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 Adminsitration (FDA)-approved closure devices (e.g., the Gore Helex Septal Occulder) medically necessary in pediatric or adult members for either of the following indications:
- For the closure of the fenestration in individuals who have undergone a fenestrated Fontan procedure; or
- For the occlusion of ASDs in secundum position.
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Ventricular Septal Defects
Aetna considers transcatheter closure of ventricular septal defects (VSDs) using FDA-approved closure devices medically necessary for complex VSDs in pediatric or adult members who are considered to be at high-risk for standard transatrial or transarterial surgical closure.
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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.
Background
Despite the success of standard operative repair with its mortality rate of less than 1 %, the risks and morbidity of open-heart surgery remain. Over the last 2 decades, interventional cardiac catheterization techniques have evolved to a point where percutaneous transcatheter devices can be offered as an alternative to their open counterparts to repair certain cardiac defects, particularly in younger patients. All of the devices require transesophageal echocardiographic guidance for optimal placement, and most procedures are performed under general anesthesia with transesophageal echocardiographic and/or fluoroscopic guidance to verify optimal placement, and to access the immediate results of the procedure.
In recent years many different systems for transcatheter closure of an atrial septal defect (ASD) have been developed and tested. Initially, acute failures and complications were primarily due to poor selection of cases with too large a defect or selection of a defective device. Over the years, stricter implantation and patient selection criteria have lead to more successful deployment of the devices in stable positions without inducing functional abnormality or anatomical obstruction. Of utmost importance in choosing appropriate patients is the echocardiographic morphology of the ASD with reference to size, position in the interatrial septum, proximity to surrounding structures, and adequacy of septal rim. Equally essential is accurate assessment of the stretched diameter of the inter-atrial communication by balloon sizing during catheterization to determine proper size of the ASD closure device. Many of the ASD closure devices initially approved by the Food and Drug Administration (FDA) for investigational use have been withdrawn from the market due to complications (e.g., Clamshell double-umbrella device, and Angel Wing). The most frequent complications include device embolization and thrombus formation. Some ASD closure devices have been modified a number of times to improve technical feasibility, safety, and effectiveness. Devices currently under investigation for ASD closure include the Buttoned Device, CardioSEAL Septal Occluder, StarFlex, Atrial Septal Defect Occluding System (ASDOS), Guardian Angel, and the Helex.
The Amplatzer septal occluder (AGA Medical Corp., Golden Valley, MN) received FDA approval in 2001. It is a self-centering device that consists of 2 round disks made of Nitinol wire mesh and linked together by a short connecting waist. Studies have reported short-term results confirming an early high occlusion rate with no major complications when strict implantation and patient selection criteria are used. According to the FDA approval, the Amplatzer septal occluder is indicated for ASD closure in individuals who have echocardiographic evidence of ostium secundum ASD and clinical evidence of right ventricular (RV) volume overload (i.e., 1.5:1 degree to left to right shunt or RV enlargement). The device is also indicated in patients who have undergone a fenestrated Fontan procedure and who now require closure of the fenestration.
Du et al (2002) compared the safety, effectiveness and clinical utility of the Amplatzer septal occluder for closure of secundum ASD with surgical closure. A multi-center, non-randomized concurrent study was performed in 29 pediatric cardiology centers from March 1998 to March 2000. Patients were assigned to either the device or surgical closure group according to the patient’s option. Baseline physical examinations and echocardiography were performed pre-procedure and at follow-up (6 and 12 months for device group, 12 months for surgical group). A total of 442 patients were in the group undergoing device closure, whereas 154 patients were in the surgical group. The median age was 9.8 years for the device group and 4.1 years for the surgical group (p < 0.001). In the device group, 395 (89.4 %) patients had a single ASD; in the surgical group, 124 (80.5 %) (p = 0.008) had a single ASD. The size of the primary ASD was 13.3 +/- 5.4 mm for the device group and 14.2 +/- 6.3 mm for the surgery group (p = 0.099). The procedural attempt success rate was 95.7 % for the device group and 100 % for the surgical group (p = 0.006).
The CardioSEAL Septal Occlusion System (Nitinol Medical Technologies, Inc., Boston, MA) is the second generation of the Clamshell occluder. It received FDA approval for use in patients with complex ventricular septal defect (VSD) of significant size to warrant closure and who are considered to be at high risk for standard transatrial or transarterial surgical closure based on anatomical conditions and/or overall medical condition. High- risk anatomical factors for transatrial or transarterial surgical closure include the following:
- Left ventriculotomy or an extensive right ventriculotomy is required;
- Multiple apical and/or anterior muscular VSDs (“Swiss Cheese Septum”);
- Posterior apical VSDs covered by trabeculae;
- Previous VSD closure that failed.
The CardioSEAL high-risk study is a prospective, multi-center trial studying the use of the CardioSEAL Septal Occlusion System to close a variety of hemodynamically significant defects. At the time the VSD data was analyzed and submitted to the FDA for approval, 74 patients with no additional anatomical lesions were enrolled in the study for closure of a VSD. The types of VSDs closed with a CardioSEAL device were: congenital muscular (n = 26) and post-operative (n = 31). The age of the patients ranged from 0.3 years to 70.1 years, with a median age of 3.7 years. The investigators reported that despite a high degree of co-morbid illness within the treated group, 72 % of the patients improved clinically at 6 months after implantation, and 84 % of the patients had a reduction in flow through the defect or reduction in the anatomical defect size. Peri-procedure events, including some serious events, occurred frequently, but all moderately serious or serious events had resolved by 6 months after the procedure. The investigators concluded that the CardioSEAL Septal Occlusion System is safe and effective in the intended patient population.
The FDA has granted humanitarian device exemptions to two transcatheter occlusion devices for repair of patent foramen ovale (PFO): the CardioSEAL Septal Occlusion System and the Amplatzer Patent Foramen Ovale Occluder. The FDA has allowed the use of these devices for closure of PFO in persons with recurrent cryptogenic stroke due to presumed paradoxical embolism through a PFO and who have failed conventional drug therapy.
At present, it should be noted that none of these afore-mentioned technologies is widely used and few devices have undergone extensive clinical trials. Many of these devices remain investigational and large-scale studies are underway to collect sufficient long-term data to validate these various applications as viable alternatives to surgery in the initial treatment of selected patients. The FDA is requiring that both Nitinol Medical Technologies, Inc and AGA Medical Corp. continue to study their products over the next 5 years to better assess their long-term safety and effectiveness (Meadows, 2002).
A randomized controlled clinical trial funded by St. Jude Medical found that closure of a PFO for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy. Meier et al (2013) investigated whether closure is superior to medical therapy. The investigators performed a multi-center, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end-points were unaware of the study-group assignments. Patients with a PFO and ischemic stroke, transient ischemic attack (TIA), or a peripheral thrombo-embolic event were randomly assigned to undergo closure of the PFO with the Amplatzer PFO occluder or to receive medical therapy. The primary end-point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population. The mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary end-point occurred in 7 of the 204 patients (3.4 %) in the closure group and in 11 of the 210 patients (5.2 %) in the medical-therapy group (hazard ratio [HR] for closure versus medical therapy, 0.63; 95 % confidence interval [CI]: 0.24 to 1.62; p = 0.34). Non-fatal stroke occurred in 1 patient (0.5 %) in the closure group and 5 patients (2.4 %) in the medical-therapy group (HR, 0.20; 95 % CI: 0.02 to 1.72; p = 0.14), and TIA occurred in 5 patients (2.5 %) and 7 patients (3.3 %), respectively (HR, 0.71; 95 % CI: 0.23 to 2.24; p = 0.56). The authors concluded that closure of a PFO for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy.
A randomized, controlled clinical trial funded by NMT Medical (Furlan et al, 2012) found that, in patients with cryptogenic stroke or TIA who had a PFO, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA. The investigators conducted a multi-center, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or TIA and had a PFO. The primary end-point was a composite of stroke or TIA during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years. A total of 909 patients were enrolled in the trial. The cumulative incidence (Kaplan-Meier estimate) of the primary end-point was 5.5 % in the closure group (447 patients) as compared with 6.8 % in the medical-therapy group (462 patients) (adjusted HR, 0.78; 95 % CI: 0.45 to 1.35; p = 0.37). The respective rates were 2.9 % and 3.1 % for stroke (p = 0.79) and 3.1 % and 4.1 % for TIA (p = 0.44). No deaths occurred by 30 days in either group, and there were no deaths from neurologic causes during the 2-year follow-up period. A cause other than paradoxical embolism was usually apparent in patients with recurrent neurologic events.
In the primary intention-to-treat analysis, a randomized controlled clinical trial demonstrated no significant benefit associated with closure of a PFO in adults who had had a cryptogenic ischemic stroke. Carroll et al (2013) conducted a trial to evaluate whether closure is superior to medical therapy alone in preventing recurrent ischemic stroke or early death in patients 18 to 60 years of age. In this prospective, multi-center, randomized, event-driven trial, investigators randomly assigned patients, in a 1:1 ratio, to medical therapy alone or closure of the PFO. The primary results of the trial were analyzed when the target of 25 primary end-point events had been observed and adjudicated. The investigators enrolled 980 patients (mean age of 45.9 years) at 69 sites. The medical-therapy group received 1 or more anti-platelet medications (74.8 %) or warfarin (25.2 %). Treatment exposure between the 2 groups was unequal (1,375 patient-years in the closure group versus 1,184 patient-years in the medical-therapy group, p = 0.009) owing to a higher drop-out rate in the medical-therapy group. In the intention-to-treat cohort, 9 patients in the closure group and 16 in the medical-therapy group had a recurrence of stroke (HR with closure, 0.49; 95 % CI: 0.22 to 1.11; p = 0.08). The between-group difference in the rate of recurrent stroke was significant in the pre-specified per-protocol cohort (6 events in the closure group versus 14 events in the medical-therapy group; HR, 0.37; 95 % CI: 0.14 to 0.96; p = 0.03) and in the as-treated cohort (5 events versus 16 events; HR, 0.27; 95 % CI: 0.10 to 0.75; p = 0.007). Serious adverse events occurred in 23.0 % of the patients in the closure group and in 21.6 % in the medical-therapy group (p = 0.65). Procedure-related or device-related serious adverse events occurred in 21 of 499 patients in the closure group (4.2 %), but the rate of atrial fibrillation (AF) or device thrombus was not increased. The authors concluded that, in the primary intention-to-treat analysis, there was no significant benefit associated with closure of a PFO in adults who had had a cryptogenic ischemic stroke. However, closure was superior to medical therapy alone in the pre-specified per-protocol and as-treated analyses, with a low rate of associated risks.
- stroke;
- TIA; and
- all-cause mortality.
Chen et al (2014) stated that the optimal treatment for secondary prevention in patients who have a PFO and history of cryptogenic stroke is still uncertain and controversial. In view of this, these researchers performed a systematic review of RCTs to investigate whether PFO closure was superior to medical therapy for prevention of recurrent stroke or TIA in patients with PFO after cryptogenic stroke. These investigators searched the Cochrane Central Register of Controlled Trials, Embase, PubMed, Web of Science, and ClinicalTrials.gov. Three RCTs with a total of 2,303 patients were included and analyzed. A fixed-effect model was used by Review Manager 5.2 (RevMan 5.2) software. The pooled risk ratio (RR) of recurrent stroke or TIA was 0.70, with 95 % CI: 0.47 to 1.04, p = 0.08. The results were similar in the incidence of death and adverse events, and the pooled RR was 0.92 (95 % CI: 0.34 to 2.45, p = 0.86) and 1.08 (95 % CI: 0.93 to 1.26, p = 0.32), respectively. The authors concluded that the data of this systematic review did not show superiority of closure over medical therapy for secondary prevention after cryptogenic stroke. Moreover, they stated that due to some limitations of the included studies, more RCTs are needed for further investigation regarding this field.
