Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2011008
Category:	Medicine
Initiated:	May 2011
Last Review:	November 2023

Left Atrial Appendage Occlusion, Closure Devices

Description:

Stroke prevention in patients with atrial fibrillation (AF) is an important goal of treatment. Treatment with anticoagulant medications is the most common approach to stroke prevention. Because most embolic strokes originate from the left atrial appendage, occlusion of the left atrial appendage may offer a nonpharmacologic alternative to anticoagulant medications to lower the risk of stroke. Multiple percutaneously deployed devices are being investigated for left atrial appendage closure (LAAC). Two types of left atrial appendage devices (the Watchman and Amplatzer Amulet devices) have approval from the U.S. Food and Drug Administration (FDA) for stroke prevention in patients with AF.

Atrial fibrillation (AF) is the most common type of irregular heartbeat, affecting at least 2.7 million people in the U.S. Risk of AF has been found to be lower in Black, Hispanic, and Asian patients relative to White patients, including following adjustment for demographic and AF risk factors (Mou, 2018; Dewland, 2013). Stroke is the most serious complication of AF. The estimated incidence of stroke in nontreated patients with AF is 5% per year; despite a lower risk of AF, Black and Hispanic patients have an increased risk of stroke compared with White patients (Gardner, 2020; Guo, 2021). Stroke associated with AF is primarily embolic, tends to be more severe than the typical ischemic stroke, and causes higher rates of mortality and disability. As a result, stroke prevention is a main goal of AF treatment.

Stroke AF occurs primarily as a result of thromboembolism from the left atrium. The lack of atrial contractions in atrial fibrillation leads to blood stasis in the left atrium, and this low flow state increases the risk for thrombosis. The area of the left atrium with the lowest blood flow in atrial fibrillation, and, therefore, the highest risk of thrombosis, is the left-atrial appendage (LAA). It has been estimated that 90% of left-atrial thrombi occur in the LAA.

The main treatment for stroke prevention in AF is anticoagulation, which has proven efficacy. The risk for stroke among patients with AF is stratified on the basis of several factors. Two commonly used scores include the CHADS2 score and the and the CHA2DS2-VASc score, The CHADS2 assigns one point each for the presence of congestive heart failure, hypertension, age greater than or equal to 75 years, diabetes, or prior stroke or transient ischemic attack. The CHA2DS2-VASc score includes sex, more age categories, and the presence of vascular disease, in addition to the risk factors used in the CHADS2 score.

Warfarin is the predominant agent in clinical use. A number of newer anticoagulant medications, including dabigatran, rivaroxaban apixaban, and edoxaban have received U.S. Food and Drug Administration (FDA) approval for stroke prevention in nonvalvular AF and have demonstrated noninferiority to warfarin in clinical trials. While anticoagulation is effective for stroke prevention, there is an increased risk of bleeding. Also, warfarin requires frequent monitoring and adjustments as well as lifestyle changes. Newer agents do not require the frequent monitoring seen with warfarin therapy. However, specific reversal agents do not exist for all of these agents. The 2018 American College of Chest Physicians guidelines (updated from 2012) recommend that CHA2DS2VASc be used to evaluate stroke risk, and patients initially identified as having a low stroke risk should not be given antithrombotic therapy. In addition, they recommend bleeding risk assessments be given to every patient at every patient contact and that “potentially modifiable bleeding risk factors” should be the initial focus.

Bleeding is the primary risk associated with systemic anticoagulation. Risk scores have been developed to estimate the risk of significant bleeding in patients treated with systemic anticoagulation, such as the HAS-BLED score, which has been validated to assess the annual risk of significant bleeding in patients with AF treated with warfarin (Lip, 2011). The score ranges from 0 to 9, based on clinical characteristics, including the presence of hypertension, renal and liver function, history of stroke, bleeding, labile international normalized ratios, age, and drug/alcohol use. Scores of 3 or greater are considered to be associated with a high risk of bleeding, potentially signaling the need for closer monitoring of patients for adverse risks, closer monitoring of international normalized ratios, or differential dose selections of oral anticoagulants or aspirin (January, 2014).

Surgical removal, or exclusion, of the LAA is often performed in patients with atrial fibrillation who are undergoing open heart surgery for other reasons. Percutaneous LAA closure devices have been developed as a nonpharmacologic alternative to anticoagulation for stroke prevention in AF. The devices may prevent stroke by occluding the LAA, thus preventing thrombus formation.

Several versions of LAA occlusion devices have been developed. The PLAATO system (ev3 Endovascular) was the first device to be approved by the FDA for LAA occlusion. The device was discontinued in 2007 for commercial reasons, and intellectual property was sold to manufacturers of the Watchman system. The Watchman™ left atrial appendage system (Boston Scientific, Maple Grove, MN) is a self-expanding nickel titanium device. It has a polyester covering and fixation barbs for attachment to the endocardium. Implantation is performed percutaneously through a catheter delivery system, using venous access and transseptal puncture to enter the left atrium. Transesophageal echocardiography and fluoroscopy are used to guide the procedure. Following implantation, patients are anticoagulated with warfarin or alternative agents for approximately 1 to 2 months. After this period, patients are maintained on antiplatelet agents (i.e., aspirin and/or clopidogrel) indefinitely. The Watchman FLX device is a next-generation Watchman device that is also FDA-approved for LAAC. This device is based on the design of the Watchman device, is fully recapturable and repositionable, and was made to occlude a wider size range of LAA than the original Watchman device (FDA, 2021). The Amplatzer cardiac plug (St. Jude Medical), is FDA-approved for closure of atrial septal defects but not for LAAC. A second-generation device, the Amplatzer Amulet, has been developed for the specific indication of LAAC and was FDA approved August 2021 (FDA, 2021). The Amplatzer Amulet consists of a nitinol mesh disc to seal the ostium of the LAA and a nitinol mesh distal lobe, to be positioned within the LAA. The device is preloaded within a delivery sheath. The Percutaneous LAA Transcatheter Occlusion device (ev3) has also been evaluated in research studies but has not received the FDA approval. The Occlutech® (Occlutech) Left Atrial Appendage Occluder has received a CE mark for coverage in Europe. The Cardioblate® closure device (Medtronic) is currently being tested in clinical studies.

The Lariat® Loop Applicator is a suture delivery device approved by the FDA that is intended to close a variety of surgical wounds. It is not specifically approved for LAAC. While the Watchman and other devices are implanted in the endocardium, the Lariat is a non-implant epicardial device.

In September 2021, the FDA sent a letter to healthcare providers indicating that women undergoing percutaneous LAA closure may be at higher risk of adverse procedural outcomes than men (FDA, 2022).,This was based on an analysis of registry data from 49,357 patients who underwent LAA closure with the Watchman device (Darden, 2021).,When adjusted for multiple confounding factors, the study found women were more likely than men to experience any adverse event, major adverse events, and major bleeding. Women also had a significantly higher risk of death (adjusted odds ratio [OR], 2.01; 95% confidence interval [CI] 1.31 to 3.09) but absolute risk was low for both women and men (0.3% vs. 0.1%). In their letter, the FDA stated that they believe the benefits continue to outweigh the risks for approved LAA closure devices when used in accordance with their instructions for use.

The optimal study design for evaluating the efficacy of percutaneous LAAC for the prevention of stroke in AF is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. The rate of ischemic stroke during follow-up is the primary outcome of interest, along with rates of systemic embolization, cardiac events, bleeding complications, and death. For the LAAC devices, the appropriate comparison group could be oral anticoagulation, no therapy (for patients who have a prohibitive risk for oral anticoagulation), or open surgical repair.

