Coverage Policy Manual
Policy #: 2001032
Category: Medicine
Initiated: December 2001
Last Review: June 2018
  Closure Devices for Atrial or Ventricular Septal Defects (ASD, VSD) or Patent Foramen Ovale (PFO), Percutaneous

Description:
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. Prior to birth, the foramen ovale is held open by the large flow of blood into the left atrium from the inferior vena cava. Over a course of months after birth, an increase in left atrial pressure and a decrease in right atrial pressure result in the permanent closure of the foramen ovale in most patients.  However, a patent foramen ovale (PFOs) may be detected in 10%–15% of adult patients. Although common, PFOs are typically clinically insignificant and are not associated with right to left shunting of blood. 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, resulting in a stroke or transient ischemic attack (TIA). In addition, a possible link between PFO and migraine headache has been noted. Therefore, there has been interest in either open surgery or transcatheter approaches to close the PFO in patients with a history of embolic stroke of unknown cause and in patients with migraine. Current therapy of cryptogenic stroke with demonstrated PFO includes standard risk factor modification, statins, blood pressure control, etc, and sometimes chronic Coumadin therapy, based in part on the theory that clotting disorders may be present in patients with embolic stroke.
 
Septal Defects
In contrast to patent foramen ovale, 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 according to their anatomy. Ostium secundum describes defects that are 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 defects  are located in the mid-atrial septum near the fossa ovalis.  Ostium primum defects lie immediately adjacent to the atrioventricular valves, are often associated with a cleft mitral valve, and occur commonly in patients with Down's 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 one of 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.
 
 
Repair of ASDs is recommended for those with a pulmonary to systemic flows ratio (Qp:Qs) exceeding 1.5:1.0.  Despite the success of operative repair, there has been interest in developing a catheter-based approach to ASD repair in order to avoid the risks and morbidity of open heart surgery.  A variety of devices have been researched over the past 20 years; technical challenges include minimizing the size of device so that smaller catheters can be used; developing techniques to properly center the device across the ASD, and ensuring that the device can be easily retrieved or repositioned if necessary. Late failures due to mechanical fatigue have also been a concern..
 
Ventricular septal defects (VSDs)  may be present at birth but may also occur following myocardial infarction or as a result of corrective surgery for congenital heart disease.  Small congenital VSDs may never be detected.  A large VSD can allow substantial left-to-right shunting and can produce pulmonary hypertension.  Septal defects may also be created during surgical repair of certain types of congenital heart defects, such as hypoplastic left ventricle syndrome.  A hole is made in the septum of the repaired section of the heart (Fontan fenestration) to improve recovery from the surgery.  The fenestration is intended to be closed at a later time.
 
Regulatory Status
Several devices have been developed to treat PFO via a transcatheter approach, including the CardioSEAL® STARFlex™ Septal Occlusion System (NMT Medical), the Amplatzer® PFO Occluder (Amplatzer Inc., now St. Jude Medical, St. Paul, MN), the Figulla® ASD Occluder (Occlutech GmbH, Jena, Germany), and the CeraFlex™ ASD Occluder (Lifetech Scientific, Shenzhen, China). The STARFlex system is no longer manufactured. Transcatheter PFO occluders consist of a single or paired wire mesh discs that are 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 disks that are passed via catheter to cover the ASD.
 
ASD Closure Devices
At present, 2 devices are FDA approved for ASD closure: the Amplatzer™ Septal Occluder (St. Jude Medical, Minneapolis, MN), and the GORE HELEX™ Septal Occluder (W.L. Gore & Associates, Inc., Newark, DE). The Amplatzer Septal Occluder was approved through the FDA’s premarket approval process in June 2002. The Amplatzer device is intended for the occlusion of ASDs in the secundum position or in patients who have undergone 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.
The Gore Helix Septal Occluder was approved through the premarket approval process in August 2006. It is indicated for the percutaneous, transcatheter closure of ostium secundum ASDs.
 
CPT codes 93580 and 93581 include right-heart catheterization, and codes 93451-93453, 93455-93461, 93530-93533, 93564-93566 should not be reported with these codes.

Policy/
Coverage:
Effective June 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Closure of Atrial Septal Defects
 
Closure of ostium secundum atrial septal defects using a transcatheter approach with an FDA-approved device meets member benefit certificate primary coverage criteria for effectiveness for patients who meet FDA labeled indications for the device and the following criteria are met:
 
    • have echocardiographic evidence of an ostium secundum atrial septal defect; AND
    • clinical evidence of right ventricular volume overload (i.e., 1.5:1 degree of left to right shunt or RV enlargement);
 
Closure of Patent Foramen Ovale
 
The percutaneous transcatheter closure of a patent foramen ovale using AMPLATZERPFO Occluder meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to reduce the risk of recurrent ischemic stroke if the patient 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 pacification 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 AND
 
NONE of the following are present:
      • 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.
 
Closure of Ventricular Septal Defects
 
Closure of  ventricular septal defects using a transcatheter approach with an FDA-approved device meets member benefit certificate primary coverage criteria for effectiveness for patients who meet FDA labeled indications for the device.
 
The CardioSEAL Septal Occlusion System and the Amplatzer Muscular VSD Occluder meet member benefit certificate primary coverage criteria for effectiveness for use in patients with complex ventricular septal defects (VSD) of significant size to warrant closure who are considered to be at high risk for standard transatrial or transarterial surgical closure based on anatomical conditions and/or based on overall medical condition.  High risk anatomical factors for transatrial or transarterial surgical closure include patients:
 
        • Requiring a left ventriculotomy or an extensive right ventriculotomy;
        • With a failed previous VSD closure;
        • With multiple apical and/or anterior muscular VSDs ("Swiss Cheese Septum"); or
        • With posterior apical VSDs covered by trabeculae.
 
The STARFlex Septal Occlusion System (NMT Medical) meets member benefit certificate primary coverage criteria for use in patients with a complex ventricular septal defect of a significant size to warrant closure, but based on its location, cannot be closed with standard transatrial or transarterial approaches.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Percutaneous transcatheter closure for any indication not listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, percutaneous transcatheter closure for any indication not listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates.
 
Effective Prior to June 2018
Closure of atrial or ventricular septal defects using a transcatheter approach with an FDA-approved device meets member benefit certificate primary coverage criteria for effectiveness for patients who meet FDA labeled indications for the device.
 
* Patients indicated for ASD closure must have echocardiographic evidence of an ostium secundum atrial septal defect and clinical evidence of right ventricular volume overload (i.e., 1.5:1 degree of left to right shunt or RV enlargement).
  
The Amplatzer Septal Occluder device meets member benefit certificate primary coverage criteria for effectiveness for:
        • Occlusion of atrial septal defects (ASDs) in secundum position;
        • Patients who have undergone a fenestrated Fontan procedure and who now require closure of the fenestration.   
  
