BlueCross and BlueShield of Montana Medical Policy/Codes
Transcatheter Closure Devices for Cardiac Defects: Atrial Septal Defects (ASD), Patent Foramen Ovale (PFO), Patent Ductus Arteriosus (PDA), and/or Ventricular Septal Defects (VSD)
Chapter: Surgery: Procedures
Current Effective Date: February 01, 2014
Original Effective Date: May 01, 2006
Publish Date: January 15, 2014
Revised Dates: January 11, 2007; May 1, 2007; November 1, 2007; October 27, 2010; February 13, 2012; November 09, 2012; July 15, 2013; January 15, 2014
Description

Atrial septal defects (ASDs)

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.  For example, ostium secundum ASD are the third most common form of congenital heart disorder and one of the most common congenital cardiac malformations in adults, accounting for 30%–40% of people over the age of 40.  Ostium secundum describes defects that are located mid-septally and are typically near the fossa ovalis.  Ostium primum defects lie immediately adjacent to the atrioventricular valves 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.  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; less than 50% of patients survive beyond 40 to 50 years due to heart failure or pulmonary hypertension related to the left-to right shunt.  Patients with ASDs are also at risk for paradoxical emboli.

Repair of ASDs is recommended for those with pulmonary systemic flows exceeding 1.5:1.0.  Despite the success of operative repair, there has been interest in developing a catheter-based approach to ASD repair to avoid the risks and morbidity of open heart surgery.  A variety of devices has 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.  Early devices such as the Rashkind hook device and the Lock Clamshell device were limited by their large size and technical malfunctions.  Current devices under investigation include the:

  • Sideris buttoned device,
  • Angel Wing® device,
  • Amplatzer® device, the CardioSeal® device, AND
  • HELEX® septal occluder. 

While most devices attempt to patch the ASD, the Atrial Septal Defect Occluding System (ASDOS), is unique in that it consists in part of an atherogenic stent designed to promote thrombosis of the ASD. In December 2001, the ASDOS received FDA approval for the occlusion of atrial septal defects in secundum position.

Patent Ductus Arteriosus (PDA)

The ductus arteriosus is the vascular remnant of the left sixth aortic arch, connecting the main pulmonary artery to the aorta. A patent ductus arteriosus (PDA) is the persistent opening of the channel beyond its expected time of closure during the first few days of life. Symptoms are related to the size of the ductus; a large nonrestrictive ductus with a left to right shunt can cause cardiac failure, while small restrictive PDAs are associated with an increased risk of infective endarteritis. Because of the twin threats of heart failure or endarteritis, it is recommended that all PDAs that persist after the age of 2 years be surgically closed with ligation or division of the PDA.

Open surgical treatment of the PDA is a low-risk procedure, if performed electively. However, over the past several decades there has been interest in developing a catheter-based technique to close PDAs, thus eliminating the need for general anesthesia, a thoracotomy, and an extended hospital stay and convalescence. A number of devices have been developed for this purpose.

The Gianturco coil, also referred to as the Cook embolization coil, is an arterial and venous occlusive device that was marketed prior to 1976, when the U.S. Food and Drug Administration (FDA) formally acquired regulatory authority over devices. (The Gianturco coil is entirely different than the Gianturco stent, which is used in coronary arteries.) Therefore, the Gianturco device has never undergone formal FDA approval but is available for clinical use. Transcatheter insertion of the coil is typically an outpatient procedure performed in the catheterization lab. General anesthesia may only be required in those very young patients who cannot reliably hold still during the procedure. General anesthesia in a child younger than 1 year-old may require overnight hospitalization.

In 2003, the Amplatzer™ Duct Occluder (St Jude Medical®, St. Paul, MN) received FDA approval, with the specific indication for nonsurgical closure of patent ductus arteriosus. This device is a self-expandable device made from a Nitinol wire mesh and polyester fabric. As the occluder is implanted, it expands outward, and the wires push against the wall of the ductus. The polyester fabric induces thrombosis, which closes the communication.

The Nit-Occlud® PDA device (PFM Medical, Carlsbad, CA) received premarket approval (PMA) approval from the FDA in August 2013. The device is indicated for small- to medium-sized PDAs with an angiographic diameter of less than 4 mm.

Ventricular septal defects (VSD)

The CardioSEAL Septal Occlusion System (Nitinol Medical Technologies, Inc., Boston, MA) is the second generation of the Clamshell occluder.  It received FDA approval for use in patients with complex ventricular septal defect (VSD) of significant size to warrant closure and who are considered to be at high risk for standard transatrial or transarterial surgical closure based on anatomical conditions and/or overall medical condition.  High- risk anatomical factors for transatrial or transarterial surgical closure include the following:

  • Left ventriculotomy or an extensive right ventriculotomy is required,
  • Multiple apical and/or anterior muscular VSDs (“Swiss Cheese Septum”),
  • Posterior apical VSDs covered by trabeculae, and
  • Previous VSD closure that failed

Patent Foramen Ovale (PFO)

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 (PFO) may be detected in up to 25% of adults.  Although common, PFOs are typically clinically insignificant and are not associated with right to left shunting with 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).  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, also known as cryptogenic stroke.

