Cryptogenic Embolism Research Articles

Utilizing RNA sequencing to identify gene expression markers of stroke-causing thrombi origin: A pilot study

IntroductionStroke embolic source have an unknown origin in 30-40% of cases. Mechanical thrombectomy for acute large vessel occlusion stroke has provided us with a method to directly retrieve the thrombi from patients for analysis. By collecting stroke-causing thrombi from known sources, we can then use high-throughput RNA sequencing (RNAseq) technology to directly measure the gene expression signatures of these clots. This may allow us to identify genetic markers to predict the cause of cryptogenic embolism. MethodsThis is a prospective study in which RNAseq was used to analyze cerebral thrombi retrieved by mechanical thrombectomy devices in acute ischemic stroke patients. Samples were separated into two groups based on known stroke thrombus etiology, including Carotid group (patients with ipsilateral >70% carotid stenosis) and Atrial fibrillation (AF) group (patients with atrial fibrillation). Gene expression was compared by RNAseq analysis between the groups. ResultsFrom October 2016 to September 2017, 8 thrombi (4 in Carotid group, 4 in Afib group) were included in this study. There were 131 genes that were significantly up- or down-regulated between the two groups defined as a false discovery rate ≤ 0.05 and a fold change ≥ 2. Twenty-six genes were selected as candidate gene biomarkers based on the criteria in the methods section. Candidate genes HSPA1B, which encodes a heatshock protein, and GPRC5B, which encodes a G-protein, showed the greatest fold differences in expression between the two groups. ConclusionThis study has shown that RNA sequencing of acute ischemic stroke thrombi is feasible and indentified potential novel biomarkers for identifying stroke-causing thrombi origin, especially in cryptogenic stroke.

Occlusion of functional high-volume intra-atrial shunts in older patients after embolic stroke of undetermined source.

Intra-atrial shunts are associated with an elevated risk of embolic stroke of undetermined source (ESUS). Percutaneous occluder implantation is recommended as secondary prevention in younger patients. This study aims to compare the outcome after shunt occlusion between younger and older patients with a history of presumed paradox embolism and to evaluate the impact of high-volume shunting in an elderly population. We conducted a single-center, retrospective, observational study, involving 187 patients who underwent interventional percutaneous PFO or ASD occlusion at our center between 2013 and 2023. The mean age of participants was 51.8 ± 11.8 years, with 76 patients aged ≤50 years and 111 patients aged >50 years. Older patients presented more cardiovascular risk factors. The presence of atrial septum aneurysm or large shunting was evenly distributed (ASA 26.3% vs. 28.8%, p = 0.833, mean shunt defect size 6.67 vs. 7.23 mm, p = 0.151). There were no significant differences in procedural or intrahospital complications. The event rate during the 6-month follow-up was low. Recurrence of arterial embolism occurred in 1.6% of the younger and 3.8% of the older patients (p = 0.817). Comparison of high-volume shunts (defect size ≥10 mm or passage ≥20 bubbles during bubble study) with low-volume shunts in this elderly cohort with a mean age ≥50 years showed no significant difference in outcomes. There was a statistically non-significant trend toward a higher rate of residual shunt at the end of the procedure in the high-volume shunt group (2.9% vs. 9.8%, p = 0.0894). This difference was not observed at the 6-month follow-up anymore (14.5 vs. 12.1%, p = 0.628). Two unsuccessful implantation attempts were reported in the high-volume shunt group, while none were observed in the low-volume shunt group (p = 0.372). No intervention-related deaths occurred in this patient cohort during follow-up. Occlusion of relevant, intra-atrial shunting is a safe and effective option for secondary prevention of cryptogenic embolism in patients over 50 years of age. The beneficial outcome was irrespective of a high-volume shunting before implantation.

