Medical Policy

This document addresses the transcatheter closure of patent foramen ovale and transcatheter or open left atrial appendage (LAA) closure. The procedures may be performed to prevent stroke using cardiac occlusion devices.

Note: This document does not address the percutaneous transcatheter closure of atrial septal defects (ASDs).

Note: This document does not address surgical ligation or amputation of the LAA when the surgical method does not involve use of an LAA device.

Note: Please see the following related document for additional information:

• SURG.00096 Surgical and Ablative Treatments for Chronic Headaches

Medically Necessary:

Transcatheter closure of a patent foramen ovale (PFO) using a U.S. Food and Drug Administration (FDA) approved device approved for that indication is considered medically necessary for:

1. The prevention of subsequent stroke in individuals with a history of cryptogenic stroke when either criteria set below are met:
   1. 60 years old and younger and the following:
      1. an atrial septal aneurysm; or
      2. a large interatrial shunt (see definition section).
   2. Any age and the following:
      1. Have failed conventional drug therapy (for example, warfarin); or
      2. Are not candidates for conventional drug therapy.

Transcatheter closure of left atrial appendage (LAA) is considered medically necessary in individuals when the following criteria are met:

1. Non-valvular atrial fibrillation; and
2. For prevention of stroke; and
3. Candidate for long-term anticoagulation therapy based upon their estimated risk of stroke and other thromboembolic events; and
4. Ineligible for long-term oral anticoagulation therapy (for example, a direct oral anticoagulant [apixaban, dabigatran, edoxaban, or rivaroxaban] or warfarin) due to the presence of contraindication(s) (for example, an increased risk of bleeding), but is expected to be able to tolerate short-term oral anticoagulation necessary for device implantation.

Not Medically Necessary:

Transcatheter closure of a PFO for the prevention of stroke is considered not medically necessary when the criteria above are not met.

Transcatheter closure of a left atrial appendage is considered not medically necessary when the criteria above are not met.

Investigational and Not Medically Necessary:

Transcatheter closure of a PFO is considered investigational and not medically necessary for all other indications (for example, migraines, decompression sickness, and platypnea-orthodeoxia syndrome).

Left atrial appendage closure via surgical (non-percutaneous) implantation of a device is considered investigational and not medically necessary for all indications.

Transcatheter Closure of Patent Foramen Ovale (PFO)

A transcatheter PFO occluder is a permanently implanted device that provides a non-surgical method for PFO closure, blocking clots from passing from the right atrium to the left atrium.

On October 28, 2016, the FDA granted premarket approval for the AMPLATZER^™ PFO Occluder (Abbott Medical, Plymouth, MN). The device is indicated for percutaneous transcatheter closure of a PFO to reduce the risk of recurrent ischemic stroke in individuals (predominantly between ages 18 to 60 years of age) who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke. On September 27, 2021, the FDA granted premarket approval for the AMPLATZER^™ Talisman^™ PFO Occluder (Abbott Medical, St. Paul, MN); a line extension of the current AMPLATZER PFO Occluder Product Family (AMPLATZER Talisman PFO Occluder Product Information, 2021).

In 2013, Carroll and colleagues conducted the RESPECT trial (NCT00465270), a prospective, multicenter, randomized study that enrolled individuals aged 18 to 60 years with a PFO and history of a cryptogenic stroke. Participants were randomized (1:1) to either the device group with PFO closure using the AMPLATZER PFO Occluder or the medical management group with four medical regimens allowed (aspirin alone, Coumadin alone, clopidogrel alone, or aspirin combined with dipyridamole). The primary efficacy endpoint was a composite outcome, which included recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization (for example, death from any cause within 30 days after implantation or 45 days after randomization, whichever occurred later, and in the medical-therapy group, death from any cause within 45 days after randomization). Secondary efficacy endpoints included complete closure of the PFO on the 6-month follow-up transesophageal echocardiography (TEE), the absence of recurrent symptomatic nonfatal ischemic stroke or cardiovascular death, and absence of a TIA. The investigators designed the trial to have 80% power and a 2-sided alpha level of 0.05 to detect a 75% relative risk reduction (based on the assumption that the 2-year primary endpoint rate would be 4.3% in the medical management group and 1.05% in the closure group). A total of 980 individuals participated with 499 randomly assigned to the closure group and 481 to the medical management group. In the intention-to-treat (ITT) analysis, a total of 25 primary end-point events occurred (9 in the closure group and 16 in the medical management group), all of which were nonfatal ischemic strokes (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.22 to 1.11; p=0.08). The rates of recurrent stroke differed in the per-protocol and medical management group (p=0.03) and the as-treated group and medical management group (p=0.007). There was no difference in the rate of serious adverse events between the groups. The authors concluded that:

In patients between 18 and 60 years of age who had had a cryptogenic ischemic stroke, there was no significant benefit of closure of a patent foramen ovale over medical therapy alone in the intention-to-treat analysis. The superiority of closure with the use of the Amplatzer PFO Occluder was shown in two prespecified secondary analyses, with a low rate of associated risks.

In 2017, Saver and colleagues conducted an exploratory analysis to report long-term results from the RESPECT trial (NCT00465270) that compared PFO closure with AMPLATZER PFO Occluder (PFO closure group) to medical therapy alone (that is, aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole) for individuals at risk of recurrence of ischemic stroke who had cryptogenic stroke. Of the 980 individuals who enrolled in the original trial, 716 (73.1%) were included in the long-term analysis. Median follow-up was 5.9 years with a greater dropout rate in the medical therapy only group. In the ITT population, there were 18 participants in the PFO closure group that had recurrent ischemic stroke and in the medical therapy alone group there were 28 participants. A total of 10 participants in the PFO closure group and 23 participants in the medical therapy alone group had recurrent ischemic stroke of undetermined cause. The authors found that:

The rate of venous thromboembolism in both groups exceeded that in healthy populations, which suggests that persons who have had a cryptogenic stroke and also have a PFO have a mildly elevated long-term risk of venous thromboemboli. In our trial, the lower intensity of antithrombotic therapy, including the less common agents, in the PFO closure group than in the medical-therapy group may have contributed to the higher rate of venous thromboembolism in the PFO closure group.

Among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up. The relative difference in the rate of recurrent ischemic stroke between PFO closure and medical therapy alone was large (45% lower with PFO closure), but the absolute difference was small (0.49 fewer events per 100 patient-years with PFO closure).

In summary, the authors found that during the follow-up period, participants with a history of cryptogenic stroke due to PFO that underwent PFO closure had a lower rate of recurrent ischemic strokes than those that received medical therapy alone.

 In 2017, Mas and colleagues reported results from the CLOSE study (NCT00562289), a multicenter, randomized (1:1:1), open-label study that evaluated participants who had a recent cryptogenic stroke (if no retinal ischemia): stroke (or retinal stroke) with no identifiable cause other than PFO with or without aspirin, based on a detailed etiological work-up, performed under the neurologist’s responsibility. Participants who enrolled had cryptogenic stroke attributed to PFO, with atrial septal aneurysm (defined as excursion of the septum primum greater than 10 mm on TEE); or large interatrial shunt (defined as presence of more than 30 microbubbles in the left atrium within three cardiac cycles after opacification of the right atrium, based on transthoracic echocardiography [TTE] or TEE). Exclusion criteria included any other cause of stroke associated with PFO, other medical indications for long-term anticoagulant or antiplatelet therapy, or increased bleeding risks. Participants (16 to 60 years of age) were assigned to either PFO closure plus long-term antiplatelet therapy (PFO group; n=238), anticoagulation alone group (n=187), or antiplatelet-only group (n=235); participants that had identified contraindication to anticoagulation therapy or PFO closure were assigned to alternative non-contraindicated treatment or to antiplatelet therapy. There were no reported strokes among the PFO group, 14 strokes occurred among the antiplatelet-only group (HR, 0.03; 95% CI, 0 to 0.26; p<0.001). Procedural complications were reported in 14 (5.9%) participants in the PFO closure group. Among the groups, adverse events did not differ significantly. The authors concluded that:

In conclusion, among patients 16 to 60 years of age who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure plus long-term antiplatelet therapy than with antiplatelet therapy alone. The effects of oral anticoagulant therapy as compared with antiplatelet therapy on the risk of stroke recurrence could not be determined.

In April 2018, the FDA granted premarket approval for the GORE^® CARDIOFORM Septal Occluder (W.L. Gore & Associates, Inc., Flagstaff, AZ), a permanently implanted device indicated in PFO to reduce the risk of recurrent ischemic stroke in individuals (predominantly between 18-60 years of age) who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke. The device is contraindicated in individuals who are unable to take antiplatelet or anticoagulation therapy. The FDA approval is based on data reported by Sondergaard and colleagues (2017) from the REDUCE (NCT00738894) study, an international, prospective, randomized (2:1 ratio), controlled, open-label trial that evaluated participants who underwent PFO closure plus antiplatelet therapy (PFO group; n=441) or received antiplatelet therapy alone (antiplatelet-only group; n=223). During a median follow-up of 3.2 years, 6 participants (1.4%) in the PFO group and 12 participants (5.4%) in the antiplatelet-only group had a clinical ischemic stroke (HR, 0.23; 95% CI, 0.09 to 0.62; p=0.002). There was a lower incidence of brain infarctions reported in the PFO group (n=22; 5.7%) versus the antiplatelet group only (n=20; 11.3%). Fewer serious adverse events were reported among the PFO group than the antiplatelet-only group, 23.1% versus 27.9%, respectively. The authors concluded that:

In conclusion, among patients who had cryptogenic stroke most likely attributed to PFO, the risk of recurrent stroke and now brain infarction were significantly lower with closure of the PFO plus antiplatelet therapy than with antiplatelet therapy alone.

Lee and colleagues (2018) reported results from the DEFENSE PFO (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients with High-Risk Patent Foramen Ovale) trial. The study enrolled 120 participants with history of cryptogenic stroke and high-risk PFO, and participants underwent randomization and were divided between PFO closure group and medication-only group. The study primary endpoint was a composition of stroke, vascular death, or thrombosis in myocardial infarction (TIMI) - defined major bleeding during a 2-year follow-up period. All participants in the PFO group had a successful PFO closure, therefore no event of primary endpoint occurred in the PFO closure group. The primary endpoint occurred in 6 of 60 participants in the medication-only group; 2-year event rate: 12.9% (95% CI), 2-year rate of ischemic stroke: 10.5% (p=0.023). In the medication-only group, the events included ischemic stroke (n=2), and transient ischemic attack (n=1). Nonfatal procedural complications included development of atrial fibrillation (n=2), pericardial effusion (n=1), and pseudoaneurysm (n=1). In summary, the authors concluded that:

In patients who had a recent cryptogenic stroke attributed to PFO with a large PFO, atrial septal aneurysm, or hypermobility, the rate of primary composite endpoint as well as stroke recurrence was lower with combined PFO closure in combination with medication than with medication therapy alone.

