Catheter-Directed Cardiac Procedures
Number: 0292
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses catheter-directed cardiac procedures.
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Medical Necessity
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Atrial Septal Defects
Aetna considers transcatheter closure of atrial septal defects (ASDs) using Food and Drug Administration (FDA)-approved closure devices (e.g., Amplatzer Septal Occluder, Gore Cardioform Septal Occluder, Occlutech ASD Occluder) medically necessary in pediatric or adult members for any of the following indications:
- Closure of a fenestration as a result of the Fontan procedure; or
- Occlusion of ASDs in secundum position with ratio of pulmonary to systemic blood flow (Qp:Qs) greater than or equal to 1.5, right ventricular enlargement, and one of the following:
- Pulmonary vascular resistance (PVR) less than 5 Wood units; or
- PVR 5-8 Wood units that decreased to less than 5 Wood units with medical treatment for pulmonary arterial hypertension (PAH); or
- Occlusion of ASD with strong suspicion of paradoxical embolism.
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Ventricular Septal Defects
Aetna considers transcatheter closure of ventricular septal defects (VSDs) using FDA-approved closure devices to be 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.
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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.
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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.
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Experimental, Investigational, or Unproven
The following procedures are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
- Closure devices not approved by the FDA for transcatheter occlusion of patent ductus arteriosus
- Left atrial to coronary sinus shunting (the APTURE Transcatheter Shunt System) for the treatment of heart failure
- Neovasc Reducer (coronary sinus reducer) for relief of angina symptoms
- Nit-Occlud Lê VSD coil for transcatheter closure of a peri-membranous ventricular septal defect
- Percutaneous transcatheter implantation of inter-atrial septal shunt device for the treatment of heart failure
- Transcatheter closure of atrial septal defects (ASDs) for migraine prophylaxis and for all other indications not listed above (e.g., coronary sinus atrial septal defect, ostium primum atrial septal defect, and sinus venosus atrial septal defect; not an all-inclusive list)
- Transcatheter closure of patent foramen ovale (PFO) for migraine prophylaxis, stroke prevention, and for all other indications not listed above (e.g., orthodeoxia-platypnea and unexplained oxygen desaturation)
- Transcatheter closure of ventricular septal defects (VSDs) for all other indications not listed above
- Transcatheter occlusion of PFO for persons with transient ischemic attacks, or arterial emboli due to presumed paradoxical embolism through a PFO.
- Transcatheter removal or debulking of intra-cardiac mass (e.g., the AngioVac System)
- Transmyocardial transcatheter/perventricular closure of ventricular septal defects with implants.
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Related Policies
- CPB 0008 - Color-Flow Doppler Echocardiography and Myocardial Strain Imaging
- CPB 0021 - Cardiac Rehabilitation: Outpatient
- CPB 0228 - Cardiac Computed Tomography (CT), Coronary CT Angiography, Calcium Scoring and CT Fractional Flow Reserve
- CPB 0353 - Transcranial Doppler Ultrasonography
- CPB 0791 - Cardiac Devices and Procedures for Occlusion of the Left Atrial Appendage
Background
Despite the success of standard operative repair, with a mortality rate of less than 1%, the risks and morbidity associated with open-heart surgery remain significant. Over the last two decades, interventional cardiac catheterization techniques have evolved to the point where percutaneous transcatheter devices can be offered as alternatives to their open counterparts for repairing certain cardiac defects, particularly in younger patients. All of these 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 assess the immediate results of the procedure.
Catheter‑directed cardiac procedures encompass a range of minimally invasive transcatheter techniques designed to diagnose and treat structural heart defects without the need for open‑heart surgery. Using image‑guided vascular access, interventional cardiologists can navigate specialized catheters through the vasculature to deliver closure devices directly to intracardiac defects. Applications include transcatheter closure of atrial septal defects (ASD) and ventricular septal defects (VSD), and transcatheter occlusion techniques in patent foramen ovale (PFO) and patent ductus arteriosus (PDA). These approaches aim to restore normal cardiac physiology by sealing abnormal communications between cardiac chambers or great vessels, while reducing perioperative morbidity, shortening recovery time, and providing a less invasive alternative to surgical repair.
Atrial Septal Defects
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 case selection, such as choosing defects that were too large or selecting defective devices. Over the years, stricter implantation and patient selection criteria have led to more successful deployment of the devices in stable positions without inducing functional abnormalities or anatomical obstructions. Of utmost importance in choosing appropriate patients is the echocardiographic morphology of the ASD, considering factors such as size, position in the interatrial septum, proximity to surrounding structures, and adequacy of the septal rim. Equally essential is the accurate assessment of the stretched diameter of the interatrial communication through balloon sizing during catheterization to determine the 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 multiple 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), and Guardian Angel.
The Amplatzer Septal Occluder (AGA Medical Corp., Golden Valley, MN) received FDA approval in 2001. It is a self-centering device that consists of two round disks made of Nitinol wire mesh, linked together by a short connecting waist. Studies have reported short-term results confirming a high occlusion rate with no major complications when strict implantation and patient selection criteria are applied. 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., a 1.5:1 degree of left-to-right shunt or RV enlargement). The device is also indicated for patients who have undergone a fenestrated Fontan procedure and 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 based on the patient's preference. Baseline physical examinations and echocardiography were performed pre-procedure and at follow-up (6 and 12 months for the device group, 12 months for the surgical group). A total of 442 patients were in the device closure group, while 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%) had a single ASD (p = 0.008). The size of the primary ASD was 13.3 ± 5.4 mm for the device group and 14.2 ± 6.3 mm for the surgical 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 American Heart Association (AHA) (Feltes et al., 2011) provides specific recommendations for transcatheter atrial septal defect (ASD) closure in pediatric patients. According to these guidelines, Class I recommendations state that transcatheter closure of secundum ASD is indicated for patients with hemodynamically significant ASDs that possess suitable anatomic features (Level of Evidence: B). Class IIa recommendations suggest that it is reasonable to perform transcatheter closure in patients with transient right-to-left shunting at the atrial level who have experienced complications from paradoxical emboli, such as stroke or recurrent transient ischemic attacks (Level of Evidence: B). Additionally, it is considered reasonable to perform the procedure in symptomatic patients with transient right-to-left shunting who experience cyanosis but do not require the ASD for maintaining adequate cardiac output (Level of Evidence: B). Conversely, transcatheter ASD closure is contraindicated for patients with a secundum ASD and advanced pulmonary vascular obstructive disease (Level of Evidence: C).
Rao (2013) discussed how and when to treat the most common acyanotic congenital heart defects (CHD). The indications and timing of intervention are determined by the severity of the lesion. Transcatheter closure methods are currently preferred for ostium secundum ASDs; the indications for occlusion are right ventricular volume overload as determined by echocardiogram. Ostium primum, sinus venosus, and coronary sinus ASDs require surgical closure. For all ASDs, elective closure around ages 4 to 5 years is recommended or as soon as detected beyond that age. For the more common peri-membranous 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 an Amplatzer duct occluder if they are moderate to large, and Gianturco coils if they are small. Surgical and video-thoracoscopic closure are 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.”
The Gor Helex Septal Occluder was discontinued by the manufacturer in June 2015. This FDA-approved percutaneous device was used to close secundum atrial septal defects (ASDs). It featured a nitinol wire frame covered with expanded polytetrafluoroethylene (ePTFE), forming a double-disc shape. The device was replaced with the newer Cardioform device following its FDA approval in March 2018.
The American College of Cardiology/American Heart Association guidelines recommend atrial septal defect (ASD) closure for patients with right atrial (RA) and right ventricular (RV) enlargement, regardless of symptoms (Class I). Small ASDs, defined as those with a diameter of less than 5 mm and without evidence of RV enlargement or pulmonary hypertension, do not require closure, as they are not deemed significant enough to impact the clinical course or hemodynamics of the patient. However, smaller ASDs associated with paradoxical embolism or platypnea-orthodeoxia may be considered for closure according to guideline recommendations (Class IIa). The only absolute contraindication for ASD closure is in patients with irreversible pulmonary hypertension (pulmonary vascular resistance greater than 8 Wood units) and no evidence of left-to-right shunting (Class III). Potential indications for ASD closure include isolated secundum ASDs with a pulmonary/systemic flow (Qp/Qs) ratio of 1.5:1 and signs of right ventricular volume overload. Contraindications include small ASDs with a Qp/Qs ratio of less than 1.5:1 or no signs of RV volume overload, a single defect too large for closure (greater than 38 mm), multiple ASDs unsuitable for percutaneous closure, defects located too close to the superior vena cava, inferior vena cava, pulmonary veins, atrioventricular valves, or coronary sinus, rims (anterior, posterior, superior, or inferior) measuring less than 5 mm, abnormal pulmonary venous drainage, associated congenital abnormalities requiring cardiac surgery, ASDs with severe pulmonary arterial hypertension and bidirectional or right-to-left shunting, and the presence of intracardiac thrombi diagnosed by echocardiography (Silvestry et al., 2015).
The AHA/ATS 2015 pediatric pulmonary hypertension guidelines outline recommendations for children with significant structural heart disease, such as atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus (PDA), who have not undergone early repair, typically defined as before 1 to 2 years of age based on the specific lesion and overall clinical status. It is recommended that cardiac catheterization be considered to measure the pulmonary vascular resistance index (PVRI) and assess operability (Class II; Level of Evidence B). Repair should be considered if the PVRI is less than 6 Wood units (WU)·m² or if the PVR/SVR ratio is less than 0.3 at baseline (Class I; Level of Evidence B). For children exhibiting right-to-left shunting, if cardiac catheterization shows a PVRI of 6 WU·m² or greater or a PVR/SVR ratio of 0.3 or greater, repair may be beneficial if acute vasodilator testing (AVT) indicates reversibility of pulmonary arterial hypertension (PAH) with an absolute PVRI of less than 6 WU·m² and a PVR/SVR ratio of less than 0.3 (Class IIa; Level of Evidence C). Conversely, if cardiac catheterization reveals a PVRI of 6 WU·m² or greater or a PVR/SVR ratio of 0.3 or greater with minimal responsiveness to AVT, repair is not indicated (Class III; Level of Evidence A). In such cases, it is reasonable to initiate PAH-targeted therapy, followed by repeat catheterization with AVT after 4 to 6 months, and to consider repair if the PVRI falls below 6 WU (Class IIb; Level of Evidence C).
Fraisse et al. (2018) report that safe and effective closure of atrial septal defects (ASDs) in patients weighing less than 15 kg has been demonstrated in multiple studies and is now routinely performed in high-volume centers. Successful interventional ASD closures have also been reported in children weighing less than 10 kg, and even as low as 8 kg, with positive outcomes, including in those with extracardiac comorbidities such as bronchopulmonary dysplasia in previously premature infants. Percutaneous closure can be safely performed in symptomatic children without significantly increasing risk. A recent nationwide study in France involving 1,326 children who underwent ASD device closure at nine tertiary institutions found a low rate of periprocedural complications and favorable long-term outcomes, with no reported deaths or cases of cardiac erosion, even among a significant number of patients with large defects. However, it was noted that children weighing less than 15 kg and those with large ASDs faced a higher risk of complications.
