Transcatheter Closure of Septal Defects

Number: 0292

Policy

1. Atrial Septal Defects

   Aetna considers transcatheter closure of atrial septal defects (ASDs) using Food and Drug Adminsitration (FDA)-approved closure devices (e.g., the Gore Helex Septal Occulder) medically necessary in pediatric or adult members for either of the following indications:

   1. For the closure of the fenestration in individuals who have undergone a fenestrated Fontan procedure; or
   2. For the occlusion of ASDs in secundum position.

   Aetna considers transcatheter closure of ASDs experimental and investigational for migraine prophylaxis and for all other indications (e.g., coronary sinus atrial septal defect, ostium primum atrial septal defect, and sinus venosus atrial septal defect; not an all-inclusive list) because its effectiveness for these indications has not been established.

2. Ventricular Septal Defects

   Aetna considers transcatheter closure of ventricular septal defects (VSDs) using FDA-approved closure devices medically necessary for complex VSDs in pediatric or adult members who are considered to be at high-risk for standard transatrial or transarterial surgical closure.

   Aetna considers transcatheter closure of VSDs experimental and investigational for all other indications because its effectiveness for indications other than the one listed above has not been established.

   Aetna considers the Nit-Occlud Lê VSD coil experimental and investigational for transcatheter closure of a peri-membranous ventricular septal defect because the effectiveness of this approach has not been established.

3. Patent Foramen Ovale

   Aetna considers transcatheter occlusion of patent foramen ovale (PFO) by a FDA-approved device medically necessary for adults (18 to 60 years of age) who have had a cryptogenic stroke.
   

   Aetna considers transcatheter occlusion of PFO experimental and investigational for persons with transient ischemic attacks, or arterial emboli due to presumed paradoxical embolism through a PFO.

   Aetna considers transcatheter closure of PFO experimental and investigational for migraine prophylaxis, stroke prevention, and for all other indications (e.g., orthodeoxia-platypnea and unexplained oxygen desaturation) because its effectiveness for these indications has not been established.

4. Patent Ductus Arteriosus

   Aetna considers transcatheter occlusion of patent ductus arteriosus (PDA) medically necessary using the Amplatzer duct occluder or other closure devices approved by the FDA for this indication.

   Aetna considers closure devices not approved by the FDA for transcatheter occlusion of PDA experimental and investigational for this indication.

5. Transmyocardial Transcatheter/Perventricular Closure of Septal Defects

   Aetna considers transmyocardial transcatheter/perventricular closure of ventricular septal defects with implants experimental and investigational because of an absence of published literature on the effectiveness of this approach.

6. Percutaneous Transcatheter Implantation of Inter-Atrial Septal Shunt Device

   Aetna considers percutaneous transcatheter implantation of inter-atrial septal shunt device experimental and investigational for the treatment of heart failure because the effectiveness of this approach has not been established.

Background

Despite the success of standard operative repair with its mortality rate of less than 1 %, the risks and morbidity of open-heart surgery remain.  Over the last 2 decades, interventional cardiac catheterization techniques have evolved to a point where percutaneous transcatheter devices can be offered as an alternative to their open counterparts to repair certain cardiac defects, particularly in younger patients.  All of the devices require transesophageal echocardiographic guidance for optimal placement, and most procedures are performed under general anesthesia with transesophageal echocardiographic and/or fluoroscopic guidance to verify optimal placement, and to access the immediate results of the procedure.

In recent years many different systems for transcatheter closure of an atrial septal defect (ASD) have been developed and tested.  Initially, acute failures and complications were primarily due to poor selection of cases with too large a defect or selection of a defective device.  Over the years, stricter implantation and patient selection criteria have lead to more successful deployment of the devices in stable positions without inducing functional abnormality or anatomical obstruction.  Of utmost importance in choosing appropriate patients is the echocardiographic morphology of the ASD with reference to size, position in the interatrial septum, proximity to surrounding structures, and adequacy of septal rim.  Equally essential is accurate assessment of the stretched diameter of the inter-atrial communication by balloon sizing during catheterization to determine proper size of the ASD closure device.  Many of the ASD closure devices initially approved by the Food and Drug Administration (FDA) for investigational use have been withdrawn from the market due to complications (e.g., Clamshell double-umbrella device, and Angel Wing).  The most frequent complications include device embolization and thrombus formation.  Some ASD closure devices have been modified a number of times to improve technical feasibility, safety, and effectiveness.  Devices currently under investigation for ASD closure include the Buttoned Device, CardioSEAL Septal Occluder, StarFlex, Atrial Septal Defect Occluding System (ASDOS), Guardian Angel, and the Helex. 

The Amplatzer septal occluder (AGA Medical Corp., Golden Valley, MN) received FDA approval in 2001.  It is a self-centering device that consists of 2 round disks made of Nitinol wire mesh and linked together by a short connecting waist.  Studies have reported short-term results confirming an early high occlusion rate with no major complications when strict implantation and patient selection criteria are used.  According to the FDA approval, the Amplatzer septal occluder is indicated for ASD closure in individuals who have echocardiographic evidence of ostium secundum ASD and clinical evidence of right ventricular (RV) volume overload (i.e., 1.5:1 degree to left to right shunt or RV enlargement).  The device is also indicated in patients who have undergone a fenestrated Fontan procedure and who now require closure of the fenestration. 

Du et al (2002) compared the safety, effectiveness and clinical utility of the Amplatzer septal occluder for closure of secundum ASD with surgical closure.  A multi-center, non-randomized concurrent study was performed in 29 pediatric cardiology centers from March 1998 to March 2000.  Patients were assigned to either the device or surgical closure group according to the patient’s option.  Baseline physical examinations and echocardiography were performed pre-procedure and at follow-up (6 and 12 months for device group, 12 months for surgical group).  A total of 442 patients were in the group undergoing device closure, whereas 154 patients were in the surgical group.  The median age was 9.8 years for the device group and 4.1 years for the surgical group (p < 0.001).  In the device group, 395 (89.4 %) patients had a single ASD; in the surgical group, 124 (80.5 %) (p = 0.008) had a single ASD.  The size of the primary ASD was 13.3 +/- 5.4 mm for the device group and 14.2 +/- 6.3 mm for the surgery group (p = 0.099).  The procedural attempt success rate was 95.7 % for the device group and 100 % for the surgical group (p = 0.006).

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;
• Previous VSD closure that failed.

The CardioSEAL high-risk study is a prospective, multi-center trial studying the use of the CardioSEAL Septal Occlusion System 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.

The FDA has granted humanitarian device exemptions to two transcatheter occlusion devices for repair of patent foramen ovale (PFO): the CardioSEAL Septal Occlusion System and the Amplatzer Patent Foramen Ovale Occluder.  The FDA has allowed the use of these devices for closure of PFO in persons with recurrent cryptogenic stroke due to presumed paradoxical embolism through a PFO and who have failed conventional drug therapy.

At present, it should be noted that none of these afore-mentioned technologies is widely used and few devices have undergone extensive clinical trials.  Many of these devices remain investigational and large-scale studies are underway to collect sufficient long-term data to validate these various applications as viable alternatives to surgery in the initial treatment of selected patients.  The FDA is requiring that both Nitinol Medical Technologies, Inc and AGA Medical Corp. continue to study their products over the next 5 years to better assess their long-term safety and effectiveness (Meadows, 2002).

A randomized controlled clinical trial funded by St. Jude Medical found that closure of a PFO for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy.  Meier et al (2013) investigated whether closure is superior to medical therapy.  The investigators performed a multi-center, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end-points were unaware of the study-group assignments.  Patients with a PFO and ischemic stroke, transient ischemic attack (TIA), or a peripheral thrombo-embolic event were randomly assigned to undergo closure of the PFO with the Amplatzer PFO occluder or to receive medical therapy.  The primary end-point was a composite of death, nonfatal stroke, TIA, or peripheral embolism.  Analysis was performed on data for the intention-to-treat population.  The mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group.  The primary end-point occurred in 7 of the 204 patients (3.4 %) in the closure group and in 11 of the 210 patients (5.2 %) in the medical-therapy group (hazard ratio [HR] for closure versus medical therapy, 0.63; 95 % confidence interval [CI]: 0.24 to 1.62; p = 0.34).  Non-fatal stroke occurred in 1 patient (0.5 %) in the closure group and 5 patients (2.4 %) in the medical-therapy group (HR, 0.20; 95 % CI: 0.02 to 1.72; p = 0.14), and TIA occurred in 5 patients (2.5 %) and 7 patients (3.3 %), respectively (HR, 0.71; 95 % CI: 0.23 to 2.24; p = 0.56).  The authors concluded that closure of a PFO for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy.

A randomized, controlled clinical trial funded by NMT Medical (Furlan et al, 2012) found that, in patients with cryptogenic stroke or TIA who had a PFO, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA.  The investigators conducted a multi-center, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or TIA and had a PFO.  The primary end-point was a composite of stroke or TIA during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years.  A total of 909 patients were enrolled in the trial.  The cumulative incidence (Kaplan-Meier estimate) of the primary end-point was 5.5 % in the closure group (447 patients) as compared with 6.8 % in the medical-therapy group (462 patients) (adjusted HR, 0.78; 95 % CI: 0.45 to 1.35; p = 0.37).  The respective rates were 2.9 % and 3.1 % for stroke (p = 0.79) and 3.1 % and 4.1 % for TIA (p = 0.44).  No deaths occurred by 30 days in either group, and there were no deaths from neurologic causes during the 2-year follow-up period.  A cause other than paradoxical embolism was usually apparent in patients with recurrent neurologic events.

