EMBOLIC STROKE OF UNDETERMINED SOURCE (ESUS): A FOLLOW-UP ANALYSIS IN 86 PATIENTS

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=<0.001), less likely to have hypertension (p<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 <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.

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Detection of atrial fibrillation in patients with embolic stroke of undetermined source by prolonged monitoring with implantable loop recorders

Thrombosis and Haemostasis ◽

10.1160/th17-02-0072 ◽

2017 ◽

Vol 117 (10) ◽

pp. 1962-1969 ◽

Cited By ~ 38

Author(s):

Carsten Israel ◽

Alkisti Kitsiou ◽

Malik Kalyani ◽

Sameera Deelawar ◽

Lucy Ekosso Ejangue ◽

...

Keyword(s):

Atrial Fibrillation ◽

Magnetic Resonance Tomography ◽

Embolic Stroke ◽

Secondary Stroke Prevention ◽

Detection Algorithms ◽

Therapeutic Consequences ◽

Cerebral Microangiopathy ◽

Implantable Loop Recorders ◽

Work Up

SummaryRecently, the clinical entity embolic stroke of undetermined source (ESUS) has been defined for patients with ischemic strokes, where neither a cardioembolic nor a non-cardiac source can be detected. These patients may suffer from asymptomatic atrial fibrillation (AF), terminating spontaneously and thus eluding detection. Implantable loop recorders (ILR) with automatic AF detection algorithms can detect short-lasting, subclinical AF. The aim of this study was to prospectively assess and predict AF detection in patients with ESUS using ILR with daily remote interrogation. Patients with acute ESUS received an ILR, were seen every 6 months and additionally interrogated their ILR daily using remote monitoring. The incidence of AF detection was assessed and parameters which might predict AF detection (clinical and from magnetic resonance tomography) were analysed. ILR implantation was performed in 123 patients on average 20 days after stroke. During a mean follow-up of 12.7±5.5 months, AF was documented and manually confirmed in 29 of 123 patients (23.6%). First AF detection occurred on average after 3.6±3.4 months of monitoring. Patients with AF were on average older, had a higher CHA2DS2-VASc score and more often cerebral microangiopathy. In conclusion, AF can be documented in approximately 25% of patients with the diagnosis of ESUS after careful work-up within a year of monitoring by an ILR and daily remote interrogation. This had important therapeutic consequences (initiation of anticoagulation for secondary stroke prevention) in these patients.

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122 Are We Effective Prescribers? A Retrospective Audit of DOAC Prescribing Post Embolic Stroke for Non Valvular Atrial Fibrillation

Age and Ageing ◽

10.1093/ageing/afz103.70 ◽

2019 ◽

Vol 48 (Supplement_3) ◽

pp. iii17-iii65

Author(s):

Karen Dennehy ◽

Joseph Morris ◽

Diarmaid Hughes ◽

Kate Donlon ◽

Thomas Walsh

Keyword(s):

Atrial Fibrillation ◽

Renal Function ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Embolic Stroke ◽

Haemorrhagic Transformation ◽

Retrospective Audit ◽

Online Laboratory ◽

Number Of Patients

Abstract Background Direct oral anticoagulants (DOAC) are indicated for stroke prophylaxis in non-valvular atrial fibrillation, which is responsible for up to 20% of all ischaemic strokes(1). We performed a retrospective audit of all consecutive stroke patients in an Irish teaching hospital over a 1-year period to investigate the rate of incorrect dosing and any risk factors for this occurring. Methods We assessed our hospital stroke database from January to December 2017. Our research focused on DOAC prescribing in non valvular atrial fibrillation post embolic stroke. We collected data on baseline characteristics, choice of anticoagulation, dosing, and assessment of renal function, with follow up renal function if available. We reviewed electronic discharge summaries, online laboratory systems and completed a chart review. Results There was a total of 116 people with atrial fibrillation who developed an embolic stroke in our centre, of which 68 were eligible for anticoagulation using a DOAC (59). The main reasons for omission were CKD and haemorrhagic transformation. Patients were discharged on either Apixaban (32 patients), Rivaroxoban (32 patients), or Dabigatran (4 patients). Following our review, we established that 54/68 (79%) of patients were correctly anticoagulated. Over 20% of patients were incorrectly dosed and there was a clear tendency to under-dose 13/14 (93%). There were significant differences between the correct and incorrect dosing groups, with the latter group of patients being older and more at risk of polypharmacy. Renal function did not differ significantly between the groups at discharge or follow up and none of the incorrectly dosed patients were on a concurrent anti platelet. Conclusion A significant number of patients prescribed DOAC in hospital were not appropriately anticoagulated (21%), a majority of which were under-dosed. The patients who were under-dosed were older and more likely to be on 5 or more medications.