Qureshi et al. (2024) report that the Gore Cardioform ASD Occluder (GCA, W. L. Gore & Associates) was approved in 2019 for the closure of ostium secundum atrial septal defects (ASDs). This study aimed to present the combined results of the pivotal and continued access cohorts from the ASSURED trial (Safety and Efficacy Study of Transcatheter Closure of Ostium Secundum ASDs) over a 36-month period. The prospective, multicenter, single-arm trial evaluated the procedural and clinical outcomes of ASD closure using the GCA, with primary endpoints including 6-month closure success following device implantation and composite clinical success, which encompassed device deployment/retention, safety, and closure. Secondary endpoints assessed technical and procedural success, safety, clinically significant new arrhythmias (CSNA), and wire frame fractures (WFF) through fluoroscopy at 6 and 36 months. Among the 569 patients (median age of 10.4 years and median weight of 35.0 kg) who underwent attempted secundum ASD closure, 526 achieved technical success, with a mean stop-flow ASD diameter of 17.6 ± 5.3 mm. All 478 patients with 6-month imaging demonstrated closure success, while composite clinical success was observed in 87.6% (468/534) of patients at 6 months and 84.0% (351/418) at 36 months. Technical failure occurred in 8.1% (43/548) of cases, with 30-day device- or procedure-related serious adverse events in 3.9% (21/534) and 6-month device events in 2.8% (15/534) of patients. At 30 days, 3.7% (21 of 569) of patients experienced CSNA, while WFFs were noted in 31.7% (138 of 436) at 6 months and 56.8% (105 of 185) at 36 months, all without clinical sequelae. In conclusion, the GCA demonstrated acceptable results in this large congenital ASD device trial, with WFFs being common but not leading to any adverse clinical outcomes, thereby expanding the options for secundum ASD closure. (Safety and Efficacy Study of Transcatheter Closure of Ostium Secundum ASDs [ASSURED]; NCT02985684).
The 2025 ACC/AHA/HRS/ISACHD/SCAI guidelines for managing adults with congenital heart disease provide several recommendations for atrial septal defect (ASD) management. For adults with an isolated unrepaired secundum ASD, transcatheter closure is generally preferred over surgical repair to reduce length of stay and recovery time (COR 1). In cases where there is an unrepaired ASD with evidence of or strong suspicion for paradoxical embolism, closure is recommended to prevent recurrent embolism (COR 1). Additionally, for adults with an unrepaired ASD who exhibit a significant left-to-right shunt (Qp:Qs ≥ 1.5), right ventricular dilation, and pulmonary arterial hypertension (PAH) with pulmonary vascular resistance (PVR) between 5-8 Wood units, closure can be beneficial if targeted PAH therapy can reduce PVR to less than 5 Wood units, thereby improving medium-term functional status (COR 2a).
Ventricular Septal Defects
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 defects (VSDs) of significant size that 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 comorbid 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 a 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.
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, six patients underwent attempted perventricular MVSD closure. The mean age was 9.8 ± 9.1 months, and the mean weight was 7.2 ± 3.7 kg. In five patients, closure was successful without the use of bypass. In one 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, while two patients had mild, hemodynamically insignificant shunting, and one 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, sparing the need for cardiopulmonary bypass and its associated comorbidities. However, in some instances, successful deployment of the device may not be possible. These mid-term results demonstrated overall success but identified possible complications that may not be immediately recognized 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 long-term success.
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 accordance with conventional techniques of perventricular device closure. The mean procedural duration was 31.1 ± 9.1 minutes. 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 and 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.
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 DCVSDs 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 the pleural space. Two parallel purse-string sutures were placed on the right ventricular outflow tract for puncture. Under transesophageal 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 subsequently deployed. Successful device closure of the defects was achieved in 58 of 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%) were implanted with an eccentric occluder. The mean intra-cardiac manipulation time was 14 ± 13 minutes (range of 2 to 60). The procedure time was 66 ± 15 minutes (range of 42 to 98). During the follow-up period of 180 to 1860 days (median of 880), 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 months, 96% at 2 years, and 100% at 3 years of 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.
Yang et al. (2021) stated that post-infarction ventricular septal defect (PIVSD) is a severe complication of acute myocardial infarction (AMI). Trans-catheter closure (TCC) is presented as an alternative option to surgical repair. In a meta-analysis, these investigators examined the published literature to provide objective evidence regarding TCC. They conducted a comprehensive search of significant medical and publisher databases, with two reviewers assessing the quality of the studies and extracting data. Eligible studies included both single-arm and comparative studies. The analysis estimated weighted means, pooled event rates, effectiveness outcomes, and odds ratios (ORs) for immediate shunt reduction (ISR), presence of cardiogenic shock (CS), NYHA class IV, time from AMI to VSD, and time to VSD closure. A total of 27 single-arm studies involving 462 patients were included. The pooled event rate for successful device implantation was 89.7% (95% CI: 0.772 to 1.021), 80.9% (95% CI: 0.645 to 0.972) for ISR, 31.5% (95% CI: 0.149 to 0.482) for 30-day mortality, and 25.3% (95% CI: 0.072 to 0.434) for 30-day mortality of primary closure at the acute phase. CS (OR = 3.607, 95% CI: 2.301 to 5.653), NYHA class IV (OR = 6.491, 95% CI: 1.444 to 29.188), and time to VSD closure were identified as risk predictors for TCC. There was no correlation between defect size (OR = 2.592, 95% CI: 0.380 to 17.661) and mortality. The authors concluded that TCC should be considered a relatively safe and minimally invasive method for PIVSD, with an excellent successful device implantation rate and an acceptable low 30-day mortality. They emphasized that while the procedure appears promising, its safety and effectiveness can only be verified through randomized controlled trials (RCTs), highlighting the need for future comparative trials to assess mortality data comparing surgery to TCC.
Yi et al. (2023) noted that ventricular septal defects (VSDs) are one of the mechanical complications of AMI. Due to the high risks of mortality and postoperative complications, a new alternative method is needed. With advancements in interventional medicine, TCC has been increasingly performed for post-MI VSDs (PMIVSDs). In a systematic review and meta-analysis, these investigators examined the feasibility and safety of TCC for PMIVSDs. The included studies were primarily single-arm studies of TCC for PMIVSDs. The researchers compared VSD size, device size, preoperative risk factors, and interventions among PMIVSD patients. They analyzed the TCC success rate, the 30-day mortality rate, and the incidence of residual shunts. A total of 12 single-arm articles involving 284 patients were included. The combined incidences of preoperative hypertension, hyperlipidemia, and diabetes mellitus were 66% (95% CI: 0.56 to 0.75), 54% (95% CI: 0.40 to 0.68), and 33% (95% CI: 0.21 to 0.46), respectively. Multiple studies reported the combined incidences of preoperative percutaneous coronary intervention (PCI), intra-aortic balloon pump (IABP), and coronary artery bypass grafting (CABG), which were 46% (95% CI: 0.15 to 0.80), 60% (95% CI: 0.44 to 0.75), and 8% (95% CI: 0.02 to 0.18). Eleven studies reported the number of successful closures and the 30-day mortality rate, with a success rate of 90% (95% CI: 0.86 to 0.94) and a 30-day mortality rate of 27% (95% CI: 0.86 to 0.94). The authors concluded that for patients with PMIVSD, TCC in the acute phase can be used as a rescue measure, while in the chronic phase, it is more effective and has a lower mortality rate; however, the effect of selection bias should be considered. They noted that residual shunts were a long-term complication with a high incidence and lasting effects on patients. The researchers stated that more large, multi-center RCTs are needed to confirm the safety and reliability of TCC for PMIVSDs.
The authors acknowledged several drawbacks in their analysis. First, they found no RCTs examining surgical repair and transcatheter occlusion for the treatment of PMIVSD, leading them to conduct a single-arm meta-analysis to discuss the safety and effectiveness of TCC for PMIVSD. Second, the sample size of available evidence was small, with most studies being retrospective, which introduced selection bias into the results. Third, the probability of VSD occurring in patients with AMI is very low, resulting in a small number of patients eligible for intervention. The small patient population and inherent selection bias in almost all studies made it difficult to compare TCC results with those of published surgical series. This review included 12 multi-case studies, and while the researchers considered comparing TCC in the acute and chronic phases of PMIVSD and the incidence of residual shunts at different periods after TCC, they could not make comparisons due to variable baseline information, likely stemming from individual differences among patients, leading to greater heterogeneity. They concluded that whether patients with PMIVSD could undergo TCC should be determined based on individual circumstances.
Cadogan et al. (2023) stated that post-infarction VSD is a mechanical complication of AMI. The incidence of this complication is low in the primary percutaneous coronary intervention (PCI) era; however, the associated mortality is very high at 94% with medical management alone. Open surgical repair or percutaneous TCC still has an in-hospital mortality of over 40%. Retrospective comparisons between both closure methods are limited by observation and selection bias. These investigators discussed the assessment and optimization of patients before repair, the optimal timing of repair, and the limitations in current data. The authors concluded that there remains debate on the optimal pre-procedure optimization, timing of repair, and modality of treatment. They emphasized that these issues will remain uncertain without prospective evidence to guide clinicians. Moreover, they stated that the heterogeneity of retrospective data often results in more questions than answers. They suggested that the formation of an expert steering group and a national/international prospective PIVSD registry may help address these issues, guide further research, and optimize care.
Patent Foramen Ovale
The FDA has granted humanitarian device exemptions to two transcatheter occlusion devices for the 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 aforementioned 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).
Irwin and Bay (2012) stated that migraine with aura has been linked with PFO. A recent meta-analysis suggested an association, but the only 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 it 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.
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 endpoint 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 endpoint 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.
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 endpoints were unaware of the study-group assignments. Patients with a PFO and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the PFO with the Amplatzer PFO occluder or to receive medical therapy. The primary endpoint 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 endpoint 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.
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 experienced 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 endpoint 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 one or more antiplatelet medications (74.8%) or warfarin (25.2%). Treatment exposure between the two 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 dropout 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 experienced 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.
- stroke;
- TIA; and
- all-cause mortality.
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 endpoint (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 endpoint) 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 two 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 whether 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, involving 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 a 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 a 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. They 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 involving 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 endpoint 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 the meta-analysis of RCTs assessing 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.
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.
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. Transesophageal or transthoracic 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 was required. Procedural complications occurred in 3%, and later complications (e.g., AF, atrial ectopics, and device thrombus) occurred 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, is needed.
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 transesophageal echocardiography [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 the 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.
Mas and associates (2017) stated that studies of PFO closure to prevent recurrent stroke have been inconclusive. These investigators examined whether patients with cryptogenic stroke and echocardiographic features representing a risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. In a multicenter, randomized, open-label trial, these researchers assigned, in a 1:1:1 ratio, patients aged 16 to 60 years who had experienced a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative non-contraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was the occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet 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 antiplatelet-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 atrial fibrillation (AF) was higher in the PFO closure group than in the antiplatelet-only group (4.6% versus 0.9%, p = 0.02). The number of serious adverse events (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 anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. The authors concluded that among patients who had experienced 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 antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, 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 endpoint events, these researchers randomly assigned patients aged 18 to 60 years who had a PFO and had experienced 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 endpoint 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 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 two 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 dropout 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 experienced 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 antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new brain infarctions. In this multinational trial involving patients with a PFO who had experienced a cryptogenic stroke, these investigators randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet-only group). Imaging of the brain was performed at baseline screening and at 24 months. The co-primary endpoints 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 antiplatelet-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 antiplatelet-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). Serious adverse events (SAEs) occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet-only group (p = 0.22). Serious device-related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and AF occurred in 29 patients (6.6%) after PFO closure. The authors concluded that among patients with a PFO who had experienced a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and AF.
In an editorial that accompanied the aforementioned 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.”