Increased incidence of ischemic stroke in young: A population-based stroke registry study from 2008 to 2018

BackgroundStudying changing patterns in stroke incidence is essential since strokes represent a burden for public health. The aim of our study was to evaluate the epidemiological trend of strokes from 2008 to 2018 in the population-based Brest Stroke Registry (BSR) focusing on patients under 60. MethodsAll first-ever-stroke, patients aged 15 and older, with imaging, in the Pays-de-Brest from January 1st 2008 to December 31st 2017 were included. Cumulative incidence was calculated, by periods of two years, and temporal trends were evaluated by age group, sex, stroke subtype (ischemic or hemorrhagic) using a Poisson regression. Trends in stroke variables were specifically studied for young people. Ischemic stroke mechanism subtypes were analysed according to TOAST and SSS-TOAST classifications. ResultsOver a 10-year study period, there were 6043 first-ever-strokes: 738 intracerebral hemorrhage (ICH) and 5305 ischemic strokes (IS). Mean age was 73.55±14.25years, 82.2% were older than 60 and 51.8% were women. IS incidence increased in young people from 30.4 [95% CI: 27.4; 33.8] to 37.3 [95% CI: 33.9; 41.0] per 100,000 inhabitants (P=0.0025). IS incidence≥60 decreased except for last studied period. ICH remained stable for older people but decreased in young from 5.6 [4.3; 7.1] to 2.8 [2.0; 4.0] per 100,000 inhabitants (P=0.0250). Under 60, the main risk factors were smoking (68.6%); hypertension (27.8%); high-alcohol intake (24.4%) and dyslipidemia (21%). Most IS were minor. Work-up in the IS young population was for the large majority brain magnetic resonance imaging (MRI) (74.5%); cardiac monitoring (80%): echocardiography (83.5%); and imaging of the neck vessels (89.9%). Among IS, 19.8% were taking antihypertensive drugs and 10.9% statins. According to the TOAST classification, there were 46.7% cryptogenic strokes, which was reduced to 25.5% for other cryptogenic strokes, and 2.3% for cryptogenic embolism according SSS-TOAST classification. In IS, risk profiles, clinical parameters and prior-stroke treatments did not significantly change. Dyslipidemia and use of statins were fluctuant. Diagnostic work-up improved but the frequencies of IS mechanism subtypes remained stable. ConclusionIS incidence increased while ICH incidence declined in young people. Major use of MRI may have contributed to the IS trend. The traditional risk factors studied remained stable and did not explain the increase in IS incidence. Improvement in diagnostic work-up did not lead to any change in subtypes of stroke mechanisms. Using the SSS-TOAST classification reduced the rate of cryptogenic strokes. The role of non-traditional risk factors may be explored in an attempt to explain increased incidence.

A novel etiological classification in patients with intracranial large vessel occlusion and endovascular treatment: discordance with the classic and SSS TOAST systems: A retrospective cohort study

Purpose: Among patients with acute ischemic stroke (AIS), those with intracranial large vessel occlusion (LVO) should undertake endovascular treatment (EVT) based on mechanical thrombectomy. Although the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system has been used in overall population of patients with AIS, especially for secondary prevention. In the current study, a new classification system for the LVO population is proposed.Methods: The classic TOAST and Stop Stroke Study TOAST (SSS TOAST) were applied to the LVO population. Based on discordance with those systems, a new LVO classification system was developed and applied to the LVO population. The new system comprised extracranial atherosclerosis (ECAS), intracranial atherosclerosis (ICAS), cardioembolism (CE), cryptogenic embolism, stroke of undetermined etiology (SUE; two or more etiologies), and stroke of other determined etiology (SOE) where small artery occlusion was removed.Results: The LVO classification system comprised 43 ECAS (6.52%), 141 ICAS (21.36%), 303 CE (45.91%), 75 cryptogenic embolism (11.36%), 75 SUE (11.36%; cardioembolic source in 98.67%), and 23 SOE (3.48%) patients. The ICAS group had a significantly longer median onset-to-puncture time than the other groups. In the ICAS group, 102 of 141 (72.34%) remained partial recanalization after EVT.Conclusion: The LVO classification system differentiating ECAS and ICAS in patients with large artery atherosclerosis and classifying cryptogenic embolism is more suitable for patients with EVT for intracranial LVO. Further studies for predicting underlying ICAS and planning treatment strategy should be performed.

Nonstenotic intracranial atherosclerosis as an emerging mechanism in cryptogenic cerebral embolism.

Nonstenotic intracranial atherosclerosis as an emerging mechanism in cryptogenic cerebral embolism.