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Embolic stroke of undetermined source: a retrospective analysis from an Italian Stroke Unit

Italian Journal of Medicine ◽

10.4081/itjm.2016.690 ◽

2016 ◽

Vol 10 (3) ◽

pp. 202 ◽

Cited By ~ 1

Author(s):

Marco Masina ◽

Annalena Cicognani ◽

Carla Lofiego ◽

Simona Malservisi ◽

Riccardo Parlangeli ◽

...

Keyword(s):

Stroke Unit ◽

Cerebral Arteries ◽

Real Life ◽

Antiplatelet Agents ◽

Embolic Stroke ◽

Recurrence Rates ◽

Stroke Type ◽

Mean Time ◽

Real Life Condition

The new clinical construct of embolic stroke of undetermined source (ESUS) suggests that many cryptogenic strokes are related to minor-risk covert embolic cardiac sources or to embolus from non-occlusive plaques in the aortic arch or in the cerebral arteries. The authors analyzed the prevalence of ESUS in a real-life condition in Italy and compared the recurrence rates in cryptogenic strokes, cardioembolic strokes, and ESUS. The authors retrospectively reassessed according to ESUS criteria 391 consecutive admissions in a stroke unit where extensive diagnostic search was routinely performed. Recurrences in each stroke type within a 3-year follow-up period (mean time: 25.44 months - standard deviation: 9.42) were also compared. The prevalence of ESUS in the aforementioned cohort was 10.5%. All ESUS patients received antiplatelet agents. Warfarin was prescribed in 56.9% of cardioembolic strokes. The recurrence rate in ESUS patients was 4.4% per year, slightly higher than in cardioembolic strokes (3.5%) and significantly higher than in cryptogenic non-ESUS (1.2%) (P<0.0001). This is the first description of a cohort of ESUS patients in an Italian stroke unit. Patients with ESUS have a significantly higher risk of recurrence than in those with non-ESUS cryptogenic strokes, and slightly higher than in those with cardioembolic strokes. Results support the hypothesis of a more extensive diagnostic evaluation in cryptogenic strokes and the feasibility of such approach.

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Apixaban for treatment of embolic stroke of undetermined source (ATTICUS) randomized trial – update of patient characteristics and study timeline after interim analysis

European Heart Journal ◽

10.1093/eurheartj/ehab724.2070 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

S Poli ◽

C Meissner ◽

H J Baezner ◽

A Kraft ◽

F Hillenbrand ◽

...

Keyword(s):

