BACKGROUND

Patent Foramen Ovale

The foramen ovale, a component of fetal cardiovascular circulation, consists of a communication between the right and left atrium that functions as a vascular bypass of the uninflated lungs. The ductus arteriosus is another feature of the fetal cardiovascular circulation, consisting of a connection between the pulmonary artery and the distal aorta. Before birth, the foramen ovale is held open by the large flow of blood into the left atrium from the inferior vena cava. Over the course of months after birth, an increase in left atrial pressure and a decrease in right atrial pressure result in permanent closure of the foramen ovale in most individuals. However, a patent foramen ovale (PFO) is a common finding in 25% of asymptomatic adults.^1, In some epidemiologic studies, PFO has been associated with cryptogenic stroke, defined as an ischemic stroke occurring in the absence of potential cardiac, pulmonary, vascular, or neurologic sources. Studies have also shown an association between PFO and migraine headache.

Atrial Septal Defects

Unlike PFO, which represents the postnatal persistence of normal fetal cardiovascular physiology, atrial septal defects (ASDs) represent an abnormality in the development of the heart that results in free communication between the atria. ASDs are categorized by their anatomy. Ostium secundum describes defects located midseptally and are typically near the fossa ovalis. Ostium primum defects lie immediately adjacent to the atrioventricular valves and are within the spectrum of atrioventricular septal defects. Primum defects occur commonly in patients with Down syndrome. Sinus venous defects occur high in the atrial septum and are frequently associated with anomalies of the pulmonary veins.

Ostium secundum ASDs are the third most common form of congenital heart disorder and among the most common congenital cardiac malformations in adults, accounting for 30% to 40% of these patients older than age 40 years. The ASD often goes unnoticed for decades because the physical signs are subtle and the clinical sequelae are mild. However, virtually all patients who survive into their sixth decade are symptomatic; fewer than 50% of patients survive beyond age 40 to 50 years due to heart failure or pulmonary hypertension related to the left-to-right shunt. Symptoms related to ASD depend on the size of the defect and the relative diastolic filling properties of the left and right ventricles. Reduced left ventricular compliance, and mitral stenosis will increase left-to-right shunting across the defect. Conditions that reduce right ventricular compliance and tricuspid stenosis will reduce left-to-right shunting or cause a right-to-left shunt.Symptoms of an ASD include exercise intolerance and dyspnea, atrial fibrillation, and less commonly, signs of right heart failure. Patients with ASDs are also at risk for paradoxical emboli.

Treatment of Atrial Septal Defects

Repair of ASDs is recommended for those with a pulmonary-to-systemic flow ratio (Q_p: Q_s) exceeding 1.5:1.0. Despite the success of surgical repair, there has been interest in developing a transcatheter-based approach to ASD repair to avoid the risks and morbidity of open heart surgery. A variety of devices have been researched. Technical challenges include minimizing the size of the device so that smaller catheters can be used, developing techniques to center the device properly across the ASD, and ensuring that the device can be easily retrieved or repositioned, if necessary.

Individuals with ASDs and a history of cryptogenic stroke are typically treated with antiplatelet agents, given an absence of evidence that systemic anticoagulation is associated with outcome improvements.

Transcatheter Closure Devices

Transcatheter PFO and ASD occluders consist of a single or paired wire mesh discs covered or filled with polyester or polymer fabric that are placed over the septal defect. Over time, the occlusion system is epithelialized. ASD occluder devices consist of flexible mesh discs delivered via catheter to cover the ASD.

Regulatory Status
Patent Foramen Ovale Closure Devices

The U.S. Food and Drug Administration (FDA) has approved 3 devices for ASD closure through the premarket approval process or a premarket approval supplement: the Amplatzer Septal Occluder, the GORE HELEX Septal Occluder (discontinued), and the GORE CARDIOFORM Septal Occluder (see Table 1).FDA product code: MLV.

In 2002, 2 transcatheter devices were cleared for marketing by the FDA through a humanitarian device exemption as treatment for patients with cryptogenic stroke and PFO: the CardioSEAL® Septal Occlusion System (NMT Medical; device no longer commercially available) and the Amplatzer® PFO Occluder (Amplatzer, now St. Jude Medical). Following the limited FDA approval, use of PFO closure devices increased by more than 50-fold, well in excess of the 4000 per year threshold intended under the humanitarian device exemption,^2, prompting the FDA to withdraw the humanitarian device exemption approval for these devices in 2007. The Amplatzer PFO Occluder was approved through the premarket approval process in 2016.

In March 2018, the FDA granted an expanded indication to the Gore Cardioform Septal Occluder to include closure of PFO to reduce the risk of recurrent stroke (see Table 1). The new indication was based on results of the REDUCE pivotal clinical trial.^3,

Table 1. Patent Foramen Ovale Closure Devices Approved by the U.S. Food and Drug Administration

Device	Manufacturer	PMA Approval Date	Indications
Amplatzer™ PFO Occluder	St. Jude Medical	Nov 2016	For percutaneous transcatheter closure of a patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, 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.4,
GORE HELEX Septal Occluder	W.L. Gore & Associates	Aug 2006(discontinued)	Percutaneous, transcatheter closure of ostium secundum ASDs
GORE CARDIOFORM Septal Occluder	W.L. Gore & Associates	Mar 2018(supplement)	PFO closure to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, 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

PMA: premarket approval. FDA product code: MLV.
Atrial Septal Defect Closure Devices

The FDA has approved 3 devices for SD closure through the premarket approval process or a premarket approval supplement: the Amplatzer Septal Occluder, the GORE HELEX Septal Occluder (discontinued), and the GORE CARDIOFORM Septal Occluder (see Table 2). FDA product code: MLV.

Table 2. Atrial Septal Defect Closure Devices Approved by the U.S. Food and Drug Administration

Device	Manufacturer	PMA Approval Date	Indications
Amplatzer™ Septal Occluder	St. Jude Medical (Abbot Medical)	Dec 2001	Occlusion of ASDs in the secundum position Use in patients who have had a fenestrated Fontan procedure who require closure of the fenestration Patients indicated for ASD closure have echocardiographic evidence of ostium secundum ASD and clinical evidence of right ventricular volume overload.
GORE HELEX Septal Occluder	W.L. Gore & Associates	Aug 2006 (discontinued)	Percutaneous, transcatheter closure of ostium secundum ASDs
GORE CARDIOFORM ASD Occluder (formerly GORE CARDIOFORM Septal Occluder)	W.L. Gore & Associates	May 2019 (supplement; name change) Oct 2016 (supplement)	Percutaneous, transcatheter closure of ostium secundum ASDs

ASD: atrial septal defect; PMA: premarket approval.

Related Policies

• None

The percutaneous transcatheter closure of a patent foramen ovale using a device that has been approved by the U.S. Food and Drug Administration for that purpose is considered medically necessary to reduce the risk of recurrent ischemic stroke if the member meets all of the following:
• Between 18 and 60 years of age
• Diagnosed with patent foramen ovale with a right-to-left interatrial shunt confirmed by echocardiography with at least one of the following characteristics:
  • PFO with large shunt, defined as >30 microbubbles in the left atrium within 3 cardiac cycles, after opacification of the right atrium.
  • PFO associated with atrial septal aneurysm on transesophageal examination: septum primum excursion >10 mm
• Documented history of cryptogenic ischemic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude any other identifiable cause of stroke, including large vessel atherosclerotic disease and small vessel occlusive disease

• Uncontrolled vascular risk factors, including uncontrolled diabetes or uncontrolled hypertension
• Other sources of right-to-left shunts, including an atrial septal defect and/or fenestrated septum.
• Active endocarditis or other untreated infections
• Inferior vena cava filter.

Transcatheter closure of secundum atrial septal defects is considered medically necessary when using a device that has been approved by the U.S. Food and Drug Administration for that purpose and used according to the labeled indications including:
• Members with echocardiographic evidence of ostium secundum atrial septal defect;
AND either of the following:
• Clinical evidence of right ventricular volume overload (i.e., 1.5:1 degree of left-to-right shunt or right ventricular enlargement); OR
• Clinical evidence of paradoxical embolism.

FIDE-SNP Coverage:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2006 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through March 9, 2020.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Transcatheter Device Closure of Patent Foramen Ovale for Stroke
Clinical Context and Therapy Purpose

The purpose of patent foramen ovale (PFO) closure with a transcatheter device in patients who have PFO and cryptogenic stroke is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does PFO closure with a transcatheter device improve the net health outcome in patients with cryptogenic stroke?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with PFO and cryptogenic stroke.

