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Causes of Recurrent Focal Neurologic Events After Transcatheter Closure of Patent Foramen Ovale With the CardioSEAL Septal Occluder
Causes of Recurrent Focal Neurologic Events After Transcatheter Closure of Patent Foramen Ovale With the CardioSEAL Septal Occluder Shelby Kutty, MDa, Kimberly Brown, RNb, Jeremy D. Asnes, MDc, John F. Rhodes, MDd, and Larry A. Latson, MDb,* Transcatheter patent foramen ovale (PFO) closure has been undertaken to eliminate paradoxical emboli as a cause for recurrent strokes/transient ischemic attacks (TIAs). We report the results of investigations to determine causes of all significant focal neurologic events (FNEs) after PFO closure reported to our center. Records of 216 consecutive patients who underwent PFO closure were reviewed. Patients had to have had >1 preceding clinical event consistent with stroke/TIA considered by a neurologist to be consistent with an embolic episode. Follow-up was recommended at 24 hours, 1 month, 6 months, 1 year, and every 1 to 2 years thereafter. All patients were requested to report any new FNE possibly suggestive of stroke/TIA to our center. Reports of evaluations were reviewed in detail. Twenty patients had an FNE 0.1 month to 40.2 months after PFO closure over 438 person-years of follow-up (mean 2.1 years, range 1 month to 7.1 years). There were 4 recurrent strokes, 2 likely directly device related. Ten patients had TIA and 6 patients had clear evidence of pathology unrelated to the device. Event rate for recurrent strokes was 0.9% per year (95% confidence interval for difference 0.3 to 2.4) and combined event rate for stroke/TIA was 3.4% per year (95% confidence interval for difference 2 to 5.6). In conclusion, transcatheter PFO occlusion can be accomplished as an outpatient procedure with minimal immediate morbidity. Patients may have multiple possible causes of recurrent FNE. Recurrence rate of cryptogenic FNE compares favorably with reports of medical management. Analysis of results from ongoing randomized trials of transcatheter PFO closure versus medical management may improve our ability to select the best treatment for individual patients. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;101:1487–1492)
A patent foramen ovale (PFO) has been found to be present more often in patients with cryptogenic stroke than in the general population1,2 or in patients with stroke and an identified cause.1– 4 Patients with PFO and presumed paradoxical embolism are at increased risk of recurrent thromboembolic events.5,6 Since the initial report in 1992,7 transcatheter closure of PFO has been undertaken in many centers to eliminate paradoxical emboli as a cause for recurrent strokes/transient ischemic attacks (TIAs) in patients with cryptogenic stroke/TIA. Various subsequent studies have described the safety and efficacy of this procedure using a variety of closure devices.8 –11 Recurrent focal neurologic events (FNEs) have been seen in a small percentage of patients during follow-up in all large series of cryptogenic stroke treated medically or by closure of the PFO. Details of the apparent causes of these recurrent FNEs have not been clearly described. We present the results of invesa
Herma Heart Center, Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin; bDepartment of Pediatric Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio; cSection of Pediatric Cardiology, Yale University School of Medicine, New Haven, Connecticut; and dDivision of Pediatric Cardiology, Duke University Medical Center, Durham, North Carolina. Manuscript received December 16, 2007; revised manuscript received and accepted January 21, 2008. *Corresponding author: Tel: 216-445-6532; fax: 216-445-3692. E-mail address: [email protected] (L. Latson). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.01.028
tigations performed to determine causes of all significant recurrent FNEs in patients from our center who underwent transcatheter PFO closure over a period of 5.5 years. Methods Records of all 216 patients who underwent transcatheter PFO closure from March 2000 to September 2005 were reviewed. Seventeen patients (7.8%) were lost to follow-up before the 1-month planned follow-up visit and were removed from subsequent analysis. We elected to use a primarily image-based definition of stroke in our evaluations. Stroke was defined as an FNE with an accompanying lesion on magnetic resonance imaging (MRI) or computed tomogram (CT) even if the deficit lasted ⬍24 hours. Focal neurologic symptoms persisting for ⬎24 hours were also considered to be a stroke even in the absence of new lesions on MRI/CT. A TIA was defined as an FNE lasting ⬍24 hours without an accompanying MRI/CT lesion in the brain. Cryptogenic FNE was defined as a sudden FNE in the absence of an identifiable cause, such as aneurysm, uncontrolled hypertension, intracranial hemorrhage, ipsilateral carotid lesion, atrial fibrillation, intracardiac thrombus, degenerative neurologic disorder, neoplasm, etc. To be considered for transcatheter PFO closure at our center, patients had to have had ⱖ1 preceding FNE consistent with stroke/TIA considered by a neurologist to be most www.AJConline.org
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likely caused by a paradoxical embolus. We did not have other specific inclusion or exclusion criteria in our standard approach to these patients. Patients with previous stroke of defined cause were included if they had also had a stroke that was felt to be likely due to paradoxical embolism. Uncertainty of the exact role of PFO closure in the treatment of cryptogenic stroke was explained in detail to all patients. The CardioSEAL septal occluder (NMT Medical, Inc., Boston, Massachusetts) was used for those who wished to proceed with closure despite this uncertainty. All patients had an MRI and/or CT of the brain and 155 (72%) had MRI/CT changes consistent with a preceding stroke. The remaining patients were considered to have had a TIA if clinical symptoms lasted ⬍24 hours. Arterial disease, hypertension, diabetes, migraines, and arrhythmias were evaluated but did not contraindicate PFO closure if they did not seem causative of the most recent stroke/TIA. The population included patients with potential sources for neurologic events other than PFO such as small vessel disease, history of atrial fibrillation (not around the time of the most recent event), mild carotid artery disease, or coagulation disorders. In each case, however, it was felt by the evaluating neurologist that paradoxical embolism was the most likely cause for at least the most recent stroke/TIA in each patient. No specific age was considered a contraindication to treatment. All patients were encouraged to enter the closure 1 trial (NMT Medical, Inc.) carried out in the institution, but the present study includes patients who refused to participate or were ineligible. Informed consent was obtained from patients for device implantation in compliance with requirements of the institutional review board. The CardioSEAL device was deployed in all patients using the standard implantation technique for this device. General anesthesia and transesophageal echocardiography were used early in our experience, and since 2001 intracardiac echocardiography and conscious sedation were used in most patients. A complete right-sided hemodynamic catheterization and right atrial angiography was performed to assess the anatomy of the PFO. A guidewire was positioned in the left upper pulmonary vein through a venous catheter advanced through the PFO. A sizing balloon (NuMED, Inc., Hopkinton, New York) was advanced over the guidewire and incompletely inflated (⬍1 atm) until a distinct indentation in the balloon and elimination of any shunting by color Doppler was identified. We did not inflate the balloon fully to avoid the possibility of inadvertently enlarging the defect. The diameter of the indentation was measured angiographically and by echocardiography. An 11Fr Mullins sheath (Cook, Inc., Bloomington, Indiana) was advanced over the wire across the PFO and into the left upper pulmonary vein. Device size was selected by the individual operator without a center-specific protocol. The device was delivered through the Mullins sheath. After deployment, an 8Fr angiographic catheter was advanced through the Mullins sheath into the low right atrium and a hand injection of agitated saline and/or right atrial angiography was performed to assess for residual right-to-left shunt. The optimal anticoagulation regimen for medical treatment of cryptogenic stroke is controversial. All patients were therefore advised to continue with the anticoagulation/
Table 1 Patient characteristics at implantation (n ⫽ 216) Age (yrs) Men/women Body weight (kg) Systemic hypertension Smoking Migraine headaches PFO stretch diameter (mm)
50 (19–77) 107/109 85 (47–157) 65 (30%) 48 (22%) 39 (18%) 11 (4–24)
Values are means (ranges) or numbers of patients (percentages).
