Abstract
Background: The AmplatzerTM PFO Occluder was approved for marketing in Japan in May 2019, and the Amplatzer PFO Occluder Japan Post-marketing Surveillance (PFO Japan PMS) study was initiated in December 2019. This analysis presents 30-day clinical outcomes for PFO Japan PMS study patients.
Methods and Results: PFO Japan PMS is a prospective single-arm non-randomized multicenter clinical study. Eligible patients were indicated for patent foramen ovale (PFO) closure and underwent an implant attempt with the AmplatzerTM PFO Occluder. Technical success was defined as successful delivery and release of the occluder; procedural success was defined as technical success with no serious adverse events (SAEs) within 1 day of the procedure. The primary safety endpoint includes predefined device- and/or procedure-related SAEs through 30 days after the procedure. From December 2019 to July 2021, 500 patients were enrolled across 53 Japanese sites. The mean (±SD) patient age was 52.7±15.4 years, and 29.8% of patients were aged >60 years. Technical and procedural success rates were both high (99.8% and 98.8%, respectively). Further, there was only one primary safety endpoint event (0.2%): an episode of asymptomatic paroxysmal atrial fibrillation that occurred 26 days after the procedure.
Conclusions: In this real-world Japanese study with almost one-third of patients aged >60 years, PFO closure with the AmplatzerTM PFO Occluder was performed successfully and safely, with a low incidence of procedure-related atrial arrhythmias.
A patent foramen ovale (PFO) is a congenital flap-like opening between the right and left atria that is present in approximately 15–25% of adults.1,2 Although in most cases it is benign and requires no treatment, in some individuals it can be a cause of ischemic stroke via paradoxical embolism, commonly referred to as a PFO-associated stroke. In fact, this mechanism is likely responsible for approximately 5% of all ischemic strokes.3–5 A patient-level analysis of 6 randomized controlled trials found that in patients who had experienced a PFO-associated stroke, transcatheter PFO closure combined with medical therapy reduced the risk of recurrent PFO-associated stroke by 75% compared with medical therapy alone.6
The AmplatzerTM PFO Occluder, a transcatheter PFO closure device, received Conformité Européenne (CE) approval in 1998 and US Food and Drug Administration (FDA) approval in 2016, and has been used to treat over 180,000 patients worldwide. This analysis presents early clinical outcomes from real-world use of the AmplatzerTM PFO Occluder in a Japanese population.
Methods
Study Design and Patient Population
The AmplatzerTM PFO Occluder Japan Post-Marketing Surveillance (PFO Japan PMS) study is a prospective single-arm non-randomized multicenter clinical study that aims to assess the safety and effectiveness of transcatheter PFO closure with the AmplatzerTM PFO Occluder to reduce the risk of recurrent ischemic stroke in patients who have had a PFO-associated stroke. The target sample size for the study was 500 patients.
The study on going performed in accordance with the Declaration of Helsinki and was approved by the ethics committee at each participating institution. Eligible patients had to have experienced a PFO-related cryptogenic cerebral infarction (including diagnosed paradoxical cerebral embolism), with either symptoms persisting ≥24 h or for <24 h but associated with magnetic resonance imaging or computed tomography findings of a new neuroanatomically relevant cerebral infarct. In addition, eligible patients must have subsequently undergone implant attempt with an AmplatzerTM PFO Occluder. There were no other eligibility criteria in the study, and sites were instructed to seek consent from all eligible consecutive patients.
Key baseline requirements included parenchymal imaging, cardiac monitoring, and transesophageal echocardiography (TEE) with agitated saline microbubble assessment (“bubble study”) at rest and the Valsalva maneuver (Supplementary Methods). Beyond these study requirements, sites were instructed to perform their standard-of-care evaluation to screen for and assess the PFO and to rule out other causes of ischemic stroke. Finally, sites were instructed to follow the procedural guidelines outlined in the instructions for use of the AmplatzerTM PFO Occluder (International site: https://www.cardiovascular.abbott/us/en/hcp/products/structural-heart/structural-interventions.amplatzer-talisman.html); there were no other study-specific procedural requirements.