Interventions

The therapy being considered is PFO closure with a transcatheter device.

PFO closure is performed by cardiac surgeons in a hospital setting.

Comparators

The following therapies are currently being used to manage PFO closure in patients with cryptogenic stroke: conventional therapy for cryptogenic stroke, which consists of antiplatelet therapy (aspirin, clopidogrel, or dipyridamole given alone or in combination) or oral anticoagulation with warfarin. In general, patients with a known clotting disorder or evidence of preexisting thromboembolism are treated with warfarin, and patients without these risk factors are treated with antiplatelet agents.

Patients with PFO are managed by cardiologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are overall survival, morbid events, treatment-related mortality, and treatment-related morbidity.

Based on identified clinical trials, long-term follow-up of ≥ 10 years would be preferable to determine outcomes for patients who undergo PFO.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought
• Studies with duplicative or overlapping populations were excluded.

Transcatheter Patent Foramen Ovale Closure With Device Versus Medical Management

Three RCTs, the Patent Foramen Ovale and Cryptogenic Embolism (PC)-Trial^5,, the Patent Foramen Ovale Closure or Medical Therapy After Stroke (RESPECT) trial^6,, and the Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale (DEFENSE-PFO) trial—have been published and reported on outcomes comparing the Amplatzer PFO Occluder with medical management. Trial characteristics and results are summarized in Tables 3 and 4.

In the PC-Trial (2013), the primary endpoint (composite of death, nonfatal stroke, transient ischemic attack [TIA], or peripheral embolism after independent adjudication) did not differ significantly between the closure and medical groups either on intention-to-treat (ITT) analysis or per-protocol analysis. Also, there were no significant differences in the rates of the individual components of the primary outcome or the outcomes on subgroup analyses. The adverse event rate was 34.8% in the closure group and 29.5% in the medical therapy group. This trial was designed to have 80% power to detect a reduction of 66% in primary endpoint (from 3% per year in the medical therapy group vs. 1% per year in the closure group). However, the observed event rate in the trial was less than half of the anticipated event rate used in the power calculation and, as reported by authors, the trial had less than 40% power to detect a 66% reduction.

RESPECT (2013) also compared closure with medical management, with 2 notable differences from the PC-Trial: TIA was not included as a component of the primary composite endpoint, and all endpoints were adjudicated in a blinded fashion. These protocol differences were attempts to address shortcomings observed in the PC-Trial where authors noted that TIA as a component in the primary endpoint might have diluted effects, as suggested by the difference in the estimated hazard ratios (HRs) for stroke (0.20) and TIA (0.71). Trialists had also noted the possibility of selective reporting of potential events in the PC-Trial owing to the open-label nature of the trial.

Results of the RESPECT trial have been reported in 3 publications^6,7,8, with each publication reporting longer follow-up. The primary endpoint was a stroke or early death, 30 and 45 days after implantation or randomization, respectively.

Carroll et al (2013) (2013), reported in the first publication a median follow-up of 2.3 years and no difference in the primary endpoint with ITT analysis.^6, The ITT analysis (n = 980) included 3 patients from the closure group who had recurrent ischemic stroke before device implantation. However, the per-protocol cohort (n = 944; patients as randomized who adhered to the protocol-mandated medical treatment, and did not have a major inclusion or exclusion violation) and as-treated cohort (n = 958; patients with a protocol-approved treatment who adhered to the protocol-mandated medical treatment, and were classified by treatment actually received) showed statistically significant improvements in primary endpoint in both analyses (hazard ratio [HR] = 0.37; 95% confidence interval [CI], 0.14 to 0.96; P=.03; HR = 0.27; 95% CI, 0.10 to 0.75; P=.007, respectively). The number needed to treat (NNT) after 5 years in the ITT population was 27. The rate of serious, device- or procedure-related complications was 4.5%. There was no difference in major bleeding between arms, but there was a higher incidence of deep vein thrombosis and pulmonary thromboembolism in the device arm. This was attributed to a ninefold increased use of warfarin in the medical group.

Rogers et al (2017) published an overview of the U.S. Food and Drug Administration (FDA) assessment of the Amplatzer PFO Occluder that included analysis of data with approximately 5 years of follow-up.^8,The FDA conducted ITT, per-protocol, as-treated, and device-in-place analyses, and results are summarized in Table 5. Although the FDA panel had some disagreements about using non-ITT analysis because excluding patients compromises randomization, the panel agreed that a 50% relative risk reduction in stroke—especially in a younger patient population—is clinically significant. All 3 analyses (ie, per-protocol, as-treated, and device-in-place) reported statistically significant relative reductions of more than 50% in the risk of recurrent strokes. Note that with extended follow-up analyses, the event-free survival curves converged, and the NNT after 5 years in the ITT population rose from 27 to 43. However, the FDA concluded that it might be reasonable for conclusions drawn from RESPECT to be limited to the select subgroup of at-risk patients with stroke and PFO in whom other causes of ischemic stroke have been excluded by a neurologist.

Saver et al (2017) also published results from the RESPECT trial, reporting on a median of 5.9 years of follow-up.^7,Rogers et al (2016) reported similar findings. (2016).^8, The relative difference in the rate of recurrent ischemic stroke between closure and medical therapy alone was large (45% lower with closure), but the absolute difference was small (0.49 fewer events per 100 patient-years with closure).

Lee et al (2018) reported on the DEFENSE-PFO randomized open-label superiority trial.^9, The trial compared PFO closure using the Amplatzer PFO Occluder plus medical therapy with medical therapy alone. Patients included in the trial had experienced ischemic stroke within the last 6 months for no apparent cause other than a high-risk PFO with right-to-left shunting. All patients were prescribed either antiplatelet or anticoagulation medication. The trial’s recruitment rate was lower than expected, and the CLOSE trial was completed and published during the course of DEFENSE-PFO. Based on the results of CLOSE, the investigators agreed to stop enrollment early for the patients’ safety. The trial and its results are described in Tables 3 and 4.

Table 3. Summary of Key RCT Characteristics for the Amplatzer PFO Occluder

Trial	Countries	Sites	Dates	Participants	Interventions		Median DOF, y
					Active	Comparator
Meier et al (2013)5,; PC-Trial	European Union, Canada, Brazil, Australia	29	2000- 2009	With PFO <60 y and history of ischemic stroke, TIA, or a peripheral TE event	Amplatzer PFO Occluder	Medical treatmenta	4.1
Carroll et al (2013)6,; RESPECT	United States, Canada	69	2003-2011	With PFO 18-60 y and cryptogenic ischemic stroke	Amplatzer PFO Occluder	Medical treatmentb	2.1
Saver et el (2017)7,; RESPECT	United States, Canada	69	2003- 2011	With PFO 18-60 y and cryptogenic ischemic stroke	Amplatzer PFO Occluder	Medical treatmentb	5.9
Lee et al (2018)9,; DEFENSE-PFO	South Korea	2	2011-2017	With cryptogenic stroke and high-risk PFO.	Amplatzer PFO Occluder with medical treatment	Medical treatmentb	2.8

DOF: duration of follow-up; PFO: patent foramen ovale; TE: thromboembolic; RCT: randomized controlled trial; TIA: transient ischemic attack.
PC-Trial: Patent Foramen Ovale and Cryptogenic Embolism; RESPECT: Patent Foramen Ovale Closure or Medical Therapy After Stroke; DEFENSE-PFO: Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale.

^a Antithrombotic as per physician discretion and could have included antiplatelet therapy or oral anticoagulation, provided that patients received at least 1 antithrombotic drug.
^bAspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole.

