Introduction

Atrial fibrillation (AF) is the most commonly encountered sustained tachyarrhythmia,^1-4 with a prevalence in the United States of roughly 6 million patients, and an incidence that continues to rise.⁵ AF carries with it attendant risks for the occurrence of heart failure,⁶ dementia,⁷ cerebrovascular accident (CVA),⁸ and mortality.⁹ Of these, CVA is particularly worrisome as a severe complication of AF that occurs, in some patient populations, at relatively high rates. CVA risk reduction has been an active area of investigation for decades, with recent novel pharmacological and mechanical approaches evolving essentially in parallel.

In patients with non-valvular AF, embolic stroke is thought to occur from thrombi forming in the left atrium. Autopsy and imaging investigations have demonstrated that the left atrial appendage (LAA) is the site of thrombus formation in approximately 90% of patients with central sources of thromboembolism,¹⁰ making "local" intervention targeted at the LAA an appealing concept. A number of devices, both endovascular (WATCHMAN, AMPLATZER) and extravascular (LARIAT), are currently in use to exclude blood flow from the LAA, thereby reducing thrombus formation and CVA risk. This brief review focuses on the early experiences with those devices and their current role in CVA risk reduction for non-valvular AF patients.

Devices for LAA Closure

AMPLATZER

Two endovascular devices have been employed for LAA occlusion and CVA risk reduction – the AMPLATZER Cardiac Plug (now redesigned as the AMPLATZER Amulet), and the WATCHMAN. Both are placed via transseptal left atrial access, under fluoroscopic and transesophageal echocardiography (TEE) guidance, to obstruct the ostium of the LAA. Experience with the AMPLATZER device has been presented largely in the form of registry data,¹¹ with conclusions about risk reduction for CVA and bleeding inferred from comparison of observed events in treated patients, to estimated event rates (both CVA and bleeding) in similar patient cohorts. This is in contrast to the randomized clinical trials performed with the WATCHMAN device (see below).

A multicenter experience with the AMPLATZER device was recently reported, detailing outcomes in 1,047 patients followed for an average of 13 months.¹¹ Device implantation was successful in 97.3% of cases. Acute complications occurred in nearly 5% of cases; complications with the AMPLATZER device have included immediate CVA post-implant and pericardial effusion with tamponade. In patients treated with the AMPLATZER device, CVA and transient ischemic attack (TIA) were seen in 0.9% and 0.9%, respectively, during follow-up. Compared to anticipated CVA rates, the authors contend that this represents a 59% risk reduction. A similar risk reduction (61%) was seen in major bleeding rates. Experience with the AMPLATZER device continues to evolve, with introduction of a modified device (AMPLATZER Amulet) that may improve implant efficacy and safety.¹²

WATCHMAN

The WATCHMAN device (Boston Scientific) has been more rigorously investigated in a series of prospective, randomized clinical trials.^13-15 In Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF (PROTECT-AF),¹³ 707 patients with a CHA₂DS₂-VASC score of ≥1 were randomized in 2:1 fashion to LAA occlusion with the WATCHMAN device (n=463) or to ongoing warfarin therapy (n=244). Patients treated by WATCHMAN implantation were reassessed by TEE at 45 days, and if LAA occlusion was deemed satisfactory, warfarin was discontinued and replaced with anti-platelet therapy. The primary endpoint was to determine whether the WATCHMAN device was non-inferior to warfarin in preventing a combined endpoint of CVA, cardiovascular or unexpected death, and systemic embolism. Mean patient follow-up was 18 months, with an aggregate of 1,065 patient-years assessment. PROTECT-AF did indeed show non-inferiority of the LAA occlusion strategy to ongoing warfarin. However, concerns about peri-procedural safety (and particularly a 5.2% rate of pericardial effusion) and patient selection (with a significant number of patients with CHA₂DS₂-VASC score of 1) led the U.S. Food and Drug Administration (FDA) to request additional investigation of the WATCHMAN device.

The PREVAIL (Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) study¹⁴ enrolled 407 patients randomized to LAA occlusion (n=269) versus ongoing warfarin therapy (n=138); enrollment included a generally older patient population (with CHA₂DS₂-VASC scores of 3.8 and 3.9 in the treatment and control groups, respectively), and new centers and implanters were included at pre-specified rates. The results of PREVAIL were notable for several findings, including 1) failure to demonstrate non-inferiority of the WATCHMAN versus warfarin therapy at preventing the combined primary endpoint of CVA, cardiovascular or unexplained death, or systemic thromboembolism, largely driven by very low event rates in the warfarin arm; 2) success in meeting pre-specified safety outcomes surrounding implant; and 3) demonstration that the WATCHMAN device was non-inferior to warfarin in preventing late ischemic events.

