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1.  Systematic review of percutaneous closure versus medical therapy in patients with cryptogenic stroke and patent foramen ovale 
BMJ Open  2014;4(3):e004282.
To provide a comprehensive comparison of patent foramen ovale (PFO) closure versus medical therapy in patients with cryptogenic stroke or transient ischaemic attack (TIA) and demonstrated PFO.
Systematic review with complete case meta-analysis and sensitivity analyses. Data sources included MEDLINE and EMBASE from 1980 up to May 2013. All randomised controlled trials (RCTs) comparing treatment with percutaneous catheter-based closure of PFO to anticoagulant or antiplatelet therapy in patients with cryptogenic stroke or TIA and echocardiographically confirmed PFO or atrial septal defect (ASD) were eligible.
1967 participants with prior stroke or TIA and echocardiographically confirmed PFO or ASD.
Primary outcome measures
The primary outcome of interest was recurrence of ischaemic stroke. We utilised data from complete cases only for the primary endpoint and combined data from trials to estimate the pooled risk ratio (RR) and associated 95% CIs calculated using random effects models.
We identified 284 potentially eligible articles of which three RCTs including 2303 patients proved eligible and 1967 patients had complete data. Of the 1026 patients randomised to PFO closure and followed to study conclusion 22 experienced non-fatal ischaemic strokes, as did 34 of 941 patients randomised to medical therapy (risk ratio (RR) 0.61, 95% CI 0.34 to 1.07; heterogeneity: p=0.34, I2=8%, confidence in estimates low due to risk of bias and imprecision). Analyses for ischaemic stroke restricted to ‘per-protocol’ patients or patients with concomitant atrial septal aneurysm did not substantially change the observed RRs. Complication rates associated with either PFO closure or medical therapy were low.
Pooled data from three RCTs provides insufficient support that PFO closure is preferable to medical therapy for secondary prevention of cryptogenic stroke in patients with PFO.
PMCID: PMC3948581  PMID: 24607561
2.  The Risk of Paradoxical Embolism (RoPE) Study: Developing risk models for application to ongoing randomized trials of percutaneous patent foramen ovale closure for cryptogenic stroke 
Trials  2011;12:185.
Despite the diffusion into practice of percutaneous closure of a patent foramen ovale (PFO) in patients with cryptogenic stroke (CS), the benefits have not been demonstrated, and remain unclear. For any individual presenting with a PFO in the setting of CS, it is not clear whether the PFO is pathogenically-related to the index event or an incidental finding. Further, the overall rate of stroke recurrence is low in patients with CS and PFO. How patient-specific factors affect the likelihood that a discovered PFO is related to an index stroke or affect the risk of recurrence is not well understood. These probabilities are likely to be important determinants of the benefits of PFO closure in CS.
The goal of the Risk of Paradoxical Embolism (RoPE) Study is to develop and test a set of predictive models that can identify those patients most likely to benefit from preventive treatments for PFO-related stroke recurrence, such as PFO closure. To do this, we will construct a database of patients with CS, both with and without PFO, by combining existing cohort studies. We will use this pooled database to identify patient characteristics associated with the presence (versus the absence) of a PFO, and to use this "PFO propensity" to estimate the patient-specific probability that a PFO was pathogenically related to the index stroke (Model #1). We will also develop, among patients with both a CS and a PFO, a predictive model to estimate patient-specific stroke recurrence risk based on clinical, radiographic and echocardiographic characteristics. (Model #2). We will then combine Models #1 and #2 into a composite index that can rank patients with CS and PFO by their conditional probability that their PFO was pathogenically related to the index stroke and the risk of stroke recurrence. Finally, we will apply this composite index to completed clinical trials (currently on-going) testing endovascular PFO closure against medical therapy, to stratify patients from low-expected-benefit to high-expected-benefit.
PMCID: PMC3170216  PMID: 21794121
3.  Multidisciplinary management of patent foramen ovale (PFO) and cryptogenic stroke/TIA 
Patent foramen ovale (PFO) has been implicated as a risk factor for cryptogenic ischemic stroke (CS). However, there is still a lack of widely accepted, undisputed indications for PFO closure. The present study describes the concept of the multidisciplinary PFO conference and a decision making process for closure versus no closure that was developed into a formalized clinical algorithm, and presents the results of implementing these, in terms of number and proportion of PFO closures as well as repeat referrals.
Five specialists in neurology, cardiology, internal medicine, thromboembolism, and echocardiography evaluated the clinical data of 311 patients at PFO conferences during 2006 to 2009. The main criteria for closure were patients with first-ever CS with PFO and atrial septal aneurysm, or patients with recurrent CS and PFO without atrial septal aneurysm.
A total of 143 patients (46%) were accepted for closure and 167 patients were rejected. Patients accepted for closure were younger (mean 50 years versus 58 years) (P < 0.001). The acceptance rate for PFO closure was similar throughout these years, with an average of 45%. Three of 167 patients (1.8%) initially rejected for PFO closure were re-referred due to recurrent stroke, and the PFO closure was subsequently performed.
The acceptance rate of less than 50% in the present study underscores the complex relationship between CS and PFO. Whatever the criteria used for PFO closure, any unit caring for these patients needs to have a rigorous process to avoid overtreatment as well as undertreatment and to ensure that personal preferences and economic incentives do not steer the selection process. Our algorithm provides a stable acceptance rate and a low rate of repeat referrals.
