Abstract: Background. Randomized trials for percutaneous closure of patent foramen ovale (PFO) have demonstrated a lower rate of recurrent ischemic events compared with medical therapy. The aim of this long-term follow-up analysis was to validate the impact of PFO closure on recurrent ischemic events. Methods and Results. A total of 570 patients were enrolled. Patients were followed for recurrent ischemic events for a median of 7.2 years. Mean age at the time of procedure was 49.3 ± 13.1 years. PFO closure was performed with the Amplatzer occluder in 44.9% of patients and with BioStar, Cardia or Premere occluders in 55.1% of patients. Within 10 years of follow-up, recurrent ischemic stroke occurred in 5.1% of patients in the Amplatzer group vs 7.6% with the other occluders (log rank P=.61). There was no difference in the rate of recurrent transient ischemic attack (1.86% vs 1.51%; log rank P=.52) or all-cause mortality (2.9% vs 3.8%; log rank P=.84) between the two groups, in patients with or without an atrial septal aneurysm or with respect to grade of preprocedural shunt. Recurrent stroke was lower in patients <45 years old at the time of occluder implantation (hazard ratio, 4.14; 95% confidence interval, 0.94-18.8; log rank P=.05). Conclusion. In this long-term follow-up after PFO closure, the rate of recurrent stroke was low. There were no significant differences in event rates between different occluder devices, the existence of an atrial septal aneurysm, or grade of preprocedural shunt at baseline. Patients <45 years old had lower rates of recurrent ischemic stroke.
J INVASIVE CARDIOL 2019;31(8):E242-E248.
Key words: outcomes, PFO, stroke
About one-third of ischemic strokes are cryptogenic. Patent foramen ovale (PFO) is thought to be a major cause of cryptogenic ischemic events.1 Percutaneous closure has been demonstrated to be efficient in reducing recurrent ischemic events2 compared with medical therapy. Although the first randomized trials did not show a significant reduction of recurrent ischemic events,3-5 meta-analyses on a patient level were able to demonstrate this benefit.6,7 The per-protocol analysis in the RESPECT trial5 on the Amplatzer PFO device (St. Jude Medical) and the CLOSURE trial3 on the Starflex PFO occluder (NMT Medical) demonstrated a reduction of recurrent ischemic events compared with medical therapy, with a limited follow-up. Within an extended follow-up period of a median of 5.9 years in the RESPECT trial,8 there was a significant benefit in the intention-to-treat analysis. Patients with cryptogenic ischemic events are usually younger, and have a PFO device within the body over several decades. Long-term follow-up data in a real-world population undergoing percutaneous PFO closure are scarce.
The aim of this PFO study was to validate the long-term efficacy and safety of PFO closure on recurrent ischemic and thromboembolic events in a real-world population.
Patient selection. Patients were prospectively enrolled in this observational study. This analysis includes 570 patients undergoing percutaneous PFO closure for cryptogenic ischemic events. The baseline data included age, sex, diabetes mellitus, body mass index, history of atrial fibrillation, coronary artery disease, and index event. Stroke or transient ischemic attack (TIA) was diagnosed by neurologists using cranial computed tomography or cranial magnetic resonance imaging in combination with the clinical presentation of the patient. All patients underwent a diagnostic evaluation with routine laboratory testing, carotid duplex ultrasonography, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE). TEE was performed with a multiplane, phased-array 4-7 MHz probe on an ATL HDI 5000 CV (Philips Medical Systems) or iE33 xMATRIX (Philips Deutschland GmbH). Valsalva-induced right-to-left shunt was graded according to the number of bubbles crossing the interatrial septum after the injection of 10 mL of agitated hydroxy-ethyl starch solution or agitated saline solution via a cubital vein. No shunt was defined as zero bubbles, trace shunt as 1-9 bubbles, moderate shunt as 10-19 bubbles, and severe shunt as ≥20 bubbles. Bubble testing was performed three times with the proper Valsalva maneuver, as described elsewhere.9 PFO size and morphology were assessed by TEE. PFO diameter was measured in the short axis as the maximum opening of the communicating channel. Closure was defined as no or trace residual shunt assessed by TEE. An atrial septal aneurysm (ASA) was defined as an excursion of the atrial septum >10 mm.10 Patients with a cryptogenic ischemic event based on neurological and cardiological tests were usually scheduled for PFO closure with device implantation if there was a moderate or severe shunting by bubble passage during Valsalva maneuver or in combination with an ASA. Patients were scheduled for TEE at 3 months and 12 months post device implantation. Patients were followed in the outpatient clinic or via telephone contact. A standardized questionnaire was used to assess ischemic and thromboembolic events. The study was approved by the ethics committee of the University of Ulm and written informed consent was obtained from all patients. The study was done in compliance with the Declaration of Helsinki.