Patients were considered enrolled upon insertion of the AmplatzerTM PFO Occluder delivery system into the body, at which point safety reporting also started. In the case of a failed implant attempt, follow-up was not required unless any in-hospital procedure-related adverse events occurred. The seriousness and relatedness of any adverse events to the procedure or device were determined by the site investigator. Data were collected at a baseline visit, during the procedure, at discharge or 7 days (whichever occurs first), at 30 days, and at 1, 2, and 3 years.
Endpoints
The primary safety endpoint of this study was predefined device- and/or procedure-related serious adverse events (SAEs) through 30 days, including: atrial fibrillation (AF); pulmonary embolism (PE); deep vein thrombosis (DVT); device thrombus, erosion, or embolization; ischemic stroke; hemorrhagic stroke; major bleeding requiring transfusion or surgical or endovascular intervention; vascular access site complications requiring surgical intervention; and device- and/or procedure-related SAEs leading to death.
Other short-term endpoints were technical success (successful delivery and release of the AmplatzerTM PFO Occluder) and procedural success (technical success with no SAEs within 1 day of the procedure).
Statistical Analysis
Baseline patient clinical characteristics were summarized using descriptive statistics. Continuous variables are summarized as the mean±SD, and categorical variables are summarized as proportions (n/N). A performance goal was prespecified for the primary safety endpoint and set to 3.5% as a clinically acceptable rate. Assuming the primary safety endpoint rate in the present study to be equal to the corresponding rate observed in the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial of 2.1%,7 the 95% upper confidence limit (UCL) for a sample size of 500 patients would be equal to the performance goal of 3.5%. Thus, the sample size was set to 500 patients. The primary safety endpoint was considered met if the 95% UCL was less than the performance goal. All enrolled patients were included in the analysis.
Risk of Paradoxical Embolism (RoPE) score analysis and PFO-Associated Stroke Causal Likelihood (PASCAL) classification were performed on all patients for whom sufficient data were available. The RoPE score uses patient age, infarct topography, and the presence of atherosclerotic risk factors to quantify the likelihood of a PFO causal association to stroke, rated on a scale of 0–10, with a higher score indicating a greater likelihood.8 The PASCAL classification incorporates the RoPE score and the presence or absence of high-risk PFO features, namely a large shunt and/or an atrial septal aneurysm, to categorize the likelihood that the PFO was causally related to the ischemic stroke as “Probable”, “Possible”, or “Unlikely”.6 If baseline shunt assessments were performed via both TEE and transthoracic echocardiography (TTE) for a given patient, the maximum overall shunt grade observed was used to characterize shunt size.
Results
Patient Enrollment and Follow-up
In all, 500 patients were enrolled at 53 Japanese sites from December 2019 to July 2021 and will be followed through a 3-year visit (Supplementary Table 1). The number of patients enrolled per site varied from 1 to 50, with a median of 7 enrollments. Of the 500 patients enrolled, 483 completed the 30-day visit (Figure 1). Of those who did not complete the visit, 1 patient was withdrawn due to unsuccessful implant (see below), 4 patients were lost to follow-up, and 12 patients had missed visits, which were largely related to COVID-19.
Patient Characteristics
Most patients in the PFO Japan PMS study were male (62.4%; Table 1). The proportion of study patients aged >60 years at enrollment was 29.8%, and the mean age at enrollment was 52.7±15.4 years.
Table 1.