PMCID: PMC3785383  PMID: 24082787
patent foramen ovale; cryptogenic stroke; clinical algorithm; patent foramen ovale closure
4.  Risk and fate of residual interatrial shunting after transcatheter closure of patent foramen ovale: a long term follow up study 
Percutaneous transcatheter closure of patent foramen ovale (PFO) in cryptogenic stroke is an alternative to medical therapy. There is still debate on different outcome for each currently available device. The impact of residual shunting after PFO-clo- sure on recurrent arterial embolism is unknown.
(i) To evaluate the prevalence of residual interatrial shunting after device- closure of PFO, (ii) to identify risk factors predicting residual interatrial shunting after device implantation, and (iii) to investigate the outcome of patients after PFO-closure during long- term follow- up (FU).
Methods and results
Between 2000- 2005 PFO-closure was performed in 124 patients using four different devices: Amplatzer PFO-(n = 52), CardioSeal (n = 33), Helex (n = 23) and Premere (n = 16) occluder. All patients underwent serial contrast-enhanced transesophageal echocardiography (TEE) for 24 months after PFO- closure; clinical FU was at minimum 5 years up to 9.75 years (mean 6.67 ± 1.31 years). Overall-closure rate was 87% at 2 years, device-specific closure time curves differed significantly (p-logrank = 0.003). Independent risk factors for residual-shunting were implantation of a Helex occluder (hazard ratio [HR] 12.6, 95% confidence interval [CI] 2.6- 57.4, p = 0.002), PFO- canal- lengths (HR 1.2, 95%CI 1.1- 1.3, p = 0.004) and extend of atrial-septal-aneurysm (HR 1.1, 95%CI 0.9- 1.3; p = 0.05). 4 (3.2%) arterial embolic events occurred during a FU-period of 817.2 patient-years, actuarial annual thromboembolic-risk was 0.49%. All ischemic events were not related to residual PFO-shunting or device-related thrombus- formation.
Success rates of PFO- closure are mainly dependent on occluder-type, extend of concomitant atrial-septum-aneurysm and PFO-canal- length. Importantly, residual shunting after PFO-closure was not associated with recurrence of arterial embolism during long-term follow-up.
PMCID: PMC3351944  PMID: 21345765
5.  Neuroimaging Findings in Cryptogenic Stroke Patients with and without PFO 
Patent foramen ovale (PFO) and cryptogenic stroke (CS) are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related etiology. We examined whether specific radiological findings are associated with PFO among subjects with CS and known PFO status.
We analyzed the Risk of Paradoxical Embolism (RoPE) database of subjects with CS and known PFO status, for associations between PFO and: 1) index stroke seen on imaging, 2) index stroke size, 3) index stroke location, 4) multiple index strokes, and 5) prior stroke on baseline imaging. We also compared imaging with purported “high risk” echocardiographic features.
Subjects (n=2680) were significantly more likely to have a PFO if their index stroke was large (OR 1.36, p=0.0025), seen on index imaging (OR 1.53, p=0.003), and superficially located (OR 1.54, p<0.0001). A prior stroke on baseline imaging was associated with not having a PFO (OR 0.66, p<0.0001). Finding multiple index strokes was unrelated to PFO status (OR 1.21, p=0.161). No echocardiographic variables were related to PFO status.
This is the largest study to report the radiological characteristics of patients with CS and known PFO status. Strokes that were large, radiologically apparent, superficially located, or unassociated with prior radiological infarcts were more likely to be PFO associated than were unapparent, smaller, or deep strokes, and those accompanied by chronic infarcts. There was no association between PFO and multiple acute strokes nor between specific echocardiographic PFO features with neuroimaging findings.
PMCID: PMC3595100  PMID: 23339957
Patent Foramen Ovale; Cryptogenic Stroke; Imaging
6.  An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke 
Neurology  2013;81(7):619-625.
We aimed to create an index to stratify cryptogenic stroke (CS) patients with patent foramen ovale (PFO) by their likelihood that the stroke was related to their PFO.
Using data from 12 component studies, we used generalized linear mixed models to predict the presence of PFO among patients with CS, and derive a simple index to stratify patients with CS. We estimated the stratum-specific PFO-attributable fraction and stratum-specific stroke/TIA recurrence rates.
Variables associated with a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or TIA. The 10-point Risk of Paradoxical Embolism score is calculated from these variables so that the youngest patients with superficial strokes and without vascular risk factors have the highest score. PFO prevalence increased from 23% (95% confidence interval [CI]: 19%–26%) in those with 0 to 3 points to 73% (95% CI: 66%–79%) in those with 9 or 10 points, corresponding to attributable fraction estimates of approximately 0% to 90%. Kaplan-Meier estimated stroke/TIA 2-year recurrence rates decreased from 20% (95% CI: 12%–28%) in the lowest Risk of Paradoxical Embolism score stratum to 2% (95% CI: 0%–4%) in the highest.
Clinical characteristics identify CS patients who vary markedly in PFO prevalence, reflecting clinically important variation in the probability that a discovered PFO is likely to be stroke-related vs incidental. Patients in strata more likely to have stroke-related PFOs have lower recurrence risk.
PMCID: PMC3775694  PMID: 23864310
7.  Prevalence of patent foramen ovale in a consecutive cohort of 261 patients undergoing routine “coronary” 64-multi-detector cardiac computed tomography 
The Ulster Medical Journal  2011;80(2):72-75.