PFO occluder devices. Percutaneous PFO closure was done in the catheterization laboratory as described else-where.11,12 Deployment and position of the device were controlled by fluoroscopy and usually by periprocedural TEE. The following devices were implanted: (1) The BioStar septal repair implant (NMT Medical) is an innovative bioabsorbable device. It consists of a purified porcine intestinal collagen-layer matrix mounted on the MP35N StarFlex double-umbrella framework, coated with a heparin benzalkonium chloride complex. Nitinol microsprings between the right and left atrial discs allow self-centering of the device. The collagen matrix is absorbed and entirely replaced by host tissue over a period of approximately 24 months. (2) The Amplatzer PFO occluder is a self-expandable, double-disc device made from a nitinol wire mesh. The two flat discs, which are linked by a connecting waist, contain thin polyester fabric. In this series, the Amplatzer PFO occluder, the Amplatzer septal occluder, and the Amplatzer cribriform occluder were implanted. (3) The Cardia PFO Occluder (Cardia, Inc) is made of two polyvinyl-alcohol sails, mounted on six nitinol wires for each sail, connected by a center post. In this series, patients received generation I-III Cardia PFO or Cardia ASD occluders. (4) The Premere PFO closure system (St. Jude Medical) includes thin, flexible, nitinol anchors. An adjustable tether connects the left and right anchors, allowing an adaptation to different tunnel lengths. The Amplatzer and Cardia devices were used for the entire study period. There were two consecutive series with the Premere device and the BioStar device, in which the Amplatzer and Cardia devices served as back-up devices at the discretion of the operator in a more complex anatomy (eg, a very large PFO or septal aneurysm).
Patients received a combined antiplatelet therapy for up to 6 months with acetylsalicylic acid 100 mg per day and clopidogrel 75 mg per day. Patients were scheduled for follow-up TEE at 3 months and 12 months post device implantation, according to institutional routine practice.
Study endpoints. The primary endpoint was recurrent ischemic events during follow-up for the Amplatzer device versus all other devices. The secondary endpoint was the combination of all-cause mortality, stroke, or TIA.
Statistical analysis. Categorical parameters are presented as counts and percentages and were compared by Pearson’s Chi-square test and the Fisher’s exact test, as appropriate. Continuous variables are presented as mean ± standard deviation. Groups were compared with the two-sample t-test or Mann-Whitney U-test. Subgroup analyses were done for presence of age, ASA, occluder devices, and grade of preprocedural shunt. Survival analyses were done with the use of Kaplan-Meier estimates and were compared with the log-rank test and Cox proportional regression hazard ratio. A P-value <.05 was considered to be statistically significant. Statistical analysis was performed using Statistica (StatSoft).