antiplatelet regimen established before device placement for 6 months after placement. Endocarditis prophylaxis precautions were recommended for 1 year after implantation. Discontinuation of the initial anticoagulant/antiplatelet agents was felt to be reasonable after 6 months if there were no other conditions necessitating prolonged medication. Continuation after 6 months was left to the discretion of the referring physician. Low-dose aspirin therapy was recommended indefinitely after the first 6 months if other agents were discontinued. Follow-up visits to a cardiologist with clinical evaluation, transthoracic echocardiogram, and electrocardiogram were recommended at 24 hours, 1 month, 6 months, 1 year, and every 1 to 2 years thereafter. All patients were requested to report any new symptoms of an FNE possibly suggestive of stroke/TIA to our center. Patients with recurrent FNEs were directed to undergo additional cardiologic and neurologic evaluations. Reports of evaluations of all cases were reviewed in detail. All patients with a recurrent FNE had repeat MRI/CT and other tests as clinically indicated. These patients also underwent transesophageal echocardiography to assess for thrombus or the presence of a residual right-to-left leak. Contrast echocardiography was not part of our routine follow-up in asymptomatic patients. Data are presented as mean ⫾ SD. Estimation of survival free from stroke/TIA was performed by the Kaplan-Meier method as implemented in Proc Lifetest. Because the exact event times for some of the TIA recurrences were unknown and only a time range was available, the survival curve was estimated using Newton-Raphson Ridge maximization of the likelihood, as implemented in the %ICE macro in the SAS Sample Library (SAS Institute, Cary, North Carolina). Recurrent event rate was calculated by dividing the number of observed events by the observed number of personmonths at risk. A confidence interval for this assessment was obtained using Poisson regression. A p value ⬍0.05 represented statistical significance. Data analysis was performed using SAS 9.1 (SAS Institute). Results Patient characteristics at time of implantation are listed in Table 1. There were 107 men and 109 women in the study population of 216 patients. One hundred eleven patients (51%) received a 23-mm device, 94 (44%) received a 28-mm device, and 11 (5%) received a 33-mm device. None had trans-septal puncture for device placement. PFO diameters under gentle balloon inflation were 4 to 24 mm (mean 11). Successful implantation was achieved in all patients.
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Table 2 Recurrent events after CardioSEAL occlusion of patent foramen ovale: noncardioembolic events Time to Event (mos)
Device Size (mm)
Event Type
40
23
Subdural hemorrhage
6
23
—
23
36 5 12
23 28 28
Progressive neurologic deficits due to brain tumor Progressive neurologic deficits due to brain tumor Intracranial hemorrhage Stroke Retinal hemorrhage
Anticoagulation Before Event
Other Factors at Time of Event
Died
Warfarin
0
0
0
Warfarin
0
⫹ (1 mo after event due to cancer) ⫹ (4 mos after event due to cancer) 0
Warfarin Warfarin —
Severely increased INR Carotid plaque rupture 0
⫹ (34 mos after event) 0 0
— ⫽ no information available; INR ⫽ international normalized ratio. Table 3 Recurrent events after CardioSEAL occlusion of patent foramen ovale: embolic strokes Time to Event (mos)
Device Size (mm)
Residual Shunt
Device Abnormality
37
33
⫹
1
23
0
6
28
0
Thrombus attached to device, device fracture Thrombus attached to device 0
15
28
0
0
Anticoagulation Before Event
Other Factors at Time of Event
Outcome
Clopidogrel
0
Device removed
Clopidogrel
Factor V Leiden deficiency Graves’ disease, Hodgkin lymphoma LA appendage thrombus
Device removed
Warfarin, aspirin Clopidogrel
On follow-up Thrombus surgically removed; device left
LA ⫽ left atrial. Table 4 Recurrent events after CardioSEAL occlusion of patent foramen ovale: transient ischemic attacks Time to Event (mos)
Device Size (mm)
Residual Shunt
Device Abnormality
Anticoagulation Before Event
Other Factors at Time of Event
6
23
0
0
Clopidogrel, aspirin
4 3 1 0.1 1 — 3 and 19 6 12
28 33 28 28 23 23 28 28 28
0 0 0 0 0 0 0 ⫹ 0
0 Thrombus 0 0 0 0 0 0 0
Clopidogrel, aspirin Aspirin Warfarin, aspirin Warfarin, aspirin Warfarin, aspirin — Warfarin Warfarin Aspirin, warfarin
Small vessel disease, carotid artery calcium, coagulopathy (cardiolipin) 0 0 0 0 0 0 History of brain tumor Hemiplegic migraines Coagulopathy (cardiolipin)
Abbreviation as in Table 2.