In the primary intention-to-treat analysis, a randomized controlled clinical trial demonstrated no significant benefit associated with closure of a PFO in adults who had had a cryptogenic ischemic stroke. Carroll et al (2013) conducted a trial to evaluate whether closure is superior to medical therapy alone in preventing recurrent ischemic stroke or early death in patients 18 to 60 years of age.  In this prospective, multi-center, randomized, event-driven trial, investigators randomly assigned patients, in a 1:1 ratio, to medical therapy alone or closure of the PFO.  The primary results of the trial were analyzed when the target of 25 primary end-point events had been observed and adjudicated.  The investigators enrolled 980 patients (mean age of 45.9 years) at 69 sites.  The medical-therapy group received 1 or more anti-platelet medications (74.8 %) or warfarin (25.2 %).  Treatment exposure between the 2 groups was unequal (1,375 patient-years in the closure group versus 1,184 patient-years in the medical-therapy group, p = 0.009) owing to a higher drop-out rate in the medical-therapy group.  In the intention-to-treat cohort, 9 patients in the closure group and 16 in the medical-therapy group had a recurrence of stroke (HR with closure, 0.49; 95 % CI: 0.22 to 1.11; p = 0.08).  The between-group difference in the rate of recurrent stroke was significant in the pre-specified per-protocol cohort (6 events in the closure group versus 14 events in the medical-therapy group; HR, 0.37; 95 % CI: 0.14 to 0.96; p = 0.03) and in the as-treated cohort (5 events versus 16 events; HR, 0.27; 95 % CI: 0.10 to 0.75; p = 0.007).  Serious adverse events occurred in 23.0 % of the patients in the closure group and in 21.6 % in the medical-therapy group (p = 0.65).  Procedure-related or device-related serious adverse events occurred in 21 of 499  patients in the closure group (4.2 %), but the rate of atrial fibrillation (AF) or device thrombus was not increased.  The authors concluded that, in the primary intention-to-treat analysis, there was no significant benefit associated with closure of a PFO in adults who had had a cryptogenic ischemic stroke.  However, closure was superior to medical therapy alone in the pre-specified per-protocol and as-treated analyses, with a low rate of associated risks.

Chen et al (2014) stated that the optimal treatment for secondary prevention in patients who have a PFO and history of cryptogenic stroke is still uncertain and controversial.  In view of this, these researchers performed a systematic review of RCTs to investigate whether PFO closure was superior to medical therapy for prevention of recurrent stroke or TIA in patients with PFO after cryptogenic stroke.  These investigators searched the Cochrane Central Register of Controlled Trials, Embase, PubMed, Web of Science, and ClinicalTrials.gov.  Three RCTs with a total of 2,303 patients were included and analyzed.  A fixed-effect model was used by Review Manager 5.2 (RevMan 5.2) software.  The pooled risk ratio (RR) of recurrent stroke or TIA was 0.70, with 95 % CI: 0.47 to 1.04, p = 0.08.  The results were similar in the incidence of death and adverse events, and the pooled RR was 0.92 (95 % CI: 0.34 to 2.45, p = 0.86) and 1.08 (95 % CI: 0.93 to 1.26, p = 0.32), respectively.  The authors concluded that the data of this systematic review did not show superiority of closure over medical therapy for secondary prevention after cryptogenic stroke.  Moreover, they stated that due to some limitations of the included studies, more RCTs are needed for further investigation regarding this field.

In October 2016, the FDA approved the Amplatzer PFO Occluder for percutaneous transcatheter closure of a patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke (FDA, 2016). The FDA concluded that there is "reasonable assurance of safety and effectiveness" of this device when used in accordance with the indications for use. In support of the approval, the manufacturer sponsored the RESPECT Trial, a prospective, multi-center, randomized (1:1), event driven, unblinded clinical study designed to evaluate whether PFO closure with the AMPLATZER PFO Occluder (the Device) is superior to standard of care medical management (MM) in reducing the risk of recurrent embolic stroke. Patients were enrolled at 69 investigational sites between August 23, 2003 and December 28, 2011. The database for this PMA reflected data collected through August 14, 2015 and included 980 randomized patients. All patients were scheduled to return for follow-up examinations at discharge, 1 month, 6 months, 12 months, 18 months, 2 years, and annually until study termination. The primary effectiveness endpoint was the composite of recurrent nonfatal stroke, fatal ischemic stroke, and all-cause mortality. The secondary effectiveness endpoints included the absence of transient ischemic attack (TIA) and the rate of complete PFO closure (assessed by TEE bubble study) at 6 months follow-up (in the Device group only). There were two data locks for the analyses of the RESPECT trial: a May 20, 2012 initial data lock and an August 14, 2015 extended follow-up data lock. In the intention-to-treat (ITT) population, all primary endpoint events were non-fatal ischemic strokes. In the initial data lock ITT analysis, there were 25 total primary endpoint events: 9 in the Device group (rate of 0.61 per 100 patient-years) versus 16 in the MM group (rate of 1.25 per 100 patient-years), corresponding to a 50% relative risk reduction in favor of the Device group which did not achieve statistical significance (p=0.089). In the extended follow-up data lock analysis, there were 42 total primary endpoint events (18 in the Device group and 24 in the MM group) and a numerically smaller relative risk reduction (35%) compared with the initial data lock analysis in favor of the Device group. Although the difference in the rate of recurrent ischemic stroke was lower in the Device group versus the MM group in the ITT population (the pre-specified primary analysis cohort), the difference did not achieve statistical significance. The risk of device- or implantation procedure-related serious adverse events (SAEs) in patients undergoing an AMPLATZER PFO Occluder implantation procedure was 4.2% in the Device group in the RESPECT trial. There were no device- or implantation procedure-related deaths. However, it should be noted that the Device group experienced a numerically higher rate of atrial fibrillation, deep venous thrombosis, and pulmonary embolism compared to the MM group. As a condition of approval, the FDA is requiring the manufacturer to complete a study to evaluate the long-term safety and effectiveness of the AMPLATZER PFO Occluder and the effectiveness of a training program for new operators. This will be a prospective, open-label, multi-center evaluation of the AMPLATZER PFO Occluder consisting of at least 1,214 US participants that receive the device post-approval. The primary effectiveness endpoint, which is the rate of recurrent ischemic stroke through 5 years, will be compared to a performance goal (PG) of 3.9%. The primary safety endpoint, which is the cumulative incidence of device- or procedure-related serious adverse events through 30 days includes the following events: atrial fibrillation, pulmonary embolism, deep vein thrombosis, device thrombus, device erosion, device embolization, ischemic stroke (if subject was not successfully implanted with a device), hemorrhagic stroke, major bleeding requiring transfusion or surgical or endovascular intervention, vascular access site complication requiring surgical intervention, and device- or procedure-related serious adverse event leading to death. The primary safety endpoint will be compared to a PG of 4.14%. The study will enroll 1,214 subjects who will provide 84.5% and 98.5% power at a significance level of 2.5% to reject the null hypothesis for effectiveness and safety, respectively.

Knerr et al (2014) stated that limited data are available regarding the safety and effectiveness of the Gore septal occluder (GSO) for PFO closure.  These researchers evaluated the safety and effectiveness of the GORE® Septal Occluder (GSO) at 1-, 6-, and 12-month follow-up in patients with a clinical indication for PFO closure.  A total of 60 consecutive patients with an embolic event, migraine, or risk of decompression sickness were enrolled.  Trans-esophageal or trans-thoracic echocardiography and clinical follow-up were performed at 1, 6 and 12 months after implantation.  All patients received 100 mg aspirin and 75 mg clopidogrel for 6 months.  Procedures were technically successful in 98.3 % (59/60).  In 1 case, the anterior inter-atrial septal rim proved too short to allow safe GSO implantation and, instead, a different occluder was implanted.  One patient developed transient neurological symptoms during the procedure without evidence for a stroke by magnetic resonance imaging.  At 6-month follow-up, the closure rate was 86.6 % (52/60).  The complete closure rate after 1 year was 93.3 % (56/60).  Stroke, thrombus formation and atrial fibrillation (AF)/flutter occurred in 1 (1.7 %), 1 (1.7 %), and 5 (8.3 %) patients, respectively.  The authors concluded that PFO closure with the GSO is accompanied by a high technical success rate and closure rates similar to other currently used devices.  The incidence of AF was higher than reported with most other devices.  This may be a chance finding but warrants further investigation in larger trials.

Thomson et al (2014) reported procedural outcome and short-term follow-up data for the GSO, a new device for closure of PFO.  Data from 9 centers in the United Kingdom implanting the GSO device, submitted to an electronic registry for evaluation were used for analysis.  A total of 229 patients undergoing PFO closure from June 2011 to October 2012 were included.  Indications for closure were secondary prevention of paradoxical cerebral emboli (83.4 %), migraine (2.1 %), platypnea orthodeoxia (3.9 %), and other (10.5 %).  Median PFO size was 8 mm and 34 % and 39 %, respectively, had long tunnel anatomy or atrial septal aneurysms.  A GSO was successfully implanted in all cases.  A single device was used in 98 % but in 4 patients the initial device was removed and a second device required.  Procedural complications occurred in 3 % and later complications (e.g., AF, atrial ectopics, and device thrombus) in 5.7 % of cases.  All patients have undergone clinical and echocardiographic follow-up and all devices remain in position.  Early bubble studies (median 0 months) with Valsalva maneuver in 67.2 % were negative in 89 %.  The authors concluded that the GSO is an effective occlusion device for closure of PFO of all types.  Moreover, they stated that longer-term follow-up particularly to document later closure rates are needed.