Cryptogenic stroke is defined as an ischemic stroke occurring in the absence of potential cardiac, pulmonary, vascular, or neurological sources.  An ischemic stroke is classified as cryptogenic in up to 40% of cases, and may be even higher in younger populations.  Conventional medical therapy consists of either antiplatelet therapy (aspirin, clopidrogel, or dipyramidole given alone or in combination) or oral anticoagulation with warfarin.  In general, patients with a known clotting disorder or evidence of pre-existing thromboembolism are treated with warfarin, and patients without these risk factors are treated with antiplatelet agents.

Two transcatheter devices received approval for marketing from the U.S. Food and Drug Administration (FDA) in 2002 as a treatment for patients with cryptogenic stroke and patent foramen ovale: the CardioSeal Septal Occlusion System and the Amplatzer Patent Foramen Ovale occluder.  Both received approval by the FDA through a Humanitarian Device Exemption (HDE), a category of FDA-approval that is applicable to devices that are designed to treat a patient population of fewer than 4,000 patients per year.  This approval process requires the manufacturer to submit data on the safety and the probable clinical benefit.  Clinical trials validating the device effectiveness are not required.  The labeled indications of both limits the use of these devices to closure of PFO in patients with recurrent cryptogenic stroke due to presumed paradoxical embolism through a patent foramen ovale and who have failed conventional drug therapy.

Following this limited FDA HDE approval, the use of PFO closure devices increased by over 50-fold, well in excess of the 4,000 per year threshold intended under the HDE.  As a result, in 2006, the FDA withdrew the HDE approval for these devices.  At this time, the FDA also reiterated the importance of randomized, controlled trials of PFO closure devices versus medical therapy, and noted that ongoing trials were hampered by slow enrollment.  Withdrawal of the HDE approval was, in part, intended to spur greater enrollment in ongoing randomized, controlled trials of these devices.  Currently, all uses of closure devices to treat PFO are off-label uses.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there is any exclusion or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Transcatheter closure of secundum atrial septal defects (ASD) using a Food and Drug Administration (FDA) approved device according to labeled indications may be considered medically necessary in patients with:

  • Echocardiographic evidence of ostium secundum atrial septal defect; AND
  • Clinical evidence of right ventricular volume overload (i.e., 1.5:1 ratio of left to right shunt or right ventricular enlargement).

NOTE: At present there are two FDA-approved devices for ASD closure, the AMPLATZER™ Septal Occluder, and the GORE HELEX™ Septal Occluder.

Transcatheter closure of a patent ductus arteriosus (PDA) using FDA-approved devices may be considered medically necessary. 

Transcatheter closure of ventricular septal defects (VSD) using an FDA-approved device according to the labeled indications may be considered medically necessary when all the following criteria are met:

  • Complex VSDs of significant size to warrant closure; AND
  • 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 who:
    1. Require a left ventriculotomy or an extensive right ventriculotomy;
    2. Failed previous VSD closure;
    3. Have multiple apical and/or anterior muscular VSDs [swiss cheese septum]; or
    4. Have posterior apical VSDs covered by trabeculae.

Transcatheter closure of patent foramen ovale (PFO) is considered experimental, investigational and/or unproven. 

All other transcatheter closure devices not meeting criteria listed above are considered experimental, investigational, and/or unproven.

Rationale

This policy was originally developed in 2006 and has been updated with searches of scientific literature through October 2013. This section of the current policy has been substantially revised.

Atrial septal defects (ASDs)

Evidence supporting the efficacy of devices for closure of ASD consists of nonrandomized comparative studies and case series. However, in contrast to the situation of PFO and cryptogenic stroke, the relationship of closure of the ASD and improved clinical outcomes is direct and convincing, since the alternative treatment is open surgery. Results generally show a high success rate in achieving closure and low complication rates. The FDA approval of the AMPLATZER Septal Occluder was based on the results of a multicenter, nonrandomized study comparing the device to surgical closure of ASDs; 423 patients received 433 devices. (18) This study was subsequently published with slightly different numbers but similar quantitative findings. (19) All patients had an ostium secundum atrial septal defect and clinical evidence of right ventricular volume overload. The results for the septal occluder group, showed comparably high success rates to surgery; the 24-month closure success rate was 96.7% in the septal occluder group compared to 100% in the surgical group. While the pattern of adverse events was 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.

A systematic review of percutaneous closure versus surgical closure was published by Butera et al. in 2011. (20) Thirteen non-randomized comparative studies that enrolled at least 20 patients were included, with a total of 3,082 patients. The rate of procedural complications was higher in the surgical group (31%, 95% CI: 21-41%) compared to the percutaneous group (6.6%, 95% CI: 3.9-9.2%), with an odds ratio for total procedural complications of 5.4 (95% CI: 2.96-9.84, p<0.0001). There was also an increased rate of major complications for the surgical group (6.8%, 95% CI: 4-9.5%) compared to the percutaneous group (1.9%, 95% CI: 0.9-2.9%), for an odds ratio of 3.81 (95% CI: 2.7-5.36, p=0.006).