In October 2016, the FDA approved the Amplatzer PFO Occluder for percutaneous transcatheter closure of a patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke (FDA, 2016). The FDA concluded that there is "reasonable assurance of safety and effectiveness" of this device when used in accordance with the indications for use. In support of the approval, the manufacturer sponsored the RESPECT Trial, a prospective, multi-center, randomized (1:1), event driven, unblinded clinical study designed to evaluate whether PFO closure with the AMPLATZER PFO Occluder (the Device) is superior to standard of care medical management (MM) in reducing the risk of recurrent embolic stroke. Patients were enrolled at 69 investigational sites between August 23, 2003 and December 28, 2011. The database for this PMA reflected data collected through August 14, 2015 and included 980 randomized patients. All patients were scheduled to return for follow-up examinations at discharge, 1 month, 6 months, 12 months, 18 months, 2 years, and annually until study termination. The primary effectiveness endpoint was the composite of recurrent nonfatal stroke, fatal ischemic stroke, and all-cause mortality. The secondary effectiveness endpoints included the absence of transient ischemic attack (TIA) and the rate of complete PFO closure (assessed by trans-esophageal 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 subject was not successfully implanted with a device), hemorrhagic stroke, major bleeding requiring transfusion or surgical or endovascular intervention, vascular access site complication requiring surgical intervention, and device- or procedure-related serious adverse event leading to death. The primary safety endpoint will be compared to a PG of 4.14%. The study will enroll 1,214 subjects who will provide 84.5% and 98.5% power at a significance level of 2.5% to reject the null hypothesis for effectiveness and safety, respectively.
Knerr et al (2014) stated that limited data are available regarding the safety and effectiveness of the Gore septal occluder (GSO) for PFO closure. These researchers evaluated the safety and effectiveness of the GORE® Septal Occluder (GSO) at 1-, 6-, and 12-month follow-up in patients with a clinical indication for PFO closure. A total of 60 consecutive patients with an embolic event, migraine, or risk of decompression sickness were enrolled. Trans-esophageal or trans-thoracic echocardiography and clinical follow-up were performed at 1, 6 and 12 months after implantation. All patients received 100 mg aspirin and 75 mg clopidogrel for 6 months. Procedures were technically successful in 98.3 % (59/60). In 1 case, the anterior inter-atrial septal rim proved too short to allow safe GSO implantation and, instead, a different occluder was implanted. One patient developed transient neurological symptoms during the procedure without evidence for a stroke by magnetic resonance imaging. At 6-month follow-up, the closure rate was 86.6 % (52/60). The complete closure rate after 1 year was 93.3 % (56/60). Stroke, thrombus formation and atrial fibrillation (AF)/flutter occurred in 1 (1.7 %), 1 (1.7 %), and 5 (8.3 %) patients, respectively. The authors concluded that PFO closure with the GSO is accompanied by a high technical success rate and closure rates similar to other currently used devices. The incidence of AF was higher than reported with most other devices. This may be a chance finding but warrants further investigation in larger trials.
Thomson et al (2014) reported procedural outcome and short-term follow-up data for the GSO, a new device for closure of PFO. Data from 9 centers in the United Kingdom implanting the GSO device, submitted to an electronic registry for evaluation were used for analysis. A total of 229 patients undergoing PFO closure from June 2011 to October 2012 were included. Indications for closure were secondary prevention of paradoxical cerebral emboli (83.4 %), migraine (2.1 %), platypnea orthodeoxia (3.9 %), and other (10.5 %). Median PFO size was 8 mm and 34 % and 39 %, respectively, had long tunnel anatomy or atrial septal aneurysms. A GSO was successfully implanted in all cases. A single device was used in 98 % but in 4 patients the initial device was removed and a second device required. Procedural complications occurred in 3 % and later complications (e.g., AF, atrial ectopics, and device thrombus) in 5.7 % of cases. All patients have undergone clinical and echocardiographic follow-up and all devices remain in position. Early bubble studies (median 0 months) with Valsalva maneuver in 67.2 % were negative in 89 %. The authors concluded that the GSO is an effective occlusion device for closure of PFO of all types. Moreover, they stated that longer-term follow-up particularly to document later closure rates are needed.
Percutaneous transcatheter closure of patent ductus arteriosus (PDA) is an established procedure in the pediatric field. In a multi-center clinical trial (n = 484, median age of the patients at catheterization was 1.8 years, with a range 0.2 to 70.7 years), Pass et al (2004) found that moderate to large PDAs can be effectively and safely closed using the Amplatzer ductal occluder, with excellent initial and 1-year results. These authors concluded that this device should obviate the need for multiple coils or surgical intervention for these defects. Butera et al (2004) reported that in experienced hands, percutaneous closure of moderate to large PDA in very young symptomatic children is safe, effectively closes the PDA, and solves clinical problems. An assessment of endovascular closure of PDA conducted by the National Institute for Clinical Excellence (NICE, 2004) concluded that there is adequate evidence to support the use of this procedure.
Migraine headache (MHA) is present in 12 % of adults and has been associated with inter-atrial communications. Azarbal et al (2005) examined the relationship between PFO or ASD with the incidence of MHA and evaluated if closure of the inter-atrial shunt in patients with MHA would result in improvement of MHA. A sample of 89 (66 PFO/23 ASD) adult patients underwent transcatheter closure of an inter-atrial communication using the CardioSEAL (n = 22), Amplatzer PFO (n = 43), or the Amplatzer ASD (n = 24) device. Before the procedure, MHA was present in 42 % of patients (45 % of patients with PFO and 30 % of patients with ASD). At 3 months after the procedure, MHA disappeared completely in 75 % of patients with MHA and aura and in 31 % of patients with MHA without aura. Of the remaining patients, 40 % had significant improvement (greater than or equal to 2 grades by the Migraine Disability Assessment Questionnaire) of MHA. These investigators concluded that transcatheter closure of PFO or ASD results in complete resolution of MHA in 60 % of patients (75 % of patients with migraine and aura) and improvement in symptoms in 40 % of the remaining patients. They noted that inter-atrial communications may play a role in the etiology of MHA either through paradoxic embolism or humoral factors that escape degradation in bypassing the pulmonary circulation. The authors stated that a randomized trial is needed to ascertain if transcatheter closure of inter-atrial shunts is an effective treatment for MHA compared with medical therapy.
Reisman et al (2005) examined the effects of transcatheter PFO closure on the frequency of MHA in patients with paradoxical cerebral embolism. A total of 162 consecutive patients underwent transcatheter PFO closure for prevention of recurrent cryptogenic stroke or transient ischemic attack. A 1-year retrospective analysis of migraine symptoms before and after PFO closure was performed. Active MHA was present in 35 % (57 of 162) of patients, and 68 % (39 of 57) experienced migrainous aura; 50 patients were available for analysis at 1 year. Complete resolution of migraine symptoms occurred in 56 % (28 of 50) of patients, and 14 % (7 of 50) of patients reported a significant greater than or equal to 50 %) reduction in MHA frequency. Patients reported an 80 % reduction in the mean number of MHA episodes per month after PFO closure (6.8 +/- 9.6 before closure versus 1.4 +/- 3.4 after closure, p < 0.001). Results were independent of completeness of PFO closure at 1 year. These researchers concluded that in patients with paradoxical cerebral embolism, MHA are more frequent than in the general population, and transcatheter closure of the PFO results in complete resolution or marked reduction in frequency of MHA.
In an editorial that accompanied the studies by Azarbal et al (2005) as well as Reisman et al (2005), Tsimikas (2005) stated that "before PFO closure can be proposed for migraine, a healthy skepticism should be in place, considering the high frequency of both migraine and PFO in the general population. It will be necessary to obtain definitive evidence with randomized controlled trials and to define the appropriate clinical indications".
Spies and Schrader (2006) stated that reviewed the epidemiology and pathophysiology of MHA, its association with PFO, and the impact of PFO closure on MHA. These researchers noted that primarily retrospective case-control studies demonstrated a link between PFO closure and improvement of MHA. Few prospective data confirm the initial results. However, the only randomized, controlled trial finished to date analyzing the effect of PFO closure on MHA failed to reach its primary outcome of resolution of migraine following the intervention. The authors concluded that evidence of a benefit on MHA following PFO closure is not convincing, but certainly intriguing. With currently ongoing trials, more information related to this topic can be expected.
Diener et al (2007) stated that although the results of uncontrolled observational studies suggest the PFO closure may have a beneficial effect on migraine frequency, a large randomized trial failed to support such a conclusion. Until there is more evidence from ongoing large controlled trials, PFO closure should not be performed in clinical practice for the prophylaxis of migraine.
In a prospective, multi-center, double-blind, sham-controlled study, Dowson et al (2008) examined the effectiveness of PFO closure with the STARFlex septal repair implant to resolve refractory migraine headache. Patients who suffered from migraine with aura, experienced frequent migraine attacks, had previously failed greater than or equal to 2 classes of prophylactic treatments, and had moderate or large right-to-left shunts (RLS) consistent with the presence of a PFO were randomized to transcatheter PFO closure with the STARFlex implant or to a sham procedure. Patients were followed-up for 6 months. The primary efficacy endpoint was cessation of migraine headache 91 to 180 days after the procedure. In total, 163 of 432 patients (38 %) had RLS consistent with a moderate or large PFO. A total of 147 patients were randomized. No significant difference was observed in the primary endpoint of migraine headache cessation between implant and sham groups (3 of 74 versus 3 of 73, respectively; p = 0.51). Secondary endpoints also were not achieved. On exploratory analysis, excluding 2 outliers, the implant group demonstrated a greater reduction in total migraine headache days (p = 0.027). As expected, the implant-arm experienced more procedural serious adverse events. All events were transient. The authors concluded that this trial confirmed the high prevalence of RLS in patients with migraine with aura. Although no significant effect was found for primary or secondary endpoints, the exploratory analysis supports further investigation.
Rundek et al (2008) examined the association between PFO and migraine among stroke-free individuals in an elderly, multi-ethnic cohort. As a part of the ongoing Northern Manhattan Study (NOMAS), 1,101 stroke-free subjects were assessed for self-reported history of migraine. The presence of PFO was assessed by transthoracic echocardiography. The mean age of the group was 69 +/- 10 years; 58 % were women; 48 % were Caribbean Hispanic, 24 % were white, 26 % were black, and 2 % were another race/ethnicity. The prevalence of self-reported migraine was 16 % (13 % migraine with aura). The prevalence of PFO was 15 %. Migraine was significantly more frequent among younger subjects, women, and Hispanics. The prevalence of PFO was not significantly different between subjects who had migraine (26/178, or 14.6 %) and those who did not (138/923, or 15.0 %; p = 0.9). In an adjusted multi-variate logistic regression model, the presence of PFO was not associated with increased prevalence of migraine (odds ratio 1.01, 95 % confidence interval [CI]: 0.63 to 1.61). Increasing age was associated with lower prevalence of migraine in both subjects with a PFO (odds ratio [OR] 0.94, 95 % CI: 0.90 to 0.99 per year) and those without PFO (odds ratio 0.97, 95 % CI: 0.95 to 0.99 per year). The observed lack of association between PFO and migraine (with or without aura) was not modified by diabetes mellitus, hypertension, cigarette smoking, or dyslipidemia. The authors concluded that in this multi-ethnic, elderly, population-based cohort, PFO detected with transthoracic echocardiography and agitated saline was not associated with self-reported migraine. The causal relationship between PFO and migraine remains uncertain, and the role of PFO closure among unselected patients with migraine remains questionable. In an editorial that accompanied the afore-mentioned article, Kurth et al (2008) stated that detection of PFO or PFO closure should not be recommended to patients who only have migraine.