Percutaneous transcatheter closure of patent ductus arteriosus (PDA) is an established procedure in the pediatric field.  In a multi-center clinical trial (n = 484, median age of the patients at catheterization was 1.8 years, with a range 0.2 to 70.7 years), Pass et al (2004) found that moderate to large PDAs can be effectively and safely closed using the Amplatzer ductal occluder, with excellent initial and 1-year results.  These authors concluded that this device should obviate the need for multiple coils or surgical intervention for these defects.  Butera et al (2004) reported that in experienced hands, percutaneous closure of moderate to large PDA in very young symptomatic children is safe, effectively closes the PDA, and solves clinical problems.  An assessment of endovascular closure of PDA conducted by the National Institute for Clinical Excellence (NICE, 2004) concluded that there is adequate evidence to support the use of this procedure.

Migraine headache (MHA) is present in 12 % of adults and has been associated with inter-atrial communications.  Azarbal et al (2005) examined the relationship between PFO or ASD with the incidence of MHA and evaluated if closure of the inter-atrial shunt in patients with MHA would result in improvement of MHA.  A sample of 89 (66 PFO/23 ASD) adult patients underwent transcatheter closure of an inter-atrial communication using the CardioSEAL (n = 22), Amplatzer PFO (n = 43), or the Amplatzer ASD (n = 24) device.  Before the procedure, MHA was present in 42 % of patients (45 % of patients with PFO and 30 % of patients with ASD).  At 3 months after the procedure, MHA disappeared completely in 75 % of patients with MHA and aura and in 31 % of patients with MHA without aura.  Of the remaining patients, 40 % had significant improvement (greater than or equal to 2 grades by the Migraine Disability Assessment Questionnaire) of MHA.  These investigators concluded that transcatheter closure of PFO or ASD results in complete resolution of MHA in 60 % of patients (75 % of patients with migraine and aura) and improvement in symptoms in 40 % of the remaining patients.  They noted that inter-atrial communications may play a role in the etiology of MHA either through paradoxic embolism or humoral factors that escape degradation in bypassing the pulmonary circulation.  The authors stated that a randomized trial is needed to ascertain if transcatheter closure of inter-atrial shunts is an effective treatment for MHA compared with medical therapy.

Reisman et al (2005) examined the effects of transcatheter PFO closure on the frequency of MHA in patients with paradoxical cerebral embolism.  A total of 162 consecutive patients underwent transcatheter PFO closure for prevention of recurrent cryptogenic stroke or transient ischemic attack.  A 1-year retrospective analysis of migraine symptoms before and after PFO closure was performed.  Active MHA was present in 35 % (57 of 162) of patients, and 68 % (39 of 57) experienced migrainous aura; 50 patients were available for analysis at 1 year.  Complete resolution of migraine symptoms occurred in 56 % (28 of 50) of patients, and 14 % (7 of 50) of patients reported a significant greater than or equal to 50 %) reduction in MHA frequency.  Patients reported an 80 % reduction in the mean number of MHA episodes per month after PFO closure (6.8 +/- 9.6 before closure versus 1.4 +/- 3.4 after closure, p < 0.001).  Results were independent of completeness of PFO closure at 1 year.  These researchers concluded that in patients with paradoxical cerebral embolism, MHA are more frequent than in the general population, and transcatheter closure of the PFO results in complete resolution or marked reduction in frequency of MHA.

In an editorial that accompanied the studies by Azarbal et al (2005) as well as Reisman et al (2005), Tsimikas (2005) stated that "before PFO closure can be proposed for migraine, a healthy skepticism should be in place, considering the high frequency of both migraine and PFO in the general population.  It will be necessary to obtain definitive evidence with randomized controlled trials and to define the appropriate clinical indications".

Spies and Schrader (2006) stated that reviewed the epidemiology and pathophysiology of MHA, its association with PFO, and the impact of PFO closure on MHA.  These researchers noted that primarily retrospective case-control studies demonstrated a link between PFO closure and improvement of MHA.  Few prospective data confirm the initial results.  However, the only randomized, controlled trial finished to date analyzing the effect of PFO closure on MHA failed to reach its primary outcome of resolution of migraine following the intervention.  The authors concluded that evidence of a benefit on MHA following PFO closure is not convincing, but certainly intriguing.  With currently ongoing trials, more information related to this topic can be expected.

Diener et al (2007) stated that although the results of uncontrolled observational studies suggest the PFO closure may have a beneficial effect on migraine frequency, a large randomized trial failed to support such a conclusion.  Until there is more evidence from ongoing large controlled trials, PFO closure should not be performed in clinical practice for the prophylaxis of migraine.

In a prospective, multi-center, double-blind, sham-controlled study, Dowson et al (2008) examined the effectiveness of PFO closure with the STARFlex septal repair implant to resolve refractory migraine headache.  Patients who suffered from migraine with aura, experienced frequent migraine attacks, had previously failed greater than or equal to 2 classes of prophylactic treatments, and had moderate or large right-to-left shunts (RLS) consistent with the presence of a PFO were randomized to transcatheter PFO closure with the STARFlex implant or to a sham procedure.  Patients were followed-up for 6 months.  The primary efficacy endpoint was cessation of migraine headache 91 to 180 days after the procedure.  In total, 163 of 432 patients (38 %) had RLS consistent with a moderate or large PFO.  A total of 147 patients were randomized.  No significant difference was observed in the primary endpoint of migraine headache cessation between implant and sham groups (3 of 74 versus 3 of 73, respectively; p = 0.51).  Secondary endpoints also were not achieved.  On exploratory analysis, excluding 2 outliers, the implant group demonstrated a greater reduction in total migraine headache days (p = 0.027).  As expected, the implant-arm experienced more procedural serious adverse events.  All events were transient.  The authors concluded that this trial confirmed the high prevalence of RLS in patients with migraine with aura.  Although no significant effect was found for primary or secondary endpoints, the exploratory analysis supports further investigation.

Rundek et al (2008) examined the association between PFO and migraine among stroke-free individuals in an elderly, multi-ethnic cohort.  As a part of the ongoing Northern Manhattan Study (NOMAS), 1,101 stroke-free subjects were assessed for self-reported history of migraine.  The presence of PFO was assessed by transthoracic echocardiography.  The mean age of the group was 69 +/- 10 years; 58 % were women; 48 % were Caribbean Hispanic, 24 % were white, 26 % were black, and 2 % were another race/ethnicity.  The prevalence of self-reported migraine was 16 % (13 % migraine with aura).  The prevalence of PFO was 15 %.  Migraine was significantly more frequent among younger subjects, women, and Hispanics.  The prevalence of PFO was not significantly different between subjects who had migraine (26/178, or 14.6 %) and those who did not (138/923, or 15.0 %; p = 0.9).  In an adjusted multi-variate logistic regression model, the presence of PFO was not associated with increased prevalence of migraine (odds ratio 1.01, 95 % confidence interval [CI]: 0.63 to 1.61).  Increasing age was associated with lower prevalence of migraine in both subjects with a PFO (odds ratio [OR] 0.94, 95 % CI: 0.90 to 0.99 per year) and those without PFO (odds ratio 0.97, 95 % CI: 0.95 to 0.99 per year).  The observed lack of association between PFO and migraine (with or without aura) was not modified by diabetes mellitus, hypertension, cigarette smoking, or dyslipidemia.  The authors concluded that in this multi-ethnic, elderly, population-based cohort, PFO detected with transthoracic echocardiography and agitated saline was not associated with self-reported migraine.  The causal relationship between PFO and migraine remains uncertain, and the role of PFO closure among unselected patients with migraine remains questionable.  In an editorial that accompanied the afore-mentioned article, Kurth et al (2008) stated that detection of PFO or PFO closure should not be recommended to patients who only have migraine.

In a review on dynamic optimization of chronic migraine treatment, Mathew (2009) stated that it is premature to recommend device-based treatments (e.g., occipital nerve stimulation, vagal nerve stimulation, and PFO closure) for chronic migraine because clinical trials are in the preliminary stages.  Furthermore, additional studies are needed to evaluate if RLS-associated migraine can be clinically identified.

Garg and colleagues (2010) evaluated the assumption of an association between MHA and the presence of PFO.  These investigators conducted a case-control study to assess the prevalence of PFO in subjects with and without migraine.  Case subjects were those with a history of migraine (diagnosed by neurologists at a specialty academic headache clinic).  Control subjects were healthy volunteers without migraine 1:1 matched on the basis of age and sex with case subjects.  Presence of PFO was determined by transthoracic echocardiogram with second harmonic imaging and transcranial Doppler ultrasonography during a standardized procedure of infused agitated saline contrast with or without Valsalva maneuver and a review of the results by experts blinded to case-control status.  Patent foramen ovale was considered present if both studies were positive.  Odds ratios were calculated with conditional logistic regression in the matched cohort (n = 288).  In the matched analysis, the prevalence of PFO was similar in case and control subjects (26.4 % versus 25.7 %; OR 1.04, 95 % CI: 0.62 to 1.74, p = 0.90).  There was no difference in PFO prevalence in those with migraine with aura and those without (26.8 % versus 26.1 %; OR 1.03, 95 % CI: 0.48 to 2.21, p = 0.93).  The authors concluded that they found no association between MHA and the presence of PFO in this large case-control study nor any association between migraine severity and PFO size.