Follow-up was 1 month to 7.1 years (mean 2.1) for a total of 438 patient-years. Eight patients died during follow-up due to non– central nervous system pathology unrelated to the device such as coronary artery disease and malignancy. Twenty patients had ⱖ1 recurrent FNE after device implantation (Tables 2 to 4). Fourteen patients were identified to have recurrent, probably embolic, FNEs. Of these, 4 patients had recurrent stroke and the remaining 10 had TIAs. Six patients had a recurrent FNEs clearly related to pathology other than a possible paradoxical embolus (Table 2). Two patients had new focal symptoms and MRI changes indicating that the original MRI lesions were actually brain tumors. One
patient with known carotid artery disease had an ipsilateral carotid plaque rupture and recurrent stroke. This occurred 4 days after warfarin was discontinued and transesophageal echocardiogram was negative for device abnormality or residual leak. Ruptured left carotid plaque was seen on angiogram. Warfarin was restarted and there has been no subsequent event. The other 3 had FNEs related to their anticoagulation medications. One patient had an intracranial hemorrhage with a severely increased international normalized ratio. Subdural hemorrhage was reported in 1 patient 40 months after device placement, and retinal hemorrhage occurred in 1 patient 12 months after device implantation.
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Figure 1. Event-free survival shown as estimated proportion of patients without stroke (solid line) and without stroke or TIA (dashed line) by time since operation. Patients were censored at the end of follow-up or at the time of death from other causes. N ⫽ number of patients still being followed at appropriate time point.
Four patients had recurrence of apparent embolic stroke by MRI without evidence of vascular disease (Table 3). Two of them were felt to be likely directly device related. In 1 patient, the 33-mm device was abnormally configured and was found to have arm fractures and poor septal apposition. Recurrent stroke occurred while the patient was on warfarin with a therapeutic international normalized ratio. The patient underwent surgical removal of the device and the right atrial arms of the device were seen protruding into the right atrium with 1 left atrial arm displaced away from the septum. There was no residual leak or thrombus identified on or near the device at the time of recurrent stroke. There have been no subsequent FNEs in this patient. The second patient had device-related recurrence of stroke 1 month after placement. This patient had factor V Leiden deficiency and had anticoagulation treatment with clopidogrel alone. There was found to be thrombus associated with the device and, hence, the device was surgically removed. Two patients had cryptogenic strokes with no evidence of relation to the CardioSEAL device. One had left atrial appendage thrombi at the time of his initial stroke, i.e., before device placement, without a history of atrial fibrillation or an identified clotting abnormality. This patient had received warfarin for 1 year after device placement and was changed to an antiplatelet regimen (aspirin plus clopidogrel) by the referring physician. Recurrence of stroke occurred after the change. The patient underwent surgical removal of a pedunculated left atrial thrombus that was identified remote from the device. The device was found to be completely endothelialized and was left in place. The other patient with recurrent stroke had the event 6 months after device placement. Other medical issues in this patient included Graves’ disease and Hodgkin lymphoma (remission phase). There was no evidence of a residual shunt or thrombus on the device. Recurrent TIA occurred in 10 patients (Table 4). One patient had 2 TIAs, making a total of 11 TIAs on follow-up. All patients had transesophageal echocardiograms after the event. Only 1 of these patients had a residual leak. One
patient had thrombi attached to the device. No other devicerelated issues were identified. Other coexistent issues in the recurrent TIA group were increased cardiolipin (in 2 patients), small vessel disease (in 1 patient), and previously treated brain tumor (in the patient with 2 TIAs). Seven patients with nonspecific symptoms were evaluated and not felt to have symptoms consistent with FNEs. Six had transient visual symptoms (spots, no specific field defects) only. One patient had a near syncopal episode. At the time of this analysis, 199 patients with follow-up information were evaluated for 438 person-years after closure. The event rate for recurrent strokes was 0.91% per year or 9.1 per 1,000 person-years (95% confidence interval for difference 3.4 to 24.3). The combined event rate for stroke/TIA was 3.42% per year or 34.2 per 1,000 personyears (95% confidence interval for difference 20.7 to 56.8). Survival curves for recurrent strokes and stroke/TIA are shown in Figure 1. Discussion Detailed analysis of all FNEs on follow-up of a large series of patients who have undergone percutaneous PFO closure after a presumed paradoxical embolus has not previously been presented. We found that 6 of 20 patients (30%) with a recurrent FNE had clear evidence of pathology unrelated to a cardioembolic source (brain tumor, carotid plaque rupture, intracerebral bleeding). Recurrence of stroke clearly related to the presence of an occluder device occurred in only 2 of our 216 patients. Other potential risk factors in these patients were pre-existent coagulopathy in 1 and an abnormal device configuration in the other. The abnormal configuration was most likely due to a fractured arm of the large device placed in this patient. We no longer use 33-mm devices for PFO closure because we believe the device is too large to conform well to the atrial anatomy in most cases. Furthermore, such large devices are not necessary to achieve closure of a PFO (which by definition has little or
Miscellaneous/Recurrent Events After PFO Closure