Due to concerns that LAA occlusion is most logically targeted at patients for whom systemic anticoagulation is contraindicated, the ASAP (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology) study¹⁵ was performed to assess WATCHMAN safety and efficacy and reducing the same combined PROTECT-AF and PREVAIL endpoint in patients treated only with dual anti-platelet therapy for 6 months after implant, with lifelong aspirin thereafter. In 150 patients (average CHA₂DS₂-VASC score of 4.4) followed prospectively for an average of 14 months, ischemic and hemorrhagic CVA were seen in 1.7% and 0.6% of cases, respectively. The rate of ischemic CVA was lower than that expected (7.3%) for the cohort.

LARIAT

Finally, the LARIAT device is an extravascular soft-tissue snare that has been used to occlude the LAA via a pericardial approach. The snare is introduced into the pericardial space and guided under fluoroscopic and TEE imaging, and by use of a magnet-based guide rail in the LAA and pericardial space, to capture and cinch off the LAA at the ostium. The LARIAT experience has largely been presented in the form of prospectively collected clinical series. Recently, a multicenter experience was published on results in 712 patients.¹⁶ Acute procedural success was 95.5%, with 30 aborted procedures due to issues with pericardial access, early complication, or failure to place the snare properly. Acute complications included 1 death and 10 surgical repairs for cardiac perforation, 14 effusions managed with drainage only, and vascular injury in 4 patients; complication rates fell with introduction of micropuncture techniques for pericardial access. Late TEEs showed LAA leak of 2-5mm in 6.5% and thrombus in 2.5% of patients. The LARIAT device has not been tested in a randomized, controlled clinical trial.

Bleeding Risk and Patient Selection

Pharmacological therapy for CVA risk reduction in patients with non-valvular AF has evolved significantly in the past decade, driven particularly by the introduction of oral direct thrombin¹⁷ and factor Xa inhibitors.^18,19 These agents address many of the concerns that clinicians and patients have faced with warfarin, including limited time in therapeutic range and requisite monitoring regimens. However, while there is compelling data suggesting that the newer anticoagulants have desirable efficacy and safety profiles,²⁰ there remains the simple fact that risk of embolic CVA in the setting of non-valvular AF and risk of bleeding while anticoagulated are driven by a largely overlapping set of comorbidities. As one might anticipate, then, rates of bleeding and discontinuation of anticoagulant therapy are high in this population. This fact, and emerging data on the efficacy, safety, and cost-effectiveness of LAA occlusion therapy, raises the question of appropriate strategies for CVA risk reduction in various populations.

At this point, there is clearly a population of patients who should not undergo LAA occlusion: patients with valvular AF (with attendant high rates of non-LAA clot burden); those with another indication for ongoing systemic anticoagulation; and (arguably) those with an established history of safe and effective ongoing anticoagulation for CVA risk reduction in the setting of non-valvular AF. At the other end of the spectrum, patients with strict contraindication for systemic anticoagulation, with a history of systemic thromboembolism despite ongoing therapy with oral anticoagulants, or with a bleeding risk disproportionately higher than risk of systemic embolism seem appropriate for consideration of mechanical LAA occlusion. That leaves, of course, a vast middle ground of patients with concurrently high CHA₂DS₂-VASC scores and bleeding risks, for which a tailored discussion of CVA risk reduction is likely appropriate. It appears clear that the safety profile of the occlusion devices is improving rapidly; rates of acute complications in the latter part of PROTECT-AF were significantly lower than in the opening phase, and those lower rates were translated to subsequent studies.²¹ It seems reasonable to expect that as the technical aspects of LAA occlusion continue to improve, the proportion of patients appropriate for LAA occlusion will increase commensurately.

References

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14. 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.
15. Reddy VY, Möbius-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.
16. 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.
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21. Holmes DR, Reddy VY. Left Atrial Appendage and Closure: Who, When, and How. Circ Cardiovasc Interv. 2016;9:e002942.

Keywords: Anticoagulants, Atrial Appendage, Atrial Fibrillation, Blood Platelets, Comorbidity, Dementia, Echocardiography, Transesophageal, Embolism, Factor Xa Inhibitors, Heart Failure, Ischemic Attack, Transient, Pericardial Effusion, Pericardium, Registries, Risk Reduction Behavior, Stroke, Tachycardia, Thrombin, Thromboembolism, Thrombosis, Ticlopidine, Vascular System Injuries, Warfarin

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