Baseline Characteristics (n=500)
| Age (years) |
| Mean±SD (n) |
52.7±15.4 (500) |
| Median |
53.0 |
| Range (minimum–maximum) |
14.0–89.0 |
| Male sex |
62.4 (312/500) |
| Medical history |
| CHF |
0.4 (2/500) |
| Peripheral vascular disease |
0.6 (3/500) |
| COPD |
1.6 (8/500) |
| Deep vein thrombosis |
16.6 (83/500) |
| Coronary artery disease |
3.0 (15/500) |
| Migraine headaches |
9.6 (48/500) |
| Other sources of right-to-left shuntA |
1.0 (5/500) |
| MI within the past 1 month |
0.4 (2/500) |
| Pulmonary embolism |
8.0 (40/500) |
| CHF with LVEF <30% |
0.2 (1/500) |
| Stroke risk factors |
| None |
31.0 (155/500) |
| Family history of cerebral infarction (parent or sibling) |
7.2 (36/500) |
| Hypertension |
34.8 (174/500) |
| Chronic, persistent or paroxysmal AF or Afl |
1.2 (6/500) |
| Diabetes |
6.6 (33/500) |
| Hypercholesterolemia |
22.8 (114/500) |
| Obesity |
7.2 (36/500) |
| Hyperlipidemia |
11.6 (58/500) |
| Birth control/hormone replacement therapy |
0.8 (4/500) |
| Current smoker |
10.8 (54/500) |
| Former smoker |
23.6 (118/500) |
Unless indicated otherwise, data are given as % (n/N). AOther sources of left-to-right shunt included atrial septal defect and/or fenestrated septum. AF, atrial fibrillation; Afl, atrial flutter; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction.
Approximately one-third (31.0%) of patients had no stroke risk factors. The most common risk factors for stroke were hypertension (34.8%), current or former tobacco use (34.4%), hypercholesterolemia (22.8%), and hyperlipidemia (11.6%). Among the 398 patients with sufficient data to allow for calculation of the RoPE score, the median RoPE score was 6 (interquartile range 5–8); further, 229 (57.5%) of these patients had a RoPE score <7 (Supplementary Figure).
Notably, 83 (16.6%) patients had a history of DVT and 40 (8.0%) had a history of PE; among these 123 patients, 28 (5.6%) had a history of both DVT and PE. Finally, 48 (9.6%) patients had a history of migraine headaches.
Baseline Shunt Assessments and PFO Measurements
Baseline shunt assessments via the bubble study were performed using TEE in 472 (94.4%) patients, TTE in 275 (55%) patients, and transcranial Doppler (TCD) in 64 (12.8%) patients (Supplementary Table 2). (Many patients had shunt assessments performed using multiple modalities.) The maximum shunt grade obtained via TEE and/or TTE (performed at rest and/or during the Valsalva maneuver) was Grade III (≥20 bubbles) or Grade IV (opacification, only classified using TTE) in 81.1% of patients.
The mean PFO height was 3.0±2.0 mm and the mean PFO tunnel length was 9.7±4.4 mm (approximately half [49.0%] the patients had a PFO tunnel length ≥10 mm). An atrial septal aneurysm, defined as a ≥10 mm excursion of the septum primum from the midline, was identified in just over one-quarter (25.7%) of patients, whereas Eustachian valve and Chiari network were identified in 17.6% and 10.4% of patients, respectively.
PASCAL Classification
PASCAL classification as applied to the PFO Japan PMS population, as shown in Figure 2. In all, 393 study patients had PFO assessments performed as well as sufficient data to compute the RoPE score, thus allowing for their PASCAL classification. Of these patients, 57.5% had a low (<7) RoPE score; however, 85.5% had ≥1 high-risk PFO features. As a result, the vast majority of these patients were categorized as either “Probable” (35.9%) or “Possible” (56.2%), with only 7.9% labeled as “Unlikely”.
Time to PFO Closure
The distribution of time from the occurrence of the index stroke to the PFO closure procedure is shown in Figure 3. Almost three-quarters (73.0%) of patients underwent PFO closure in the first year after the index stroke, with more than half (50.6%) the procedures occurring within the first 6 months after the index stroke. The median time to closure was 177 days.
Technical and Procedural Success
The rate of technical success was 99.8% (499/500) because there was only 1 procedure without successful delivery and release of the AmplatzerTM PFO Occluder (Table 2). In this procedure, a device deformation was observed when the left atrial disc of a 30-mm AmplatzerTM PFO Occluder was opened in the left atrium. The device was withdrawn, and an Amplatzer Cribriform Multi-Fenestrated Septal Occluder was subsequently implanted successfully. Because this was not a study device, the procedure was not considered a technical success, and the patient was withdrawn.
Table 2.