no septal tissue deficiency) even if the potential maximal diameter of the door-like opening of the PFO by balloon sizing is in excess of 20 mm. Numerous uncontrolled studies have shown an apparent benefit to medical treatment or PFO closure in patients after a cryptogenic stroke. However, the best treatment, medical with an antiplatelet or anticoagulant versus PFO closure versus a combination of treatments, remains controversial. Our study was not designed to answer this question, but elucidates some of the difficulties in simply reporting the number of recurrent FNEs without evaluating the underlying causes in more detail. We have demonstrated that recurrent FNEs after PFO closure in a heterogenous population of patients with presumed cryptogenic stroke have many causes. Detailed and comprehensive investigation of any recurrent event after device closure of PFO is crucial. Identification of a potentially “treatable” cause may avoid further events. Furthermore, comprehensive preclosure screening is necessary to avoid changes in anticoagulation regimens in patients with other potential sources of thromboembolism. In patients treated with antiplatelet agents or oral anticoagulants, an average annual recurrence rate of stroke and TIA of approximately 3.4% has been reported at a mean follow-up period of 1.9 years.5 Other cohort studies have shown similar annual stroke or TIA recurrence rates of 4% to 6% with medical therapy. The Lausanne study of 140 patients with stroke and PFO showed that, although PFO was associated with stroke recurrence, recurrence itself was quite rare, i.e., 1.9% per year at a mean follow-up of 3 years.6 The Patent Foramen Ovale in Cryptogenic Stroke Study consisted of 630 patients followed for 2 years and found that in patients with stroke on medical therapy, aspirin or warfarin, presence of a PFO did not increase the risk of recurrence or death, regardless of PFO size or presence of atrial septal aneurysm.4 In the largest series on surgical closure of PFO for a previous ischemic event, there were 8 patients with recurrent TIA at a mean follow-up of 2 years, and overall freedom from TIA recurrence was 92.5 ⫾ 3.2% at 1 year and 83.4 ⫾ 6.0% at 4 years.12 The event rate for recurrent strokes in our series was 0.91% per year and the combined event rate for stroke/TIA was 3.42% per year. Hung et al10 reported a similar recurrence risk for stroke/TIA after device placement at 3.2% per year in a series of 63 patients who underwent PFO closure with the Clamshell, CardioSEAL, or Buttoned devices. Windecker et al8 reported an annual stroke/TIA recurrence rate of 3.4% after PFO closure with a mean follow-up of 1.6 years. A study that used CardioSEAL and Amplatzer devices in most patients and with a follow-up of 19.4 ⫾ 16.2 months reported a 2.6%-per-year TIA recurrence.13 Sievert et al9 reported an actuarial risk (for stroke/TIA) of 4.3% at 1 year and 5.9% at 3 years in 281 patients who underwent PFO closure using 7 different devices. Another series reported a 0.9% annual risk of stroke/TIA recurrence after closure using CardioSEAL or buttoned devices at a mean follow-up of 2.3 years.14 Two large prospective series using multiple devices reported actuarial risks of recurrent stroke/ TIA/peripheral emboli of 4.9% at 1 year and 9.4% at 2 and 6 years,15 and the second series reported 2% at 1 year, 3% at 2 years, and 4% at 5 and 10 years.16 Another prospective
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study with the PFO-Star device reported 1.7% for TIA and 0% for stroke at 1 year.17 Khairy et al18 after an organized literature review found that the 1-year recurrence rate of stroke/TIA with transcatheter therapy was 0% to 4.9% versus 3.8% to 12.0% with medical management. There was a trend toward an increased incidence of recurrent events with increasing mean age per study for transcatheter closure and medical therapy. Most of the published studies employed multiple device types for PFO closure. A recent nonrandomized study compared the risk of recurrent events in patients with cryptogenic stroke and PFO who underwent device closure with those who received medical treatment alone.19 PFO closure was at least as effective as medical treatment for prevention of recurrent events in the overall study group and possibly superior in 2 subgroups, namely in patients with complete occlusion after intervention and in those with ⬎1 stroke/ TIA at baseline.19 Another nonrandomized study reported a lower incidence of stroke/TIA per year for a PFO closure group (0% vs14.75%) compared with an antiplatelet therapy group.20 The recurrent stroke rate found in this study after CardioSEAL occlusion of PFO is comparable to rates from studies that evaluated recurrence of stroke and TIA in patients with PFO and cryptogenic stroke placed on various regimens of medical prophylaxis. We have noted a very strong dislike of warfarin in our patients and found that complications of aggressive anticoagulation regimens seem to be at least as high as complications directly attributable to the PFO closure device (3 cerebral or retinal hemorrhages compared with 3 patients with thrombi on a device or residual shunt). Because we are unable to clearly identify which patients may have other causes for cryptogenic stroke and an incidental PFO, our practice is to encourage patients to continue the relatively safe and inexpensive regimen of low-dose aspirin therapy even after complete healing of the PFO device. There is a need for more data to elucidate the best approach to treatment of patients with cryptogenic stroke and PFO. Results from randomized trials of transcatheter PFO closure versus medical management that are ongoing should hopefully improve our ability to select the best treatment options for an individual patient. Acknowledgments: The authors thank Aniko Szabo, PhD, and Qun Xiang, MS, Division of Biostatistics, Medical College of Wisconsin, for statistical assistance. 1. Lechat P, Mas JL, Lascault G, Loron P, Theard M, Klimczac M, Drobinski G, Thomas D, Grosgogeat Y. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148 –1152. 2. Cabanes L, Mas JL, Cohen A, Amarenco P, Cabanes PA, Oubary P, Chedru F, Guerin F, Bousser MG, de Recondo J. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993;24:1865–1873. 3. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000;55: 1172–1179. 4. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP, for the PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: patent