A patent foramen ovale (PFO) is strongly associated with cryptogenic stroke (CS), neurological and other phenomena. The reported prevalence of PFO varies according to the imaging technique used and population studied.
To measure prospectively, the prevalence of PFO in a cohort of consecutive patients attending for routine “coronary” CT angiography using standard, everyday coronary protocols including low-dose prospective ECG gated studies.
Standard coronary imaging protocols were used. PFOs were graded according to the classification of Williamson et al.1
261 patients were studied. A PFO was identified in 22.6% (11.5% grade 1 (closed flap), 6.5% grade 2 (open flap) and 4.6% grade 3 (open flap with jet)). A further 6.1% had an atrial septal aneurysm.
The prevalence of all grades of PFO (22.6%) and open flap PFO (11.1% = grade 2 and 3) with this technique compares with 24.3% by trans-oesophageal echocardiography (TOE) and 14.9% by saline contrast echocardiography (SCE)2, 3 Further comparative studies are required but we believe an open flap PFO or ASA should be identified and recorded during cardiac CT. This approach may identify those at risk of cryptogenic stroke as well as avoid unnecessary tests in stroke patients.
PMCID: PMC3229849  PMID: 22347746
Patent foramen ovale; atrial septum; cardiac anatomy; computed tomographic angiography; non-invasive angiography
8.  Intermediate and Long-Term Results of Transcatheter Closure of Patent Foramen Ovale Using the Amplatzer Patent Foramen Ovale Occluder: One Case of Pulmonary Embolism Irrespective of Patent Foramen Ovale Closure 
Korean Circulation Journal  2011;41(7):356-362.
Background and Objectives
Patent foramen ovale (PFO) has been implicated in the pathogenesis of cryptogenic stroke or transient ischemic attack (TIA) due to paradoxical embolism, and in the pathogenesis of migraine. This paper reports the intermediate and long-term results of transcatheter closure of PFO associated with cerebrovascular accidents (CVAs), TIAs and migraine, using the Amplatzer PFO occluder. This paper also reports a case of pulmonary embolism which developed in one patient after PFO closure.
Subjects and Methods
From January 2003 to May 2010, 16 patients with PFO (seven males and nine females) with a history of at least one episode of cryptogenic stroke/TIA, CVA, or migraine and who underwent percutaneous transcatheter closure of PFO using the Amplatzer occluder. All the procedures were performed under general anesthesia and were assisted by transesophageal echocardiography.
The device was implanted without any significant complications in all the patients, and the PFOs were effectively closed. At an average follow-up period of 54 months, the 15 patients with TIA/CVA had no recurrence of any thromboembolic event. The symptoms in one patient with migraine subsided after occlusion of the PFO. In this study, pulmonary embolism occurred five months after PFO closure in one patient, but the cause of pulmonary embolism was not identified. However, it is believed that the pulmonary embolism occurred without stroke recurrence because occlusion of the PFO was performed when the patient had a stroke event.
It can be concluded that according to the intermediate and long-term follow-up results, transcatheter PFO closure is an effective and safe therapeutic modality in the prevention of thromboembolic events, especially in the patients with cryptogenic stroke/TIA, and PFO closure is helpful in the treatment of migraine. However, this study involved a small number of patients and also the follow-up period was not long enough. Hence, randomized, controlled trials are necessary to determine if this approach is preferable to medical therapy for the prevention of recurrent stroke or as primary treatment for patients with migraine headache.
PMCID: PMC3152729  PMID: 21860636
Patent foramen ovale; Stroke; Transient ischemic attack; Migraine; Pulmonary embolism
9.  Randomized clinical trial comparing percutaneous closure of patent foramen ovale (PFO) using the Amplatzer PFO Occluder with medical treatment in patients with cryptogenic embolism (PC-Trial): rationale and design 
Trials  2011;12:56.
Several studies have shown an association of cryptogenic stroke and embolism with patent foramen ovale (PFO), but the question how to prevent further events in such patients is unresolved. Options include antithrombotic treatment with warfarin or antiplatelet agents or surgical or endovascular closure of the PFO. The PC-Trial was set up to compare endovascular closure and best medical treatment for prevention of recurrent events.
The PC-Trial is a randomized clinical trial comparing the efficacy of percutaneous closure of the PFO using the Amplatzer PFO occluder with best medical treatment in patients with cryptogenic embolism, i.e. mostly cryptogenic stroke. Warfarin for 6 months followed by antiplatelet agents is recommended as medical treatment. Randomization is stratified according to patients age (<45 versus ≥45 years), presence of atrial septal aneurysm (ASA yes or no) and number of embolic events before randomization (one versus more than one event). Primary endpoints are death, nonfatal stroke and peripheral embolism.
patients were randomized in 29 centers of Europe, Canada, and Australia. Randomization started February 2000. Enrollment of 414 patients was completed in February 2009. All patients will be followed-up longitudinally. Follow-up is maintained until the last enrolled patient is beyond 2.5 years of follow-up (expected in 2011).
Trial Registration
Trial listed in as NCT00166257 and sponsored by AGA Medical, Plymouth, MN, USA
PMCID: PMC3058012  PMID: 21356042
10.  Percutaneous Closure versus Medical Therapy Alone for Cryptogenic Stroke Patients with a Patent Foramen Ovale: Meta-Analysis of Randomized Controlled Trials 
Texas Heart Institute Journal  2014;41(4):357-367.