Ischemic Stroke ◽

Secondary Prevention ◽

Embolic Stroke ◽

High Rate ◽

Cardiac Monitoring ◽

Severe Bleeding ◽

Current Standard ◽

Private Company ◽

The Impact

Abstract Background Secondary prevention after embolic stroke of undetermined source (ESUS) has not yet been established. ESUS is associated with high risk of recurrent ischemic stroke and clinically silent ischemic lesions. Secondary prevention with aspirin is the current standard therapy in ESUS patients, despite high prevalence of occult atrial fibrillation (AF). Purpose To determine whether the direct oral factor Xa inhibitor apixaban, started within 28 days after index stroke, is superior to aspirin in preventing new ischemic lesions in subjects with remote cardiac monitoring. Primary endpoint was detection of new ischemic lesions in flair and diffusion-weighted (DWI) MR imaging at 12 months follow-up. Methods The study enrolled ESUS patients with risk profile for cardiac thromboembolism (i.e., left atrium (LA) size >45 mm, spontaneous echo contrast in LA appendage, LA appendage flow velocity ≤0.2 cm/s, atrial high rate episodes, CHA2DS2-Vasc score ≥4, patent foramen ovale). Patients were randomized 1:1 into the aspirin and apixaban arms. Study drug was initiated within 3–28 days after minor/moderate stroke and 14–28 days after major stroke. MRI (Flair/DWI) was conducted within 7 days of AF detection by remote cardiac monitors and at 12 months. ClinicalTrials.gov Identifier: NCT02427126. Funding: The trial is supported by BMS-Pfizer Alliance. Results Enrollment was stopped after interims analysis (including 200 patients) due to futility. Overall, 373 patients were screened with 353 being enrolled (178 and 175 in apixaban and ASA arms, respectively). So far, 130 (73.0%) and 120 (68.6%) subjects from apixaban and ASA arms, respectively, completed the study. 2% death, 1.7% withdrawal, and 1.7% were lost to follow-up. 3.9% did not completed the study for other reasons. Mean age of the ATTICUS population was 68.5 years with 51% males. 80% of the subjects suffered from hypertension. Mean systolic blood pressure at enrollment was 132 mmHg, BMI was 27.7, and CHA2DS-VASc-Score was 4.9. So far, adverse events (AE) occurred in 63% of the subjects, 30% was documented as severe. 6.8% cases of recurrent ischemic stroke and no case of hemorrhagic stroke were reported. Only 1 case of severe bleeding was reported in the aspirin arm. Newly detected AF was reported in 80 patients (23%), 42 occurring in the aspirin arm. As required by protocol, latter were immediately switched from aspirin to apixaban. Due to ongoing data clearing, numbers and % will change until presentation. Conclusions In contrast to the recently published NAVIGATE and RESPECT ESUS trials, patients enrolled in ATTICUS need to exhibit additional AF predicting factors. Furthermore, mandatory cardiac remote monitoring will help to elucidate the impact of AF and the effects of early oral anticoagulation with apixaban compared to antiplatelet therapy with aspirin on the incidence of new ischemic lesions after ESUS. Preliminary data will be presented and discussed in the context of current literature. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): The trial is supported by BMS-Pfizer Alliance.

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P5350Atrial fibrillation prediction using P wave signal-averaged ECG in patients with embolic stroke of undetermined source

European Heart Journal ◽

10.1093/eurheartj/ehz746.0317 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Shin ◽

M Jung ◽

J Song ◽

J Kim ◽

K Park ◽

...

Keyword(s):

Atrial Fibrillation ◽

Odds Ratio ◽

Unknown Origin ◽

Embolic Stroke ◽

P Wave ◽

Stroke Recurrence ◽

Wave Duration ◽

P Wave Duration ◽

Potential Association

Abstract Background Approximately 10–25% of ischemic strokes are of unknown origin. Determining their potential association with subclinical atrial fibrillation (SCAF) is important for proper secondary prevention. We investigated whether SCAF can be predicted by assessing the atrial substrate with signal-averaged electrocardiography (SAECG). Methods Between April 2015 and February 2018, we recruited 125 consecutive patients with embolic stroke of undetermined source (ESUS) and 125 patients with paroxysmal atrial fibrillation (AF) patients as control. All participants underwent P wave SAECG at baseline and ESUS patients were followed up with ECG and Holter ECG, at baseline, 3, 6, and 12 months after discharge, and every 12 months thereafter. Results In the ESUS group (69 males, 68.4±12.1 years), 32 (25.6%) patients were diagnosed with SCAF during follow-up. There were no significant differences between both groups in terms of P wave duration [PWD] (ESUS vs. AF, P=0.321). PWD demonstrated a significant predictive efficacy for SCAF detection during follow-up (C-index of standard PWD=0.657, 95% confidence interval (CI) 0.552–0.761, P=0.008). Stroke recurrence occurred in 22 patients (17.6%) and was significantly associated with PWD but not SCAF (odds ratio 2.756, 95% CI 1.061–7.161, P=0.037). Conclusion PWD, an ECG biomarker associated with atrial substrate directly contributes to AF and ESUS, is useful for predicting SCAF. The potential for using this simple ECG biomarker for screening for SCAF amongst ESUS patients merits further exploration.

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P4139Prediction of atrial fibrillation in embolic stroke of unknown source

European Heart Journal ◽

10.1093/eurheartj/ehz745.0711 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

F T Range ◽

D P Peters ◽

T Zeus ◽

S Jander ◽

P Mueller ◽

...