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foramen ovale in Cryptogenic Stroke Study. Circulation 2002;105: 2625–2631. Mas JL, Zuber M. Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal aneurysm, or both and cryptogenic stroke or transient ischemic attack. French Study Group on Patent Foramen Ovale and Atrial Septal Aneurysm. Am Heart J 1995;130: 1083–1088. Bogousslavsky J, Garazi S, Jeanrenaud X, Aebischer N, Van Melle G. Stroke recurrence in patients with patent foramen ovale: the Lausanne Study. Lausanne Stroke with Paradoxical Embolism Study Group. Neurology 1996;46:1301–1305. Bridges ND, Hellenbrand W, Latson L, Filiano J, Newburger JW, Lock JE. Transcatheter closure of patent foramen ovale after presumed paradoxical embolism. Circulation 1992;86:1902–1908. Windecker S, Wahl A, Chatterjee T, Garachemani A, Eberli FR, Seiler C, Meier B. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism: long-term risk of recurrent thromboembolic events. Circulation 2000;101:893– 898. Sievert H, Horvath K, Zadan E, Krumsdorf U, Fach A, Merle H, Scherer D, Schrader R, Spies H, Nowak B, Lissmann-Jensen H. Patent foramen ovale closure in patients with transient ischemia attack/stroke. J Interv Cardiol 2001;14:261–266. Hung J, Landzberg MJ, Jenkins KJ, King ME, Lock JE, Palacios IF, Lang P. Closure of patent foramen ovale for paradoxical emboli: intermediate-term risk of recurrent neurological events following transcatheter device placement. J Am Coll Cardiol 2000;35:1311– 1316. Braun M, Gliech V, Boscheri A, Schoen S, Gahn G, Reichmann H, Haass M, Schraeder R, Strasser RH. 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. Eur Heart J 2004;25:424 – 430. Dearani JA, Ugurlu BS, Danielson GK, Daly RC, McGregor CG, Mullany CJ, Puga FJ, Orszulak TA, Anderson BJ, Brown RD Jr,
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Schaff HV. Surgical patent foramen ovale closure for prevention of paradoxical embolism-related cerebrovascular ischemic events. Circulation 1999;100(suppl):II171–II175. Beitzke A, Schuchlenz H, Gamillscheg A, Stein JI, Wendelin G. Catheter closure of the persistent foramen ovale: mid-term results in 162 patients. J Interv Cardiol 2001;14:223–229. Martin F, Sanchez PL, Doherty E, Colon-Hernandez PJ, Delgado G, Inglessis I, Scott N, Hung J, King ME, Buonanno F, et al. Percutaneous transcatheter closure of patent foramen ovale in patients with paradoxical embolism. Circulation 2002;106:1121–1126. Wahl A, Meier B, Haxel B, Nedeltchev K, Arnold M, Eicher E, Sturzenegger M, Seiler C, Mattle HP, Windecker S. Prognosis after percutaneous closure of patent foramen ovale for paradoxical embolism. Neurology 2001;57:1330 –1332. Wahl A, Kunz M, Moschovitis A, Nageh T, Schwerzmann M, Seiler C, Mattle HP, Windecker S, Meier B. Long-term results after fluoroscopy guided closure of patent foramen ovale for secondary prevention of paradoxical embolism. Heart 2008;94:336-341. Braun MU, Fassbender D, Schoen SP, Haass M, Schraeder R, Scholtz W, Strasser RH. Transcatheter closure of patent foramen ovale in patients with cerebral ischemia. J Am Coll Cardiol 2002;39:2019 – 2025. Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med 2003;139:753– 760. Windecker S, Wahl A, Nedeltchev K, Arnold M, Schwerzmann M, Seiler C, Mattle HP, Meier B. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke. J Am Coll Cardiol 2004;44:750 –758. Thanopoulos BV, Dardas PD, Karanasios E, Mezilis N. Transcatheter closure versus medical therapy of patent foramen ovale and cryptogenic stroke. Catheter Cardiovasc Interv 2006;68:741–746.
A patent foramen ovale (PFO) has been found to be present more often in patients with cryptogenic stroke than in the general population1,2 or in patients with stroke and an identified cause.1– 4 Patients with PFO and presumed paradoxical embolism are at increased risk of recurrent thromboembolic events.5,6 Since the initial report in 1992,7 transcatheter closure of PFO has been undertaken in many centers to eliminate paradoxical emboli as a cause for recurrent strokes/transient ischemic attacks (TIAs) in patients with cryptogenic stroke/TIA. Various subsequent studies have described the safety and efficacy of this procedure using a variety of closure devices.8 –11 Recurrent focal neurologic events (FNEs) have been seen in a small percentage of patients during follow-up in all large series of cryptogenic stroke treated medically or by closure of the PFO. Details of the apparent causes of these recurrent FNEs have not been clearly described. We present the results of invesa
Herma Heart Center, Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin; bDepartment of Pediatric Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio; cSection of Pediatric Cardiology, Yale University School of Medicine, New Haven, Connecticut; and dDivision of Pediatric Cardiology, Duke University Medical Center, Durham, North Carolina. Manuscript received December 16, 2007; revised manuscript received and accepted January 21, 2008. *Corresponding author: Tel: 216-445-6532; fax: 216-445-3692. E-mail address: [email protected] (L. Latson). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.01.028
tigations performed to determine causes of all significant recurrent FNEs in patients from our center who underwent transcatheter PFO closure over a period of 5.5 years. Methods Records of all 216 patients who underwent transcatheter PFO closure from March 2000 to September 2005 were reviewed. Seventeen patients (7.8%) were lost to follow-up before the 1-month planned follow-up visit and were removed from subsequent analysis. We elected to use a primarily image-based definition of stroke in our evaluations. Stroke was defined as an FNE with an accompanying lesion on magnetic resonance imaging (MRI) or computed tomogram (CT) even if the deficit lasted ⬍24 hours. Focal neurologic symptoms persisting for ⬎24 hours were also considered to be a stroke even in the absence of new lesions on MRI/CT. A TIA was defined as an FNE lasting ⬍24 hours without an accompanying MRI/CT lesion in the brain. Cryptogenic FNE was defined as a sudden FNE in the absence of an identifiable cause, such as aneurysm, uncontrolled hypertension, intracranial hemorrhage, ipsilateral carotid lesion, atrial fibrillation, intracardiac thrombus, degenerative neurologic disorder, neoplasm, etc. To be considered for transcatheter PFO closure at our center, patients had to have had ⱖ1 preceding FNE consistent with stroke/TIA considered by a neurologist to be most www.AJConline.org