0829 Workup of Nocturnal Hypoxemia Leads to Diagnosis of Patent Foramen Ovale

Abstract Introduction Patent foramen ovale (PFO) in adults often remains asymptomatic until clinical manifestations such as cryptogenic stroke, migraine headache, air embolism, hypoxemia, or platypnea-orthodeoxia syndrome occur. In this case, prior workup of cryptogenic stroke failed to identify a PFO that was diagnosed after further investigation of polycythemia which revealed nocturnal hypoxemia on polysomnogram. Report of Cases: A 60-year-old male with history of recurrent venous thromboembolic events (VTE), secondary polycythemia, and cryptogenic strokes was referred for a polysomnogram during the evaluation of polycythemia. Over the span of six years, he had multiple cryptogenic strokes and VTEs in the setting of polycythemia and normal hypercoagulability labs. Further evaluation suggested secondary polycythemia after serum erythropoietin and JAK2 mutation testing were negative. The patient was a never smoker without evidence of malignancy or renal disease leading to suspicion that his polycythemia was due to hypoxemia despite normal oxygen saturations during point of care evaluations. He frequently reported shortness of breath during appointments. During a polysomnogram, the patient was found to have a total apnea-hypopnea index of fewer than 5 events per hour but demonstrated hypoxemia with 49.7% of total sleep time spent below an oxygen saturation of 90%. He was referred to pulmonology for further evaluation that showed normal resting oxygen saturation, no desaturation on a six-minute walk test, mild restrictive defect on pulmonary function testing, and a normal chest computed tomography with angiography. Prior transthoracic echocardiogram had demonstrated an atrial septal aneurysm without communication between the atrial chambers. No evidence suggestive of a right-to-left shunt was found on lateral imaging of the brain during a ventilation-perfusion scan. Further evaluation of the aneurysmal atrial septum on transesophageal echocardiogram with an agitated saline bubby study demonstrated a patent foramen ovale with a right-to-left shunt. In the setting of hypoxia leading to secondary polycythemia, the patient was scheduled for PFO closure. Conclusion Hypoxemia out of proportion to sleep-disordered breathing on polysomnogram should prompt further evaluation. Despite multiple prior strokes, our patient’s PFO had gone undiagnosed until polycythemia prompted a polysomnogram that demonstrated isolated nocturnal hypoxemia and prompted a further workup. Clinically significant hypoxemia is an indication for PFO closure. Support (If Any)

Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE) - study protocol for a randomised controlled trial.

Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events.Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone. CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat. The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal). CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke. First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023.

Patent Foramen Ovale Attributable Cryptogenic Embolism With Thrombophilia Has Higher Risk for Recurrence and Responds to Closure.

The aim of this study was to investigate the effect of management on the risk for recurrent events among patients with cryptogenic ischemic stroke or transient ischemic attack. The combination of patent foramen ovale (PFO) and hypercoagulability may greatly increase the risk for paradoxical embolism. However, previous randomized controlled trials evaluating the efficacy of PFO closure excluded these potential high-risk patients. Patients diagnosed with PFO attributable cryptogenic embolism were prospectively, without randomization, recruited from January 2005 to March 2018. The relationship between thrombophilia and recurrent events was evaluated in overall patients. Multivariate Cox regression was conducted to assess the relative risk for recurrence in PFO closure and medical therapy groups. A total of 591 patients with cryptogenic embolism with PFO were identified. The median duration of follow-up was 53months, and thrombophilia significantly increased the risk for recurrent events (hazard ratio [HR]: 1.85; 95% confidence interval [CI]: 1.09 to 3.16; p=0.024). PFO closure was superior to medical therapy in overall patients (HR:0.16; 95%CI: 0.09 to 0.30; p<0.001). Of the 134 patients (22.7%) with thrombophilia, there was a difference in the risk for recurrence events between the PFO closure (6 of 89) and medical therapy (15 of 45) groups (HR: 0.25; 95%CI: 0.08 to 0.74; p=0.012). There was no potential heterogeneity in the further subgroup analysis. Patients with cryptogenic stroke with PFO and hypercoagulable state had increased risk for recurrent stroke or transient ischemic attack. PFO closure provided a lower risk for recurrent events compared with medical therapy alone.

Patent Foramen Ovale, the Role of Antiplatelet Therapy Alone or Anticoagulant Therapy Alone Versus Device Closure for Cryptogenic Stroke: A Review of the Literature and Current Recommendations.