The GORE HELEX Septal Occluder meets member benefit certificate primary coverage criteria for effectiveness for the percutaneous, transcatheter closure of single-defect ostium secundum atrial septal defects (ASDs) measuring <=18 mm.
 
The CardioSEAL Septal Occlusion System and the Amplatzer Muscular VSD Occluder meets member benefit certificate primary coverage criteria for effectiveness for use in patients with complex ventricular septal defects (VSD) of significant size to warrant closure who are considered to be at high risk for standard transatrial or transarterial surgical closure based on anatomical conditions and/or based on overall medical condition.  High risk anatomical factors for transatrial or transarterial surgical closure include patients:
        • Requiring a left ventriculotomy or an extensive right ventriculotomy;
        • With a failed previous VSD closure;
        • With multiple apical and/or anterior muscular VSDs ("Swiss Cheese Septum"); or
        • With posterior apical VSDs covered by trabeculae.
 
The STARFlex Septal Occlusion System (NMT Medical) meets member benefit certificate primary coverage criteria for use in patients with a complex ventricular septal defect of a significant size to warrant closure, but based on its location, cannot be closed with standard transatrial or transarterial approaches.
 
Any other use of these or other septal defect closure devices does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
 
For contracts without Primary Coverage Criteria, any other use of these or other septal defect closure devices is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
 
Atrial septal closure is not covered for migraine headache because this use of percutaneous septal closure is under study in phase III trials to determine safety and effectiveness, and therefore this use does not meet member benefit certificate primary coverage criteria for effectiveness.  For those contracts which do not have Primary Coverage Criteria, closure for treatment of migraine headaches is considered investigational.
 
Percutaneous closure of patent foramen ovale does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This use of these devices is not FDA approved.  Percutaneous closure of patent foramen ovale is considered investigational for member contracts that do not contain primary coverage criteria.
 
 

Rationale:
Patent Foramen Ovale
While it has seemed logical to think that patients with cryptogenic stroke and patent foramen ovale would benefit from closure of the PFO, this has not been proven.  A 2003 systematic review (Khairy, 2003) covered 10 studies (1355 patients) with percutaneous PFO closure after an embolic event along with 6 studies (895 patients) treated with  medical therapy (anticoagulant or antiplatelet drugs). At one year, 0-4.9% of the closure patients and 3.8-12% of the medical therapy patients had a recurrent neurologic event (Nedeltchev, 2002).  However, the closure group had a 1.5% rate of major complications, including death. None of these studies were randomized.
 
Subsequently, three studies have addressed the question.  First, (Windecker, 2004) about 300 patients were treated with either percutaneous PFO closure or anticoagulant/antiplatelet agent.  Though not randomized, there were near equal numbers of patients in each group.  At 4 years, the incidence of death or recurrent events was significantly lower in the closure group than in the aspirin group, but there was no significant difference in outcomes between the closure group and the warfarin group.  Second, (Braun, 2004) in 307 patients with PFO and a prior embolic event, 24 months after PFO closure the annual recurrence rate for TIA was 0.6% and for peripheral embolism 0.2%.  Third, (Spies, 2006) in 403 patients treated with PFO closure, the annual incidence of embolic events was 3.1% pre-procedure and 2% post-procedure.
 
These retrospective, non-randomized data are insufficient to determine net health outcomes from PFO closure.  The CLOSURE I trial (NMT Medical) is comparing medical therapy to PFO closure in patients who have experienced stroke or TIA.  The Respect, Prima, and Premium trials (AGA Medical Corp) are also evaluating PFO closure for migraine headaches.
 
In fact, The 2004 American Academy of Neurology practice parameter concluded that PFO alone is not associated with a meaningfully increased risk of recurrent stroke or death in patients who have already had a cryptogenic stroke, although a small increase or decrease in risk cannot be excluded by current data (Messe, 2004).
 
Patients with PFO may have an increased incidence of associated migraine headaches, but the trend in recent findings has resulted in decreased enthusiasm for PFO closure as a treatment for migraines (Kurth, 2008; Wood, 2008).   
 
A metaanalysis has been reported (Almekhalafi, 2009) of 1081 medically treated patients with previous cryptogenic stroke in 4 controlled observational studies, comparing patients with and without PFOs.  During mean follow-up of 31-42 months, the risk for recurrent stroke or TIA was not significantly different in patients with or without a PFO.  
 
Two devices have been used for percutaneous closure of a PDA: the Amplatzer PFO Occluder by AGA Medical and the CardioSEAL Septal Occlusion System from Nitinol Medical Technologies.  For a time these were used under a humanitarian device exemption (HDE) for patients with recurrent embolic stroke despite anticoagulation in the setting of a PFO.  However, because the HDE was found to cover more than 4000 patients per year, the HDE was withdrawn in October 2006.  Currently, these and other devices are available for PFO closure only through clinical trials. The BioSTAR® (NMT Medical is currently not available in the United States; the STARFlex® (NMT Medical) is available in the United States through a clinical trial.  
 
In 2009 the American Heart Association, American Stroke Association, and the American College of Cardiology Foundation published a science advisory urging that patients with cryptogenic stroke and PFO be considered for referral for enrollment in a trial of medical therapy vs. PFO closure, since “the optimal therapy for prevention of recurrent stroke or transient ischemic attack in patients with cryptogenic stroke and patent foramen ovale has not been defined.”  (O’Gara, 2009) Ongoing trials referenced in this advisory include RESPECT (using the Amplatzer PFO occluder), CLOSURE-I (using the STARFlex septal closure system, PC trial (using the Amplatzer PFO occluder), CLOSE (using any of several devices), and Gore REDUCE (using the GORE HELIX septal occluder).  
 
Atrial Septal Defect
Most ASD’s smaller than 8 mm diameter close spontaneously. Those which do not close during infancy are unlikely to close later in life.  Symptoms of ASD include heart failure, paradoxical embolism, fatigue, dyspnea, exercise intolerance, atrial fibrillation and flutter.  Other than the presence of symptoms, there has been no clear Qp/Qs level at which repair is indicated.  Recommendations range from 2:1 to 1.5:1.  At least in patients under age 22, the American Heart Association recommends repair at a Qp/Qs >= 1.5.
 
At the present time, the Amplatzer Septal Occluder and the Gore HELEX Septal Occluder have received FDA approval for the closure of ASDs.  Percutaneous closure is appropriate only for secundum ASD’s.
 