A total of 570 patients who underwent percutaneous PFO closure were included in this study. Mean patient age was 49.3 ± 13.1 years. In 256 procedures (44.9%), PFO closure was performed with the Amplatzer occluder, with the remaining 55.1% performed with the BioStar (n = 74), Cardia (n = 148), Premere (n = 82), or other occluders like the Flatstent (Abbott) (n = 10). The Amplatzer group had a higher percentage of male patients (66.8% vs 58.3% in the non-Amplatzer group; P=.04). Otherwise, baseline characteristics, including arterial hypertension, diabetes mellitus, history of smoking, body mass index, hyperlipidemia, and coronary artery disease, were similar (Table 1). The index event was ischemic stroke in 69.3%, TIA in 24.9%, and peripheral embolic events in the remaining patients. Index events were similar between the Amplatzer group and the non-Amplatzer group. Preprocedural characteristics of PFO as assessed by TEE showed presence of ASA in 72.8% of cases, with no significant difference between the Amplatzer group and the non-Amplatzer group (76.8% vs 70.1%, respectively; P=.10). PFO diameter was larger in the Amplatzer group (13.6 ± 4.5 mm vs 12.6 ± 3.9 mm in the non-Amplatzer group; P=.05). Grading of preprocedural shunt was moderate in 15.5% of cases and severe in 75.7% of patients, with no difference between groups.
Complications were assessed within the periprocedural period of 30 days. Within this period, a total of 18 complications were noted (3.2%); the majority were new-onset atrial fibrillation (n = 10 patients; 1.8%) (Table 2). There was no significant difference in complication rates between the Amplatzer group vs the non-Amplatzer group.
Within 12-month follow-up, complete closure was confirmed on TEE in 96.4% of all cases, with similar closure rates between groups (95.8% in the Amplatzer group vs 96.9% in the non-Amplatzer group; P=.55).
Clinical follow-up included a total of 3207 patient years. Follow-up was available in 438 patients (76.8%) for a median of 7.2 years (interquartile range, 3.4-10.5 years). The longest follow-up in the Amplatzer group was 12.5 years, whereas it was 16.8 years for the non-Amplatzer group, as implantation of the Amplatzer device was started later. Patients were usually recommended to maintain dual-antiplatelet therapy for a period after device implantation, followed by single-antiplatelet therapy indefinitely. A total of 417 patients continued on single-antiplatelet therapy, which was given for a mean period of 5.2 ± 4.4 years. Thirty-eight patients were on anticoagulants plus clopidogrel for 6 months after device implantation, and 33 of these patients continued on oral anticoagulation for deep venous thrombosis or pulmonary embolism. A total of 120 patients stopped antiplatelet therapy after the dual-antiplatelet therapy period. Recurrent stroke, TIA, and all-cause death were assessed as primary efficacy endpoints. Overall, a total of 73 primary endpoints occurred, including 20 recurrent strokes (0.62 events per 100 patient years), 6 recurrent TIAs (0.19 events per 100 patient years), and 18 deaths (0.56 events per 100 patient years). Within long-term follow-up, there was no difference in recurrent stroke between the Amplatzer group and the non-Amplatzer group (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.20-1.41; log rank P=.81) (Figure 1A), recurrent TIA (HR, 1.28; 95% CI, 0.25-6.46; log rank P=.52) (Figure 1B), and the combined endpoint of stroke, TIA, and all-cause death (HR, 1.12; 95% CI, 0.51-2.46; log rank P=.26) (Figure 1C).
Subgroup analysis by age. In a subgroup analysis of patients <45 years vs ≥45 years, there were significantly higher rates of diabetes (1% vs 6.2%, respectively; P<.01), arterial hypertension (14.4% vs 51.2%, respectively; P<.01), hyperlipidemia (22.4% vs 42.6%, respectively; P<.01), and coronary artery disease (4.0% vs 8.9%, respectively; P=.03) in older patients. Otherwise, baseline characteristics and index events were similar. Within long-term follow-up, there was a numerically higher rate of recurrent stroke in patients ≥45 years (HR, 4.14; 95% CI, 0.94-18.8; log rank P=.05) (Figure 2A), but this did not reach statistical significance. Recurrent TIA was similar between groups (HR, 0.88; 95% CI, 0.16-4.86; log rank P=.86). The combined endpoint of recurrent stroke, TIA, and all-cause death, however, was significantly lower in patients <45 years (HR, 4.22; 95% CI, 1.46-12.14; log rank P<.01) (Figure 2B).
Subgroup analysis by ASA. In the subgroup analysis of ASA patients (72.8%) vs non-ASA patients (27.2%), those with ASA were significantly older (P<.01); otherwise, baseline characteristics, index events, PFO diameters, and grading of preprocedural shunt were similar. Closure rates were similar (96.2% in the ASA subgroup vs 95.6% in the non-ASA subgroup; P=.67). Within long-term follow-up, rates of recurrent stroke (HR, 1.09; 95% CI, 0.38-3.11; log rank P=.53) (Figure 3A) and the combined endpoint of recurrent stroke, TIA, and death (HR, 1.12; 95% CI, 0.51-2.46; P=.26) (Figure 3B) were similar between groups.
Subgroup analysis by shunting. In the subgroup of patients with moderate and severe shunting (91.2%) vs mild shunting (8.8%) on preprocedural TEE, there was no difference within long-term follow-up regarding recurrent stroke (HR, 1.42; 95% CI, 0.18-11.23; log rank P=.82) and the combined endpoint (HR, 0.65; 95% CI, 0.21-2.01; log rank P=.35).
This real-world population with up to 16 years of follow-up using different PFO devices for closure of PFO in patients with cryptogenic ischemic events demonstrates the following: (1) recurrent stroke rate was low over a mean 7.2-year follow-up period; and (2) event rates were similar in patients with different PFO occluder types and were independent from the presence of ASA and the amount of preprocedural shunting.
Randomized trials have recently demonstrated a significant reduction of recurrent ischemic events for percutaneous PFO closure compared with medical therapy.3,5 Long-term data, however, are scarce and patients in those randomized trials do not represent a real-world population. Follow-up in the CLOSURE I trial3 was 2 years, with median follow-up of 4 years in the PC trial,5 3.2 years in the Gore REDUCE trial,13 and 5.3 years in the CLOSE trial,14 and long-term follow-up of 5.9 years in the RESPECT trial.8 The median follow-up of 7.2 years up to 16 years in the present study therefore represents one of the longest follow-ups in a large patient population to date.
The CLOSURE I trial3 and PC trial5 failed to show superiority of the interventional approach compared with medical therapy. In the RESPECT trial,8 a significant benefit for percutaneous closure with the Amplatzer device was only shown in the per-protocol analysis, and not in the intention-to-treat analysis.
The long-term analysis over a follow-up of 5.9 years in the RESPECT trial,8 however, demonstrated a superiority in the intention-to treat analysis (P=.046) regarding recurrent stroke, with a rate of 0.58/100 patient years in the PFO closure group vs 1.07/100 patient years in the medical therapy group. The Gore REDUCE trial13 on the Gore Helix occluder showed a significant benefit (P<.01), with a rate of recurrent stroke of 0.39/100 patients years in the interventional group vs 1.71/100 patient years in the medical therapy group. Hence, the rates of recurrent stroke in our large-scale real-world population of 0.62/100 patient years are in line with previously published data from the large randomized trials, yet include a longer follow-up in a real-world setting.