Cryptogenic stroke and its relation to the Patent Foramen Ovale (PFO) is a long-debated topic. Recent clinical trials have unequivocally established the relationship between cryptogenic strokes and paradoxical embolism across the PFO. This slit-like communication exists in everyone before birth, but most often closes shortly after birth. PFO may persist as a narrow channel of communication between the right and left atria in approximately 25-27% of adults. In this review, we examine the clinical relevance of the PFO with analysis of the latest trials evaluating catheter-based closure of PFO's for cryptogenic stroke. We also review the current evidence examining the use of antiplatelet medications versus anticoagulants for stroke prevention in those patients with PFO who do not qualify for closure per current guidelines.

Risk of Paradoxical Embolism (RoPE)-Estimated Attributable Fraction Correlates With the Benefit of Patent Foramen Ovale Closure: An Analysis of 3 Trials.

In patients with cryptogenic stroke and patent foramen ovale (PFO), the Risk of Paradoxical Embolism (RoPE) Score has been proposed as a method to estimate a patient-specific "PFO-attributable fraction"-the probability that a documented PFO is causally-related to the stroke, rather than an incidental finding. The objective of this research is to examine the relationship between this RoPE-estimated PFO-attributable fraction and the effect of closure in 3 randomized trials. We pooled data from the CLOSURE-I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale), RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment), and PC (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism) trials. We examine the treatment effect of closure in high RoPE score (≥7) versus low RoPE score (<7) patients. We also estimated the relative risk reduction associated with PFO closure across each level of the RoPE score using Cox proportional hazard analysis. We estimated a patient-specific attributable fraction using a PC trial-compatible (9-point) RoPE equation (omitting the neuroradiology variable), as well as a 2-trial analysis using the original (10-point) RoPE equation. We examined the Pearson correlation between the estimated attributable fraction and the relative risk reduction across RoPE strata. In the low RoPE score group (<7, n=912), the rate of recurrent strokes per 100 person-years was 1.37 in the device arm versus 1.68 in the medical arm (hazard ratio, 0.82 [0.42-1.59] P=0.56) compared with 0.30 versus 1.03 (hazard ratio, 0.31 [0.11-0.85] P=0.02) in the high RoPE score group (≥7, n=1221); treatment-by-RoPE score group interaction, P=0.12. The RoPE score estimated attributable fraction anticipated the relative risk reduction across all levels of the RoPE score, in both the 3-trial (r=0.95, P<0.001) and 2-trial (r=0.92, P<0.001) analyses. The RoPE score estimated attributable fraction is highly correlated to the relative risk reduction of device versus medical therapy. This observation suggests the RoPE score identifies patients with cryptogenic stroke who are likely to have a PFO that is pathogenic rather than incidental.

The paradoxical embolism phenomenon in patients with embolic cryptogenic stroke

Patent foramen ovale (PFO) is an important cause of embolic cryptogenic stroke (ECS) in young patients. The main mechanism in this case is paradoxical embolism (PE), the basis for which is a right-to-left (R-L) shunt. Objective: to comparatively characterize patients who have undergone ECS, with and without an R-L shunt, as evidenced by transcranial Doppler with the bubble test (TCD-BT). Patients and methods . In 40 patients with acute ECS, an R-L shunt was sought using TCD-BT, followed by transesophageal echocardiography (TEE). The left atrial volume index (LAVI) was additionally calculated. Brain damage was analyzed by probabilistic mapping of foci according to magnetic resonance imaging. Results and discussion. The mean age of the examined patients was 51.5 (39.5–60.0) years; of them there were 22 women and 18 men. An RL shunt was detected in 24 (60.0%) of patients with cryptogenic embolism that was mainly grades 2 and 3 (41.0 and 35.0%). TEE could visualize PFO (1.0 to 5.5 mm in size) in 16 (40%) patients and atrial septal aneurysm in 3 (7.5%). PFO was not found in 5 patients with positive results of TCD-BT, which may suggest that there is either a pulmonary shunt or a false-negative TEE. The patients with an R-L shunt versus those without an R-L-shunt showed lower LAVIs (23.9 and 26.5 mL/m2) (p=0.016). This fact may additionally confirm the causative role of PFO in the development of stroke, whereas higher LAVIs in the non R-L shunt subgroup should alert to the presence of atrial cardiopathy and initiate an appropriate diagnostic search for latent atrial fibrillation. According to the presence or absence of an R-L shunt, the groups did not significantly differ in gender, age, and clinical characteristics of the stroke. In patients with PFO, a lesion focus was most commonly localized in the middle cerebral artery bed (35.3%), cerebellum (23.5%), and posterior cerebral artery (17.6%). Five (29.0%) patients were ascertained to have several foci of acute stroke. There was a trend towards the larger size of cerebral infarction foci and their specific localization in the vertebrobasilar bed in PE, which determined the high (35.3%) incidence of ataxia with the onset of the disease. Conclusion. PE causes ECS in 60.0% of cases. The distinctive feature of patients with an R-L shunt is lower LAVIs and a trend towards the larger size of cerebral infarction foci and their specific localization in the vertebrobasilar bed.