Ideally, percutaneous LAAC devices would represent an alternative to oral anticoagulation for the prevention of stroke in patients with AF However, during the postimplantation period the LAAC device may be associated with increased thrombogenicity, therefore, anticoagulation is used during the periprocedural period. Most studies evaluating percutaneous LAAC devices have included patients who are eligible for anticoagulation.

Regulatory Status

In 2002, the PLAATO system (ev3 Endovascular) was the first device to be approved by the FDA for LAA occlusion. The device was discontinued in 2007 for commercial reasons, and intellectual property was sold to manufacturers of the Watchman system.

In 2015, the Watchman™ Left Atrial Appendage Closure Technology (Boston Scientific) was approved by the FDA through the premarket approval process by the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients with Atrial Fibrillation randomized controlled trial (FDA, 2015). In 2020, the Watchman FLX device (Boston Scientific) was approved by the FDA based on the single-arm, nonrandomized PINNACLE FLX study (FDA, 2021). The Amplatzer™ Amulet™ Left Atrial Appendage Occluder (Abbott) received FDA approval in 2021 through the premarket approval process based on results from the Amplatzer Amulet Left Atrial Appendage Occluder Randomized Controlled Trial (Amulet IDE Trial) (FDA, 2021). The Watchman and Amplatzer Amulet devices are indicated to reduce the risk of thromboembolism from the left atrial appendage (LAA) in patients with nonvalvular atrial fibrillation who:

Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy;
Are deemed by their physicians to be suitable for warfarin; and
Have an appropriate rationale to seek a nonpharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin.

(FDA product code: NGV)

Several other devices have been evaluated for LAA occlusion but are not approved in the United States for percutaneous closure of the LAA. In 2006, the Lariat® Loop Applicator device (SentreHEART, Redwood City, CA), a suture delivery system, was cleared for marketing by the FDA through the 510(k) process. The intended use is to facilitate suture placement and knot tying in surgical applications where soft tissues are being approximated or ligated with a pretied polyester suture. The Amplatzer Cardiac Plug device (St. Jude Medical) and WaveCrest® (Johnson & Johnson Biosense Webster) have CE approval in Europe for LAA closure but are not currently approved in the United States for this indication.

Coding

There is a specific CPT category I code for this procedure:

33340: Percutaneous transcatheter closure of the left atrial appendage with endocardial implant, including fluoroscopy, transseptal puncture, catheter placement(s), left atrial angiography, left atrial appendage angiography, when performed, and radiological supervision and interpretation.

Policy/
Coverage:

Effective November 2022

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The use of a device with U.S. Food and Drug Administration (FDA) approval for percutaneous left atrial appendage closure (eg, the Watchman or Amplatzer Amulet) for the prevention of stroke in patients with atrial fibrillation meets member benefit certificate primary coverage criteria when the following criteria are met:

There is an increased risk of stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc score and systemic anticoagulation therapy is recommended; AND
The long-term risks of systemic anticoagulation outweigh the risks of the device implantation.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of a device with FDA approval for percutaneous left atrial appendage closure (eg, the Watchman or Amplatzer Amulet) for stroke prevention in patients who do not meet the above criteria does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of a device with FDA approval for percutaneous left atrial appendage closure (eg, the Watchman or Amplatzer Amulet) for stroke prevention in patients who do not meet the above criteria is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of other percutaneous left atrial appendage closure devices, including but not limited to the Lariat and Amplatzer Cardiac Plug devices, for stroke prevention in patients with atrial fibrillation does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of other percutaneous left atrial appendage closure devices, including but not limited to the Lariat, for stroke prevention in patients with atrial fibrillation is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of surgical left atrial appendage occlusion (e.g., AtriClip device) for prevention of stroke in individuals with atrial fibrillation undergoing open or thoracoscopic cardiac procedures does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for improving health outcomes. For members with contracts without primary coverage criteria, the use of surgical left atrial appendage occlusion (e.g., AtriClip device) for prevention of stroke in individuals with atrial fibrillation undergoing open or thoracoscopic cardiac is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of surgical left atrial appendage occlusion (e.g., AtriClip device) for stroke prevention as a stand-alone procedure in individuals with atrial fibrillation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for improving health outcomes. For members with contracts without primary coverage criteria, the use of surgical left atrial appendage occlusion (e.g., AtriClip device) for stroke prevention as a stand-alone procedure in individuals with atrial fibrillation is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective July 2022 through October 2022

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

There is an increased risk of stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc score and systemic anticoagulation therapy is recommended; AND
The long-term risks of systemic anticoagulation outweigh the risks of the device implantation.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

For members with contracts without primary coverage criteria, the use of a device with FDA approval for percutaneous left atrial appendage closure (eg, the Watchman or Amplatzer Amulet) for stroke prevention in patients who do not meet the above criteria is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, the use of other percutaneous left atrial appendage closure devices, including but not limited to the Lariat, for stroke prevention in patients with atrial fibrillation is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Open or thorascopic exclusion of left atrial appendage for prevention of stroke does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for improving health outcomes.

For members with contracts without primary coverage criteria, open or thorascopic exclusion of left atrial appendage for prevention of stroke is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective January 2022 through July 2022

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

There is an increased risk of stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc score and systemic anticoagulation therapy is recommended; AND
The long-term risks of systemic anticoagulation outweigh the risks of the device implantation.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of other percutaneous left atrial appendage closure devices, including but not limited to the Lariat, for stroke prevention in patients with atrial fibrillation does not meet member benefit certificate primary coverage criteria.

Effective November 2021 through December 2021

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

There is an increased risk of stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc score and systemic anticoagulation therapy is recommended; AND
The long-term risks of systemic anticoagulation outweigh the risks of the device implantation.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective June 2018 through October 31, 2021

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The use of a device with U.S. Food and Drug Administration (FDA) approval for percutaneous left atrial appendage closure (eg, the Watchman) for the prevention of stroke in patients with atrial fibrillation meets member benefit certificate primary coverage criteria when the following criteria are met:

There is an increased risk of stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc score and systemic anticoagulation therapy is recommended; AND
The long-term risks of systemic anticoagulation outweigh the risks of the device implantation.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of a device with FDA approval for percutaneous left atrial appendage closure (eg, the Watchman) for stroke prevention in patients who do not meet the above criteria does not meet member benefit certificate primary coverage criteria.

For members with contracts without primary coverage criteria, the use of a device with FDA approval for percutaneous left atrial appendage closure (eg, the Watchman) for stroke prevention in patients who do not meet the above criteria is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of other percutaneous left atrial appendage closure devices, including but not limited to the Lariat and Amplatzer devices, for stroke prevention in patients with atrial fibrillation does not meet member benefit certificate primary coverage criteria.

For members with contracts without primary coverage criteria, the use of other percutaneous left atrial appendage closure devices, including but not limited to the Lariat and Amplatzer devices, for stroke prevention in patients with atrial fibrillation is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

EFFECTIVE PRIOR TO JUNE 2018

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

There is an increased risk of stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc score and systemic anticoagulation therapy is recommended;

AND

The long-term risks of systemic anticoagulation outweigh the risks of the device implantation.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of other percutaneous left atrial appendage closure devices, including but not limited to the Lariat, PLAATO, and Amplatzer devices, for stroke prevention in patients with atrial fibrillation does not meet member benefit certificate primary coverage criteria.