Trial	Primary Endpoint	Secondary Endpoint	Stroke
Meier et al (2013)5,; PC-Trial	414	414	414
Amplatzer, n/N (%)	7/204 (3.4)a	5/204 (2.5%)b	1/204 (0.5%)
Medical treatment, n/N (%)	11/210 (5.2)a	11/210 (5.2%)b	5/210 (2.4%)
HR (95% CI); P-value	0.63 (0.24 to 1.62);.34a	0.45 (0.16 to 1.29);.14b	0.20 (0.02 to 1.72);.14
Carroll et al (2013)6,; RESPECT	980
Amplatzer, n/N (%)	9/499 (1.8)c	NA	9/499 (1.8)
Medical treatment, n/N (%)	16/481 (3.3)c	NA	16/481 (3.3)
HR (95% CI); P-value	0.49 (0.22 to 1.11);.08c	NA	0.49 (0.22 to 1.11);.08
Saver et el (2017)7,; RESPECT
Amplatzer, n/N (%)	NR	NA	18/499 (3.6)
Medical treatment, n/N (%)	NR	NA	28/481 (5.8)
HR (95% CI); P-value	NR	NA	0.55 (0.31 to 0.99);.04
Lee et al (2018)9,; DEFENSE-PFO	120		120
Amplatzer, n/N (%)d,e	0/60 (0.0)e	NA	0/60 (0.0)
Medical treatment, n/N (%)d,e	6/60 (12.9)e	NA	5/60 (10.5)
(95% CI); P-value	(3.2 to 22.6);.013	NA	(NR).023

^a Composite of death, nonfatal stroke, TIA, or peripheral embolism.
^b Composite of stroke, TIA, or peripheral embolism.
^c Composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization.
^d Intention-to-treat analysis.
^e Kaplan-Meier estimates.
^f Composite of stroke, vascular death, or Thrombolysis In Myocardial Infarction (TIMI)-defined major bleeding within 2 years of procedure.

^a Adherence to guidelines-directed medical therapy defined as ≥67% cumulative compliance over the duration of the study.
^b p<.05 was considered statistically significant.

Two RCTs - the REDUCE and CLOSE trials—have been published and reported on outcomes comparing various closure devices plus medical management with medical management alone. They are summarized in Tables 6 and 7. Note that both the REDUCE and CLOSE trials enrolled more patients with a moderate-to-large interatrial shunt size (58.4% and 75.2%) compared with 16.7% and 19.3% of patients with a large interatrial shunt size in the PC-Trial and RESPECT trial, all respectively.

In the REDUCE trial (2017), the blinded adjudicated coprimary endpoints of freedom from ischemic stroke (reported as the percentage of patients who had a stroke recurrence) and incidence of new brain infarction (clinical ischemic stroke plus silent brain infarction on imaging) 2 years after randomization were significantly lower in the PFO closure plus antiplatelet therapy than the antiplatelet therapy alone group in ITT analysis, the per-protocol analysis, and the as-treated population analysis (see Table 7).^10, The number of patients who needed to be treated to prevent 1 stroke in 24 months was approximately 28 patients. Previous trials such as RESPECT, PC-Trial, and CLOSURE allowed discontinuation of antithrombotic therapy after PFO closure, and the use of anticoagulants in the medical therapy group was at the discretion of the treating physician. Such a design may have led to the confounding of results and bias within the medical therapy groups in favor of control because of increased protection from the risk of stroke due to causes other than PFO. Serious adverse events occurred in 23.1% of patients in the PFO closure group and 27.8% of patients in the antiplatelet-only group (P=.22).

In the CLOSE trial (2017), 663 patients were randomized to PFO closure plus antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group).^11, The primary blinded adjudicated outcome of stroke was significantly lower in the PFO closure versus antiplatelet therapy in ITT analysis as well as per-protocol analysis (see Table 6). The 5-year stroke risk, using the Kaplan-Meier probability estimate, was 4.9 percentage points lower in the PFO closure group than in the antiplatelet-only group, which would result in 1 stroke avoided at 5 years for every 20 treated patients (95% CI, 17 to 25). The rate of atrial fibrillation was higher in the PFO closure group (4.6%) than in the antiplatelet-only group (0.9%; P =.02). The number of serious adverse events did not differ significantly between treatment groups (P=.56).

No clinical trials have focused specifically on patients who failed medical therapy, as defined by recurrent stroke or TIA while on therapy. Many published studies have included patients with first cryptogenic stroke patients with recurrent stroke or TIA and have generally not analyzed these patient populations separately. As a result, it is not possible to determine from the evidence whether PFO closure in patients who have failed medical therapy reduces the risk of subsequent recurrences.

Table 6. Summary of Key RCT Characteristics

Trial	Countries	Sites	Dates	Participants	Interventions		Median DOF, y
					Active	Comparator
Søndergaard et al (2017)10,; REDUCE	US, Europe	63	2008-2015	With PFO 18-60 y and cryptogenic ischemic stroke	HELEX or CARDIOFORM plus antiplatelet therapya	Antiplatelet therapy alonea	3.2
Mas et al (2017)11,; CLOSE	France, Germany	34	2008-2016	With PFO 16-60 y and cryptogenic ischemic stroke	Multiple closure devices plus antiplatelet therapyb	Antiplatelet therapy alonec	5.4-5.2d

DOF: duration of follow-up; PFO: patent foramen ovale; RCT: randomized controlled trial.
REDUCE: GORE® Septal Occluder Device for Patent Foramen Ovale (PFO) Closure in Stroke Patients; CLOSE: Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence.

^a Antiplatelet therapy could consist of aspirin alone (75-325 mg once daily), a combination of aspirin (50-100 mg daily) and dipyridamole (225-400 mg daily), or clopidogrel (75 mg once daily).
^b Dual antiplatelet therapy (aspirin 75 mg plus clopidogrel 75 mg per day) for 3 months followed by single antiplatelet therapy throughout the remainder of the trial.
^c Antiplatelet therapy (aspirin, clopidogrel, or aspirin combined with extended release dipyridamole).
^d Duration of follow-up in device closure group and antiplatelet-only group.

^a Freedom from ischemic stroke (reported as percentage of patients who had a recurrence of stroke) 2 years after randomization.
^bIncidence of new brain infarction (clinical ischemic stroke or silent brain infarction on imaging) 2 years after randomization.
^c Composite outcome of stroke, transient ischemic attack, or systemic embolism.

A large number of systematic reviews and meta-analyses have evaluated outcomes related to the percutaneous transcatheter closure of a PFO. systematic reviews, by Kent et al (2016) and Li et al (2015) pooled data from 3 RCTs (CLOSURE I, PC-Trial, RESPECT) in their systematic reviews.^12,13, However, the findings of analyses published prior 2018 may no longer be relevant because (1) they pooled data across multiple devices (STARFlex septal closure system is no longer available), which might differ in terms of efficacy and safety, and (2) did not incorporate results of multiple RCTs with long-term follow-up of up to 5 years published in 2017. Therefore, systematic reviews published before 2017 are not discussed further.

Two meta-analyses published in 2018 included data from PC-Trial, RESPECT extended follow-up, REDUCE, and CLOSE but excluded CLOSURE I trial data because it used the STARFlex PFO closure device (Tables 8 and 9).^14,15, Shah et al (2018) reported that PFO closure reduced the absolute risk of recurrent stroke by 3.2% (95% CI, 1.4% to 5.0%). De Rosa et al (2018) reported that the PFO closure reduced the absolute risk of stroke or TIA by 2.9% (95% CI, 1.2% to 5.4%). Shah et al (2018) concluded that the association of device therapy with new-onset atrial fibrillation was inconclusive because of marked heterogeneity between trials and extremes in CIs reported in some cases. On the other hand, De Rosa et al (2018) reported a statistically significant increase in risk of atrial fibrillation with PFO closure devices. In the REDUCE trial, more than 80% of episodes of atrial fibrillation were observed within 45 days from randomization and resolved within 2 weeks.^10, Similarly, in the CLOSE trial, more than 90% of atrial fibrillation cases in the PFO closure group were observed during the first month and did not recur.^11, In the PC-Trial, new-onset atrial fibrillation was reported in 6 (2.9%) patients in the PFO closure group and was transient in 5 of these cases.^5,

Alushi et al (2018) included all 5 trials and reported outcomes as pooled HRs or odds ratios (ORs) in a third meta-analysis (Tables 8 and 9, row 3).^16, Results were similar to previous systematic reviews: There was a 48% reduction in the composite primary outcome of TIA or stroke but no significant reduction in risk of TIA (Table 5). There was an increased risk of atrial fibrillation but no difference between groups in the risk of major bleeding.

Table 8. Systematic Reviews & Meta-Analysis Characteristics

Study	Dates	Trials	Participants	N (Range)	Designs	Duration
Shah et al (2018)14,	1966-2017	4	Adults with PFO and cryptogenic stroke	4866 (NR)	RCTs	No restrictions
De Rosa et al (2018)15,	2004-2017	4	Adults with PFO and cryptogenic stroke	2932 (67-622)	RCTs	No restrictions
Alushi et al (2018)16,	1990-2017	5	Adults with PFO and cryptogenic stroke	3440 (414-980)	RCTs	No restrictions

NR: not reported; PFO: patent foramen ovale; RCT: randomized controlled trial.