In an editorial that accompanied the afore-mentioned study, Gersony and Gersony  (2010) stated that "[a]lthough in rare instances, exceptions may be proposed, closure of PFO for migraine should not be considered standard medical practice".

Rigatelli and Ronco (2010) provided a comprehensive review of the main concepts about PFO management.  Therapy is a controversial issue, since data on these patients are variable and accepted guidelines are missing.  Recurrent strokes are the most diffuse and accepted indication for transcatheter closure of PFO, but severe refractory migraine with aura, unexplained oxygen desaturation, orthodeoxia-platypnea (related to aortic elongation, allowing significant right-to-left shunt), and other conditions have been suggested to benefit from PFO closure.  Different devices and techniques have been proposed for this procedure, mainly depending on operator experience and preferences.  The authors concluded that PFO management is still a debated field: indications, pathophysiology and ideal closure techniques remain to be fully clarified and investigated before considering PFO closure a routine procedure.

Butera et al (2010) examined the role of transcatheter closure of PFO on the occurrence of migraine.  BioMedCentral, Google Scholar, and PubMed from January 2000 to December 2008 were systematically searched for pertinent clinical studies.  Secondary sources were also used.  Secondary prevention studies of transcatheter closure for PFO were required to include at least more than 10 patients followed for more than 6 months.  The primary end-point was the rate of cured or significantly improved migraine after percutaneous PFO closure.  After excluding 637 citations, these investigators included a total of 11 studies for a total of 1,306 patients.  Forty percent of the subjects included suffered from migraine, while most had a previous history of transient ischemic attack/stroke and were investigated retrospectively.  Quantitative synthesis showed that complete cure of migraine in 46 % (95 % CI: 25 to 67 %), while resolution or significant improvement of migraine occurred in 83 % (95 % CI: 78 to 88 %) of cases.  The authors concluded that notwithstanding the limitations inherent in the primary studies, this systematic review suggested that a significant group of subjects with migraine, in particular if treated after a neurological event, may benefit from percutaneous closure of their PFO.  However, the authors notedthat many questions remain unsolved.

Bendaly et al (2011) reported the mid-term results of perventricular device closure of muscular VSD (MVSD) at a single institution.  Between January 2004 and December 2009, 6 patients underwent attempted perventricular MVSD closure.  Mean age was 9.8 +/- 9.1 months; mean weight was 7.2 +/- 3.7 kg.  In 5 patients, closure was successful without use of bypass.  In 1 patient, the device embolized to the left ventricle after release and patch closure of the MVSD was performed on cardiopulmonary bypass.  The mean interval from the procedure to the most recent echocardiogram for the patients with successful perventricular closure was 39.8 +/- 25.2 months.  Three patients demonstrated no residual shunt at the last echocardiogram.  Two patients had mild, hemodynamically insignificant shunting; 1 had a left ventricular pseudoaneurysm that was embolized during repeat catheterization.  The authors concluded that perventricular closure of MVSDs is attractive because it overcomes the limitations of surgery and catheterization.  Additionally, it spares the need for cardiopulmonary bypass and its comorbidities.  In some instances, however, successful deployment of the device is not possible.  These mid-term results demonstrated overall success but identify possible complications that are not immediately identified in the short-term.

Zhang et al (2012) examined the feasibility of transthoracic echocardiographic (TTE) guidance for minimally invasive periventricular device closure of peri-membranous VSDs.  From June 2011 to September 2011, these researchers enrolled 18 young children with peri-membranous VSDs to receive minimally invasive device closure in their hospital.  All of the patients were examined by TTE to determine the VSD morphology, diameter, and rims.  During intra-operative device closure, real-time bedside TTE alone was used to guide device implantation.  Device implantation using TTE guidance was successful in 16 patients.  Symmetric devices were used in 14 patients, and asymmetric devices were used in 2 patients.  Only 1 patient experienced mild aortic regurgitation, and there were no instances of residual shunt, significant arrhythmias, thromboembolism, or device displacement.  Two patients were transferred to surgical closure, 1 due to residual shunting and the other as a result of unsuccessful wire penetration of the VSD gap.  The authors concluded that these findings indicated that TTE-guided VSD closure is feasible in young children, although a longer follow-up may be needed to document the long-term success.

Irwin and Bay (2012) stated that migraine with aura has been linked with PFO.  A recent meta-analysis suggested an association, but the one prospective population study did not.  The well-publicized and controversial MIST Trial is the only randomized trial of device closure in patients with migraines yet published, and failed to demonstrate a convincing benefit from device closure.  Other conditions such as platypnea-orthodeoxia syndrome and prevention of decompression sickness in divers, may justify device closure.  Evidence for a role of PFO in the etiology of cryptogenic stroke and migraine is contradictory.  The authors concluded that it is possible that some patients might benefit from PFO closure, but there is scant evidence of sufficient quality to justify routine PFO closure in either group.

Rao (2013) discussed how and when to treat the most common acyanotic congenital heart defects (CHD).  The indications and timing of intervention are decided by the severity of the lesion.  Transcatheter closure methods are currently preferred for ostium secundum ASDs; the indications for occlusion are right ventricular volume over-load by echocardiogram.  Ostium primum, sinus venosus, and coronary sinus ASDs require surgical closure.  For all ASDs elective closure around age 4 to 5 years is recommended or as and when detected beyond that age.  For the more common peri-membraneous VSDs of large size, surgical closure should be performed prior to 6 to 12 months of age.  Muscular VSDs may be closed with devices.  Patent ductus arteriosus may be closed with Amplatzer duct occluder if they are moderate-to-large and Gianturco coils if they are small.  Surgical and video-thoracoscopic closure are the available options at some centers.  In the presence of pulmonary hypertension appropriate testing to determine suitability for closure should be undertaken.  An UpToDate review on “Management of atrial septal defects in adults” (Connolly, 2012) states that “Surgery is required for closure of ostium primum ASD, sinus venosus ASD, and coronary sinus septal defects.

Zhu and colleagues (2013) investigated perventricular device closure as a salvage technique in pediatric patients who had post-operative residual muscular ventricular septal defects.  From February 2009 through June 2011, a total of 14 pediatric patients at the authors’ hospital had residual muscular ventricular septal defects after undergoing surgical repair of complex congenital heart defects.  Ten patients met selection criteria for perventricular device closure of the residual defects: significant left-to-right shunting (Qp/Qs greater than 1.5) or substantial hemodynamic instability (a defect greater than or equal to 2 mm in size).  The patients' mean age was 20.4 ± 13.5 months, and their mean body weight was 10 ± 3.1 kg.  The median diameter of the residual defects was 4.2 mm (range of 2.5 to 5.1 mm).  These investigators deployed a total of 11 SQFDQ-II Muscular VSD occluders (Shanghai Shape Memory Alloy Co., Ltd.; Shanghai, China) in the 10 patients, in accord with conventional techniques of perventricular device closure.  The mean procedural duration was 31.1 ± 9.1 mins.  These researchers recorded the closure and complication rates peri-operatively and during a 12-month follow-up period.  Complete closure was achieved in 8 patients; 2 patients had persistent trivial residual shunts.  No deaths, conduction block, device embolism, or other complications occurred throughout the study period.  The authors concluded that perventricular device closure is a safe, effective salvage treatment for post-operative residual muscular ventricular septal defects in pediatric patients.  Moreover, they stated that long-term studies with larger cohorts might further confirm this method's feasibility.

Furthermore, an UpToDate review on “Management of isolated ventricular septal defects in infants and children” (Dummer and Fulton, 2014) does not mention the use of perventricular closure of ventricular septal defects as a therapeutic option.

Hakeem et al (2013) stated that controversy persists regarding the management of patients with cryptogenic stroke and PFO.  These researchers performed a meta-analysis of RCTs comparing PFO closure with medical therapy.  A prospective protocol was developed and registered using the following data sources: PubMed, Cochrane Register of Controlled Trials, conference proceedings, and Internet-based resources of clinical trials.  Primary analyses were performed using the intention-to-treat method.  A total of 3 randomized trials comparing percutaneous PFO closure versus medical therapy for secondary prevention of embolic neurological events formed the data set.  Baseline characteristics were similar.  During long-term follow-up, the pooled incidence of the primary end-point (composite of stroke, death, or fatal stroke) was 3.4 % in the PFO closure arm and 4.8 % in the medical therapy group [RR 0.7 (0.48 to 1.06); p = 0.09].  The incidence of recurrent neurological events (secondary end-point) was 1.7 % for PFO closure and 2.7 % for medical therapy [RR 0.66 (0.35 to 1.24), p = 0.19].  There was no difference in terms of death or adverse events between the 2 groups.  The authors concluded that while this meta-analysis of RCTs demonstrated no statistical significance in comparison to medical therapy, there was a trend towards overall improvement in outcomes in the PFO closure group.