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likely caused by a paradoxical embolus. We did not have other specific inclusion or exclusion criteria in our standard approach to these patients. Patients with previous stroke of defined cause were included if they had also had a stroke that was felt to be likely due to paradoxical embolism. Uncertainty of the exact role of PFO closure in the treatment of cryptogenic stroke was explained in detail to all patients. The CardioSEAL septal occluder (NMT Medical, Inc., Boston, Massachusetts) was used for those who wished to proceed with closure despite this uncertainty. All patients had an MRI and/or CT of the brain and 155 (72%) had MRI/CT changes consistent with a preceding stroke. The remaining patients were considered to have had a TIA if clinical symptoms lasted ⬍24 hours. Arterial disease, hypertension, diabetes, migraines, and arrhythmias were evaluated but did not contraindicate PFO closure if they did not seem causative of the most recent stroke/TIA. The population included patients with potential sources for neurologic events other than PFO such as small vessel disease, history of atrial fibrillation (not around the time of the most recent event), mild carotid artery disease, or coagulation disorders. In each case, however, it was felt by the evaluating neurologist that paradoxical embolism was the most likely cause for at least the most recent stroke/TIA in each patient. No specific age was considered a contraindication to treatment. All patients were encouraged to enter the closure 1 trial (NMT Medical, Inc.) carried out in the institution, but the present study includes patients who refused to participate or were ineligible. Informed consent was obtained from patients for device implantation in compliance with requirements of the institutional review board. The CardioSEAL device was deployed in all patients using the standard implantation technique for this device. General anesthesia and transesophageal echocardiography were used early in our experience, and since 2001 intracardiac echocardiography and conscious sedation were used in most patients. A complete right-sided hemodynamic catheterization and right atrial angiography was performed to assess the anatomy of the PFO. A guidewire was positioned in the left upper pulmonary vein through a venous catheter advanced through the PFO. A sizing balloon (NuMED, Inc., Hopkinton, New York) was advanced over the guidewire and incompletely inflated (⬍1 atm) until a distinct indentation in the balloon and elimination of any shunting by color Doppler was identified. We did not inflate the balloon fully to avoid the possibility of inadvertently enlarging the defect. The diameter of the indentation was measured angiographically and by echocardiography. An 11Fr Mullins sheath (Cook, Inc., Bloomington, Indiana) was advanced over the wire across the PFO and into the left upper pulmonary vein. Device size was selected by the individual operator without a center-specific protocol. The device was delivered through the Mullins sheath. After deployment, an 8Fr angiographic catheter was advanced through the Mullins sheath into the low right atrium and a hand injection of agitated saline and/or right atrial angiography was performed to assess for residual right-to-left shunt. The optimal anticoagulation regimen for medical treatment of cryptogenic stroke is controversial. All patients were therefore advised to continue with the anticoagulation/
Table 1 Patient characteristics at implantation (n ⫽ 216) Age (yrs) Men/women Body weight (kg) Systemic hypertension Smoking Migraine headaches PFO stretch diameter (mm)
50 (19–77) 107/109 85 (47–157) 65 (30%) 48 (22%) 39 (18%) 11 (4–24)
Values are means (ranges) or numbers of patients (percentages).
antiplatelet regimen established before device placement for 6 months after placement. Endocarditis prophylaxis precautions were recommended for 1 year after implantation. Discontinuation of the initial anticoagulant/antiplatelet agents was felt to be reasonable after 6 months if there were no other conditions necessitating prolonged medication. Continuation after 6 months was left to the discretion of the referring physician. Low-dose aspirin therapy was recommended indefinitely after the first 6 months if other agents were discontinued. Follow-up visits to a cardiologist with clinical evaluation, transthoracic echocardiogram, and electrocardiogram were recommended at 24 hours, 1 month, 6 months, 1 year, and every 1 to 2 years thereafter. All patients were requested to report any new symptoms of an FNE possibly suggestive of stroke/TIA to our center. Patients with recurrent FNEs were directed to undergo additional cardiologic and neurologic evaluations. Reports of evaluations of all cases were reviewed in detail. All patients with a recurrent FNE had repeat MRI/CT and other tests as clinically indicated. These patients also underwent transesophageal echocardiography to assess for thrombus or the presence of a residual right-to-left leak. Contrast echocardiography was not part of our routine follow-up in asymptomatic patients. Data are presented as mean ⫾ SD. Estimation of survival free from stroke/TIA was performed by the Kaplan-Meier method as implemented in Proc Lifetest. Because the exact event times for some of the TIA recurrences were unknown and only a time range was available, the survival curve was estimated using Newton-Raphson Ridge maximization of the likelihood, as implemented in the %ICE macro in the SAS Sample Library (SAS Institute, Cary, North Carolina). Recurrent event rate was calculated by dividing the number of observed events by the observed number of personmonths at risk. A confidence interval for this assessment was obtained using Poisson regression. A p value ⬍0.05 represented statistical significance. Data analysis was performed using SAS 9.1 (SAS Institute). Results Patient characteristics at time of implantation are listed in Table 1. There were 107 men and 109 women in the study population of 216 patients. One hundred eleven patients (51%) received a 23-mm device, 94 (44%) received a 28-mm device, and 11 (5%) received a 33-mm device. None had trans-septal puncture for device placement. PFO diameters under gentle balloon inflation were 4 to 24 mm (mean 11). Successful implantation was achieved in all patients.