In 2020 the American Academy of Neurology (AAN) Guideline Subcommittee provided a practice advisory update summary: Patent Foramen Ovale and Secondary Stroke Prevention. The committee found evidence that PFO may play a role in some individuals with cryptogenic stroke older than 60 years. The subcommittee recommended that:

PFO closure may be offered in other populations, such as for a patient who is aged 60-65 years with a very limited degree of traditional vascular risk factors (for example, hypertension, diabetes, hyperlipidemia, or smoking) and no other mechanism of stroke detected following a thorough evaluation, including prolonged monitoring for atrial fibrillation.

Pristipino and colleagues (2019) published a multi-society European position paper “The Management of  Patients with PFO-General approach and left circulation thromboembolism” which states:

The position of our societies is to perform percutaneous closure of a PFO in carefully selected patients aged from 18 to 65 years with a confirmed cryptogenic stroke, TIA, or systemic embolism and an estimated high probability of a causal role of the PFO as assessed by clinical, anatomical and imaging features. PFO closure can also be considered in patients >65 or <18 years of age, taking into account on a case-by-case basis the lack of evidence, the age-related confounders and additional risks of interventional and drug therapies.

However, the 2022 Society for Cardiovascular Angiography and Interventions (SCAI) Guidelines for the  Management of Patent Foramen Ovale provides the following recommendation:

1.7 In persons with a history of TIA and without a prior PFO-associated stroke, the SCAI guideline panel suggests against PFO closure (conditional recommendation, very low certainty of evidence).
Other considerations:
By definition, TIA patients have normal neuroimaging and no persistent clinical neurologic deficits, so an ischemic etiology for any given neurologic clinical presentation cannot be proven with confidence. Therefore, a suspected TIA cannot be differentiated from complex migraine nor from any other cause of transient neurological symptoms. The guideline panel determined that there is very uncertain benefit from PFO closure in this population. Further research is necessary to ascertain the benefits and harms of closure in this population.

The 2021 AHA/American Stroke Association (ASA) Guideline for the Prevention of Stroke in Individuals With Stroke and Transient Ischemic Attack also does not recommend PFO closure outside of individuals with a non-lacunar ischemic stroke (on neuroimaging) of undetermined cause and a PFO.

Farjat-Pasos and colleagues (2023) published a multicenter study including 1012 consecutive participants that underwent PFO closure after a cryptogenic thromboembolic event between 2001and 2020 in two high-volume tertiary-care centers. Outcomes were compared in participants grouped according to the index event; TIA (n=183 [18%]), and stroke (n=829 [82%]). TIA was defined as a temporary ischemic dysfunction causing transient neurological symptoms lasting <1 hour and without signs of acute brain damage. Stroke was confirmed with either CT or MRI  brain imaging. The diagnoses were confirmed by a neurologist in all cases. The diagnosis of PFO was made by a right-to-left shunt during TEE examination with an agitated saline contrast test with and without Valsalva maneuver. The median follow-up was 3 years, which was completed by 98% of participants. The results showed that there were no significant differences between groups except for a lower Risk of Paradoxical Embolism (RoPE) score in the TIA group (6.1 versus 6.9 in the stroke group, p<0.001). PFO closure was successful 100% of participants with less than 1% of complications in both groups. There were no differences between groups in the incidence of AF (0.42 versus 0.73 per 100 patient-years in the TIA and stroke groups, respectively; p=0.266), deep vein thromboses (DVT)/PE (0.16 versus 0.16 per 100 patient-years in the TIA and stroke groups, respectively; p=0.949), and bleeding events (0.86 versus 0.71 per 100 patient-years in the TIA and stroke groups, respectively, p=0.599). Additionally, there were no differences in the incidence of neurologic events during long-term follow-up between groups; there was 1 stroke event in the TIA group and 6 in the stroke group (0.08 versus 0.17 per 100 patients-years, p=0.584). The authors concluded that individuals with cryptogenic TIA presented the same clinical profile as those with stroke except for a slightly lower RoPE score, transcatheter  PFO closure was safe for individuals with PFO related TIA, and transcatheter PFO closure in individuals with PFO-related TIA may be as effective as in individuals with a PFO-related stroke as shown by similarly low rates of recurrent thromboembolic events during follow-up. Study limitations included the retrospective nature. A prospective comparative clinical trial of individuals with a PFO-related TIA who did not undergo PFO closure is needed to appropriately conclude that PFO closure is effective in individuals with a PFO-related TIA. Further comparative RCTs are needed.

PFO closure in individuals with only a history of a TIA (but without a prior cryptogenic stroke) has not been rigorously evaluated; studies directly investigating the effect of PFO closure in individuals with TIA are lacking and currently there is insufficient clinical evidence to support the use of PFO closure for the treatment of TIAs.

Decompression Sickness

Decompression sickness/illness (DCS/I), also called generalized barotrauma or The Bends, refers to injuries caused by a rapid decrease in the pressure of either air or water that surrounds an individual. Most commonly DCS occurs in scuba or deep-sea divers, it also can occur during high-altitude ascent or unpressurized air travel. Defects through which there may be transient right-to-left shunting, for example PFO, can increase the risk of paradoxical air emboli in individuals with DCS.

Lee and colleagues (2023) published a single center prospective study which recruited 100 volunteer adult divers who did >50 dives per year. TTE, TEE, and transcranial Doppler (each with agitated saline contrast without and with Valsalva maneuver) were performed to determine the presence of a PFO. Participants were divided into high-risk, defined as divers with one of the following conditions: atrial septal aneurysm, hypermobility, PFO size (maximum separation of the septum primum from the secundum) 2 mm or greater, or right-to-left shunt in the resting state during TEE or TCD evaluation, and low-risk groups. Follow-up included a self-reported questionnaire that was blinded examiners to PFO status. The primary outcome measured was the 3-year cumulative incidence of PFO-related DCS (defined as cutaneous or neurological DCS events, DCS symptoms requiring hyperbaric treatment, DCS symptoms within 30 minutes after surfacing, or unexplained death within 2 weeks after diving), to determine the odds ratio of PFO-related DCS. PFO was seen in 68 divers (68%; 37 [54% of all PFOs] high-risk and 31 [46% of all PFOs] low-risk). Mean follow-up was approximately 29 months. The results demonstrated that PFO-related DCS occurred in 12 divers in the PFO group (all cutaneous or neurological, no deaths, and only 1 diver underwent hyperbaric treatment). The incidence of a DCS event per 10,000 dives was 0 in non-PFO divers versus 8.4 in high-risk PFO divers versus 2.0 in low-risk PFO divers (p=0.001). Multivariable analysis showed that high-risk PFO was independently associated with an increased risk for PFO-related DCS (95% CI, 1.95-44.88; p=0.005).

The 2022 SCAI Guidelines for the Management of Patent Foramen Ovale recommendations regarding DCS state:

1.2. In self-contained underwater breathing apparatus (SCUBA) divers with prior decompression illness (DCS) and without a prior PFO-associated stroke, suggests against the routine use of PFO closure to prevent DCS (conditional recommendation, very low certainty of evidence).

Currently there is insufficient clinical evidence to support the use of PFO closure for the treatment of DCS.

Migraine

Migraine with arura may be associated with PFO and right-to-left cardiac shunting. PFO closure has been evaluated as a treatment. A study by Dowson and colleagues (2008) investigated PFO closure for migraine in a randomized, double-blind, sham-controlled trial. Individuals that experienced migraine with aura, frequent migraine attacks, had previously failed > or = 2 classes of prophylactic treatments, and had moderate or large right-to-left shunts consistent with the presence of a PFO were randomized to transcatheter PFO closure with the STARFlex implant or to a sham procedure. The primary efficacy measure was cessation of migraine headache 91-180 days post-procedure; 432 participants were screened, 163 (38%) had right-to-left shunts consistent with a moderate or large PFO. Subsequently 147 participants were randomized and followed for 6 months. No significant difference was observed in migraine headache cessation between implant and sham groups (3 of 74 versus 3 of 73, respectively; p=0.51). The implant group demonstrated a greater reduction in total migraine headache days (p=0.027). Adverse events were reported in both groups, most commonly attributed to trial antiplatelet medication. Serious adverse events occurred in 16 individuals. Procedural complications included pericardial effusion in 2 individuals, 1 of which required percutaneous drainage, and a retroperitoneal bleed in 1 individual in the implant group. The authors concluded that the results confirmed a high prevalence of right-to-left shunts in individuals experiencing migraine with aura, however, no significant effect was found from PFO closure. Larger trials are needed to further  investigate the benefits of PFO closure in this population.

Mattle and colleagues (2016) published the results of a multicenter, randomized control trial (RCT) that investigated the effect of percutaneous PFO closure in individuals that were refractory to medical treatment. Participants were randomized to PFO closure or medical treatment groups, both groups were given ASA 75-100 mg/day for 6 months and clopidogrel 75 mg/day for 3 months. The primary outcome measured was reduction in monthly migraine days during months 9-12 after randomization compared with a 3-month baseline phase before randomization; 107 participants were randomized to treatment with an Amplatzer PFO Occluder (n=53) or control with medical management (n=54). The trial was terminated prematurely due to slow enrolment, 83 participants (40 occluder, 43 control) completed 12-month follow-up. Mean migraine days at baseline were 8 (±4.7 SD) in the closure group and 8.3 (±2.4) in controls. The primary outcome was negative with -2.9 days after PFO closure versus -1.7 days in control group (p=0.17). PFO closure caused 5 adverse events without permanent sequelae. The authors concluded that in individuals with refractory migraine with aura PFO closure did not reduce overall monthly migraine days.

Liu and colleagues (2021) published a review that examined the relationship between migraine and PFO to better understand the pathophysiological mechanisms and improve understanding of the risks and benefits of treatment with PFO closure. The incidence of PFO in individuals with migraines varies amongst several studies. Several studies found that migraines with atypical aura were closely associated with PFO, and the presence of right-to-left shunt increased the likelihood of aura attacks. The authors stated:

We consider the PFO having a closer relationship in migraine patients with aura, especially  atypical aura, although non-migraine with aura is also correlated with the presence of the PFO. The frequency of headache onset, but not its clinical features, is also correlated with PFO, which seems to suggest that right-to-left shunt may trigger the onset of migraine without directly affecting the migraine symptoms. In addition, the type and size of the foramen ovale are also associated with migraine. Persistent PFO, larger PFO, and complex tissue structures may cause more right-to-left shunt of the blood to increase the incidence of migraine. Taken together, these support the “dose-response” relationship between right-to-left shunt and migraine.

However, in RCTs the results were unremarkable. The authors concluded that the findings did not support PFO occlusion for the improvement of headaches in individuals with migraines, and that PFO closure may carry a small risk of adverse events including stroke, pericardial tamponade, atrial fibrillation and death.   

In 2022 the American Headache Society noted that several clinical trials were conducted to determine if closing a PFO is helpful for migraine, none of the studies showed the PFO closure was significantly effective in reducing migraine in all migraine sufferers. However, a secondary analysis suggested that individuals who had aura with most of their migraines did respond well to PFO closure. They concluded that it is important to note that an association does not indicate causation and that based upon the evidence to date clinical trials do not provide evidence to support PFO closures in migraine sufferers. Further research is needed to better understand the potential role for PFO in migraine.