Ntaios et al (2013) examined if PFO closure is superior to medical therapy in preventing recurrence of cryptogenic ischemic stroke or TIA.  These investigators searched PubMed for randomized trials that compared PFO closure with medical therapy in cryptogenic stroke/TIA using the items: "stroke or cerebrovascular accident or TIA" and "patent foramen ovale or paradoxical embolism" and "trial or study".  Among 650 potentially eligible articles, 3 were included including 2,303 patients.  There was no statistically significant difference between PFO-closure and medical therapy in ischemic stroke recurrence (1.91 % versus 2.94 %, respectively, OR: 0.64, 95 % CI: 0.37 to 1.10), TIA (2.08 % versus 2.42 %, respectively, OR: 0.87, 95 % CI: 0.50 to 1.51) and death (0.60 % versus 0.86 %, respectively, OR: 0.71, 95 % CI: 0.28 to 1.82).  In subgroup analysis, there was significant reduction of ischemic strokes in the AMPLATZER PFO Occluder arm versus medical therapy (1.4 % versus 3.04 %, respectively, OR: 0.46, 95 % CI: 0.21 to 0.98, relative-risk-reduction: 53.2 %, absolute-risk-reduction: 1.6 %, number-needed-to-treat: 61.8) but not in the STARFlex device (2.7 % versus 2.8 % with medical therapy, OR: 0.93, 95 % CI: 0.45 to 2.11).  Compared to medical therapy, the number of patients with new-onset AF was similar in the AMPLATZER PFO Occluder arm (0.72 % versus 1.28 % respectively, OR: 1.81, 95 % CI: 0.60 to 5.42) but higher in the STARFlex device (0.64 % versus 5.14 %, respectively, OR: 8.30, 95 % CI: 2.47 to 27.84).  The authors concluded that this meta-analysis did not support PFO closure for secondary prevention with unselected devices in cryptogenic stroke/TIA.  In subgroup analysis, selected closure devices may be superior to medical therapy without increasing the risk of new-onset AF.  However, they stated that this observation should be confirmed in further trials using inclusion criteria for patients with high likelihood of PFO-related stroke recurrence.

Udell and colleagues (2014) noted that PFO might be a risk factor for unexplained (cryptogenic) stroke or TIA.  These researchers determined the safety and effectiveness of transcatheter PFO closure compared with anti-thrombotic therapy for secondary prevention of cerebrovascular events among patients with cryptogenic stroke.  These investigators performed a systematic review and meta-analysis of MedLine and Embase (from inception to March 2013) for RCTs that compared transcatheter PFO closure with medical therapy in subjects with cryptogenic stroke.  Data were independently extracted on trial conduct quality, baseline characteristics, efficacy, and safety events from published articles and appendices.  Risk ratios and 95 % CIs for the composite of stroke or TIA, and adverse cardiovascular events including AF/flutter were constructed.  Three RCTs of 2,303 subjects with previous stroke, TIA, or systemic arterial embolism (mean age of 45.7 years; 47.3 % women; mean follow-up, 2.6 years) were included.  Patent foramen ovale closure did not significantly reduce the risk of recurrent stroke/TIA (3.7 % versus 5.2 %; RR, 0.73; 95 % CI: 0.50 to 1.07; p = 0.10); however, an increased risk of incident AF/flutter was detected (3.8 % versus 1.0 %; RR, 3.67; 95 % CI: 1.95 to 6.89; p < 0.0001).  No significant heterogeneity was detected for any end-point among subgroups of patients stratified according to age, sex, index cardiovascular event, device type, inter-atrial shunt size, and presence of an atrial septal aneurysm (all p interactions ≥ 0.09).  The authors concluded that meta-analysis of RCTs that assessed transcatheter PFO closure for secondary prevention of cerebrovascular events in subjects with cryptogenic stroke did not demonstrate benefit compared with anti-thrombotic therapy, and suggested potential risks.

An UpToDate review on “Cryptogenic stroke” (Prabhakaran and Elkind, 2014) states that “Atrial septal abnormalities, including patent foramen ovale, atrial septal aneurysm and atrial septal defect, have been associated with cryptogenic stroke, although the strength and clinical significance of this association is uncertain …. While retrospective data suggest that there is an increased prevalence of patent foramen ovale (PFO) and atrial septal aneurysm (ASA) in patients who have had a cryptogenic stroke, particularly in patients < 55 years old, population-based studies suggest that PFO and large PFO are not independent risk factors for stroke.  In addition, prospective data suggest 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 …. There is a high degree of uncertainty regarding the optimal management of patent foramen ovale (PFO), atrial septal aneurysm (ASA), and atheromatous aortic disease.  The management of specific coagulation disorders and the role of hematologic testing are also unclear at the moment.  Therefore, for the majority of patients with cryptogenic stroke, antiplatelet therapy is recommended.  Selected patients might benefit from anticoagulant therapy”.

Hongxin et al (2015) noted that it is infeasible to occlude a doubly committed juxta-arterial ventricular septal defect (DCVSD) percutaneously.  The previous perventricular device closure technique was performed through an inferior median sternotomy approach.  These researchers evaluated the feasibility, safety and effectiveness of perventricular device closure of DCVSDs through a left para-sternal approach.  A total of 62 patients, with the DCVSD of less than 6 mm in diameter, were enrolled in this study.  The pericardial space was approached through a left para-sternal mini-incision without entering into the pleural space.  Two parallel purse-string sutures were placed on the right ventricular outflow tract for puncture.  Under trans-esophageal echocardiographic guidance, a new delivery sheath loaded with the device was inserted into the right ventricle and advanced through the defect into the left ventricle.  The device, connected with a device stay suture, was deployed subsequently.  Successful device closure of the defects was achieved in 58/62 patients (94 %).  The DCVSD failed to close in 4 (6 %) patients due to device-related aortic regurgitation and device migration.  The mean DCVSD diameter was 3.4 ± 1.0 mm (range of 2.0 to 6.0 mm).  The implanted device size was 5.2 ± 1.3 mm (range of 4 to 8 mm); 44 out of 58 patients (76 %) was implanted with an eccentric occluder.  The mean intra-cardiac manipulation time was 14 ± 13 mins (range of 2 to 60).  The procedure time was 66 ± 15 mins (range of 42 to 98).  During the follow-up period of 180 to 1860 (median of 880) days, new mild pulmonary regurgitation occurred in 2 patients.  No other device-related complications were found.  The complete closure rate was 95 % at discharge, 98 % at 1-, 6- and 12-month, 96 % at 2-year, and 100 % at 3-year follow-up.  The authors concluded that perventricular device closure of a DCVSD through a left para-sternal approach is feasible, safe, and effective in selected patients.  These mid-term results need to be validated by long-term follow-up studies.

In a review on “Current topics in surgery for multiple ventricular septal defects”, Yoshimura et al (2016) discussed several topics, including the sandwich technique, the trans-atrial re-endocardialization technique, the limited apical left ventriculotomy approach and device closure.  The sandwich technique was introduced for the closure of muscular VSD by sandwiching the septum between 2 felt patches placed in the left and right ventricle.  This technique requires neither the transection of muscular trabeculae nor ventriculotomy.  Although the sandwich technique has resulted in the improvement of surgical outcomes, cases of post-operative cardiac dysfunction have been reported.  Multiple smaller VSDs have been closed with trans-atrial re-endocardialization.  Septal dysfunction may be avoided through this technique, in which the septal trabeculae are approximated in 2 layers of superficial, endocardial running sutures.  Recently, a number of reports have recommended a limited apical left ventriculotomy approach.  With this technique, a much shorter incision of around 1 cm at the apex of the left ventricle may be sufficient for achieving the complete closure of apical muscular VSDs.  The transcatheter or perventricular device closure of muscular VSDs has increasingly been performed with good results.  However, the authors stated that although favorable early and mid-term results of device closure have been reported, this method is not always safer or less invasive than surgical closure.  They stated that long-term evaluations should be performed to determine whether the right and left ventricular functions are affected by treatment with relatively large devices in the heart.

Closure of Patent Foramen Ovale for Cryptogenic Stroke

Mas and associates (2017) stated that studies of PFO closure to prevent recurrent stroke have been inconclusive.  These investigators examined if patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anti-coagulation, as compared with anti-platelet therapy.  In a multicenter, randomized, open-label trial, these researchers assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term anti-platelet therapy (PFO closure group), anti-platelet therapy alone (anti-platelet-only group), or oral anti-coagulation (anticoagulation group) (randomization group 1).  Patients with contraindications to anti-coagulants or to PFO closure were randomly assigned to the alternative non-contraindicated treatment or to anti-platelet therapy (randomization groups 2 and 3).  The primary outcome was occurrence of stroke.  The comparison of PFO closure plus anti-platelet therapy with anti-platelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anti-coagulation with anti-platelet therapy alone was performed with combined data from randomization groups 1 and 3.  A total of 663 patients underwent randomization and were followed for a mean (± SD) of 5.3 ± 2.0 years.  In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the anti-platelet-only group (HR, 0.03; 95 % CI: 0 to 0.26; p < 0.001).  Procedural complications from PFO closure occurred in 14 patients (5.9 %).  The rate of AF was higher in the PFO closure group than in the anti-platelet-only group (4.6 % versus 0.9 %, p = 0.02).  The number of SAEs did not differ significantly between the treatment groups (p = 0.56).  In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anti-coagulants and in 7 of 174 patients assigned to anti-platelet therapy alone.  The authors concluded that among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with anti-platelet therapy than among those assigned to anti-platelet therapy alone; PFO closure was associated with an increased risk of AF.