Table 9. Systematic Reviews & Meta-Analysis Results

Study	Stroke	TIA	Stroke or TIA	Major Bleeding	AF
Shah et al (2018)14,
N	2892	2892	NA	1912	663
ARR (95% CI)	-3.2 (-5.0 to -1.4)	-0.4 (-1.7 to 1.0)	NA	-.2.1 (-5.1 to 0.9)	6.1 (NR)
NNT (95% CI)	NR	NR	NA	NR	NR
I2 (P-value)	3.62 (.38)	0 (.81)	NA	0 (.92)	82.5 (<.001)
De Rosa et al (2018)15,
N	2531	NA	2531	2531	2531
ARR (95% CI)	-3.1 (-5.1 to -1.0)	NA	-2.9 (-5.0 to -7)	-0.2 (-1.2 to 0.7)	3.3 (1.2 to 5.4)
NNT (95% CI)	NR	NA	NR	NR	NR
I2 (P-value)	61 (.003)	NA	33.79 (.29)	28 (.60)	66 (.002)
Alushi et al (2018)16,
Total N	3440	2776 (Excludes REDUCE)	3440	3440	3440
HR/OR (95% CI); P-value	HR 0.39 (0.19 to 0.83);<.01	HR 0.73 (0.49 to 1.09);.12	HR 0.52 (0.26 to 0.77);<.01	OR 0.97 (0.44 to 2.17);.95	OR 3.75 (2.44 to 5.78);<.01
NNT	37	NA	33	NA	49
I2 (range)	56 (0 to 84)	0	26	39	0

AF: atrial fibrillation; ARR: absolute risk reduction; CI: confidence interval; NNT: number needed to treat; NR: not reported; TIA: transient ischemic attack; HR: hazard ratio; OR: odds ratio.

Observational Studies

There is a large evidence base of observational studies. Because multiple RCTs with more than 5 years of follow-up are available, data from these observational studies are not discussed except where such studies provide longer duration of follow-up, specifically related to durability of results and adverse events (revealed by larger populations or longer length of follow-up than in trials). Rigatelli et al (2016) reported safety outcomes on a series of 1000 consecutive patients who were treated with catheter-based closure using different devices and prospectively identified, with mean follow-up of 12.3 years.^17, Permanent atrial fibrillation occurred in 0.5%, device thrombosis occurred in 0.5%, new-onset or worsening of mitral valve regurgitation was observed in 0.2% whereas recurrent cerebral ischemic events occurred in 0.8% patients. The occlusion rate was 93.8%. No aortic or atrial free wall erosion was reported.

Wintzer-Wehekind et al (2019) reported on long-term outcomes for 201 consecutive patients who had had a cryptogenic embolism (stroke, 76%; TIA, 32%; systemic embolism, 1%) and underwent PFO closure.^18, Median follow-up, completed by 96% of the patients, was 12 years (range, 10-17 years). Patients also had follow-up at between 1 and 6 months that included an echocardiographic examination with a bubble test. No cases of late device embolization, dislocation, or thrombosis, or late pericardial effusion were found; however, 6 patients had a residual shunt, 1 of which required a second closure following a recurrent TIA. Thirteen patients (6.5%) died during the follow-up period, but no deaths were caused by cardiovascular events. Seven (3.5%) had at least 1 TIA or stroke. At the time of final follow-up, 20.9% (42/201) had been off antithrombotic therapy for a mean of 10 years (±4 y). There were no significant differences in rates of ischemic events or death between the group that went off antithrombotic medication and those who stayed on it.

Section Summary: Transcatheter Device Closure of Patent Foramen Ovale for Stroke

The results of RCTs of PFO closure compared with medical management have reported point estimates of HRs ranging from 0.03 to 0.78, suggesting that PFO closure is more effective than medical therapy for reducing event rates. These results were not statistically significant by ITT analyses in the early trials (CLOSURE I, PC-Trial, RESPECT), but were significant in later trials (RESPECT extended follow-up, REDUCE, CLOSE). Initially, inadequate power was blamed for demonstrating the lack of superiority of PFO closure in the early RCTs but the reasons are probably multifactorial. The RESPECT, REDUCE, and CLOSE trials enrolled patients when off-label PFO closure had decreased, allowing for inclusion for patients with vascular anatomic features (eg, large intra-arterial shunt size) associated with relatively higher risk of stroke among those with PFO. In addition, other factors such as requirement of neuroimaging confirmation of stroke prior to enrollment, exclusion of lacunar infarcts, longer follow-up, and selection of patients with associated atrial septal aneurysm in RESPECT, REDUCE, and CLOSE possibly contributed to selection of a trial population that adequately excluded other causes of cryptogenic stroke, yielding a sample at higher risk of cryptogenic stroke and therefore amenable to risk modification by PFO closure. It is important to acknowledge that higher rates of atrial fibrillation have been reported in a few of the individual trials and meta-analysis that incorporate evidence from RESPECT, REDUCE, and CLOSE trials. Thus, patient selection is crucial when assessing the risks and benefits of PFO closure over medical management.

Transcatheter Patent Foramen Ovale Closure for Migraine
Clinical Context and Therapy Purpose

The purpose of PFO closure with a transcatheter device in patients who have PFO and migraine is to provide a treatment option that is an alternative to or an improvement on existing therapies.
The question addressed in this policy is: Does PFO closure with a transcatheter device improve the net health outcome in patients with migraine?
The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with migraine headache.

Migraine headache has been associated with PFO in epidemiologic studies, and noncontrolled observational studies have reported improvement in migraine headaches after PFO closure.

Interventions

The therapy being considered is PFO closure with a transcatheter device. Alternative interventions such as transcatheter device closure of PFO have been considered for patients who have persistent or recurrent migraine headaches not controlled by medical therapy.

PFO closure is performed by cardiac surgeons in a hospital setting.

Comparators

The following therapies are currently being used to make decisions about PFO closure with a transcatheter device: guideline-based preventive and abortive treatment with medical therapy.

Patients with migraines are managed by neurologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are overall survival, morbid events, treatment-related mortality, and treatment-related morbidity.

Based on identified clinical trials, long-term follow-up of ≥10 years would be preferable to determine outcomes for patients who undergo PFO.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought
• Studies with duplicative or overlapping populations were excluded.

Dowson et al (2008) published results of the Migraine Intervention With STARFlex Technology (MIST) trial, a sham-controlled randomized trial of PFO closure for refractory migraine headache.^19, In this trial, no significant difference was observed in the primary endpoint of migraine headache cessation (3/74 in the implant group vs. 3/73 in the sham group, P=.51). The results of this trial cast some doubt on the causal relation between PFO and migraine.

Mattle et al (2016) published results of the Percutaneous Closure of Patent Foramen Ovale in Migraine with Aura (PRIMA) trial, a randomized, open-label trial with blinded endpoint evaluation comparing transcatheter PFO closure with medical management in patients who had a migraine with aura.^20, The trial enrolled 107 subjects with refractory migraine and PFO with a right-to-left shunt, who were randomized to PFO closure with the Amplatzer PFO Occluder (n = 53) or medical management (n = 54). The trial's power calculations required enrollment of 72 in each group. The trial was stopped prematurely due to slow enrollment, and there was a relatively high loss to follow-up (22%). In the device group, 45 of 53 patients agreed to have the PFO occluder implanted, and of those 41 underwent implantation. This suggests that the trial might have been underpowered to detect differences between groups. For the primary endpoint (reduction in mean migraine days at 1 year postrandomization), there were no significant differences between the groups (-2.9 [95% CI, -4.4 to -1.4] for PFO closure vs. -1.7 [95% CI, -2.5 to -1.0] for medical management; P=.168).

Tobis et al (2017) reported on the results of the Percutaneous Closure of Patent Foramen Ovale in Patients with Migraine (PREMIUM) trial (NCT00355056), which compared PFO closure (Amplatzer PFO Occluder) with a sham procedure in 230 patients with 6 to 14 days of a migraine per month, had failed at least 3 migraine preventive medications, and had significant right-to-left shunt identified by transcranial Doppler.^21, The primary endpoint (50% reduction in migraine attacks) did not differ between the PFO closure (45/117) and the control (33/103) groups. One serious adverse event (transient atrial fibrillation) occurred in the 205 subjects who underwent PFO closure.