Keyword(s):

Atrial Fibrillation ◽

Real Life ◽

Patient Characteristics ◽

Embolic Stroke ◽

Baseline Heart Rate ◽

Loop Recorder ◽

Chads2 Score ◽

Unknown Source ◽

Significant Difference

Abstract Background Atrial fibrillation (AF) is one of the leading cardiogenic causes for embolic stroke of unknown source (ESUS). Its incidence is growing with patients' age. Detection and rule out of AF is complex and cumbersome. The best method is an implantable loop recorder (ILR). In patients elder than 60 years, incidence of AF is reported incongruently and reliable patient characteristics that can predict a low or high risk for AF are scarce. Purpose This study reports real life incidences of AF in a group of patients undergoing ILR after ESUS. It aims to depict age dependency of AF and to identify potential confounding factors. Methods In a single center study, we analysed 111 patients (age=62±13 years, nmale=65) who received an ILR in our centre following ESUS. Patient characteristics, brain imaging, hemodynamic monitoring, blood pressure, electrocardiography, holter ecg and echocardiography data from the initial hospital stay and ILR follow-up over a mean of 460 days were analysed. Primary endpoint was the recording of AF during follow-up. Results AF was detected in 23% of all patients. Patients with AF were significantly elder than those without AF (p=0.01). Incidence of AF was in Patients <60y: 14%, 60–69y: 13%, 70–79y: 45%, >80y: 67%. We observed a significant difference in AF incidence comparing patients younger and elder than 70 years (p=0.034). Both, CHADS-Vasc (p=0.036) and HATCH-scores (p=0.018) were higher in the AF group while the simple CHADS2 Score missed significance (p=0.068). PQ duration was longer in AF patients (p=0.022) and baseline heart rate at admission was lower (p=0.027). NIHSS scores were lower in the AF group at admission (2.97 vs. 4.10; p=0.049) but due to less neurological improvement in the AF group, this difference faded until dismission (1.09 vs 1.79 p=ns). Conclusions In our real life ILR group following ESUS, strongest predictor of AF was age. Pivot point rather was at 70 than at 60 years of age.

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Abstract 14899: Personalized Computational Modeling Identifies Embolic Stroke of Undetermined Source Patients With Potential Arrhythmic Substrate

Circulation ◽

10.1161/circ.142.suppl_3.14899 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Savannah Bifulco ◽

Griffin D Scott ◽

Sakher Sarairah ◽

Zeinab Birjandian ◽

Caroline Roney ◽

...

Keyword(s):

Computational Modeling ◽

Left Atrial ◽

Computational Models ◽

Embolic Stroke ◽

Potential Explanation ◽

Significant Difference ◽

Mri Scans ◽

Modeling Study

Introduction: Late-gadolinium enhanced (LGE)-MRI has revealed atrial fibrotic remodeling in embolic stroke of undetermined source (ESUS) patients. Curiously, fibrosis levels in ESUS patients are the same as those observed in AF. A potential explanation is that ESUS patients have pre-clinical arrhythmic substrate, but lack the triggers needed to initiate AF. Hypothesis: Simulations in computational models reconstructed from LGE-MRI scans can determine if the fibrotic substrate of a particular ESUS patient has the capacity to sustain reentry. Methods: ESUS (per standard criteria) was verified by a neurologist. 45 ablation-naïve AF patients and 45 ESUS patients within three months of stroke underwent LGE-MRI for fibrosis assessment. Left atrial (LA) models were built from LGE-MRI scans. Fiber orientations were mapped into each LA model using universal atrial coordinates. Burst pacing from 15 sites was used to test inducibility of arrhythmia sustained by reentry (Fig A). Results: In 23/45 (51%) ESUS and 29/45 (64%) AF models, we observed sustained reentry. Fibrosis burden was significantly higher for patients in whom simulations suggested the existence of pre-clinical arrhythmic substrate; however, within the inducible and non-inducible sub-groups, there was no significant difference in fibrosis burden for ESUS vs. AF patients (Fig B). This suggests that the presence of pre-clinical substrate in ESUS is correlated with fibrosis burden, although exceptions to this supposition were not uncommon (i.e., inducible low-fibrosis and non-inducible high-fibrosis models; Fig C). Conclusions: In this modeling study, pro-arrhythmic properties of fibrosis in ESUS and AF are indistinguishable. This suggests that some ESUS patients have pre-clinical fibrotic substrate, but do not have AF due to a lack of suitable triggers. Ongoing clinical follow-up will test whether abundance of pre-clinical substrate is predictive of incident AF.

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