The 2022 SCAI Guidelines for the Management of Patent Foramen Ovale recommendations include the following:

1.1. In persons experiencing migraines without a prior PFO-associated stroke, the panel suggests against the routine use of PFO closure for the treatment of migraine (conditional recommendation, moderate certainty of evidence).

Currently there is insufficient clinical evidence to support the use of PFO closure for the treatment of migraine headaches.

Platypnea-orthodeoxia syndrome

PFO‐associated platypnea-orthodeoxia syndrome is a rare disorder characterized by orthostatic accentuation of a right-to-left shunt, resulting in both dyspnea (platypnea) and arterial desaturation (orthodeoxia) in the upright position that improves in the supine position.

The 2022 SCAI Guidelines for the Management of Patent Foramen Ovale recommendations regarding platypena-orthodeoxia syndrome state:

1.3. In persons with platypnea-orthodeoxia syndrome (POS) and without a prior PFO-associated stroke, in whom other causes of hypoxia have been excluded, the SCAI guideline panel suggests PFO closure rather than no PFO closure (conditional recommendation, very low certainty of evidence).

Based upon the SCAI conditional recommendation, the very low certainty of evidence, and the lack of rigorous studies investigating the effect of PFO closure in individuals with POS there is insufficient clinical evidence to support the use of PFO closure for the treatment of this condition.

Left Atrial Appendage (LAA) (Transcatheter or Non-percutaneous) Closure

Transcatheter closure of an LAA is a treatment strategy that prevents travel of an LAA thrombus out of the LAA in individuals with non-valvular atrial fibrillation (AF). The LAA closure system is introduced in the right atrium and then passed into the left atrium through a PFO or through a puncture hole. The Holmes and colleagues (2009) randomized non-inferiority trial compared LAA closure using the WATCHMAN^™ LAA Closure Device (Boston Scientific, Marlborough, MA) versus warfarin therapy for prevention of stroke in individuals with AF. The study evaluated efficacy between the interventional group and the warfarin group based upon the primary endpoint of reported cardiovascular death (n=5 versus n=10), all types of stroke (n=16 versus n=12), and systemic embolism (n=2 versus n=0). Researchers reported a higher occurrence of primary safety events in the interventional group compared to the warfarin therapy group; serious adverse events included major bleeding, pericardial effusion and device embolization. The authors concluded:

Thus, our strategy for closing the LAA was non-inferior to warfarin therapy in terms of primary efficacy endpoint of all stroke, cardiovascular death, and systemic embolism. Although there is a higher initial safety event rate for device implantation, adverse events were without long term sequelae for most patients. Closure of the LAA might provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with non-valvular atrial fibrillation.

A study by Reddy and colleagues (2011) reported on preliminary outcomes from the Watchman LAA System for Embolic Protection in Patients with AF (PROTECT AF) trial and Continued Access PROTECT AF Registry (CAP Registry). Although with improved procedural experience there was a decline in safety events reported, there remains a higher risk of complications. The FDA granted PMA approval March 2015 for the WATCHMAN LAA Closure Device in individuals with non-valvular AF in facilities equipped for heart surgery as an alternative option to long-term warfarin therapy. According to the manufacturer, Boston Scientific Corporation:

WATCHMAN is indicated to reduce the risk of thromboembolism from the left atrial appendage in patients with non-valvular atrial fibrillation who are at increased risk for stroke and systemic embolism based on CHADS₂ or CHA₂DS₂-VASc scores, are deemed by their physicians to be suitable for warfarin; and have an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin.

In 2014, Reddy and colleagues reported long-term outcomes of the PROTECT AF trial. The randomized, multicenter study enrolled 707 participants with nonvalvular AF (NVAF) and at least one additional stroke risk factor (CHADS₂ score greater than or equal to 1) who were randomized 2:1 to undergo LAAC with the WATCHMAN LAA Closure Device (n=463, treatment group) or warfarin therapy (n=244, control group). The trial demonstrated a noninferior rate of cardiovascular death, stroke or systemic embolism, compared with warfarin alone. The authors concluded:

After 3.8 years of follow-up among patients with nonvalvular AF at elevated risk for stroke, percutaneous LAA closure met criteria for both noninferiority and superiority, compared with warfarin, for preventing the combined outcome of stroke, systemic embolism, and cardiovascular death, as well as superiority for cardiovascular and all-cause mortality.

A multicenter, randomized, clinical trial PREVAIL assessed safety and efficacy of the WATCHMAN LAA Closure device versus long-term warfarin in individuals with NVAF who had a CHADS₂ score of 2 or more (CHADS₂ score of 1 and another risk factor were eligible) (Holmes, 2014). Exclusion criteria included contraindication to warfarin or aspirin, stroke/transient ischemic attack within the last 90 days, symptomatic carotid disease, PFO or atrial septal defect (ASD), thromboembolism or bleeding. PREVAIL enrolled 407 participants, assigned randomly (2:1 ratio) to the device group (n=269) or control group (n=138). Unlike the PROTECT AF trial the PREVAIL did not demonstrate noninferiority in overall efficacy. The authors report that:

At 18 months, the rate of the first co-primary efficacy endpoint (composite of stroke, systemic embolism [SE], and cardiovascular/unexplained death was 0.064 in the device group versus 0.063 in the control group (rate ratio 1.07 [95% credible interval (Crl): 0.57 to 1.89]) and did not achieve the pre-specified criteria noninferiority (upper boundary of 95% Crl ≥1.75). The rate for the second coprimary efficacy endpoint (stroke or SE > 7 days’ post randomization) was 0.0253 versus 0.0200 (risk difference 0.0053 [95% Crl: -0.0190 to 0.0273], achieving noninferiority. Early safety events occurring in 2.2% of the Watchman arm, significantly lower than in PROTECT AF, satisfying the pre-specified safety performance goal. Using a broader, more inclusive definition of adverse events, these still were lower in PREVAIL (Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trial than in PROTECT AF (4.2% versus 8.7%; p=0.004). Pericardial effusions requiring surgical repair decreasing from 1.6% to 0.4% (p=0.36), although the number of events was small.

LAA occlusion was noninferior to warfarin for ischemic stroke prevention or SE >7 days post-procedure. Although noninferiority was not achieved for overall efficacy, event rates were low and numerically comparable in both arms. Procedural safety has significantly improved. This trial provides additional data that LAA occlusion is a reasonable alternative to warfarin therapy for stroke prevention in patients with NVAF who do not have an absolute contraindication to short-term warfarin therapy.

Two randomized controlled trials have compared use of the WATCHMAN device for LAA closure in individuals with AF eligible for anticoagulation therapy. The peer-reviewed published literature suggests that the WATCHMAN is associated with an increased periprocedural ischemic stroke risk. There is limited evidence supporting the net benefit of transcatheter closure of an LAA with the WATCHMAN LAA Closure device, in individuals with non-valvular AF who are deemed eligible for systemic anticoagulation. Further studies are needed to determine if the long-term risk of systemic anticoagulation exceeds the periprocedural risk of device implantation.

Reddy and colleagues (2017) reported final results from the PREVAIL trial and as part of a meta-analysis with PROTECT AF trial followed for 5 years. Participants underwent LAAC with the WATCHMAN or treatment with warfarin. The authors reported results:

For the PREVAIL trial, the first composite coprimary endpoint of stroke, systemic embolism (SE), or cardiovascular/unexplained death did not achieve noninferiority (posterior probability for noninferiority = 88.4%), whereas the second coprimary endpoint of post-procedure ischemic stroke/SE did achieve noninferiority) posterior probability for noninferiority = 97.5%); the warfarin arm maintained an unusually low ischemic stroke rate (0.73%). In the meta-analysis, the composite endpoint was similar between groups (hazard ratio [HR]: 0.820; p=0.27), as were all-stroke/SE (HR: 0.961; p=0.87). The ischemic stroke/SE rate was numerically higher with LAAC, but this difference did not reach statistical significance (HR: 1.71; p=0.080). However, differences in hemorrhagic stroke, disabling/fatal stroke, cardiovascular/unexplained death, all-cause death, and post-procedure bleeding favored LAAC (HR: 0.20; p=0.0022; HR: 0.45; p=0.03; HR: 0.59; p=0.027; HR: 0.73; p=0.0003, respectively).

The 2019 American Heart Association (AHA)/ American College of Cardiology (ACC)/ Heart Rhythm Society (HRS) focused update of the 2014 AHA/ACC/HRS guidelines for the management of atrial fibrillation issued a category IIb (weak) recommendation, indicating “percutaneous LLA occlusion may be considered in patients with AF at increased risk of stroke who have contraindications to long-term anticoagulation” (January, 2019). The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drug/alcohol concomitantly) score is used to assess major bleeding risk factors in individuals with AF being considered for anticoagulation. The CHADS₂ score (congestive heart failure, hypertension, age > 75 years, diabetes mellitus, stroke/transient ischemia attack/thromboembolism) and the CHA₂DS₂-VASc score (congestive heart failure, hypertension, age ≥ 75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism [doubled], vascular disease, age 65 to 74 years, sex category) are commonly used for stroke risk stratification in individuals with AF. The authors further concluded:

Oral anticoagulation remains the preferred therapy for stroke prevention for most patients with AF and elevated stroke risk. However, for patients who are poor candidates for long-term oral anticoagulation (because of the propensity for bleeding or poor drug tolerance or adherence), the Watchman device provides an alternative. There are important differences in wording between the FDA approval and the Centers for Medicare & Medicaid Services (CMS) approval. In the FDA approval, the device was restricted to patients who were deemed suitable for long-term warfarin (mirroring the inclusion criteria for enrollment in the clinical trials) but had an appropriate rationale to seek a nonpharmacological alternative to warfarin. Conversely, CMS states that the device is an option for patients who are suitable for short-term warfarin but deemed unable to take long-term oral anticoagulation. CMS has specified that patients should have a CHADS₂ score ≥2 or a CHA₂DS₂-VASc score ≥3 to be considered for the device. A number of unresolved issues remain, including the optimal patient selection and periprocedural antithrombotic regimen.

The current FDA labeling specifies that patients should be deemed suitable for anticoagulation and, in particular, a period of periprocedural anticoagulation. Patients unable to take oral anticoagulation were excluded from the Watchman RCTs [randomized control trial]. However, there is increasing experience outside the United States with LAA closure in oral anticoagulation–ineligible patients using an antiplatelet regimen only, and this is the focus of an ongoing RCT.