Amplatzer Septal Occluder
The FDA approval of the Amplatzer Septal Occluder was based on the results of a multicenter, non-randomized study comparing the device to surgical closure of ASDs; 423 patients received 433 devices.  All patients had an ostium secundum atrial septal defect and clinical evidence of right ventricular volume overload. The major adverse cardiac events included cardiac arrhythmias, device embolization, delivery system failure, pericardial effusion, pulmonary edema, repeat surgery, and surgical wound adverse events. While the pattern of adverse events was necessarily different in the 2 groups, overall, those receiving a septal occluder had a significantly lower incidence of major adverse events (p=0.03). Similarly, there was a significantly lower incidence of minor adverse events in the septal occluder group (p<0.001). It should be noted that the mean age of patients of the 2 groups was significantly different; in the septal occluder group the mean age was 18 years, compared to 6 years in the surgically treated group. The rationale for the different treatment selection is not available, but may be related to patient size.  Effectiveness was measured in terms of technical and procedural success, measured at 5, 12, and 24 months. The results for the septal occluder group, although lower than the surgical group, were roughly comparable; for example the 24-month closure success rate was 96.7% in the septal occluder group compared to 100% in the surgical group.  
 
Approval of the HELEX device was based on three US clinical studies.  These included a Feasibility Study, a Pivotal Study (multi-center, non-randomized), and a Continued Access Study (multi-center, single arm, prospective). The Pivotal study compared the device to surgical closure (case-matched).  In 247 young patients treated with surgery or percutaneous closure (Jones, 2007); defects were <= 22 mm in diameter.  At 12 months, the device proved non-inferior to surgery in the primary endpoints of safety, repeat procedures, or successful closure.  The device embolized and required catheter retrieval in 1.7% of patients. This device has the advantage of conforming to a non-curvilinear surface and having a mechanism for removal after deployment.
 
Basically, the data suggest that success rate is slightly better with surgery, but the complication rate and length of stay are lower with the percutaneous devices.
 
Other devices still under study include the Buttoned device, Angel wings, and the atrial septal defect occlusion system (ASDOS).  
 
Ventricular Septal Defect Closure
Indications for closure of a VSD is complex and involves consideration of Qp/Qs, pulmonary vascular resistance, pulmonary artery pressure, potential damage to the aortic valve in subpulmonic and membranous defects, and age of the patient. Percutaneous closure of muscular defects can be accomplished in situations where surgical repair is difficult or impossible (Lock, 1988; Knauth, 2004).  In a single-center study, STARFlex implantation was highly successful, though there were significant complications.  In March 2009 the FDA approved the STARFlex VSD Occluder for use in patients with a complex ventricular septal defect of a significant size to warrant closure, but based on location, cannot be closed with standard transatrial or transarterial approaches.
 
The CardioSEAL device is approved for repair of some complex VSD’s (see coverage policy).  There have been several studies of this device, the most recent publication being from the CardioSEAL VSD registry (Lim, 2007), which confirms the safety of the device when used in a multi-center setting to close high-risk VSDs.
 
There has been limited experience with percutaneous closure of acute VSD related to myocardial infarction (Wacinski, 2007).
 
2011 Update
Patent foramen ovale
Dr. Anthony Furlan, one of the principal investigators in the CLOSURE I trial (NCT00201461), reported trial results at the Late-Breaking Clinical Trials Session of the AHA meeting in Chicago in November 2010.  The multicenter study included 900 patients with PFO, post stroke or TIA, randomized to device closure with medical therapy or medical therapy.  The STARFlex® device was used for closure.  At the two-year follow up period, the recurrent event rate was 5.9% with STARFlex® versus 7.7% for medical therapy, not statistically significant.  The rate of recurrent stroke was approximately 3% in both arms.  The results also demonstrated that recurrent stroke and TIA had multiple possible causes, often unrelated to paradoxical embolism.  
 
An observational, nonrandomized study involving 238 patients in Italy was reported by Paciaroni and colleagues (2011).  The percutaneous PFO closure group (n=121) more commonly had an atrial septal aneurysm.  Stroke as the qualifying event was more common in the antithrombotic group (n=117).  Eight patients had a nonfatal complication during percutaneous PFO closure.  At the two-year followup there were 17 recurrent events (TIA or stroke); 7 in the percutaneous PFO closure group and 10 in the medical therapy group.  The rate of recurrent stroke was 0.4% per year and 3.4% per year in patients who had PFO closure and medical therapy respectively.  The authors concluded that controlled randomized clinical trials comparing percutaneous closure with medical management are required.  
 
2012 Update
A search of the MEDLINE database was conducted for this policy review.  Results of the CLOSURE I trial (discussed in the 2011 Update) were published (Furlan, 2012). Results of this trial do not support the use of percutaneous closure of patent foramen ovale. No other published literature was identified that would change the coverage statement.
 
2013 Update
 
Randomized, controlled trials
The 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 I) study was a multicenter, randomized, open-label trial of percutaneous closure versus medical therapy (Furlan, 2012). A total of 909 patients between the ages of 18 and 60 years old with cryptogenic stroke or transient ischemic attack (TIA), and a PFO were enrolled. Patients in the closure group received treatment with the STARflex device and also received anti-platelet therapy. Patients in the medical therapy group were treated with aspirin, warfarin, or both at the discretion of the treating physician. The primary endpoint was a composite of stroke/TIA at two years, death from any cause during the first 30 days after treatment, and death from neurologic causes at two years.
 
Of 405 patients in the closure group, 362 (89.4%) had successful implantation without procedural complications. At six months, echocardiography revealed effective closure in 315/366 patients (86.1%). The composite primary outcome was reached by 5.5% of patients in the closure group and 6.8% of patients in the medical therapy group (adjusted hazard ratio 0.78, 95% confidence interval [CI] 0.45-1.35, p=0.37). Kaplan-Meier estimates of the two-year rate of stroke were 2.9% in the closure group and 3.1% in the medical therapy group (adjusted hazard ratio 0.90, 95% CI 0.41-1.98). Serious adverse events were reported by16.9% of patients in the closure group versus 16.6% in the medical group. Adverse events that were increased in the closure group included vascular procedural complications (3.2% vs. 0, p<0.001) and atrial fibrillation (5.7% vs. 0.7%, p<0.001).
 
In 2013, results of two randomized controlled trials were published (Carroll, 2013; Meier, 2013). Neither study showed superiority of PFO closure over medical therapy alone in the intention-to-treat analyses. In the RESPECT trial (Carroll, 2013) 9 of 499 patients in the control group had recurrence of stroke compared to 16  of 481 patients in the group that received medical treatment alone. Serious adverse events occurred in 23% of patients in the closure group and 21.6% in the medical therapy group.
 
The PC Trial (Meier, 2013) had similar results. In this trial, patients with a patent foramen ovale who had previously experienced an ischemic stroke, transient ischemic attack or a peripheral thromboembolic event were randomly assigned to receive treatment with either medical therapy or surgical closure with the Amplatzer PFO Occluder. The primary end point was a composite of death, nonfatal stroke, TIA or peripheral embolism. The primary endpoint occurred in 7 of the 204 patients in the closure group and 11 of the 210 patients in the medical therapy group.
 