Other nonrandomized studies comparing transcatheter closure to surgery show similar success rates. Suchon et al., in a study of 100 patients, had a 94% success rate in the transcatheter closure group compared to a 100% success rate in the surgical group. (21) A study by Berger et al. showed identical 98% success rate in both treatment groups. (22) A non-randomized comparative analysis by Kotowycz et al. (23) reported that mortality rates at 5-year follow-up did not differ between transcatheter and surgical closure (5.3% vs. 6.35% respectively, p=1.00), but that reintervention rates were higher for patients undergoing transcatheter closure (7.9% vs. 0.3% respectively, p<0.004).

Single-arm studies show high success rates of ASD closure. The U.S Food and Drug Administration (FDA) study discussed previously was the largest series, with an enrollment of 423 patients. Fischer and colleagues reported on use of the AMPLATZER device in 236 patients with secundum ASD. (24) In this evaluation study, closure was achieved in 84.7% of patients, and intermediate results were reported as excellent. Other smaller studies have reported favorable results for transcatheter closure of ASD. In Du et al., transcatheter closure of ASD in 23 patients with deficient ASD rims was compared to transcatheter closure of 48 patients with sufficient ASD rims. (25) The authors reported no significant differences in closure rates between the groups (91% for deficient rims and 94% for sufficient rims) along with no major complications at 24 hours and 6-month follow-up. Oho and colleagues also reported a successful closure rate of 97% at 1-year follow-up in 35 patients receiving transcatheter closure of ASD, while only 1 patient complication of second-degree atrioventricular block was noted. (26) Finally, Brochu and colleagues evaluated 37 New York Heart Association (NYHA) Class I or II patients who underwent transcatheter closure of ASD. (29) At 6-month follow-up, maximal oxygen uptake improved significantly, and the dimensions of the right ventricle decreased significantly while 20 patients moved from NYHA Class II to Class I and improved exercise capacity. Numerous other small, single-arm studies report similar results, with procedural success approaching 100% and successful closure on follow-up reported in the 90-100% range. (1, 3)

Practice Guidelines and Position Statements

Guidelines issued by the ACC/AHA in 2008 on the management of congenital heart disease recommend closure of an ASD by either percutaneous or surgical methods for several indications. (33) For sinus venosus, coronary sinus, or primum ASD, however, surgical rather than percutaneous closure is recommended.

Summary

For patients with an ASD, nonrandomized comparative studies and single-arm case series show high success rates of closure using closure 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 advantages of percutaneous closure over open surgery, the use of percutaneous ASD closure devices can be considered medically necessary.

For patients with ASD that require closure, nonrandomized comparative studies and single-arm case series show high success rates of closure using closure 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. Since the main alternative to percutaneous closure is open surgery, this evidence is sufficient to conclude that percutaneous closure achieves similar outcomes with less risk compared to the alternative. If the percutaneous approach is unsuccessful, ASD closure can be achieved using surgery. Because of the advantages of percutaneous closure over open surgery, the use of percutaneous ASD closure devices can be considered medically necessary for this purpose.

Patent Ductus Arteriosus (PDAs)

A number of different devices have been used to close patent ductus arteriosus (PDAs), including coils and occlusion devices. The evidence on the efficacy of percutaneous closure devices for PDA primarily consists of clinical series and a small number of nonrandomized comparative studies. A representative sample of some of the larger studies is discussed below.

Efficacy of closure devices for PDA

The Gianturco coil has been successfully adapted for use in closure of PDAs. Studies suggest a success rate of more than 90% in abolishing a clinically detectable shunt. (35, 36) Postoperative angiography and/or Doppler echocardiography frequently detect the persistence of a subclinical or trace shunt. The clinical significance of this finding is thought to be minimal. For example, Latson points out that using the Rashkind device, there have been no late cases of infection in more than 1,800 patient years of follow-up in postimplantation patients who have had no clinical evidence of a residual shunt. (37)

One nonrandomized comparative trial compared percutaneous closure to open surgery. In this study from China, Chen et al. (38) compared 72 patients treated with percutaneous closure with 183 patients treated with open surgery. The choice of procedure was made at the discretion of the patient and/or treating physician. There were more procedure-related events in the open surgery group compared to the percutaneous group (13.7% vs.1.4%, p=0.004), and recovery time was longer for the open surgery group (8.7 days vs. 1.3 days, p<0.001). Freedom from persistent residual shunt was higher in the percutaneous group (98.6% vs. 91.3%, p=0.04). Other clinical outcomes such as pulmonary arterial hypertension and left ventricular size were similar between groups.