Boersma and colleagues (2019) reported periprocedural, 2-year outcome data from the prospective, multicenter, multinational EWOLUTION registry (Evaluating Real-life Clinical Outcomes in Atrial Fibrillation Patients Receiving the WATCHMAN Left Atrial Appendage Closure Technology). Overall safety and efficacy data are presented in a subgroup of participants who are at very high-risk of stroke or bleeding, including those with a history of ischemic and hemorrhagic stroke and those with prior bleeding episodes. In total, 1020 participants (age 73.4±8.9 years) underwent implantation with the WATCHMAN device. While 72 percent of participants were deemed unsuitable for oral anticoagulation by their physicians, data was not readily provided on the reason for contraindication to anticoagulation therapy. At the time of hospital discharge, after successful WATCHMAN placement, 94% of participants were on some form of anticoagulation or antiplatelet drug, and by study-end, 86% were using some form of anticoagulation therapy or antiplatelet drug (8% were using oral anticoagulation, 7% were on dual antiplatelet therapy and 71% were on single antiplatelet therapy). At 2-year follow-up, 16.4% (n=161) of participants that underwent a WATCHMAN LAAC had died; 4.5% (n=46) had a cardiovascular reason (most commonly reported was heart failure) and 1% (n=10) were from fatal bleeding (6 were gastrointestinal bleeds while the other 4 were cerebral; only 1 participant was not taking an anticoagulant at time of death). The composite risk of ischemic stroke/TIA/embolic event was 2.0/100 patient-years (46 thromboembolic events in 35 participants, of which 22 were ischemic stroke (5 disabling), 23 were TIA, and one was an systemic embolism), which the authors compare to a historical rate of 10.0/100 patient-years based on CHA₂DS₂-VASc (congestive heart failure, hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease 65 to 74 years of age, female; left ventricular ejection fraction) score. In 835 participants with imaging of the LAA, a total of 34 cases of device-related thrombus (4.1%) were observed, resulting in 21 participants initiating treatment, and 1 major GI bleed which resolved. By study-end, resolution occurred in all but 1 participant (6 were lost to followed-up), no subsequent reports of embolic events were reported. Stroke and bleeding rates did not appear to differ by anticoagulation treatment strata, although it is difficult to draw conclusions based on the registry nature of the study. In summary, the study is limited by its registry design; determining the absolute or relative benefit and risks of the WATCHMAN device versus standard treatment in the population studied is unclear given the lack of a randomized comparable prospective treatment arm. A high number of participants enrolled in EWOLUTION also died during the 2 years of follow-up. A majority of individuals also remained on some form of anticoagulation therapy or antiplatelet drug despite being deemed unsuitable for short- or long-term oral anticoagulation at the time of implant, thus continued use of any form of oral anticoagulation or antiplatelet drug may play a role in thromboembolic event prevention.

In June 2020, the FDA approved the next generation WATCHMAN FLX Left Atrial Appendage Closure Device, which is the first device to be fully recapturable for repositioning and redeployment. This generation of the device is available in various sizes and a reduced device length to accommodate a variety of LAA anatomy.

In 2021, Kar and colleagues published results from the Protection Against Embolism for Nonvalvular AF (NVAF) Patients: Investigational Device Evaluation of the Watchman FLX LAA Closure Technology (PINNACLE FLX) trial. This prospective, nonrandomized, multicenter trial evaluated safety and effectiveness of the WATCHMAN FLX LAA closure device. Eligible participants had NVAF, a CHA₂DS₂-VASc score of ≥ 2 for men or ≥ 3 for women, able to take the postimplant antithrombotic medication, had rationale for a nonpharmacologic stroke prevention, and no comorbid conditions that would require long-term anticoagulation therapy. After placement of the new device, follow-up visits occurred at 45 days, and 6, 12, 18 and 24 months. Participants received directly acting oral anticoagulant (DOAC) treatment and concomitant low dose aspirin through at least the 45-day follow-up appointment. With evidence of an adequate LAA seal (leak ≤ 5 mm) at the 45-day visit, participants were instructed to discontinue DOAC therapy and begin dual antiplatelet therapy with 75 mg of clopidogrel and low-dose aspirin until 6 months after implantation, followed by low-dose aspirin indefinitely. With evidence of a leak > 5 mm, participants continued DOAC therapy plus aspirin and were reevaluated at 6 months post implantation. The primary safety endpoint was the occurrence of death, ischemic stroke, systemic embolism, or device or procedure-related events requiring cardiac surgery within 7 days after the procedure or by hospital discharge. The performance goal established for the primary safety endpoint was 4.21%. For this outcome, the investigators determined that a sample size of 400 individuals would yield 92% or 77% power (1-sided α = 0.05 or 2-sided α = 0.05, respectively). The primary effectiveness endpoint was incidence of effective LAA closure (peri-device flow ≤ 5 mm), as assessed by the echocardiography core laboratory at the 12-month follow-up visit. The performance goal established for the effectiveness endpoint was 97.0%, and 400 individuals would yield 92% or 81% power (1-sided α = 0.05 or 2-sided α = 0.05, respectively). A total of 400 individuals were enrolled. The mean age was 73.8 ± 8.6 years, 64.5% were men, and 94% were White. A total of 395 (98.8%) achieved implant procedure success. The incidence of the primary safety end point was 0.5%, with a 2-sided 95% CI of 1.8%, which was below the performance goal of 4.21% (p<0.0001). The incidence of the primary effectiveness end point of LAA closure was 100%, with a 2-sided 95% CI of 98.9%, above the performance goal of 97.0% (p<0.0001). A total of 7 individuals experienced device-related thrombus. The investigators concluded:

The PINNACLE FLX study results demonstrate that the next-generation LAA closure device, in combination with a 6-week postprocedural regimen of a DOAC and low-dose aspirin, is associated with a low incidence of safety events and high incidence of effective appendage closure.

In 2019, Holmes and colleagues reported long-term follow-up data from two U.S. FDA LAAC mandated registries (CAP [continued access PROTECT-AF] and CAP2 [continued access PREVAIL]) for safety and efficacy of LAAC for stroke prevention in participants with NVAF. The CAP registry included 566 participants (average follow-up 50.1 months) and CAP2 registry included 578 participants (average follow-up 50.3 months); these registries represent the longest follow-up for participants that have been implanted with the WATCHMAN LAAC Device. The CAP registry enrolled participants who met identical inclusion/exclusion criteria as the original PROTECT-AF RCT; similarly, the CAP2 registry used identical inclusion/exclusion criteria as PREVAIL. Participants had documented paroxysmal, persistent, or permanent non-valvular AF, were eligible for long-term warfarin therapy, had CHADS₂ score of 2 or greater. Individuals with a CHADS₂ score of 1 were included but had to meet additional ACC/AHA/ESC 2006 guidelines for the management of AF for participants requiring warfarin therapy. Notably, both registries excluded warfarin-contraindicated individuals. Participants enrolled in CAP2 were significantly older (≥ 75 years of age) and had higher CHA₂DS₂-VASc scores (4.51 versus 3.88; p<0.001). In both the CAP and CAP2 the procedural success was similar (94%). In the CAP registry, full 5-year follow-up was completed in 68% of participants; inability to obtain full follow-up was related to mortality, which occurred in 17.8% of participants; initial failure to implant the device, which occurred in 5.7%, loss to follow-up, which occurred in 5.1%, and another 3.5% of participants withdrew permission and consent. At 60 months, 94.8% of participants remained off warfarin. Similar results were reported in the CAP2 registry, although a higher percent of participants died before follow-up completion (21.8%). The primary composite endpoint – stroke (ischemic and hemorrhagic), cardiovascular death, and systemic embolism – occurred in 12.4% of CAP and 17.6% of CAP2 participants; events contributing to the composite endpoint included mostly cardiovascular death and ischemic stroke. The most frequent adverse event in the CAP registry was gastrointestinal bleeding (5.8%), followed by pericardial effusion with cardiac tamponade (1.2%); device-related thrombus occurred in 2.6% of CAP and 3.9% of CAP2 participants. Given the lack of a comparator arm, it is difficult to assess the long-term effectiveness and safety of the WATCHMAN LAAC device versus tandard of care, particularly direct oral anticoagulant therapy. Furthermore, for participants unable to tolerate long-term anticoagulation, the results of the CAP and CAP2 registries provide no additional data. Both registries were subject to high rates of loss to follow-up (mostly related to mortality), which complicates attempts to compare relative ischemic stroke reductions with expected rates (based on CHA₂DS₂-VASc scores estimated in the absence of therapy).

Cardiovascular outcomes may vary by gender, socioeconomic status, and ethnicity/race. A cross-sectional study by Darden and colleagues (2021) compared outcomes of males and females who underwent LAAO. Individuals in this study were enrolled in the National Cardiovascular Data LAAO Registry. Outcomes included aborted or canceled procedure (no venous access was performed), major adverse event, any in-hospital adverse event (death, cardiac arrest, ischemic stroke, hemorrhagic stroke, undetermined stroke, TIA, intracranial hemorrhage, systemic arterial embolism, major bleeding, major vascular complication, myocardial infarction, pericardial effusion requiring drainage, and device embolization), and prolonged hospital stay (> 1 day). Multivariate logistic regression was performed to adjust for age, race/ethnicity, body mass index, congestive heart failure, hypertension, type 1 or 2 diabetes, stroke, vascular disease, coronary artery disease, left ventricular ejection fraction, glomerular filtration rate, prior P2Y12 inhibitor or oral anticoagulant prescription, and hospital region. A total of 49,357 individuals were included, of whom 20,388 (41.3%) were natal females. Natal females were more likely than natal males to experience any adverse and major adverse events, had lengths of stays longer than 1 day, and while a rare occurrence, in-hospital death (p<0.001 for all). In addition, Alkhouli and colleagues (2022) evaluated gender-specific short- and long-term outcomes by gender after LAAO in the Amulet IDE trial. A total of 1833 individuals (1099 males and 734 [40%] females) underwent attempted device implantation (917 with the Amulet and 916 with the WATCHMAN). There were no differences in the rate of implantation success, as well as rates of ischemic stroke, TIA, hemorrhagic stroke, major bleeding, cardiovascular death, or all-cause death between natal males and natal females. However, natal females experienced higher rates of major in-hospital adverse events compared to males (p<0.001) due to pericardial effusions that required intervention and major bleeding (p<0.01 for both). Investigators in both studies indicated that additional research is needed to reduce adverse events in natal females  who undergo LAAO implantation.

Diverse populations have not been included in large LAAO trials. In the PROTECT-AF (Reddy 2014), PREVAIL (Homes 2014), and PINNACLE FLX (Kar 2021) trials, most of the populations were White, 91%, 94%, and 94%, respectively. A cross-sectional study by Khan and colleagues (2021) evaluated differences in clinical characteristics and in-hospital outcomes by race/ethnicity of individuals with AF who underwent WATCHMAN implantation. Data for this study was derived from the National Inpatient Sample database. The study sample was stratified into 4 groups: White, Black, Hispanic, and Other races. Multivariate logistic regression was performed to adjust for age, sex, CHA₂DS₂-VASc score, median income, and 29 Elixhauser comorbidities (Quan 2005). A total of 34,960 individuals were included. Of those, 86% were White, 5.9% Hispanic, 4.2% Black, and 3.7% Other races. Individuals who were Black and Hispanic had higher prevalence rates of heart failure, hypertension, obesity, and renal failure compared to White individuals (p<0.01 for all). After adjusting for confounding factors, individuals who were Black, Hispanic, and Other races, had higher likelihoods of having a major complication from the procedure, and prolonged lengths of stays (> 1 day) compared with White individuals (p<0.01 for both). The investigators concluded that non-white individuals with AF who underwent WATCHMAN implantation had higher rates of select comorbidities and experienced higher WATCHMAN-related adverse events. They also stated that additional research is needed to clarify why these differences exist.