Kitsios et al. published a systematic review of observational studies and the single RCT in 2012 (Kitsios, 2012). This review included 52 single-arm studies, seven non-randomized comparative studies, and one RCT. The combined incident rate for recurrent stroke was lower for patients treated with PFO (0.36 events/100 patient-years, 95% CI 0.24-0.56) compared to patients treated medically (2.53 events/100 patient-years, 95% CI 1.91-3.35). The incident rate ratio was 0.19 (95% CI 0.18-0.98) which indicated an approximately 80% reduction in the rate of strokes for the closure group. This systematic review noted that the incident rate for recurrent strokes in patients treated with closure devices was much lower in the RCT compared to the observational studies, while the incident rate for recurrent stroke in patients treated medically was only slightly lower in the RCT compared to observational studies. This finding raises the possibility that ascertainment bias in the observational studies may have led to a spuriously low rate of recurrent stroke reported for patients treated with PFO closure.
 
Non-randomized, comparative studies
 A number of nonrandomized comparative studies of closure devices versus medical therapy have been published. Wall et al. performed a non-randomized comparative study using propensity matching in 308 consecutive patients with stroke or TIA that was presumed due to a PFO (Wahl, 2012). A total of 103 pairs of matched patients were compared on the primary composite outcome of stroke, TIA or peripheral embolism. After a mean of 9 years’ follow-up, the primary endpoint was reached by 11% of patients in the closure group compared to 21% in the medical therapy group (hazard ratio 0.43, 95% CI 0.20-0.94, p=0.039). The main difference in the outcome measure seemed to be driven by differences in TIA which occurred in 5% of closure patients compared to 14% of medical therapy patients.
 
The results of one RCT do not support the conclusion that closure devices improve outcomes for patients with cryptogenic stroke and PFO. This trial of 909 patients reported that there was no significant difference at two years in the rate of stroke, or in the combined rate of stroke/TIA, between patients receiving closure devices and medical therapy. These results contrast with the results of nonrandomized, comparative studies and systematic reviews of observational studies, which report lower rates of recurrent events following closure of PFO. The discrepancy in these results may arise from selection bias, since selection for either closure devices or medical therapy may vary, resulting in populations that may have unequal distribution of confounders. Also, the rate of recurrent stroke for patients treated with closure devices in the RCT was much higher than combined estimates from observational studies. This raises the possibility that ascertainment bias in the observational studies may have resulted in a spuriously low stroke rate for patients treated with a closure device.
 
Ongoing Clinical Trials
There have been numerous randomized, controlled trials comparing PFO closure with medical therapy planned in the last two decades Albers, 2004; Furlan, 2010; Khattab, 2011). However, these trials have been hampered by slow enrollment and some of the trials have been terminated due to low enrollment. A search of the ClinicalTrials.Gov website using the keywords patent foramen ovale returned numerous studies. Five of these studies were RCTs that are listed as still ongoing:
 
  • NCT00562289. Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence. This is an RCT comparing PFO closure with medical therapy in patients with PFO and cryptogenic stroke. The primary endpoints are fatal and nonfatal stroke, all-cause mortality, and vascular death. Planned enrollment is for 900 patients with completion date estimated to be December 2012.
 
  •  NCT01550588 Defense-PFO study. Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients with High-Risk Patent Foramen Ovale. This is an RCT comparing PFO closure with medical therapy. Primary endpoints are non-fatal stroke, vascular death, and major bleeding. Planned enrollment is for 210 patients with an estimated completion date of February 2017.
 
  • NCT00738894 Gore REDUCE study. GORE HELEX™ Septal Occluder for Patent Foramen Ovale (PFO) Closure in Stroke Patients. This is an RCT of PFO closure compared to medical therapy in patients with cryptogenic stroke. The primary endpoint is freedom from recurrent stroke/TIA at two years. Planned enrollment is for 664 patients, with an estimated completion date of August 2015.
 
  • NCT00355056 Premium Migraine Trial. A phase 2, randomized study assessing the impact of the Amplatzer PFO Occluder for the treatment of migraine headaches versus sham procedure. The primary endpoint is reduction in migraine headache attacks over 12 months. Planned enrollment is 230 with an estimated completion date of March 2014. The study is currently recruiting patients.
 
  • NCT00505570 PRIMA PFO Migraine Trial. A phase 2, randomized trial to assess the effectiveness of PFO closure using the Amplatzer PFO Closure device versus standard medical management. The study is planned to enroll 144 patients with an estimated completion date of January 2013. The study is ongoing but not recruiting patients.
 
2014 Update
A literature search conducted through August 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Meta-analyses of the same 3 RCTs were reported by Chen et al (Chen, 2014), Hakeem et al (Hakeem, 2013), Khan et al (Kahn, 2013), Kwong et al (Kwong, 2013),  Nagaraja et al (Nagaraja, 2013), Ntaios et al (Ntaios, 2013),  Pandit et al (Pandit, 2014),  and Pineda et al (Pineda, 2013). Results from these meta-analyses generally supported findings from previous meta-analyses. For the primary outcome of recurrent stroke or TIA, Chen et al found a pooled risk ratio with PFO device closure for recurrent stroke or TIA of 0.70 (95% CI 0.47 to 1.04; P=0.08). Hakeem et al reported a pooled risk ratio for a composite outcome of death or recurrent stroke or TIA of 0.71 (95% CI 0.48 to 1.06; P=0.09). Neither the Chen et al nor the Hekeem et al meta-analyses found significant differences between PFO device closure and medical management for the risk of death or adverse events. Khan et al reported pooled analyses for the primary outcome of recurrent stroke, with a pooled effect-estimated hazard ratio for the primary outcome of recurrent stroke in patients treated with PFO device closure compared with medical management was 0.67 (95% CI 0.44 to 1.00). In analysis of only the RESPECT and PC trials, which used the Amplatzer PFO occluder device, the hazard ratio for recurrent stroke in patients treated with PFO device closure was 0.54 (95% CI: 0.29 to 1.01). Similarly, Pandit et al reported sensitivity analyses including only the RESPECT and PC trials, and found that patients who received the Amplatzer PFO occluder device had a lower risk of recurrent strokes compared with medical therapy (HR 0.44, 95% CI 0.21 to 0.94; P=0.03). In addition to pooled estimates for the risk of the primary outcomes of recurrent stroke, TIA, or death, Kwong et al. reported pooled outcomes for risk of new-onset atrial fibrillation, and found that PFO closure was associated with a significantly higher incidence of new-onset atrial fibrillation compared with medical therapy (OR 3.77, 95% CI 1.44 to 9.87; P=0.007). In the analysis by Ntaios et al, the risk of new-onset atrial fibrillation with device closure compared with medical therapy was not higher in patients who received the Amplatzer PFO Occluder device (1.28% vs 0.72%; OR 1.81; 95% CI 0.60 to 5.42), but was higher in patients who received the STARFlex device (5.14% vs 0.64%; OR 8.30; 95% CI 1.44 to 9.87).
 