In a review on dynamic optimization of chronic migraine treatment, Mathew (2009) stated that it is premature to recommend device-based treatments (e.g., occipital nerve stimulation, vagal nerve stimulation, and PFO closure) for chronic migraine because clinical trials are in the preliminary stages. Furthermore, additional studies are needed to evaluate if RLS-associated migraine can be clinically identified.
Garg and colleagues (2010) evaluated the assumption of an association between MHA and the presence of PFO. These investigators conducted a case-control study to assess the prevalence of PFO in subjects with and without migraine. Case subjects were those with a history of migraine (diagnosed by neurologists at a specialty academic headache clinic). Control subjects were healthy volunteers without migraine 1:1 matched on the basis of age and sex with case subjects. Presence of PFO was determined by transthoracic echocardiogram with second harmonic imaging and transcranial Doppler ultrasonography during a standardized procedure of infused agitated saline contrast with or without Valsalva maneuver and a review of the results by experts blinded to case-control status. Patent foramen ovale was considered present if both studies were positive. Odds ratios were calculated with conditional logistic regression in the matched cohort (n = 288). In the matched analysis, the prevalence of PFO was similar in case and control subjects (26.4 % versus 25.7 %; OR 1.04, 95 % CI: 0.62 to 1.74, p = 0.90). There was no difference in PFO prevalence in those with migraine with aura and those without (26.8 % versus 26.1 %; OR 1.03, 95 % CI: 0.48 to 2.21, p = 0.93). The authors concluded that they found no association between MHA and the presence of PFO in this large case-control study nor any association between migraine severity and PFO size.
In an editorial that accompanied the afore-mentioned study, Gersony and Gersony (2010) stated that "[a]lthough in rare instances, exceptions may be proposed, closure of PFO for migraine should not be considered standard medical practice".
Rigatelli and Ronco (2010) provided a comprehensive review of the main concepts about PFO management. Therapy is a controversial issue, since data on these patients are variable and accepted guidelines are missing. Recurrent strokes are the most diffuse and accepted indication for transcatheter closure of PFO, but severe refractory migraine with aura, unexplained oxygen desaturation, orthodeoxia-platypnea (related to aortic elongation, allowing significant right-to-left shunt), and other conditions have been suggested to benefit from PFO closure. Different devices and techniques have been proposed for this procedure, mainly depending on operator experience and preferences. The authors concluded that PFO management is still a debated field: indications, pathophysiology and ideal closure techniques remain to be fully clarified and investigated before considering PFO closure a routine procedure.
Butera et al (2010) examined the role of transcatheter closure of PFO on the occurrence of migraine. BioMedCentral, Google Scholar, and PubMed from January 2000 to December 2008 were systematically searched for pertinent clinical studies. Secondary sources were also used. Secondary prevention studies of transcatheter closure for PFO were required to include at least more than 10 patients followed for more than 6 months. The primary end-point was the rate of cured or significantly improved migraine after percutaneous PFO closure. After excluding 637 citations, these investigators included a total of 11 studies for a total of 1,306 patients. Forty percent of the subjects included suffered from migraine, while most had a previous history of transient ischemic attack/stroke and were investigated retrospectively. Quantitative synthesis showed that complete cure of migraine in 46 % (95 % CI: 25 to 67 %), while resolution or significant improvement of migraine occurred in 83 % (95 % CI: 78 to 88 %) of cases. The authors concluded that notwithstanding the limitations inherent in the primary studies, this systematic review suggested that a significant group of subjects with migraine, in particular if treated after a neurological event, may benefit from percutaneous closure of their PFO. However, the authors notedthat many questions remain unsolved.
Bendaly et al (2011) reported the mid-term results of perventricular device closure of muscular VSD (MVSD) at a single institution. Between January 2004 and December 2009, 6 patients underwent attempted perventricular MVSD closure. Mean age was 9.8 +/- 9.1 months; mean weight was 7.2 +/- 3.7 kg. In 5 patients, closure was successful without use of bypass. In 1 patient, the device embolized to the left ventricle after release and patch closure of the MVSD was performed on cardiopulmonary bypass. The mean interval from the procedure to the most recent echocardiogram for the patients with successful perventricular closure was 39.8 +/- 25.2 months. Three patients demonstrated no residual shunt at the last echocardiogram. Two patients had mild, hemodynamically insignificant shunting; 1 had a left ventricular pseudoaneurysm that was embolized during repeat catheterization. The authors concluded that perventricular closure of MVSDs is attractive because it overcomes the limitations of surgery and catheterization. Additionally, it spares the need for cardiopulmonary bypass and its comorbidities. In some instances, however, successful deployment of the device is not possible. These mid-term results demonstrated overall success but identify possible complications that are not immediately identified in the short-term.
Zhang et al (2012) examined the feasibility of transthoracic echocardiographic (TTE) guidance for minimally invasive periventricular device closure of peri-membranous VSDs. From June 2011 to September 2011, these researchers enrolled 18 young children with peri-membranous VSDs to receive minimally invasive device closure in their hospital. All of the patients were examined by TTE to determine the VSD morphology, diameter, and rims. During intra-operative device closure, real-time bedside TTE alone was used to guide device implantation. Device implantation using TTE guidance was successful in 16 patients. Symmetric devices were used in 14 patients, and asymmetric devices were used in 2 patients. Only 1 patient experienced mild aortic regurgitation, and there were no instances of residual shunt, significant arrhythmias, thromboembolism, or device displacement. Two patients were transferred to surgical closure, 1 due to residual shunting and the other as a result of unsuccessful wire penetration of the VSD gap. The authors concluded that these findings indicated that TTE-guided VSD closure is feasible in young children, although a longer follow-up may be needed to document the long-term success.
Irwin and Bay (2012) stated that migraine with aura has been linked with PFO. A recent meta-analysis suggested an association, but the one prospective population study did not. The well-publicized and controversial MIST Trial is the only randomized trial of device closure in patients with migraines yet published, and failed to demonstrate a convincing benefit from device closure. Other conditions such as platypnea-orthodeoxia syndrome and prevention of decompression sickness in divers, may justify device closure. Evidence for a role of PFO in the etiology of cryptogenic stroke and migraine is contradictory. The authors concluded that it is possible that some patients might benefit from PFO closure, but there is scant evidence of sufficient quality to justify routine PFO closure in either group.
Rao (2013) discussed how and when to treat the most common acyanotic congenital heart defects (CHD). The indications and timing of intervention are decided by the severity of the lesion. Transcatheter closure methods are currently preferred for ostium secundum ASDs; the indications for occlusion are right ventricular volume over-load by echocardiogram. Ostium primum, sinus venosus, and coronary sinus ASDs require surgical closure. For all ASDs elective closure around age 4 to 5 years is recommended or as and when detected beyond that age. For the more common peri-membraneous VSDs of large size, surgical closure should be performed prior to 6 to 12 months of age. Muscular VSDs may be closed with devices. Patent ductus arteriosus may be closed with Amplatzer duct occluder if they are moderate-to-large and Gianturco coils if they are small. Surgical and video-thoracoscopic closure are the available options at some centers. In the presence of pulmonary hypertension appropriate testing to determine suitability for closure should be undertaken. An UpToDate review on “Management of atrial septal defects in adults” (Connolly, 2012) states that “Surgery is required for closure of ostium primum ASD, sinus venosus ASD, and coronary sinus septal defects.
Zhu and colleagues (2013) investigated perventricular device closure as a salvage technique in pediatric patients who had post-operative residual muscular ventricular septal defects. From February 2009 through June 2011, a total of 14 pediatric patients at the authors’ hospital had residual muscular ventricular septal defects after undergoing surgical repair of complex congenital heart defects. Ten patients met selection criteria for perventricular device closure of the residual defects: significant left-to-right shunting (Qp/Qs greater than 1.5) or substantial hemodynamic instability (a defect greater than or equal to 2 mm in size). The patients' mean age was 20.4 ± 13.5 months, and their mean body weight was 10 ± 3.1 kg. The median diameter of the residual defects was 4.2 mm (range of 2.5 to 5.1 mm). These investigators deployed a total of 11 SQFDQ-II Muscular VSD occluders (Shanghai Shape Memory Alloy Co., Ltd.; Shanghai, China) in the 10 patients, in accord with conventional techniques of perventricular device closure. The mean procedural duration was 31.1 ± 9.1 mins. These researchers recorded the closure and complication rates peri-operatively and during a 12-month follow-up period. Complete closure was achieved in 8 patients; 2 patients had persistent trivial residual shunts. No deaths, conduction block, device embolism, or other complications occurred throughout the study period. The authors concluded that perventricular device closure is a safe, effective salvage treatment for post-operative residual muscular ventricular septal defects in pediatric patients. Moreover, they stated that long-term studies with larger cohorts might further confirm this method's feasibility.
Furthermore, an UpToDate review on “Management of isolated ventricular septal defects in infants and children” (Dummer and Fulton, 2014) does not mention the use of perventricular closure of ventricular septal defects as a therapeutic option.
Hakeem et al (2013) stated that controversy persists regarding the management of patients with cryptogenic stroke and PFO. These researchers performed a meta-analysis of RCTs comparing PFO closure with medical therapy. A prospective protocol was developed and registered using the following data sources: PubMed, Cochrane Register of Controlled Trials, conference proceedings, and Internet-based resources of clinical trials. Primary analyses were performed using the intention-to-treat method. A total of 3 randomized trials comparing percutaneous PFO closure versus medical therapy for secondary prevention of embolic neurological events formed the data set. Baseline characteristics were similar. During long-term follow-up, the pooled incidence of the primary end-point (composite of stroke, death, or fatal stroke) was 3.4 % in the PFO closure arm and 4.8 % in the medical therapy group [RR 0.7 (0.48 to 1.06); p = 0.09]. The incidence of recurrent neurological events (secondary end-point) was 1.7 % for PFO closure and 2.7 % for medical therapy [RR 0.66 (0.35 to 1.24), p = 0.19]. There was no difference in terms of death or adverse events between the 2 groups. The authors concluded that while this meta-analysis of RCTs demonstrated no statistical significance in comparison to medical therapy, there was a trend towards overall improvement in outcomes in the PFO closure group.
Ntaios et al (2013) examined if PFO closure is superior to medical therapy in preventing recurrence of cryptogenic ischemic stroke or TIA. These investigators searched PubMed for randomized trials that compared PFO closure with medical therapy in cryptogenic stroke/TIA using the items: "stroke or cerebrovascular accident or TIA" and "patent foramen ovale or paradoxical embolism" and "trial or study". Among 650 potentially eligible articles, 3 were included including 2,303 patients. There was no statistically significant difference between PFO-closure and medical therapy in ischemic stroke recurrence (1.91 % versus 2.94 %, respectively, OR: 0.64, 95 % CI: 0.37 to 1.10), TIA (2.08 % versus 2.42 %, respectively, OR: 0.87, 95 % CI: 0.50 to 1.51) and death (0.60 % versus 0.86 %, respectively, OR: 0.71, 95 % CI: 0.28 to 1.82). In subgroup analysis, there was significant reduction of ischemic strokes in the AMPLATZER PFO Occluder arm versus medical therapy (1.4 % versus 3.04 %, respectively, OR: 0.46, 95 % CI: 0.21 to 0.98, relative-risk-reduction: 53.2 %, absolute-risk-reduction: 1.6 %, number-needed-to-treat: 61.8) but not in the STARFlex device (2.7 % versus 2.8 % with medical therapy, OR: 0.93, 95 % CI: 0.45 to 2.11). Compared to medical therapy, the number of patients with new-onset AF was similar in the AMPLATZER PFO Occluder arm (0.72 % versus 1.28 % respectively, OR: 1.81, 95 % CI: 0.60 to 5.42) but higher in the STARFlex device (0.64 % versus 5.14 %, respectively, OR: 8.30, 95 % CI: 2.47 to 27.84). The authors concluded that this meta-analysis did not support PFO closure for secondary prevention with unselected devices in cryptogenic stroke/TIA. In subgroup analysis, selected closure devices may be superior to medical therapy without increasing the risk of new-onset AF. However, they stated that this observation should be confirmed in further trials using inclusion criteria for patients with high likelihood of PFO-related stroke recurrence.