For members with contracts without primary coverage criteria, the use of other percutaneous left atrial appendage closure devices, including but not limited to the Lariat, PLAATO, and Amplatzer devices, for stroke prevention in patients with atrial fibrillation is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

EFFECTIVE PRIOR TO MARCH 2016

The use of left-atrial appendage closure devices for the prevention of stroke in patients with atrial fibrillation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of left-atrial appendage closure devices for the prevention of stroke in patients with atrial fibrillation is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Assessment of efficacy for therapeutic interventions such as the left atrial appendage (LAA) closure devices involves a determination of whether the intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes, but are prone to biases. For the use of LAA closure devices, the appropriate comparison group could be oral anticoagulation, no therapy (for patients who have prohibitive risk for oral anticoagulation), or open surgical repair.

The evidence on the efficacy of LAA closure devices consists of numerous case series of various occlusion devices, and 2 published RCTs of the Watchman™ device that compared LAA closure with warfarin anticoagulation. Evidence on each different device will be reviewed separately, because the devices are not similar in design, and each may have its own unique considerations.

Watchman Device

The review of the evidence related to the efficacy of the Watchman device is based, in part, on a Blue Cross Blue Shield Association TEC Assessment developed in June 2014, which evaluated use of the Watchman device for patients who were eligible and ineligible for anticoagulation therapy and determined that it does not meet Technology Evaluation Criteria (TEC, 2014). The TEC assessment made the following conclusions about the use of LAA closure in patients without contraindications to anticoagulation:

“We identified 2 randomized controlled trials (RCTs) and 1 case series evaluating the Watchman™ device. The RCTs were non-inferiority trials and compared LAAC with anticoagulation. The first trial showed a lower rate of a composite outcome (stroke, death, and embolism) in patients receiving LAAC [left atrial appendage closure] and met non-inferiority criteria compared with anticoagulation, but FDA [Food and Drug Administration] review noted problems with patient selection, potential confounding with other treatments, and losses to follow-up. The second trial, which incorporated the first trial’s results as a discounted informative prior in a Bayesian analysis, showed similar rates of the same composite outcome but did not meet non-inferiority criteria. The second trial met its second principal outcome non-inferiority criteria in 1 of 2 analyses and a performance goal for short-term complication rate. When assessing the results of both trials, the relative performance of LAAC and anticoagulation is uncertain.”

Although the Watchman device and other LAA closure devices would ideally represent an alternative to oral anticoagulation for the prevention of stroke in patients with AF, during the postimplantation period, the device may be associated with increased thrombogenicity and, therefore, anticoagulation is used during the periprocedural period. Most studies evaluating the Watchman device have included patients who are eligible for anticoagulation.

Patients Who Are Eligible for Anticoagulation

Two RCTs, the PROTECTAF and PREVAIL trials, have evaluated the Watchman device for stroke prevention in patients with atrial fibrillation (AF).

Meta-Analyses

In 2015, Holmes et al reported results of a patient-level meta-analysis that included data from the industry-sponsored PROTECT AF and PREVAIL trials, described below, together with both studies’ continued access registries (Holmes, 2009). The PROTECT AF and PREVAIL registries were designed to include patients with similar baseline characteristics as their respective RCTs. The meta-analysis included a total of 2406 patients, 1877 treated with the Watchman device and 382 treated with warfarin alone. Mean patient follow-up durations were 0.58 years and 3.7 years, respectively, for the PREVAIL continued access registry and the PROTECT AF continued access registry. In a meta-analysis of 1114 patients treated in the RCTs, compared with warfarin, LAA closure met the study’s non-inferiority criteria for the primary composite efficacy end point of all-cause stroke, systemic embolization, and cardiovascular death (hazard ratio [HR], 0.79, 95% confidence interval [CI], 0.52 to 1.2; p=0.22). All-cause stroke rates did not differ significantly between groups (1.75 per 100 patient-years for LAA closure vs 1.87 per 100 patient-years for warfarin; HR=1.02; 95% CI, 0.62 to 1.7; p=0.94). However, LAA closure‒treated patients had higher rates of ischemic stroke (1.6 events/100 patient-years vs 0.9 events/100 patient-years; HR=1.95, p=0.05) when procedure-related strokes were included, but had lower rates of hemorrhagic stroke (0.15 events/100 patient-years vs 0.96 events/100 patient-years; HR=0.22; 95% CI, 0.08 to 0.61; p=0.004).

PROTECT-AF

The first RCT published was the PROTECT AF study (Holmes, 2009), which was a randomized, unblinded trial that evaluated the non-inferiority of an LAA closure device compared with warfarin for stroke prevention in AF. The trial randomized 707 patients from 59 centers in the United States and Europe to the Watchman device or warfarin treatment in a 2:1 ratio. Mean follow-up was 18±10 months. The primary efficacy outcome was a composite end point of stroke (ischemic or hemorrhagic), cardiovascular or unexplained death, or systemic embolism. There was also a primary safety outcome, a composite end point of excessive bleeding (intracranial or gastrointestinal [GI] bleeding) and procedure-related complications (pericardial effusion, device embolization, procedure-related stroke).

The primary efficacy outcome occurred at a rate of 3.0 per 100 patient years in the LAA closure group compared with 4.9 per 100 patient years in the warfarin group (rate ratio [RR], 0.62; 95% credible interval [CrI], 0.35 to 1.25). Based on these outcomes, the probability of non-inferiority was greater than 99.9%. For the individual components of the primary outcome, cardiovascular/unexplained death and hemorrhagic stroke were higher in the warfarin group. In contrast, ischemic stroke was higher in the LAA closure group at 2.2 per 100 patient years compared with 1.6 per 100 patient years in the warfarin group (RR=1.34; 95% CrI, 0.60 to 4.29).

The primary safety outcome occurred more commonly in the LAA closure group, at a rate of 7.4 per 100 patient years compared with 4.4 per 100 patient years in the warfarin group (RR=1.69; 95% CrI, 1.01 to 3.19). The excess in adverse event rates for the LAA closure group was primarily the result of early adverse events associated with placement of the device. The most frequent type of complication related to LAA closure device placement was pericardial effusion requiring intervention, which occurred in 4.8% of patients (22/463).

Longer term follow-up from the PROTECT AF study was reported by Reddy et al in 2013 (Reddy, 2013). At a mean follow-up of 2.3 years, the results were similar to the initial report. The relative risk for the composite primary outcome in the Watchman group compared with anticoagulation was 0.71, and this met non-inferiority criteria with a confidence of greater than 99%. Complications were more common in the Watchman group, with an estimated rate of 5.6%/year in the Watchman group compared with 3.6%/year in the warfarin group. Outcomes through 4 years of follow-up were reported by Reddy et al in 2014.9 Mean follow-up was 3.9 years in the LAA closure group and 3.7 years in the warfarin group. In the LAA closure group, warfarin was discontinued in 345 of 370 patients (93.2%) by the 12 month follow-up evaluation. During the follow-up period, the relative risk for the composite primary outcome in the Watchman group compared with anticoagulation was 0.60 (8.4% in the device group vs 13.9% in the anticoagulation group; 95% CrI, 0.41 to 1.05), which met the non-inferiority criteria with a confidence of greater than 99.9%. Fewer hemorrhagic strokes occurred in the Watchman group (0.6% vs 4.0%; RR=0.15; 95% CrI, 0.03 to 0.49), and fewer cardiovascular events occurred in the Watchman group (3.7% vs 0.95%; RR=0.40; 95% CrI, 0.23 to 0.82). Rates of ischemic stroke did not differ significantly between groups, but Watchman group patients had lower all-cause mortality than anticoagulation group patients (12.3% vs 18.0%; HR=0.66; 95% CI, 0.45 to 0.98; p=0.04).