Cappodano et al published an updated systematic review and meta-analysis of studies that compared outcomes associated with medical management or PFO closure among patients with cryptogenic stroke (aCapodanno, 2014). This analysis included the 3 RCTs described above, along with 11 observational studies. In the randomized trials, PFO closure was not associated with significantly lower rates of stroke than medical therapy (hazard ratio [HR] 0.62, 95% CI 0.34 to 1.11; P=0.10) or with lower rates of TIA (HR 0.77, 95% CI 0.46 to 1.32; P=0.34). When the analysis was restricted to the RESPECT and PC trials, which used the Amplatzer PFO occluder device, PFO closure was significantly associated with lower recurrent stroke risk (HR 0.44, 95% CI 0.20 to 0.95; P=0.04). In the observational studies, which included 2,231 patients, PFO closure was significantly associated with lower rates of stroke than medical therapy (HR 0.23, 95% CI 0.11 to 0.49; P<0.01)
 
Similarly, Wolfrum et al conducted a systematic review and meta-analysis of controlled trials that compared outcomes for PFO closure with medical management among patients with cryptogenic stroke, including 3 RCTs and 11 nonrandomized studies (Wolfrum, 2014). Again, among the RCTs, there was no significant improvement in stroke risk with PFO closure compared with medical management. However, among the non-RCT studies, PFO closure was associated with a reduced risk of stroke (RR 0.37; 95% CI 0.20 to 0.67; P<0.001). In a time-to-stroke analysis that included 3 RCTs and 2 non-RCTs that had multivariable adjustments, PFO closure was associated with a borderline significant stroke risk reduction compared with medical therapy (HR 0.58; 95% CI 0.33 to 0.99; P=0.047.)
 
Abaci et al conducted a systematic review and meta-analysis of studies of both PFO and ASD device closure procedures (Abaci, 2013). The authors reviewed 203 articles, 111 of which reported ASD closure, 61 of which reported PFO closure, and 31 of which reported both ASD and PFO closures. Among patients undergoing PFO closure, the pooled rate of major complications was 1.1% (95% CI 0.9 to 1.3%), most commonly device embolization requiring surgery.
 
Alushi et al reported results from a prospective, single-center study comparing outcomes after PFO device closure or medical management in 418 patients presenting with PFO and cryptogenic stroke or TIA (Alushi, 2014). Two hundred sixty two patients underwent percutaneous PFO closure, while 156 were treated medically. The choice of medical intervention versus device closure was determined by the treating physician and patient. Percutaneous device closure was preferably advised for patients under age 55, with recurrent cerebrovascular events, large interatrial right-to-left shunt, and nonlacunar ischemic events on neuroimaging. Patients undergoing percutaneous closure were younger and more frequently presented with a larger interatrial right-to-left shunt, previous venous thromboembolism, and hypercoagulability state. Patients treated medically presented more frequently with multiple cerebrovascular accident risk factors. In a multivariable model to predict the composite outcome of TIA, stroke, or all-cause mortality, treatment strategy (percutaneous closure vs medical management) was not significantly associated with the outcome (adjusted OR 1.1 [95% CI 0.44 to 2.74], P=0.81), after controlling for age, multiple prior cerebrovascular events, and the presence of aspirin.
 
Butera et al reported results from a registry that included 122 consecutive patients who underwent PFO closure with the Gore Septal Occluder device, 110 of whom underwent closure for previous stroke or TIA, and 12 of whom underwent closure for a history of migraines (Butera, 2013). During a median follow-up of 9 months (range 1-18 months), 7 patients experienced atrial arrhythmias, 4 of whom required medical treatment. On chest x-ray, 2 patients were found to have evidence of wire fractures in the device; the devices were not removed and the patients had no evidence of further problems from the wire fractures at 12 months of follow up. Three patients experienced neurological problems, 1 of which was recurrent migraines. None of these patients were found to have residual shunt or intracardiac or device thrombi.
Other single-arm studies of transcathether PFO closure in patients presenting with stroke or TIA and PFO generally report high rates of freedom from embolic events (Eeckhout, 2014; Inglessis, 2013; Nagpal, 2013; Rhodes, 2014; Thomson, 2014; Wallenborn, 2013).
 
No clinical trials focus specifically on patients who have failed medical therapy, as defined by recurrent stroke or TIA while on therapy. Many of the published studies include both patients with first cryptogenic stroke, as well as patients with recurrent stroke or TIA, and generally do not analyze 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.
 
Section Summary.
The results of 3 RCTs do not support the conclusion that closure devices improve outcomes for patients with cryptogenic stroke and PFO. These trials, which included a total of 1,108 patients who underwent PFO closure and 1,178 patients who received medical management, did not report significant improvement in outcomes with PFO closure. These results contrast with the results of nonrandomized, comparative studies and systematic reviews of observational studies, which report lower rates of recurrent events following closure of PFO. The discrepancy in these results may arise from selection bias, since selection for either closure devices or medical therapy may vary, resulting in populations that may have unequal distribution of confounders. Also, the rate of recurrent stroke for patients treated with closure devices in the RCT was much higher than combined estimates from observational studies. This raises the possibility that ascertainment bias in the observational studies may have resulted in a spuriously low stroke rate for patients treated with a closure device. Multiple meta-analyses of the 3 RCTs, with or without the addition of nonrandomized studies, have come to varied conclusions, with some reporting a statistically significant reduction in recurrent events on pooled analysis and others reporting a trend for benefit that does not reach statistical significance. While these results suggest that a benefit might be present, the evidence is not definitive and the risk/benefit ratio is not well-defined.
 
Patent Foramen Ovale Closure for Migraine
Non-controlled observational studies have reported improvement in migraine headaches after PFO closure.
 
In 2014, Lip et al published a primarily descriptive systematic review of studies that reported either the prevalence of PFO and migraine or the effects of PFO-related interventions on migraine attacks (Lip, 2014). The authors included 20 studies that evaluated the prevalence of PFO in patients with migraines and 21 studies that presented data on the effects of PFO closure. 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 case control studies, the prevalence of PFO in control patients ranged from 16.0 to 25.7%, while the prevalence of PFO in patients with migraine-with-aura or aura migraine-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 aura and migraine 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 and medication for migraines, with intervention, improvement in migraine symptoms occurred in 83 to 87%, compared with 0-21% of those managed medically. The single RCT identified (Dowson et al38) did not identify significant improvements in migraine symptoms in the PFO closure group.
 