Saver and colleagues (2017) noted that whether closure of a PFO reduces the risk of recurrence of ischemic stroke in patients who have had a cryptogenic ischemic stroke is unknown.  In a multi-center, randomized, open-label trial, with blinded adjudication of end-point events, these researchers randomly assigned patients 18 to 60 years of age who had a PFO and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group).  The primary efficacy end-point was a composite of recurrent non-fatal ischemic stroke, fatal ischemic stroke, or early death after randomization.  The results of the analysis of the primary outcome from the original trial period have been reported previously; the current analysis of data from the extended follow-up period was considered to be exploratory.  These investigators enrolled 980 patients (mean age of 45.9 years) at 69 sites.  Patients were followed for a median of 5.9 years.  Treatment exposure in the 2 groups was unequal (3,141 patient-years in the PFO closure group versus 2,669 patient-years in the medical-therapy group), owing to a higher drop-out rate in the medical-therapy group.  In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval [CI], 0.31 to 0.999; P=0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (HR, 0.38; 95 % CI, 0.18 to 0.79; p = 0.007).  Venous thromboembolism (which comprised events of pulmonary embolism [PE] and deep-vein thrombosis [DVT]) was more common in the PFO closure group than in the medical-therapy group.  The authors concluded that among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up.

Sondergaard and co-workers (2017) stated that the effectiveness of closure of a PFO in the prevention of recurrent stroke after cryptogenic stroke is uncertain.  These researchers examined the effect of PFO closure combined with anti-platelet therapy versus anti-platelet therapy alone on the risks of recurrent stroke and new brain infarctions.  In this multi-national trial involving patients with a PFO who had had a cryptogenic stroke, these investigators randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus anti-platelet therapy (PFO closure group) or to receive anti-platelet therapy alone (anti-platelet-only group).  Imaging of the brain was performed at the baseline screening and at 24 months.  The co-primary end-points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24-month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging.  These researchers enrolled 664 patients (mean age of 45.2 years), of whom 81 % had moderate or large inter-atrial shunts.  During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4 %) in the PFO closure group and in 12 of 223 patients (5.4 %) in the anti-platelet-only group (HR, 0.23; 95 % CI: 0.09 to 0.62; p = 0.002).  The incidence of new brain infarctions was significantly lower in the PFO closure group than in the anti-platelet-only group (22 patients [5.7 %] versus 20 patients [11.3 %]; RR, 0.51; 95 % CI: 0.29 to 0.91; p = 0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (p = 0.97); SAEs occurred in 23.1 % of the patients in the PFO closure group and in 27.8 % of the patients in the anti-platelet-only group (p = 0.22).  Serious device-related AEs occurred in 6 patients (1.4 %) in the PFO closure group, and AF occurred in 29 patients (6. %) after PFO closure.  The authors concluded that among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with anti-platelet therapy than among those assigned to anti-platelet therapy alone; however, PFO closure was associated with higher rates of device complications and AF.

In an editorial that accompanied the afore-mentioned studies, Ropper (2017) stated that “The evidence for causation of embolic stroke in any given person is, of course, circumstantial (e.g., atrial fibrillation or carotid stenosis), and it seems reasonable that the presence of a PFO and a sizable interatrial shunt should similarly no longer result in the categorization of a stroke as cryptogenic.  One conclusion from the six trials described above is that the potential benefit from closure is determined on the basis of the positive characteristics of the PFO rather than on the basis of exclusionary factors that make a stroke cryptogenic.  Restricting PFO closure entirely to patients with high-risk characteristics of the PFO may perhaps be too conservative, but the boundaries of the features that support the procedure are becoming clearer”.

Messe and colleagues (2020) updated the 2016 American Academy of Neurology (AAN) practice advisory for patients with stroke and patent foramen ovale (PFO).  The guideline panel followed the AAN 2017 guideline development process to systematically review studies published through December 2017 and formulated recommendations.

• In patients being considered for PFO closure, clinicians should ensure that an appropriately thorough evaluation has been performed to rule out alternative mechanisms of stroke (level B).
• In patients with a higher risk alternative mechanism of stroke identified, clinicians should not routinely recommend PFO closure (level B).
• Clinicians should counsel patients that having a PFO is common; that it occurs in about 1 in 4 adults in the general population; that it is difficult to determine with certainty whether their PFO caused their stroke; and that PFO closure probably reduces recurrent stroke risk in select patients (level B).
• In patients younger than 60 years with a PFO and embolic-appearing infarct and no other mechanism of stroke identified, clinicians may recommend closure following a discussion of potential benefits (absolute recurrent stroke risk reduction of 3.4 % at 5 years) and risks (peri-procedural complication rate of 3.9 % and increased absolute rate of non-periprocedural atrial fibrillation of 0.33 % per year) (level C).
• In patients who opt to receive medical therapy alone without PFO closure, clinicians may recommend an antiplatelet medication such as aspirin or anticoagulation (level C).

Transcatheter Device Closure of Peri-Membranous Ventricular Septal Defect

Santhanam and colleagues (2018) noted that while transcatheter device closure of VSDs is gaining popularity, concerns remain about AEs; especially heart block in peri-membranous VSDs (pmVSDs).  In a meta-analysis, these researchers examined outcomes of transcatheter device closure of pmVSDs.  A PubMed and Scopus search for studies in English on device closure of pmVSDs published till end-February 2017 was performed.  Exclusion criteria included case series already included in multi-center studies, sample size of less than 5, and VSD acquired following myocardial infarction (MI).  Pooled estimates of success and complications was obtained using the random effects model.  A total of 54 publications comprising 6,762 patients with pmVSDs were included.  The mean age of patients ranged from 1.6 to 37.4 years.  The pooled estimate of successful device implantation was 97.8 % (95 % CI: 96.8 to 98.6).  The most common complication was residual shunt (15.9 %; 95 % CI: 10.9 to 21.5).  Other complications included arrhythmias (10.3 %; 95 % CI: 8.3 to 12.4) and valvular defects (4.1 %; 95 % CI: 2.4 to 6.1).  The pooled estimate of complete atrio-ventricular block (cAVB) was 1.1 % (95 % CI: 0.5 to 1.9).  The authors concluded that the findings of this meta-analysis suggested that device closure of pmVSDs was a safe and effective procedure.  The complication of cAVB was low but significant.  The risk is expected to further reduce with newer devices which are less stiff with improved profiles.  They stated that further studies validating this will be useful in formulating guidelines for device closure of pmVSDs.

Li and colleagues (2020) stated that treatments for pmVSD mainly include conventional surgical repair (CSR), transcatheter device closure (TDC), and periventricular device closure (PDC).  These researchers carried out a network meta-analysis to compare the 3 approaches in patients with pmVSD.  They searched for comparative studies on device closure and conventional repair for pmVSD to April 2020.  A network meta-analysis was carried out under the frequentist frame with RR and 95 % CI.  The main outcome was the procedural success rate.  Additional outcomes were post-operative complications, including residual shunt, intra-cardiac conduction block, valvular insufficiency, incision infection, and pericardial effusion.  A total of 24 studies of 8,113 patients were included in the comparisons.  The pooled estimates of success rate favored the CSR compared with the PDC.  No significant differences of success rate were found in the TDC versus CSR and the PDC versus TDC.  The pooled estimates of incidences of the residual shunt, new tricuspid regurgitation, incision infection, and pericardial effusion favored the PDC compared with the CSR.  There were no significant differences between the PDC and TDC approaches in all outcomes except new aortic regurgitation.  The authors concluded that the PDC technique not only reduced the risk of significant complications compared with the CSR, but also produced non-inferior results compared with the TDC in selected pmVSD patients.  The PDC technique appeared to be a safe and effective option for selected patients with pmVSD.

The authors stated that this study had several drawbacks.  First, most studies were from China, and this might have resulted in regional bias.  Second, some included studies involving different design and patients with different VSD types might lead to heterogeneity.  It was difficult to segregate different VSD types in some studies.  To incorporate heterogeneity in treatment effects, these researchers used random-effects model and excluded studies reported patients with unclear or other types of VSD.  Third, the follow-up intervals in different studies were different and no more than 5 years.  Studies with long-term follow-up are needed.  Fourth, because of the limited number of 3-arm studies, many pooled estimates of the PDC versus TDC were just from indirect comparison without the test of inconsistency.

Transcatheter Closure of Patent Foramen Ovale to Prevent Stroke Recurrence in Patients with Otherwise Unexplained Ischemic Stroke

Mas and colleagues (2019) noted that unlike previous RCTs, recent trials and meta-analyses have shown that transcatheter closure of PFO reduces stroke recurrence risk in young and middle-aged adults with an otherwise unexplained PFO-associated ischemic stroke.  These investigators produced an expert consensus on the role of transcatheter PFO closure and anti-thrombotic drugs for secondary stroke prevention in patients with PFO-associated ischemic stroke.  A total of 5 neurologists and 5 cardiologists with extensive experience in the relevant field were nominated by the French Neurovascular Society and the French Society of Cardiology to make recommendations based on evidence from RCTs and meta-analyses.  The experts recommended that any decision concerning treatment of patients with PFO-associated ischemic stroke should be taken after neurological and cardiological evaluation, bringing together the necessary neurovascular, echocardiography and interventional cardiology expertise.  Transcatheter PFO closure is recommended in patients fulfilling all the following criteria: age of 16 to 60 years; recent (less than or equal to 6 months) ischemic stroke; PFO associated with atrial septal aneurysm (greater than 10 mm) or with a right-to-left shunt of greater than 20 microbubbles or with a diameter of greater than or equal to 2 mm; PFO felt to be the most likely cause of stroke after thorough etiological evaluation by a stroke specialist.  Long-term oral anti-coagulation may be considered in the event of contraindication to or patient refusal of PFO closure, in the absence of a high bleeding risk.  After PFO closure, dual anti-platelet therapy with aspirin (75 mg/day) and clopidogrel (75 mg/day) is recommended for 3 months, followed by monotherapy with aspirin or clopidogrel for greater than or equal to 5 years.  The authors concluded that although a big step forward that will benefit many patients has been taken with recent trials, many questions remain unanswered.  These researchers stated that pending results from further studies, decision-making regarding management of patients with PFO-associated ischemic stroke should be based on a close coordination between neurologists / stroke specialists and cardiologists.