Udell and colleagues (2014) noted that PFO might be a risk factor for unexplained (cryptogenic) stroke or TIA. These researchers determined the safety and effectiveness of transcatheter PFO closure compared with anti-thrombotic therapy for secondary prevention of cerebrovascular events among patients with cryptogenic stroke. These investigators performed a systematic review and meta-analysis of MedLine and Embase (from inception to March 2013) for RCTs that compared transcatheter PFO closure with medical therapy in subjects with cryptogenic stroke. Data were independently extracted on trial conduct quality, baseline characteristics, efficacy, and safety events from published articles and appendices. Risk ratios and 95 % CIs for the composite of stroke or TIA, and adverse cardiovascular events including AF/flutter were constructed. Three RCTs of 2,303 subjects with previous stroke, TIA, or systemic arterial embolism (mean age of 45.7 years; 47.3 % women; mean follow-up, 2.6 years) were included. Patent foramen ovale closure did not significantly reduce the risk of recurrent stroke/TIA (3.7 % versus 5.2 %; RR, 0.73; 95 % CI: 0.50 to 1.07; p = 0.10); however, an increased risk of incident AF/flutter was detected (3.8 % versus 1.0 %; RR, 3.67; 95 % CI: 1.95 to 6.89; p < 0.0001). No significant heterogeneity was detected for any end-point among subgroups of patients stratified according to age, sex, index cardiovascular event, device type, inter-atrial shunt size, and presence of an atrial septal aneurysm (all p interactions ≥ 0.09). The authors concluded that meta-analysis of RCTs that assessed transcatheter PFO closure for secondary prevention of cerebrovascular events in subjects with cryptogenic stroke did not demonstrate benefit compared with anti-thrombotic therapy, and suggested potential risks.
An UpToDate review on “Cryptogenic stroke” (Prabhakaran and Elkind, 2014) states that “Atrial septal abnormalities, including patent foramen ovale, atrial septal aneurysm and atrial septal defect, have been associated with cryptogenic stroke, although the strength and clinical significance of this association is uncertain …. While retrospective data suggest that there is an increased prevalence of patent foramen ovale (PFO) and atrial septal aneurysm (ASA) in patients who have had a cryptogenic stroke, particularly in patients < 55 years old, population-based studies suggest that PFO and large PFO are not independent risk factors for stroke. In addition, prospective data suggest that PFO alone is not associated with a meaningfully increased risk of recurrent stroke or death in patients who have already had a cryptogenic stroke …. There is a high degree of uncertainty regarding the optimal management of patent foramen ovale (PFO), atrial septal aneurysm (ASA), and atheromatous aortic disease. The management of specific coagulation disorders and the role of hematologic testing are also unclear at the moment. Therefore, for the majority of patients with cryptogenic stroke, antiplatelet therapy is recommended. Selected patients might benefit from anticoagulant therapy”.
Hongxin et al (2015) noted that it is infeasible to occlude a doubly committed juxta-arterial ventricular septal defect (DCVSD) percutaneously. The previous perventricular device closure technique was performed through an inferior median sternotomy approach. These researchers evaluated the feasibility, safety and effectiveness of perventricular device closure of DCVSDs through a left para-sternal approach. A total of 62 patients, with the DCVSD of less than 6 mm in diameter, were enrolled in this study. The pericardial space was approached through a left para-sternal mini-incision without entering into the pleural space. Two parallel purse-string sutures were placed on the right ventricular outflow tract for puncture. Under trans-esophageal echocardiographic guidance, a new delivery sheath loaded with the device was inserted into the right ventricle and advanced through the defect into the left ventricle. The device, connected with a device stay suture, was deployed subsequently. Successful device closure of the defects was achieved in 58/62 patients (94 %). The DCVSD failed to close in 4 (6 %) patients due to device-related aortic regurgitation and device migration. The mean DCVSD diameter was 3.4 ± 1.0 mm (range of 2.0 to 6.0 mm). The implanted device size was 5.2 ± 1.3 mm (range of 4 to 8 mm); 44 out of 58 patients (76 %) was implanted with an eccentric occluder. The mean intra-cardiac manipulation time was 14 ± 13 mins (range of 2 to 60). The procedure time was 66 ± 15 mins (range of 42 to 98). During the follow-up period of 180 to 1860 (median of 880) days, new mild pulmonary regurgitation occurred in 2 patients. No other device-related complications were found. The complete closure rate was 95 % at discharge, 98 % at 1-, 6- and 12-month, 96 % at 2-year, and 100 % at 3-year follow-up. The authors concluded that perventricular device closure of a DCVSD through a left para-sternal approach is feasible, safe, and effective in selected patients. These mid-term results need to be validated by long-term follow-up studies.
In a review on “Current topics in surgery for multiple ventricular septal defects”, Yoshimura et al (2016) discussed several topics, including the sandwich technique, the trans-atrial re-endocardialization technique, the limited apical left ventriculotomy approach and device closure. The sandwich technique was introduced for the closure of muscular VSD by sandwiching the septum between 2 felt patches placed in the left and right ventricle. This technique requires neither the transection of muscular trabeculae nor ventriculotomy. Although the sandwich technique has resulted in the improvement of surgical outcomes, cases of post-operative cardiac dysfunction have been reported. Multiple smaller VSDs have been closed with trans-atrial re-endocardialization. Septal dysfunction may be avoided through this technique, in which the septal trabeculae are approximated in 2 layers of superficial, endocardial running sutures. Recently, a number of reports have recommended a limited apical left ventriculotomy approach. With this technique, a much shorter incision of around 1 cm at the apex of the left ventricle may be sufficient for achieving the complete closure of apical muscular VSDs. The transcatheter or perventricular device closure of muscular VSDs has increasingly been performed with good results. However, the authors stated that although favorable early and mid-term results of device closure have been reported, this method is not always safer or less invasive than surgical closure. They stated that long-term evaluations should be performed to determine whether the right and left ventricular functions are affected by treatment with relatively large devices in the heart.
Closure of Patent Foramen Ovale for Cryptogenic Stroke
Mas and associates (2017) stated that studies of PFO closure to prevent recurrent stroke have been inconclusive. These investigators examined if patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anti-coagulation, as compared with anti-platelet therapy. In a multicenter, randomized, open-label trial, these researchers assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term anti-platelet therapy (PFO closure group), anti-platelet therapy alone (anti-platelet-only group), or oral anti-coagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anti-coagulants or to PFO closure were randomly assigned to the alternative non-contraindicated treatment or to anti-platelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus anti-platelet therapy with anti-platelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anti-coagulation with anti-platelet therapy alone was performed with combined data from randomization groups 1 and 3. A total of 663 patients underwent randomization and were followed for a mean (± SD) of 5.3 ± 2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the anti-platelet-only group (HR, 0.03; 95 % CI: 0 to 0.26; p < 0.001). Procedural complications from PFO closure occurred in 14 patients (5.9 %). The rate of AF was higher in the PFO closure group than in the anti-platelet-only group (4.6 % versus 0.9 %, p = 0.02). The number of SAEs did not differ significantly between the treatment groups (p = 0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anti-coagulants and in 7 of 174 patients assigned to anti-platelet therapy alone. The authors concluded that among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with anti-platelet therapy than among those assigned to anti-platelet therapy alone; PFO closure was associated with an increased risk of AF.
Saver and colleagues (2017) noted that whether closure of a PFO reduces the risk of recurrence of ischemic stroke in patients who have had a cryptogenic ischemic stroke is unknown. In a multi-center, randomized, open-label trial, with blinded adjudication of end-point events, these researchers randomly assigned patients 18 to 60 years of age who had a PFO and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end-point was a composite of recurrent non-fatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The results of the analysis of the primary outcome from the original trial period have been reported previously; the current analysis of data from the extended follow-up period was considered to be exploratory. These investigators enrolled 980 patients (mean age of 45.9 years) at 69 sites. Patients were followed for a median of 5.9 years. Treatment exposure in the 2 groups was unequal (3,141 patient-years in the PFO closure group versus 2,669 patient-years in the medical-therapy group), owing to a higher drop-out rate in the medical-therapy group. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval [CI], 0.31 to 0.999; P=0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (HR, 0.38; 95 % CI, 0.18 to 0.79; p = 0.007). Venous thromboembolism (which comprised events of pulmonary embolism [PE] and deep-vein thrombosis [DVT]) was more common in the PFO closure group than in the medical-therapy group. The authors concluded that among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up.
Sondergaard and co-workers (2017) stated that the effectiveness of closure of a PFO in the prevention of recurrent stroke after cryptogenic stroke is uncertain. These researchers examined the effect of PFO closure combined with anti-platelet therapy versus anti-platelet therapy alone on the risks of recurrent stroke and new brain infarctions. In this multi-national trial involving patients with a PFO who had had a cryptogenic stroke, these investigators randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus anti-platelet therapy (PFO closure group) or to receive anti-platelet therapy alone (anti-platelet-only group). Imaging of the brain was performed at the baseline screening and at 24 months. The co-primary end-points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24-month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging. These researchers enrolled 664 patients (mean age of 45.2 years), of whom 81 % had moderate or large inter-atrial shunts. During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4 %) in the PFO closure group and in 12 of 223 patients (5.4 %) in the anti-platelet-only group (HR, 0.23; 95 % CI: 0.09 to 0.62; p = 0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the anti-platelet-only group (22 patients [5.7 %] versus 20 patients [11.3 %]; RR, 0.51; 95 % CI: 0.29 to 0.91; p = 0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (p = 0.97); SAEs occurred in 23.1 % of the patients in the PFO closure group and in 27.8 % of the patients in the anti-platelet-only group (p = 0.22). Serious device-related AEs occurred in 6 patients (1.4 %) in the PFO closure group, and AF occurred in 29 patients (6. %) after PFO closure. The authors concluded that among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with anti-platelet therapy than among those assigned to anti-platelet therapy alone; however, PFO closure was associated with higher rates of device complications and AF.
In an editorial that accompanied the afore-mentioned studies, Ropper (2017) stated that “The evidence for causation of embolic stroke in any given person is, of course, circumstantial (e.g., atrial fibrillation or carotid stenosis), and it seems reasonable that the presence of a PFO and a sizable interatrial shunt should similarly no longer result in the categorization of a stroke as cryptogenic. One conclusion from the six trials described above is that the potential benefit from closure is determined on the basis of the positive characteristics of the PFO rather than on the basis of exclusionary factors that make a stroke cryptogenic. Restricting PFO closure entirely to patients with high-risk characteristics of the PFO may perhaps be too conservative, but the boundaries of the features that support the procedure are becoming clearer”.
Messe and colleagues (2020) updated the 2016 American Academy of Neurology (AAN) practice advisory for patients with stroke and patent foramen ovale (PFO). The guideline panel followed the AAN 2017 guideline development process to systematically review studies published through December 2017 and formulated recommendations.
- In patients being considered for PFO closure, clinicians should ensure that an appropriately thorough evaluation has been performed to rule out alternative mechanisms of stroke (level B).
- In patients with a higher risk alternative mechanism of stroke identified, clinicians should not routinely recommend PFO closure (level B).
- Clinicians should counsel patients that having a PFO is common; that it occurs in about 1 in 4 adults in the general population; that it is difficult to determine with certainty whether their PFO caused their stroke; and that PFO closure probably reduces recurrent stroke risk in select patients (level B).
- In patients younger than 60 years with a PFO and embolic-appearing infarct and no other mechanism of stroke identified, clinicians may recommend closure following a discussion of potential benefits (absolute recurrent stroke risk reduction of 3.4 % at 5 years) and risks (peri-procedural complication rate of 3.9 % and increased absolute rate of non-periprocedural atrial fibrillation of 0.33 % per year) (level C).
- In patients who opt to receive medical therapy alone without PFO closure, clinicians may recommend an antiplatelet medication such as aspirin or anticoagulation (level C).
Transcatheter Device Closure of Peri-Membranous Ventricular Septal Defect
Santhanam and colleagues (2018) noted that while transcatheter device closure of VSDs is gaining popularity, concerns remain about AEs; especially heart block in peri-membranous VSDs (pmVSDs). In a meta-analysis, these researchers examined outcomes of transcatheter device closure of pmVSDs. A PubMed and Scopus search for studies in English on device closure of pmVSDs published till end-February 2017 was performed. Exclusion criteria included case series already included in multi-center studies, sample size of less than 5, and VSD acquired following myocardial infarction (MI). Pooled estimates of success and complications was obtained using the random effects model. A total of 54 publications comprising 6,762 patients with pmVSDs were included. The mean age of patients ranged from 1.6 to 37.4 years. The pooled estimate of successful device implantation was 97.8 % (95 % CI: 96.8 to 98.6). The most common complication was residual shunt (15.9 %; 95 % CI: 10.9 to 21.5). Other complications included arrhythmias (10.3 %; 95 % CI: 8.3 to 12.4) and valvular defects (4.1 %; 95 % CI: 2.4 to 6.1). The pooled estimate of complete atrio-ventricular block (cAVB) was 1.1 % (95 % CI: 0.5 to 1.9). The authors concluded that the findings of this meta-analysis suggested that device closure of pmVSDs was a safe and effective procedure. The complication of cAVB was low but significant. The risk is expected to further reduce with newer devices which are less stiff with improved profiles. They stated that further studies validating this will be useful in formulating guidelines for device closure of pmVSDs.
Li and colleagues (2020) stated that treatments for pmVSD mainly include conventional surgical repair (CSR), transcatheter device closure (TDC), and periventricular device closure (PDC). These researchers carried out a network meta-analysis to compare the 3 approaches in patients with pmVSD. They searched for comparative studies on device closure and conventional repair for pmVSD to April 2020. A network meta-analysis was carried out under the frequentist frame with RR and 95 % CI. The main outcome was the procedural success rate. Additional outcomes were post-operative complications, including residual shunt, intra-cardiac conduction block, valvular insufficiency, incision infection, and pericardial effusion. A total of 24 studies of 8,113 patients were included in the comparisons. The pooled estimates of success rate favored the CSR compared with the PDC. No significant differences of success rate were found in the TDC versus CSR and the PDC versus TDC. The pooled estimates of incidences of the residual shunt, new tricuspid regurgitation, incision infection, and pericardial effusion favored the PDC compared with the CSR. There were no significant differences between the PDC and TDC approaches in all outcomes except new aortic regurgitation. The authors concluded that the PDC technique not only reduced the risk of significant complications compared with the CSR, but also produced non-inferior results compared with the TDC in selected pmVSD patients. The PDC technique appeared to be a safe and effective option for selected patients with pmVSD.
The authors stated that this study had several drawbacks. First, most studies were from China, and this might have resulted in regional bias. Second, some included studies involving different design and patients with different VSD types might lead to heterogeneity. It was difficult to segregate different VSD types in some studies. To incorporate heterogeneity in treatment effects, these researchers used random-effects model and excluded studies reported patients with unclear or other types of VSD. Third, the follow-up intervals in different studies were different and no more than 5 years. Studies with long-term follow-up are needed. Fourth, because of the limited number of 3-arm studies, many pooled estimates of the PDC versus TDC were just from indirect comparison without the test of inconsistency.
Transcatheter Closure of Patent Foramen Ovale to Prevent Stroke Recurrence in Patients with Otherwise Unexplained Ischemic Stroke
Mas and colleagues (2019) noted that unlike previous RCTs, recent trials and meta-analyses have shown that transcatheter closure of PFO reduces stroke recurrence risk in young and middle-aged adults with an otherwise unexplained PFO-associated ischemic stroke. These investigators produced an expert consensus on the role of transcatheter PFO closure and anti-thrombotic drugs for secondary stroke prevention in patients with PFO-associated ischemic stroke. A total of 5 neurologists and 5 cardiologists with extensive experience in the relevant field were nominated by the French Neurovascular Society and the French Society of Cardiology to make recommendations based on evidence from RCTs and meta-analyses. The experts recommended that any decision concerning treatment of patients with PFO-associated ischemic stroke should be taken after neurological and cardiological evaluation, bringing together the necessary neurovascular, echocardiography and interventional cardiology expertise. Transcatheter PFO closure is recommended in patients fulfilling all the following criteria: age of 16 to 60 years; recent (less than or equal to 6 months) ischemic stroke; PFO associated with atrial septal aneurysm (greater than 10 mm) or with a right-to-left shunt of greater than 20 microbubbles or with a diameter of greater than or equal to 2 mm; PFO felt to be the most likely cause of stroke after thorough etiological evaluation by a stroke specialist. Long-term oral anti-coagulation may be considered in the event of contraindication to or patient refusal of PFO closure, in the absence of a high bleeding risk. After PFO closure, dual anti-platelet therapy with aspirin (75 mg/day) and clopidogrel (75 mg/day) is recommended for 3 months, followed by monotherapy with aspirin or clopidogrel for greater than or equal to 5 years. The authors concluded that although a big step forward that will benefit many patients has been taken with recent trials, many questions remain unanswered. These researchers stated that pending results from further studies, decision-making regarding management of patients with PFO-associated ischemic stroke should be based on a close coordination between neurologists / stroke specialists and cardiologists.
Nit-Occlud Lê VSD Coil for Transcatheter Closure of a Peri-Membranous Ventricular Septal Defect
In a single-center study, El Shedoudy and El-Doklah (2019) examined the safety, efficacy and follow-up results of transcatheter closure of VSD using Nit-Occlud Lê VSD Coil. Between January 2012 and December 2013 in the cardiology department, Tanta University Hospital, Tanta, Egypt, a total of 80 patients underwent percutaneous VSD closure using Nit-Occlud Lê VSD Coil. Early and mid- term follow-up was carried out for 3 years, follow-up was concluded in 2016. The mean age of patients was 5.34 ± 3 years, and their mean weight was 17.24 ± 8.17 kg. Overall, 77 of 80 patients had peri-membranous VSD (pmVSD) with aneurysmal tissue; 8 had multiple RV exits, 14 had deficient aortic rim, 2 had high outlet muscular, and 1 had Gerbode defect. The procedure was successful in 98.75 % of patients, and was aborted in 1 patient because of the development of complete heart block and the coil had to be removed. The mean procedure time was 104.98 ± 9.50 mins. The mean fluoroscopy time was 30.58 ± 2.79 mins. The immediate complete occlusion rate was 62 %, which increased to 82.3 % on the 2nd day, and 94.9 % by the 3rd month, and 97.5 % by 1 year. There was a significant decrease in mitral incompetence after 6 months of follow-up (p = 0.002), and only 1 patient had trivial aortic incompetence prior to the procedure that remained the same during follow-up period. The authors concluded that the use of Nit-Occlud Lê VSD-Coil to close VSD was safe and feasible in VSDs with various morphology. The main drawbacks of this study were its retrospective, single-center design. These researchers stated that larger, prospective, and perhaps randomized multi-center studies are needed.
Houeijeh and associates (2020) stated that transcatheter pmVSD closure remains challenging and is seldom used in France given the risk of AVB; and pmVSD closure with the Nit-Occlud Lê VSD coil was recently introduced in France as an alternative to occluder devices. In a multi-center study, these researchers examined the safety and feasibility of pmVSD closure with the Nit-Occlud Lê VSD coil. All consecutives cases of pmVSD closure with the Nit-Occlud Lê VSD coil in 20 tertiary French centers were included between January 2015 and December 2018. Among 46 procedures in 5 centers, indications for pmVSD closure were left ventricle (LV) over-load (76.1 %), exertional dyspnea (17.4 %), history of infective endocarditis (4.3 %) and mild pulmonary hypertension (2.2 %). The median (inter-quartile range [IQR]) age of the patients was 13.9 (5.7 to 31.8) years. Aneurismal tissue was identified in 91.3 % of patients; VSD median (IQR) size was 8 (7 to 10) mm on the LV side and 5 (4 to 6) mm on the RV side. Implantation was successful in 40 patients (87.0 %; 95 % CI: 73.7 to 95.1 %). Severe complications occurred in 6 patients (13.0 %, 95 % CI: 4.9 to 26.3 %), mainly severe hemolysis (8.7 %, 95 % CI: 2.4 to 20.8 %); 1 aortic valve lesion required surgical aortic valvuloplasty. Occurrence of severe complications was significantly related to the presence of hemolysis (p = 0.001), residual shunt (p = 0.007) and multi-exit VSD (p = 0.005). Residual shunt was observed in 40 % of cases with the implanted device shortly after closure and 15 % after a median follow-up of 27 months. No immediate or delayed device embolization or cAVB was recorded. The authors concluded that pmVSD closure with the Nit-Occlud Lê VSD Coil was feasible in older children and adults. However, residual shunting (leading to hemolysis) was a dreaded complication that should not be tolerated. These researchers stated that pmVSD closure with the Nit-Occlud Lê VSD as a therapeutic strategy remains controversial and is limited to selected patients.
Furthermore, an UpToDate review on “Management of isolated ventricular septal defects in infants and children” (Fulton and Saleeb, 2020) states that “For most patients who require VSD closure, primary patch surgical closure is the preferred procedure and is associated with excellent outcomes with low risk of mortality and low complication and reoperation rates. Transcatheter closure is generally reserved for patients with defects that are not amenable to surgical repair (e.g., multiple muscular defects that may be difficult to visualize at the time of surgery). Transcatheter VSD closure is technically challenging and should be performed only in centers with considerable experience and expertise in interventional catheterization techniques and with surgical backup”.
Percutaneous Transcatheter Implantation of Inter-Atrial Septal Shunt Device for the Treatment of Heart Failure
Sondergaard and colleagues (2014) stated that heart failure with preserved or mildly reduced ejection fraction (HFpEF) is common and therapeutic options are limited. Increased left atrial pressure (LAP) is a key contributor to the symptoms associated with HFpEF, especially during physical activity. In a pilot study, these investigators reported the 30-day outcome of patients treated with a novel device intended to lower LAP by creating an 8-mm permanent shunt in the atrial septum. A total of 11 patients were enrolled in this trial. Key inclusion criteria were: EF greater than 45%; baseline pulmonary capillary wedge pressure (PCWP) of greater than or equal to 15 mmHg (rest), or greater than or equal to 25 mmHg (exercise); and greater than or equal to 1 hospitalization for HF within the past 12 months, or persistent New York Heart Association (NYHA) class III/IV for at least 3 months. Mean age, LVEF, and NYHA class were 70 ± 12 years, 57 ± 9 %, and 3.2 ± 0.4, respectively. Most patients had significant co-morbidities. The inter-atrial septal device (IASD) device was implanted using percutaneous trans-septal access via the femoral vein. The device was successfully implanted in all patients. At 30 days, LV filling pressures were significantly reduced by 5.5 mmHg (19.7 ± 3.4 versus 14.2 ± 2.7; p = 0.005), and NYHA class was improved by 2 classes in 2 patients, 1 class in 5 patients, and worsened by 1 class in 1 patient. No patient developed pulmonary hypertension; 2 SAE occurred; HF re-hospitalization; and implant mal-position successfully treated with a new device. The authors concluded that contemporary management of HFpEF patients was confounded by the lack of effective therapies. The use of a device-based approach to reduce LAP provided a novel means to improve hemodynamic and symptomatic status in HFpEF patients and further investigation is needed. Moreover, these researchers stated that these findings should be interpreted with caution because of the limited size of the patient cohort (n = 11) in this study, and the lack of a control group.