Giacoppo et al. (2018) aimed to evaluate the pooled evidence from recent trials that demonstrated a significant reduction in stroke risk following transcatheter patent foramen ovale closure (tPFOc), despite the limited statistical power of individual studies. They conducted a comprehensive search of major electronic databases and identified six trials involving 3,560 patients. With a median follow-up of 3.6 years (13,930 person-years), the analysis revealed that the risk of stroke was significantly lower after tPFOc compared to antithrombotic therapy alone (ATA), with a hazard ratio of 0.28 (95% CI: 0.12-0.64, p=0.003). Although significant heterogeneity was noted (I²=66.1%), individual trials did not significantly affect the overall results. The reconstructed time-to-event data indicated that the benefits of tPFOc began to accrue after approximately one year and continued over time without significant fluctuations (96.4% versus 88.0%; HR 0.25, 95% CI: 0.09-0.66, p=0.005; NNT=11). While a greater benefit was observed in patients under 45 years old, male patients, and those with substantial shunts, the interaction between subgroups was not statistically significant. Trial sequential analysis suggested that the accumulated evidence was sufficient; however, tPFOc did not provide protection against transient ischemic attacks (TIA; HR 0.69, 95% CI: 0.31-1.54, p=0.365), and a significant increase in the risk of atrial fibrillation was noted (OR 4.99, 95% CI: 1.99-10.10, p<0.001), although this was generally early and transient. The rates of major bleeding and migraine were comparable between the two treatment groups. In conclusion, tPFOc significantly reduces the long-term risk of stroke compared to ATA, but does not confer benefits for TIA, and is associated with a higher risk of atrial fibrillation, while major bleeding and migraine risks remain similar between treatments.
Giacoppo et al. acknowledged several limitations in their study. They noted that, like any meta-analysis, their findings depend on the original studies and share similar limitations, including a lack of access to the complete dataset. Despite this, they reconstructed the original data using a validated methodology, which introduced a minimal but unavoidable margin of imprecision. The significant margin of significance versus non-significance in the pooled estimates, along with strong consistency across various analyses, supports the robustness of their conclusions. Specific limitations included the use of odds ratios (ORs) instead of hazard ratios (HRs) due to mixed reporting of atrial fibrillation and major bleeding endpoints across trials. In the Gore REDUCE trial, events were reported as either atrial fibrillation or atrial flutter, with very few cases of the latter. Additionally, the endpoint of transient ischemic attack (TIA) was not reported as an HR in the Gore REDUCE trial, but the authors addressed this by using a "borrowing of strength" approach in their analysis. They also noted that in the CLOSURE I trial, results were based on per-protocol analysis, while they used as-randomized denominators for consistency with other trials. Furthermore, slight differences in age cut-offs for subgroup analyses in the CLOSE and Gore REDUCE trials were deemed insignificant. Lastly, the DEFENSE-PFO trial did not report on major clinical subgroups or outcomes related to atrial fibrillation, major bleeding, or migraine.
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.
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).
Kleindorfer et al. (2021) discuss the 2021 AHA guideline for the prevention of stroke in patients with stroke and TIA, highlighting substantial epidemiological evidence that suggests a causal role of patent foramen ovale (PFO) in stroke, which has led to randomized trials of PFO device closure in patients under 60 years of age with strokes of undetermined origin. The first three trials compared device closure with either antiplatelet or anticoagulant treatment, with two showing a nonsignificant trend toward the benefit of device closure. Two subsequent trials compared device closure with antiplatelet treatment alone, both demonstrating significant benefits. An additional positive trial did not restrict medical treatment to antiplatelets but limited eligibility to patients with high-risk anatomic PFO features, such as larger shunt size and atrial septal aneurysm. A meta-analysis of all trials found that the number needed to treat with device closure to prevent one recurrent stroke was 131 during one person-year of follow-up or 13 during ten person-years, which may be clinically significant in this generally young population. Analysis of administrative claims data indicated a 4.9% rate of serious periprocedural complications, including atrial fibrillation, in patients aged 60 years or younger, while RCT data on PFO closure in patients over 60 are extremely limited, with a significantly higher rate of serious complications (10.9%) in this older age group. Recommendations for secondary stroke prevention in patients with a PFO should involve collaboration between a neurologist specializing in vascular neurology and a cardiologist experienced in PFO closure. Although one small trial included some patients over 60, it should not be interpreted as evidence of benefit for this age group, and the procedure should rarely be performed in older patients except in very unusual circumstances. A thorough evaluation must confirm that there is no alternative cause for the stroke, as all studies showing benefit from PFO closure excluded lacunar strokes, making the requirement for a cryptogenic stroke equivalent to a non-lacunar stroke of undetermined source or ESUS. Clinical judgment is essential, as many strokes in the ESUS category may not have a definite cause but could be attributed to lower-competing-risk conditions, such as proximal large artery disease with 40% stenosis. Observational data suggest that younger patients without other vascular risk factors are more likely to have PFOs related to their strokes, and the anatomic characteristics of the PFO should also be considered in decision-making. Recent trials comparing device closure to antiplatelet therapy and long-term follow-up from earlier trials have shown benefits of device closure, particularly in patients with high-risk anatomic features, including larger shunt size and atrial septal aneurysm. The individual patient-level meta-analysis of the first three trials found a slightly greater benefit among patients with these characteristics, although the differences did not reach statistical significance. The RESPECT trial indicated significant interactions between treatment and both larger shunt size and atrial septal aneurysm, with benefits observed only when either was present. A pooled analysis from medically treated patients found that atrial septal aneurysm, but not shunt size, was independently associated with recurrent stroke. A meta-analysis of PFO closure trials indicated that closure benefits patients with high-risk anatomic features, although this finding may be confounded by the higher proportion of high-risk features in trials showing benefit. If the PFO is deemed low risk based on anatomic features, it is crucial to consider other clinical factors to determine whether the PFO is likely related to the stroke or is incidental. The Risk of Paradoxical Embolism score can help stratify patients with cryptogenic stroke and PFO by their likelihood of a PFO-related stroke mechanism, with higher scores indicating a greater probability that the PFO is stroke-related. The evidence suggests that PFO closure in appropriately selected patients is superior to aspirin, but it remains unclear whether closure is superior to warfarin. A post hoc analysis of recurrent stroke in the CLOSE trial found no events in the device closure group and three in the warfarin group, but this difference was not statistically significant. Additionally, the long-term benefits of closure with a transcatheter device for preventing recurrent stroke in patients planned for long-term warfarin treatment are unknown. The authors emphasize the need for future research, including individual-level meta-analyses of all randomized trial data in patients with ESUS under 60 years of age to assess the benefits of PFO closure compared to aspirin in those without high-risk anatomic features, as well as studies comparing PFO closure to long-term anticoagulation. They also call for large, long-term prospective registries of patients with PFO closure to evaluate the risks of device-associated atrial fibrillation and complications such as device erosion, fracture, and endocarditis.
The 2021 AHA/ASA guideline for secondary stroke prevention recommends that in patients aged 18–60 years with a non-lacunar ischemic stroke of undetermined cause and PFO with high-risk anatomic features, PFO closure is reasonable after a multidisciplinary discussion and shared decision-making (Class IIa, Level of Evidence B-R). For patients without high-risk features or with competing mechanisms of stroke, medical therapy (antiplatelet or, in selected situations, anticoagulation) is preferred.
“In patients between the ages of 18 and 60 with a prior PFO‐associated stroke, the SCAI guideline panel recommends PFO closure rather than antiplatelet therapy alone (strong recommendation, moderate certainty of evidence). This recommendation is independent of patient anatomy (i.e., presence of ASA, size of shunt) due to limited clinical data on these sub‐populations. A Risk of Paradoxical Embolism Score of 7 may identify patients who are likely to receive greater benefit from PFO closure" (Kavinsky et al., 2022).
Kavinsky et al. (2022) discuss the SCAI guidelines regarding percutaneous patent foramen ovale (PFO) closure versus antiplatelet therapy in adults with a history of PFO-associated stroke. For patients aged 18 to 60, the guidelines strongly recommend PFO closure over antiplatelet therapy alone, regardless of patient anatomy, due to limited clinical data on specific sub-populations; a RoPE (risk of paradoxical embolism) score of 7 or higher may help identify those who would benefit most from closure. In patients aged 60 and older, the guidelines suggest PFO closure instead of long-term antiplatelet therapy, although this is a conditional recommendation with very low certainty of evidence, and patients may choose to decline the procedure if they prioritize the uncertain benefits over potential risks. For individuals with a history of atrial fibrillation who have experienced an ischemic stroke, the guidelines advise against routine PFO closure. In patients with thrombophilia who are on antiplatelet therapy but not anticoagulation and have had a prior PFO-associated stroke, PFO closure is suggested over antiplatelet therapy alone, although patients may opt out if they weigh the risks more heavily. The guidelines also refer to the previous recommendations for patients with high-risk anatomy or those evaluated with a RoPE score. Lastly, the SCAI panel does not provide recommendations regarding PFO closure based on the duration of time since the stroke, indicating a knowledge gap in this area.
In a 2024 AHA commentary on the need for guideline updates, it is noted that while the PASCAL Classification System is important for optimal treatment selection, it is not included in any current US clinical practice guidelines, rendering them outdated and suboptimal. The existing guidelines diverge from the latest evidence in significant ways that reflect the biases of the specialty groups that developed them. For instance, the SCAI interventional cardiology society guidelines are overly aggressive, recommending closure for more patients than current evidence supports, including some who may incur net harm. Conversely, the AAN guidelines are overly cautious, advocating for closure in fewer patients and with less certainty than the evidence now suggests. The multispecialty SC AHA guidelines occupy a middle ground; however, where they do provide recommendations, they tend to be overly cautious, suggesting closure for fewer patients than the evidence supports, while also indicating weak support for closure in additional patients, despite evidence showing that closure is indicated for some and contraindicated for others. The proposed updated recommendation states that for patients aged 18 to 60 years with an ischemic stroke of undetermined cause after thorough evaluation, and with either a PFO exhibiting high-risk anatomic features, a RoPE score of ≥7, or both, it is recommended or reasonable to opt for closure with a transcatheter device and long-term antiplatelet therapy over antiplatelet therapy alone for preventing recurrent stroke (Class of Recommendation 1 or 2a, Level of Evidence A or B-R) (Saver, 2024).
According to the European Stroke Organisation (ESO) 2024 guidelines, PFO is frequently identified in young patients with cryptogenic ischemic stroke, with potential stroke mechanisms including paradoxical embolism from a venous clot that traverses the PFO. Transient Ischemic Attack (TIA) is generally not regarded as an index event in this context, as only one randomized controlled trial (RCT) has included TIA patients; however, the ESO subgroup analysis showed no significant differences in outcomes between TIA and stroke. To assist clinicians in assessing the likelihood of stroke causality from a PFO in patients with cryptogenic stroke, two risk scores have been developed alongside a comprehensive clinical evaluation. The first, the Risk of Paradoxical Embolism (RoPE), primarily emphasizes clinical features, while the second, the PFO-Associated Stroke Causal Likelihood (PASCAL), is a classification system that integrates both the RoPE score and anatomical features. The PASCAL classification system evaluates the presence of features that heighten the likelihood of PFO-stroke mechanisms, such as high-risk physiological and structural characteristics like a large shunt or atrial septal aneurysm; and evaluates the absence of features that indicate alternative non-PFO stroke mechanisms, including older age, vascular risk factors, and specific stroke topography. For patients aged 18–60 years with possible or probable PFO-related stroke according to the PASCAL classification, the guidelines recommend PFO closure in addition to antiplatelet therapy (Quality of Evidence: moderate; Strength of Recommendation: strong for intervention). In the same age group with possible or probable PFO-related stroke, there is ongoing uncertainty regarding the risks and benefits of long-term anticoagulation versus PFO closure; however, the guidelines suggest PFO closure with antiplatelet therapy instead of long-term oral anticoagulants alone, based on the cumulative risk of major bleeding associated with long-term anticoagulation, and the demonstrated superiority of PFO closure over antithrombotic therapy in pivotal RCTs (Quality of Evidence: low; Strength of Recommendation: weak for intervention). For patients aged 18–60 years with unlikely PFO-related stroke according to the PASCAL classification, the guidelines advise against PFO closure unless there is a high probability of clinical causality (Quality of Evidence: low; Strength of Recommendation: weak against intervention). A majority of Module Working Group (MWG) members (7 out of 9 experts) recommend PFO closure in various scenarios that suggest a high probability of clinical causality, including non-cerebral embolism, deep venous thrombosis and/or pulmonary embolism close to the index stroke, pulmonary arterial hypertension, a history of sleep apnea or other hypoxic conditions associated with PFO, Valsalva maneuvers at stroke onset, migraine aura, recent prolonged immobility, recent airline travel, presence of venous thrombophilia, decompression illness in divers, platypnea-orthodeoxia syndrome, or anatomical features on echocardiography that increase the risk of paradoxical embolism.