Abstract WP264: Frequency of Hypercoagulability in Patients With Embolic Stroke of Undetermined Source and Patent Foramen Ovale

Introduction: Patent foramen ovale (PFO) is more commonly found in patients with cryptogenic stroke and paradoxical embolism is commonly assumed to be the primary mechanism. Our objective was to determine the frequency of hypercoagulability in cryptogenic stroke patients and PFO. Methods: Consecutive patients with embolic stroke of undetermined source (ESUS) seen at the Emory Clinic from January 1, 2017 to June 30, 2019 who underwent echocardiogram with bubble study and markers of coagulation and hemostatic activation (MOCHA) testing (serum d-dimer, prothrombin fragment 1.2, thrombin-antithrombin complex, fibrin monomer) were included; abnormal MOCHA was defined as ≥ 2 elevated markers. Venous thromboembolism, malignancy, other defined hypercoagulable state, and the composite outcome were assessed at routine follow-up and compared across groups based on PFO status. Results: Of 172 patients (mean age 63 ± 16 years, 60% female), 40 (23%) had a PFO. Compared to the PFO- group, the PFO+ group was younger (p=&lt;0.001), less likely to have hypertension (p&lt;0.001) and diabetes (p=0.011), and had a higher ROPE score (p=0.007) (Table 1). There was no difference in the frequency of abnormal MOCHA between groups and the composite outcome was less frequent in PFO+ versus PFO- patients (p=0.017). In the subgroup of patients &lt;60 years old, there was no difference in the frequency of abnormal MOCHA and the composite outcome. Conclusion: Hypercoagulability as measured by MOCHA was not associated with the presence of PFO in ESUS patients. Based on our results, ESUS patients should undergo a detailed evaluation for alternative causes of stroke other than paradoxical embolism.

Cierre percutáneo del foramen oval permeable en pacientes mayores de 60 años con ictus criptogénico

Introduction and objectivesRandomized trials have shown the efficacy of transcatheter closure of patent foramen ovale (PFO) in patients aged ≤ 60 years with cryptogenic embolism. We aimed to assess the long-term safety and efficacy of PFO closure in patients aged> 60 years. MethodsOf 475 consecutive patients with cryptogenic embolism who underwent PFO closure, 90 older patients aged> 60 years (mean, 66±5 years) were compared with 385 younger patients aged ≤ 60 years (mean, 44±10 years). ResultsOlder patients had a higher prevalence of cardiovascular risk factors (CVRF) (hypertension, dyslipidemia, diabetes; P <.01 for all vs younger patients). There were no differences in periprocedural complications between the 2 groups. During a median follow-up of 8 (4-12) years, there were a total of 17 deaths, all from noncardiovascular causes (7.8% and 2.6% in the older and younger patient groups, respectively; HR, 4.12; 95%CI, 1.56-10.89). Four patients had a recurrent stroke (2.2% and 0.5% in the older and younger patient groups, respectively; HR, 5.08; 95%CI, 0.71-36.2), and 12 patients had a transient ischemic attack (TIA) (3.3% and 2.3% in the older and younger patient groups, respectively; HR, 1.71; 95%CI, 0.46-6.39). There was a trend toward a higher rate of the composite of stroke/TIA in older patients (5.5% vs 2.6%; HR, 2.62; 95%CI, 0.89-7.75; P=.081), which did not persist after adjustment for CVRF (HR, 1.97; 95%CI, 0.59-6.56; P=.269). ConclusionsIn older patients with cryptogenic embolism, PFO closure was safe and associated with a low rate of ischemic events at long-term. However, older patients exhibited a tendency toward a higher incidence of recurrent stroke/TIA compared with younger patients, likely related to a higher burden of CVRF.