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Table 2 Recurrent events after CardioSEAL occlusion of patent foramen ovale: noncardioembolic events Time to Event (mos)
Device Size (mm)
Event Type
40
23
Subdural hemorrhage
6
23
—
23
36 5 12
23 28 28
Progressive neurologic deficits due to brain tumor Progressive neurologic deficits due to brain tumor Intracranial hemorrhage Stroke Retinal hemorrhage
Anticoagulation Before Event
Other Factors at Time of Event
Died
Warfarin
0
0
0
Warfarin
0
⫹ (1 mo after event due to cancer) ⫹ (4 mos after event due to cancer) 0
Warfarin Warfarin —
Severely increased INR Carotid plaque rupture 0
⫹ (34 mos after event) 0 0
— ⫽ no information available; INR ⫽ international normalized ratio. Table 3 Recurrent events after CardioSEAL occlusion of patent foramen ovale: embolic strokes Time to Event (mos)
Device Size (mm)
Residual Shunt
Device Abnormality
37
33
⫹
1
23
0
6
28
0
Thrombus attached to device, device fracture Thrombus attached to device 0
15
28
0
0
Anticoagulation Before Event
Other Factors at Time of Event
Outcome
Clopidogrel
0
Device removed
Clopidogrel
Factor V Leiden deficiency Graves’ disease, Hodgkin lymphoma LA appendage thrombus
Device removed
Warfarin, aspirin Clopidogrel
On follow-up Thrombus surgically removed; device left
LA ⫽ left atrial. Table 4 Recurrent events after CardioSEAL occlusion of patent foramen ovale: transient ischemic attacks Time to Event (mos)
Device Size (mm)
Residual Shunt
Device Abnormality
Anticoagulation Before Event
Other Factors at Time of Event
6
23
0
0
Clopidogrel, aspirin
4 3 1 0.1 1 — 3 and 19 6 12
28 33 28 28 23 23 28 28 28
0 0 0 0 0 0 0 ⫹ 0
0 Thrombus 0 0 0 0 0 0 0
Clopidogrel, aspirin Aspirin Warfarin, aspirin Warfarin, aspirin Warfarin, aspirin — Warfarin Warfarin Aspirin, warfarin
Small vessel disease, carotid artery calcium, coagulopathy (cardiolipin) 0 0 0 0 0 0 History of brain tumor Hemiplegic migraines Coagulopathy (cardiolipin)
Abbreviation as in Table 2.
Follow-up was 1 month to 7.1 years (mean 2.1) for a total of 438 patient-years. Eight patients died during follow-up due to non– central nervous system pathology unrelated to the device such as coronary artery disease and malignancy. Twenty patients had ⱖ1 recurrent FNE after device implantation (Tables 2 to 4). Fourteen patients were identified to have recurrent, probably embolic, FNEs. Of these, 4 patients had recurrent stroke and the remaining 10 had TIAs. Six patients had a recurrent FNEs clearly related to pathology other than a possible paradoxical embolus (Table 2). Two patients had new focal symptoms and MRI changes indicating that the original MRI lesions were actually brain tumors. One
patient with known carotid artery disease had an ipsilateral carotid plaque rupture and recurrent stroke. This occurred 4 days after warfarin was discontinued and transesophageal echocardiogram was negative for device abnormality or residual leak. Ruptured left carotid plaque was seen on angiogram. Warfarin was restarted and there has been no subsequent event. The other 3 had FNEs related to their anticoagulation medications. One patient had an intracranial hemorrhage with a severely increased international normalized ratio. Subdural hemorrhage was reported in 1 patient 40 months after device placement, and retinal hemorrhage occurred in 1 patient 12 months after device implantation.
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Figure 1. Event-free survival shown as estimated proportion of patients without stroke (solid line) and without stroke or TIA (dashed line) by time since operation. Patients were censored at the end of follow-up or at the time of death from other causes. N ⫽ number of patients still being followed at appropriate time point.
Four patients had recurrence of apparent embolic stroke by MRI without evidence of vascular disease (Table 3). Two of them were felt to be likely directly device related. In 1 patient, the 33-mm device was abnormally configured and was found to have arm fractures and poor septal apposition. Recurrent stroke occurred while the patient was on warfarin with a therapeutic international normalized ratio. The patient underwent surgical removal of the device and the right atrial arms of the device were seen protruding into the right atrium with 1 left atrial arm displaced away from the septum. There was no residual leak or thrombus identified on or near the device at the time of recurrent stroke. There have been no subsequent FNEs in this patient. The second patient had device-related recurrence of stroke 1 month after placement. This patient had factor V Leiden deficiency and had anticoagulation treatment with clopidogrel alone. There was found to be thrombus associated with the device and, hence, the device was surgically removed. Two patients had cryptogenic strokes with no evidence of relation to the CardioSEAL device. One had left atrial appendage thrombi at the time of his initial stroke, i.e., before device placement, without a history of atrial fibrillation or an identified clotting abnormality. This patient had received warfarin for 1 year after device placement and was changed to an antiplatelet regimen (aspirin plus clopidogrel) by the referring physician. Recurrence of stroke occurred after the change. The patient underwent surgical removal of a pedunculated left atrial thrombus that was identified remote from the device. The device was found to be completely endothelialized and was left in place. The other patient with recurrent stroke had the event 6 months after device placement. Other medical issues in this patient included Graves’ disease and Hodgkin lymphoma (remission phase). There was no evidence of a residual shunt or thrombus on the device. Recurrent TIA occurred in 10 patients (Table 4). One patient had 2 TIAs, making a total of 11 TIAs on follow-up. All patients had transesophageal echocardiograms after the event. Only 1 of these patients had a residual leak. One
patient had thrombi attached to the device. No other devicerelated issues were identified. Other coexistent issues in the recurrent TIA group were increased cardiolipin (in 2 patients), small vessel disease (in 1 patient), and previously treated brain tumor (in the patient with 2 TIAs). Seven patients with nonspecific symptoms were evaluated and not felt to have symptoms consistent with FNEs. Six had transient visual symptoms (spots, no specific field defects) only. One patient had a near syncopal episode. At the time of this analysis, 199 patients with follow-up information were evaluated for 438 person-years after closure. The event rate for recurrent strokes was 0.91% per year or 9.1 per 1,000 person-years (95% confidence interval for difference 3.4 to 24.3). The combined event rate for stroke/TIA was 3.42% per year or 34.2 per 1,000 personyears (95% confidence interval for difference 20.7 to 56.8). Survival curves for recurrent strokes and stroke/TIA are shown in Figure 1. Discussion Detailed analysis of all FNEs on follow-up of a large series of patients who have undergone percutaneous PFO closure after a presumed paradoxical embolus has not previously been presented. We found that 6 of 20 patients (30%) with a recurrent FNE had clear evidence of pathology unrelated to a cardioembolic source (brain tumor, carotid plaque rupture, intracerebral bleeding). Recurrence of stroke clearly related to the presence of an occluder device occurred in only 2 of our 216 patients. Other potential risk factors in these patients were pre-existent coagulopathy in 1 and an abnormal device configuration in the other. The abnormal configuration was most likely due to a fractured arm of the large device placed in this patient. We no longer use 33-mm devices for PFO closure because we believe the device is too large to conform well to the atrial anatomy in most cases. Furthermore, such large devices are not necessary to achieve closure of a PFO (which by definition has little or