Paradoxical embolism is traditionally understood as the migration of a thrombus from the venous system through a right-to-left shunt into the arterial circulation. Conditions that transiently elevate right atrial pressure, such as Valsalva maneuvers, coughing, and straining, can open the foramen ovale flap even without persistent right-to-left pressure gradients. While anticoagulation reduces venous thrombus formation, it does not completely eliminate it, allowing residual thrombi, even small ones, to cross the shunt. Consequently, the anatomical conduit remains, creating a pathway for stroke whenever transient pressure reversal occurs. Not all patent foramen ovale (PFO) cases are the same; high-risk features associated with increased odds of stroke or higher recurrence on medical therapy include a large right-to-left shunt, atrial septal aneurysm, long PFO tunnel, and prominent Eustachian valve or Chiari network. These characteristics have been consistently linked to a higher probability that the PFO is causal and to a greater benefit from closure compared to medical therapy, including anticoagulation. Modern PFO closure trials, such as RESPECT (long-term), CLOSE, REDUCE, and DEFENSE-PFO, predominantly enrolled patients aged 18–60 years with recent cryptogenic strokes, non-lacunar infarct patterns, and a PFO, randomizing participants to device closure plus antiplatelet therapy versus medical therapy (antiplatelet or anticoagulant) alone. The RoPE score estimates the likelihood that a detected PFO is causally related to a cryptogenic stroke rather than being incidental, incorporating factors such as age, cortical stroke location, history of hypertension, diabetes, prior stroke/TIA, and smoking status. Higher RoPE scores, typically seen in younger patients with fewer vascular risk factors and cortical infarcts, suggest a greater probability that the PFO is pathogenic; however, the RoPE score does not account for PFO anatomical features. The PASCAL classification, proposed by Kent and colleagues, combines the RoPE score with high-risk anatomical features (large shunt and atrial septal aneurysm) to categorize patients into groups where the PFO is considered unlikely, possible, or probable as the cause of stroke. It is important to note that both the RoPE score and PASCAL classification have not yet been fully validated in prospective studies, so their application in individual patient decision-making requires clinical judgment, serving as general guides to risk stratification rather than definitive criteria (Bhagat, 2026).
Patent Ductus Arteriosus
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 of 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 by 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 reduction (greater than or equal to 50%) 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 the 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 the 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 they 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 that 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 of 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 multivariate 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 aforementioned 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. The 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 aforementioned 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 regarding PFO management. Therapy remains a controversial issue, as data on these patients are variable and accepted guidelines are lacking. Recurrent strokes are the most common and widely accepted indication for transcatheter closure of PFO; however, severe refractory migraine with aura, unexplained oxygen desaturation, orthodeoxia-platypnea (related to aortic elongation, allowing significant right-to-left shunt), and other conditions have also been suggested to benefit from PFO closure. Various devices and techniques have been proposed for this procedure, primarily depending on operator experience and preferences. The authors concluded that PFO management is still a debated field, with indications, pathophysiology, and ideal closure techniques yet 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. They systematically searched BioMedCentral, Google Scholar, and PubMed from January 2000 to December 2008 for pertinent clinical studies, also utilizing secondary sources. Secondary prevention studies of transcatheter closure for PFO were required to include at least 10 patients followed for more than 6 months. The primary endpoint was the rate of cured or significantly improved migraine after percutaneous PFO closure. After excluding 637 citations, the investigators included a total of 11 studies involving 1,306 patients. Forty percent of the subjects included suffered from migraine, while most had a previous history of transient ischemic attack or stroke and were investigated retrospectively. Quantitative synthesis showed that complete cure of migraine occurred 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, particularly if treated after a neurological event, may benefit from percutaneous closure of their PFO. However, the authors noted that many questions remain unresolved.
The updated AAP 2025 clinical report on patent ductus arteriosus (PDA) in preterm infants provides an evidence-based framework for managing hemodynamically significant PDAs. Ambalavanan et al. (2025) note that despite extensive research involving thousands of infants over decades, uncertainty and controversy remain regarding the significance, assessment, and management of PDAs in preterm infants, leading to considerable variability in clinical practices. This report aims to review the existing evidence to guide the evaluation and treatment of preterm infants with prolonged ductal patency. Delayed closure of the PDA is common, especially in extremely immature infants, and echocardiography is crucial for confirming the presence of a PDA and assessing its hemodynamic significance. Medical closure using ibuprofen or acetaminophen is an option for hemodynamically significant PDAs (hsPDAs), but recent clinical trials have shown no benefits of prophylactic or early medical closure (before 2 weeks of age) compared to expectant management, leading to a recommendation against these practices. There is insufficient data to provide firm management recommendations for infants with hsPDAs beyond 2 weeks of age, as the relative benefits and risks of expectant management, pharmacologic closure, or procedural closure have not been adequately defined. Many clinicians still attempt medical closure of hsPDAs beyond this age, and if the PDA persists despite medical therapy or if such therapy is contraindicated, transcatheter closure or surgical ligation may be considered. Surgical closure has become less common in recent years, with transcatheter closure being more frequently utilized in many centers. While the adverse effects of hsPDAs are recognized, there is a lack of evidence to guide management, highlighting the need for balanced treatment options and further trials to expand the evidence base, particularly regarding long-term cardiopulmonary and neurodevelopmental outcomes. Key recommendations include that prophylactic medical treatment is not advised at any gestational age or birth weight, early closure (before 14 days of life) has not been shown to improve outcomes and is not recommended, and a conservative approach that allows for spontaneous closure may minimize unnecessary medical or procedural interventions. Beyond two weeks of life, management data for hsPDAs are limited, and further studies are needed to evaluate the risks and benefits of conservative management, pharmacologic therapy, transcatheter closure, and surgical ligation. Many clinicians may attempt medical closure with one or two courses of ibuprofen, with acetaminophen or indomethacin as acceptable alternatives, and transcatheter closure may be considered for infants with a persistent hsPDA beyond two weeks of life.
Catheter-Directed Therapy for Pulmonary Embolism in Pediatrics
Keller et al. (2024) stated that catheter-directed treatment (CDT) is an innovative approach for patients with elevated-risk pulmonary embolism (PE) aimed at resolving emboli and restoring pulmonary perfusion. This study analyzed the use and benefits of CDT in PE patients in Germany. The researchers utilized the German nationwide inpatient sample to include all hospitalizations of patients with PE from 2005 to 2020. PE patients were stratified based on CDT usage, and temporal trends along with the impact of CDT on case fatality and other outcomes were examined. A total of 1,373,084 hospitalizations of patients with PE were included, with 55.9% aged 70 years or older and 53.0% being women. Among these, 427,238 (31.1%) patients were categorized as having elevated-risk PE, and only 3,330 (0.2%) were treated with CDT, with an annual increase from 0.17% in 2005 to 0.51% in 2020. Younger age, male sex, previous surgery, and elevated-risk PE were associated with higher rates of CDT treatment. In patients with elevated-risk PE, CDT was linked to a lower observed rate of major adverse cardiac and cerebrovascular events (MACCE; 28.2% versus 34.2%; p < 0.001) and in-hospital case fatality (24.9% versus 31.0%; p < 0.001). CDT was associated with reduced MACCE (OR, 0.91; 95% CI: 0.83 to 0.99) and a trend toward lower case fatality (OR, 0.92; 95% CI: 0.84 to 1.01). The benefit of CDT regarding case fatality was found to be age-dependent. The authors concluded that although the annual rate of CDT increased in Germany between 2005 and 2020, only 0.2% of PE patients were treated with this method. They emphasized that careful patient selection is crucial to optimize outcomes and minimize risks, reinforcing the value of CDT in modern PE management strategies. However, they noted that randomized clinical trials are needed to provide more definitive answers regarding the role of CDT in PE.
The authors acknowledged several drawbacks in their study. First, the data were based on ICD discharge codes and OPS codes, which may be prone to under-reporting or mis-coding. Second, detailed baseline data such as concomitant medications, plasma cardiac troponin concentrations, and echocardiographic parameters were unavailable. Additionally, for vital signs recorded as continuous variables, exact values (e.g., heart rate or systolic blood pressure) were not available in the German nationwide inpatient sample; however, ICD coding allows for categorical analysis of those variables (such as tachycardia and shock). Third, the exact timing and course of hemodynamic instability and elevated-risk PE could not be determined. Fourth, the exact cause of death could not be obtained from the German NIS, although previous studies have indicated that most in-hospital deaths were related to the acute PE episode or complications of its treatment. Fifth, the selection of PE patients for different treatments was inconsistent and could not be controlled by the researchers, as they analyzed nationwide German inpatient statistics rather than randomized trials. They attempted to address this issue by adjusting for age, sex, and several comorbidities in their multi-variable regressions. However, they acknowledged that additional important selection criteria, such as approaching end of life in cancer patients, high risk of complications, and multi-morbid conditions, might have significantly impacted the decision not to use CDT in these patients. Sixth, due to the nature of administrative data regarding hospitalization, the authors could only provide data from the time-frame of hospitalization and had no data on later follow-ups, thus preventing them from providing data regarding 30-day mortality. Seventh, the term “elevated-risk PE” was only an approximation toward the categorization of the European Society of Cardiology guideline, reflecting patients who were at an elevated risk of death. The data included in the German NIS represent all population segments of Germany; however, information on socio-cultural determinants of health and race/ethnicity of the study population was unavailable, which may limit the transferability of the study results to other populations.
Zhang et al. (2025) noted that the recently published PEERLESS Trial compared CDT and catheter-based thrombectomy (CBT) in acute PE. However, it included a low proportion of patients with contraindications to thrombolytic therapy (4.4%), leaving uncertainty regarding how CDT would perform relative to CBT in a real-world cohort with higher bleeding risk. In a retrospective analysis, these investigators addressed this gap by comparing real-world outcomes of CDT and CBT in patients with acute PE. This trial included patients who underwent CDT and CBT at two tertiary care centers from January 2020 to January 2024. The primary outcome was a composite of 30-day mortality, resuscitated cardiac arrest, or hemodynamic decompensation. Secondary outcomes included major bleeding and intracranial hemorrhage (ICH). Inverse probability treatment weighting (IPTW) was employed to adjust for baseline variables. A total of 162 patients (mean age of 58 years, 45.7% women, 17.3% high-risk, 28% contraindication to lytics, 28% CDT, 72% CBT) were included, with 12.4% experiencing the primary outcome. There was no difference in the rates of the primary outcome between CBT and CDT (11.2% versus 15.2%; IPTW HR: 0.80; 95% CI: 0.27 to 2.38, p = 0.69). CBT was associated with a lower risk of hemodynamic decompensation (5% versus 21.7%, p = 0.036), major bleeding (7.8% versus 17.4%, IPTW HR 0.26; 95% CI: 0.07 to 0.95, p = 0.042), and ICH (0% versus 4.3%, p = 0.024) compared to CDT. The authors concluded that among a real-world cohort of patients with acute PE with a higher bleeding risk than those in the PEERLESS trial undergoing catheter-based therapies, CBT was associated with a lower rate of hemodynamic deterioration, major bleeding, and ICH, with a similar rate of the primary composite outcome when compared with CDT. They emphasized that additional RCTs are needed to validate these findings.