In 2020, Osmancik and colleagues reported data from the Left Atrial Appendage versus Novel Anticoagulation Agents in Atrial Fibrillation (PRAGUE-17, NCT02426944) trial. This was a multicenter, prospective, open-label, randomized, non-inferiority that compared LAAC and DOAC in high-risk cohort (CHA₂DS₂-VASc: 4.7± 1.5) with NVAF. The study randomly assigned 402 participants with NVAF to receive DOACs (n=201 or undergo LAAC (n=201). A total of 181 participants (90.0%) had a successful LAAC implantation, 6 participants (3.4%) experienced device-related thrombus. At a median 19.9 months of follow-up, the annual rates of primary outcomes in the LAAC group compared to the DOAC group were 10.99% and 13.42% (the HR CI spanned from 0.53 to 1.31). Between the LAAC and DOAC group there were no differences in stroke/transient ischemic attacks, clinically significant bleeding or cardiovascular death. There were nine major LAAC-related complication that occurred and two procedure and/or device related deaths reported in the LAAC group. In summary, the authors concluded that noninferiority was demonstrated, composite endpoints are challenging to interpret, and components of the composite endpoint were not powered for comparisons.

On August 14, 2021 Abbott received PMA approval for its percutaneous transcatheter device, the Amplatzer^™ Amulet^™ Left Atrial Appendage Occluder (Abbott Medical, St. Paul, MN) to treat individuals with AF who are at risk of ischemic stroke. The LAA occluder provides a double-seal technology for the complete and immediate sealing of the LAA. The Amulet LAA occluder is intended to reduce the risk of thrombus embolization from the LAA in individuals with NVAF and who are at increased risk for stroke and systemic embolism based on CHADS₂ or CHA₂DS₂-VASc scores, who are suitable for short term anticoagulation therapy, and have appropriate rationale to seek a non-pharmacologic alternative to oral anticoagulation, taking into consideration the safety and effectiveness of the device.

The FDA approval of the Amplatzer Amulet LAA Occluder is based on findings from the Amulet IDE trial (NCT02879448), a multicenter, open label, controlled trial evaluating safety and effectiveness of the Amulet occluder. Lakkireddy and colleges (2021) reported results from the Amulet IDE trial which enrolled 1878 participants who were randomized 1:1 to undergo percutaneous implantation of an LAA occluder with Amulet occluder (n=915) or with the WATCHMAN device (n=916). Eligible participants were 18 years of age or older with documented NVAF (paroxysmal, persistent or permanent) and an increased risk of stroke or systemic embolism (CHADS₂ score ≥ 2 or a CHA₂DS₂-VASc score of ≥ 3). In summary the authors found the Amulet occluder to be noninferior to the WATCHMAN device for the primary safety endpoint (14.5% versus 14.7%; difference=-0.14; 95% CI, -3.42-3.13; p<0.001 for noninferiority). The Amulet occluder was also noninferior to the WATCHMAN device for primary effectiveness endpoint (2.8% versus 2.8%; difference=0.00; 95% CI, -1.55-1.55; p<0.001 for noninferiority). The authors stated, “Procedure-related complications were higher with the Amulet device and decreased with operator experience.”

The previously discussed Amulet IDE trial was the largest randomized head-to-head trial that compared the  Amulet and Watchman 2.5 LAAO devices. The factors impacting differences in peri-device leak rates (PDLs) between the two devices were assessed in a post hoc analysis by Lakkireddy and colleagues (2023). Of the 1878 participants randomized in the Amulet IDE trial, successful implants occurred in 903 Amulet participants and 885 Watchman participants. An independent lab analyzed images from the protocol-mandated TEE’s at 45 days (801 Amulet, 792 Watchman) and at 12 months (673 Amulet, 618 Watchman), for the presence or absence of severe PDL defined as >5 mm. The results demonstrated 42 severe PDLs (Amulet 10, Watchman 32). Amulet had fewer severe PDLs than the Watchman device at 45 days (1.1 versus 3.2%, p< 0.001) and at 12 months (0.1 versus 1.1%, p< 0.001). Larger LAA dimensions were predictors for severe PDL with the Watchman device, however, there were no significant anatomical limitations noted with the Amulet occluder. Furthermore, the majority of Watchman severe PDLs did not resolve over time through 18 months. The authors concluded that the dual-occlusive mechanism (Amulet) demonstrated fewer severe PDLs through 12 months compared with the single-occlusive  device (Watchman 2.5). Jaiswal and colleagues (2023) published the results of a systematic review and meta-analysis of 3 RCTs that evaluated the safety and clinical outcomes in 150 participants undergoing percutaneous LAA closure with Amplatzer Amulet versus the Watchman device. The mean age was 75 and 76 years in the Amplatzer and the Watchman groups, respectively. The odds of procedure-related complications were higher among participants with Amplatzer compared to the Watchman group (1.80 [95% CI: 1.21–2.67], p<0.001). However, the odds of all-cause mortality (0.75 (95% CI: 0.49–1.16), p=0.20), stroke (0.79 [95% CI: 0.47–1.34], p =0.39), pulmonary embolism (1.34 [95% CI: 0.30–6.04], p=0.70), and major bleeding (1.10 [95% CI: 0.83–1.48], p=0.50) were comparable between the devices. The odds of device related thrombus (0.72 [95% CI: 0.46–1.14], p=0.17) was comparable between both groups, however the incidence of PDLs was lower in the Amulet group (0.41 [95% CI: 0.26–0.66], p< 0.001) compared with Watchman group. The analysis was limited by the fact that some trials included both the 1st generation (Watchman 2.5) as well as 2nd generation (Watchman FLX), which may have impacted results such as the lower incidence of PDLs in the Amulet group. The meta-analysis had minimal-to-low heterogeneity across studies strengthening the results, thus the authors concluded that the Amulet was not superior to the Watchman device in terms of safety and efficacy, however, the Amulet was associated with a higher incidence of procedure-related complications and lower PDL rates. Further large RCTs with longer follow up are needed to examine outcomes such as mortality and stroke.

Najim and colleagues (2023) completed a meta-analysis that compared the safety and efficacy of the Watchman FLX and the Watchman 2.5 devices from inception to March 2023; 5 studies including 54,727 participants were analyzed. The primary outcome measured was a composite of device thrombosis, device embolism, and major bleeding. Secondary outcomes measured were mortality, stroke, pericardial effusion, and procedural success rate. The analysis demonstrated that the Watchman FLX was associated with increased success (95% CI 1.98-28.26, p=0.02), and reductions in mortality (95% CI 0.51-0.54, p<0.01), major bleeding (95% CI 0.51-0.64, p<0.01), device embolism (95% CI 0.18-0.70, p=0.02), and pericardial effusion (95% CI 0.26-0.41, p<0.01). The rates of device-related thrombus and stroke were similar. The authors concluded that the findings indicated improved safety outcomes with the Watchman FLX and favor its use. Additional studies examining the long-term safety outcomes of the device are needed.

Yasmin and colleagues (2024) completed a systematic review and meta-analysis of 8 studies, with a total of 3,408 participants with a median follow-up of 12 months (1897 Watchman, 1511 Amulet). The analysis compared the safety and efficacy of Watchman 2.5 and Amplatzer Amulet devices from inception until June 2023. The safety outcomes evaluated were device success, device-related thrombus, device embolization perioperatively and at follow-up, perioperative pericardial perfusion events, and perioperative cardiac tamponade events. Efficacy outcomes measured were all-cause mortality, cardiovascular mortality at follow-up, stroke, both major and minor bleeding events at follow-up, TIA in the follow-up period, thromboembolic events in the follow-up period, and PDLs in the perioperative period. The data demonstrated that device success was non-significantly reduced in the Watchman group when compared with Amulet (p=0.57), device-related thrombus was non-significantly increased in the Watchman 2.5 group in comparison to Amulet (p=0.11). There were no significant differences between groups in device embolization in the perioperative (p=0.38) and follow up (p=0.13) periods. There were also no significant differences in the risks of pericardial effusion (p= 0.98) and cardiac tamponade (p=0.76) perioperatively. Efficacy outcomes showed no significant differences observed in all-cause mortality between devices both perioperatively (p=0.32) and at follow-up (p=0.56). Cardiovascular mortality was non-significantly reduced in the Watchman group compared with Amulet (p=0.20). The Amulet device was not superior to the Watchman device in terms of stroke at follow-up (p=0.63). There was no significant difference in major and minor bleeding events (p=0.63) between the two devices. No difference was observed for TIA (p= 0.24) or thromboembolic events (p=0.96) at follow-up. No significant difference was observed between devices for PDLs in the perioperative period (p=0.05). The authors concluded that LAAC is safe and efficacious irrespective of device used, and that Watchman 2.5 is non-superior to Amulet in terms of safety and efficacy.

Ongoing trials include the ASAP-TOO (assessment of the WATCHMAN device in individuals unsuitable for oral anticoagulation) trial, a multicenter prospective randomized trial designed to establish the safety and effectiveness of the WATCHMAN LAAC device in individuals with NVAF that are considered ineligible for oral anticoagulants (NCT02928497); the estimated study completion date is December 2025 (Holmes, 2017).

Sedaghat and colleagues (2021) reported findings from the multinational European-Canadian (EUROC)-DRT registry which included individuals in whom a device-related thrombus (DRT) was diagnosed after LAAC during clinical follow-up. While DRT is relatively rare, registry data assessing individuals with DRT suggests that DRT may occur long after LAAC. An analysis of 156 DRT cases from the EUROC-DRT registry found that DRT was detected after a median of 93 days (interquartile range, 54-161 days) with 17.9% being detected > 6 months after LAAC. The authors concluded that “the relevance of DRT after LAAC remains uncertain.”

SCAI’s previously published statements provided overview of LAAC technology and institutional and operator requirements (2015, 2016). Since then subsequent results from trials and registries have been published, technical expertise and clinical practice has matured, and device and imaging technologies have evolved. In 2023 the SCAI/HRS published a joint Expert Consensus Statement on Transcatheter LAAC that included the following updates:

• Transcatheter LAAC is appropriate for patients with NVAF with high thromboembolic risk who are not suited for long-term oral anticoagulation and who have adequate life expectancy (minimum >1 year) and quality of life to benefit from LAAC. There should be patient-provider discussion for shared decision making.
• Physicians performing LAAC should have a prior experience, including > 50 prior left-sided ablations or structural procedures and > 25 transseptal punctures (TSP). Interventional imaging physicians should have experience in guiding > 25 TSPs before supporting any LAAC procedures independently.
• Technical aspects of the procedure, including venous access, anticoagulation, TSP, delivery sheath selection and placement, left atrial pressure measurement, and device deployment, should be performed in accordance with the labeling of each specific LAAC device.
• Device-related thrombus should be treated with anticoagulation. Repeat imaging at 45- to 90-day intervals can be performed to assess for resolution with eventual cessation of anticoagulation.
• Routine closure of iatrogenic atrial septal defects associated with LAAC should not be performed.
• Patients should be prescribed antithrombotic therapy with warfarin, direct oral anticoagulants, or dual antiplatelet therapy after LAAC according to the studied regimen and instructions for use for each specific device and tailored to the bleeding risks of each patient.
• Combined procedures with LAAC (for example, structural interventions, pulmonary vein isolation) are not routinely recommended, as data are pending from ongoing randomized controlled trials.