Alli et al reported quality-of-life parameters, as measured by change in scores on the Short-Form 12-Item Health Survey from baseline to 12-month follow-up, for a subset of 547 subjects in the PROTECT AF study (Alli, 2013). For the subset of PROTECT AF subjects included in the present analysis, at baseline, control group subjects had a higher mean CHADS2 score (2.4 vs 2.2; p=0.052) and were more likely to have a history of coronary artery disease (49.5% vs 39.6%; p=0.028). For subjects in the Watchman group, the total physical score improved in 34.9% and was unchanged in 29.9%; for those in the warfarin group, the total physical score improved in 24.7% and was unchanged in 31.7% (p=0.01).

PREVAIL

A second RCT, the PREVAIL trial, was conducted after the 2009 FDA decision on the Watchman device to address some of the limitations of the PROTECT AF study, including its inclusion of patients with low stroke risk (CHADS2 scores of 1), high rates of adjunctive antiplatelet therapy use in both groups, and generally poor compliance with warfarin therapy in the control group. Results from the PREVAIL trial were initially presented in FDA documentation (FDA, 2013) and published in peer-reviewed form by Holmes et al in 2014 (Holmes, 2014). In the PREVAIL trial, 461 subjects enrolled at 41 sites were randomized in a 2:1 fashion to either the Watchman™ device or control, which consisted of either initiation or continuation of warfarin therapy with a target international normalized ratio (INR) of 2.0 to 3.0. Subjects had nonvalvular AF and required treatment for prevention of thromboembolism based on a CHADS2 score of 2 or higher (or ≥1 with other indications for warfarin therapy based on American College of Cardiology/American Heart Association/European Society of Cardiology guidelines) and were eligible for warfarin therapy. In the device group, warfarin and low-dose aspirin were continued until 45 days postprocedure; if a follow-up echocardiogram at 45 days showed occlusion of the LAA, warfarin therapy could be discontinued. Subjects who discontinued warfarin were treated with aspirin and clopidogrel for 6 months post-device implantation and with 325 mg aspirin indefinitely after that. Three non-inferiority primary efficacy end points were specified: (1) occurrence of ischemic or hemorrhagic stroke, cardiovascular or unexplained death, and systemic embolism (18-month rates); (2) occurrence of late ischemic stroke and systemic embolization (beyond 7 days post-randomization, 18-month rates); and (3) occurrence of all-cause death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring open cardiac surgery or major endovascular intervention (eg, pseudoaneurysm repair, arteriovenous fistula repair, or other major endovascular repair) occurring within 7 days of the procedure or by hospital discharge, whichever was later. The 18-month event rates were determined using Bayesian statistical methods to integrate data from the PROTECT-AF study. All patients had a minimum follow-up of 6 months. For randomized subjects, mean follow-up was 11.8 months and median follow-up was 12.0 months (range, 0.03-25.9 months).

The first primary end point, the 18-month modeled RR between the device and control groups was 1.07 (95% CrI, 0.57 to 1.89). Because the upper bound of the 95% CrI was above the preset non-inferiority margin of 1.75, the non-inferiority criteria were not met. For the second primary end point of late ischemic stroke and systemic embolization, the 18-month RR between the device and control groups was 1.6 (95% CrI, 0.5 to 4.2), with an upper bound of the 95% CrI above the preset non-inferiority margin of 2.0. The rate difference between the device and control groups was 0.005 (95% CrI, -0.019 to 0.027). The upper bound of the 95% CrI was lower than the non-inferiority margin of 0.0275, so the non-inferiority criterion was met for the rate difference. For the third primary end point, major safety issues, the non-inferiority criterion was met.

Noncomparative Studies

In addition to these RCTs, a number of case series have reported on outcomes for the Watchman device. A number of small published case series are primarily intended to establish safety and feasibility of the device (Lam, 2011, Montenegro, 2012; Park, 2011; Reddy, 2011; Swaans, 2012). A larger case series of 143 patients from Europe was published in 2011 (Park, 2011). This series reported successful implantation in 96% (137/143) of patients and serious complications in 7.0% (10/143). Complications included stroke (n=3), device embolization (n=2), and pericardial effusion (n=5). Another larger series was reported by Reddy et al, (Reddy, 2011) primarily focusing on the adverse event rate from a registry of 460 patients who received the Watchman device. Serious pericardial effusion occurred in 2.2% of patients, and there were no deaths or periprocedural strokes reported. Matsuo et al reported results from a case series of 179 patients who underwent LAA closure at a single center, most (n=172) of whom received a Watchman device.18 Device deployment was successful in 98.9% of patients. The overall complication rate was 11.2%; major complications occurred in 3.3% (tamponade in 2 cases; possible transient ischemic attack [TIA] in 1 case; device dislocation in 3 cases). At 45-day follow-up, 99.4% of patients (164/166) had closure of the LAA.

Section Summary: Watchman Device in Patients Eligible for Anticoagulation

The most relevant evidence related to the use of the Watchman device for LAA closure in patients who are eligible for anticoagulation is from 2 industry-sponsored RCTs and a patient-level meta-analysis of those studies. These studies suggest that the Watchman is associated with an increased periprocedural ischemic stroke risk, which is balanced against a decreased hemorrhagic stroke risk.

Patients With Contraindications to Anticoagulation

The PROTECT AF and PREVAIL studies included only patients who were candidates for oral anticoagulation therapy based on stroke risk and were able to receive oral anticoagulation. As such, uncertainty remains about the role of the Watchman device in patients with AF who have absolute contraindications to oral anticoagulants. Reddy et al conducted a multicenter, prospective, nonrandomized trial to evaluate the safety and efficacy of LAA closure with the Watchman device in patients with nonvalvular AF with a CHADS2 score 1 or higher who were considered ineligible for warfarin (Reddy, 2013). Postimplantation, patients received 6 months of clopidogrel or ticlopidine and lifelong aspirin therapy. Thirteen patients (8.7%) had a procedure- or device-related serious adverse event, most commonly pericardial effusion (3 patients). Over a mean 14.4 months of follow-up, all-cause stroke or systemic embolism occurred in 4 patients.

Chun et al compared the Watchman™ device with the Amplatzer cardiac plug among patients with nonvalvular AF, who were at high risk for stroke and had a contraindication to or were not willing to accept oral anticoagulants (Chun, 2013). Eighty patients were randomized to LAA occlusion with the Watchman™ or the Amplatzer device. After device implantation, either preexisting oral anticoagulation therapy or dual platelet inhibition with aspirin and clopidogrel was continued for 6 weeks. A follow-up transesophageal echocardiogram was performed at 6 weeks postprocedure; if a device-related thrombus had formed, patients received intensive antithrombotic therapy for 6 weeks. Aspirin was continued indefinitely for all patients. The primary end point of successful device implantation occurred in 98% of patients. There were no statistically significant differences in procedure time, fluoroscopy time, or major safety events between the 2 groups. At a median 364 days of follow-up, there were no cases of stroke/TIA or other bleeding complications.

Lariat® Device

The available evidence on the efficacy of the Lariat device for LAA closure consists of a number of small case series. The largest case series was reported by Price et al in 2014 in retrospective multicenter study of early outcomes after use of the Lariat device (Price, 2014). This study included 154 patients with a median CHADS2 score of 3. Device success, defined as suture deployment and a residual shunt less than 5 mm, was achieved in 94% of patients. Procedural success, defined as device success and no major complication (death, MI, stroke, major bleeding, or emergency surgery) at hospital discharge, was achieved in 86% of patients. Fifteen patients (10%) had at least 1 major periprocedural complication, and 10% had significant pericardial effusion. Of the 134 patients (87%) who had out-of-hospital outcome data available, the composite out-of-hospital outcome of death, MI, or stroke occurred in 4 patients (2.9%).