Nit-Occlud Lê VSD Coil for Transcatheter Closure of a Peri-Membranous Ventricular Septal Defect

In a single-center study, El Shedoudy and El-Doklah (2019) examined the safety, efficacy and follow-up results of transcatheter closure of VSD using Nit-Occlud Lê VSD Coil.  Between January 2012 and December 2013 in the cardiology department, Tanta University Hospital, Tanta, Egypt, a total of 80 patients underwent percutaneous VSD closure using Nit-Occlud Lê VSD Coil.  Early and mid- term follow-up was carried out for 3 years, follow-up was concluded in 2016.  The mean age of patients was 5.34 ± 3 years, and their mean weight was 17.24 ± 8.17 kg.  Overall, 77 of 80 patients had peri-membranous VSD (pmVSD) with aneurysmal tissue; 8 had multiple RV exits, 14 had deficient aortic rim, 2 had high outlet muscular, and 1 had Gerbode defect.  The procedure was successful in 98.75 % of patients, and was aborted in 1 patient because of the development of complete heart block and the coil had to be removed.  The mean procedure time was 104.98 ± 9.50 mins.  The mean fluoroscopy time was 30.58 ± 2.79 mins.  The immediate complete occlusion rate was 62 %, which increased to 82.3 % on the 2nd day, and 94.9 % by the 3rd month, and 97.5 % by 1 year.  There was a significant decrease in mitral incompetence after 6 months of follow-up (p = 0.002), and only 1 patient had trivial aortic incompetence prior to the procedure that remained the same during follow-up period.  The authors concluded that the use of Nit-Occlud Lê VSD-Coil to close VSD was safe and feasible in VSDs with various morphology.  The main drawbacks of this study were its retrospective, single-center design.  These researchers stated that larger, prospective, and perhaps randomized multi-center studies are needed.

Houeijeh and associates (2020) stated that transcatheter pmVSD closure remains challenging and is seldom used in France given the risk of AVB; and pmVSD closure with the Nit-Occlud Lê VSD coil was recently introduced in France as an alternative to occluder devices.  In a multi-center study, these researchers examined the safety and feasibility of pmVSD closure with the Nit-Occlud Lê VSD coil.  All consecutives cases of pmVSD closure with the Nit-Occlud Lê VSD coil in 20 tertiary French centers were included between January 2015 and December 2018.  Among 46 procedures in 5 centers, indications for pmVSD closure were left ventricle (LV) over-load (76.1 %), exertional dyspnea (17.4 %), history of infective endocarditis (4.3 %) and mild pulmonary hypertension (2.2 %).  The median (inter-quartile range [IQR]) age of the patients was 13.9 (5.7 to 31.8) years.  Aneurismal tissue was identified in 91.3 % of patients; VSD median (IQR) size was 8 (7 to 10) mm on the LV side and 5 (4 to 6) mm on the RV side. Implantation was successful in 40 patients (87.0 %; 95 % CI: 73.7 to 95.1 %).  Severe complications occurred in 6 patients (13.0 %, 95 % CI: 4.9 to 26.3 %), mainly severe hemolysis (8.7 %, 95 % CI: 2.4 to 20.8 %); 1 aortic valve lesion required surgical aortic valvuloplasty.  Occurrence of severe complications was significantly related to the presence of hemolysis (p = 0.001), residual shunt (p = 0.007) and multi-exit VSD (p = 0.005).  Residual shunt was observed in 40 % of cases with the implanted device shortly after closure and 15 % after a median follow-up of 27 months.  No immediate or delayed device embolization or cAVB was recorded.  The authors concluded that pmVSD closure with the Nit-Occlud Lê VSD Coil was feasible in older children and adults.  However, residual shunting (leading to hemolysis) was a dreaded complication that should not be tolerated.  These researchers stated that pmVSD closure with the Nit-Occlud Lê VSD as a therapeutic strategy remains controversial and is limited to selected patients.

Furthermore, an UpToDate review on “Management of isolated ventricular septal defects in infants and children” (Fulton and Saleeb, 2020) states that “For most patients who require VSD closure, primary patch surgical closure is the preferred procedure and is associated with excellent outcomes with low risk of mortality and low complication and reoperation rates.  Transcatheter closure is generally reserved for patients with defects that are not amenable to surgical repair (e.g., multiple muscular defects that may be difficult to visualize at the time of surgery).  Transcatheter VSD closure is technically challenging and should be performed only in centers with considerable experience and expertise in interventional catheterization techniques and with surgical backup”.

Percutaneous Transcatheter Implantation of Inter-Atrial Septal Shunt Device for the Treatment of Heart Failure

Sondergaard and colleagues (2014) stated that heart failure with preserved or mildly reduced ejection fraction (HFpEF) is common and therapeutic options are limited.  Increased left atrial pressure (LAP) is a key contributor to the symptoms associated with HFpEF, especially during physical activity.  In a pilot study, these investigators reported the 30-day outcome of patients treated with a novel device intended to lower LAP by creating an 8-mm permanent shunt in the atrial septum.  A total of 11 patients were enrolled in this trial.  Key inclusion criteria were: EF greater than 45%; baseline pulmonary capillary wedge pressure (PCWP) of greater than or equal to 15 mmHg (rest), or greater than or equal to 25 mmHg (exercise); and greater than or equal to 1 hospitalization for HF within the past 12 months, or persistent New York Heart Association (NYHA) class III/IV for at least 3 months.  Mean age, LVEF, and NYHA class were 70 ± 12 years, 57 ± 9 %, and 3.2 ± 0.4, respectively.  Most patients had significant co-morbidities.  The inter-atrial septal device (IASD) device was implanted using percutaneous trans-septal access via the femoral vein.  The device was successfully implanted in all patients.  At 30 days, LV filling pressures were significantly reduced by 5.5 mmHg (19.7 ± 3.4 versus 14.2 ± 2.7; p = 0.005), and NYHA class was improved by 2 classes in 2 patients, 1 class in 5 patients, and worsened by 1 class in 1 patient.  No patient developed pulmonary hypertension; 2 SAE occurred; HF re-hospitalization; and implant mal-position successfully treated with a new device.  The authors concluded that contemporary management of HFpEF patients was confounded by the lack of effective therapies.  The use of a device-based approach to reduce LAP provided a novel means to improve hemodynamic and symptomatic status in HFpEF patients and further investigation is needed.  Moreover, these researchers stated that these findings should be interpreted with caution because of the limited size of the patient cohort (n = 11) in this study, and the lack of a control group.

Shad and associates (2018) noted that in patients with HF and left ventricular ejection fraction (LVEF) equal to or greater than 40 %, an IASD reduces exercise PCWP and is safe compared with sham control treatment at 1 month of follow-up.  The longer-term safety and patency of the IASD has not yet been demonstrated in the setting of a RCT.  In a double-blind, 1-to-1 sham-controlled, multi-center, phase-II RCT, these researchers examined the 1-year safety and clinical outcomes of the IASD compared with a sham control treatment.  This study of IASD implantation versus a sham procedure (femoral venous access and imaging of the inter-atrial septum without IASD) was carried out in 22 centers in the Australia, Europe, and the U.S. on patients with NYHA class III or ambulatory class IV HF, LVEF equal to or greater than 40 %, exercise PCWP equal to or greater than 25 mm Hg, and PCWP-right atrial pressure (RAP) gradient equal to or greater than 5 mm Hg.  Safety was evaluated by major adverse cardiac, cerebrovascular, or renal events (MACCRE).  Exploratory outcomes evaluated at 1 year were hospitalizations for HF, NYHA class, quality of life (QOL), a 6-minute walk test (6MWT), and device patency.  After 1 year, shunts were patent in all IASD-treated patients; MACCRE did not differ significantly in the IASD arm (2 of 21 [9.5 %]) versus the control arm (5 of 22 [22.7 %]; p = 0.41), and no strokes occurred.  The yearly rate of hospitalizations for HF was 0.22 in the IASD arm and 0.63 in the control arm (p = 0.06).  Median improvement in NYHA class was 1 class in the IASD arm (IQR, -1 to 0) versus 0 in the control arm (IQR, -1 to 0; p = 0.08); QOL and 6MWT distance were similar in both groups.  At 6 months, there was an increase in right ventricular size in the IASD arm (mean [SD], 7.9 [8.0] ml/m2) versus the control arm (-1.8 [9.6] ml/m2; p = 0.002), consistent with left-to-right shunting through the device; no further increase occurred in the IASD arm at 12 months.  The authors concluded that the REDUCE LAP-HF I phase-II, sham-controlled RCT confirmed the longer-term patency of the IASD.  These researchers noted that through 1 year of follow-up, IASD treatment appeared safe, with no significant differences in MACCRE in patients receiving IASD compared with those who received sham control treatment.  Moreover, these researchers stated that these findings were encouraging; however, they needed a larger study for further clinical evaluation.  These investigators stated that a larger-scale, blinded, sham-controlled, pivotal RCT is currently underway to determine the clinical efficacy of the IASD in HF and EF equal to or greater than 40 %.