Shad and associates (2018) noted that in patients with HF and left ventricular ejection fraction (LVEF) equal to or greater than 40 %, an IASD reduces exercise PCWP and is safe compared with sham control treatment at 1 month of follow-up. The longer-term safety and patency of the IASD has not yet been demonstrated in the setting of a RCT. In a double-blind, 1-to-1 sham-controlled, multi-center, phase-II RCT, these researchers examined the 1-year safety and clinical outcomes of the IASD compared with a sham control treatment. This study of IASD implantation versus a sham procedure (femoral venous access and imaging of the inter-atrial septum without IASD) was carried out in 22 centers in the Australia, Europe, and the U.S. on patients with NYHA class III or ambulatory class IV HF, LVEF equal to or greater than 40 %, exercise PCWP equal to or greater than 25 mm Hg, and PCWP-right atrial pressure (RAP) gradient equal to or greater than 5 mm Hg. Safety was evaluated by major adverse cardiac, cerebrovascular, or renal events (MACCRE). Exploratory outcomes evaluated at 1 year were hospitalizations for HF, NYHA class, quality of life (QOL), a 6-minute walk test (6MWT), and device patency. After 1 year, shunts were patent in all IASD-treated patients; MACCRE did not differ significantly in the IASD arm (2 of 21 [9.5 %]) versus the control arm (5 of 22 [22.7 %]; p = 0.41), and no strokes occurred. The yearly rate of hospitalizations for HF was 0.22 in the IASD arm and 0.63 in the control arm (p = 0.06). Median improvement in NYHA class was 1 class in the IASD arm (IQR, -1 to 0) versus 0 in the control arm (IQR, -1 to 0; p = 0.08); QOL and 6MWT distance were similar in both groups. At 6 months, there was an increase in right ventricular size in the IASD arm (mean [SD], 7.9 [8.0] ml/m2) versus the control arm (-1.8 [9.6] ml/m2; p = 0.002), consistent with left-to-right shunting through the device; no further increase occurred in the IASD arm at 12 months. The authors concluded that the REDUCE LAP-HF I phase-II, sham-controlled RCT confirmed the longer-term patency of the IASD. These researchers noted that through 1 year of follow-up, IASD treatment appeared safe, with no significant differences in MACCRE in patients receiving IASD compared with those who received sham control treatment. Moreover, these researchers stated that these findings were encouraging; however, they needed a larger study for further clinical evaluation. These investigators stated that a larger-scale, blinded, sham-controlled, pivotal RCT is currently underway to determine the clinical efficacy of the IASD in HF and EF equal to or greater than 40 %.
The authors stated that this study was limited by its relatively small sample size (n = 44; 21 received IASD); thus, it did not provide adequate power to definitively evaluate clinical benefit or safety. Although there were no statistically significant differences in clinical characteristics among groups, the control group had lower 6MWT distance and a higher frequency of HF hospitalization in the year before the study began. These imbalances did not affect the main 1-year results; however, these differences between treatment groups were also indicative of the limitation of a small sample size.
Kaye and co-workers (2019) noted that impaired LV diastolic function leading to elevated LAP, especially during exertion, is a key driver of symptoms and outcomes in HFpEF. Insertion of an IASD to reduce LAP in HFpEF has been shown to be associated with short-term hemodynamic and symptomatic benefit. These investigators examined the potential effects of IASD placement on HFpEF survival and HF hospitalization (HFH). Patients with HFpEF participating in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure study of an IASD were followed for a median duration of 739 days. The theoretical impact of IASD implantation on HFpEF mortality was examined by comparing the observed survival of the study cohort with the survival predicted from baseline data using the Meta-analysis Global Group in Chronic Heart Failure HF risk survival score. Baseline and post-IASD implant parameters associated with HFH were also examined. Based upon the individual baseline demographic and cardiovascular profile of the study cohort, the Meta-analysis Global Group in Chronic Heart Failure score-predicted mortality was 10.2/100 patient years. The observed mortality rate of the IASD-treated cohort was 3.4/100 patient years, representing a 33 % lower rate (p = 0.02). By Kaplan-Meier analysis, the observed survival in IASD patients was greater than predicted (p = 0.014). Baseline parameters were not predictive of future HFH events; however, poorer exercise tolerance and a higher workload-corrected exercise PCWP at the 6 months post-IASD study were associated with HFH. The authors concluded that the findings of this study suggested that IASD implantation may be associated with a reduction in mortality in HFpEF. Moreover, these researchers stated that large-scale, randomized, double‐blind, sham procedure-controlled studies are currently underway to further examine the utility of this therapeutic approach in HFpEF.
The authors stated that the findings of this study should be interpreted in the context of several limitations. First, the study was an open‐label study. Second, although the predicted survival was consistent with other reports in HFpEF patients, the use of the Meta‐analysis Global Group in Chronic Heart Failure (MAGGIC) score to derive a comparator survival curve may have generated an over-estimation of the true survival in a contemporaneous group. Finally, while protocol‐driven safety outcome follow‐up was available at up to 3 years, complete NYHA class at 3 years was unavailable, and systematic echocardiography was not required after 12 months.
Burlacu and associates (2019) noted that HFpEF is a common disorder generating high mortality and important morbidity prevalence, with a very limited medical treatment available. Studies have shown that the pathophysiological hallmark of this condition is an elevated LAP, exertional dyspnea being its clinical manifestation. The increasing pressure from LA is not based on volume overload (such as in heart failure with reduced ejection fraction) but on a diastolic LV dysfunction combined with an inter-atrial dyssynchrony mimicking a pseudo-pacemaker syndrome. These investigators summarized current knowledge and discussed future directions of the newest interventional percutaneous therapies of HFpEF. Novel interventional approaches developed to counter these mechanisms are as follows: LA decompression (IASDs), enhancement of LV compliance (LV expanders), and inter-atrial re-synchronization therapy (LA permanent pacing). To-date, IASDs are the most studied, being the only devices currently tested in a phase-III clinical trial. Recent data showed that IASDs are feasible, safe, and have a short-term clinical benefit in HFpEF patients. LV expanders and LA pacing therapy present with a smaller clinical benefit compared with IASDs, but they are safe, without any major adverse outcomes currently noted. With further development and improvement of these mechanism-specific devices, it will be interesting to determine if in the future a complex intervention of multiple HFpEF device implantation will be safe and have further benefits in HFpEF patient.
Berry and colleagues (2020) stated that a randomized, sham-controlled study in patients with HF and LVEF of greater than or equal to 40 % demonstrated reductions in PCWP with a novel transcatheter IASD. Whether this hemodynamic effect will translate to an improvement in cardiovascular outcomes and symptoms requires additional study. The REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP HF-II) Trial is a prospective, randomized, blinded, sham-controlled, multi-center study designed to examine the clinical efficacy of the IASD in symptomatic HF and elevated LAP. Up to 608 HF patients age of greater than or equal to 40 years with LVEF of greater than or equal to 40 %, PCWP of greater than or equal to 25 mm Hg during supine ergometer exercise, and PCWP of greater than or equal to 5 mm Hg higher than RAP will be randomized 1:1 to the IASD versus sham control. Key exclusion criteria include hemodynamically significant valvular disease, evidence of pulmonary arterial hypertension, and right heart dysfunction. The primary endpoint is a hierarchical composite, analyzed by the Finkelstein-Schoenfeld methodology, that includes cardiovascular mortality or 1st non-fatal ischemic stroke through 12 months; total (1st plus recurrent) HF hospitalizations or healthcare facility visits for intravenous diuretics up to 24 months, analyzed when the last randomized patient completes 12 months of follow-up; as well as change in Kansas City Cardiomyopathy Questionnaire overall summary score from baseline to 12 months. Follow-up echocardiography will be performed at 6, 12, and 24 months to evaluate shunt flow and cardiac chamber size/function. Patients will be followed for a total of 5 years after the index procedure. The authors stated that the REDUCE LAP-HF II is designed to evaluate the clinical efficacy of the IASD device in patients with symptomatic HF with elevated LAP and LVEF of greater than or equal to 40 %.
Miyagi and associates (2021) noted that HFpEF is a syndrome with an unfavorable prognosis, and the number of the patients continues to grow. Because there is no effective therapy established as a standard, including pharmacotherapies, a movement to develop and evaluate device-based therapies is an important emerging area in the treatment of HFpEF patients. Many devices have set their target to reduce the LAP or PCWP because they are strongly related to the symptoms and prognosis of HFpEF; however, the methodology to achieve it varies based on the devices. These researchers summarized and categorized these devices into the following: IASDs, left ventricle expander, electrical therapy, left ventricular assist devices (LVADs), as well as mechanical circulatory support devices under development. They described the features and specifications of device-based therapies currently under development and those at more advanced stages of pre-clinical testing.
Furthermore, an UpToDate review on “Overview of surgical management of heart failure” (Fang, 2021) does not mention inter-atrial shunt as a management / therapeutic option.
Neovasc Reducer (Coronary Sinus Reducer) for Relief of Angina Symptoms
Neovasc Reducer (Reducer) implant procedure refers to transcatheter implantation of a coronary sinus (CS) reduction device for the relief of angina symptoms by altering the blood flow within the cardiac myocardium and increasing the perfusion of oxygenated blood to ischemic areas of the myocardium. The CS Reducer is implanted by means of a minimally invasive transvenous procedure that is similar to the insertion of a coronary stent and is usually completed in about 20 mins.
Giannini and colleagues (2018) stated that the CS Reducer is a novel device that aid in the management of patients with severe angina symptoms refractory to optimal medical therapy and not amenable to further re-vascularization. In a single-center study, these researchers examined the safety and efficacy of the CS Reducer in a cohort of patients presenting with refractory angina. A total of 50 patients with refractory angina and objective evidence of myocardial ischemia who were judged unsuitable for re-vascularization were treated with CS Reducer implantation between March 2015 and August 2016. Safety endpoints were procedural success and the absence of device-related adverse events (AEs). Efficacy endpoints, assessed at 4- and 12-month follow-up, were a reduction in Canadian Cardiovascular Society (CCS) angina class, improvement in QOL evaluated by using the Seattle Angina Questionnaire (SAQ), improvement in exercise tolerance examined using the 6MWT, and reduction in anti-anginal drugs. Procedural success was achieved in all patients, with no device-related AEs during the procedure or at follow-up. Regarding the efficacy endpoint, 40 patients (80 %) had at least 1 reduction in CCS class, and 20 patients (40 %) had at least 2 class reductions, with a mean class reduction to 1.67 ± 0.83 versus 2.98 ± 0.52 (p < 0.001) at 4-month follow-up. All SAQ items improved significantly (p < 0.001 for all). A significant increment in 6MWT to 388.6 ± 119.7 m versus 287.0 ± 138.9 m (p = 0.004) was observed; 16 patients (32 %) and 3 patients (6 %) demonstrated reductions of at least 1 or 2 anti-anginal drugs, respectively. The benefit of CS Reducer implantation observed at 4-month follow-up was maintained at 1 year. The authors concluded that implantation of the CS Reducer appeared safe and was associated with reduction in anginal symptoms and improvement in QOL in patients with refractory angina who were not candidates for further re-vascularization.
The authors stated that the main drawbacks of this study were the absence of a control group and the small number of patients enrolled (n = 50). Another drawback was the absence of an objective measurement of myocardial ischemia reduction following Reducer implantation. To this end, very preliminary data with the use of stress perfusion cardiac magnetic resonance before and after CS Reducer implantation have recently been reported.
