-month rate of the second co-primary end point (stroke or systemic embolism more than 7 days post-randomization), which was 0.0200 in the WATCHMAN group vs 0.0253 in the warfarin group.16 Overall, this study provided additional support for the use of LAA closure as a reasonable alternative to warfarin therapy in patients with AF. Indeed, subsequent to the publication of this study, the FDA panel returned a positive vote for the safety, efficacy, and risk-benefit of the WATCHMAN device.23
An additional meta-analysis of all of the above-mentioned data regarding the WATCHMAN device, including the associated CAP (Continued Access to PROTECT AF) and CAP2 (Continued Access to PREVAIL) registries, was published in 2015. This meta-analysis, which included 2406 patients with 5931 patient-years of follow-up, provided the most statistically robust assessment of the WATCHMAN device to date. In this study, with a mean follow-up time of 2.69 years, patients receiving the WATCHMAN device showed superiority to traditional warfarin therapy in the following measures: markedly decreased incidence of hemorrhagic strokes (0.15 vs 0.96 events per 100 patient-years), cardiovascular/unexplained death (1.1 vs 2.3 events per 100 patient-years), and major nonprocedural-related bleeding (6.0% vs 11.3%). Although all-cause stroke/systemic embolism was found to be similar between both groups (1.75. vs 1.87 events per 100 patient-years), and there were actually slightly more ischemic strokes in the device group, the meta-analysis nevertheless worked to establish the WATCHMAN device and LAA closure as viable strategies in the treatment of AF.20
The LARIAT system, which utilizes percutaneous epicardial suture ligation, is a lesser studied approach to LAA closure. In one prospective observational study published in 2013, investigators followed a group of patients with AF who underwent percutaneous LAA ligation using the LARIAT system. Immediate closure of the LAA was achieved in 96% (ie, 85 of 89 patients) of the patients in this study, with follow-up TEE at 1 year showing that the closure was permanent. 18 With regard to overall safety, the most common periprocedural event was chest pain. Of note, the incidence of persistent pericarditis was 2.4% (n=2); this was effectively treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Other adverse outcomes included late pericardial effusion (n=1), sudden unexplained death (n=2), and late strokes (n=2), which were thought to be nonembolic in etiology. Thus, as compared to the WATCHMAN device, the LARIAT system resulted in decreased incidence of device embolization, perforation, or erosion resulting in pericardial effusions.18 It is worth noting that for the WATCHMAN device, the incidence of these issues decreased with more operator experience.16 Thus, the LARIAT system may serve as an possible alternative therapy in patients with AF who are poor candidates for anticoagulation therapy.18 However, to further assess the utility of the LARIAT suture delivery device, more research is needed; specifically, a prospective, noninferiority trial comparing the LARIAT to the WATCHMAN and/or warfarin therapy.
One notable advantage of the LARIAT system over the WATCHMAN device is that postprocedural short-term anticoagulation therapy can be completely avoided, as there is no indwelling intracardiac device following percutaneous intervention with the LARIAT system.18 In all trials involving the WATCHMAN device, warfarin was continued for at least 45 days following device implantation to attain a therapeutic INR goal of 2.0 to 3.0. At 45 days, if TEE showed either LAA closure and/or residual peri-device flow less than 5 mm in width, warfarin was stopped, and the patient was continued on aspirin 81 mg/325 mg and clopidogrel 75 mg for an additional 6 months, with aspirin 325 mg continued indefinitely thereafter. Patients with absolute contraindications to anticoagulation therapy are perhaps better suited for the LARIAT procedure compared with implantation of the WATCHMAN device. Additionally, as the LARIAT system serves to “debulk” the left atrium, there have been some data to suggest that this provides the concurrent benefit of AF ablation in these patients.24
AMPLATZER Cardiac Plug
The AMPLATZER cardiac plug has also been investigated for LAA closure. One study, published in 2013, aimed to evaluate the utility of the AMPLATZER cardiac plug in patients with AF and absolute contraindications to anticoagulation therapy.25 In this study, 52 patients with AF underwent implantation of the AMPLATZER cardiac plug, with most patients receiving either dual or single antiplatelet therapy (aspirin 81 mg/325 mg plus clopidogrel 75 mg, aspirin 81 mg/325 mg alone, or clopidogrel 75 mg alone) according to the operator’s discretion for 30 to 180 days thereafter. Subsequently, single antiplatelet therapy was continued. The procedure was found to be successful in 98.1% of the patients. In terms of overall safety, the main periprocedural events included device embolization (1.9%) and pericardial effusion (1.9%). There were no cases of periprocedural stroke. Rates of death as determined at mean follow-up at 20 months were 5.8% for stroke, 1.9% for systemic embolism, and 1.9% for major bleeding, thus, establishing the AMPLATZER cardiac plug as a potentially viable method of LAA closure in patients with absolute contraindications to anticoagulation therapy such as warfarin.25
Given that increased age portends a greater risk of AF and bleeding in the presence of anticoagulation therapy, it becomes clear that alternative methods of stroke prevention are needed. LAA closure is an intervention that works to directly address this issue. Although the above-mentioned published data supporting LAA closure as a means of stroke prevention is encouraging, there still exists a need for further refinements in both device technology and procedural expertise before implementation of these devices in a wider cohort of patients. There is much ongoing research in this area, which will help to facilitate these advancements. Overall, it appears that LAA closure as a means of preventing stroke in patients with AF is an intervention with much promise, and certainly potential for widespread use in the foreseeable future.
- Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114(2):119-1125.
- Waks JW, Manning WJ. Left atrial appendage closure to reduce the risk of thromboembolic complications in atrial fibrillation. J Am Coll Cardiol. 2015;65(24):2624-2627.
- Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12): 857-867.
- Bungard TJ, Ghali WA, Teo KK, Mcalister FA, Tsuyuki RT. Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med 2000;160(1):41-46.
- van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006;129(5):1155-1166.
- Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. warfarin use among ambulatory patients with nonvalvular atrial fibrillation: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. Ann Intern Med. 1999;131(12): 927-934.
- Connolly SJ, Ezekowitz MD, Yusuf Salim, et al; and the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl Med. 2009;361(12):2671-2675.
- Patel MR, Mahaffey KW, Garg J, et al; for the Rocket AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med. 2011;365(10):883-891.
- Connolly SJ, Eikelboom J, Joyner C, et al; for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817.
- Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6): 511-520.
- Tung R, Buch E, Shivkumar K. Clinician update: catheter ablation of atrial fibrillation. Circulation. 2012;126:223-229.
- Holmes DR, Reddy VY, Turi ZG; for the PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374(9689):534-542.
- Cardona L, Ana G, Lufsa B, et al. Images in cardiovascular medicine: thrombus formation on a left atrial appendage closure device. Circulation. 2011;124:1595-1596.
- Al-Saady NM, Obel OA, Camm AJ. Left atrial appendage: structure, function, and role in thromboembolism. Heart. 1999;82(5):547-554.
- Manning WJ, Silverman DI, Keighley CS, Oettgen P, Douglas PS. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol. 1995;25(6):1354-1361.
- Holmes DR, 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. J Am Coll Cardiol. 2014;64(1):1-12.
- Lin AC, Knight B. Left atrial appendage closure. Prog Cardiovasc Dis. 2015;58:195-201.
- Bartus K, Han FT, Bednarek J, et al. Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation. J Am Coll Cardiol. 2013;62(2):108-118.
- Lam SC, Bertog S, Gafoor S, et al. Left atrial appendage closure using the Amulet device: an initial experience with the second generation AMPLATZER cardiac plug. Cath Cardiovasc Inter. 2014;85(2):297-303.
- Holmes DR, 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(24):2614-2623.
- Holmes DR, Reddy VY, Turi ZG; for the PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet. 2009;374(9689):534-542.
- Reddy VY, Doshi SK, Sievert H; for the PROTECT AF Investigators. 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(6):720-720.
- US Food and Drug Administration. 2015 Device Approvals. WATCHMAN LAA Closure technology – P130013. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm440621.htm. Updated April 2, 2015. Accessed November 5, 2015.
- Lakkireddy D, Mahankali AS, Kanmanthareddy A, et al. Left atrial appendage ligation and ablation for persistent atrial fibrillation. JACC:Clin Electrophysiol. 2015;1(3):153-160.
- Urena M, Rodés-Cabau J, Freixa X, et al. Percutaneous left atrial appendage closure with the AMPLATZER cardiac plug device in patients with nonvalvular atrial fibrillation and contraindications to anticoagulation therapy. J Am Coll Cardiol. 2013;62(2):96-102.