In 2013, Bartus et al reported results of a case series that enrolled 89 patients with AF and either a contraindication to warfarin or previous warfarin failure (Bartus, 2013). A total of 85 of 89 (96%) had successful left atrial ligation, and 81 of 89 (91%) had complete closure immediately. There were 3 access-related complications, 2 cases of severe pericarditis postoperatively, 1 late pericardial effusion, and 2 cases of unexplained sudden death. There were 2 late strokes, which the authors did not attribute to an embolic source. At 1-year follow-up, complete closure was documented by echocardiography in 98% of available patients (n=65). In a smaller, earlier series from the same research group,(Bartus, 2011) 13 patients were treated with the Lariat device, 11 of whom were treated as part of percutaneous radiofrequency ablation for AF. One of the 11 procedures was terminated due to unsuccessful placement, and the other 10 procedures were successful, with complete closure verified on echocardiography. There was 1 procedural complication in which the snare could not be removed and were retrieved by thoracoscopy.

In 2015, Stone et al reported outcomes for 27 patients with AF, a high stroke risk (CHADS2 score ≥2), and contraindications or intolerance to anticoagulation who underwent percutaneous LAA ligation with the Lariat device (Stone, 2015). Acute procedural success was 92.6%; periprocedural complications included 3 cases of pericarditis and 1 periprocedural stroke associated with no long-term disability. A follow-up transesophageal echo was performed in 22 patients at an average of 45 days postprocedure, which demonstrated successful LAA exclusion in all 22. Follow-up was for an average of 4 months, during which time 1 stroke and no deaths occurred.

Massumi et al reported on 21 patients with AF and contraindications to anticoagulation (Massumi, 2013). Twenty of 21 patients had successful atrial closure, which was documented by echocardiography to be intact at a mean follow-up of 96 days. No patients had a stroke during a mean follow-up of approximately 1 year. Complications were reported in 5 of 21 patients. One patient had right ventricular perforation and tamponade requiring surgical intervention. One patient developed pleuroperidicarditis that required multiple drainage procedures. Three additional patients developed pericarditis within 30 days of the procedure.

Amplatzer® Cardiac Plug Device

The available evidence on use of the Amplatzer device for left atrial occlusion consists of a number of case series. The largest series identified was by Nietlispach et al, which included 152 patients from a single institution in Europe (Nietlispach, 2013). Short-term complications occurred in 9.8% (15/152). Longer term adverse outcomes occurred in 7% of patients, including 2 strokes, 1 peripheral embolization, and 4 episodes of major bleeding. Device embolization occurred in 4.6% (7/152) of patients.

Other series of patients treated with the Amplatzer device include a series of 90 patients from Belgium,(Kefer, 2013) 86 patients from Portugal,(Guerios, 2012) 37 patients from Italy, (Danna, 2013) 35 patients from Spain,(Lopez-Minguez, 2013) 21 patients from Poland,(Streb, 2013) and 20 patients from China (Lam, 2012). All series reported high procedural success, as well as various complications such as vascular complications, air embolism, esophageal injury, cardiac tamponade, and device embolization.

Several studies have reported the use of the Amplatzer device in patients with a contraindication to oral anticoagulation therapy. The largest study reported outcomes, up to 4 years postprocedure, for 134 patients with nonvalvular AF and a long-term contraindication to oral anticoagulation treated with the Amplatzer device (Santoro, 2014). Patients had a median CHA2DS2-VASc score of 4 and were generally considered at high risk for bleeding complications. Postprocedural antithrombotic therapy was tailored to the patient’s individual risk profile, but the authors described that, generally, short-term dual antiplatelet therapy (1-2 months) and subsequent indefinite single antiplatelet therapy were prescribed after successful device implantation. Procedural success occurred in 93.3%, and 3 major procedure-related complications (2 cases of cardiac tamponade, 1 case of pericardial effusion requiring drainage or surgery) occurred. Over a mean follow-up of 680 days, observed annual rates of ischemic strokes and any thromboembolic events were 0.8% and 2.5%, respectively.

Meerkin et al reported outcomes for 100 patients with AF, a CHADS2 score of 2 or higher, and a contraindication to oral warfarin who were treated with the Amplatzer device at a single institution (Meerkin, 2013). All patients were treated with heparin during the procedure; they were maintained on clopidogrel for 1 month postprocedure and daily aspirin indefinitely. Successful deployment occurred in all patients. There were 2 significant periprocedural complications, including 1 pericardial effusion with tamponade and 1 case of acute respiratory distress with pulmonary edema.

Wiebe et al reported results of a retrospective cohort of 60 patients with nonvalvular AF who had a CHADS2-VASc score of at least 1 and contraindications to warfarin anticoagulation who underwent percutaneous LAA closure with the Amplatzer device (Wiebe, 2014). Contraindications to warfarin included contraindications as defined in the warfarin product label, a history of severe bleeding while receiving anticoagulant therapy, as well as a history of bleeding tendencies in the absence of anticoagulation or blood dyscrasia, along with patients who were unable to maintain a stable INR and those with a known hypersensitivity to warfarin or a high-risk of falling who were also included. Patients received heparin during the closure procedure; they were maintained on clopidogrel for 3 months postprocedure and daily aspirin indefinitely. Device implantation was successful in 95% of patients. Over a median follow-up of 1.8 years, no patients experienced a stroke. The rate of major bleeding complications was 1.9%/year of follow-up.

Urena et al reported results from a similar cohort of 52 patients with nonvalvular AF who had a CHADS2-VASc score of at least 2 and contraindication to oral anticoagulation therapy who underwent percutaneous LAA closure with the Amplatzer device (Urena, 2013). Device implantation was successful in all but 1 patient. There were no periprocedural strokes or death. Over the follow-up period (mean, 20 months), rates of death, stroke, and systemic embolism were 5.8 (3/52), 1.9% (1/52), and 0%, respectively.

Other smaller case series of patients with contraindication to oral anticoagulation include studies by Danna et al,(Danna, 2013) which included 37 patients and reported a 1-year stroke rate of 2.94%, and Horstmann et al,(Horstmann, 2014) which included 20 patients and reported no episodes of strokes over a mean follow-up of 13.6 months.

Gloekler et al compared outcomes for nonvalvular AF patients treated with the first-generation Amplatzer cardiac plug (n=50) and those treated with the second-generation Amulet device (n=50) in a retrospective analysis of prospectively collected data (Gloekler, 2015). There were no significant differences between devices in terms of safety outcomes.

PLAATO Device

The available evidence on outcomes following use of the PLAATO device for stroke prevention in AF comes from case series and cohort studies. Bayard et al reported on 180 patients with nonrheumatic AF and a contraindication to warfarin and who were treated with the Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) device (Bayard, 2010). Placement was successful in 90% of patients. Two patients died within 24 hours of the procedure (1.1%), and 6 patients had cardiac tamponade (3.3%), with 2 requiring surgical drainage. Other case reports and small case series report complications, including multiple reports of thrombus formation at the site of device placement (Cruz-Gonzalez, 2011; Viles-Gonzalez, 2012).