Of cryptogenic stroke patients younger than 55 years of age, up to 61% have had a patent foramen ovale (PFO). Observational studies have revealed reductions in recurrent neurologic events through PFO closure versus medical therapy, and randomized controlled trials have shown nonsignificant trends toward benefit. We systematically searched for randomized controlled trials of percutaneous PFO closure with medical therapy versus medical therapy alone in patients with cryptogenic stroke and performed a meta-analysis of treatment outcomes. The primary endpoint was combined death, stroke, and transient ischemic attack.
We included 3 trials. Of 2,303 total patients, 1,150 underwent PFO closure and 1,153 received medical therapy (median follow-up period, 2.6 yr). The pooled incidence of the primary endpoint was 1.2 events per 100 patient-years in the closure group (95% confidence interval [CI], 0.2–2.3) and 1.8 in the therapy group (95% CI, 0.7–2.9) (P=0.32); the number needed to treat was 167 (range, 100–500). The corresponding pooled hazard ratio was 0.67 (95% CI, 0.44–1.01; P=0.054) in favor of closure. Closure was associated with an increased risk of atrial fibrillation: relative risk=3.51 (95% CI, 1.44–8.55; P=0.006). When stratified by device, use of the Amplatzer™ PFO Occluder resulted in significant stroke-prevention benefit over medical therapy alone: hazard ratio=0.44 (95% CI, 0.21–0.95; P=0.037).
When compared with medical therapy alone, PFO closure with medical therapy showed a trend toward a decreased hazard of combined events, although the absolute event reduction was small and the number needed to treat was high.
PMCID: PMC4120497  PMID: 25120387
Cerebral infarction/etiology; foramen ovale, patent/complications/drug therapy/economics/surgery; ischemic attack, transient/etiology/prevention & control; logistic models; meta-analysis; odds ratio; randomized controlled trials as topic; risk factors; septal occluder device; stroke/drug therapy/etiology/prevention & control
11.  Investigation of Association between PFO Complicated by Cryptogenic Stroke and a Common Variant of the Cardiac Transcription Factor GATA4 
PLoS ONE  2011;6(6):e20711.
Patent foramen ovale (PFO) is associated with clinical conditions including cryptogenic stroke, migraine and varicose veins. Data from studies in humans and mouse suggest that PFO and the secundum form of atrial septal defect (ASDII) exist in an anatomical continuum of septal dysmorphogenesis with a common genetic basis. Mutations in multiple members of the evolutionarily conserved cardiac transcription factor network, including GATA4, cause or predispose to ASDII and PFO. Here, we assessed whether the most prevalent variant of the GATA4 gene, S377G, was significantly associated with PFO or ASD. Our analysis of world indigenous populations showed that GATA4 S377G was largely Caucasian-specific, and so subjects were restricted to those of Caucasian descent. To select for patients with larger PFO, we limited our analysis to those with cryptogenic stroke in which PFO was a subsequent finding. In an initial study of Australian subjects, we observed a weak association between GATA4 S377G and PFO/Stroke relative to Caucasian controls in whom ASD and PFO had been excluded (OR = 2.16; p = 0.02). However, in a follow up study of German Caucasians no association was found with either PFO or ASD. Analysis of combined Australian and German data confirmed the lack of a significant association. Thus, the common GATA4 variant S377G is likely to be relatively benign in terms of its participation in CHD and PFO/Stroke.
PMCID: PMC3108965  PMID: 21673957
12.  Transesophageal Echocardiography in Cryptogenic Stroke and PFO: The Analysis of Putative High Risk Features from the Risk of Paradoxical Embolism (RoPE) Database 
Patent foramen ovale (PFO) is associated with cryptogenic stroke (CS), though the pathogenicity of a discovered PFO in the setting of CS is typically unclear. Transesophageal echocardiography (TEE) features such as PFO size, an associated hypermobile septum, and presence of a right-to-left shunt at rest have all been proposed as markers of risk. The association of these TEE features with other markers of pathogenicity has not been examined.
Methods and Results
We used a recently derived score based on clinical and neuroimaging features to stratify patients with PFO and CS by the probability that their stroke is PFO-attributable. We examined whether high risk TEE features are seen more frequently in patients more likely to have had a PFO-attributable stroke (n = 637) compared to those less likely to have a PFO attributable stroke (n = 657). Large physiologic shunt size was not more frequently seen among those with probable PFO-attributable strokes (OR=0.92; p = 0.53). Neither the presence of a hypermobile septum nor a right-to-left shunt at rest were detected more often in those with a probable PFO-attributable stroke (OR=0.80; p = 0.45 and OR=1.15; 0.11 respectively).
We found no evidence that the proposed TEE risk markers of large PFO size, hypermobile septum, and presence of right-to-left shunt at rest are associated with clinical features suggesting that a CS is PFO-attributable. Additional tools to describe PFOs may be useful in helping to determine whether an observed PFO is incidental or pathogenically related to CS.
PMCID: PMC3934652  PMID: 24214884
cerebrovascular disease/stroke; echocardiography; cardiovascular imaging; risk factor; congenital heart disease
13.  Transcatheter patent foramen ovale closure versus medical therapy for cryptogenic stroke: a meta-analysis of randomized clinical trials 
There is an association between cryptogenic stroke and patent foramen ovale (PFO). The optimal treatment strategy for secondary prevention remains unclear. The purpose of this study was to analyze aggregate data examining the safety and efficacy of transcatheter device closure versus standard medical therapy in patients with PFO and cryptogenic stroke.