Safety and Effectiveness Endpoint Analysis (n=500)
| |
% (number) |
95% UCL |
Performance
goal (%) |
P value |
| Safety (primary) |
| Procedure-/device-related SAE through 30 daysA |
0.2 (1/500) |
0.95 |
3.5 |
<0.0001 |
| Effectiveness (secondary) |
| Technical successB |
99.8 (499/500) |
|
|
|
| Procedural successC |
98.8 (494/500) |
|
|
|
APredefined procedure- and/or device-related serious adverse events (SAEs) through 30 days included: atrial fibrillation; pulmonary embolism; deep vein thrombosis; device thrombus, erosion, or embolization; ischemic stroke; hemorrhagic stroke; major bleeding requiring transfusion or surgical or endovascular intervention; vascular access site complications requiring surgical intervention; and device- and/or procedure-related SAEs leading to death. BSuccessful delivery and release of the AmplatzerTM PFO Occluder. CTechnical success with no SAEs within 1 day of the procedure. There were 5 SAEs within 1 day of successful procedures: air embolism, hypopharyngeal perforation, urination disorder, atrial fibrillation, and vascular arteriovenous fistula. UCL, upper confidence limit.
The rate of procedural success was 98.8% (494/500) because there were 5 patients with SAEs within 1 day of successful implant procedures (and 1 patient with an unsuccessful procedure, as described above). These events were air embolism, hypopharyngeal perforation, urination disorder, AF, and vascular arteriovenous (AV) fistula. Of these, the air embolism, hypopharyngeal perforation, and vascular AV fistula were determined by the implanting physician to be procedure related; none of the events was deemed device related and none met the predefined criteria for the primary safety endpoint.
Safety
Only 1 (0.2%) device- and/or procedure-related adverse event meeting primary safety endpoint criteria occurred in the study (Table 2): an episode of asymptomatic paroxysmal AF. This patient had an implantable cardiac monitor (ICM) inserted prior to PFO closure in order to rule out AF as a cause of stroke. No AF was observed, and PFO closure was performed. The patient was 66 years old at the time of procedure. At the patient’s 1-month follow-up visit, it was noted that 26 days after the procedure the ICM had recorded a 19-h episode of AF. A TTE was subsequently performed, which showed the device was in place. No medication was administered, and no further episodes were reported at the 1-year follow-up.
Because the 95% UCL (0.95%) was lower than the performance goal (3.5%), the primary safety endpoint was met for the study.
In all, 21 adverse events occurred in 17 (3.4%) patients through the 30-day follow-up, with 16 SAEs in 12 patients (2.4%; Table 3). There were 8 events of AF in 8 (1.6%) patients, with 3 of the events determined to be SAEs. Seven of the AF events were paroxysmal; in the remaining case, there was a cardioversion within 24 h. Three AF events were determined to be related to the procedure, and 5 were determined to be related to the device. Three AF events were observed periprocedurally, and 4 were detected after closure via the ICM (including the primary safety endpoint event discussed above). Finally, 1 AF event was detected by an electrocardiogram (ECG) monitor the day after the procedure. This patient was previously diagnosed with AF during an earlier health examination (prior to PFO closure), but never shared the diagnosis with study personnel. Two patients were prescribed anticoagulant medication following their episodes of AF.
Table 3.
All Adverse Events Through 30 Days in the 500 Patients in the Study
| Adverse event |
No. patients
with eventsA (%) |
Total no.
events |
No. SAEs |
No. procedure-related
events |
No. device-related
events |
| Air embolism |
1 (0.2) |
1 |
1 |
1 |
0 |
| Atrial fibrillation |
8 (1.6) |
8 |
3 |
3 |
5 |
| Atrial flutter |
2 (0.4) |
2 |
2 |
0 |
1 |
| TIA |
1 (0.2) |
1 |
1 |
0 |
0 |
| Vascular AV fistula |
1 (0.2) |
1 |
1 |
1 |
0 |
| Vascular access site complications |
1 (0.2) |
1 |
1 |
1 |
0 |
| Epidural hematoma |
1 (0.2) |
1 |
1 |
0 |
0 |
| Hypopharyngeal perforation |
1 (0.2) |
1 |
1 |
1 |
0 |
| Ischemic enteritis |
1 (0.2) |
1 |
1 |
0 |
0 |
| Periapical periodontitis |
1 (0.2) |
1 |
1 |
0 |
0 |
| Radicular cyst |
1 (0.2) |
1 |
1 |
0 |
0 |
| Subcutaneous hematoma |
1 (0.2) |
1 |
1 |
0 |
0 |
| Urination disorder |
1 (0.2) |
1 |
1 |
0 |
0 |
| Total no. events |
17 (3.4) |
21 |
16 |
7 |
6 |
APatients may have had multiple events. AV, arteriovenous; SAEs, serious adverse events; TIA, transient ischemic attack.