Zhang and colleagues (2024) completed a systematic review to explore the feasibility and safety of LAAC for individuals with left atrial appendage thrombus (LAATs), the 26 studies examined included 136 participants with LAATs that had successful LAAC. The Amulet Amplatzer device was most frequently used (48.5%). The majority of procedures adhered to a standard protocol, however, in some cases modifications were made to enhance safety. Among these individuals 77 (56.6%) had absolute contraindications to anticoagulation therapy. Cerebral protection devices were used with 47 participants (34.6%). Warfarin and novel oral anticoagulants were the main medications used prior to the procedure. Dual antiplatelet therapy was primarily used post-procedure. During a mean follow-up period of 13.2 ± 11.5 months, there was 1 case of fatality, 1 case of stroke, 3 major bleeding events, 3 instances of device-related thrombus, and 8 cases PDLs. The authors concluded that the findings demonstrate preliminary effectiveness and safety of the LAAC procedure in individuals with persistent LAAT. However, future large-scale RCTs with varied LAAT characteristics and LAAC device types are needed to corroborate these findings for decision making in clinical practice.

In conclusion, oral anticoagulation remains the standard of care therapy for stroke prevention for most individuals with AF and elevated stroke risk. Those who are poor candidates for long-term oral anticoagulation may be eligible candidates for WATCMAN LAA Closure Device placement based on observational data, including registry data suggesting improved outcomes as compared to historical controls, in accordance with generally accepted standards of medical practice.

LAA as an adjunct to open cardiac surgery

Exclusion of the LAA may be performed at the same time as another open cardiac procedure. Examples of devices used for this procedure may include the Amplatzer Cardiac Plug, Lariat Suture Delivery Device, the AtriClip^® LAA Exclusion System (AtriCure, Inc., Mason, OH), and the WATCHMAN LAA Closure Device. On August 20, 2019, the FDA granted clearance for the AtriClip LAA Exclusion System, indicated for the exclusion of the heart’s left atrial appendage, performed under direct visualization and in conjunction with other open cardiac surgical procedures. AtriClip’s FDA authorization was obtained via the 510k process, based on substantial equivalence (in material composition) to predicate FDA cleared devices. The predicate devices for the AtriClip LAA Exclusion System are the Weck Hem-O-Lok® Ligating Clip and Clip Applier (K030311), Medtronic VNUS U-Clip and Applier (K031623), Tyco AutoSuture TA and GIA Staplers (K032696), Power Medical SurgASSIST® Straight Linear 4 Row No Knife DLUs with Reloads (K040398), Demetech Braided Nonabsorbable Polyester Suture and needle driver (K023030) and Gore SEAMGUARD® Bioabsorbable Staple Line Reinforcement Material (K043056). The FDA indications for use were based on animal data and preliminary clinical data reported by Ailawadi and colleagues (2011) from the EXCLUDE trial, a prospective, non-randomized study (NCT00779857) of 70 participants (mean age, 73 years), half of whom had no history of atrial fibrillation, demonstrating successful clip placement in 95.7% of participants (n=67) during concomitant cardiac surgery. In 61 participants evaluated at 3 months with a CT scan, left atrial appendage exclusion was demonstrated in all but one participant. No claims on efficacy can be made based on this limited data.

The 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guidelines for the management of atrial fibrillation; the panel offers a IIb (weak) recommendation for surgical occlusion of the LAA with AF in individuals undergoing cardiac surgery as a component of an overall heart team approach to the management of AF. Surgical occlusion involves surgical ligation or amputation of the LAA (a procedure not addressed by this document); the guideline does not mention the AtriClip device as a surgical method to exclude the LAA.

In 2021, Whitlock and colleagues conducted a multicenter, RCT which enrolled 4111 participants (mean age of 71 years) with AF and a CHADS₂ score ≥ 2 (mean of 4.2), scheduled for cardiac surgery for another indication. Study participants included were randomly assigned to LAAO during surgery (n=2379 in the final analysis) or not (n=2391 in the final analysis). During the follow-up period (mean of 3.8 years) participants were expected to receive usual care, including oral anticoagulation, during follow-up. The study’s primary outcome was the occurrence of ischemic stroke (including transient ischemic attack with positive neuroimaging) or systemic embolism. Study participants, research personnel, and primary care physicians (other than the surgeons) were blinded to the trial-group assignments. At the time of hospital discharge, 83.4% of the participants in the occlusion group and 81.0% of those in the no-occlusion group were receiving oral anticoagulation, respectively. At year 3 of follow-up, 76.8% of the study participants continued to receive oral anticoagulation. The primary outcome, stroke or systemic embolism had occurred in 114 participants (4.8%) in the LAAO group and in 168 participants (7.0%) in the non-occlusion group (HR, 0.67; 95% CI, 0.53 to 0.85; p= 0.001). A total of 538 participants in the occlusion group (22.6%) and in 537 (22.5%) in the non-occlusion group (HR, 1.00; 95% CI, 0.89 to 1.13). Hospitalization for heart failure (either prolongation of index hospitalization or new hospitalization) occurred in 183 participants (7.7%) in the occlusion group and in 162 (6.8%) in the non-occlusion group (HR, 1.13; 95% CI, 0.92 to 1.40). The incidence of major bleeding or myocardial infarction was similar in the two groups. In this study, LAAO was performed during cardiac surgery with the use of any of the following techniques: amputation and closure (56%), stapler closure (11%), closure from within (14%), or closure with an FDA approved surgical occlusion device (e.g., AtriClip [15%]). In the current study, amputation and closure was the preferred technique (56%), whereas use of an FDA approved closure device occurred in a minority of participants (15%); outcome data stratified by closure technique was not provided. Potential risks associated with closure device include, but are not limited to, erosion and perforation. TigerPaw II, another surgical LAA closure device, was recalled in 2017 after reports involving issues with the TIGERPAW System II resulting in possible tissue tearing on left atrial wall and bleeding during use of the device.

The 2023 SCAI/HRS joint Expert Consensus Statement on Transcatheter LAAC states:

Combined procedures with LAAC (for example, structural interventions, pulmonary vein isolation) are not routinely recommended, as data are pending from ongoing randomized controlled trials.

Currently there is insufficient clinical evidence to support the use of surgical occlusion of the LAA with a cardiac device performed at the same time as another open cardiac procedure for the management of AF.

According to the Centers for Disease Control and Prevention there are nearly 6 million people in the United States (US) with AF. In 2019 AF was the underlying cause of 26,535 deaths and contributes to about 183,000 deaths annually. It is estimated that 12.1 Americans will have the disease by 2030. AF is associated with an increased risk of stroke, reported to be the cause of 1 in 7 strokes, with a four- to fivefold increased risk of ischemic stroke (CDC, 2022).

Patent Foramen Ovale (PFO)

PFO describes the persistence of a component of the fetal circulation between the right and left atrium. Although PFOs are found in 10-15% of adults, they are typically clinically insignificant. However, they may be associated with paradoxical embolus, in which an embolus arising in the venous circulation gains access to the arterial circulation through the PFO.

PFO size is inferred from the degree of right-to-left shunting demonstrated on echocardiography in conjunction with agitated saline contrast (bubble study) based on the number of microbubbles appearing in a single frame in the left atrium either spontaneously or after a Valsalva maneuver within three cardiac cycles after opacification of the right atrium. Methods used to detect a right-to-left shunt associated with PFO include TTE, TEE, and transcranial doppler (TCD). TCD cannot confirm the location of the shunt (intracardiac or extracardiac), identify an atrial septal aneurysm, or rule out other cardioembolic sources. Therefore when TCD is positive, imaging, usually with TEE is performed to visualize the type, site, and size of the shunt. 

It is estimated that individuals with a history of PFO and paradoxical embolism have a 3.4% and 3.8% yearly risk of recurrent stroke or transient ischemic attack. Therefore, there has been interest in either open surgery or transcatheter approaches to close the PFO, in individuals with a history of embolic stroke of unknown cause. Treatment alternatives include chronic warfarin therapy, based, in part, on the theory that clotting disorders may be present in individuals with embolic stroke. To date, the AMPLATZER PFO Occluder is the only device which has received FDA approval for transcatheter closure of a PFO to reduce risk of stroke in individuals who had cryptogenic stroke due to presumed paradoxical embolism, after a comprehensive clinical evaluation (by neurologist and cardiologist) has been conducted to rule out other causes of stroke. Contraindications for the AMPLATZER PFO Occluder include: active endocarditis, untreated infection, other heart defects, or a tumor or blood clot in the vessels along the path of the heart. The GORE^® HELEX^® Septal Occluder/ GORE^® Septal Occluder (W.L. Gore & Associates, Inc., Flagstaff, AZ) provides another potential treatment option for PFO closure in individuals who had a cryptogenic stroke.

In the CLOSE study, Mas and colleagues (2017) defined cryptogenic stroke or retinal ischemia as follows:

Cryptogenic stroke (or retinal ischemia): with no identifiable cause other than PFO with or without ASA, based on a detailed etiological work-up, performed under the neurologist’s responsibility. The following examinations, which are part of the standard etiological work-up for stroke in young adults, will be performed before randomization:

• At least one of the following arterial investigations, performed in the 30 days following the qualifying event, as a complement to or instead of Doppler ultrasound of supra-aortic vessels and/or transcranial Doppler: (a) MRA (magnetic resonance angiography), with intracranial and extracranial investigation; (b) CT angiography, with intracranial and extracranial investigation; (c) arteriography by catheter, with extracranial and intracranial investigation.
• Biological work-up comprising blood count, ESR, CRP, fasting blood glucose, lipid survey, serum creatinine, ASAT, ALAT, PT, aPTT, antiphospholipid antibodies (at least including screening for circulating anticoagulant and anticardiolipin antibodies)
• Transthoracic and transesophageal echocardiography (see appendix)
• ECG and search for emboligenic arrhythmia: cardiac monitoring at the acute phase of stroke and/or 24h-Holter ECG
• Any other examination necessary to confirm a cause suspected on clinical data and/or the initial etiological work-up.

Ischemic stroke: Sudden onset of focal neurological symptoms with the presence of cerebral infarction in the appropriate territory on brain imaging (CT or MRI), regardless of the duration of the symptoms (less than or greater than 24 hours).

Retinal ischemia: Sudden onset of monocular visual deficit accompanied by objective signs of retinal infarction in the appropriate region of the retina. This diagnosis must be confirmed by the appropriate investigations.