Other evidence on the efficacy of closure devices consists of case series. A large case series of 1,291 attempted PDA coil occlusions was reported from the European Paediatric Cardiology Registry. (39) Immediate occlusion was demonstrated in 59% of patients, and this increased to 95% 1 year after the procedure. A suboptimal outcome occurred in 10% of patients, defined as failure to implant, coil embolization, residual leak, hemolysis, duct recanalization and flow impairment to adjacent structures. Increasing size of the PDA greater than 2 mm and PDAs that were tubular in shape were associated with an increased likelihood of unfavorable outcome.

In 2003, the Amplatzer Duct Occluder device received FDA approval for closure of PDA. (40) The clinical data submitted to the FDA as part of the FDA approval process consisted of results from a multi-center nonrandomized pivotal study that enrolled 441 patients. The primary efficacy measure was complete closure and was achieved in greater than 98.6% of patients at 12 months. A total of 1.3% of patients was reported to have serious or major adverse events, and 4.8% were reported to have a minor adverse event.

The Multicenter USA Amplatzer patent ductus arteriosus device trial (41) reported periprocedural and 1-year outcomes in 484 patients from 25 U.S. centers. Of the 484 patients enrolled, the Amplatzer device implantation was not attempted in 45; due to the size of the PDA or the morphology of the PDA was more suited for treatment with a coil. Of the 439 patients in whom implantation was attempted, the device was successfully implanted in 435 patients (99%). Immediate postprocedure occlusion was reported in 76% of patients, which increased to 89% on postprocedure day 1 and to 99% at 1 year. At last evaluation, PDA occlusion was documented in 98% of patients. At 1-year follow-up, 359/360 (99.7%) evaluable patients have no evidence of a left to right shunt on echocardiography. Complications were uncommon, with one periprocedural death and major events reported in 2.3% (10/439) of patients. Examples of major events included device embolization (n=2), partial obstruction of the pulmonary artery (n=2), and bleeding requiring transfusion (n=2). Minor events occurred in 7.1% (31/439) of patients.

Other case series of both the Amplatzer device and the Gianturco coils report similar outcomes. (42-47) These series vary in terms of patient selection, types of device, and outcomes reported. However, the case series are consistent in reporting a high rate of procedural success, a high rate of successful closure of the PDA, and a low rate of serious complications.

Comparative efficacy of different devices and/or different techniques

Wang et al. (48) compared outcomes among 214 patients undergoing percutaneous closure with coils and 134 patients undergoing closure by an occluder device. Patients were selected for either group by the size of the PDA, with coils utilized for small to moderate PDAs and the occluder device utilized for larger PDAs. The procedural success rate was high for both the coils (96.7%) and the occluder (98.5%), with no significant difference between groups. There were higher complication rates reported for the coil group. Distal embolization occurred in 8.9% (19/214) of patients in the coil group compared with 1.5% (2/136) patients in the occluder group (p<0.01). Pulmonary artery stenosis occurred in 4.2% (9/214) patients in the coil group compared with zero in the occluder group (p<0.05).

In a nonrandomized study, Chen et al. compared PDA occlusion using the transcatheter Amplatzer occluder in 98 patients to video-assisted thoracoscopic surgery in 196 patients. (49) No deaths or late recanalizations occurred in either group. However, residual shunt and left ventricular overload occurred in 4 (4.3%) patients in the transcatheter occluder group compared to zero patients in the thoracoscopic group. Acute complications related to the procedures occurred in 10.2% of the transcatheter occluder group compared to 1.5% of the video-assisted thoracoscopic surgery group (p<0.05). After follow-up of 3.1 to 8 years (mean, 5.4 ± 1.2 years) in the transcatheter occluder group and 3-8 years (mean, 5.6 ± 2.8 years) in the thoracoscopic surgery group, heart structures in both groups returned to normal. While fewer complications occurred in the thoracoscopic group, the nonrandomized nature of the study limits interpretation of the results.

Hongxin and colleagues reported on a parasternal, perpulmonary approach for PDA device closure in a cohort study of 79 patients. (50) Complete PDA occlusion occurred in 61 (78%) patients immediately after device placement while 7 (9%) patients required device redeployment. Complete PDA closure was found by echocardiogram in 76 (97%) patients during the follow-up period of 3 months to 2 years. While this minimally invasive approach is theoretically designed to avoid or reduce the disadvantages of other PDA occlusion procedures and devices, such as the trauma of thoracotomy and risk of transcatheter device embolization, these devices are not available in the United States, and this approach still requires general anesthesia.

A number of nonrandomized studies have compared newer, non-FDA approved occluders with the Amplatzer Duct Occluder device. (51-54)   These non-approved devices were generally targeted toward uses that are off label for the Amplatzer occluder, such as in small infants younger than 6 months of age, or in PDAs that were outside the suggested range of sizes. The devices used in these trials include the Amplatzer Duct Occluder II additional sizes (St Jude Medical®, St. Paul, MN) and the Cardi-O-Fix device (Stairway Medical Technology®, Beijing, CHN).