In a study not included in the Lip et al systematic review, Biasco et al retrospectively compared transcatheter PFO closure with medical therapy in terms of impact on daily activities (Biasco, 2014). The study included 217 patients with migraine and echocardiographic evidence of PFO, of whom 89 were managed with percutaneous PFO closure and 128 were 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 1,299 days, both groups demonstrated significant improvements in scores on the Migraine Disability Assessment Questionnaire (MIDAS). However, there were no significant differences in MIDAS score between groups (P=0.204). The degree of residual right-to-left shunt was not associated with symptom perception.
 
Section Summary.
Although observational studies have shown a possible association between PFO closure and improvement in migraine symptoms, one sham-controlled RCT did not demonstrate significant improvements in migraine symptoms after PFO closure. Nonrandomized studies show highly variable rates of migraine improvement after PFO closure.
 
Patent Foramen Ovale Closure for Other Indications
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 (Tobis, 2012). Evidence about clinical outcomes related to these conditions after PFO closure is limited to case reports and case series.
 
Systematic Reviews
In the Abaci et al systematic review and meta-analysis of periprocedural complications after ASD/PFO device closures referenced above, for ASD closure, the pooled rate of major complications after ASD closures was 1.6% (95% CI 1.4 to 1.8%) (Abaci, 2013).
 
Nonrandomized, Comparative Studies
Xu et al reported a retrospective analysis of transcathether (n=35) and surgical (n=43) closure of ASD in patients with ASD and pulmonary stenosis (Xu, 2014). Complication rates were not significantly different between groups, and all patients in both groups were reported to have complete correction of their ASD.
 
Single-Arm Studies in Pediatrics.
Several single-arm studies have reported outcomes from transcathether ASD closure in children and adolescents. Grohmann et al reported outcome from a single-center series of children aged 3 to 17 years (median 6) who were treated with the Gore Septal Occluder, with technical success in 41 of 45 patients in whom closure was attempted (91%) (Grohmann, 2014). Nyboe et al reported outcomes from 22 patients with secundum ASD who underwent ASD closure with the Gore Septal Occluder, 10 of whom were children under the age of 15, with technical success in all patients (Nyboe, 2013). Yilmazer et al reported improvements in echocardiographic parameters in a series of 25 pediatric patients (mean age 9.02) who underwent successful transcathether closure of secundum ASD (Yilmazer, 2013).
 
Ongoing and Unpublished Clinical Trials
A search of the online database ClinicalTrials.gov on August 6, 2014, identified the following interventional trials evaluating device closure for atrial septal defects and patent foramen ovale that are currently ongoing.
  • Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE) (NCT00562289) (NCT00562289) – This is an RCT comparing PFO closure with medical therapy (vitamin K antagonists and antiplatelet drugs) in patients with PFO and cryptogenic stroke. The primary endpoints are fatal and nonfatal stroke, all-cause mortality, and vascular death. Planned enrollment is for 900 patients with completion date estimated to be December 2016.
  • Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale (DEFENSE-PFO) (NCT01550588) This is an RCT comparing PFO closure with the Amplatzer PFO occluder device with medical therapy. Primary endpoints are nonfatal stroke, vascular death, and major bleeding. Planned enrollment is for 210 patients with an estimated completion date of February 2017.
  • 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) (NCT00738894) – This is an RCT of PFO closure compared to medical therapy in patients with cryptogenic stroke. The primary endpoint is freedom from recurrent stroke/TIA at 2 years. Planned enrollment is for 664 patients, with an estimated completion date of January 2018.
  • 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) (NCT01960491) – This is a noncomparative pilot study to evaluate the effectiveness and safety of a novel bioabsorbable intracardiac septal closure device in patients with isolated ASD or PFO. Enrollment is planned for 10 subjects; the estimated study completion date is July 2015.
  • Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management (PREMIUM) (NCT00355056) – PREMIUM is a randomized, double-blind, sham-controlled trial to compare PFO closure with the Amplatzer PFO Occluder device with medical management in patients with migraine. The primary outcome is reduction in migraine attacks. Enrollment is planned for 230 subjects; the estimated study completion date is listed as March 2014. No results have been posted.
 
PFO closure devices have been investigated as a treatment for refractory migraines and for other medical conditions. The evidence on the use of PFO device closure for the treatment of migraines is limited to nonrandomized studies and one RCT that showed no benefit to migraine symptoms from PFO device closure. The evidence for the use of PFO closure for conditions other than stroke prevention and refractory migraines is limited to case reports and case series.
 
In addition to the limitations in the evidence base, there are no PFO closure devices that are currently FDA-approved for use in the United States. Therefore closure devices are considered investigational for prevention of paradoxical emboli in patients with PFO and cryptogenic stroke.
 
 
Closure devices are not discussed.
 
Previously published guidelines from the American College of Chest Physicians 2008 guidelines compared outcomes from medical management and percutaneous closure in patients with patent foramen ovale and cryptogenic stroke and concluded that there was no difference in risk of death or between major adverse clinical events between patients with cryptogenic stroke who underwent medical management and those who underwent percutaneous closure procedures (ACCP, 2008).
 
The American Heart Association and the American Stroke Association published guidelines on the prevention of stroke in patients with ischemic stroke or transient ischemic attack (TIA) in 2006 that makes the following recommendations about the management of patients with a PFO (Sacco, 2006):
  • For patients with an ischemic stroke or TIA and a PFO, antiplatelet therapy is reasonable to prevent a recurrent event (Class IIa, Level of Evidence B). Warfarin is reasonable for high-risk patients who have other indications for oral anticoagulation such as those with an underlying hypercoagulable state or evidence of venous thrombosis (Class IIa, Level of Evidence C).  
  • Insufficient data exist to make a recommendation about PFO closure in patients with a first stroke and a PFO. PFO closure may be considered for patients with recurrent cryptogenic stroke despite optimal medical therapy (Class IIb, Level of Evidence C).  
 
2015 Update
A literature search conducted through August  2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Udell et al and Pickett et al reported no significant association between overall risk of recurrent stroke or TIA and PFO device closure. However, after stratifying by device type, Pickett et al reported lower stroke risk after Amplatzer PFO device closure (HR=0.44; 95% CI, 0.21 to 0.95; p=0.037) (Udell, 2014; Pickett, 2014).
 
Stortecky and colleagues reported results of a network meta-analysis comparing percutaneous PFO closure with medical therapy among patients with cryptogenic stroke (Stortecky, 2015).  The authors included 10 publications on 4 RCTs, the PC and RESPECT trials which compared the Amplatzer PFO occluder with medical therapy, the CLOSURE I trial which compared the Starflex PFO occluder with medical therapy, and an additional trial which was a head-to-head comparison of the Amplatzer, Starflex, and Helix PFO occluder devices. Overall, patients randomized to PFO closure with the Amplatzer PFO occluder device were less likely to experience a stroke than those randomized to medical therapy (rate ratio [RR], 0.39, 95% CI 0.17 to 0.84). No significant differences were found between PFO closure with the Starflex device in stroke risk or in TIA risk across treatment strategies.
 