Alqeeq et al. (2025) noted that acute PE is a serious and potentially fatal condition that is relatively rare in the pediatric population. In patients presenting with massive or sub-massive PE, CDT presents an emerging therapeutic option. These investigators conducted a systematic review, searching electronic databases through May 2024, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines. A total of 16 case reports and series were included in the quantitative analysis, encompassing a total population of 40 children diagnosed with PE, of whom 21 were females and 19 were males. Massive PE was diagnosed in 15 patients, while sub-massive PE was diagnosed in 17 patients. Complete resolution of PE occurred at a rate of 68% (95% CI: 46% to 80%). Mortality was encountered at a rate of 18% (95% CI: 0.7% to 36%). PE recurred after CDT at a rate of 15% (95% CI: 2% to 28%). Non-major bleeding complications occurred at a rate of 46% (95% CI: 25% to 66%, p = 0.163). The authors concluded that CDT can be used in the management of PE in children as a potential therapeutic option for selected patients. They emphasized that while the results of CDT interventions for pediatric PE are promising, further investigations, including well-conducted cohort studies, are needed to validate these findings.
The authors noted that while this was the first meta-analysis to examine the use of CDTs in the treatment of acute PE in the pediatric population, it had two main drawbacks. First, due to the paucity of existing literature on this topic (i.e., no randomized trials or strong observational studies), the data incorporated into this analysis were primarily collected from case reports and case series, which are considered to have low strength of evidence. Second, the analysis was limited by the small number of included patients and the lack of data needed to carry out comparative analyses between systemic thrombolysis and CDTs, as well as to examine the performance of different catheter types and models.
In a retrospective cohort study, Zhang et al. (2025) examined the impact of early versus delayed CDTs on clinical outcomes in patients with acute intermediate-risk PE. These investigators analyzed data from two academic centers involving patients with intermediate-risk PE from January 2020 to January 2024. Subjects were divided into early (less than 12 hours) and delayed CDT (12 hours or longer) groups. The primary outcome was a composite of 30-day mortality, resuscitated cardiac arrest, hemodynamic instability, and 90-day re-admission. Secondary outcomes included a composite of 30-day mortality, resuscitated cardiac arrest, and hemodynamic instability. Inverse probability of treatment weighting was used to balance covariates. A total of 133 patients were included (mean age of 58.3 years; 44% women; 29% catheter-directed thrombolysis; 68% mechanical thrombectomy; and 3% both). The median time to intervention was 6.1 hours in the early group and 20.8 hours in the delayed group (p < 0.001). A total of 16 patients (12% of patients) experienced the primary composite outcome. Early CDT was associated with a significantly lower rate of the primary composite outcome (4% versus 18%; log-rank p < 0.001; IPTW HR, 0.13; 95% CI: 0.03 to 0.58; p = 0.007) and secondary composite outcome (0% versus 9%; log-rank p = 0.02). The early CDT group also had a shorter intensive care unit (ICU) stay (3.0 days versus 3.4 days; p = 0.01) and hospital length of stay (5.0 days versus 6.1 days; p = 0.046). When patients were stratified by timing of CDT (early/late) and the composite PE shock score (high 3 or higher; low less than 3), all 16 patients who experienced the primary composite outcome had a high composite PE shock score, with 14 out of 16 (87.5%) having a high composite PE shock score and delayed intervention. The authors concluded that early CDT was associated with improved clinical outcomes in patients with acute intermediate-risk PE. They suggested that the composite PE shock score may aid in identifying patients who will benefit from early CDT. Furthermore, they stated that further prospective studies are needed to validate these findings.
Left Atrial to Coronary Sinus Shunting (the APTURE Transcatheter Shunt System)
Hibbert et al. (2023) stated that heart failure (HF) is associated with both mortality and a significant decline in health status. Inter-atrial shunting is increasingly being examined as a novel therapeutic option. The ALT FLOW Early Feasibility Study was a non-blinded, single-arm study designed to assess the safety of the Edwards left atrial to coronary sinus APTURE Transcatheter Shunt System in patients with symptomatic HF. A total of 18 centers enrolled patients with symptomatic HF who had a pulmonary capillary wedge pressure (PCWP) greater than 15 mm Hg at rest or 25 mm Hg during exercise. Between May 2018 and September 2022, 87 patients underwent attempted APTURE shunt implantation. The mean age of participants was 71 years, and 53% were men. At baseline, the mean left ventricular ejection fraction (LVEF) was 59%, with 90% of the patients classified as New York Heart Association (NYHA) functional class III. Device success was achieved in 78 patients (90%), with no device occlusions or associated adverse events (AEs) identified after implantation. The primary safety outcome occurred in only 2 patients (2.3%) at 30 days. At 6 months, health status improved significantly: 67% of participants achieved NYHA functional class I to II status, with a 23-point improvement (p < 0.0001; 95% CI: 17 to 29 points) in the Kansas City Cardiomyopathy Questionnaire overall summary score. Additionally, the 20-W exercise PCWP was 7 mm Hg lower (p < 0.0001; 95% CI: -11 to -4 mm Hg) at 6 months, with no change in right atrial pressure or other right heart function indices. The authors concluded that in this single-arm experience, the APTURE Transcatheter Shunt System was observed to be safe and resulted in a reduction in pulmonary capillary wedge pressure and clinically meaningful improvements in HF symptoms and quality of life (QOL) indices. They emphasized that a definitive randomized, sham-controlled study is needed to establish the impact on clinical outcomes in the treatment of patients with HF.
The authors acknowledged that as an early feasibility study, the sample size was small (n = 87), which only allowed for conclusions regarding the feasibility and safety of implantation, as well as some estimates of an effectiveness signal, albeit for the relatively short follow-up period of 6 months. They noted the lack of a sham-control arm and blinding, which means the impact and potential magnitude of a placebo effect on the results could not be estimated or discounted. However, they expressed hope that the use of core laboratories and independent clinical event adjudication would make these findings more likely to be reproducible in a more definitive clinical trial.
Neovasc Reducer (Coronary Sinus Reducer) for Relief of Angina Symptoms
The Neovasc Reducer (Reducer) implant procedure involves the transcatheter implantation of a coronary sinus (CS) reduction device aimed at relieving angina symptoms by altering blood flow within the cardiac myocardium and increasing the perfusion of oxygenated blood to ischemic areas. The CS Reducer is implanted through a minimally invasive transvenous procedure, similar to the insertion of a coronary stent, typically completed in about 20 minutes.
Giannini and colleagues (2018) described the CS Reducer as a novel device that aids in managing patients with severe angina symptoms refractory to optimal medical therapy and not amenable to further revascularization. In a single-center study, they examined the safety and efficacy of the CS Reducer in a cohort of patients with refractory angina. A total of 50 patients with refractory angina and objective evidence of myocardial ischemia, deemed unsuitable for revascularization, underwent CS Reducer implantation between March 2015 and August 2016. Safety endpoints included procedural success and the absence of device-related adverse events (AEs). Efficacy endpoints, assessed at 4- and 12-month follow-up, included a reduction in Canadian Cardiovascular Society (CCS) angina class, improvement in quality of life (QOL) measured by the Seattle Angina Questionnaire (SAQ), improvement in exercise tolerance evaluated using the 6-minute walk test (6MWT), and reduction in anti-anginal medications. Procedural success was achieved in all patients, with no device-related AEs during the procedure or follow-up. Regarding efficacy, 40 patients (80%) experienced at least a 1-class reduction in CCS class, and 20 patients (40%) had at least a 2-class reduction, with a mean class reduction from 2.98 ± 0.52 to 1.67 ± 0.83 (p < 0.001) at 4-month follow-up. All SAQ items improved significantly (p < 0.001). A significant increase in 6MWT distance was observed (388.6 ± 119.7 m versus 287.0 ± 138.9 m; p = 0.004), and 16 patients (32%) and 3 patients (6%) demonstrated reductions of at least 1 or 2 anti-anginal drugs, respectively. The benefits of CS Reducer implantation observed at 4 months were maintained at 1 year. The authors concluded that CS Reducer implantation appeared safe and was associated with a reduction in anginal symptoms and improvement in QOL for patients with refractory angina who were not candidates for further revascularization. They noted the main drawbacks of the study included the absence of a control group and the small sample size (n = 50), as well as the lack of objective measurement of myocardial ischemia reduction following implantation.
In a systematic review, Bazoukis and associates (2018) examined the efficacy of the CS Reducer in patients with refractory angina. They conducted a systematic search of the Medline and Cochrane library databases for studies describing the safety and efficacy of the CS Reducer from January 1, 2000, to May 12, 2018, using the search terms "coronary sinus (reducer OR reducing) device." Efficacy was defined as a greater than or equal to 1-unit improvement in the CCS score. The search yielded 6 studies (5 observational studies and 1 randomized clinical trial) involving 196 patients. The CS Reducer was effective in 146 of 186 (78.5%) patients, with the CCS score improving from 3.2 at baseline to 1.9 after an average follow-up of 8.6 months. Efficacy was also demonstrated through improvements in SAQ scores, dobutamine echocardiography, thallium single-photon emission computed tomography (SPECT) perfusion studies, 6MWT, and myocardial perfusion reserve index. Implantation failed in 4 of 196 (2%) patients, and 5 patients (2.5%) experienced complications during the 30-day follow-up. The authors concluded that the CS Reducer is a promising therapeutic option for patients with refractory angina who are not candidates for revascularization; however, larger randomized controlled trials (RCTs) with long-term follow-up are needed to clarify its role.
In a health technology assessment (HTA), Stanak et al. (2020) examined the evidence on the safety and effectiveness of coronary sinus reducing stent (CSRS) therapy for refractory angina pectoris (AP). They conducted a systematic literature search across four common databases and summarized the evidence according to GRADE methodology. The HTA was performed using the HTA Core Model for Rapid Relative Effectiveness Assessment. Primary outcomes for clinical effectiveness included the proportion of patients with improvement in 2 or more CCS angina score classes, overall mean reduction of CCS class, and SAQ QOL score improvement. Safety outcomes included adverse device effects (ADEs) and serious adverse device effects (SADEs). The researchers identified 1 RCT, which showed statistically significant differences favoring CSRS over sham treatment in terms of CCS angina score improvement of 1 or 2 classes, overall mean reduction of CCS class, and SAQ QOL score improvement. Regarding safety, the sham-controlled trial data indicated fewer SADEs in the intervention group (19%) compared to the control group (46%). SADEs reported in observational studies ranged from none to 30%, with the most frequently reported SADEs being death and stable angina. The only death in the RCT occurred in the control group. The authors concluded that it was unclear if the CSRS could improve CCS angina score and QOL without causing more SADEs than the sham intervention, based on moderate quality evidence. They cited inconsistent results, incomplete safety data regarding dual antiplatelet therapy, inappropriate inclusion criteria, insufficient sample size, and incomplete blinding in the RCT as limitations. They emphasized the need for better-powered RCTs with longer follow-up to determine the role of treatment modalities for specific subgroups and ascertain benefits beyond placebo effects.