Ongoing Clinical Trials

A search of online site ClinicalTrials.gov identified 2 ongoing nonrandomized studies of PDA occluders. In a Phase I study, the safety and PDA closure outcomes of a new PDA occluder by Occlutech is being evaluated in 50 patients (NCT01479218). This trial is expected to be completed in January 2014 and is listed as active, not recruiting patients. In the Amplatzer Duct Occluder II (ADOII) study, the safety and PDA closure outcomes of the Amplatzer Duct Occluder II will be evaluated in 192 patients (NCT00713700). This study is ongoing but is no longer recruiting patients and is expected to be completed in July 2016.

Practice Guidelines and Position Statements

In 2008 the American College of Cardiology/American Hospital Association (ACC/AHA) published guidelines on the management of adults with congenital heart disease. (55)

Class I indications for closure of a PDA were listed as:

  • Left atrial enlargement, left ventricular enlargement, pulmonary arterial hypertension, or left-to-right shunt (Level of evidence C)
  • Prior endarteritis (Level of evidence C)

Class IIa indications for closure of a PDA were:

  • It is reasonable to close an asymptomatic small PDA by catheter device (Level of evidence C)
  • PDA closure is reasonable for patients with pulmonary arterial hypertension with a net left-to-right shunt (Level of evidence C)

Summary

The ductus arteriosus is the vascular remnant of the left sixth aortic arch connecting the main pulmonary artery to the aorta. A patent ductus arteriosus (PDA) is the persistent opening of the channel beyond its expected time of closure during the first few days of life. Catheter-based techniques have been developed to close PDAs to eliminate the need for general anesthesia, a thoracotomy, and an extended hospital stay and convalescence associated with open surgical PDA closure.

The use of percutaneous closure devices has become the procedure of choice for closure of patent ductus arteriosus in suitable patients. The evidence base for percutaneous closure of PDAs consists of a large number of case series that report high success rates with low rates of adverse events. A few nonrandomized comparative trials compare outcomes of different devices and techniques, and one such study reports better outcomes with a thoracoscopic approach compared to a percutaneous approach. However, these nonrandomized studies are not adequately rigorous to form conclusions because there is a high likelihood of selection bias, resulting in populations that are not comparable. Based on the evidence that percutaneous closure achieves high success rates and avoids the morbidity of open surgery, this technique may be considered medically necessary.

Ventricular septal defects (VSD)

In the CardioSEAL high-risk study (a prospective, multi-center trial) the CardioSEAL Septal Occlusion System was utilized to close a variety of hemodynamically significant defects.  At the time the VSD data was analyzed and submitted to the FDA for approval, 74 patients with no additional anatomical lesions were enrolled in the study for closure of a VSD.  The types of VSDs closed with a CardioSEAL device were congenital muscular (n = 26) and post-operative (n = 31).  The age of the patients ranged from 0.3 years to 70.1 years, with a median age of 3.7 years.  The investigators reported that despite a high degree of co-morbid illness within the treated group, 72 % of the patients improved clinically at 6 months after implantation, and 84 % of the patients had a reduction in flow through the defect or reduction in the anatomical defect size.  Peri-procedure events, including some serious events, occurred frequently, but all moderately serious or serious events had resolved by 6 months after the procedure.  The investigators concluded that the CardioSEAL Septal Occlusion System is safe and effective in the intended patient population. (34)

Patent Foramen Ovale (PFO)

Conventional therapy for cryptogenic stroke consists of either 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 pre-existing thromboembolism are treated with warfarin, and patients without these risk factors are treated with antiplatelet agents. Closure devices are non-pharmacologic alternatives to medical therapy for cryptogenic stroke in patients with a patent foramen ovale (PFO).

Evidence on the efficacy of PFO closure devices consists of 3 randomized controlled trials (RCT), a few nonrandomized, comparative studies, and numerous case series. Meta-analyses of the published studies have also been performed.

Randomized, Controlled Trials

Closure I trial. (1)

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. A total of 909 patients between the ages of 18 and 60 years, 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 2 years, death from any cause during the first 30 days after treatment, and death from neurologic causes at 2 years. 

Of 405 patients in the closure group, 362 (89.4%) had successful implantation without procedural complications. At 6 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 [HR]: 0.78, 95% confidence interval [CI]: 0.45-1.35, p=0.37). Kaplan-Meier estimates of the 2-year rate of stroke were 2.9% in the closure group and 3.1% in the medical therapy group (adjusted HR: 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).

RESPECT trial. (2)

The RESPECT trial was a multicenter RCT comparing PFO closure with medical therapy in 980 patients between the ages of 18 and 60 years with a previous cryptogenic stroke and documented PFO.  Patients were randomly assigned to PFO closure with the Amplatzer Occluder, or to medical therapy. Medical therapy consisted of 1 of 4 regimens prescribed at the discretion of the treating physician: aspirin, aspirin plus dipyridamole, clopidogrel, or warfarin. The primary endpoint was a composite of fatal ischemic stroke, nonfatal ischemic stroke, or early death within 30 days of randomization. Mean follow-up for the entire group was 2.6+2.0 years.