In a systematic review, Bazoukis and associates (2018) examined the efficacy of the CS Reducer in patients with refractory angina. Two independent investigators systematically searched the Medline and Cochrane library databases for studies describing the safety and efficacy of the CS Reducer in patients with refractory angina from January 1, 2000 to May 12, 2018 using the following terms: "coronary sinus (reducer OR reducing) device". Efficacy was defined as greater than or equal to 1-unit improvement in the CCS score. The search strategy came up with 6 studies (5 observational studies and 1 randomized clinical trial) with 196 patients. The CS Reducer was effective in 146/186 (78.5 %) patients; CCS score improved from 3.2 at baseline to 1.9 after 8.6 months of follow-up. The efficacy of the CS Reducer also demonstrated as an improvement in SAQ score, 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 %) had a complication during 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 re-vascularization; however, larger RCTs with long-term follow-up are needed to elucidate its role.
In a health technology assessment (HTA), Stanak et al (2020) examined the evidence on the safety and effectiveness of CS reducing stent (CSRS) therapy in the treatment of patients with refractory angina pectoris (AP). These investigators carried out a systematic literature search in common databases (n = 4). The evidence obtained was summarized according to GRADE methodology. A HTA was performed using the HTA Core Model for Rapid Relative Effectiveness Assessment. Primary outcomes for the clinical effectiveness domain were 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. Outcomes for the safety domain were adverse device effects (ADEs) and serious adverse device effects (SADEs). These researchers identified 1 RCT. Outcomes that showed statistically significant differences between CSRS and sham treatment (in favor of CSRS) were CCS angina score improvement of 1 or 2 classes, overall mean reduction of CCS class, and SAQ QoL score improvement. Concerning safety, the sham-controlled trial data indicated that there were fewer SADEs in the intervention group (19 %) than in the control group (46 %). SADEs reported in observation studies ranged from none to 30 %. The most frequently reported SADEs were death and stable angina. In the RCT, the only case of death occurred in the control group. Concerning clinical effectiveness, the risk of bias (RoB) was rated to be low, and concerning safety, the RoB was rated to range from low-to-moderate. As evaluated by GRADE, the overall strength of evidence for safety and effectiveness was moderate; internal and external validity of the evidence base were low. 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 of evidence). This was because of inconsistent results, incomplete safety data with regard to dual anti-platelet therapy, inappropriate inclusion criteria in the studies, insufficient sample size, and incomplete blinding in the RCT. These researchers stated that the potential of the CSRS to fulfill the therapeutic gap should be considered against the backdrop of its unclear mechanism of action, the lack of a long-term safety profile, and additional potential SADEs. Furthermore, the cost-effectiveness of the CSRS could only be established once the effectiveness of CSRS is established. In this regard, owing to the inconsistencies with internal and external validity of the evidence base, even the conclusions regarding placebo effects could not be taken for granted. These researchers stated that better powered RCTs with longer follow-up are needed to determine the role of treatment modalities for specific subgroups, for decreasing non-responder rates, and for ascertaining benefits beyond placebo effects.
D'Amico and co-workers (2021) noted that the CS Reducer is a novel device designed for the management of patients with severe angina symptoms refractory to optimal medical therapy and not amenable to further re-vascularization. In a country-level, multi-center, cohort study, these investigators examined the safety and efficacy of the CS Reducer device in patients presenting with refractory angina pectoris. This trial included patients affected by refractory angina pectoris who underwent CS Reducer implantation in 16 centers. Clinical follow-up was performed as per each center's protocol. A total of 187 patients were included; technical and procedural success were attained in 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 the CS Reducer implantation, and 80 (49 %) patients at least 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 benefit was also reflected in a significant improvement in QOL scores and in a reduction of the mean number of anti-ischemic drugs prescribed for patient. The authors concluded that the implantation of the CS Reducer in patients with refractory angina pectoris was safe and effective in reducing of angina pectoris and improving QOL. This appeared to be an extension of the afore-mentioned 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. It is increasing in frequency, due to the success of current medical and interventional therapies in improving the prognosis of coronary artery disease (CAD). Long-term mortality is similar to that of patients with asymptomatic stable disease; however, it affects patients' QOL, and has a significant impact on health care resources. Several therapeutic targets have been examined, most with disappointing results. Many of the techniques have been abandoned because of lack of efficacy, safety issues, or economic and logistic limitations to wider applicability. The primary focus of this review was the coronary sinus Reducer, supporting evidence for which, although scarce, is promising regarding safety and efficacy in improving anginal symptoms and QOL. It is also 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, when implanted in the coronary sinus, is designed to alleviate anginal symptoms; however, the available clinical data are sparse. The FDA assembled the Circulatory Systems Devices Panel to discuss the Reducer's safety and effectiveness. Because of the coronavirus disease 2019 pandemic, this meeting was held virtually. In this manuscript, the authors detailed the deliberation and discussion among the circulatory panel members, including their final vote.
Konigstein et al (2021) the long-term benefit of the CS Reducer in the treatment of patients suffering from refractory angina is unclear. In a prospective, multi-center, observation study, patients undergoing successful CS Reducer implantation were enrolled to clinical registries at 3 medical centers. Those with more than 2-years of follow-up were included in the present analysis. Peri-procedural data, data regarding AEs, and current evaluation of angina severity (CCS class) were collected. A total of 99 consecutive patients (77 % men, mean age of 69.8 ± 9.4 years) with severe angina were enrolled between September 2010 and October 2017 and included in the present analysis. No procedure-related complications were recorded. During a median follow-up time of 3.38 years (IQR 2.95 to 4.40), 15.1 % of the patients died, 9 % experienced MI and 21 % underwent percutaneous coronary intervention (PCI). Mean CCS class was 3.1 ± 0.5 at baseline, improved to 1.66 ± 0.8 at 1 year (p < 0.001), and remained low through 2-years and at last follow-up (1.72 ± 0.8 and 1.71 ± 0.8, p > 0.5 for both, in comparison to 1 year). At baseline 91 % of patients reported severe disabling angina (CCS class 3 to 4), at 1 year only 17.9 % suffered from disabling angina (p < 0.001), and this portion remained low over time (19 % at last follow-up). The authors concluded that 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 of angina symptoms, was maintained over time. Moreover, these investigators stated that however, it is still to be examined in larger long‐term studies, using objective methods of assessment of myocardial ischemia, whether the objective reduction in ischemic burden is also maintained over time.
The authors stated that this study had several drawbacks. First, the observational nature of this study precluded these researchers from attenuating the placebo effect, which was widely reported in previous refractory angina studies. However, objective improvement in indices of myocardial ischemia has been demonstrated in previous studies; and clinical benefit was already tested in a randomized sham‐controlled study. Second, as data regarding AEs were partially collected retrospectively, from clinical documents and patient interviews, it was possible that some events were not captured. Third, differences in data collection and event definitions could exist between centers and might have influenced these findings. Fourth, these investigators reported the outcomes of patients who completed 2 years of follow-up. This methodology 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 a poor QOL and increased healthcare resource utilization. In this growing population of patients, multiple mechanism(s) of ischemia may co-exist, 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 CAD; thus, the mechanism of ischemia was thought attributable to coronary microvascular dysfunction (CMD) in the context of HCM. In view of her significant symptoms and large burden of left-sided myocardial ischemia, a 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. Moreover, these researchers stated 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 the treatment of refractory angina in patients unsuitable for coronary re-vascularization; however, its effect could be influenced by the significant heterogeneity in the anatomy of the cardiac venous system. These investigators 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 the coronary disease, the patient was considered ineligible for percutaneous or surgical re-vascularization; and she was regarded as a good candidate for a CSR. Since coronary venous angiography showed the middle cardiac vein (MCV) to be at least as relevant as the CS, successful implantation of 2 devices, the 1st in the CS and the 2nd in the MCV, was carried out. At 6-month follow-up, the patient reported a significant improvement in angina, resulting in a reduction of the CCS class from grade-IV to grade-III. The authors concluded that in patients affected by refractory angina and regarded as good candidates for CSR implantation, a thorough comprehension of the cardiac venous pathway drainage is of pivotal importance to guarantee the therapeutic success of the procedure. In this patient, since the CS and the MCV appeared to contribute equally to coronary venous drainage, CSR implantation in both vessels allowed to obtain a significant improvement of symptoms. Moreover, these researchers stated that the clinical effectiveness of this strategy needs to be validated in randomized clinical trials.
Transcatheter Removal or Debulking of Intra-Cardiac Mass (e.g., the AngioVac System)
Hameed and colleagues (2019) noted that AngioVac is a new device for filtering intravascular thrombi and emboli. Publications on the device are limited and under-powered to objectively estimate its safety and efficacy. These researchers aimed to overcome this by performing a meta-analysis on the results of AngioVac System for treating venous thromboses and endocardial vegetations. They carried out a systematic literature review to identify all articles reporting cardiac vegetation and/or thrombosis extraction using AngioVac. Endpoints were successful removal, operative mortality, conversion to open surgery, hospital length of stay (LOS), recurrent thromboembolism, and follow-up mortality. Random effect model was used, and pooled event rates (PERs) and incidence rate (IR) were calculated. A total of 42 studies with 182 patients (81 vegetation and 101 thrombosis) were included. Overall mean follow-up times were 3.1 and 0.7 years in vegetation and thrombosis patients, respectively. The PERs for successful removal were 74.5 (CI: 48.2 to 90.2), 80.5 (CI: 70.0 to 88.0), and 32.4 (CI: 17.0 to 52.8) in vegetation, right atrial/caval venous thrombi, and pulmonary emboli (PE) patients, respectively. The PERs for operative mortalities were 14.6 (CI: 7.7 to 25.8), 14.8 (CI: 8.5 to 24.5), and 32.3 (CI: 15.1 to 56.3), respectively. The PERs for conversion to open surgery were 25.0 (CI: 9.3 to 51.9) and 12.3 (CI: 5.4 to 25.6) in vegetation and thrombosis patients, respectively. 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; 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 was a viable option for extracting right-sided vegetations and right atrial/caval venous thrombi. Rates of successful extraction and mortality were significantly worse for PE.
Kiani and associates (2019) noted that consensus statements on percutaneous lead extraction gave consideration to open surgical removal in the setting 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 provide an opportunity to mitigate these risks. These researchers retrospectively identified all patients undergoing percutaneous lead extraction at their institution for endovascular infection from 2012 to 2018 and stratified them into 2 groups based on presence of adjunctive VD (n = 6) or without VD (no-VD, n = 39); VD was performed with the AngioVac System. Across the cohort, mean age was 62 ± 15 years, ejection fraction (EF) was 41 ± 16 %, and 39 % had end-stage renal disease (ESRD) on dialysis. Defibrillator systems were present in 71 %, and 22 % had cardiac re-synchronization devices. Mean duration of the oldest extracted lead was 6.3 ± 4.9 years. There were no significant differences in baseline co-variates between groups. 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. 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. Moreover, these researchers stated that the relative safety and efficacy of this removal approach requires further study.
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 given its high mortality rate. These investigators 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, obviating a more invasive surgical approach. The patient tolerated the procedure well and rapidly improved following removal of the vegetation. The authors concluded that this case report highlighted the use of a novel, minimally invasive approach (the AngioVac System) for the management of cardiac masses. These researchers stated 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 stated that the main drawbacks regarding the use of the AngioVac System are availability of the device and local expertise. In the pediatric population, one must also consider the size of peripheral access vessels for the introduction of the large diameter aspiration and re-perfusion cannulas limiting its current use to older children. It is conceivable that smaller caliber, low-profile aspiration, and re-perfusion 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. These researchers presented a case where pulmonary thromboendarterectomy was required for treatment. A 55-year old man with a history of MI 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; thus, he underwent pulmonary endarterectomy (PTE). The authors concluded that this case of CIED-associated IE demonstrated the importance of early aggressive treatment of such infections. Guidelines recommended complete CIED system removal when there is associated infection. These researchers stated that the AngioVac System is a novel system for removal of right-sided vegetations and thrombi; however, complications such as distal embolization could occur.