Potential causes of stroke

• Atherosclerosis: presence of stenosis ≥ 30% of an artery supplying the brain or atherosclerosis of the aortic arch (plaque ≥ 4 mm). In the case of arterial occlusion in the appropriate territory, the diagnosis of atherosclerosis will be adopted if the individual presents at least two cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, smoking) OR a history of myocardial infarction or arterial disease of the lower limbs OR an atherosclerotic stenosis (≥ 30%) of another artery supplying the brain OR plaques of the aortic arch.
• Potentially emboligenic heart disease, other than PFO or ASA.
• Small artery disease, defined by the presence of a small deep infarction (< 1.5 cm in diameter) corresponding to the clinical signs, in an individual with chronic hypertension or diabetes OR at least one old small infarction or vascular leukoencephalopathy. Individuals with only one small deep infarction, without hypertension or diabetes, can be included in the study.
• Other defined or probable causes of stroke (not exhaustive):
  • Non-atherosclerotic arterial disease (e.g.: dissection or arteritis)
  • Coagulopathy requiring long-term anticoagulant therapy (> 6 months).
  • Hematological malignancies (e.g.: thrombocythemia)
  • Recent intravenous drug use (in previous 6 months).

Left Atrial Appendage

According to the Centers for Disease Control (CDC) and Prevention, in the U.S., AF is the most prevalent sustained cardiac arrhythmia, resulting in a four- to five-fold greater risk of stroke due to migration of clots that may form in the LAA (CDC, 2020). As confirmed by echocardiography and autopsy, LAA is identified as a leading source of thrombi in individuals with non-valvular AF. By closing off the LAA, the occlusion device is designed to reduce risk of stroke and other cardiovascular complications. The WATCHMAN LAA Closure Device is the first of its kind treatment giving individuals with non-valvular AF an alternative option to long-term warfarin therapy. The AMPLATZER^™ Cardiac Plug (ACP) (St. Jude Medical, St. Paul, MN) and LARIAT^® Suture Delivery Device and Accessories provide other potential alternatives to closure, currently being studied as alternatives to standard anticoagulation therapy.

The CHADS (cardiac failure, hypertension, age, diabetes, stroke) score is a risk assessment tool that is based on a point system, in which 2 points are assigned for a history of stroke or TIA, and 1 point each is assigned for age over 75 and a history of hypertension, diabetes or recent HF. The adjusted stroke rate can be assessed based on the CHADS score. For example, a CHADS score of 2 is associated with an adjusted stroke rate of 4% per year (Fuster, 2006).

Simple risk stratification used to predict thromboembolism in AF:
CHADS₂ (Congestive heart failure, Hypertension, Age >75, Diabetes, prior Stroke/transient ischemic attack)

• Low risk: Score 0
• Intermediate risk: Score 1
• High risk: Score 2-6

Current guidelines divide individuals at risk for ischemic stroke with a CHA₂DS₂-VASc scores into 3 categories:

• low-risk = 0
• intermediate = 1-2
• high risk ≥ 3

CHADS₂ and CHA₂DS₂-VASc scores to predict ischemic stroke risk in individuals with AF (Lip, 2011)

In 2010, Pisters and colleagues provides the HAS-BLED bleeding risk score, a practical tool to assess individuals bleeding risk in real-world individuals with AF, supporting clinical decision making regarding antithrombotic therapy in individuals with AF.

Clinical Characteristics Composing the HAS-BLED Bleeding Risk Score

Bleeding is the primary risk associated with systemic anticoagulation. The HAS-BLED bleeding risk score has been developed to estimate the risk of significant bleeding in individuals treated with systemic anticoagulation, which has been validated to assess the annual risk of significant bleeding in individuals with AF treated with warfarin. 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. Examples of medication usage predisposing to bleeding include clopidogrel or non-steroidal anti-inflammatory drugs. A HAS-BLED score of 3 or greater is considered to be associated with a high risk of bleeding potentially signaling the need for closer monitoring of individuals for adverse risks, closer monitoring of international normalized ratio (INR), or differential dose selections of oral anticoagulants or aspirin.

Atrial fibrillation: A condition where there is disorganized electrical conduction in the atria, resulting in ineffective pumping of blood into the ventricle.

Atrial septal aneurysm: Redundant interatrial tissue, encompassing the fossa ovalis, with resulting hypermobility of the septum primum and excursion greater than 10 mm on TEE.

Cryptogenic stroke: Cerebral infarction that despite evaluation is not attributable to other well-established singular etiologies including cardioembolism, large artery atherosclerosis, or thromboembolism, or small vessel occlusion.

Decompression Sickness (also known as Decompression Illness, Caisson Disease, or The Bends): Occurs when rapid pressure reduction (for example, during ascent from a dive, exit from a caisson or hyperbaric chamber, or ascent to altitude) causes gas previously dissolved in blood or tissues to form bubbles in blood vessels. Symptoms may include pain, neurologic symptoms, or both, severe cases can be fatal. Risk factors include right-to-left cardiac shunts (Merk Manual Professional, 2023).

High risk of bleeding: A HAS-BLED score of 3 or greater is considered to be associated with a high risk of potential bleeding in persons requiring anticoagulation.

High risk of stroke: A CHADS₂ score of greater than or equal to 2 or a CHA₂DS₂-VASc score of greater than or equal to 3 are considered high risk of stroke or systemic embolism for individuals with AF.

Large interatrial shunt: Presence of more than 30 microbubbles in the left atrium within three cardiac cycles after opacification of the right atrium, based on TTE or TEE.

Left atrial appendage (LAA): A muscular pouch attached to the upper portion of the left atrium.

Migraine aura: A “warning stage” that sometimes occurs before the onset of a migraine headache. Aura refers to any number of sensory disturbances including visual, sensorimotor, or dysphasia (Cleveland Clinic 2021).

Patent foramen ovale (PFO): A component of the fetal circulation that consists of a communication between the left and right atria that generally closes after birth; if an opening remains after birth, the possibility of an embolus (blood clot that breaks free in the blood) getting to the brain exists, resulting in a stroke or transient ischemic attack.

Platypnea-orthodeoxia syndrome (POS): A rare disorder characterized by both dyspnea (platypnea) and arterial desaturation (orthodeoxia) in the upright position with improvement in the supine position.

Transient Ischemic Attack (TIA): A stroke that lasts only a few minutes, it occurs when the blood supply to part of the brain is briefly interrupted. Symptoms, usually occur suddenly and disappear within an hour, although they may persist for up to 24 hours. Symptoms can include numbness or weakness in the face, arm, or leg, especially on one side of the body, trouble seeing in one or both eyes, difficulty with walking, dizziness, confusion or difficulty in talking or understanding speech, loss of balance and coordination (NIH 2024).

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Transcatheter closure of patent foramen ovale
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met.

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for all other diagnoses not listed [with the exception of other atrial septal defects not addressed].

Closure of left atrial appendage
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure codes listed above when criteria are not met.