Transcatheter closure of patent foramen ovale in patients older than 60 years of age with cryptogenic embolism.

Randomized trials have shown the efficacy of transcatheter closure of patent foramen ovale (PFO) in patients aged ≤ 60 years with cryptogenic embolism. We aimed to assess the long-term safety and efficacy of PFO closure in patients aged> 60 years. Of 475 consecutive patients with cryptogenic embolism who underwent PFO closure, 90 older patients aged> 60 years (mean, 66±5 years) were compared with 385 younger patients aged ≤ 60 years (mean, 44±10 years). Older patients had a higher prevalence of cardiovascular risk factors (CVRF) (hypertension, dyslipidemia, diabetes; P <.01 for all vs younger patients). There were no differences in periprocedural complications between the 2 groups. During a median follow-up of 8 (4-12) years, there were a total of 17 deaths, all from noncardiovascular causes (7.8% and 2.6% in the older and younger patient groups, respectively; HR, 4.12; 95%CI, 1.56-10.89). Four patients had a recurrent stroke (2.2% and 0.5% in the older and younger patient groups, respectively; HR, 5.08; 95%CI, 0.71-36.2), and 12 patients had a transient ischemic attack (TIA) (3.3% and 2.3% in the older and younger patient groups, respectively; HR, 1.71; 95%CI, 0.46-6.39). There was a trend toward a higher rate of the composite of stroke/TIA in older patients (5.5% vs 2.6%; HR, 2.62; 95%CI, 0.89-7.75; P=.081), which did not persist after adjustment for CVRF (HR, 1.97; 95%CI, 0.59-6.56; P=.269). In older patients with cryptogenic embolism, PFO closure was safe and associated with a low rate of ischemic events at long-term. However, older patients exhibited a tendency toward a higher incidence of recurrent stroke/TIA compared with younger patients, likely related to a higher burden of CVRF.

The Fragility Index in Randomized Controlled Trials for Patent Foramen Ovale Closure in Cryptogenic Stroke

Background and Purpose: The routine use of percutaneous transcatheter patent foramen ovale closure (PPFOC) to prevent recurrent stroke in patients with cryptogenic stroke is still a matter of debate after completion major randomized controlled trials (RCTs). Methods: The fragility index of RCTs evaluating effect of PPFOC against medial therapy alone in stroke prevention was calculated to assess the robustness of statistically significant findings. Results: Literature search with PubMed identifies 6 RCTs on PPFOC. Median number of patients who underwent PPFOC and medical treatment were 340 and 229, respectively. Median number of the patients lost to follow-up was 20 in PPFOC and 18 in medical group. Fragility index was 0 for 4 studies. Median fragility index was also 0 for both “stroke” (interquartile range: 0-5.3) and “combined stroke and TIA” (interquartile range: 0-2) endpoints. In all studies except CLOSE, fragility index was smaller than or equal to the number of the subjects lost to follow-up. Conclusions: Recent positive results of PFO closure studies should be interpreted cautiously because of their fragile characteristics. Routine PFO closure should be reserved for prevention of recurrence when suspicion for paradoxical embolism is high. Detailed individualized decision-making is crucial before ordering PPFOC for stroke prevention in patients with cryptogenic embolism.

Impact of Discontinuation of Antithrombotic Therapy Following Closure of Patent Foramen Ovale in Patients With Cryptogenic Embolism