Systematic Reviews

Lip and Lip (2014) published a descriptive, systematic review that assessed 20 studies evaluating the prevalence of PFO in patients with migraines and 21 studies on the effects of PFO closure.^22, In case series and cohort studies of patients with migraines, the prevalence of PFO in patients with migraines ranged from 14.6% to 66.5%. In the case-control studies, the prevalence of PFO in control patients ranged from 16.0% to 25.7%, while the prevalence of PFO in patients who had a migraine with and without aura ranged from 26.8% to 96.0% and 22.6% to 72.4%, respectively. In the 18 case series that reported migraine outcomes after PFO closure, rates of resolution for migraine with and without aura ranged from 28.6% to 92.3% and 13.6% to 82.9%, respectively. In 2 case-control studies that compared PFO closure with no medical intervention or preventive migraine medication, improvement in migraine symptoms occurred in 83% to 87% of those who underwent PFO closure compared with 0% to 21% of those who received not intervention or who were managed medically. The single RCT included (Dowson et al [2008]^19,) did not identify significant improvements in migraine symptoms in the PFO closure group.

Observational Studies

Biasco et al (2014), which was not included in the Lip and Lip (2014) systematic review, retrospectively compared transcatheter PFO closure with medical therapy to assess their impact on daily activities.^23, The study included 217 patients with migraine and echocardiographic evidence of PFO, 89 of whom were managed with percutaneous PFO closure and 128 medically managed. PFO device closure was recommended for patients with migraine associated with previous suspected paradoxical embolic events, or for those without a history of suspected embolic events only in the case of severely disabling symptoms not controlled by multiple therapies. At a mean follow-up of 1299 days, both groups demonstrated significant reductions in Migraine Disability Assessment scores. However, there were no significant differences in the Migraine Disability Assessment scores between groups (P=.204). The degree of residual right-to-left shunt was not associated with symptom perception.

Snijder et al (2016) reported on an observational case-control study that evaluated the association between a migraine with aura and PFO among patients who underwent an agitated saline transesophageal echocardiogram over a 4-year period at a single outpatient cardiology clinic and had completed a validated headache questionnaire (n = 889).^24, In this sample, a PFO with atrial septal aneurysm was significantly associated with a migraine with aura ( OR, 2.71; 95% CI, 1.23 to 5.95; P=.01), while PFO alone was not.

Section Summary: Transcatheter Patent Foramen Ovale Closure for Migraine

Although observational studies have shown a possible association between PFO closure and reduction in migraine symptoms, one sham-controlled randomized trial did not demonstrate significant improvements in migraine symptoms after PFO closure. Nonrandomized studies have shown highly variable rates of migraine improvement after PFO closure.

Transcatheter Patent Foramen Ovale Closure for Other Indications
Clinical Context and Therapy Purpose

The purpose of PFO closure with a transcatheter device in patients who have PFO and conditions associated with PFO other than cryptogenic stroke or migraine is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does PFO closure with a transcatheter device improve the net health outcome in patients conditions associated with PFO other than cryptogenic stroke or migraine?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with PFO and conditions associated with PFO other than cryptogenic stroke or migraine. Several other medical conditions have been reported to occur more frequently in patients with PFOs, including platypnea-orthodeoxia syndrome, myocardial infarction with normal coronary arteries, decompression illness in response to change in environmental pressure, high-altitude pulmonary edema, and obstructive sleep apnea.^25,

Interventions

The therapy being considered is PFO closure with a transcatheter device.

PFO closure is performed by cardiac surgeons in a hospital setting.

Comparators

The following therapies and practices are currently being used to make decisions about PFO closure with a transcatheter device; condition-specific medical therapy and related interventions.

Outcomes

The general outcomes of interest are overall survival, morbid events, treatment-related mortality, and treatment-related morbidity.

Based on identified clinical trials, long-term follow-up of ≥10 years would be preferable to determine outcomes for patients who undergo PFO.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought
• Studies with duplicative or overlapping populations were excluded.

Section Summary: Transcatheter Patent Foramen Ovale Closure for Other Indications

The body of evidence on other medical conditions treated with PFO closure only consists of small case series and case reports, which is an insufficient basis on which to draw conclusions about efficacy.

Transcatheter Device Closure for Atrial Septal Defects
Clinical Context and Therapy Purpose

The purpose of atrial septal defect (ASD) closure with a transcatheter device in patients who have ASD is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does ASD closure with a transcatheter device improve the net health outcome in patients with ASD?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with ASD and evidence of left-to-right shunt or right ventricular overload.

ASDs represent an abnormality in the development of the heart that results in free communication between the atria. ASDs are categorized by their anatomy. Ostium secundum describes defects located midseptally and are typically near the fossa ovalis. Ostium primum defects lie immediately adjacent to the atrioventricular valves and are within the spectrum of atrioventricular septal defects. Primum defects occur commonly in patients with Down syndrome. Sinus venous defects occur high in the atrial septum and are frequently associated with anomalies of the pulmonary veins.

Interventions

The therapy being considered is ASD closure with a transcatheter device. Repair of ASDs is recommended for those with a pulmonary-to-systemic flow ratio (Q_p: Q_s) exceeding 1.5:1.0. Despite the success of surgical repair, there has been interest in developing a transcatheter-based approach to ASD repair to avoid the risks and morbidity of open heart surgery. A variety of devices have been researched. Technical challenges include minimizing the size of the device so that smaller catheters can be used, developing techniques to center the device properly across the ASD, and ensuring that the device can be easily retrieved or repositioned, if necessary.

ASD closure is performed by cardiac surgeons in a hospital setting.

Comparators

The following therapies and practices are currently being used to make decisions about ASD closure with a transcatheter device: individuals with ASDs and a history of cryptogenic stroke are typically treated with antiplatelet agents, given an absence of evidence that systemic anticoagulation is associated with outcome improvements. Depending on the size of the ASD and the left-to-right shunt or right ventricular overload, open surgical intervention to repair the defect may be performed.

Patients with ASD are managed by cardiologists and cardiac surgeons in a clinical or surgical setting.

Outcomes

The general outcomes of interest are overall survival, morbid events, treatment-related mortality, and treatment-related morbidity.

Based on identified clinical trials, long-term follow-up of ≥10 years would be preferable to determine outcomes for patients who undergo PFO.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews

Butera et al (2011) published a systematic review comparing percutaneous closure with surgical closure by Butera et al (2011).^28, Thirteen nonrandomized comparative studies that enrolled at least 20 patients were included ( N = 3082 patients). The rate of procedural complications was higher in the surgical group (31%; 95% CI, 21% to 41%) than in the percutaneous group (6.6%; 95% CI, 3.9% to 9.2%), with an OR for total procedural complications of 5.4 (95% CI, 2.96 to 9.84; p<.000). There was also an increased rate of major complications for the surgical group (6.8%; 95% CI, 4% to 9.5%) compared with the percutaneous group (1.9%; 95% CI, 0.9% to 2.9%), with an OR of 3.81 (95% CI, 2.7 to 5.36; P=.006).

Abaci et al (2013) reported in their meta-analysis of periprocedural complications after ASD or PFO device closures that, for ASD closure, the pooled rate of major complications was 1.6% (95% CI, 1.4% to 1.8%).^29,

Nonrandomized Comparative Studies

Other nonrandomized studies comparing transcatheter closure with surgery have shown similar success rates.

Suchon et al (2009), in a study of 100 patients, had a 94% success rate in the transcatheter closure group compared with a 100% success rate in the surgical group.^30, Berger et al (1999) showed identical 98% success rates in both treatment groups.^31,Kotowycz et al (2013) reported in their nonrandomized comparative analysis that mortality rates at 5-year follow-up did not differ between transcatheter (5.3%) and surgical closure (5 6.35%; P>.99) groups, but that reintervention rates were higher for patients undergoing transcatheter closure (7.9% vs. 0.3%, respectively, P<.004).^32,

Chen et al (2015), in a nonrandomized comparative analysis that used national-level data from Taiwan, compared in-hospital and longer-term (4-year) follow-up outcomes for adults who underwent secundum ASD repair by a surgical (n=348) or transcatheter (n=595) route.^33, After propensity-score matching, during the index hospitalization, surgical repair patients were more likely to have systemic thromboembolism (4.9% vs. 0%, P<.001), ischemic stroke (1.9% vs. 0%, P=.002), or in-hospital death (1.3% vs. 0%, P=.013). Over the 4-year follow-up, outside of the index hospitalization, transcatheter repair patients were more likely to have atrial fibrillation (1.7% vs. 0%, P=.036), while other outcomes did not differ.