The authors stated that this study was limited by its relatively small sample size (n = 44; 21 received IASD); thus, it did not provide adequate power to definitively evaluate clinical benefit or safety.  Although there were no statistically significant differences in clinical characteristics among groups, the control group had lower 6MWT distance and a higher frequency of HF hospitalization in the year before the study began.  These imbalances did not affect the main 1-year results; however, these differences between treatment groups were also indicative of the limitation of a small sample size. 

Kaye and co-workers (2019) noted that impaired LV diastolic function leading to elevated LAP, especially during exertion, is a key driver of symptoms and outcomes in HFpEF.  Insertion of an IASD to reduce LAP in HFpEF has been shown to be associated with short-term hemodynamic and symptomatic benefit.  These investigators examined the potential effects of IASD placement on HFpEF survival and HF hospitalization (HFH).  Patients with HFpEF participating in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure study of an IASD were followed for a median duration of 739 days.  The theoretical impact of IASD implantation on HFpEF mortality was examined by comparing the observed survival of the study cohort with the survival predicted from baseline data using the Meta-analysis Global Group in Chronic Heart Failure HF risk survival score.  Baseline and post-IASD implant parameters associated with HFH were also examined.  Based upon the individual baseline demographic and cardiovascular profile of the study cohort, the Meta-analysis Global Group in Chronic Heart Failure score-predicted mortality was 10.2/100 patient years.  The observed mortality rate of the IASD-treated cohort was 3.4/100 patient years, representing a 33 % lower rate (p = 0.02).  By Kaplan-Meier analysis, the observed survival in IASD patients was greater than predicted (p = 0.014).  Baseline parameters were not predictive of future HFH events; however, poorer exercise tolerance and a higher workload-corrected exercise PCWP at the 6 months post-IASD study were associated with HFH.  The authors concluded that the findings of this study suggested that IASD implantation may be associated with a reduction in mortality in HFpEF.  Moreover, these researchers stated that large-scale, randomized, double‐blind, sham procedure-controlled studies are currently underway to further examine the utility of this therapeutic approach in HFpEF.

The authors stated that the findings of this study should be interpreted in the context of several limitations.  First, the study was an open‐label study.  Second, although the predicted survival was consistent with other reports in HFpEF patients, the use of the Meta‐analysis Global Group in Chronic Heart Failure (MAGGIC) score to derive a comparator survival curve may have generated an over-estimation of the true survival in a contemporaneous group.  Finally, while protocol‐driven safety outcome follow‐up was available at up to 3 years, complete NYHA class at 3 years was unavailable, and systematic echocardiography was not required after 12 months.

Burlacu and associates (2019) noted that HFpEF is a common disorder generating high mortality and important morbidity prevalence, with a very limited medical treatment available.  Studies have shown that the pathophysiological hallmark of this condition is an elevated LAP, exertional dyspnea being its clinical manifestation.  The increasing pressure from LA is not based on volume overload (such as in heart failure with reduced ejection fraction) but on a diastolic LV dysfunction combined with an inter-atrial dyssynchrony mimicking a pseudo-pacemaker syndrome.  These investigators summarized current knowledge and discussed future directions of the newest interventional percutaneous therapies of HFpEF.  Novel interventional approaches developed to counter these mechanisms are as follows: LA decompression (IASDs), enhancement of LV compliance (LV expanders), and inter-atrial re-synchronization therapy (LA permanent pacing).  To-date, IASDs are the most studied, being the only devices currently tested in a phase-III clinical trial.  Recent data showed that IASDs are feasible, safe, and have a short-term clinical benefit in HFpEF patients.  LV expanders and LA pacing therapy present with a smaller clinical benefit compared with IASDs, but they are safe, without any major adverse outcomes currently noted.  With further development and improvement of these mechanism-specific devices, it will be interesting to determine if in the future a complex intervention of multiple HFpEF device implantation will be safe and have further benefits in HFpEF patient.

Berry and colleagues (2020) stated that a randomized, sham-controlled study in patients with HF and LVEF of greater than or equal to 40 % demonstrated reductions in PCWP with a novel transcatheter IASD.  Whether this hemodynamic effect will translate to an improvement in cardiovascular outcomes and symptoms requires additional study.  The REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP HF-II) Trial is a prospective, randomized, blinded, sham-controlled, multi-center study designed to examine the clinical efficacy of the IASD in symptomatic HF and elevated LAP.  Up to 608 HF patients age of greater than or equal to 40 years with LVEF of greater than or equal to 40 %, PCWP of greater than or equal to 25 mm Hg during supine ergometer exercise, and PCWP of greater than or equal to 5 mm Hg higher than RAP will be randomized 1:1 to the IASD versus sham control.  Key exclusion criteria include hemodynamically significant valvular disease, evidence of pulmonary arterial hypertension, and right heart dysfunction.  The primary endpoint is a hierarchical composite, analyzed by the Finkelstein-Schoenfeld methodology, that includes cardiovascular mortality or 1st non-fatal ischemic stroke through 12 months; total (1st plus recurrent) HF hospitalizations or healthcare facility visits for intravenous diuretics up to 24 months, analyzed when the last randomized patient completes 12 months of follow-up; as well as change in Kansas City Cardiomyopathy Questionnaire overall summary score from baseline to 12 months.  Follow-up echocardiography will be performed at 6, 12, and 24 months to evaluate shunt flow and cardiac chamber size/function.  Patients will be followed for a total of 5 years after the index procedure.  The authors stated that the REDUCE LAP-HF II is designed to evaluate the clinical efficacy of the IASD device in patients with symptomatic HF with elevated LAP and LVEF of greater than or equal to 40 %.

Miyagi and associates (2021) noted that HFpEF is a syndrome with an unfavorable prognosis, and the number of the patients continues to grow.  Because there is no effective therapy established as a standard, including pharmacotherapies, a movement to develop and evaluate device-based therapies is an important emerging area in the treatment of HFpEF patients.  Many devices have set their target to reduce the LAP or PCWP because they are strongly related to the symptoms and prognosis of HFpEF; however, the methodology to achieve it varies based on the devices.  These researchers summarized and categorized these devices into the following: IASDs, left ventricle expander, electrical therapy, left ventricular assist devices (LVADs), as well as mechanical circulatory support devices under development.  They described the features and specifications of device-based therapies currently under development and those at more advanced stages of pre-clinical testing.

Furthermore, an UpToDate review on “Overview of surgical management of heart failure” (Fang, 2021) does not mention inter-atrial shunt as a management / therapeutic option.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
93580	Percutaneous transcatheter closure of congenital interatrial communication (i.e., Fontan fenestration, atrial septal defect) with implant [not covered transcatheter closure of PFO for stroke prevention]
93581	Percutaneous transcatheter closure of a congenital ventricular septal defect with implant
93582	Percutaneous transcatheter closure of patent ductus arteriosus
Other CPT codes related to the CPB:
33615	Repair of complex cardiac anomalies (e.g., tricuspid atresia) by closure of atrial septal defect and anastomosis of atria or vena cava to pulmonary artery (simple Fontan procedure)
33617	Repair of complex cardiac anomalies (e.g., single ventricle) by modified Fontan procedure
93315	Transesophageal echocardiography for congenital cardiac anomalies; including probe placement, image acquisition, interpretation and report
93320 - 93350	Echocardiography
93533	Combined right heart catheterization and transseptal left heart catheterization through existing septal opening, with or without retrograde left heart catheterization, for congenital cardiac anomalies
HCPCS codes covered if selection criteria are met:
C1817	Septal defect implant system, intracardiac
HCPCS codes not covered for indications listed in the CPB:
Nit-Occlud Lê VSD coil - no specific code
Other HCPCS codes related to the CPB:
C1760	Closure device, vascular (implantable/insertable)
C2628	Catheter, occlusion
ICD-10 codes covered if selection criteria are met:
I23.1 - I23.2	Atrial or ventricular septal defect as current complication following acute myocardial infarction
I51.0	Cardiac septal defect acquired
I63.9	Cerebral infarction, unspecified [cryptogenic stroke]
Q21.0	Ventricular septal defect
Q21.1	Atrial septal defect [not covered for coronary sinus atrial septal defect or patent foramen ovale]
Q21.3	Tetralogy of Fallot
Q25.0	Patent ductus arteriosus
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
G43.00 - G43.919	Migraine
G44.1	Vascular headache, not elsewhere classified
G45.0 - G45.9	Transient cerebral ischemic attacks and related syndromes
I65.01 - I66.9	Occlusion and stenosis of precerebral and cerebral arteries
Q21.2	Atrioventricular septal defect
R06.00, R06.09	Other forms of and unspecified dyspnea
R51	Headache
R79.81	Abnormal blood-gas level
Inter-atrial septal shunt device:
CPT codes not covered for indications listed in the CPB:
0613T	Percutaneous transcatheter implantation of interatrial septal shunt device, including right and left heart catheterization, intracardiac echocardiography, and imaging guidance by the proceduralist, when performed
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
I50.1 - I50.9	Heart failure

The above policy is based on the following references: