Transcatheter closure of patent foramen ovale (PFO) in patients with paradoxical embolism

Periprocedural safety and mid-term follow-up results of three different device occluder systems

M Brauna,*, V Gliechb, A Boscheria, S Schoena, G Gahnc, H Reichmannc, M Haassd, R Schraedere and R.H Strassera

a Internal Medicine II, Department of Cardiology, Technical University of Dresden, Fetscherstr. 76, 01307 Dresden, Germany
b Internal Medicine, Department of Cardiology, Charité University of Berlin, Germany
c Department of Neurology, University of Technology Dresden, Germany
d Internal Medicine, Theresienkrankenhaus Mannheim, Germany
e Bethanien Hospital – CCB, Frankfurt/Main, Germany

* Corresponding author. Tel.: +49-351-450-1700/1701; fax: +49-351-450-1702
E-mail address: Martin.Braun{at}mailbox.tu-dresden.de

Received 30 January 2003; revised 15 September 2003; accepted 16 October 2003 See page 361 for the editorial comment on this paper1

Abstract

Aims Interventional PFO closure has previously been reported to reduce the risk for recurrent thromboembolic events. The aim of the present study was to evaluate three different occluder systems in respect to (a) the safety and practicability and (b) the mid-term risk of recurrent thromboembolic events.

Methods and results Since 08/98 until 12/02, 307 consecutive patients (138 women, 169 men, mean age 43 years) with a symptomatic PFO underwent PFO closure using the PFO-Star (), AmplatzerTM PFO occluder () and CardioSeal/Starflex (). Implantation was successful in all patients. Periinterventional complications occurred in 9 patients (5x ST-segment elevations, 1x arteriovenous fistula, 2x TIA, 1x device dislodgement). All of them were reversible and not associated with a specific type of device. During the median follow-up of 24 months (25/75th percentiles: 14/37 months), the annual risk of recurrence was 0.6% for TIA, 0% for stroke and 0.2% for peripheral embolism (PFO-Star: 0.8%, AmplatzerTM PFO occluder: 0.7% and CardioSeal/Starflex: 1.0%).

Conclusion Interventional PFO closure appears to be safe and a promising technique in symptomatic PFO patients with a low incidence of periinterventional complications and recurrent thromboembolic events using three different devices (PFO-Star, AmplatzerTM PFO occluder or the CardioSeal/Starflex).

Key Words: Embolism • Heart septal defects • Cerebral ischemia • Transcatheter closure

Introduction

Patients with a patent foramen ovale (PFO) and a history of paradoxical embolism are known to have an increased risk of recurrent thromboembolic events, ranging from 1.9% to 3.8% per year.1–4 A large PFO size or an associated atrial septal aneurysm (ASA) are morphologic characteristics of the PFO, which account for an additional risk of stroke recurrence.2,4–6

Although the optimal management of patients with a symptomatic PFO remains controversial, therapeutic options for secondary stroke prevention include long-term medical treatment (platelet antiaggregating drugs or oral anticoagulation4,7–9) and more invasive strategies such as surgical10–12 or percutaneous PFO closure.13–18 Promising results of percutaneous PFO closure have been reported in cryptogenic stroke patients by several authors during the last decade using various occlusion systems such as the Clamshell device, the Angel Wings device, the CardioSeal device, the AmplatzerTM PFO occluder, the AmplatzerTM septal occluder and the PFO-Star device. Some of these devices were unsuccessful in the periprocedural and follow-up management and are no longer been widely used in clinical practice. Major limitations of the previously published studies are small patient cohorts and/or the use of many different devices without a detailed analysis between the occluder systems. The present non-randomised, prospective study was undertaken to evaluate in 307 consecutive patients with a PFO and >=1 thromboembolic event the short and mid-term clinical and echocardiographic results after percutaneous PFO closure using three well established occlusion devices (PFO-Star, AmplatzerTM PFO occluder and CardioSeal/Starflex).

Patients and methods

Patient population
Since 08/98 until 12/02, 307 consecutive patients with a PFO and >=1 thromboembolic event underwent transcatheter PFO closure according to the study protocol approved by the local Ethic Committees. All patients gave written and informed consent. The diagnosis of cryptogenic cerebral ischemia (TIA or stroke) was confirmed by a neurologist, where the symptomatic patients presented first. All patients received cerebral imaging either by cerebral computer tomography (CT) or magnetic resonance tomography (MRT). A PFO was identified by bubble-test and by contrast transesophageal echocardiography (contrast-TEE) with spontaneous or provocable (Valsalva-Maneuver) right-to-left shunting. Patients with other identifiable causes of systemic embolism were excluded: (a) arteriosclerotic plaques in the extracranial arteries as determined by ultrasonography, (b) atrial fibrillation observed in 12-lead ECG or 24-h Holter ECG and (c) prothrombotic coagulation disturbances (protein C, protein S, antithrombin III, antiphospholipid and anticardiolipin antibodies, lupus anticoagulant, APC-resistance). Doppler ultrasonography of the lower extremities was performed in 74% of the patients to rule out deep vein thrombosis.

Degree of right-to-left shunt
Quantification of the PFO shunt volume was determined by contrast injection at rest and during Valsalva-Maneuver. A "small" shunt volume was defined as 3–20 bubbles and a "large" shunt volume as 20 bubbles passing the PFO into the left atrium. An ASA was defined as an interatrial septum of abnormal mobility with protrusion of the septum into the left or right atrium of at least 10 mm beyond baseline.6 The PFO size was additionally determined by multiplane two-dimensional TEE as recently reported by Schuchlenz et al.19

Implantation-procedure of the devices
The patients characteristics according to age, gender, cardiovascular risk factors, number of prior thromboembolic events, presence of an additional ASA and the PFO-shunt volume during contrast-TEE are shown in Table 1 for the three groups of patients undergoing closure. PFO closure was performed in groups of 4–7 patients with usually one type of device occluder system (PFO-Star-III. generation, AmplatzerTM PFO occluder or CardioSeal/Starflex, Fig. 1). The choice of the device was made in accordance to the clinical preference of the interventionalist. Based on the increasing experience during the time of the study with the PFO-Star occluder in two centers (Heart Center Dresden, Theresienkrankenhaus Mannheim), the number of patients within this subgroup was higher as compared to the other two groups. Additionally, 28 patients from an earlier evaluation18 have been included in the present study, now with a significant longer follow-up period. All of them were implanted a III generation PFO-Star device. General anesthesia was used only in patients who could not tolerate the simultaneous TEE probe (2%). Venous access was gained via the right femoral vein and the PFO was passed using a standard exchange wire and a multipurpose catheter. After changing the multipurpose catheter to a 8–9F (for Amplatzer PFO occluder) or a 10–11F (for PFO-Star and CardioSeal & Starflex) transseptal sheath, the selected type of device was advanced through the catheter and the left umbrella expanded in the left atrium under fluoroscopic and multiplane TEE-guidance. The sheath was pulled back until contact of the device to the interatrial septum was achieved and then further pulled back to expand the right atrial disc. Under echocardiographic control the device was released from the delivery forceps (PFO-Star) or the delivery cable/loading wire (Amplatzer PFO occluder, CardioSeal & Starflex occluder). The different occlusion systems were implanted in accordance to the device specific implantation recommendations.


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Table 1 Patients characteristics

 


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Fig. 1 Schematic view of the PFO-Star occluder, the AmplatzerTM PFO occluder and the CardioSeal/Starflex.

 
All patients were anticoagulated at the time of the procedure with 10.000 IE heparin and received 1.2 g amoxycillin i.v. and 0.5–1.0 mg atropin i.v. to prevent endocarditis and catheter-induced coronary spasm.

Postinterventional treatment
Postinterventional treatment included oral aspirin (100 mg/day) for 12 months, clopidogrel (75 mg/day) for 6 weeks and low dose heparin for the first 3 days ( IE s.c.) after intervention. Prophylaxis of bacterial endocarditis was recommended for 6 months according to the guidelines of the AHA.

Postprocedural control and follow-up evaluation
A two-dimensional TTE, chest X-ray and routine-ECG was performed within two days after transcatheter PFO closure before hospital discharge. Patients were followed-up prospectively by echocardiography (TTE and contrast-TEE) and clinically at 1, 6, 12 months and every 12 months thereafter including extensive neurological (by a neurologist experienced in cerebrovascular diseases) and medical examination with a 12-lead ECG and a contrast-TEE at rest and during Valsalva-Maneuver. Patients with suspected recurrent thromboembolic events were reevaluated by a cerebral CT and/or MRT. A 24-h Holter monitoring was performed in most of the patients 6 months after PFO closure.

Statistics
Values are presented as means±SD, median, range and the 25/75th percentiles. Differences between the three groups in patient characteristics were assessed using (Pearson) and one-way ANOVA testing for statistical significance. The actuarial freedom from recurrent thromboembolic events was calculated using Kaplan–Meier analysis.

Results

Patient population
Between 08/98 and 12/02, 307 consecutive patients with a PFO and >=1 thromboembolic event underwent percutaneous PFO closure. The patient characteristics are shown in Table 1. There were 138 women (45%) and 169 men (55%) with a mean age of 43±11.2 years. Fifty-one patients (17%) had a history of more than one thromboembolic event prior to PFO closure and an ASA was present in 70 patients (23%). The PFO diameter as determined by TEE was slightly but significantly smaller within the Amplatzer PFO group as compared to the other subgroups. Cardiovascular risk factors have been identified as systemic hypertension (18%), diabetes mellitus (6%), smoking (37%) and hyperlipidemia (8%).

Short-term results and periinterventional complications
Percutaneous PFO closure was performed under local (98%) or general (2%) anesthesia using three different devices (Fig. 1, Table 2): PFO-Star (), AmplatzerTM PFO occluder () and CardioSeal/Starflex (). The implantation was successful in all patients (100%). Transseptal puncture was necessary in one patient because of the short distance from the PFO-channel to the anterior mitral valve leaflet. As determined by contrast-TEE at the end of the intervention complete PFO closure was achieved in 56%, whereas an initially small shunt was present in 42% and a large shunt in 2% of the patients (see Table 2). The overall incidence of periinterventional complications was 3% (9 patients), including transient ST-segment elevations in the inferior leads (5 patients) and an arteriovenous fistula (1 patient), which was controlled by pressure bandage. Two patients suffered an intraprocedural TIA (PFO-Star, CardioSeal), presumably due to air embolism through the transseptal sheath during device delivery, which completely resolved within <=8 h. Dislodgement of the device was observed in one patient, in whom the right atrial disc was partially retracted within the relative long PFO-channel after it has been released from the delivery forceps. Repetitive TEE examination confirmed a stable device position and warfarin was recommended to avoid thrombotic aggregation on the device surface. An initial minor shunt was not present any more at the 6 months follow-up. There were no irreversible cerebral or peripheral ischemic events or death during the procedure. The subgroup analysis for the three patient groups is presented in Table 2 with a relatively low periinterventional complication rate for the three different types of implanted devices.


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Table 2 Procedural data and periinterventional complications

 
Follow-up

The median follow-up of all patients was 24 months (25/75th percentiles: 14/37 months). One patient developed an acute coronary syndrome 2.4 years after successful PFO closure, requiring angioplasty and stent implantation of the right coronary artery. Two other patients were hospitalized due to new onset tachyarrhythmia, which converted in normal sinus rhythm spontaneously or by i.v. amiodarone, and was stable under ß-blocker therapy.

Recurrent thromboembolic events
There were 5 recurrent thromboembolic events after PFO closure, 4 recurrent TIAs (3x PFO-Star occluder, 1x CardioSeal), no stroke and 1 patient with peripheral embolism (AmplatzerTM PFO occluder), resulting in an annual recurrence rate of 0.8% for the combined endpoint TIA, stroke and peripheral embolism (PFO-Star: 0.8%, AmplatzerTM PFO occluder: 0.7% and CardioSeal/Starflex: 1.0%; see Table 3). All thromboembolic events occurred within the first 8 months after device implantation and clinically resolved within <=12 h after onset. The actuarial freedom from recurrence for the combined endpoint of TIA, stroke and peripheral embolism was 99% at 6 months and 98% at 1, 2 and 4 years of follow-up in our study population (Fig. 2). One of these patients (PFO-Star occluder) with a recurrent thromboembolic event had a minor residual shunt in contrast-TEE at the time of recurrent TIA, whereas the other 4 patients had no residual shunt and all devices were in the correct position without device-related thrombotic formations. A second patient had a newly discovered arteriosclerotic lesion in the ascending aorta and the aortic arch, as possible cause of recurrent TIA. All (except for one) patients with a recurrent neurological event were >=50 years of age and had >=1 cardiovascular risk factor such as systemic hypertension, diabetes mellitus, hyperlipidemia or smoking.


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Table 3 Follow-up results

 


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Fig. 2 Kaplan–Meier analysis: Actuarial freedom from the combined endpoint of recurrent TIA, stroke or peripheral embolism after interventional PFO closure.

 
Residual shunt and echocardiography
The number of patients with complete occlusion after percutaneous PFO closure progressively increased during follow-up in all types of implanted devices. Complete PFO closure was achieved in 69%, 81%, 94% and 96% after 1 month, 6 months and 1 and 2 years of follow-up, respectively. There were no major differences in the rate of residual shunt after interventional PFO closure between the three types of implanted devices (see Table 3). However, a trend towards a higher percentage of complete PFO closure was observed in patients with an AmplatzerTM PFO occluder (see Table 3, bottom) as compared to the other devices, which in part might be explained by the smaller PFO diameter in this subgroup prior to interventional closure. All patients with a residual shunt had a significant reduction of the shunt degree after device implantation as determined by the number of microbubbles counted in the left atrium. Two patients had a moderate shunt (10–20 bubbles) at 6 months of follow-up which was still present in 1 patient at 1 and 2 years after PFO closure. In agreement with the neurologist, antithrombotic therapy with clopidogrel was recommended in this patient, who did not suffer from any recurrent thromboembolic event up to now.

Device-related complications
Two patients required surgical removal of the device due to significant device malalignment (PFO-Star) or device-adherent thrombus formation at the left atrial umbrella surface (CardioSeal). In both cases, the occluder was explanted and the PFO closed at the same time with uneventful outcome. During the whole observation period both patients were asymptomatic.

24-h Holter monitoring
Analysis of the 24-h Holter monitoring was performed in 72% of the patients 6 months after device implantation and revealed no marked differences in respect to SVES, SVT, VES or other relevant arrhythmias as compared to the data obtained before PFO closure, suggesting no proarrhythmic effect of device implantation in these patients.

Discussion

The salient findings of the present study are that in a large population of 307 consecutive patients the interventional PFO closure is safe and an effective technique with a high success rate. No relevant differences in respect to periprocedural complications, echocardiographic and clinical mid-term follow-up results have been observed between the three well established and currently widely used devices evaluated in the present study (PFO-Star occluder, AmplatzerTM PFO occluder and CardioSeal/Starflex). The relative low incidence of procedural-related complications, which in our study appears comparable or less frequent to others14–18 might be explained by the frequency of implantation procedures and the simultaneous use of fluoroscopy and TEE-guidance during device delivery.

Recurrence of thromboembolic events
During a median follow-up of 24 months after successful percutaneous PFO closure 4 patients reported a TIA and one patient a peripheral embolism, resulting in an annual recurrence rate of 0.6% for TIA, 0% for stroke and 0.2% for peripheral embolism. All recurrent thromboembolic events occurred within the first 8 months of follow-up, an observation which has also been reported by others.14,15 Our data are in good agreement with previous studies using the same or different device occluder systems14–18 and compare favorably with published data on medical therapy2–4 and surgical closure.10,11 In the multicenter French study, Mas et al. reported in 132 patients with a PFO and a prior history of stroke an annual recurrence rate of 3.4% during a mean follow-up of 23 months.2 Patients were treated with aspirin, warfarin or with one of these drugs successively. Similar recurrence rates have been demonstrated by Bogousslavsky et al.3 in the prospective Lausanne register. Furthermore, secondary prevention of paradoxical embolism with long-term oral anticoagulation seems to be of questionable benefit, since side effects include major bleeding complications, low compliance rate and recurrent thromboembolic events despite sufficient anticoagulation with an INR between 2 and 3.7–9 Surgical closure of the PFO has been suggested as an alternative option reducing recurrent cerebral ischemic events in symptomatic PFO patients. Whereas two smaller series of Devuyst et al.12 and Rucheat et al.20 reported no recurrent cerebral ischemic events during 2 years follow-up, these data were contrasted by Dearani et al. and Homma et al. reporting an annual risk of stroke recurrence by 4–9%.

Since the early report of Bridges et al.21 numerous studies have shown that percutaneous PFO closure is a safe and promising technique with a low incidence of recurrent thromboembolic events, ranging from 0% to 3% per year.14–18,22 Windecker et al. investigated the safety and follow-up results in 80 patients with a symptomatic PFO using five different devices (Amplatzer septal occluder, Sideris button device, PFO-Star, CardioSeal, Angel Wings occluder) reporting no significant differences according to the incidence of periinterventional complications, residual shunt or the risk of recurrent thromboembolic events between the occluder systems. Similar results have been reported by Wahl et al.17 in 152 consecutive patients with presumed paradoxical embolism during a mean follow-up of 1.7±1.6 years. A very recent study of Martin et al. demonstrated the immediate and long-term clinical outcome of 110 consecutive patients, in whom interventional PFO closure was performed by the implantation of either the Sideris button or the CardioSeal device.15 Successful implantation was achieved in all patients with an annual risk of stroke recurrence by 0.9% at a mean follow-up of 2.3 years. These data are in good agreement with our study, reporting that none of the three types of implanted devices appear superior to the others during follow-up evaluation. The higher percentage of complete PFO closure in the Amplatzer PFO group as compared to the PFO and CardioSeal & Starflex group is partially explained by the smaller PFO diameter in these patients prior to intervention (see Table 1). The risk of stroke recurrence in our study population was not associated with the presence of an ASA or a small residual shunt. Whether a residual shunt is associated with an increased risk for stroke recurrence is still a matter of debate and discussed controversially.14–18,22 Due to the different shunt morphology/anatomy, it seems possible that in symptomatic PFO patients a "non-closed" PFO on the one hand and a small residual shunt after interventional PFO closure on the other hand have a different impact on the recurrence rate of thromboembolic events. It is worth to mention that in all our patients the residual shunt was much smaller as compared to the PFO size before closure. These data implicate that there may be additional factors/parameters which contribute to the recurrence of thromboembolic events after PFO closure. It will be an important challenge to identify those factors in the future to avoid stroke recurrence.

Association of the PFO with an ASA
Mas et al.2,4 have demonstrated that patients with a symptomatic PFO combined with an ASA constitute a high risk population for stroke recurrence. The present study evaluated 70 patients with a PFO and ASA after interventional PFO closure. There was only one recurrent thromboembolic event in this high risk group during the median follow-up of 24 months (accounting for a relative low recurrence risk of 0.7% per year), which is in contrast to the spontaneous course. Thus, patients with the coexistence of an ASA+PFO obtain a special benefit from percutaneous closure of the PFO, which might be explained by (a) stabilization of the aneurysmatic atrial septum between the discs of the device and (b) closure of the larger PFO opening associated with an ASA.

Limitations of the study
Limitations of the present study are the non-randomised design of the patient selection within each subgroup and the low incidence of recurrent thromboembolic events during follow-up. Thus, the statistical power of any significance test to detect statistic relevant differences is limited and further studies with a larger patient population and longer follow-up intervals are necessary to draw final conclusions.

Conclusion

Interventional PFO closure in patients with a symptomatic PFO is a safe and promising technique and known to reduce the risk for recurrent thromboembolic events. The present study evaluated in a large population of 307 consecutive patients with a PFO and a history of >=1 thromboembolic event, the implantation success, periinterventional complications and mid-term follow-up results using three different devices (PFO-Star occluder, AmplatzerTM PFO occluder and CardioSeal/Starflex). The incidence of periinterventional complications and the risk of recurrent thromboembolic events after PFO closure was very low in each subgroup with none of the devices appearing superior over the others. Nevertheless, randomised clinical trials comparing medical treatment modalities with the percutaneous PFO closure in patients with symptomatic PFO are necessary to determine the optimal therapeutical strategy in this patient population.

Footnotes

1 doi:10.1016/j.ehj.2003.10.012. Back

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