A search of published data identified 3 randomized clinical trials for inclusion. The primary outcome was a composite end-point of death, stroke and transient-ischemic attack (TIA). Pre-defined subgroup analysis was performed with respect to baseline characteristics including age, sex, atrial septal aneurysm and shunt size. Data was synthesized using a random effects model and results presented as hazard ratios (HRs) with 95% confidence intervals (CIs).
A cohort of 2,303 patients with a history of cryptogenic stroke and PFO were randomized to device closure (n = 1150) and medical therapy (n = 1153). Mean follow-up was 2.5 years. Transcatheter closure was not superior to medical therapy in the secondary prevention of stroke or TIA in intention-to-treat analysis (HR: 0.66, 95% CI: 0.43 to 1.01; p = 0.056). However, the results were statistically significant using per-protocol analysis (HR: 0.64, 95% CI: 0.41 to 0.98; p = 0.043). Males had significant benefit with device closure (HR: 0.48, 95% CI: 0.24 to 0.96; p = 0.038).
In this meta-analysis, using intention-to-treat analysis, transcatheter device closure of PFO was not superior to standard medical therapy in the secondary prevention of cryptogenic stroke. Transcatheter closure was superior using per-protocol analysis.
PMCID: PMC3890573  PMID: 24330204
Patent foramen ovale; Inter atrial shunt; Transcatheter closure; Cryptogenic stroke
14.  May-Thurner Syndrome in patients with Cryptogenic Stroke and Patent Foramen Ovale – an important clinical association 
Background and Purpose
We aimed to investigate the incidence of May-Thurner syndrome (MTS) in cryptogenic stroke patients with patent foramen ovale (PFO).
This was a retrospective study. All consecutive patients with cryptogenic stroke having undergone PFO closure from January 1st 2002 to December 31st 2007 at our institute were included in this study. Pelvic magnetic resonance venography (MRV) studies of all patients were reviewed to determine if features of MTS were present. Medical records and invasive venography studies of all patients were reviewed when available. All patients with MTS features on MRV were reviewed by a vascular medicine specialist to define any previous incidence of DVT or any signs of chronic venous insufficiency. All patients also had lower limb venous duplex performed to rule out lower limb venous thrombosis.
A total of 470 patients from January 1 2002 until Dec 31 2007 with cryptogenic stroke underwent PFO closure at our institute. Thirty patients (6.3%) had features consistent with MTS on MRV. These patients were predominantly female (80%) with a mean age of 43.6 ± 11.9 years. Twelve patients (40%) had abnormalities in their laboratory thrombophilia evaluation and 13 females (54.1%) were taking hormone related birth control pills. Only two patients had a history and signs of chronic venous insuffiency. All PFOs demonstrated right-to-left shunting on transesophageal echocardiography. Atrial septal aneurysms/hypermobile atrial septa were present in 70% of patients with MTS.
May-Thurner syndrome has an important clinical association with cryptogenic stroke and PFO.
PMCID: PMC3744111  PMID: 19182088
15.  Percutaneous closure of patent foramen ovale: “Closed” door after the last randomized trials? 
Patent foramen ovale (PFO) percutaneous closure has previously been an accepted intervention for the prevention of recurrent cryptogenic stroke on the basis of observational studies. However, randomized trials have been lacking until now. Three recently published randomized trials (CLOSURE I, PC and RESPECT) do not demonstrate the superiority of this intervention versus optimal medical therapy, therefore making this practice questionable. Nonetheless, these trials have had certain pitfalls, mainly a lower than initially estimated number of patients recruited, therefore lacking sufficient statistical power. On the other hand, different closure devices were used in the three trials. In two of them (PC and RESPECT), the Amplatzer PFO Occluder was used and the STARflex device was used in the other one (CLOSURE I). Taken altogether, a meta-analysis of these three trials does not demonstrate a statistically significant benefit of percutaneous PFO closure (1.9% vs 2.9%; P = 0.11). However, if we analyze only the PC and RESPECT trials together, in which the Amplatzer PFO Occluder was used, a statistically significant benefit of percutaneous PFO closure is observed (1.4% vs 3.0%, P = 0.04). In conclusion, our interpretation of these trials is that the use of a dedicated, specifically designed Amplatzer PFO device could possibly reduce the risk of stroke in patients with PFO and cryptogenic stroke. This consideration equally applies to patients who have no contraindications for anticoagulant or antithrombotic therapy.
PMCID: PMC3920161  PMID: 24527181
Patent; Foramen; Ovale; Closure; Percutaneous; Device; Cryptogenic; Stroke; Risk
16.  Outcome of patients with cryptogenic stroke and patent foramen ovale 
Objectives. The aim was to estimate the recurrence rate and to define subgroups at increased risk for recurrent cerebral ischaemia in patients with patent foramen ovale (PFO) and so called cryptogenic stroke due to paradoxical embolism.
Methods. Patent foramen ovale was diagnosed in 318 patients with otherwise unexplained ischaemic stroke or transient ischaemic attack (TIA). One hundred and fifty nine were treated medically (oral anticoagulation 79, platelet inhibitors 80) and represent the study population. The remaining 159 patients underwent endovascular or surgical closure of the PFO and are not part of this study.