Several studies have generated the hypothesis of differences in outcome dependent on implanted occluder device.2,15,16 In this study, there was no significant difference in acute periprocedural success, complication rate, or rate of recurrent stroke (HR, 0.53; 95% CI, 0.20-1.41; log rank P=.81), TIA (HR, 1.28; 95% CI, 0.25-6.46; log rank P=.52), or the combined endpoint of stroke, TIA, and all-cause mortality (HR, 1.12; 95% CI, 0.51-2.46; log rank P=.26) between the most frequently implanted double-umbrella Amplatzer device and all other devices. Hornung et al2 demonstrated significantly lower rates of recurrent stroke within a 5-year follow-up for an Amplatzer group (1.4%) vs a CardioSeal/StarFlex group (5.9%) and a Helex group (4.1%). However, the index event in this analysis also included decompression disease and migraines, and thus these results are not comparable with the randomized trials and the present analysis, which only included stroke, TIA, and systemic embolism as index events. In this longest available follow-up, percutaneous PFO closure is associated with low recurrent ischemic event rates independent of implanted occluder device. Of note, the Amplatzer device always served as the back-up device for large PFO and patients with PFO and relevant atrial septal defect.
Whether PFO closure is also efficient in patients at an older age remains to be determined. Mariucci et al17 analyzed results in patients <55 years and >55 years, demonstrating significantly higher rates of recurrent stroke and TIA (P=.01) in the older population. The large randomized trials – PC,5 RESPECT,8 and Gore REDUCE13 – integrated subgroup analysis regarding age at the index event. In the PC trial,5 there was a trend toward a lower rate of recurrent event in the younger group (P=.09). In RESPECT (P=.78) and Gore REDUCE (P=.85), however, there was no difference in recurrent ischemic events with respect to age at the index event. However, inclusion criteria in these trials did limit the age at time of inclusion to a maximum of 60 years, and cut-off was 55 years for the subgroup analysis. In our study, there were no exclusion criteria for patients >60 years and cut-off was at 45 years, which might explain the lower rate of recurrent stroke in patients <45 years (2.44% at 10 years per Kaplan-Meier estimates vs 8.53% in patients ≥45 years). In addition, other reasons for stroke, such as atrial fibrillation or carotid artery stenosis, are more pronounced with increasing age. The combined endpoint of recurrent stroke, TIA, and all-cause mortality was significantly lower during long-term follow-up (P<.01). Compared with the younger patient population, cardiovascular risk factors were significantly more frequent in the older group, increasing the risk for ischemic and thromboembolic events. However, the decision for PFO occlusion in an older patient population should be based on a case-specific evaluation, as PFO remains one of the known risk factors for recurrent ischemic events. Two large-scale analyses of >15,000 patients with a mean age of 55 years undergoing non-cardiac surgery recently demonstrated a significant association between the presence of a PFO and the risk of perioperative stroke,18 as well as an increased risk of stroke within 1 and 2 years post surgery.19 Implementation of the RoPE score20 might be helpful to identify risk of recurrent stroke in the presence of a PFO. In a population with a mean age of 49 years, securing low rates of recurrent ischemic events and identifying patients at a higher risk of recurrent events is crucial. Additional factors that might have an impact on closure rates and efficiency of percutaneous approach are the characteristics of the PFO at the index procedure as well as the medical history for the index event. In subgroup analyses of patients with vs without ASA and in patients with moderate to severe vs low shunt fraction, there were no differences in rates of closure or in rates of recurrent stroke, TIA, or the combined endpoint.
Study limitations. This is not a randomized controlled trial, although it is a large single-center study with a long-term follow-up. The present analysis has all the drawbacks of a prospective observational registry, where treatment was open-labeled.
In this large, long-term follow-up study after percutaneous PFO closure for cryptogenic ischemic events, rate of recurrent stroke was low. There were no significant differences in event rates between different occluder device groups, or in subgroups stratified by the existence of ASA or preprocedural shunt at baseline. Patients <45 years old had lower rates of recurrent ischemic stroke.
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From the Department of Internal Medicine II - Cardiology, University of Ulm, Ulm, Germany.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 3, 2019, provisional acceptance given February 12, 2019, final version accepted April 8, 2019.
Address for correspondence: Julia Seeger, MD, Medical Campus Lake Constance, 88048 Friedrichshafen, Germany, Email: Julia.email@example.com