A total of 9 events occurred in 499 patients assigned to closure, and 16 events occurred in 464 patients assigned to medical therapy. All of the events were non-fatal strokes. The hazard ratio for this outcome was 0.49, but this result did not reach statistical significance in the intent-to-treat analysis (95% CI: 0.22-1.11, p=0.08). On per-protocol analysis, there was a statistically significant effect, with a hazard ratio of 0.37 (95% CI: 0.14-0.96, p=0.03). On subgroup analyses, there were no statistically significant differences in outcomes, although there were trends for better outcomes in the closure group for patients with a substantial right to left shunt (p=0.07) and for patients with an atrial septal aneurysm (p=0.10). The rate of serious adverse events did not differ between the closure and medical therapy groups (23.0% vs. 21.6%, p=0.65). Major bleeding (n=2) and cardiac tamponade (n=2) were the most frequent procedure-related adverse events.

PC Trial. (3) 

The PC trial was a multicenter RCT comparing PFO closure with medical therapy in 414 patients younger than 60 years of age with a prior cryptogenic stroke or peripheral embolization and a documented PFO. Patients were recruited from 29 centers worldwide and randomly assigned to PFO closure with the Amplatzer device or medical therapy. Recommended antiplatelet therapy in the closure group was aspirin plus ticlopidine, or clopidogrel alone. Medical therapy in the control group was at the discretion of the treating physician, with the requirement that patients receive at least one appropriate medication. The primary endpoint was a composite of death, nonfatal stroke, TIA, or peripheral embolism. The median duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical therapy group.

The primary outcome, after independent adjudication, occurred in 9 of 204 patients (3.4%) in the closure group compared to 11 of 210 patients (5.7%) in the medical group. The hazard ratio for this outcome was 0.63 (95% CI: 0.24-1.62, p=0.34) on intent-to-treat analysis. On per-protocol analysis, results were similar with a hazard ratio of 0.70 (95% CI: 0.27-1.85, p=0.48). There were no significant differences in the rate of the individual components of the primary outcome, and there were no significant differences in outcome on subgroup analyses. The adverse event rate was 34.8% in the closure group compared to 29.5% in the medical therapy group.

Systematic Reviews

Several systematic reviews with meta-analysis of the 3 available RCTs have been published; 2 representative studies are summarized here. Rengifo-Moreno et al. (4) performed a combined analysis of the 3 RCTs previously discussed. The analysis included a total of 1,150 patients randomized to PFO closure and 1,153 patients randomized to medical therapy followed for a mean of 3.5 years. Two endpoints were included, recurrent vascular events and a combined endpoint of death plus recurrent vascular events. On combined analysis, there was a statistically significant reduction in recurrent vascular events with a pooled hazard ratio of 0.59 (95% CI: 0.36-0.97, p=0.04). For the composite outcome of death plus recurrent vascular events, combined analysis revealed a reduction for the closure group of borderline statistical significance (HR: 0.67, 95% CI: 0.12-1.03, p=0.05). On subgroup analysis, there was a trend for greater benefit in patients with a substantial right to left shunt, although this result did not reach statistical significance (HR: 0.35, 95% CI: 0.12-1.03, p=0.06).

Another meta-analysis of the same 3 RCTs was reported by Kitsios et al. (5)   This study used recurrent stroke as the primary outcome. The authors noted that the rates of recurrent stroke varied widely across the studies, thereby raising the possibility of ascertainment bias for this outcome. On combined analysis, the difference between groups did not reach statistical significance, with a hazard ratio of 0.55 (95% CI: 0.26-1.18). Combined analysis was also performed for the composite outcomes reported in the trials, even though the composite outcomes were not defined in the same way. The combined result for the composite outcome was of borderline statistical significance, with a HR of 0.67 (95% CI: 0.44-1.00). There were no significant differences found on combined analysis of the subgroup analyses from the trials.

A number of systematic reviews of the observational studies have also been published, comparing outcomes of PFO closure with medical therapy. (6-8) These reviews are consistent in reporting that the combined rate of recurrent stroke is lower for patients treated with a closure device compared to medical therapy.

Kitsios et al. published a systematic review of observational studies and the single RCT in 2012. (9) This review included 52 single-arm studies, 7 nonrandomized comparative studies, and 1 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.