Results. Mean age was 50.7 (SD 13.5) years. The event leading to the diagnosis of PFO was a TIA in 38 patients (23.9%), an ischaemic stroke in 119 (74.8%), and an amaurosis fugax in two patients (1.3%). Forty four patients (27.7%) had experienced multiple cerebrovascular ischaemic events before the diagnosis of the PFO. During mean follow up of 29 (SD 23) months 21 patients (13.4%) had a recurrent cerebrovascular event (seven strokes and 14 TIAs). The average annual rate of recurrent strokes was 1.8% and that of recurrent strokes or TIAs was 5.5%. When patients with PFO with multiple cerebrovascular events before the diagnosis of the PFO were analyzed separately, the average annual rates of recurrent cerebral ischaemia were 3.6% for recurrent strokes and 9.9% for recurrent strokes or TIAs. These rates were significantly higher than in patients with first ever stroke or TIA (p=0.02).
Conclusions. The study confirms a risk of stroke recurrence that is similar to the rates of previously published series of patients with PFO and cryptogenic strokes. Patients with more than one previous event were at increased risk of recurrent cerebral ischaemia.
PMCID: PMC1737790  PMID: 11861693
17.  Long-term results of the amplatzer cribriform occluder for patent foramen ovale with associated atrial septal aneurysm: impact on occlusion rate and left atrial functional remodelling 
Treatment of patients with concomitant patent foramen ovale (PFO) and atrial septal aneurysm (ASA) poses a number of challenges; while some authors have suggested the off-label use of the Amplatzer Cribriform Occluder in such anatomy, the long-term outcomes of this strategy is unknown. Our study aimed to assess the long-term impact on closure rate, left atrial functional remodelling, and clinical outcomes of off-label implantation of Amplatzer ASD Cribriform Occluder in patients with PFO and ASA.
We prospectively enrolled 160 consecutive patients with previous stroke (mean age 36 ± 9.5 years, 109 females), significant PFO and ASA. All patients were treated with Amplatzer Cribriform Occluder to ensure the most complete possible coverage of the ASA. Residual shunt and LA passive and active emptying, LA conduit function, and LA ejection fraction were computed before and after 6 months from the procedure and then yearly. All patients underwent successful transcatheter closure (mean ratio device/diameter of interatrial septum = 0.74).
Incomplete ASA coverage during intraprocedural intracardiac echocardiography was observed in 71 patients. During mean follow-up of 3.6 ± 1.8 years, when compared to patients with complete coverage, there were no differences in LA functional parameters and complete occlusion achieved in 150/160 patients (93.7%). No new cerebral ischemic events, aortic erosions or device thrombosis were recorded during the follow-up.
The use of the Amplatzer ASD Cribriform to treat PFO and associated ASA seems safe and effective: relatively small Occluder devices are probably effective enough to promote left atrial functional remodelling.
PMCID: PMC3257157  PMID: 22254216
Patent foramen ovale; stroke; embolism; cardiac anatomy; echocardiography
18.  Evaluation of Patent Foramen Ovale in Young Adults with Cryptogenic Stroke 
ARYA Atherosclerosis  2011;7(2):74-77.
Stroke is a leading cause of death and long-term disability worldwide. Although a minority of ischemic strokes in the community affect younger adults, up to 40% of acute ischemic strokes in young adults are cryptogenic in nature, that is, no cause is determined. Underlying pathologies of stroke of unknown cause are multiple, including patent foramen ovale (PFO). The PFO is the most common defect of atrial septum of the heart. This study evaluated the frequency of PFO in brain stroke with unknown etiology in patients younger than 50 years of age in Kerman.
This cross-sectional study was done in Shafa Medical Center of Kerman University of Medical Sciences in 2008. For detection of the PFO, we used agitated saline test with transcranial Doppler sonography in brain stroke patients with unknown etiology and also a control group (normal persons).
PFO was found in 53% of patients. No significant difference was observed between sexes. The rate in the control group was 20%. Patients with large PFO had 2 or more attacks of stroke. Subjects in the control group did not have large PFO.
One of the most important underlying causes in young adults with cryptogenic stroke is PFO. It is better to prescribe antiplatelet drugs in patients with the first attack of stroke, but as for patients with recurrent stroke, closure of PFO must be considered.
PMCID: PMC3347844  PMID: 22577450
Stroke; Young Adults; Patent Foramen Ovale; Agitated Normal Saline Test.
19.  Princeton Conference: Is PFO a Modifiable Risk Factor for Stroke Recurrence? 
Stroke; a journal of cerebral circulation  2010;41(10 Suppl):S26-S30.
While the prevalence of patent foramena ovale (PFOs) in the general population is around 25%, it is approximately doubled among cryptogenic stroke (CS) patients. This has generally been attributed to paradoxical embolism and many physicians recommend PFO closure to prevent recurrence. However, the benefit of PFO closure in patients with stroke has not been demonstrated. Further, the epidemiology of stroke recurrence in patients with CS with PFO versus without PFO, and in those with large right-to-left shunts versus small right-to-left shunts, has yielded results that appear difficult to reconcile with the hypothesis that paradoxical embolism is an important cause of stroke recurrence. The purpose of this review is to critically examine the epidemiological evidence that PFO is a potentially modifiable risk factor for stroke recurrence in patients with cryptogenic stroke. The evidence suggests that many patients with CS and PFO have strokes that are PFO-attributable, but that many have strokes that are unrelated to their PFO.. We introduce the concept of “PFO-propensity”, defined as the patient-specific probability of finding a PFO in a patient with cryptogenic stroke based on their age and other risk factors. We show that this value is directly related to the probability that a CS is PFO-attributable. Because there is substantial heterogeneity both in PFO-propensity and in recurrence risk among patients with PFO and cryptogenic stroke, stratification for closure by these joint probabilities will likely prove crucial for appropriate patient selection.