Systematic Reviews Including RCTs and Observational Studies
In 2015, Patti and colleagues published a meta-analysis of randomized and observational studies comparing outcomes between 3 management strategies for patients with cryptogenic stroke and PFO, percutaneous closure, antiplatelet therapy, and anticoagulant therapy (Patti, 2015).  The meta-analysis included 21 studies with a total of 3311 patients. In an evaluation of the long-term efficacy and safety of PFO closure compared with “conservative therapy” (either antiplatelet or anticoagulant therapy), 11 observational studies were included, with a mean follow-up of 36 months. The incidence of recurrent stroke and/or TIA was significantly lower in patients undergoing percutaneous PFO closure than in those receiving antiplatelet therapy (4.3% vs 9.2% respectively; OR=0.50; 95% CI, 0.35 to 0.71; p<0.001), with no increased bleeding risk. The incidence of recurrent stroke and/or TIA was not significantly different between those undergoing percutaneous PFO closure and those receiving anticoagulant therapy (4.3% vs 6.3%, respectively; OR=0.66; 95% CI, 0.42 to 1.04; p=0.07); however, patients treated with PFO closure had a lower incidence of major bleeding (1% vs 7.1%; OR=0.18; 95% CI, 0.09 to 0.36; p<0.001).
 
Mojadidi and colleagues reported on a series of 17 patients who underwent transcatheter PFO closure for platypnea-orthodeoxia syndrome at a single institution, among whom 64.8% were classified as having improved oxygen saturation postprocedure (Mojadidi, 2015).
 
Single-Arm Studies
Javois and colleagues reported outcomes up to 5 years for patients enrolled in the FDA Continued Access trial of the GORE HELIX Septal Occluder, which included 137 patients who underwent device implantation (Javois, 2014). 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 seen: 2 device embolizations, both on day 1; 1 wire frame fracture incidentally discovered at 61 days postimplantation; 1 wire frame fracture associated with echocardiographic abnormalities and requiring surgical removal; and 1 unrelated death.
 
In another relatively large series including 336 patients with large secundum ASDs (balloon-stretched diameter ³34 mm in adults or echocardiographic diameter greater than 15 mm/m2 in children) managed with the Amplatzer closure device, Baruteau and colleagues reported closure rates of 92.6% (Baruteau, 2014).
 
Because of the advantages 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.
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below:
 
(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); planned enrollment 10: projected completion date July 2015.
 
(NCT00562289) Closure of Patent Foramen Ovale or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence: planned enrollment 900: projected completion date December 2016.
 
(NCT01550588) Device Closure Versus Medical Therapy for Secondary Prevention in Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale : DEFENSE-PFO: planned enrollment 210: projected completion date February 2017.
 
(NCT00738894) 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) (an industry-sponsored or cosponsored trial): planned enrollment 64: projected completion date February 2017.
 
(NCT00355056) Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management: planned enrollment 230: projected completion date June 2019.
 
Summary of Evidence
The evidence for ASD closure with a catheter-based closure device in individuals with ASD and evidence of left-to-right shunt or right-ventricular overload 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 show high success rates of closure using closure 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 advantages 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. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.
 
The evidence for PFO closure with a catheter-based closure device in individuals with PFO and cryptogenic stroke includes 3 randomized controlled trials (RCTs) comparing device-based PFO closure with medical therapy, multiple nonrandomized comparative studies, and multiple systematic reviews and meta-analyses of these studies. Relevant outcomes include overall survival, morbid events, and treatment-related morbidity and mortality. None of the 3 trials reported statistically significant improvements on their main outcome using intention-to-treat analysis. In all 3 trials, low numbers of outcome events in both groups limited the power to detect differences between groups. One trial showed a significant benefit for the closure group on per protocol analysis and another showed significant benefit on secondary outcomes. Meta-analyses of these trials have also come to different conclusions, with some reporting a statistically significant reduction in recurrent events on pooled analysis and others reporting a trend for benefit that does not reach statistical significance. While these results suggest that a benefit might be present, the evidence is not definitive and the risk/benefit ratio of transcatheter PFO closure as an alternative to medical therapy is not well-defined. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
The evidence for PFO closure with a catheter-based closure device in individuals with PFO and migraines includes 1 randomized, sham-controlled trial of PFO closure, along with 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 RCT did not demonstrate significant improvements in migraine symptoms after PFO closure. Nonrandomized studies show highly variable rates of migraine improvement after PFO closure. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
The evidence for PFO closure with a catheter-based closure device in individuals with PFO and a variety of other conditions, including platypnea-orthodeoxia syndrome, myocardial infarction with normal coronary arteries, decompression illness, high altitude pulmonary edema, and obstructive sleep apnea, 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 consists of only small case series and case reports. Comparative studies are needed to evaluate outcomes in similar patient groups who are treated with and without PFO closure. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
American Heart Association and American Stroke Association
In 2014, the American Heart Association (AHA) and American Stroke Association published updated guidelines on the prevention of stroke in patients with ischemic stroke or TIA. The guidelines list the following recommendations for device-based closure for patent foramen ovale (PFO) (Kernan, 2014):
  • For patients with a cryptogenic ischemic stroke or TIA and a PFO without evidence for DVT, available data do not support a benefit for PFO closure (Class III recommendation; 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).
 
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Stortecky and colleagues reported results of a network meta-analysis comparing percutaneous PFO closure with medical therapy among patients with cryptogenic stroke (Stortecky, 2015). The authors included 10 publications on 4 RCTs, the PC and RESPECT trials which compared the Amplatzer PFO occluder with medical therapy, the CLOSURE I trial which compared the STARFlex PFO occluder with medical therapy, and an additional trial which was a head-to-head comparison of the Amplatzer, STARFlex, and Helix PFO occluder devices. Overall, patients randomized to PFO closure with the Amplatzer PFO occluder device were less likely to experience a stroke than those randomized to medical therapy (rate ratio [RR], 0.39; 95% CI, 0.17 to 0.84). No significant differences were found between PFO closure with the STARFlex device in stroke risk, or in TIA risk across treatment strategies.
 