Wohrle (8) compared the results of 12 series of PFO closure (n=2,016) with 8 series (n=998 patients) of medical therapy. At 2 years of follow-up, the range of recurrent stroke was 0–1.6% for PFO closure and 1.8–9.0% for medical therapy. The combined annual incidence of stroke or TIA was 1.3% (95% CI: 1.0–1.8%) following PFO closure compared with 5.2% (95% CI: 4.4–6.2) for medical therapy. In an earlier review, Khairy et al. (6) analyzed 6 series of medical therapy (n=895 patients) and 10 series of PFO closure (n=1,355 patients). These authors noted differences in key clinical characteristics among patients in the 2 treatment groups. Patients treated with medical therapy were older, had a greater proportion of men, and higher rates of smoking and diabetes. Patients treated with PFO closure were more likely to have had more than one cerebrovascular event. The recurrence rate at 1 year ranged from 0–4.9% with PFO closure, compared with 3.8–12.0% with medical therapy. There was an estimated major complication rate (death, hemorrhage requiring transfusion, tamponade, need for surgical intervention, and pulmonary embolus) for PFO closure of 1.5%, and a minor complication rate of 7.9%.

Nonrandomized, comparative studies

A number of nonrandomized comparative studies of closure devices versus medical therapy have been published. Wahl 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. (9) 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 [HR]: 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.

Windecker et al. (10) compared 150 patients who underwent patent foramen ovale (PFO) closure between 1994 and 2000 with 158 medically treated patients over the same period. The choice of therapy was based on clinician and/or patient preference. The patients who received closure differed from the medically treated patients on key clinical variables, including the percentage with more than one cerebrovascular event and the size of the PFO. At 4 years’ follow-up, there was a trend toward lower recurrence of stroke or transient ischemic attack (TIA) in the PFO group that did not reach statistical significance (7.8% vs. 22.2%, p=0.08).

Harrer et al. (11) reported on 124 patients with cryptogenic stroke and PFO treated over a 10-year period. Eighty-three patients were treated with medical therapy, 34 were treated with percutaneous PFO closure, and 7 were treated with surgical closure. After a mean follow-up of 52 +/- 32 months, annual recurrence rates of stroke were not different between medical therapy and PFO closure (2.1% vs. 2.9%, respectively, p=NS).

Paciaroni et al. (12) performed a prospective observational study on 238 consecutive patients with cryptogenic stroke and PFO treated at 13 Italian centers. A total of 117 patients were treated with anti-thrombotic therapy, and 121 patients were treated with a closure device, with the treatment decision made according to patient and physician preference. Procedure-related adverse events were reported in 8/121 (6.8%) patients treated with a closure device (4 patients with tachycardia, 2 patients with allergic reaction, 1 patient with atrial fibrillation, 1 patient with sepsis). After a follow-up of 2 years, 10/117 patients (8.5%) in the medical therapy group had a recurrent neurologic event (stroke or TIA), compared with 7/121 patients (5.8%, p=0.28) in the closure device group. For recurrent stroke, the difference between the groups was statistically significant, with 8/117 (6.8%) in the medical therapy group compared with 1/121 (0.8%, p=0.018) in the closure device group. On multivariate analysis, treatment with a closure device was a significant predictor of a reduced stroke rate (odds ratio [OR]: 0.1, 95% CI: 0.0-1.0, p=0.05) but was not a significant predictor of the combined outcome of stroke or TIA (OR: 0.1, 95% CI: 0.02-1.5, p=0.10).

Single-arm case series.

Many case series report on outcomes of PFO closure in an uncontrolled fashion; some examples of these series are as follows. Cifarelli et al. (13) reported on 202 consecutive patients treated with a closure device for secondary prevention of thromboembolism. They reported no periprocedural deaths or strokes, and one case of device migration 24 hours after placement. Recurrence-free survival was reported in 99% of patients 55 years of age or younger and 84% in patients older than age 55 years. Recurrence of thromboembolism was associated with a septal aneurysm, with all patients who experienced recurrence of thromboembolism having a septal aneurysm. Onorato et al. (14) reported on 256 patients with paradoxical embolism who received transcatheter closure of PFO. The authors reported a 98.1% full closure rate of the PFO and no neurologic events at a mean follow-up of 19 months. Martin and colleagues (15) also reported on a study of 110 patients with paradoxical embolism who received transcatheter closure of PFO. While the full closure rate of PFO was 71% at 2 years, only 2 patients had experienced a recurrent neurologic event. Windecker and colleagues (16) reported on a case series of 80 patients with a history of at least 1 paradoxical embolic event and who underwent closure of a PFO with a variety of transcatheter devices. Patients were followed up for a mean of 1.6 years. During 5 years of follow-up, the risk of an embolic event (either TIA, stroke, or peripheral embolism) was 3.4%, considered comparable to either medical therapy with anticoagulation or open surgical approaches. The presence of a postprocedural shunt was a predictor of recurrent thromboembolic events, emphasizing the importance of complete closure.

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.

A sham-controlled randomized clinical trial of PFO closure for the indication of refractory migraine headache was published in 2008. (17) Migraine headache is another condition that has been associated with PFO in epidemiologic studies. In this study, there was no significant difference observed in the primary endpoint of migraine headache cessation (3 of 74 in the implant group, 3 of 73 in the sham group, p=0.51). The results of this study cast some doubt on the causal relationship between PFO and migraine.