Miscellaneous/Recurrent Events After PFO Closure
no septal tissue deficiency) even if the potential maximal diameter of the door-like opening of the PFO by balloon sizing is in excess of 20 mm. Numerous uncontrolled studies have shown an apparent benefit to medical treatment or PFO closure in patients after a cryptogenic stroke. However, the best treatment, medical with an antiplatelet or anticoagulant versus PFO closure versus a combination of treatments, remains controversial. Our study was not designed to answer this question, but elucidates some of the difficulties in simply reporting the number of recurrent FNEs without evaluating the underlying causes in more detail. We have demonstrated that recurrent FNEs after PFO closure in a heterogenous population of patients with presumed cryptogenic stroke have many causes. Detailed and comprehensive investigation of any recurrent event after device closure of PFO is crucial. Identification of a potentially “treatable” cause may avoid further events. Furthermore, comprehensive preclosure screening is necessary to avoid changes in anticoagulation regimens in patients with other potential sources of thromboembolism. In patients treated with antiplatelet agents or oral anticoagulants, an average annual recurrence rate of stroke and TIA of approximately 3.4% has been reported at a mean follow-up period of 1.9 years.5 Other cohort studies have shown similar annual stroke or TIA recurrence rates of 4% to 6% with medical therapy. The Lausanne study of 140 patients with stroke and PFO showed that, although PFO was associated with stroke recurrence, recurrence itself was quite rare, i.e., 1.9% per year at a mean follow-up of 3 years.6 The Patent Foramen Ovale in Cryptogenic Stroke Study consisted of 630 patients followed for 2 years and found that in patients with stroke on medical therapy, aspirin or warfarin, presence of a PFO did not increase the risk of recurrence or death, regardless of PFO size or presence of atrial septal aneurysm.4 In the largest series on surgical closure of PFO for a previous ischemic event, there were 8 patients with recurrent TIA at a mean follow-up of 2 years, and overall freedom from TIA recurrence was 92.5 ⫾ 3.2% at 1 year and 83.4 ⫾ 6.0% at 4 years.12 The event rate for recurrent strokes in our series was 0.91% per year and the combined event rate for stroke/TIA was 3.42% per year. Hung et al10 reported a similar recurrence risk for stroke/TIA after device placement at 3.2% per year in a series of 63 patients who underwent PFO closure with the Clamshell, CardioSEAL, or Buttoned devices. Windecker et al8 reported an annual stroke/TIA recurrence rate of 3.4% after PFO closure with a mean follow-up of 1.6 years. A study that used CardioSEAL and Amplatzer devices in most patients and with a follow-up of 19.4 ⫾ 16.2 months reported a 2.6%-per-year TIA recurrence.13 Sievert et al9 reported an actuarial risk (for stroke/TIA) of 4.3% at 1 year and 5.9% at 3 years in 281 patients who underwent PFO closure using 7 different devices. Another series reported a 0.9% annual risk of stroke/TIA recurrence after closure using CardioSEAL or buttoned devices at a mean follow-up of 2.3 years.14 Two large prospective series using multiple devices reported actuarial risks of recurrent stroke/ TIA/peripheral emboli of 4.9% at 1 year and 9.4% at 2 and 6 years,15 and the second series reported 2% at 1 year, 3% at 2 years, and 4% at 5 and 10 years.16 Another prospective
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study with the PFO-Star device reported 1.7% for TIA and 0% for stroke at 1 year.17 Khairy et al18 after an organized literature review found that the 1-year recurrence rate of stroke/TIA with transcatheter therapy was 0% to 4.9% versus 3.8% to 12.0% with medical management. There was a trend toward an increased incidence of recurrent events with increasing mean age per study for transcatheter closure and medical therapy. Most of the published studies employed multiple device types for PFO closure. A recent nonrandomized study compared the risk of recurrent events in patients with cryptogenic stroke and PFO who underwent device closure with those who received medical treatment alone.19 PFO closure was at least as effective as medical treatment for prevention of recurrent events in the overall study group and possibly superior in 2 subgroups, namely in patients with complete occlusion after intervention and in those with ⬎1 stroke/ TIA at baseline.19 Another nonrandomized study reported a lower incidence of stroke/TIA per year for a PFO closure group (0% vs14.75%) compared with an antiplatelet therapy group.20 The recurrent stroke rate found in this study after CardioSEAL occlusion of PFO is comparable to rates from studies that evaluated recurrence of stroke and TIA in patients with PFO and cryptogenic stroke placed on various regimens of medical prophylaxis. We have noted a very strong dislike of warfarin in our patients and found that complications of aggressive anticoagulation regimens seem to be at least as high as complications directly attributable to the PFO closure device (3 cerebral or retinal hemorrhages compared with 3 patients with thrombi on a device or residual shunt). Because we are unable to clearly identify which patients may have other causes for cryptogenic stroke and an incidental PFO, our practice is to encourage patients to continue the relatively safe and inexpensive regimen of low-dose aspirin therapy even after complete healing of the PFO device. There is a need for more data to elucidate the best approach to treatment of patients with cryptogenic stroke and PFO. Results from randomized trials of transcatheter PFO closure versus medical management that are ongoing should hopefully improve our ability to select the best treatment options for an individual patient. Acknowledgments: The authors thank Aniko Szabo, PhD, and Qun Xiang, MS, Division of Biostatistics, Medical College of Wisconsin, for statistical assistance. 1. Lechat P, Mas JL, Lascault G, Loron P, Theard M, Klimczac M, Drobinski G, Thomas D, Grosgogeat Y. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148 –1152. 2. Cabanes L, Mas JL, Cohen A, Amarenco P, Cabanes PA, Oubary P, Chedru F, Guerin F, Bousser MG, de Recondo J. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993;24:1865–1873. 3. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000;55: 1172–1179. 4. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP, for the PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: patent
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