Systematic Reviews Including RCTs and Observational Studies
In 2015, Patti and colleagues published a meta-analysis of randomized and observational studies comparing outcomes between 3 management strategies for patients with cryptogenic stroke and PFO, percutaneous closure, antiplatelet therapy, and anticoagulant therapy (Patti, 2015). The meta-analysis included 21 studies with a total of 3311 patients. In an evaluation of the long-term efficacy and safety of PFO closure compared with “conservative therapy” (either antiplatelet or anticoagulant therapy), 11 observational studies were included, with a mean follow-up of 36 months. The incidence of recurrent stroke and/or TIA was significantly lower in patients undergoing percutaneous PFO closure than in those receiving antiplatelet therapy (4.3% vs 9.2% respectively; OR=0.50; 95% CI, 0.35 to 0.71; p<0.001), with no increased bleeding risk. The incidence of recurrent stroke and/or TIA did not differ significantly between those undergoing percutaneous PFO closure and those receiving anticoagulant therapy (4.3% vs 6.3%, respectively; OR=0.66; 95% CI, 0.42 to 1.04; p=0.07); however, patients treated with PFO closure had a lower incidence of major bleeding (1% vs 7.1%; OR=0.18; 95% CI, 0.09 to 0.36; p<0.001).
 
PFO Closure for Other Indications
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. Evidence about clinical outcomes related to these conditions after PFO closure is limited to case reports and case series. For example, Mojadidi and colleagues reported on a series of 17 patients who underwent transcatheter PFO closure for platypnea-orthodeoxia syndrome at a single institution, among whom 64.8% were classified as having improved oxygen saturation postprocedure (Mojadidi, 2015).
 
Single-Arm Studies
Javois and colleagues reported outcomes up to 5 years for patients enrolled in the FDA Continued Access trial of the GORE HELIX Septal Occluder, which included 137 patients who underwent device implantation (Javois, 2014).  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 seen: 2 device embolizations, both on day 1; 1 wire frame fracture incidentally discovered at 61 days postimplantation; 1 wire frame fracture associated with echocardiographic abnormalities and requiring surgical removal; and 1 unrelated death.
 
In another relatively large series including 336 patients with large secundum ASDs (balloon-stretched diameter 34 mm in adults or echocardiographic diameter >15 mm/m2 in children) managed with the Amplatzer closure device, Baruteau and colleagues reported closure rates of 92.6% (Baruteau, 20154).
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review:
 
Ongoing
(NCT00562289) Closure of Patent Foramen Ovale or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence; planned enrollment 900; completion date December 2016.
 
(NCT01550588) Device Closure Versus Medical Therapy for Secondary Prevention in Cryptogenic Stroke Patients with High-Risk Patent Foramen Ovale: DEFENSE-PFO; planned enrollment 2010; completion date February 2017.
 
(NCT00738894) an industry sponsored or cosponsored trial. GORE®, HELEX®, Septal Occluder / GORE®, and Antiplatelet Medical Management for Reduction of Recurrent Stroke or Imaging-Confirmed TIA in Patients with Foramen Ovale (PFO); planned enrollment 64; completion date February 2017.
 
(NCT00355056) Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management; planned enrollment 230; completion date June 2016.
 
Unpublished
 
(NCT01960491)  Prospective Single Center Pilot Clinical Study to Evaluate the Safety and Effectiveness of an Intracardiac Septal Closure Device With Biodegradable Framew ork in Patients With Clinically Significant Atrial Septum Defect (ASD) or Patent Foramen Ovale (PFO); planned enrollment 10; completion date July 2015.
 
Summary of Evidence
The evidence for ASD closure with a catheter-based closure device in individuals who have ASD and evidence of left-to-right shunt or right-ventricular overload 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 show high success rates of closure using closure 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 advantages 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. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.
 
The evidence for PFO closure with a catheter-based closure device in individuals who have PFO and cryptogenic stroke includes 3 randomized controlled trials (RCTs) comparing device-based PFO closure with medical therapy, multiple nonrandomized comparative studies, and multiple systematic reviews and meta-analyses of these studies. Relevant outcomes include overall survival, morbid events, and treatment-related morbidity and mortality. None of the 3 trials reported statistically significant improvements on their main outcome using intention-to-treat analysis. In all 3 trials, low numbers of outcome events in both groups limited the power to detect differences between groups. One trial showed a significant benefit for the closure group on per protocol analysis and another showed significant benefit on secondary outcomes. Meta-analyses of these trials have also come to different conclusions, with some reporting a statistically significant reduction in recurrent events on pooled analysis and others reporting a trend for benefit that does not reach statistical significance. While these results suggest that a benefit might be present, the evidence is not definitive and the risk/benefit ratio of transcatheter PFO closure as an alternative to medical therapy is not well-defined. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
The evidence for PFO, closure with a catheter-based closure device in individuals who have PFO and migraines, includes 1 randomized, sham-controlled trial of PFO closure, along with 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 RCT did not demonstrate significant improvements in migraine symptoms after PFO closure. Nonrandomized studies show highly variable rates of migraine improvement after PFO closure. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
The evidence for PFO closure with a catheter-based closure device in individuals who have PFO and a variety of other conditions (eg, platypnea-orthodeoxia syndrome, myocardial infarction with normal coronary arteries, decompression illness, high altitude pulmonary edema, obstructive sleep apnea) 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 consists of only small case series and case reports. Comparative studies are needed to evaluate outcomes in similar patient groups who are treated with and without PFO closure. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
American Heart Association and American Stroke Association
In 2014, the American Heart Association (AHA) and American Stroke Association published updated guidelines on the prevention of stroke in patients with ischemic stroke or TIA. The guidelines list the following recommendations for device-based closure for patent foramen ovale (PFO) (Kernan, 2014).
  • “For patients with a cryptogenic ischemic stroke or TIA and a PFO without evidence for DVT, 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).”
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
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) (Mas, 2017). The primary blinded adjudicated outcome of stroke was significantly lower in the PFO closure vs antiplatelet therapy in ITT analysis as well as per-protocol analysis. 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=0.02). The number of serious adverse events did not differ significantly between treatment groups (p=0.56).
 
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.
 
A large number of systematic reviews and meta-analyses have evaluated outcomes related to the percutaneous transcatheter closure of a PFO. Of these, 2 systematic reviews, by Kent et al and Li et al, have pooled data from 3 RCTs (CLOSURE I, PC trial, RESPECT) (Kent, 2016; Li, 2015). 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.
 
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 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 (Rigatelli, 2016). 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.
 
Dowson et al published results of the MIST trial, a sham-controlled randomized trial of PFO closure for refractory migraine headache (Dowson, 2008). In this trial, no significant difference was observed in the primary end point of migraine headache cessation (3/74 in the implant group vs 3/73 in the sham group, p=0.51). The results of this trial cast some doubt on the causal relation between PFO and migraine.
  

CPT/HCPCS:
93580Percutaneous transcatheter closure of congenital interatrial communication (ie, Fontan fenestration, atrial septal defect) with implant
93581Percutaneous transcatheter closure of a congenital ventricular septal defect with implant

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