D'Amico and co-workers (2021) noted that the CS Reducer is a novel device designed for managing patients with severe angina symptoms refractory to optimal medical therapy and not amenable to further revascularization. In a country-level, multi-center cohort study, these investigators examined the safety and efficacy of the CS Reducer device in patients with refractory angina pectoris. The trial included patients who underwent CS Reducer implantation in 16 centers, with clinical follow-up performed according to each center's protocol. A total of 187 patients were included; technical and procedural success rates were 98% and 95%, respectively. Minor peri-procedural complications were observed in 8 patients. During a median follow-up of 18.4 months, 135 (82.8%) patients demonstrated at least 1 CCS class reduction following CS Reducer implantation, and 80 (49%) patients had at least a 2 CCS class reduction. Mean CCS class improved from 3.05 ± 0.53 at baseline to 1.63 ± 0.98 at follow-up (p < 0.001). Treatment benefits were also reflected in significant improvements in QOL scores and a reduction in the mean number of anti-ischemic drugs prescribed. The authors concluded that CS Reducer implantation in patients with refractory angina pectoris was safe and effective in reducing angina symptoms and improving QOL, extending the findings of the 2018 study by Giannini et al. with additional participants.
Madeira and associates (2021) stated that refractory angina is defined as persistent angina (greater than or equal to 3 months) despite optimal medical and interventional therapies. The frequency of refractory angina is increasing due to the success of current therapies in improving the prognosis of coronary artery disease (CAD). Long-term mortality rates are similar to those of patients with asymptomatic stable disease; however, refractory angina significantly impacts patients' QOL and healthcare resources. Several therapeutic targets have been examined, most with disappointing results, leading to the abandonment of many techniques due to lack of efficacy, safety issues, or economic and logistic limitations. The primary focus of this review was the coronary sinus Reducer, which, although evidence is scarce, shows promise regarding safety and efficacy in improving anginal symptoms and QOL. The device is accessible to virtually all interventional cardiology departments.
Medranda and colleagues (2021) noted that refractory angina is considered a devastating condition with limited medical and therapeutic options. The Neovasc Reducer device, implanted in the coronary sinus, is designed to alleviate anginal symptoms; however, available clinical data are sparse. The FDA assembled the Circulatory Systems Devices Panel to discuss the Reducer's safety and effectiveness, with the meeting held virtually due to the COVID-19 pandemic. The authors detailed the deliberations and discussions among the panel members, including their final vote.
Konigstein et al. (2021) stated that the long-term benefit of the CS Reducer in treating patients with refractory angina remains unclear. In a prospective, multi-center observational study, patients undergoing successful CS Reducer implantation were enrolled in clinical registries at three medical centers. Those with more than 2 years of follow-up were included in the analysis. Peri-procedural data, adverse event data, and current evaluations of angina severity (CCS class) were collected. A total of 99 consecutive patients (77% men, mean age 69.8 ± 9.4 years) with severe angina were enrolled between September 2010 and October 2017. No procedure-related complications were recorded. During a median follow-up of 3.38 years (IQR 2.95 to 4.40), 15.1% of patients died, 9% experienced myocardial infarction (MI), and 21% underwent percutaneous coronary intervention (PCI). Mean CCS class improved from 3.1 ± 0.5 at baseline to 1.66 ± 0.8 at 1 year (p < 0.001) and remained low at 2 years and the last follow-up (1.72 ± 0.8 and 1.71 ± 0.8, p > 0.5 for both compared to 1 year). At baseline, 91% of patients reported severe disabling angina (CCS class 3 to 4), while only 17.9% suffered from disabling angina at 1 year (p < 0.001), with this proportion remaining low over time (19% at last follow-up). The authors concluded that the long-term mortality of patients undergoing CS Reducer implantation was similar to that reported for patients with stable coronary artery disease. The previously reported short-term efficacy of the CS Reducer, reflected by significant improvement in angina symptoms, was maintained over time. However, they noted that it still needs to be examined in larger long-term studies using objective methods to assess myocardial ischemia, to determine whether the objective reduction in ischemic burden is also maintained over time.
The authors acknowledged several limitations in their study. First, the observational nature of the study precluded them from mitigating the placebo effect, which has been widely reported in previous refractory angina studies. However, objective improvement in indices of myocardial ischemia has been demonstrated in prior studies, and clinical benefit was already tested in a randomized sham-controlled study. Second, as data regarding adverse events were partially collected retrospectively from clinical documents and patient interviews, some events may not have been captured. Third, differences in data collection and event definitions could exist between centers and might have influenced the findings. Fourth, the outcomes reported were for patients who completed 2 years of follow-up, which might create a survival bias; thus, the mortality rate of the entire population (n = 197) was also provided. Finally, data regarding the cause of death were not available for all patients, and therefore only total mortality was reported.
Cheng et al. (2022) stated that refractory angina results in poor QOL and increased healthcare resource utilization. In this growing population of patients, multiple mechanisms of ischemia may coexist, including functional disorders of the coronary microcirculation. There are few evidence-based effective therapies, resulting in a large unmet clinical need. These investigators described the case of a 38-year-old woman with refractory angina, who was referred with daily chest pain despite multiple anti-anginal medications and previous PCI. Cardiac magnetic resonance imaging (MRI) demonstrated apical hypertrophic cardiomyopathy (HCM). Rubidium-82 positron emission tomography (PET) with regadenoson stress confirmed significant myocardial ischemia in the apex and apical regions (16% of total myocardium) with a global myocardial perfusion reserve (MPR) of 1.23. Coronary angiography confirmed patent stents and no epicardial coronary artery disease (CAD); thus, the mechanism of ischemia was attributed to coronary microvascular dysfunction (CMD) in the context of HCM. Given her significant symptoms and large burden of left-sided myocardial ischemia, a coronary sinus reducer (CSR) was implanted. Repeat PET imaging at 6 months showed a marked reduction in ischemia (less than 5% burden), improvement in global MPR (1.58), symptoms, and QOL. The authors concluded that in refractory angina, ischemia may be due to disorders of both the epicardial and coronary microcirculations. The CSR is a potential therapy for these patients; however, its mechanism of action has not been confirmed. This report suggested that CSR implantation may reduce myocardial ischemia and improve symptoms by acting on the coronary microcirculation. They emphasized that the effectiveness of CSR in patients with CMD and its mechanism of action on the coronary microcirculation warrant further systematic evaluation.
Picchi et al. (2022) noted that the CSR could be considered for treating refractory angina in patients unsuitable for coronary revascularization; however, its effect could be influenced by significant heterogeneity in the anatomy of the cardiac venous system. They reported on the case of a 70-year-old woman with recurrent episodes of rest angina refractory to optimal medical therapy (CCS Class IV) and inducible ischemia in a large myocardial territory. Given the diffuse and peripheral nature of her coronary disease, the patient was considered ineligible for percutaneous or surgical revascularization and was regarded as a good candidate for CSR. Since coronary venous angiography showed the middle cardiac vein (MCV) to be at least as relevant as the CS, successful implantation of two devices—one in the CS and the other in the MCV—was performed. At 6-month follow-up, the patient reported significant improvement in angina, resulting in a reduction of the CCS class from grade IV to grade III. The authors concluded that in patients with refractory angina who are good candidates for CSR implantation, a thorough understanding of the cardiac venous drainage pathway is crucial to ensure the therapeutic success of the procedure. In this patient, since both the CS and MCV appeared to contribute equally to coronary venous drainage, CSR implantation in both vessels allowed for significant symptom improvement. They stated that the clinical effectiveness of this strategy needs to be validated in randomized clinical trials.
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 the Nit-Occlud Lê VSD Coil. Between January 2012 and December 2013, at the cardiology department of Tanta University Hospital in Tanta, Egypt, a total of 80 patients underwent percutaneous VSD closure using the Nit-Occlud Lê VSD Coil. Early and mid-term follow-up was conducted for 3 years, concluding 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 the 80 patients had peri-membranous VSD (pmVSD) with aneurysmal tissue; 8 had multiple right ventricular exits, 14 had a deficient aortic rim, 2 had high outlet muscular VSDs, and 1 had a Gerbode defect. The procedure was successful in 98.75% of patients, with the procedure aborted in 1 patient due to the development of complete heart block, necessitating coil removal. The mean procedure time was 104.98 ± 9.50 minutes, and the mean fluoroscopy time was 30.58 ± 2.79 minutes. The immediate complete occlusion rate was 62%, which increased to 82.3% on the second day, 94.9% by the third month, and 97.5% by one 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, which remained unchanged during the follow-up period. The authors concluded that the use of the Nit-Occlud Lê VSD Coil to close VSDs was safe and feasible for various morphologies. However, they acknowledged the study's limitations, including its retrospective, single-center design, and suggested that larger, prospective, and possibly randomized multi-center studies are needed.
Houeijeh and associates (2020) stated that transcatheter pmVSD closure remains challenging and is seldom used in France due to the risk of atrioventricular block (AVB); 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. They included all consecutive cases of pmVSD closure with the Nit-Occlud Lê VSD coil in 20 tertiary French centers between January 2015 and December 2018. Among 46 procedures performed in 5 centers, indications for pmVSD closure included left ventricular (LV) overload (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. Aneurysmal tissue was identified in 91.3% of patients; the median (IQR) size of the VSD 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%), primarily severe hemolysis (8.7%; 95% CI: 2.4 to 20.8%); 1 patient required surgical aortic valvuloplasty due to an aortic valve lesion. The 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 in 15% after a median follow-up of 27 months. No immediate or delayed device embolization or complete atrioventricular block (cAVB) was recorded. The authors concluded that pmVSD closure with the Nit-Occlud Lê VSD Coil was feasible in older children and adults. However, they cautioned that residual shunting, which can lead to hemolysis, was a concerning complication that should not be tolerated. They noted 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, 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 outcomes 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 included an ejection fraction (EF) greater than 45%, baseline pulmonary capillary wedge pressure (PCWP) of greater than or equal to 15 mmHg at rest or greater than or equal to 25 mmHg during exercise, and greater than or equal to 1 hospitalization for heart failure within the past 12 months or persistent New York Heart Association (NYHA) class III/IV for at least 3 months. The mean age, left ventricular ejection fraction (LVEF), and NYHA class were 70 ± 12 years, 57 ± 9%, and 3.2 ± 0.4, respectively. Most patients had significant comorbidities. The inter-atrial septal device (IASD) was implanted using percutaneous trans-septal access via the femoral vein, and 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 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; two serious adverse events (SAEs) occurred: heart failure re-hospitalization and implant malposition, which was successfully treated with a new device. The authors concluded that contemporary management of HFpEF patients is 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, warranting further investigation. They cautioned that these findings should be interpreted with caution due to the limited size of the patient cohort (n = 11) and the lack of a control group.
Shad and associates (2018) noted that in patients with heart failure 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. However, the longer-term safety and patency of the IASD have not yet been demonstrated in the setting of a randomized controlled trial (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 conducted in 22 centers across Australia, Europe, and the U.S. on patients with NYHA class III or ambulatory class IV heart failure, LVEF equal to or greater than 40%, exercise PCWP equal to or greater than 25 mmHg, and a PCWP-right atrial pressure (RAP) gradient equal to or greater than 5 mmHg. Safety was evaluated by major adverse cardiac, cerebrovascular, or renal events (MACCRE). Exploratory outcomes evaluated at 1 year included hospitalizations for heart failure, 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 between 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 heart failure 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. They noted that through 1 year of follow-up, IASD treatment appeared safe, with no significant differences in MACCRE between patients receiving IASD and those receiving sham control treatment. However, they emphasized that a larger study is needed for further clinical evaluation, and a larger-scale, blinded, sham-controlled, pivotal RCT is currently underway to determine the clinical efficacy of the IASD in heart failure with an EF equal to or greater than 40%.
The authors acknowledged that this study was limited by its relatively small sample size (n = 44; 21 received IASD), which 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 heart failure hospitalization in the year before the study began. These imbalances did not affect the main 1-year results; however, they indicated the limitations of a small sample size.