Of the 8 patients who experienced AF, 4 were aged >60 years at the time of their procedure; this proportion (50.0%) is much greater than the proportion of patients aged >60 years in the overall study population (29.8%).
Other SAEs of note included 2 episodes of atrial flutter in 2 (0.4%) patients, one of which was determined to be device related and the other occurring in a patient with a history of atrial flutter. Finally, there was one transient ischemic attack (TIA), which was diffusion-weighted imaging negative and considered unrelated to both the procedure and device.
Discussion
This analysis presents 30-day clinical outcomes of patients in the PFO Japan PMS study who underwent PFO closure with the AmplatzerTM PFO Occluder to reduce the risk of recurrent PFO-associated ischemic stroke. This real-world study of Japanese clinical practice demonstrated high technical and procedural success rates of 99.8% and 98.8%, respectively. Further, it revealed an excellent short-term safety profile, with only 1 (0.2%) patient experiencing a device- and/or procedure-related SAE meeting primary safety endpoint criteria.
In the PFO Japan PMS study, the sites were instructed to seek consent from all patients indicated for PFO closure who underwent an implant attempt with the AmplatzerTM PFO Occluder. Thus, the study was not restricted by many of the eligibility criteria common to the randomized controlled trials (RCTs) on PFO closure, such as the pivotal RESPECT trial9 (which also investigated the AmplatzerTM PFO Occluder). For example, patients aged >60 years could be enrolled in the PFO Japan PMS study (such patients were excluded from RESPECT); as a result, the proportion of patients in the PFO Japan PMS study >60 years of age at enrollment was 29.8% and the mean age at enrollment was 52.7±15.4 years (vs. 45.7±9.7 years in RESPECT).9 The limited eligibility criteria of the PFO Japan PMS study allowed for a more accurate reflection of patient selection for PFO closure in contemporary Japanese clinical practice.
The inclusion of older patients in the PFO Japan PMS study also contributed to lower RoPE scores in the study compared with RCT data. In the overall RCT population, 62.5% of patients had a RoPE score ≥7.6 Meanwhile, among patients in the PFO Japan PMS study with sufficient data to allow for calculation of the RoPE score, only 42.5% had a RoPE score ≥7. In an individual patient data meta-analysis of 6 RCTs on PFO closure, the threshold of a RoPE score ≥7 was shown to be a strong indicator of clinical effectiveness (greater reduction in the risk of recurrent ischemic stroke) associated with PFO closure.6 Thus, based solely on RoPE score, the predicted clinical effectiveness of PFO closure in the PFO Japan PMS study population would be less than that of the RCT population.
However, in applying the PASCAL classification to the RCT population, Kent et al found that this method demonstrated superior precision to classification by the RoPE score alone in identifying patient populations with greater benefit from PFO closure.6 Kent et al also showed that the greatest reduction in recurrent ischemic stroke associated with PFO closure was seen in the “Probable” group, followed by the “Possible” group, and that there was no benefit in the “Unlikely” group.6 Finally, PFO closure in the “Unlikely” group led to higher rates of AF and all SAEs compared with the “Possible” and “Probable” groups.
Although the RoPE scores of the PFO Japan PMS study population were lower than those of the RCT population, a much higher proportion of patients in the PFO Japan PMS study exhibited a large shunt (81.1% vs. 43.2%).6 As a result, among patients in the PFO Japan PMS study with sufficient data to allow for PASCAL classification, only 7.9% were categorized as “Unlikely”, compared with 14.6% of patients in the RCT population. Thus, despite the fact that the PFO Japan PMS study had less stringent eligibility criteria and enrolled an older patient population, the proportion of study patients classified by PASCAL as “Unlikely” to have had a PFO-related stroke is much lower than that observed in the RCTs. This is indicative of appropriate patient selection for PFO closure in the PFO Japan PMS study according to the PASCAL framework.