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed below:

Ongoing

NCT02039167 WATCH Bleeding Episodes After Left Atrial Appendage Occlusion Versus Usual Care in Patients With Atrial FIBrillatIon and Severe to eNd-stage Chronic Kidney Disease (WatchAFIB in CKD). This study has a planned enrollment of 300 with a completion date of June 2017.

Unpublished

NCT01363895 Interventional Strategies in Treatment of Atrial Fibrillation: Percutaneous Closure of the Left Atrial Appendage Versus Catheter Ablation

NCT01628068 Efficacy of Left Atrial Appendage Closure After Gastrointestinal Bleeding

NCT01118299 AMPLATZER Cardiac Plug Clinical Trial

Summary of Evidence

The evidence for the use of the Watchman device for stroke prevention in patients with atrial fibrillation (AF) who are candidates for oral anticoagulation includes 2 randomized controlled trials (RCTs) and a patient-level meta-analysis of these trials. Relevant outcomes are overall survival, morbid events, and treatment-related morbidity. The most relevant evidence comes from 2 industry-sponsored RCTs that compared the Watchman device with anticoagulation. One trial reported non-inferiority on a composite outcome of stroke, cardiovascular/unexplained death, or systemic embolism after 2 years of follow-up, with continued benefits with the Watchman after 4 years of follow-up. The second trial did not demonstrate non-inferiority for the same composite outcome, but did demonstrate non-inferiority of the Watchman device to warfarin for late ischemic stroke and systemic embolization. A patient-level meta-analysis of the 2 trials suggested that the Watchman is associated with a periprocedural risk of ischemic stroke but a lower risk of hemorrhagic stroke over the long term. The published evidence is sufficient to determine that the Watchman device is efficacious in preventing stroke for patients with AF who are eligible to receive systemic anticoagulation. When it is determined on an individualized basis that the long-term risk of systemic anticoagulation exceeds the procedural risk of device implantation, the net health outcome will be improved. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

The evidence for the use of left atrial appendage (LAA) closure devices other than the Watchman (eg, the Lariat, PLAATO, and Amplatzer devices) for stroke prevention in patients with AF includes uncontrolled case series. Relevant outcomes are overall survival, morbid events, and treatment-related morbidity. Case series of these devices report high procedural success but also numerous complications. In addition, these devices do not have the U.S. Food and Drug Administration (FDA) approval for LAA closure. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

American College of Cardiology, Heart Rhythm Society, et al

In 2015, the American College of Cardiology (ACC), Heart Rhythm Society (HRS), and Society for Cardiovascular Angiography and Interventions published an overview of the integration of percutaneous LAA closure devices into the clinical practice of patients with AF (Masoudi, 2015). The overview was organized around questions related to the sites of care delivery for LAA closure devices, training for proceduralists, necessary follow-up data collection, identification of appropriate patient cohorts, and reimbursement. The statement provides general guidelines for facility and operator requirements, including the presence of a multidisciplinary heart team, for centers performing percutaneous LAA closures. The statement does not provide specific recommendations about the indications and patient populations appropriate for percutaneous LAA closure.

American College of Cardiology, American Heart Association, et al

In 2014, the ACC, American Heart Association, and HRS issued guidelines on the management of patients with AF (January, 2014). These guidelines recommend that surgical excision of the LAA may be considered in patients undergoing cardiac surgery (class IIB recommendation; level of evidence: C), but make no specific recommendations regarding percutaneous LAA closure.

American College of Chest Physicians

In 2012, the American College of Chest Physicians published evidence-based clinical best practice guidelines on the use of antithrombotic therapy for prevention of stroke in AF (You, 2012). In relation to the use of LAA closure devices, the guidelines state: “At this time, we make no formal recommendations regarding LAA closure devices, pending more definitive research in this field.”

2017 Update

A literature search conducted through July 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Systematic Reviews

A number of meta-analyses have been performed that combine results of the available RCTs (Bode, 2015; Briceno, 2015; Holmes, 2015; Li, 2015; Lip, 2015; Noelck, 2016; Sahay, 2017). Others have included RCTs and observational studies (Li, 2016; Wei, 2016; Tereshchenko, 2016).

Systematic reviews have used network meta-analyses to compare Watchman with novel oral anticoagulants and vitamin K antagonists (6 RCTs, total N=59,627 subjects) (Bajaj, 2016), and have compared percutaneous left atrial appendage (LAA) occlusion (5 RCTs, total N=1285 subject) with standard anticoagulant or antiplatelet therapy with device-based surgical or percutaneous LAA exclusion (Hanif, 2017).

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed below:

Ongoing:

(NCT01182441) Evaluation of the Watchman LAA closure device in patients with atrial fibrillation versus long term warfarin therapy; planned enrollment 475; projected completion date August 2017

(NCT02426944) Left Atrial Appendage Closure vs Novel Anticoagulation Agents in Atrial Fibrillation; planned enrollment 400; projected completion date May 2020

(NCT02879448) AMPLATZER™ Amulet™ Left Atrial Appendage Occluder Randomized Controlled Trial; planned enrollment 1600; projected completion date December 2023

2018 Update

Annual policy review completed with a literature search using the MEDLINE database through May 2018. The key identified literature is summarized below.

WATCHMAN DEVICE

Reddy et al presented final results of the PROTECT AF trial and PREVAIL AF trial and conducted a meta-analysis of 5-year outcomes using data from both trials (Reddy, 2017). Meta-analytic results show that the Watchman device is noninferior to warfarin alone in stroke prevention among patients with nonvalvular AF. Also, patients treated with the Watchman device experienced significantly lower bleeding and mortality.

2019 Update

A literature search was conducted through May 2019. There was no new information identified that would prompt a change in the coverage statement.

2020 Update

A literature search was conducted through May 2020. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Litwinowicz et al compared outcomes of patients undergoing LAA closure with the Lariat device (n=57) with patients receiving either warfarin or clopidogrel (n=31) (Litwinowicz, 2019). Age, sex, and comorbidities were similar between the 2 groups. Treatment prior to the study differed significantly. The Lariat group received warfarin (93%), aspirin (4%), aspirin plus clopidogrel (2%) and no anticoagulation (1%). The control group received warfarin (87%) or clopidogrel (13%). However, there was no significant difference in CHA2DS2-VAS scores between the groups at baseline. Average follow-up in the Lariat group was 59 months and average follow-up in the control group was 60 months. There were no thromboembolic events in the Lariat group, while 9.6% of the control group experienced thromboembolic events (p=.02). The bleeding risk reduction in the Lariat group was estimated at 53%.

Cruz-Gonzales et al, in their retrospective registry study, aimed to evaluate the safety and efficacy of LAA occlusion for patients with nonvalvular AF with prior stroke or TIA despite anticoagulant therapy (resistant stroke [RS]) (Cruz-Gonzales, 2020). They assessed data from the Amplatzer Cardiac Plug multicenter registry on 1047 consecutive patients with nonvalvular AF undergoing LAA occlusion. Out of the 1047, 115 had RS and 932 had other indications. There were no significant differences in baseline characteristics between the 2 groups. The RS group had a significantly higher mean CHA2-DS2-VASc score (5.5±1.5 in the RS group vs. 4.6±1.6 in the non-stroke group; p<.001) and HAS-BLED score (3.9±1.3 vs. 3.1±1.2; p<.001). There were no significant differences between groups in procedural success or periprocedural major safety events (7.8% vs. 4.5%; p=.1). All patients completed at least 1 year of follow-up. At follow-up, the observed annual rate of stroke or TIA was 2.6% (65% relative reduction of thromboembolism based on the CHA2-DS2-VASc score) in the RS group and 1.2% (78% relative risk reduction) for the non-stroke group. In addition, the observed annual major bleeding rate was 0% (100% relative reduction based on the HAS-BLED score) for RS patients and 1.2% (79% relative reduction) for those without prior stroke/TIA. Although larger controlled trials are needed, LAA occlusion showed significant benefit to patients who had had a previous stroke or TIA.