Kaye and co-workers (2019) noted that impaired left ventricular 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 heart failure 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 (MAGGIC) HF risk survival score. Based on the individual baseline demographic and cardiovascular profile of the study cohort, the MAGGIC 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 6 months post-IASD 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. They 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 noted several limitations in their study. First, it was an open-label study. Second, although the predicted survival was consistent with other reports in HFpEF patients, the use of the MAGGIC score to derive a comparator survival curve may have generated an overestimation of the true survival in a contemporaneous group. Finally, while protocol-driven safety outcome follow-up was available for up to 3 years, complete NYHA class data 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 associated with high mortality and significant morbidity, with very limited medical treatment options available. Studies have shown that the pathophysiological hallmark of this condition is elevated LAP, with exertional dyspnea being its clinical manifestation. The increasing pressure from the left atrium is not based on volume overload (as in heart failure with reduced ejection fraction) but rather on diastolic left ventricular dysfunction combined with inter-atrial dyssynchrony, mimicking a pseudo-pacemaker syndrome. These investigators summarized current knowledge and discussed future directions for the newest interventional percutaneous therapies for HFpEF. Novel interventional approaches developed to counter these mechanisms include left atrial decompression (IASDs), enhancement of left ventricular compliance (LV expanders), and inter-atrial resynchronization therapy (left atrial permanent pacing). To date, IASDs are the most studied and are the only devices currently tested in a phase-III clinical trial. Recent data indicate that IASDs are feasible, safe, and provide short-term clinical benefits in HFpEF patients. LV expanders and left atrial pacing therapy present with smaller clinical benefits compared to IASDs, but they are safe, with no major adverse outcomes currently noted. With further development and improvement of these mechanism-specific devices, it will be interesting to determine if a complex intervention involving multiple HFpEF device implantations will be safe and beneficial for HFpEF patients.
Berry and colleagues (2020) stated that a randomized, sham-controlled study in patients with heart failure and LVEF of greater than or equal to 40% demonstrated reductions in PCWP with a novel transcatheter IASD. However, 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 heart failure with elevated LAP. Up to 608 heart failure patients aged 40 years or older with LVEF of greater than or equal to 40%, PCWP of greater than or equal to 25 mmHg during supine ergometer exercise, and PCWP of greater than or equal to 5 mmHg higher than RAP will be randomized 1:1 to 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 first non-fatal ischemic stroke through 12 months; total (first plus recurrent) heart failure 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 trial is designed to evaluate the clinical efficacy of the IASD device in patients with symptomatic heart failure 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 patients continues to grow. Because there is no effective therapy established as a standard, including pharmacotherapies, the movement to develop and evaluate device-based therapies is an important emerging area in the treatment of HFpEF patients. Many devices target reducing LAP or PCWP, as these are strongly related to the symptoms and prognosis of HFpEF; however, the methodology to achieve this varies based on the devices. These researchers summarized and categorized these devices into the following: IASDs, left ventricle expanders, electrical therapy, left ventricular assist devices (LVADs), and 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 or therapeutic option.
Transcatheter Device Closure of Peri-Membranous Ventricular Septal Defect
Santhanam and colleagues (2018) noted that while transcatheter device closure of ventricular septal defects (VSDs) is gaining popularity, concerns remain about adverse events (AEs), particularly heart block in peri-membranous VSDs (pmVSDs). In a meta-analysis, these researchers examined the outcomes of transcatheter device closure of pmVSDs. They performed a PubMed and Scopus search for studies in English on device closure of pmVSDs published until the end of February 2017. Exclusion criteria included case series already included in multi-center studies, sample sizes of less than 5, and VSDs acquired following myocardial infarction (MI). Pooled estimates of success and complications were 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 atrioventricular 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. They anticipated that the risk would further reduce with newer devices that are less stiff and have improved profiles. They stated that further studies validating this would 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 conducted a network meta-analysis to compare the three approaches in patients with pmVSD. They searched for comparative studies on device closure and conventional repair for pmVSD up to April 2020. A network meta-analysis was carried out under the frequentist framework with risk ratios (RR) and 95% confidence intervals (CI). The main outcome was the procedural success rate. Additional outcomes included postoperative complications, such as residual shunt, intra-cardiac conduction block, valvular insufficiency, incision infection, and pericardial effusion. A total of 24 studies involving 8,113 patients were included in the comparisons. The pooled estimates of success rate favored CSR compared with PDC. No significant differences in success rate were found between TDC and CSR or between PDC and TDC. The pooled estimates of incidences of residual shunt, new tricuspid regurgitation, incision infection, and pericardial effusion favored PDC compared with CSR. There were no significant differences between PDC and TDC in all outcomes except for new aortic regurgitation. The authors concluded that the PDC technique not only reduced the risk of significant complications compared with CSR but also produced non-inferior results compared with TDC in selected pmVSD patients. The PDC technique appeared to be a safe and effective option for selected patients with pmVSD.
The authors acknowledged several drawbacks in their study. First, most studies were from China, which might have resulted in regional bias. Second, some included studies involved different designs and patients with different VSD types, potentially leading to heterogeneity. It was difficult to segregate different VSD types in some studies. To account for heterogeneity in treatment effects, these researchers used a random-effects model and excluded studies that reported patients with unclear or other types of VSD. Third, the follow-up intervals in different studies varied and were no longer than 5 years. Studies with long-term follow-up are needed. Fourth, due to the limited number of three-arm studies, many pooled estimates of PDC versus TDC were derived from indirect comparisons without testing for inconsistency.
Transcatheter Removal or Debulking of Intra-Cardiac Mass (e.g., the AngioVac System)
Hameed and colleagues (2019) noted that the AngioVac is a new device designed for filtering intravascular thrombi and emboli. However, publications on the device are limited and underpowered to objectively estimate its safety and efficacy. To address this gap, these researchers performed a meta-analysis on the results of the AngioVac System for treating venous thromboses and endocardial vegetations. They conducted a systematic literature review to identify all articles reporting cardiac vegetation and/or thrombosis extraction using AngioVac. The endpoints included successful removal, operative mortality, conversion to open surgery, hospital length of stay (LOS), recurrent thromboembolism, and follow-up mortality. A random effects model was used to calculate pooled event rates (PERs) and incidence rates (IR). A total of 42 studies involving 182 patients (81 with vegetation and 101 with thrombosis) were included. The overall mean follow-up times were 3.1 years for vegetation patients and 0.7 years for thrombosis patients. The PERs for successful removal were 74.5% (CI: 48.2 to 90.2) for vegetation, 80.5% (CI: 70.0 to 88.0) for right atrial/caval venous thrombi, and 32.4% (CI: 17.0 to 52.8) for pulmonary emboli patients. The PERs for operative mortality were 14.6% (CI: 7.7 to 25.8) for vegetation, 14.8% (CI: 8.5 to 24.5) for thrombosis, and 32.3% (CI: 15.1 to 56.3) for pulmonary emboli. The IR of recurrent thromboembolism was 0.18/person/year (PPY) (CI: 0.00 to 14.69) in vegetation and 0.19 PPY (CI: 0.08 to 0.48) in thrombosis patients; the IR of follow-up mortality was 0.37 PPY (CI: 0.11 to 1.21) in thrombosis patients. The authors concluded that the AngioVac System is a viable option for extracting right-sided vegetations and right atrial/caval venous thrombi, although rates of successful extraction and mortality were significantly worse for pulmonary emboli.
Kiani and associates (2019) noted that consensus statements on percutaneous lead extraction recommend considering open surgical removal in cases of large vegetations to mitigate the risk of massive embolism that may occur with percutaneous lead removal. Vacuum-assisted debulking (VD) of large vegetations as an adjunct to percutaneous lead extraction may help reduce these risks. These researchers retrospectively identified all patients undergoing percutaneous lead extraction for endovascular infection at their institution from 2012 to 2018, stratifying them into two groups based on the presence of adjunctive VD (n = 6) or without VD (no-VD, n = 39); VD was performed using the AngioVac System. The mean age across the cohort was 62 ± 15 years, with an ejection fraction (EF) of 41 ± 16%, and 39% had end-stage renal disease (ESRD) on dialysis. Defibrillator systems were present in 71%, and 22% had cardiac resynchronization devices. The mean duration of the oldest extracted lead was 6.3 ± 4.9 years. There were no significant differences in baseline covariates between groups, although those in the VD group were significantly less likely to have Staphylococcus aureus as a causative organism (p = 0.04). In the VD group, vegetations targeted for debulking ranged in size from 1.8 to 6 cm (longest dimension). There were no operative deaths or clinically evident embolic events in either group, but the overall non-fatal complication rate in the VD group was higher (33.3% versus 2.3%, p = 0.043). The authors concluded that VD can be performed as an adjunct to percutaneous lead extraction with a reasonable safety profile, but further study is needed to assess the relative safety and efficacy of this removal approach.
Koney and co-workers (2019) stated that infective endocarditis (IE) in the pediatric population is uncommon and presents with non-specific signs. Nonetheless, prompt diagnosis and management are critical due to its high mortality rate. They presented the case of a 15-year-old boy who initially presented with bilateral multi-focal pneumonia and was found to have IE with a right ventricular vegetation. The vegetation was removed percutaneously, avoiding a more invasive surgical approach. The patient tolerated the procedure well and rapidly improved following the removal of the vegetation. The authors concluded that this case report highlighted the use of a novel, minimally invasive approach (the AngioVac System) for managing cardiac masses. They suggested that the AngioVac System may play an important role as a bridge or potential alternative to more invasive surgical options, although more data are needed.
The authors acknowledged that the main drawbacks regarding the use of the AngioVac System include the availability of the device and local expertise. In the pediatric population, the size of peripheral access vessels for the introduction of the large diameter aspiration and reperfusion cannulas limits its current use to older children. They suggested that smaller caliber, low-profile aspiration and reperfusion cannulas may be developed in the future for use in younger children.
Green et al. (2020) stated that cardiac implantable electronic devices (CIED)-associated IE complicated by septic emboli and acute on chronic pulmonary hypertension is rare. They presented a case where pulmonary thromboendarterectomy was required for treatment. A 55-year-old man with a history of myocardial infarction and ischemic cardiomyopathy, status post implantable cardioverter-defibrillator (ICD) placement 8 years prior, presented with bacteremia, infected ICD, and tricuspid valve vegetation. He underwent CIED extraction along with the use of the AngioVac suction device to remove right ventricular and atrial vegetations; however, the patient had persistent valvular vegetation and bilateral sub-massive pulmonary emboli. Pulmonary angiography showed filling defects in the lobar and segmental arteries. Percutaneous attempts at embolectomy were unsuccessful, leading to pulmonary endarterectomy (PTE). The authors concluded that this case of CIED-associated IE demonstrated the importance of early aggressive treatment of such infections, noting that guidelines recommend complete CIED system removal when there is associated infection. They stated that the AngioVac System is a novel system for removing right-sided vegetations and thrombi, but complications such as distal embolization could occur.
Bangalore et al. (2021) noted that tricuspid valve endocarditis with recurrent septic pulmonary emboli is an indication for surgery. They presented the case of a 36-year-old man with tricuspid valve endocarditis and septic pulmonary emboli who underwent percutaneous extraction of the vegetation using the AngioVac System. The authors discussed the nuances of this approach and emphasized the need for more evidence in managing these complex patients.
Vera-Sarmiento et al. (2021) stated that catheter-directed thrombectomy is a promising, novel therapy with little published experience. Previous reports have described it as a useful tool in high-risk patients needing intravascular material resection. They presented a unique case of AngioVac device thrombectomy in a patient with right atrial catheter-associated thrombus and gastrointestinal (GI) bleed that contraindicated other thrombectomy therapies due to severe anemia and high bleeding risk. In their literature review, they identified a total of 45 cases of AngioVac use for thrombus aspiration, including 15 cases from a single-center report published by Donaldson et al. in 2015. In those 45 cases, the main clinical manifestation was dyspnea in 13 cases, followed by incidental findings of thrombi in 6 cases and palpitations in 5 cases. The initial diagnosis was made by transesophageal echocardiography (TEE) in 7 cases, and not specified in 9 cases, with CT scans and venograms in 7 and 4 cases, respectively. Only 3 cases were initially diagnosed by transthoracic echocardiography (TTE). In 15 cases, neither the clinical manifestations nor diagnostic approach was described. No report described upper GI bleeding as a clinical finding. The authors concluded that percutaneous thrombectomy with the AngioVac device is a promising therapy that requires more well-designed trials to examine specific outcomes and to address questions regarding precise indications and contraindications, as well as complication and failure rates.