The 2019 guidelines from the Japan Stroke Society, the Japanese Circulation Society, and the Japanese Association of Cardiovascular Intervention and Therapeutics on PFO closure state that TEE is essential for the assessment of the presence of PFO, as well as for the anatomical evaluation of the PFO; further, both TCD and TTE may be considered as screening tests for the detection of right-to-left shunts prior to TEE.10 In alignment with these guidelines, baseline PFO assessment by TEE was a requirement in the PFO Japan PMS study; this was adhered to in 99.2% of cases. (Note, in patients in whom TEE bubble studies were not performed, TEE measurements of PFO height and tunnel length, as well as the presence of atrial septal aneurysm, also qualified as baseline PFO assessments by TEE.) PFO assessments could be performed using multiple imaging modalities for a study patient; TTE was used in 55.0% of cases and TCD in 12.8%. The most common approach was a combination of TEE and TTE (46.4%), followed by TEE only (40.0%). Thus, TTE seems to be favored over TCD as an initial screening tool for right-to-left shunt in Japanese clinical practice.
The PFO closure procedure was performed highly successfully in the PFO Japan PMS study. The technical success rate of 99.8% was towards the upper end of the range of values reported among the RCTs (97.4–100.0%),6 and the procedural success rate was 98.8% (no directly comparable rates were reported from the RCTs).
Excellent safety was demonstrated as well, with only 1 (0.2%) device- and/or procedure-related event meeting primary safety endpoint criteria. This event of asymptomatic paroxysmal AF was identified 26 days after the procedure via ICM in a 66-year-old patient. Apart from 1 case in which there was a cardioversion within 24 h, all AF events in the study were paroxysmal. In addition, AF occurred disproportionately more often in patients aged >60 years, which may be expected due to the higher background rate of AF in older patients.11 Despite almost one-third (29.8%) of the study population belonging to this age group, the total AF rate in the study was low (1.6%), as was the overall rate of SAEs (2.4%).
Study Limitations
This analysis focused on the short-term measures of technical and procedural success and 30-day safety outcomes. As the study progresses, future analyses will also evaluate long-term measures, including the rate of PFO closure at 1 year (as was done in the study of Nakayama et al12); the rates of PE, DVT, ischemic stroke, and AF beyond 30 days through follow-up; and antithrombotic medication use from after the procedure through follow-up.
There were no requirements for post-procedure cardiac rhythm monitoring in the PFO Japan PMS study.
Conclusions
This analysis of short-term outcomes in the PFO Japan PMS study provides insights into real-world early Japanese adoption of transcatheter PFO closure with the AmplatzerTM PFO Occluder. Although almost one-third of study patients were over 60 years of age, the vast majority of all patients had high-risk PFO features and were therefore categorized as likely to benefit from PFO closure according to PASCAL classification. Further, the procedure was performed safely and successfully in study patients, with a low incidence of procedure-related atrial arrhythmias. Thus, these results demonstrate continued safety and effectiveness of the AmplatzerTM PFO Occluder, and indicate successful adoption of the PFO closure procedure into Japanese clinical practice.
Acknowledgments
The authors thank all the investigators and institutions participating in the PFO Japan PMS study. The authors also thank Nils Peter Borgstrom, PhD (Abbott), for his contributions to data review and manuscript preparation, and Devon Sauerer (Abbott) and Joshua Rapkin (Abbott) for their contributions to data analysis.
Sources of Funding
Abbott funded the PFO Japan PMS study. Further, Abbott designed the study and was responsible for selecting and monitoring the sites, as well as data management and analysis. The authors had full access to the data and attest to the integrity of the study and the accuracy and completeness of the reported data. No funding was provided for this analysis.
Disclosures
No authors have any conflicts of interest to declare.
IRB Information
The study was approved by Okayama University Hospital Institutional Review Board (Reference no. 24092024).
Data Availability
The deidentified patient data will not be shared.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-24-0080
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