American Heart Association

The American Heart Association, in collaboration with the American College of Cardiology and the Heart Rhythm Society, published an update of their guideline for the management of patients with atrial fibrillation (AHA, 2019). A new recommendation in the guideline states: "Percutaneous LAA occlusion may be considered in patients with AF at increased risk of stroke who have contraindications to long-term anticoagulation." The class of recommendation is IIb and the level of evidence is B_NR (moderate quality of evidence, nonrandomized). No other LAA closure devices are mentioned in the guideline.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

The therapy being considered is use of the Watchman percutaneous LAAC device and the Watchman FLX device (a next generation device based on the design of the original Watchman device) (FDA, 2021). The devices are made of nickel titanium and are implanted percutaneously through a catheter, into the left atrium. The Watchman devices come in 5 sizes and self-expand to occlude the LAA. By occluding the LAA, thrombus formation is prevented, potentially preventing stroke. Following implantation of the device, the patient receives anticoagulation for 1 to 2 months. Once it is established that there is no peridevice leak or thrombus development, the patient is then placed on antiplatelet agents indefinitely.

Osmancik et al published the LAAC versus Novel Anticoagulation Agents in AF (PRAGUE-17) study, a multicenter, randomized, noninferiority study that compared use of LAAC to direct oral anticoagulants in high risk patients with nonvalvular AF (Osmancik, 2020). Patients were included if they had a history of bleeding requiring intervention or hospitalization, history of cardioembolic event while taking an anticoagulant, or CHA2DS2-VASc score ≥3 with a HAS-BLED score ≥2. Patients either received LAAC (n=181) with either the Amulet or Watchman/Watchman FLX devices based on discretion of the implanting center, or a direct oral anticoagulant (rivaroxaban, apixaban, or dabigatran) (n=201).

The primary endpoint was a composite of ischemic or hemorrhagic stroke or transient ischemic attack (TIA), systemic embolism, clinically significant bleeding, cardiovascular death, or significant peri-procedural or device-related complications. At baseline, the mean CHA2DS2-VASc score was 4.7 and HAS-BLED score was 3.1. Follow-up was 20.8 months. Of the LAAC group, 61.3% received an Amulet, 35.9% received a Watchman device, and 2.8% received a Watchman-FLX device. The primary endpoint occurred in 41 patients (47 events) in the direct oral anticoagulant group (13.42 event rate per year) compared to 35 patients (38 events) in the LAAC group (10.99 event rate per year) (subdistribution HR, 0.84; 95% CI, 0.53 to 1.21; p-value for noninferiority, p=.004). All stroke/TIA events occurred in 9 patients (9 events) in each group, subdistribulation HR, 1.0 (95% CI, 0.40 to 2.51). Results were not divided by type of LAAC device received. Significant procedure- or device-related complications occurred in 9 patients in the LAAC group. Early complications (≤ 7 days) included device embolization (n=1), procedure-related death (n=1), and vascular complications (n=2), while late complications (>7 days) included pericardial effusion (n=2), device-related death (n=1), and other complications (n=2). The procedure-related death was due to a femoral vascular access bleed and myocardial infarction. The device-related death occurred with the Amulet device due to a pericardial effusion approximately 6 weeks after the procedure.

Landmesser et al and Hildick-Smith et al provided updated analyses on 950 patients and 864 patients from the registry series described above who had 1-year and 2-year follow-up data (Landmesser, 2018; Hildick-Smith, 2020). Oral anticoagulants were used by 6% of the patients at 3, 6, and 12 months postprocedure and 6.6% of patients at 2 years. At year 1, there were 29 ischemic strokes (27 patients), 9 patients experiencing a TIA, and no systemic embolisms reported. At year 2, there were 42 ischemic strokes (39 patients), 20 TIA events (16 patients; 9 events over the first year and 11 over the second year) and no systemic embolisms reported. The annualized bleeding rate was 10.1% per year in year 1 (103 events per 1016 patient-years) and 4.0% per year in year 2 (37 events per 917 patient-years). The proportion of patients experiencing a major bleeding event was 8.0% over the first year (87 of 1088 patients) and 3.2% over the second year (31 of 958 patients). The DRT rate was 1.6% at 2 years, with 19 events in 17 patients. There were 91 and 70 deaths reported in the first and second years, respectively, with 55 deaths considered cardiovascular-related, 71 non-cardiovascular-related, and 35 with unknown causes.

Nielsen-Kudsk et al compared patients from the Amulet Observational Registry described above (n=1088) with a successful LAAC (n=1078) compared with a control cohort of patients with AF treated with direct oral anticoagulants (n=1184) (Nielsen-Kudsk, 2021). The direct oral anticoagulant cohort consisted of patients selected by propensity score matching based on CHA2DS2-VASc and HAS-BLED covariates among patients from Danish registries. The primary outcome was a composite of ischemic stroke, major bleeding, or all-cause mortality at 2 years. At baseline, the CHA2DS2-VASc scores were 4.2 and 4.3 and the HAS-BLED scores were 3.3 and 3.4 in the LAAC and direct oral anticoagulant groups, respectively. At 2 years follow-up, 58% of patients had discontinued the direct oral anticoagulant. The primary outcome of ischemic stroke, major bleeding, and mortality was lower with LAAC (256 events; 14.5 event rate per 100 patient-years) compared with the direct oral anticoagulant group (461 events; 25.7 event rate per 100 patient-years) (HR, 0.57; 95% CI, 0.49 to 0.67). Ischemic stroke was not significantly different between groups (HR, 1.11; 95% CI, 0.71 to 1.75). Major bleeding (HR, 0.62; 95% CI, 0.49 to 0.79), all-cause mortality (HR, 0.53; 95% CI, 0.43 to 0.64), and cardiovascular mortality (HR, 0.51; 95% CI, 0.37 to 0.70) were reduced with LAAC compared to direct oral anticoagulants.

2021 Update (November)

Annual policy review completed with a literature search using the MEDLINE database through September 2021. The key identified literature is summarized below.

Lakkireddy et al in the Amulet IDE trial, a prospective, randomized, multi-center active control worldwide trial evaluated the safety and effectiveness of the Amplatzer Amulet Left Atrial Appendage Occluder versus the Boston Scientific Watchman LAA closure device. A total of 1878 patients were enrolled. Primary endpoints included safety, effectiveness, and the rate of LAA occlusion at 45 days. Pre-specified secondary endpoints included a composite of all stoke, systemic embolism or cardiovascular/unexplained death at 18 months, major bleeding at 18 months and superiority test of the three primary endpoints. The Amulet occluder was found to be noninferior to the Watdchman device for the primary safety endpoint (14.5% vs. 14.7%; difference=-0.14, 95% CI, -3.42-3.13; p<0.001 for noninferiority). Major bleeding and all-cause death were similar between groups (10.6% vs 10.0% and 3.9% vs 5.1%, respectively). Procedure-related complications were higher for the Amulet occluder (4.5% vs. 2.5%), largely related to more frequent pericardial effusion and device embolization. The Amulet occluder was noninferior to the Watchman device for the primary effectiveness endpoint (2.8% vs. 2.8%; difference=0.00, 95% CI, -1.55-1.55; p<0.001 for non-inferiority), and the composite of stroke, systemic embolism or cardiovascular/unexplained death (5.6% vs 7.7%, difference=-2.12, 95% CI, -4.45-0.21; p<0.001 for noninferiority). The rate of major bleeding was similar between groups (11.6% vs. 12.3%; difference=-0.71, 95% CI -3.72-2.31; p=0.32 for superiority). LAA occlusion was higher for the Amulet occluder compared with the Watchman device (98.9% vs. 96.8%; difference=2.03, 95% confidence interval [CI], 0.41-3.66; p<0.001 for noninferiority; p=0.003 for superiority). Lakkireddy et al concluded the Amulet occluder was non-inferior for safety and effectiveness of stroke prevention for NVAF in comparison to the Watchman device and superior for LAA occlusion. The Amulet device had a higher procedure-related complication rate but decreased with operator experience (Lakkireddy, 2021).