Furthermore, an UpToDate review on “Overview of management of infective endocarditis in adults” (Wang and Holland, 2021) does not mention AngioVac as a management or therapeutic option.
Qintar et al. (2021) stated that multiple case reports have been published on the use of the AngioVac system for right-sided clots or vegetations, with a few others reporting AngioVac use in the aorta. This case was the first to employ trans-caval access for the successful aspiration of the mobile part of a large aortic arch thrombus. The authors concluded that future studies are needed to further define this approach.
Katapadi and associates (2021) noted that intra-cardiac and intra-vascular masses previously required surgical excision, but now there are several minimally invasive options. With the advent of vacuum aspiration, specifically the AngioVac System, there exists a method with both low mortality and minor complications. However, the number of retrospective studies remains limited, and outcome data for high-risk patients are also scarce. In an observational, single-center study, these investigators described their institution's experience with the AngioVac system. Data were collected and analyzed for patients who underwent AngioVac therapy at their tertiary care center from January 2014 to December 2020. Their findings demonstrated a 93.3% intra-operative success rate and a 100% intra-operative survival rate; however, several complications, including hematomas, anemia, and hypotension, occurred. The authors concluded that the use of the AngioVac System has been demonstrated in multiple case studies and a few retrospective studies. They presented their institution's experience, showing good intra-operative survival and success despite patients being critically ill with large vegetative masses. They stated that these findings support the use of AngioVac in the cardiac catheterization laboratory as a therapeutic option for right heart masses in critically ill patients with high surgical risk. They emphasized that larger studies are needed to determine safety in large vegetations and the use of AngioVac in right-sided endocarditis. They noted that despite promising results at 30 days, the data were limited by study size at a single center, and a larger patient population is needed. Furthermore, there are no prospective studies comparing surgery or medical management to AngioVac, indicating that more studies are needed to determine if AngioVac has a mortality benefit over surgical or medical management.
Haupt et al. (2021) noted that the AngioVac system provides a method for the minimally invasive, percutaneous aspiration of thrombus formations originating from the central venous system (CNS) and solid matter (e.g., lead vegetations and right atrial thrombi). In a retrospective, observational study, these researchers reported their initial experience with the AngioVac system in 52 adult patients, focusing mainly on the development of the extracorporeal circuit to improve safety and usability. The mean patient age was 62.9 years (range of 23 to 86 years; 22 women and 30 men). Indications for percutaneous aspiration included lead vegetations (n = 36; 69.2%), right atrial thrombi (n = 9; 17.3%), central venous thrombi (n = 5; 9.6%), and pulmonary embolisms (n = 2; 3.8%). Successful aspiration was achieved in 44 cases (84.6%), with partial success in 5 patients (9.6%), and failure to remove thrombi or vegetations in 3 cases (5.8%). Their practical experience led to the installation of a shunt line for recirculation and the implementation of safety features concerning air handling, which were also employed in minimally invasive extracorporeal bypass circuits. Initial tests monitored the level of negative pressure according to differences in flow and access sites, but these still need validation on a larger scale. The authors concluded that in this initial experience, the AngioVac system appeared to be safe regarding extracorporeal circulation and the elimination of thrombi and lead vegetations.
Hammad and co-workers (2022) stated that with the ongoing intravenous drug abuse (IVDA) epidemic, the number of IVDA patients with infective endocarditis is increasing. These cases are often characterized by large vegetations complicated by valvular dysfunction, heart failure, and recurrent septic pulmonary emboli, necessitating surgical intervention. However, many patients cannot undergo surgery due to challenging medical and social complexities. The AngioVac system has been employed as an alternative therapy, but it is associated with high procedural mortality.
Enezate and colleagues (2022) noted that managing intra-cardiac masses, such as right heart thrombi and catheter-related vegetations, can be challenging. Many patients are high-risk candidates for surgical extraction due to multiple comorbidities and the risk of distal embolization. These researchers examined advancements in percutaneous approaches for treating intra-cardiac masses using the AngioVac. Since the FDA approved the AngioVac System in 2009, a growing body of evidence has shown it to be a feasible and effective tool for extracting thrombi and masses from the ilio-caval system and the right heart. The authors highlighted the feasibility of the AngioVac System based on published case series and registries. They concluded that future randomized controlled trials (RCTs) are needed to establish an algorithmic approach to treating intra-cardiac masses.
Memon et al. (2022) stated that vacuum-assisted aspiration with the AngioVac system has been well described for right-sided endocarditis, venous thrombus, lead-related infection/thrombus aspiration, and right-sided cardiac mass evacuation. However, percutaneous transeptal debulking with AngioVac for mitral valve endocarditis (MVE) in inoperable or high surgical risk patients has not been well defined. A significant proportion of high/prohibitive surgical risk patients with left-sided infective endocarditis (IE) are not offered valve surgery, as patients in the acute active phase of IE have a high surgical mortality. Nonetheless, sequelae of acute IE (i.e., stroke, sepsis, or hemodynamic instability) are associated with high morbidity and mortality without surgical treatment. These researchers presented a case report of an inoperable patient with methicillin-sensitive Staphylococcus aureus MVE who was offered mitral valve vegetation debulking with the AngioVac Gen3 C 180 MV system. They described pre-procedural planning, including optimal transeptal height puncture, the use of a sentinel cerebral protection device to decrease the risk of procedure-related cerebral embolism, and the use of a venous extracorporeal membrane cannula for reinfusion to avoid large bore arterial access-related vascular complications. The authors concluded that further randomized studies are needed to examine these procedural techniques and determine outcomes of percutaneous aspiration of left-sided IE with the AngioVac system in this high-risk, inoperable cohort of patients.
In a systematic review and meta-analysis, Mhanna et al. (2022) examined the use of AngioVac-assisted vegetation debulking (AVD) in right-sided infective endocarditis (RSIE). The AngioVac is a vacuum-based device approved in 2014 for the percutaneous removal of undesirable materials from the intravascular system. Although there have been multiple reports on the use of the AngioVac device to aspirate right-sided heart chamber thrombi, data on its use to treat RSIE were limited. These investigators conducted a comprehensive literature search for studies examining the use of AVD. The primary outcomes were procedural success, defined as the ability of AngioVac to produce a residual vegetation size of less than 50% (RVS < 50%) without serious procedural complications, and clinical success, defined as a composite of RVS < 50%, in-hospital survival, absence of recurrent bacteremia, and valve function not requiring further intervention. Secondary outcomes included the individual components of the primary outcomes and average hospital LOS. The pooled means and proportions of these data were analyzed using a random effects model and represented with 95% confidence intervals (CIs). A total of 44 studies, including 301 patients (mean age of 44.6 ± 18.2 years, 71.6% males), were included. Procedural success was achieved in 89.2% of patients (95% CI: 82.3% to 93.6%, I² = 0%). Clinical success was achieved in 79.1% of patients (95% CI: 67.9% to 87.2%, I² = 15%). The overall survival rate was 89.7% (95% CI: 83.1% to 93.9%, I² = 9%). The authors concluded that the findings of this meta-analysis showed that AVD is a promising therapeutic option for RSIE, offering a high success rate with an acceptable complication rate across a wide range of patients.
Beshai and Weinberg (2022) noted that Ogilvie syndrome is a rare disorder characterized by dilatation of part or all of the colon and rectum without intrinsic or extrinsic mechanical obstruction. Its etiology is likely multifactorial, with high mortality if left untreated. These investigators reported, for the first time, a case of Ogilvie syndrome secondary to the AngioVac procedure. Because the patient had a high operative risk, they employed the AngioVac system to debulk tricuspid valve vegetations to reduce bacterial load. The authors concluded that although the AngioVac system is considered safe overall, publications describing its side effects, safety, and effectiveness are limited. They emphasized the importance of close clinical monitoring and serial abdominal examinations following AngioVac procedures due to this rare but potentially fatal complication.
Qintar et al. (2022) stated that the AngioVac system was approved for right-sided transcatheter vacuum-assisted mass extraction (TVME) and has emerged as a safe and effective alternative to open surgical treatment. However, the use of the AngioVac device for aspiration of left-sided TVME has been limited. These researchers examined the safety and effectiveness of the AngioVac system for left-sided TVME. They included consecutive patients from two Michigan centers who underwent left-sided TVME, collecting data on patient demographics, procedural information, and in-hospital and follow-up events via electronic medical records review. Technical success was defined as aspirating 70% to 100% of the material. A total of 10 patients (mean age of 58.3 [± 17.3] years, 50% men) were included, with indications for TMVE primarily due to recurrent embolic events. All patients underwent bilateral cerebro-embolic protection using the Sentinel device. The total mean procedure time was 192.5 (± 47.5) minutes, with the mean time for active aspiration (bypass time) being 9.3 (± 4.2) minutes. The circuit configuration was arterio-venous (AV) in 4 cases and arterio-arterial (AA) in 6 cases. Successful aspiration was achieved in 80% of cases, with no complications reported (range of follow-up 1 to 16 months). The authors concluded that this small case series demonstrated the feasibility and safety of the AngioVac system in left-sided mass extraction. They stated that larger trials are needed to further demonstrate its safety and effectiveness and potentially apply for on-label use.
Chiang et al. (2023) noted that aspiration thrombectomy with the AngioVac system was approved for percutaneous removal of thrombus in the venous system. While not approved for aspiration of thrombus or other masses in the left heart or arterial system, it has been used in that setting. Patients with left heart or arterial mass are often deemed unfavorable for surgery and treated conservatively. However, this may not be the best option for all patients, as some may have lesions that represent a short-term increased risk of complications, for which intervention and aspiration could be considered reasonable. Unfortunately, femoral artery sizes often cannot accommodate the current aspiration cannula dimensions of the AngioVac system.
Nickell et al. (2023) highlight that invasive procedures for managing intravascular masses, such as vegetations from endocarditis, deep vein thrombosis, and septic emboli, often carry high rates of complications and mortality, particularly in patients with multiple pre-existing comorbidities. The AngioVac procedure, a minimally invasive technique that has gained popularity in recent years, is the focus of this single-centered, retrospective study, which examines patient comorbidities, indications for the procedure, and post-procedural outcomes. The study reviewed 33 patients who underwent the AngioVac procedure at Sanford Health between March 2014 and October 2019, collecting data on pre-existing comorbidities, procedural indications, length of hospital stay, and postoperative outcomes. The most common indications for the procedure included endocarditis (73%), intracardiac mass (15%), and deep vein thrombosis or pulmonary embolism (6%). Post-procedural blood transfusions were necessary for nearly half of the patients (45%), and almost all required intraoperative vasopressor support (94%). Following the procedure, 97% of patients were admitted to the intensive care unit, with an average length of stay of 8 days (interquartile range: 3-13). The most frequent complications included shock requiring vasopressors (39%), pleural effusion (27%), and sepsis (12%). The procedural success rate in this study was 85%, defined as a reduction in the size of the initial vegetation by more than 50% without severe intraoperative complications or the need for further valvular surgical intervention. The authors conclude that for patients at high surgical risk, the AngioVac procedure may provide a less invasive alternative for managing right-sided endocarditis that necessitates vegetation debulking, intravascular thrombi, or cardiac masses.
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The above policy is based on the following references:
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