PMCID: PMC2954503  PMID: 20876498
Patent foramen ovale; Risk factors for stroke; Secondary stroke prevention; Cryptogenic Stroke
20.  Short-Term and Two-Year Rate of Recurrent Cerebrovascular Events in Patients with Acute Cerebral Ischemia of Undetermined Aetiology, with and without a Patent Foramen Ovale 
ISRN Neurology  2011;2011:959483.
Purpose. We investigated stroke recurrence in patients with acute ischemic stroke of undetermined aetiology, with or without a patent foramen ovale (PFO). Methods. Consecutive stroke patients underwent to Transcranial Doppler and Transesophageal Echocardiography for PFO detection. Secondary stroke prevention was based on current guidelines. Results. PFO was detected in 57/129 (44%) patients. The rate of recurrent stroke did not significantly differ between patients with and without a PFO: 0.0% versus 1.4% (1 week), 1.7% versus 2.7% (1 month), and 3.5% versus 4.2% (3 months), respectively. The 2-year rates were 10.4% (5/48) in medically treated PFO and 8.3% (6/72) in PFO-negative patients (P = 0.65), with a relative risk of 1.25. No recurrent events occurred in 9 patients treated with percutaneous closure of PFO. Conclusion. PFO was not associated with increased rate of recurrent stroke. Age-related factors associated with stroke recurrence in cryptogenic stroke should be taken into account when patients older than 55 years are included in PFO studies.
PMCID: PMC3263533  PMID: 22389838
21.  Patent Foramen Ovale in Cerebral Infarction 
Current Cardiology Reviews  2010;6(3):162-174.
Recent studies support the hypothesis of a close aetiological and pathogenic association between the presence of patent foramen ovale (PFO) and cryptogenic stroke. The therapeutic options currently used in the treatment of these patients range from standard antiaggregation and standard-dose anticoagulation to the percutaneous occlusion of the PFO. The use or recommendation of treatment is based both on clinical risk factors associated with PFO, such as age, detection of states of hypercoagulability and previous history of stroke, and on the risks associated to right-to-left shunt (RLSh) and PFO, such as the size of PFO, magnitude of RLSh and the presence of atrial septal aneurysm (ASA). However, there is currently no consensus regarding the most suitable treatment and it is surprising to observe the widespread use of certain therapeutic approaches which are not supported by clinical evidence.
In this revision, we analyse the relevance of PFO in cryptogenic stroke, consider the main evidence available for determining the best management of these patients and make diagnostic and therapeutic management recommendations.
PMCID: PMC2994108  PMID: 21804775
Patent foramen ovale; right-to-left shunt; cryptogenic stroke; transcranial Doppler; echocardiography.
22.  Patent foramen ovale, cardiac valve thickening and antiphospholipid antibodies as risk factors for subsequent vascular events: The PICSS-APASS Study 
(1) Estimate risk of recurrent stroke/TIA/death in the subgroup of the Patent foramen ovale in the Cryptogenic Stroke Study (PICSS) cohort with patent foramen ovale (PFO) and antiphospholipid antibodies (aPL) and (2) Estimate risk of recurrent stroke/TIA/death in aPL positive patients who have thickened left-sided heart valves (VaT).
PFO is associated with cryptogenic ischemic stroke. Also, the presence of aPL is associated with ischemic cerebrovascular disease.
Combined data from 2 major sub studies of the Warfarin Aspirin Recurrent Stroke Trial (WARSS) were evaluated. PICSS subjects were included if they were enrolled in the Antiphospholipid Antibodies and Stroke Study (APASS) and had a baseline aPL test (lupus anticoagulant, anticardiolipin antibodies, or both) within one month of the stroke. All patients in PICSS underwent transesophageal echocardiography for PFO as well as VaT, which was performed blinded to aPL status and treatment arm (325mg/d aspirin or adjusted dose warfarin, target INR 1.4–2.8). The primary outcome event was the 2-year risk of recurrent stroke/TIA/death and was evaluated using Cox proportional hazards model. As there was no treatment effect, warfarin and aspirin groups were combined to increase power. For the combined endpoint, power to detect a HR of 2 was 47.8% for the PFO and aPL positive group, and 75.3% for the valve thickening and aPL positive group, assuming two-sided type I error of 0.05
525 subjects were tested for the combined presence of PFO and aPL and were available for evaluation. The primary outcome event rate was 23.9% (HR 1.39, 95% CI 0.75–2.59) in the PFO positive/aPL positive group, compared to 13.9% (HR 0.83, 95% CI 0.44–1.56) in the PFO positive/aPL negative group and 19.9% (HR 1.16 95% CI 0.68–1.90) in the PFO negative/aPL positive group.