No data exist on the optimal duration of antithrombotic therapy (AT) following patent foramen ovale (PFO) closure. We sought to assess the safety of AT discontinuation following PFO closure in patients with a cryptogenic ischemic event. A total of 453 consecutive patients (mean age: 48 ± 13years, men: 51%) who underwent PFO closure due to a cryptogenic ischemic event were included. All patients were on AT following PFO closure (antiplatelet therapy: 92.7%, anticoagulation: 7.3%). Ischemic and bleeding events, and AT were assessed at a median follow-up of 8 (IQR: 4 to 11) years, and follow-up was complete in 96% of patients. Stroke and transient ischemic attack occurred in 4 (0.9%) and 12 (2.6%) patients, respectively, and 27 (6.0%) patients had bleeding events (major in 6 [1.3%] patients, including 4 episodes of intracranial hemorrhage). All major bleeding events occurred under aspirin therapy. A total of 82 patients (18%) stopped the AT at a median of 7 (IQR: 5 to 34) months post-PFO closure (due to a bleeding event or gastrointestinal symptoms: 13 patients, no specific reason: 69 patients), and none of them had any ischemic event after a median time of 7 (IQR 3 to 10) years without any AT. A propensity score matched analysis including 46 patients who discontinued the AT within 1-year post-PFO closure and 120 patients with an ongoing AT showed the lack of differences in ischemic events between groups (0 vs 0.2 stroke/transient ischemic attack per 100 patient-years in the no-AT and AT groups, respectively). In conclusion, in young patients who underwent PFO closure, bleeding events occurred in ∼6% of patients after a median follow-up of 8years. AT was discontinued in about one fifth of patients (most of them within the year following PFO closure), and this was not associated with any increase in ischemic events at long-term follow-up. These results suggest that, in patients without other co-morbidities increasing the risk of stroke, temporary AT following PFO closure may be a reasonable strategy.

Abstract TP419: PFO Stroke With Thrombophilia Has Higher Risk of Recurrent Stroke and Responds to PFO Closure

Background: Hypercoagulability due to thrombophilia may increase the risk of paradoxic embolism. However, previous randomized controlled trials that evaluated the efficacy of PFO closure or medical therapy on the risk of recurrent stroke and/or transient ischemic attack (TIA) events, have excluded these potentially high-risk thrombophilia patients. In this study, we want to investigate the effect of PFO management on the risks of recurrent stroke and/or TIA among patients with thrombophilia. Methods: Patients with a PFO attributable ischemic stroke or TIA are prospectively recruited. Hypercoagulable tests for protein C, protein S, antithrombin III, homocysteine levels, IgG and IgM anticardiolipin antibodies, factor V Leiden and prothrombin gene variant were obtained. The primary outcome was occurrence of stroke and/or TIA after index event. Results: Thrombophilia is diagnosed in 120 PFO stroke patients who subsequently underwent PFO closure (n= 76) vs medical therapy (n= 44) ( Table 1 ). The mean duration of follow-up was 45 months in the closure group and 40 months in the medical-therapy group. The primary end point occurred in 5 patients (6.6%) in the closure group and in 14 (31.8%) in the medical therapy group (hazard ratio for medical therapy vs. closure, 5.797; 95% confidence interval [CI], 2.094 to 16.051; P = 0.001) ( Figure 1 ) with recurrent rate of 18.2% vs. 5.3% for TIA (P = 0.023) and 13.6% vs. 1.3% for stroke (P = 0.018) respectively. Conclusions: PFO stroke patients with hypercoagulable state had higher rate of recurrent stroke than those patients in clinical trials. Among patients who had cryptogenic embolism with thrombophilia, closure of a PFO was associated with a lower rate of recurrent stroke and/or TIA than medical therapy.

Abstract TP406: Treatment Outcome in Older Patients With Pfo Attributable Cryptogenic Embolism

Background: Recent successful randomized clinical trials showed that patent foramen ovale (PFO) closure lower risk of recurrent stroke or transient ischemic attack (TIA), compared to medical therapy. However, older patients (age≥60 years old) were excluded in these trials. In this study, we investigate the effect of PFO treatment in older adults with PFO related cryptogenic embolism. Methods: We prospectively enrolled 209 patients older than 60 years of age, with cryptogenic stroke or TIA attributed to PFO from MGH Cardio-Neurology Clinic. Extensive cryptogenic stroke workup included MRI/A, echo, and MCOT. Primary end point was a composite of recurrent ischemic stroke, TIA. Results: Of the 209 PFO stroke patients, 66 patients underwent PFO closure and 143 patients received medical therapy ( Table 1 ). The mean duration of follow-up was 49 months in the closure group and 45 months in the medical-therapy group. The primary end point occurred in 4 patients (6.1%) in the closure group and in 27(18.9%) in the medical therapy group (HR for medical therapy vs. closure, 3.763; 95% CI, 1.306 to 10.840; P = 0.014) ( Figure 1 ). The respective rates were 1.5% vs 4.9% for TIA (P = 0.426) and 4.5% vs 14.0% for stroke (P = 0.043). Conclusions: Older patients with PFO related cryptogenic embolism may also derive more benefits from PFO closure compared to medical treatment.