Xu et al (2014) reported on a retrospective analysis of transcatheter (n = 35) and surgical (n = 43) repair in patients with ASD and pulmonary stenosis.^34, Complication rates did not differ significantly between groups, and all patients had a complete correction of their ASD.

Single-Arm Studies

Single-arm studies have shown high success rates of ASD closure. The FDA study (discussed previously) was the largest series, with an enrollment of 442 patients.^27, Fischer et al (2003) reported on the use of the Amplatzer device in 236 patients with secundum ASD.^35, In this evaluation study, closure was achieved in 84.7% of patients, and intermediate results were reported as excellent.

Javois et al (2014) reported on outcomes up to 5 years for patients enrolled in the FDA Continued Access trial of the HELIX Septal Occluder, which included 137 patients who underwent device implantation.^36, Of 122 patients who completed follow-up at 1 year, 96.7% were defined as having clinical success, which was a composite of safety and efficacy. During follow-up, 5 adverse events considered major were reported: 2 device embolizations, both on day 1; 1 wireframe fracture incidentally discovered at 61 days postimplantation; 1 wireframe fracture associated with echocardiographic abnormalities and requiring surgical removal; and 1 unrelated death.

Baruteau et al (2014) reported closure rates of 92.6% in another relatively large series of 336 patients with large secundum ASDs (balloon-stretched diameter ³ 34 mm in adults or echocardiographic diameter > 15 mm/m² in children) managed with the Amplatzer closure device (2014) reported closure rates of 92.6%.^37,

Other smaller studies have also reported favorable results for transcatheter closure of ASD. Du et al (2002) compared transcatheter closure for 23 patients with deficient ASD rims with transcatheter closure of 48 patients who had sufficient ASD rims.^38, The authors reported no significant differences in closure rates between groups (91% for deficient rims vs. 94% for sufficient rims) along with no major complications at 24-hour and 6-month follow-ups. Oho et al (2002) also reported a closure rate of 97% at 1-year follow-up in 35 patients receiving transcatheter ASD closure, with only 1 patient complication (second-degree atrioventricular block) noted.^39, Brochu et al (2002) evaluated 37 patients with New York Heart Association functional class I or II physical capacity who underwent transcatheter closure of ASD.^40, At 6-month follow-up, maximal oxygen uptake improved significantly, and the dimensions of the right ventricle decreased significantly. Twenty patients moved from New York Heart Association class II to class I and improved exercise capacity. Numerous other small, single-arm studies have reported similar results, with procedural success rates approaching 100% and successful closure rates on follow-up reported in the 90% to 100% range.^5,41,

Single-Arm Studies in Pediatric Patients

Several single-arm studies have reported on outcomes for transcatheter ASD closure in children and adolescents. Grohmann et al (2014) reported on outcome from a single-center series of children ages 3 to 17 years (median, 6 years) treated with the HELEX Septal Occluder, with technical success in 41 (91%) of 45 patients in whom closure was attempted.^42, Nyboe et al (2013) reported on outcomes from 22 patients with secundum ASD who underwent ASD closure with the HELEX Septal Occluder, 10 of whom were children younger than age 15, with technical success in all patients.^43, Yilmazer et al (2013) reported improvements in echocardiographic parameters in a series of 25 pediatric patients (mean age, 9.02 years) who underwent successful transcatheter closure of secundum ASD.^44,A retrospective cohort study conducted by Jalal et al (2018) reported outcomes in 1396 children ages 7 months to 18 years (median 9 years) who had an attempted transcatheter closure of ASD with the Amplatzer Septal Occluder at one of 9 centers in France from 1998 to 2016.^45, Follow-up was obtained through medical records and telephone calls to primary care physicians and was obtained in 91.6% of the 1158 patients who had a successful ASD closure. The procedural success rate was 95.3%. After a median follow-up duration of 3.5 years (range 6 months to 18 years), no deaths occurred and 96% of patients were asymptomatic. Major periprocedural complications occurred in 24 patients (1.8%; 95% CI: 1.1% to 2.5%). Delayed complications were observed in 12 (1.04%; 95% CI: 0.5% to 1.6%) patients. Cardiac arrhythmias were the main long-term complication, most occurring in 8 patients aged 3 to 13 years, after a median period of time of 6 months (range 1 to 108 months) from the procedure. Children weighing 15 kg or less and those with 15 kg and those with large defects 20 mm/m² were subgroups identified at risk of both periprocedural and long-term complications.^45,

Section Summary: Transcatheter Device Closure of Atrial Septal Defects

For patients with an ASD, nonrandomized comparative studies and single-arm case series have reported rates of closure using catheter-based devices approaching the high success rates of surgery. The percutaneous approach has a low complication rate and avoids the morbidity and complications of open surgery. If the percutaneous approach is unsuccessful, ASD closure can be achieved using surgery. Because of the benefits of percutaneous closure over open surgery, this evidence is considered sufficient to determine that transcatheter ASD closure improves outcomes in patients with an indication for ASD closure.

Summary of Evidence

For individuals who have PFO and cryptogenic stroke who receive PFO closure with a transcatheter device, the evidence includes multiple randomized controlled trials (RCTs) comparing device-based PFO closure with medical therapy, systematic reviews, meta-analyses, and observational studies. Relevant outcomes are symptoms, change in disease status, overall survival, morbid events, and treatment-related morbidity and mortality. The RCTs comparing PFO closure with medical management have suggested that PFO closure is more effective than medical therapy in reducing event rates. Although these results were not statistically significant by intention-to-treat analyses in the first 3 trials [ie, Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale (CLOSURE), Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism (PC-Trial), and Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT; initial study)], they were statistically significant in later trials [ie, RESPECT (extended follow-up), Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE), and Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE)]. Use of appropriate patient selection criteria to eliminate other causes of cryptogenic stroke in RESPECT, REDUCE, and CLOSE trials contributed to findings of the superiority of PFO closure compared with medical management. Of note, higher rates of atrial fibrillation were reported in a few of the individual trials and in the meta-analysis that incorporated evidence from RESPECT, REDUCE, and CLOSE trials. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have PFO and migraines who receive PFO closure with a transcatheter device, the evidence includes two RCTs of PFO closure and multiple observational studies reporting on the association between PFO and migraine. Relevant outcomes are symptoms, quality of life, medication use, and treatment-related morbidity and mortality. The available sham-controlled randomized trial did not demonstrate significant improvements in migraine symptoms after PFO closure. A second RCT with blinded endpoint evaluation did not demonstrate reductions in migraine days after PFO closure but likely was underpowered. Nonrandomized studies have shown highly variable rates of migraine reduction after PFO closure. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have PFO and conditions associated with PFO other than cryptogenic stroke or migraine(eg, platypnea-orthodeoxia syndrome, myocardial infarction with normal coronary arteries, decompression illness, high-altitude pulmonary edema, obstructive sleep apnea) who receive PFO closure with a transcatheter device, the evidence includes small case series and case reports. Relevant outcomes are symptoms, change in disease status, morbid events, and treatment-related morbidity and mortality. The body of evidence only consists of small case series and case reports. Comparative studies are needed to evaluate outcomes in similar patient groups treated with and without PFO closure. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have ASD and evidence of left-to-right shunt or right ventricular overload who receive ASD closure with a transcatheter device, the evidence includes nonrandomized comparative studies and single-arm studies. Relevant outcomes are symptoms, change in disease status, and treatment-related morbidity and mortality. The available nonrandomized comparative studies and single-arm case series have shown rates of closure using transcatheter-based devices approaching the high success rates of surgery, which are supported by meta-analyses of these studies. The percutaneous approach has a low complication rate and avoids the morbidity and complications of open surgery. If the percutaneous approach is unsuccessful, ASD closure can be achieved using surgery. Because of the benefits of percutaneous closure over open surgery, it can be determined that transcatheter ASD closure improves outcomes in patients with an indication for ASD closure. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION
Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 2 academic medical centers (1 of which provided 2 responses) while this policy was under review in 2016. Input was mixed about the medical necessity of closure devices for patent foramen ovale (PFO) in patients with cryptogenic stroke or transient ischemic attack due to presumed paradoxical embolism through the PFO. There was a consensus that use of closure devices for PFO in patients with other conditions (eg, migraine, platypnea-orthodeoxia syndrome) is not medically necessary.