545 subjects tested for combined presence of aPL and left sided cardiac VaT were available for evaluation. The primary event rate was 22.6% (HR1.65, 95% CI 0.88–3.09) in the VaT positive/aPL positive group, compared to 19.4% (HR 1.50, 95% CI 0.82–2.75) in the VaT positive/aPL negative group and 20.2% (HR 1.63, 95% CI 0.81–3.25) in the VaT negative /aPL positive group.
The combined presence of aPL with either a PFO or with left sided cardiac VaT did not significantly increase risk of subsequent cerebrovascular events in this PICCS/APASS cohort of patients.
PMCID: PMC2761081  PMID: 19498198
patent foramen ovale; anti-phospholipid antibodies; cardiac valve thickening; stroke recurrence risk; stroke risk factors; Risk Factors
23.  Patent foramen ovale in patients with tension headache: is it as common as in migraineurs? An age- and sex-matched comparative study 
The Journal of Headache and Pain  2009;10(6):431-434.
The association of patent foramen ovale (PFO) and atrial septal aneurysm (ASA) with migraine headache attack (MHA) has been clearly shown. The same findings have been recently demonstrated also in cluster headache. Although tension-type headaches (TTH) are the most common kind of headache, their association with these atrial septal abnormalities has never been studied before. The study was conducted to clarify whether there was a significant association between the presence of such atrial septal abnormalities and tension headache, when compared with migraineurs. One hundred consecutive patients with migraine and 100 age- and sex-matched subjects with TTH and 50 healthy volunteers with no headache were enrolled in the study and underwent a complete transesophageal echocardiographic study with contrast injections at rest and with the Valsalva maneuver. There was no significant difference between the age and the sex of the participants of the three groups. The overall prevalence of PFO was 23% in patients with TTH and that of large PFOs was only 11%. The 23% prevalence of PFO in patients with TTH was not statistically different from 16% found in our normal control group. Furthermore, we found a significantly higher prevalence of PFO in migraineurs (50%) when compared with patients with tension headache (p < 0.001). This was also true for the collective presence of large PFOs and ASAs (35%) (p < 0.001). Although atrial septal anomalies have an association with MHA, they do not have a significant association with TTH.
PMCID: PMC3476217  PMID: 19756944
Tension-type headache; Migraine headache; Patent foramen ovale; Atrial septal aneurysm
24.  The Risk of Paradoxical Embolism (RoPE) Study: Initial description of the completed database 
Detecting a benefit from closure of patent foramen ovale (PFO) in patients with cryptogenic stroke (CS) is hampered by low rates of stroke recurrence and uncertainty about the causal role of PFO in the index event. A method to predict PFO-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence.
To develop a database to support modeling of PFO-attributable recurrence risk by combining extant data sets.
We identified investigators with extant databases including subjects with CS investigated for PFO; determined the availability and characteristics of data in each database; collaboratively specified the variables to be included in the Risk of Paradoxical Embolism (RoPE) database; harmonized the variables across databases, and collected new primary data when necessary and feasible.
The RoPE database has individual clinical, radiologic, and echocardiographic data from 12 component databases including subjects with CS both with (n=1925) and without (n=1749) PFO. In the PFO subjects, a total of 381 outcomes (stroke, TIA, death) occurred (median follow-up = 2.2yrs). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling.
While individual studies are inadequate for modeling PFO-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a PFO-related stroke recurrence who may have the greatest potential benefit from PFO closure.
PMCID: PMC4060865  PMID: 22883936
cryptogenic stroke; patent foramen ovale; secondary stroke prevention; risk modeling; endovascular closure; individual patient metaanalysis
25.  Patent Foramen Ovale, Ischemic Stroke and Migraine: Systematic Review and Stratified Meta-Analysis of Association Studies 
Neuroepidemiology  2012;40(1):56-67.
Observational data have reported associations between patent foramen ovale (PFO), cryptogenic stroke and migraine. However, randomized trials of PFO closure do not demonstrate a clear benefit either because the underlying association is weaker than previously suggested or because the trials were underpowered. In order to resolve the apparent discrepancy between observational data and randomized trials, we investigated associations between (1) migraine and ischemic stroke, (2) PFO and ischemic stroke, and (3) PFO and migraine.
Eligibility criteria were consistent; including all studies with specifically defined exposures and outcomes unrestricted by language. We focused on studies at lowest risk of bias by stratifying analyses based on methodological design and quantified associations using fixed-effects meta-analysis models.
We included 37 studies of 7,686 identified. Compared to reports in the literature as a whole, studies with population-based comparators showed weaker associations between migraine with aura and cryptogenic ischemic stroke in younger women (OR 1.4; 95% CI 0.9–2.0; 1 study), PFO and ischemic stroke (HR 1.6; 95 CI 1.0–2.5; 2 studies; OR 1.3; 95% CI 0.9–1.9; 3 studies), or PFO and migraine (OR 1.0; 95% CI 0.6–1.6; 1 study). It was not possible to look for interactions or effect modifiers. These results are limited by sources of bias within individual studies.
The overall pairwise associations between PFO, cryptogenic ischemic stroke and migraine do not strongly suggest a causal role for PFO. Ongoing randomized trials of PFO closure may need larger numbers of participants to detect an overall beneficial effect.
PMCID: PMC3707011  PMID: 23075508
Systematic review; Meta-analysis; Patent foramen ovale; Cryptogenic stroke; Migraine

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