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 2 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

  • 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 estimated completion date listed as December 2016. Last update was 9/17/2013. 
  • 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 2 years. Planned enrollment is for 664 patients, with an estimated completion date of January 2018.

Guidelines

The American College of Chest Physicians published guidelines on antiplatelet and antithrombotic therapy in 2012, (28) which were an update to previous guidelines published in 2008. (29) These guidelines contained the following statements about the treatment of patients with a PFO:

  • In patients with asymptomatic patent foramen ovale (PFO) or atrial septal aneurysm, we suggest against antithrombotic therapy (Grade 2C)
  • In patients with cryptogenic stroke and PFO or atrial septal aneurysm, we recommend aspirin (50-100 mg/d) over no aspirin (Grade 1A).
  • In patients with cryptogenic stroke and PFO or atrial septal aneurysm, who experience recurrent events despite aspirin therapy, we suggest treatment with (VKA [vitamin K antagonists] therapy (target INR, 2.5; range, 2.0-3.0) and consideration of device closure over aspirin therapy (Grade 2C).
  • In patients with cryptogenic stroke and PFO, with evidence of DVT [deep vein thrombosis], we recommend VKA therapy for 3 months (target INR, 2.5; range, 2.0-3.0) (Grade 1B) and consideration of device closure over no VKA therapy or aspirin therapy (Grade 2C).

The American College of Chest Physicians (30) and the American Academy of Neurology, (31) both published in 2004, state that the evidence is inconclusive regarding the comparative efficacy of PFO closure devices and medical therapy. Neither of these guidelines offers specific recommendations as to when PFO closure devices should be used.

The American Heart Association (AHA)/American Stroke Association guidelines (32) published in 2006 offer somewhat more specific recommendations. These guidelines do not recommend PFO closure as initial therapy for patients with a first ischemic stroke and PFO, stating that, “Insufficient data exist to make a recommendation about PFO closure in patients with a first stroke and a PFO.” They also state that “…aspirin (50-325mg/d), aspirin and extended-release dipyridamole in combination, and clopidrogel are all acceptable options for initial therapy (class IIa, level of evidence A),” and that “Warfarin is reasonable for high-risk patients who have other indications for oral anticoagulation, such as underlying hypercoagulable state or evidence of venous thrombosis (class IIa, level of evidence C).” For patients with stroke or TIA while on medical therapy, they state that, “PFO closure may be considered for patients with recurrent cryptogenic stroke despite optimal medical therapy (class IIB, level of evidence C).”

Summary

The evidence on the efficacy of closure devices for patients with patent foramen ovale (PFO) and cryptogenic stroke does not permit conclusions on whether health outcomes are improved. Three RCTs have been completed that compare closure devices to medical therapy in patients with cryptogenic stroke and PFO. None of the 3 trials reported statistically significant improvements on their main outcome using intent-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 is not well-defined.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

35.52, 35.71, 38.85, 429.71, 745.5, 745.61, 747.0, 745.2, 745.4, 745.5

ICD-10 Codes

Q21.1, Q21.2, Q25.0, 02Q53ZZ, 02Q54ZZ, 02U53JZ, 02U54JZ, 02LR3CT, 02LR3DT, 02LR3ZT, 02LR4CT, 02LR4DT

Procedural Codes: 93580, 93581, 93582, C1817
References
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  56. Closure Devices for Patent Foramen Ovale and Atrial Septal Defects Chicago, Illinois:  Blue Cross Blue Shield Association Medical Policy Reference Manual (September 2013) Medicine 2.02.09
  57. Chicago, Illinois:  Blue Cross Blue Shield Association Medical Policy Reference Manual (October 2013) Surgery 7.01.61.
History
October 2010  Added coverage for transcatheter closure of secundum atrial septal defects. 
February 2012  Policy updated with literature search. Policy statements unchanged. References 5, 8, 15 and 25 added. 
November 2012 Policy updated with literature search. References 3, 6, 7, and 30 added. No change to policy statement.
December 2012 Changed title from "Patent Foramen Ovale (PFO) Closure Devices" to "Closure Devices for Patent Foramen Ovale and Atrial Septal Defects".
July 2013 Policy formatting and language revised.  Added criteria regarding ventricular septal defects.  Title changed from "Closure Devices for Patent Foramen Ovale and Atrial Septal Defects" to "Transcatheter Closure Devices for Cardiac Defects: Atrial Septal Defects (ASD), Patent Foramen Ovale (PFO), Patent Ductus Arteriosus (PDA), and/or Ventricular Septal Defects (VSD)".  Added CPT code 93581.
February 2014  Document updated with literature review.  Coverage unchanged.  Rationale significantly revised.  CPT/HCPCS code(s) updated.
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Transcatheter Closure Devices for Cardiac Defects: Atrial Septal Defects (ASD), Patent Foramen Ovale (PFO), Patent Ductus Arteriosus (PDA), and/or Ventricular Septal Defects (VSD)