When services are Investigational and Not Medically Necessary:
For the following procedure codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Ailawadi G, Gerdisch MW, Harvey RL, et al. Exclusion of the left atrial appendage with a novel device: early results of a multicenter trial. J Thorac Cardiovasc Surg. 2011; 142(5):1002-1009.
2. Alkhouli M, Russo AM, Thaler D, et al. Sex differences in safety and effectiveness of LAAO: Insights from the Amulet IDE trial. JACC Cardiovasc Interv. 2022; 15(21):2143-2155.
3. Ando M1, Funamoto M2, Cameron DE2, Sundt TM 3rd2. Concomitant surgical closure of left atrial appendage: a systematic review and meta-analysis. J Thorac Cardiovasc Surg. 2018; 156(3):1071-1080.
4. Bartus K, Han FT, Bednarek J, et al. Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience. J Am Col Cardiol. 2013; 62(2):108-118.
5. Boersma LV, Ince H, Kische S, et al. Evaluating real-world clinical outcomes in atrial fibrillation patients receiving the WATCHMAN left atrial appendage closure technology. Final 2-year outcome data of the EWOLUTION trial focusing on history of stroke and hemorrhage. Cir Arrhythm Electrophysiol. 2019; 12:e006841.
6. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013; 368(12):1092-1100.
7. Darden D, Duong T, Du C, et al. Sex differences in procedural outcomes among patients undergoing left atrial appendage occlusion: Insights from the NCDR LAAO registry [published correction appears in JAMA Cardiol. 2021 Oct 20]. JAMA Cardiol. 2021; 6(11):1275-1284.
8. Dowson A, Mullen MJ, Peatfield R, et al. Migraine intervention with STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation. 2008; 117(11):1397-404.
9. Farjat-Pasos JI, Guedeney P, Houde C, et al. Transcatheter Patent Foramen Ovale closure in patients with Transient Ischemic Attack. Am J Cardiol. 2023; 187:148-153.
10. Freeman JV, Varosy P, Price MJ, et al. The NCDR Left Atrial Appendage Registry. J Am Coll Cardiol. 2020; 75(13): 1503-1518.
11. Friedman DJ, et al. Association between left atrial appendage occlusion and readmission for thromboembolism among patients with atrial fibrillation undergoing concomitant cardiac surgery. J American Med Assoc 2018; 319(4):365-374. DOI: 10.1001/jama.2017.20125.
12. 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.
13. 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: the PREVAIL trial. J Am Coll Cardiol. 2014; 64(1):1-12.
14. Holmes DR, Reddy VY, Buchbinder M, et al. The assessment of the Watchman Device in patients unsuitable for oral anticoagulation (ASAP-TOO) trial. Am Heart J. 2017; 189:68-74.
15. Holmes DR, Reddy VY, Gordon NT, et al. Long-term safety and efficacy in continued access left atrial appendage closure registry. J Am Coll Cardiol. 2019; 74(23): 2878-2889.
16. Holmes DR, Reddy VY, Turi ZG, et al.; PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized non-inferiority trial. Lancet. 2009; 374(9689):534-542.
17. Jaiswal V, Ang SP, Shrestha AB, et al. Amplatzer amulet versus watchman device for percutaneous left atrial appendage closure: A systematic review and meta-analysis. Medicine (Baltimore). 2023;102(26):e34185.
18. Kapadia SR. Patent foramen ovale closure: historical perspective. Cardiol Clin. 2005; 23(1):73-83.
19. Kar S, Doshi SK, Sadhu A, et al. Primary outcome evaluation of a next-generation left atrial appendage closure device: results from the PINNACLE FLX trial. Circulation. 2021; 143(18):1754-1762.
20. Kay JD, O’Laughlin MP, Ito K, et al. Five-year clinical and echocardiographic evaluation of the Das Angel Wings atrial septal occluder. Am Heart J. 2004; 147(2):361-368.
21. Khan MZ, Munir MB, Darden D, et al. Racial disparities in in-hospital adverse events among patients with atrial fibrillation implanted with a Watchman left atrial appendage occlusion device: A US national perspective. Circ Arrhythm Electrophysiol. 2021; 14(5):e009691.
22. Kuijpers T, Spencer FA, Siemieniuk RA, et al. Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy alone for management of cryptogenic stroke? A clinical practice guideline. Brit J Med. 2018; 362:k2515.
23. Lakkireddy D, Thaler D, Ellis CR, et al. Amplatzer amulet left atrial appendage occluder versus Watchman device for stroke prophylaxis (Amulet IDE): A randomized, controlled trial. Circulation. 2021; 144(19):1543-1552.
24. Lakkireddy D, Nielsen-Kudsk JE, Windecker S, et al. Mechanisms, predictors, and evolution of severe peri-device leaks with two different left atrial appendage occluders. Europace. 2023; 25(9):euad237.
25. Lee HJ, Lim DS, Lee J, et al. Decompression Illness in divers with or without Patent Foramen Ovale : A cohort study. Ann Intern Med. 2023; 176(7):934-939. Epub 2023 Jul 11.
26. Lee PH, Song JK, Kim JS, et al. Cryptogenic stroke and high-risk patent foramen ovale: the DEFENSE-PFO trial. J Am Coll Cardiol. 2018; 71(20):2335-2342.
27. Mas JL, Derumeaux B, Guillon E, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Eng J Med. 2017; 377(11):1011-1021.
28. Mattle HP, Evers S, Hildick-Smith D, et al. Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial. Eur Heart J. 2016 Jul 7;37(26):2029-36.
29. Najim M, Reda Mostafa M, Eid MM, et al. Efficacy and safety of the new generation Watchman FLX device compared to the Watchman 2.5: a systematic review and meta-analysis. Am J Cardiovasc Dis. 2023; 13(5):291-299.
30. O’Gara PT, Messa SR, Tuzcu EM, et al. Percutaneous device closure of patent foramen ovale for secondary stroke prevention: a call for completion of randomized clinical trials. A science advisory from the American Heart Association/American Stroke Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2009; 53(21):2014-2018.
31. Okumura K, Akao T, Yoshida M, et al. Low-dose edoxaban in very elderly patients with atrial fibrillation. N Eng J Med. 2020; 383(18):1735-1745.
32. Osmancik P, Herman D, Neuzil P, et al. 4-Year outcomes after left atrial appendage closure versus nonwarfarin oral anticoagulation for atrial fibrillation. J Am Coll Cardiol. 2022; 79(1):1-14.
33. Osmancik P, Herman D, Neuzil P, et al. Left atrial appendage closure versus direct oral anticoagulants in high-risk patients with atrial fibrillation. J Am Coll Cardiol. 2020; 75(25): 3122-3135.
34. Onorato E, Melzi G, Casilli F, et al. Patent foramen ovale with paradoxical embolism: mid-term results of transcatheter closure in 256 patients. J Interv Cardiol. 2003; 16(1):43-50.
35. Patel HT, Hijazi ZM. Pediatric catheter interventions: a year in review 2004-2005. Curr Opin Pediatr. 2005; 17(5):568-573.
36. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation. The Euro heart survey. Chest. 2010; 138(5):1093-1100.
37. Pisters R, van Köstenberger RJ, Knottnerus ILH, et al. The likelihood of decreasing strokes in atrial fibrillation patients by strict application of guidelines. Europace. 2010; 12(6):779-784.
38. Price MJ, Reddy VY, Valderrabano M, et al. Bleeding outcomes after left atrial appendage closure compared with long-term warfarin. JACC. 2015; 8(15):1925-1932.
39. Pristipino C, Sievert H, D'Ascenzo F, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J. 2019; 40(38):3182-3195.
40. Reddy VY, Doshi SK, Kar S, et al. 5-Year outcomes after left atrial appendage closure. From the PREVAIL and PROTECT AF trials. J Am Coll Cardiol. 2017; 70(24):2964-2975.
41. Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-year follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for embolitic protection in patients with atrial fibrillation) Trial. Stroke. 2013; 127(6):720-729.
42. Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the Watchman left atrial appendage system for embolic protection in patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation. 2011; 123(4):417-424.
43. Reddy VY, Mobius-Winkler S, Miller MA, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study with Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol. 2013; 61(25):2551-2556.
44. Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014; 312(19):1988-1998.
45. Ries M, Kampmann C, Rupprecht HJ, et al. Nickel release after implantation of the Amplatzer occluder. Am Heart J. 2003; 145(4):737-741.
46. Rome JJ, Kreutzer J. Pediatric interventional catheterization: reasonable expectations and outcomes. Pediatr Clin North Am. 2004; 51(6):1589-1610, viii.
47. Saver JL, Carrol JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med. 2017; 377(11):1022-1032.
48. Sedaghat A, Vij V, Al-Kassou B, et al. Device-related thrombus after left atrial appendage closure: data on thrombus characteristics, treatment strategies, and clinical outcomes from the EUROC-DRT-Registry. Circ Cardiovasc Interv. 2021. 14(5):544-553.
49. Sondergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Eng J Med. 2017; 377(11):1033-1042.
50. Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism: long term risk of recurrent thromboembolic events. Circulation. 2000; 101(8):893-898.
51. Yao X, et al. Association of surgical left atrial appendage occlusion with subsequent stroke and mortality among patients undergoing cardiac surgery. Journal of the American Medical Association 2018; 319(20):2116-2126.
52. Yasmin F, Ali E, Moeed A, etc. Safety and efficacy of percutaneous Watchman 2.5 device versus Amplatzer Amulet for left atrial appendage closure in patients with non-valvular atrial fibrillation: A systematic review and study-level meta-analysis. PLoS One. 2024; 19(2):e0295804.
53. Zhang Z, Zhou J, Lin Q, et al. Overcoming barriers for left atrial appendage thrombus: a systematic review of left atrial appendage closure. BMC Cardiovasc Disord. 2024; 24(1):175.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Abbott Medical Devices. AMPLATZER Amulet LAA Occluder trial (Amulet IDE). NLM Identifier: NCT02879448. Last updated July 4, 2024. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02879448?term=NCT02879448&draw=2&rank=1. Accessed on May 28, 2024.
2. Boston Scientific Corporation. Continued access to PREVAIL (CAP2). NLM Identifier: NCT01760291. Last updated on March 29, 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT01760291?term=PREVAIL+WATCHMAN&rank=2. Accessed on May 28, 2024.
3. Boston Scientific Corporation. Evaluation of the WATCHMAN LAA Closure Device in patients with atrial fibrillation versus long term warfarin therapy (PREVAIL). NLM Identifier: NCT01182441. Last updated on July 26, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT01182441?term=PREVAIL+WATCHMAN&rank=1. Accessed on May 28, 2024.
4. Boston Scientific Corporation. Investigational Device Evaluation of the WATCHMAN FLX™ LAA Closure Technology (PINNACLE FLX). NLM Identifier: NCT02702271. Last updated June 14, 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT02702271. Accessed on May 28, 2024.
5. Dhanunjaya Lakkireddy, MD, FACC, University of Kansas Medical Center Research Institute. Safety and Efficacy of Left Atrial Appendage Occlusion Devices. NCT01695564. Last updated May 2, 2019. Available at: http://clinicaltrials.gov/ct2/show/NCT01695564?term=LARIAT&rank=1. Accessed on May 28, 2024.
6. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Association and the Heart Rhythm Society. Circulation. 2006; 114(7):e257-e354. Available at: https://www.ahajournals.org/doi/full/10.1161/circulationaha.106.177292. Accessed on May 28, 2024.
7. Jae-Kwan Song. Device Closure versus medical therapy for cryptogenic stroke patients with high-risk patent foramen ovale (DEFENSE-PFO). NLM Identifier: NCT01550588. Last updated June 29, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01550588. Accessed on May 28, 2024.
8. January CT, Wann S, Alpert JS, et al. 2014 AHA/ACC/HRS practice guideline. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014; 130:e199-e267.
9. January CT, Wann SL, Calkins H, et al. 2019 AHA/ACC/HRS Focused updated of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2019; pii: S0735-1097(19)30209-8.
10. Kavinsky CJ, Szerlip M, Goldsweig AM, et al. Standards and Guidelines. SCAI guidelines for the management of patent foramen ovale. J Soc Cardiovasc Angiography Interv. 2022; [Ahead of print]
11. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack. A guideline from the American Heart Association/American Stroke Association. Stroke. 2021; 52:e364-e467.
12. Liu K, Wang BZ, Hao Y, et al. The correlation between migraine and Patent Foramen Ovale. Front Neurol. 2020; 11:543485.
13. Lip GY, Andreotti F, Fauchier L, et al. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace. 2011; 13(5):723-746.
14. Masoudi FA, Caukins H, Kavinsky CJ, et al. 2015 ACC/HRS/SCAI left atrial appendage occlusion device societal overview: a professional societal overview from the American College of Cardiology, Heart Rhythm Society, and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2015; 86(5):791-807.
15. Messe SR, Gronseth GS, Kent DM, et al. Practice advisory update summary: patent foramen ovale and secondary stroke prevention. Report of the Guideline Subcommittee of the American Academy of Neurology. Neurology. 2020; 94:1-10.
16. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics- 2015 update: a report from the American Heart Association. Circulation. 2015; 131:e29-e322.
17. Saw J, Holmes DR, Cavalcante JL, et al. SCAI/HRS Expert Consensus Statement on Transcatheter Left Atrial Appendage Closure. JACC Cardiovasc Interv. 2023;16(11):1384-1400.
18. St. Jude Medical. AMPLATZER Cardiac Plug (ACP) registry-long term follow-up protocol (ACPR). NLM Identifier: NCT01786486. Last updated on June 28, 2023. Available at: https://clinicaltrials.gov/ct2/show/NCT01786486?term=AMPLATZER+AND+left+atrial+appendage&rank=1. Accessed on May 28, 2024.
19. U.S. Food and Drug Administration (FDA). Premarket Approval (PMA). AMPLATZER PFO Occluder. No. P120021. Rockville, MD: FDA. October 28, 2016. Accessible at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P120021. Accessed on May 28, 2024.
20. U.S. Food and Drug Administration (FDA) Premarket Approval (PMA). GORE^® CARDIOFORM Septal Occluder. No. P050006/S060. Rockville, MD: FDA. March 30, 2018. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P050006S060. Accessed on May 28, 2024.
21. U.S. Food and Drug Administration (FDA). Premarket Approval (PMA). WATCHMAN™ Left Atrial Appendage Closure Device. No. P130013. Rockville, MD: FDA. March 13, 2015. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf13/p130013b.pdfAccessed on May 28, 2024.
22. U.S. Food and Drug Administration (FDA). Premarket Approval (PMA). WATCHMAN Left Atrial Appendage Closure Device with delivery system and WATCHMAN FLX Left Atrial Appendage Closure Device with delivery system. No. P130013/S035. Rockville. MD: FDA. July 21, 2020. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P130013S035. Accessed on May 28, 2024.
23. Whitlock RP, Belley-Cote EP, Paparella D, et al. Left atrial appendage occlusion during cardiac surgery to prevent stroke. N Engl J Med. 2021; 384(22):2081-2091.
24. W.L. Gore & Associates. Gore^® Helex^® septal occlude/GORE^® CARDIOFORM Septal Occlude for patent foramen ovale (PFO) closure in stroke patients - the Gore REDUCE clinical study (HLX 06-03). NLM Identifier: NCT00738894. Last updated November 20, 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT00738894. Accessed on May 28, 2024.

Applicable to Commercial HMO members in California: When a medical policy states a procedure or treatment is investigational, PMGs should not approve or deny the request. Instead, please fax the request to Anthem Blue Cross Grievance and Appeals at fax # 818-234-2767 or 818-234-3824. For questions, call G&A at 1-800-365-0609 and ask to speak with the Investigational Review Nurse.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

© CPT Only – American Medical Association