Long-Term Follow-Up After Closure of Patent Foramen Ovale in Patients With Cryptogenic Embolism

BackgroundPatent foramen ovale (PFO) closure is the gold standard for treating patients with cryptogenic stroke and PFO. However, scarce data exist on the long-term outcomes following PFO closure. ObjectivesThe purpose of this study was to determine the long-term (>10 years) clinical outcomes (death, ischemic, hemorrhagic events) following transcatheter PFO closure. MethodsWe included 201 consecutive patients (mean age: 47 ± 12 years, 51% women) who underwent PFO closure due to a cryptogenic embolism (stroke: 76%, transient ischemic attack [TIA]: 32%, systemic embolism: 1%). Echocardiographic examinations were performed at 1- to 6-month follow-up. Ischemic and bleeding events and antithrombotic medication were collected at a median follow-up of 12 years (range 10 to 17 years), and follow-up was complete in 96% of the patients. ResultsThe PFO closure device was successfully implanted in all cases, and residual shunt was observed in 3.3% of patients at follow-up echocardiography. A total of 13 patients died at follow-up (all from noncardiovascular causes), and nondisabling stroke and TIA occurred in 2 and 6 patients, respectively (0.08 strokes per 100 patient-years; 0.26 TIAs per 100 patient-years). A history of thrombophilia (present in 15% of patients) tended to associate with a higher rate of ischemic events at follow-up (p = 0.067). Bleeding events occurred in 13 patients and were major (intracranial bleeding) in 4 patients (all of them under aspirin therapy at the time of the event). A total of 42 patients stopped the antithrombotic treatment at a median of 6 months (interquartile range 6 to 14 months) post-PFO closure, and none of them had any ischemic or bleeding episode after a mean of 10 ± 4 years following treatment cessation. ConclusionsPFO closure was associated with a low rate of ischemic events (stroke, 1%) at >10 years of follow-up. Major bleeding events occurred in 2% of the patients (all of them in patients on antiplatelet therapy). One-fifth of patients stopped the antithrombotic therapy during the follow-up period (the majority within the first-year post-PFO closure), and this was not associated with any increase in ischemic events at long-term follow-up.

Patent foramen ovale closure versus medical therapy for prevention of recurrent cryptogenic embolism: updated meta-analysis of randomized clinical trials.

We performed an updated meta-analysis of all randomized-controlled trials (RCTs) comparing patent foramen ovale (PFO) closure with medical therapy for prevention of recurrent ischemic stroke. We searched Medline, EMBASE, and Cochrane databases, and proceedings of international meetings for RCTs of patients with cryptogenic stroke and PFO comparing percutaneous PFO closure versus medical therapy for prevention of recurrent ischemic stroke. The primary outcome was a composite ischemic/embolic endpoint comprising stroke, transient ischemic attack (TIA), peripheral embolism, and early death in the intention-to-treat population. Secondary outcomes were all-cause death, stroke, TIA, atrial fibrillation (AF), and major bleeding. Of 3440 enrolled patients across five RCTs, 1829 were allocated to PFO closure and 1611 to medical therapy. The follow-up ranged from 2 to 5.9years. PFO closure reduced the risk of the composite outcome [HR 0.52, (0.36-0.77); p < 0.01], and stroke, [HR 0.39, (0.19-0.83); p < 0.01], and increased the risk of AF [OR 3.75, (2.44-5.78); p < 0.01] as compared to medical therapy. NNT for stroke was 37 and NNH for AF 49, indicating a net clinical benefit of PFO closure. The meta-analysis had 95% power to detect a 50% relative risk reduction (RRR) in the primary outcome and 89% power to detect a 70% RRR in ischemic stroke. The risk of all-cause death (HR 1.08, p = 0.90), TIA [HR 0.73, (0.49-1.09); p = 0.12], and major bleeding [OR 0.97, (0.44-2.17); p = 0.95] was comparable between the groups. Among patients with cryptogenic stroke and PFO, percutaneous closure of PFO is superior to medical therapy in preventing recurrent ischemic/embolic events and stroke but is associated with an increased risk of AF.