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

A review conducted by Takeda et al included 11 observational studies (N=24,055) comparing the Watchman and Amulet devices and direct-acting oral anticoagulants (Takeda, 2022). In pooled analyses of studies of the Watchman device (5 studies) and anticoagulants (3 studies) event incidence per person-years was similar for all-cause mortality (0.06; 95% CI 0.02 to 0.10 vs. 0.03; 95% CI 0.01 to 0.04), stroke (0.02; 95% CI 0.00 to 0.04 vs. 0.01; 95% CI 0.01 to 0.02) and major bleeding (0.04; 95% CI 0.02 to 0.06) vs. 0.02; 95% CI 0.01 to 0.03).

In 2020, Osmancik et al published the LAAC versus Novel Anticoagulation Agents in AF (PRAGUE-17) study which is discussed above in the 2021 update. In 2022, longer-term results were subsequently published by Osmancik et al (Osmancik, 2022). After 3.5 years of follow-up, there was no significant difference in risk of the primary endpoint between the LAAC and direct oral anticoagulant groups (subdistribution HR, 0.81; 95% CI 0.56 to 1.18) Significant procedure- or device-related complications occurred in 9 patients in the LAAC group. Early complications (≤ 7 days) included device embolization (n=1), procedure-related death (n=1), and vascular complications (n=2), while late complications (>7 days) included pericardial effusion (n=2), device-related death (n=1), and other complications (n=2). The procedure-related death was due to a femoral vascular access bleed and myocardial infarction. The device-related death occurred with the Amulet device due to a pericardial effusion approximately 6 weeks after the procedure.

Two randomized noninferiority trials (SWISS-APERO and Amulet IDE, described below) have been reported comparing the Amplatzer Amulet and Watchman devices, but neither included an anticoagulant group (Lakkireddy, 2021; Galea, 2022). A third trial (PRAGUE-17) compared either the Amulet or Watchman device with anticoagulants, but did not report subgroup analysis according to the device. The ongoing Clinical Trial of Atrial Fibrillation Patients Comparing Left Atrial Appendage Occlusion Therapy to Non-vitamin K Antagonist Oral Anticoagulants (CATALYST; NCT04226547), comparing the Amplatzer Amulet device with non-vitamin K antagonist oral anticoagulants, is expected to have primary completion in December 2024

The Comparison of Amulet Versus Watchman/FLX Device in Patients Undergoing Left Atrial Appendage Closure (SWISS-APERO) trial conducted by Galea et al compared the Amulet and Watchman devices in 221 participants with non-valvular AF (Galea, 2022). The enrolled participants were at high risk for stroke (mean CHA2DS2-VASc score 4.3; 39% had a history of prior stroke) and bleeding (mean HAS-BLED score 3.1; 88% had a history of bleeding requiring medical evaluation). Participants were primarily male (70%) and mean age was 77 years. Outcome assessment focused on successful closure, based on a composite outcome of either treatment group crossover during the LAAC procedure or residual LAA patency at 45 days post-intervention, based on CT angiography. The study found no difference in treatment between groups in the composite outcome (RR, 0.97; 95% CI 0.80 to 1.16). Major procedure-related complications were more common with the Amulet versus the Watchman device (9.0% vs. 2.7%; p=.047) There were 6 deaths during the trial, including 2 in the Amulet group (1.8%) and 4 in the Watchman group (3.6%; p=.409). Limitations of the study include the lack of an anticoagulant control group and the short duration of follow-up, although planned trial follow-up is ongoing. In addition, the actual Watchman device used was changed during the course of the trial due to a new device (Watchman FLX) version becoming available.

Lakkireddy et al reported the results of the Amplatzer Amulet Left Atrial Appendage Occluder IDE Trial (Amulet IDE) comparing the Amulet and Watchman devices (Lakkireddy, 2021). The study enrolled 1,878 patients with non-valvular AF at high-risk for stroke (mean CHA2DS2-VASc score 4.5 and 4.7) and bleeding (mean HAS-BLED score 3.2 and 3.3). The mean age of enrolled patients was 75 years and 59% were male; race and ethnicity were not reported. Twenty-eight percent of enrolled participants had a history of major bleeding and 19 percent had a history of stroke. The primary efficacy endpoint was a composite that included ischemic stroke or systemic embolism, while the safety analysis included a primary composite outcome of all-cause mortality, major bleeding or procedure-related complications. Duration of follow-up was 18 months for efficacy outcomes and 12 months for safety outcomes. After 18 months, there was no difference in the composite efficacy outcome between the Amulet and Watchman devices (HR, 0.00; 95% CI, -1.55 to 1.55). Results were consistent in showing no difference between groups when considering ischemic stroke and systemic embolism as individual outcomes. There was also no difference between Amulet and Watchman groups for a secondary composite outcome that included any stroke, systemic embolism or sudden cardiac death (HR, -2.12; 95% CI, -4.45 to 0.21), nor were there differences between groups when these outcomes were considered individually. In terms of safety, there was no difference between the Amulet and Watchman groups for the composite safety outcome at 12 months (HR, -0.14; 95% CI, -3.42 to 3.13). When outcomes were considered separately, there was also no difference between the Amulet and Watchman groups for all-cause mortality or major bleeding. Procedure-related complications were more likely to occur with the Amulet versus the Watchman devices (HR, 1.86; 95% CI, 1.11 to 3.12). Follow-up is planned to continue through 2024.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

The AHA released a scientific statement in 2021 about managing AF in patients with heart failure and reduced ejection fraction (Gopinathannair, 2021). They state that, "It is reasonable to consider LAA closure in patients with AF and heart failure with reduced ejection fraction (HFrEF) with moderate to high stroke risk and contraindications to long-term oral anticoagulation", however, they also note that the role of LAA therapies in patients with AF with HFrEF needs to be better understood, and this is an opportunity for future research.

CPT/HCPCS:

33267	Exclusion of left atrial appendage, open, any method (eg, excision, isolation via stapling, oversewing, ligation, plication, clip)
33268	Exclusion of left atrial appendage, open, performed at the time of other sternotomy or thoracotomy procedure(s), any method (eg, excision, isolation via stapling, oversewing, ligation, plication, clip) (List separately in addition to code for primary proc
33269	Exclusion of left atrial appendage, thoracoscopic, any method (eg, excision, isolation via stapling, oversewing, ligation, plication, clip)
33340	Percutaneous transcatheter closure of the left atrial appendage with endocardial implant, including fluoroscopy, transseptal puncture, catheter placement(s), left atrial angiography, left atrial appendage angiography, when performed, and radiological supervision and interpretation

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