The authors stated that the AngioVac System is a relatively novel method for removal of material from the vasculature using veno-venous bypass. Studies have shown it to be an effective method of percutaneous removal of thrombi and right-sided vegetations. Reports have also shown it to be useful in management of vegetations associated with pacemaker and defibrillator leads. However, as in the patient presented in this study, cases of incomplete extraction and distal embolization have been reported. This may be more common with chronic or well-organized clots.
Bangalore et al (2021) noted that tricuspid valve endocarditis with recurrent septic pulmonary emboli is an indication for surgery. These researchers presented the case of a 36-year old man with tricuspid valve endocarditis and septic pulmonary emboli with percutaneous extraction of the vegetation using the AngioVac System. The authors discussed the nuances of such an approach and the need for more evidence in the management of 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 in need of intravascular material resection. These researchers presented a unique and never reported case of the AngioVac device thrombectomy use in a patient with right atrial catheter-associated thrombus and gastro-intestinal (GI) bleed that contraindicated other thrombectomy therapies due to severe anemia and high bleeding risk. In their literature review, a total of 45 cases of AngioVac use for thrombus aspiration was obtained including 15 cases of a single-center case reports published by Donaldson et al in 2015. In those 45 cases, main clinical manifestation was dyspnea in 13 cases, followed by incidental finding of the thrombi in 6 cases and palpitations in 5, which was consistent with this presented case. The initial diagnosis was made by TEE in 7 cases, and not specified in 9 cases, CT scan and venogram in 7 and 4 cases, respectively. Only 3 cases were initially diagnosed by 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, which needs more well-designed trials to examine specific outcomes and to answer questions such as precise indications and contraindications of this intervention 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 / 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 and few others report AngioVac in the aorta. This case was the 1st to employ trans-caval access for a successful aspiration of the mobile part of a large aortic arch thrombus. Th 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 a number of minimally invasive options. With the advent of vacuum aspiration, more specifically the AngioVac System, there exists a system with both low mortality and minor complications. However, the number of retrospective studies remains limited; and outcome data for high-risk patients are also limited. In a observational, single-center study, these investigators described their institution's experience with the AngioVac system. Data were collected and analyzed in patients who underwent AngioVac therapy at the authors’ tertiary care center from January 2014 to December 2020. These findings demonstrated a 93.3 % intra-operative success rate and a 100 % intra-operative survival rate; however, a number of complications, including but not limited to hematomas, anemia, and hypotension, occurred, as described below. The authors concluded that use of the AngioVac System has been demonstrated in multiple case studies and in a few retrospective studies. They had presented the experience with the system at their institution, and though patients were critically ill with large vegetative masses, their data demonstrated good intra-operative survival and success. These researchers stated that these findings appeared to further 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. Moreover, they stated that larger studies are needed to determine safety in large vegetations of use with right-sided endocarditis. These investigators stated 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. Subsequently, 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 in 52 adult patients with the AngioVac system, 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 were 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 carried out in 44 cases (84.6 %) and partial success was achieved in 5 patients (9.6 %), while failure to remove thrombi or vegetations occurred in 3 cases (5.8 %). These investigators’ practical experience led to the installation of a shunt line for re-circulation 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 have to be validated on a larger scale. The authors concluded that in this initial experience, the AngioVac system appeared to be safe regarding the 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 demanding surgical intervention. The latter cannot be offered in a good proportion of the patients due to challenging medical as well as social complexities. The AngioVac system has been employed as an alternative therapy; however, it is associated with high procedural mortality.
Enezate and colleagues (2022) noted that management of 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 co-morbidities and risk of distal embolization. These researchers examined the advancements in percutaneous approaches for treatment of intra-cardiac masses by means of the AngioVac. With the FDA approval of the AngioVac System in 2009, a growing body of evidence has proven it to be a feasible and effective tool to extract thrombi and masses from the ilio-caval system and the right heart. These investigators highlighted the feasibility of AngioVac System based on the published cases series and registries. The authors concluded that future RCTs are needed to establish an algorithmic approach in 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. Percutaneous transeptal debulking with AngioVac for mitral valve endocarditis (MVE) in the inoperable or high surgical risk patient 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, sequala of acute IE (i.e., stroke, sepsis or hemodynamic instability), in itself is 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 MV vegetation debulking with the AngioVac Gen3 C 180 MV system. Pre-procedural planning with attention to; optimal transeptal height puncture, use of sentinel cerebral protection device to decrease risk of procedure-related cerebral embolism and venous extracorporeal membrane cannula, rather than arterial cannula for re-infusion, was described to avoid large bore arterial access related vascular complications. The authors concluded that further studies in a randomized manner 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). AngioVac is a vacuum-based device that was approved in 2014 for the percutaneous removal of undesirable materials from the intravascular system. Although there were multiple reports on the use of the AngioVac device to aspirate right-sided heart chamber thrombi, data on its use to treat RSIE was limited. These investigators carried out a comprehensive literature search for studies that examined the use of AVD. The primary outcomes were the procedural success, defined as the ability of AngioVac to produce residual vegetation size of less than 50 % (RVS < 50 %) without serious procedural complications, and the clinical success, defined as composite of RVS < 50 %, in-hospital survival, absence of recurrent bacteremia, and valve function not requiring further intervention. The 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 random effects model, generic inverse variance method, and represented with 95 % 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 %). 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 multi-factorial with high mortality if left untreated. These investigators reported for the 1st time a case of Ogilvie syndrome secondary to the AngioVac procedure. Because the patient had a high operative risk, these researchers 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. Providers should be aware of this rare but potentially fatal complication and the importance of close clinical monitoring and serial abdominal examinations following AngioVac procedures.
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 for open surgical treatment. 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. Consecutive patients from 2 Michigan centers who underwent left-sided TVME were included. Data on patient demographics, procedural information, in-hospital and follow-up events were collected via electronic medical records review. Technical success was defined as aspirating of 70 % to 100 % of the material. A total of 10 patients (mean age of 58.3 [± 17.3] years, 50 % men) were included. Indications for TMVE were in large for recurrent embolic events. All patients underwent bilateral cerebro-embolic protection using the Sentinel device. The total mean procedure time was 192.5 (± 47.5) mins of which the meantime for active aspiration (bypass time) was 9.3 (± 4.2) mins. 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. No complications were reported (range of follow-up 1 to 16 months). The authors concluded that this small case series showed the feasibility and safety of the AngioVac system in left-sided mass extraction. Moreover, these researchers 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 mass 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. 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 arteries sizes often could not accommodate the AngioVac system current aspiration cannula dimensions.
Left Atrial to Coronary Sinus Shunting (the APTURE Transcatheter Shunt System)
Hibbert et al (2023) stated that 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 examine 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 with a pulmonary capillary wedge pressure of greater than 15 mm Hg at rest or 25 mm Hg during exercise. Between May 2018 and September 2022, a total of 87 patients underwent attempted APTURE shunt implantation. Mean age was 71 years, and 53 % were men. At baseline, mean LVEF was 59 % with 90 % of the patients being in NYHA functional class III. Device success was achieved in 78 patients (90 %), with no device occlusions or associated AEs identified after implantation. The primary safety outcome occurred in only 2 patients (2.3 %) at 30 days. At 6 months, health status improved: 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. Also at 6 months, 20-W exercise pulmonary capillary wedge pressure was 7 mm Hg lower (p < 0.0001; 95 % CI: -11 to -4 mm Hg) without 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 in patients with symptomatic HF was observed to be safe and resulted in reduction in pulmonary capillary wedge pressure and clinically meaningful improvements in HF symptoms and QOL indices. Moreover, these researchers stated that a definitive randomized, sham-controlled study will establish the impact on clinical outcomes in the treatment of patients with HF.
The authors stated that as an early feasibility study, the sample size was small (n = 87) and only allowed conclusions regarding feasibility and safety of implantation, and some estimates of an effectiveness signal, if only for the relatively short follow-up period of 6 months. These investigators stated that the lack of a sham-control arm and blinding, the impact and potential magnitude of a placebo effect on the results could not be estimated or discounted, although it is hoped that by means of core laboratories and independent clinical event adjudication, these findings are more likely to be reproducible in a more definitive clinical trial.
Transcatheter Closure for the Treatment of Post-Infarction Ventricular Septal Defect
Yang et al (2021) stated that post-infarction VSD (PIVSD) is a severe complication of acute MI (AMI). Trans-catheter closure (TCC) is an alternative option to surgical repair. In a meta-analysis, these investigators examined the published literature to provide objective evidence. They searched for significant medical and publisher databases; 2 reviewers checked the quality of the studies and extracted data. Eligible studies included single-arm studies, and comparative studies. Weighted means, pooled event rates, effectiveness outcomes and ORs for immediate shunt reduction (ISR), presence of cardiogenic shock (CS), NYHA class IV, time from AMI to VSD, and time to VSD closure was estimated. A total of 27 single-arm studies (462 patients) were included. The pooled event rate was 89.7 % (95 % CI: 0.772 to 1.021) for successful device implantation, 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 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 a relatively safe and minimally invasive method for PIVSD, with an excellent successful device implantation rate and acceptable low 30-day mortality. Moreover, these researchers stated that the procedure appeared promising; however, its safety and effectiveness could only be verified by RCTs; thus, the mortality of data comparing surgery to TCC compelled the need for future comparative trials.
Yi et al (2023) noted that VSDs are one of the mechanical complications of AMI. Because of the high risks of mortality and post-operative complications, a new alternative method is needed. With the advent of 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 of PMIVSDs. The included studies were mainly single-arm studies of TCC of PMIVSDs. These researchers compared VSD size, device size, pre-operative 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 (284 patients) were included. The combined incidences of pre-operative 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 pre-operative percutaneous coronary intervention (PCI), intra-aortic balloon pump (IABP), 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); 11 studies reported the number of successful closures and the 30-day mortality rate; the success rate was 90 % (95 % CI: 0.86 to 0.94), and the 30-day mortality rate reached 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. Residual shunts were a long-term complication that have a high incidence and long-lasting effects on patients. These researchers stated that more large, multi-center RCTs are needed to confirm the safety and reliability of TCC of PMIVSDs.
The authors stated that this analysis had several drawbacks. First, in the process of screening previous literature, no RCTs examining surgical repair and transcatheter occlusion for the treatment of PMIVSD were found; therefore, these investigators only carried out a single-arm meta-analysis to discuss the safety and effectiveness of TCC for PMIVSD. Second, the sample size of available evidence was small, most of them were retrospective studies, and selection bias played a role in the results. Third, for patients with AMI, the probability of VSD is very low, and the number of patients who could undergo an intervention was very small. The small number of patients and inherent selection bias in almost all such studies made it difficult to compare the results of TCC with those of published surgical series. This review included 12 multi-case studies. These researchers considered comparing the studies of TCC in the acute phase and chronic phase of PMIVSD and considered the comparison of residual shunts in different periods after TCC. However, comparisons could not be made due to variable baseline information, which may be due to individual differences among patients in such studies, with greater heterogeneity between patients. This also suggested that whether patients with PMIVSD could undergo TCC needs to be decided according to 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 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 debate remains on the optimal pre-procedure optimization, timing of repair, and modality of treatment. These issues will remain uncertain without prospective evidence to guide clinicians. Moreover, these investigators stated that the heterogeneity of retrospective data often resulted in more questions than answers being formulated. They stated that the formation of an expert steering group and a national/international prospective PIVSD registry may aid in addressing these issues, guide further research, and optimize care.
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The above policy is based on the following references:
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