Practice Guidelines and Position Statements
American College of Chest Physicians

In 2012, the American College of Chest Physicians updated its guidelines on antithrombotic therapy and the prevention of thrombosis, which made the following recommendations related to PFO and cryptogenic stroke^46,:

"We suggest that patients with stroke and PFO are treated with antiplatelet therapy following the recommendations for patients with noncardioembolic stroke…. In patients with a history of noncardioembolic ischemic stroke or TIA, we recommend long-term treatment with aspirin (75-100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended release dipyridamole (25 mg/200 mg bid), or cilostazol (100 mg bid) over no antiplatelet therapy(Grade 1A),oral anticoagulants (Grade 1B),the combination of clopidogrel plus aspirin(Grade 1B),or triflusal(Grade 2B)."

In 2016, the American Academy of Neurology updated its evidence-based guidelines on the management of patients with stroke and PFO to address whether percutaneous closure of PFO is superior to medical therapy alone.^47, Following a systematic review of the literature and structured formulation of recommendations, the Academy developed conclusions for the Amplatzer PFO Occluder devices. For patients with cryptogenic stroke and PFO, percutaneous PFO closure with the Amplatzer PFO Occluder:

• "Possibly decreases the risk of recurrent stroke-RD [risk difference] -1.68%, 95% CI [confidence interval] -3.18% to -0.19%;"
• "Possibly increases the risk of new-onset AF [atrial fibrillation]-RD 1.64%, 95% CI 0.07%-3.2% (2 Class I studies; confidence downgraded to low for risk of bias relative to magnitude of effect and imprecision);"
• "Is highly likely to be associated with a procedural complication risk of 3.4%, 95% CI 2.3%-5% (2 Class I studies)."

"Clinicians should not routinely offer percutaneous PFO closure to patients with cryptogenic ischemic stroke outside of a research setting (Level R). In rare circumstances, such as recurrent strokes despite adequate medical therapy with no other mechanism identified, clinicians may offer the AMPLATZER PFO Occluder if it is available (Level C)."

In 2014, the American Heart Association and American Stroke Association updated their guidelines on the prevention of stroke in patients with ischemic stroke or transient ischemic attack. The guidelines made the following recommendations for device-based closure for PFO^48,:

• "For patients with a cryptogenic ischemic stroke or TIA [transient ischemic attack] and a PFO without evidence for DVT [deep vein thrombosis], available data do not support a benefit for PFO closure (Class III; Level of Evidence A)."
• "In the setting of PFO and DVT, PFO closure by a transcatheter device might be considered, depending on the risk of recurrent DVT (Class IIb; Level of Evidence C)."

In 2018, the American College of Cardiology and American Heart Association updated guidelines on the management of adults with congenital heart disease.^49, The treatment recommendations are summarized in Table 10., coronary sinus, or primum atrial septal defect, however, surgery rather than percutaneous closure was recommended.

Table 10. American College of Cardiology and American Heart Association Recommendations for Treating Atrial Septal Defect

Condition	Recommendation	CORa/LOEb
Symptomatic isolated secundum ASD, right atrial and/or RV enlargement, and net left-to-right shunt sufficiency large enough to cause physiological sequelae, without cyanosis at rest or during exercise	Transcatheter or surgical closure	I1/B-NR2
Symptomatic primum ASD, sinus venosus defect, or coronary sinus defect, right atrial and/or RV enlargement, and net left-to-right shunt sufficiency large enough to cause physiological sequelae, without cyanosis at rest or during exercise	Surgical closure unless precluded by comorbidities	I1/B-NR2
Asymptomatic isolated secundum ASD, right atrial and RV enlargement, and net left-to-right shunt sufficiency large enough to cause physiological sequelae, without cyanosis at rest or during exercise	Transcatheter or surgical closure	IIa1/C-LD2
Secundum ASD when a concomitant surgical procedure is being performed and there is a net left-to-right shunt sufficiently large enough to cause physiological sequelae, and right atrial and RV enlargement without cyanosis at rest or during exercise	Surgical closure	IIa1/C-LD2
ASD when net left-to-right shunt is ≥1.5:1, PA systolic pressure and/or pulmonary vascular resistance is greater than of one-third of systemic resistance	Percutaneous or surgical closure	IIb1/B-NR2
ASD with PA systolic pressure greater than two-thirds systemic, pulmonary vascular resistance greater than two-thirds systemic, and/or a net left-to-right shunt	ASD closure should not be performed	III-Harm1/C-LD2

Adapted from Stout et al (2019)^49,.
ASD: atrial septal defect; COR: class (strength) of recommendation; LOE: level (quality) of evidence; PA: pulmonary artery; RCT: randomized controlled trial; RV: right ventricular.

^a COR key: I=strong; IIa=moderate; IIb=weak; III: No Benefit=weak; III: Harm=strong.^49,
b LOE key: A=high quality from >1 RCT, meta-analyses of high-quality RCTs, ≥1 RCT corroborated by high-quality registry studies; B-R=randomized, moderate-quality evidence from ≥1 RCT or meta-analysis of moderate-quality RCTs; B-NR=nonrandomized, moderate-quality evidence from ≥1 well-designed, well-executed nonrandomized study, observational study, or registry study, or meta-analyses of such studies; C-LD: limited data, randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, or physiological or mechanistic studies in human subjects; C-EO: expert opinion.^49,

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 11.

Table 11. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT00738894a	GORE® HELEX® Septal Occluder / GORE® Septal Occluder and Antiplatelet Medical Management for Reduction of Recurrent Stroke or Imaging-Confirmed TIA in Patients With Patent Foramen Ovale (PFO)	664	Feb 2020
NCT01550588	Device Closure Versus Medical Therapy for Secondary Prevention in Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale: DEFENSE-PFO	210	Feb 2020
NCT03867708	Outcomes of Transcatheter Closure of Secundum Atrial Septal Defect Guided by Three-dimensional Transesophageal Echocardiography	80	June 2021
NCT03309332	OBS Lead-AMPLATZER PFO Occluder New Enrollment Study	1214	Dec 2027
Unpublished
NCT01960491	Prospective Single Center Pilot Clinical Study to Evaluate the Safety and Effectiveness of an Intracardiac Septal Closure Device With Biodegradable Framework in Patients With Clinically Significant Atrial Septum Defect (ASD) or Patent Foramen Ovale (PFO)	15	Jun 2018 (updated 10/11/18)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Closure Devices for Patent Foramen Ovale and Atrial Septal Defects
Amplatzer Septal Occluder
Amplatzer PFO Occluder
Angel Wing Device
Atrial Septal Defect Occluding System (ASDOS)
CardioSEAL Septal Occlusion System
Clamshell Occluder
HELEX Septal Occluder
Patent Foramen Ovale
Raskind Clamshell Occluder
Sideris Buttoned Device
STARFlex
Transcatheter Devices for ASD Closure

References:
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2. Slottow TL, Steinberg DH, Waksman R. Overview of the 2007 Food and Drug Administration Circulatory System Devices Panel meeting on patent foramen ovale closure devices. Circulation. Aug 07 2007; 116(6): 677-82. PMID 17679629

3. U.S. Food and Drug Administration. Summary of safety and effectiveness data. Gore Cardioform Septal Occluder.March 30, 2018. https://www.accessdata.fda.gov/cdrh_docs/pdf5/P050006s060b.pdf. Accessed March 19, 2020.

4. Food and Drug Administration (FDA). Summary of Safety and Effectiveness Data (SSED): Patent Foramen Ovale (PFO) Occluder (PMA P120021). 2016; https://www.accessdata.fda.gov/cdrh_docs/pdf12/P120021B.pdf. Accessed March 19, 2020.

5. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. Mar 21 2013; 368(12): 1083-91. PMID 23514285

6. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. Mar 21 2013; 368(12): 1092-100. PMID 23514286

7. Saver JL, Carroll JD, Thaler DE, et al. Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke. N Engl J Med. Sep 14 2017; 377(11): 1022-1032. PMID 28902590

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9. Lee PH, Song JK, Kim JS, et al. Cryptogenic Stroke and High-Risk Patent Foramen Ovale: The DEFENSE-PFO Trial. J Am Coll Cardiol. May 22 2018; 71(20): 2335-2342. PMID 29544871

10. Sondergaard L, Kasner SE, Rhodes JF, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med. Sep 14 2017; 377(11): 1033-1042. PMID 28902580

11. Mas JL, Derumeaux G, Guillon B, et al. Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke. N Engl J Med. Sep 14 2017; 377(11): 1011-1021. PMID 28902593

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14. Shah R, Nayyar M, Jovin IS, et al. Device Closure Versus Medical Therapy Alone for Patent Foramen Ovale in Patients With Cryptogenic Stroke: A Systematic Review and Meta-analysis. Ann Intern Med. Mar 06 2018; 168(5): 335-342. PMID 29310136

15. De Rosa S, Sievert H, Sabatino J, et al. Percutaneous Closure Versus Medical Treatment in Stroke Patients With Patent Foramen Ovale: A Systematic Review and Meta-analysis. Ann Intern Med. Mar 06 2018; 168(5): 343-350. PMID 29310133

16. Alushi B, Lauten A, Cassese S, et al. Patent foramen ovale closure versus medical therapy for prevention of recurrent cryptogenic embolism: updated meta-analysis of randomized clinical trials. Clin Res Cardiol. Sep 2018; 107(9): 788-798. PMID 29644412

17. Rigatelli G, Pedon L, Zecchel R, et al. Long-Term Outcomes and Complications of Intracardiac Echocardiography-Assisted Patent Foramen Ovale Closure in 1,000 Consecutive Patients. J Interv Cardiol. Oct 2016; 29(5): 530-538. PMID 27500752

18. Wintzer-Wehekind J, Alperi A, Houde C, et al. Long-Term Follow-Up After Closure of Patent Foramen Ovale in Patients With Cryptogenic Embolism. J Am Coll Cardiol. Jan 29 2019; 73(3): 278-287. PMID 30678757

19. 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. Mar 18 2008; 117(11): 1397-404. PMID 18316488

20. 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. Jul 07 2016; 37(26): 2029-36. PMID 26908949

21. Tobis JM, Charles A, Silberstein SD, et al. Percutaneous Closure of Patent Foramen Ovale in Patients With Migraine: The PREMIUM Trial. J Am Coll Cardiol. Dec 05 2017; 70(22): 2766-2774. PMID 29191325

22. Lip PZ, Lip GY. Patent foramen ovale and migraine attacks: a systematic review. Am J Med. May 2014; 127(5): 411-20. PMID 24355354

23. Biasco L, Infantino V, Orzan F, et al. Impact of transcatheter closure of patent foramen ovale in the evolution of migraine and role of residual shunt. J Cardiol. Nov 2014; 64(5): 390-4. PMID 24713153

24. Snijder RJ, Luermans JG, de Heij AH, et al. Patent Foramen Ovale With Atrial Septal Aneurysm Is Strongly Associated With Migraine With Aura: A Large Observational Study. J Am Heart Assoc. Dec 01 2016; 5(12). PMID 27930349

25. Tobis J, Shenoda M. Percutaneous treatment of patent foramen ovale and atrial septal defects. J Am Coll Cardiol. Oct 30 2012; 60(18): 1722-32. PMID 23040567

26. Mojadidi MK, Gevorgyan R, Noureddin N, et al. The effect of patent foramen ovale closure in patients with platypnea-orthodeoxia syndrome. Catheter Cardiovasc Interv. Oct 2015; 86(4): 701-7. PMID 26063336

27. Du ZD, Hijazi ZM, Kleinman CS, et al. Comparison between transcatheter and surgical closure of secundum atrial septal defect in children and adults: results of a multicenter nonrandomized trial. J Am Coll Cardiol. Jun 05 2002; 39(11): 1836-44. PMID 12039500

28. Butera G, Biondi-Zoccai G, Sangiorgi G, et al. Percutaneous versus surgical closure of secundum atrial septal defects: a systematic review and meta-analysis of currently available clinical evidence. EuroIntervention. Jul 2011; 7(3): 377-85. PMID 21729841

29. Abaci A, Unlu S, Alsancak Y, et al. Short and long term complications of device closure of atrial septal defect and patent foramen ovale: meta-analysis of 28,142 patients from 203 studies. Catheter Cardiovasc Interv. Dec 01 2013; 82(7): 1123-38. PMID 23412921

30. Suchon E, Pieculewicz M, Tracz W, et al. Transcatheter closure as an alternative and equivalent method to the surgical treatment of atrial septal defect in adults: comparison of early and late results. Med Sci Monit. Dec 2009; 15(12): CR612-7. PMID 19946231

31. Berger F, Vogel M, Alexi-Meskishvili V, et al. Comparison of results and complications of surgical and Amplatzer device closure of atrial septal defects. J Thorac Cardiovasc Surg. Oct 1999; 118(4): 674-8; discussion 678-80. PMID 10504632

32. Kotowycz MA, Therrien J, Ionescu-Ittu R, et al. Long-term outcomes after surgical versus transcatheter closure of atrial septal defects in adults. JACC Cardiovasc Interv. May 2013; 6(5): 497-503. PMID 23602461

33. Chen TH, Hsiao YC, Cheng CC, et al. In-Hospital and 4-Year Clinical Outcomes Following Transcatheter Versus Surgical Closure for Secundum Atrial Septal Defect in Adults: A National Cohort Propensity Score Analysis. Medicine (Baltimore). Sep 2015; 94(38): e1524. PMID 26402807

34. Xu XD, Liu SX, Zhao XX, et al. Comparison of medium-term results of transcatheter correction versus surgical treatment for secundum type atrial septal defect combined with pulmonary valve stenosis. Int Heart J. 2014; 55(4): 326-30. PMID 24898601

35. Fischer G, Stieh J, Uebing A, et al. Experience with transcatheter closure of secundum atrial septal defects using the Amplatzer septal occluder: a single centre study in 236 consecutive patients. Heart. Feb 2003; 89(2): 199-204. PMID 12527678

36. Javois AJ, Rome JJ, Jones TK, et al. Results of the U.S. Food and Drug Administration continued access clinical trial of the GORE HELEX septal occluder for secundum atrial septal defect. JACC Cardiovasc Interv. Aug 2014; 7(8): 905-12. PMID 25147036

37. Baruteau AE, Petit J, Lambert V, et al. Transcatheter closure of large atrial septal defects: feasibility and safety in a large adult and pediatric population. Circ Cardiovasc Interv. Dec 2014; 7(6): 837-43. PMID 25423959

38. Du ZD, Koenig P, Cao QL, et al. Comparison of transcatheter closure of secundum atrial septal defect using the Amplatzer septal occluder associated with deficient versus sufficient rims. Am J Cardiol. Oct 15 2002; 90(8): 865-9. PMID 12372575

39. Oho S, Ishizawa A, Akagi T, et al. Transcatheter closure of atrial septal defects with the Amplatzer septal occluder--a Japanese clinical trial. Circ J. Sep 2002; 66(9): 791-4. PMID 12224813

40. Brochu MC, Baril JF, Dore A, et al. Improvement in exercise capacity in asymptomatic and mildly symptomatic adults after atrial septal defect percutaneous closure. Circulation. Oct 01 2002; 106(14): 1821-6. PMID 12356636

41. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. Mar 15 2012; 366(11): 991-9. PMID 22417252

42. Grohmann J, Hohn R, Fleck T, et al. Transcatheter closure of atrial septal defects in children and adolescents: single-center experience with the GORE(R) septal occluder. Catheter Cardiovasc Interv. Nov 15 2014; 84(6): E51-7. PMID 24664494

43. Nyboe C, Hjortdal VE, Nielsen-Kudsk JE. First experiences with the GORE((R)) Septal Occluder in children and adults with atrial septal defects. Catheter Cardiovasc Interv. Nov 15 2013; 82(6): 929-34. PMID 23404677

44. Yilmazer MM, Guven B, Vupa-Cilengiroglu O, et al. Improvement in cardiac structure and functions early after transcatheter closure of secundum atrial septal defect in children and adolescents. Turk J Pediatr. Jul-Aug 2013; 55(4): 401-10. PMID 24292034

45. Jalal Z, Hascoet S, Gronier C, et al. Long-Term Outcomes After Percutaneous Closure of Ostium Secundum Atrial Septal Defect in the Young: A Nationwide Cohort Study. JACC Cardiovasc Interv. Apr 23 2018; 11(8): 795-804. PMID 29673513

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47. Messe SR, Gronseth G, Kent DM, et al. Practice advisory: Recurrent stroke with patent foramen ovale (update of practice parameter): Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. Aug 23 2016; 87(8): 815-21. PMID 27466464

48. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. Jul 2014; 45(7): 2160-236. PMID 24788967

49. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. Apr 02 2019; 73(12): e81-e192. PMID 30121239

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

93580