Early Apixaban Use Following Stroke in Patients With Atrial Fibrillation: Results of the AREST Trial.

BACKGROUND AND PURPOSE: It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals. METHODS: AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS (<1.5 cm), and day 7 to 9 for medium-sized AIS (≥1.5 cm, excluding full cortical territory), to warfarin, in a 1:1 ratio at 1 week post-TIA, or 2 weeks post-AIS. RESULTS: Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%, P=0.78), death (4.9% versus 8.5%, P=0.68), fatal strokes (2.4% versus 8.5%, P=0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%, P=0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm. CONCLUSIONS: Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials. Registration: URL: https://www.clinicaltrials.gov/; Unique identifier: NCT02283294.

Risk of hemorrhagic transformation with early use of direct oral anticoagulants after acute ischemic stroke: A pooled analysis of prospective studies and randomized trials.

INTRODUCTION: Precise risk of hemorrhagic transformation (HT) in acute ischemic stroke (AIS) remains unknown, leading to delays in anticoagulation initiation for secondary stroke prevention. We sought to assess the rate of HT associated with direct oral anticoagulant (DOAC) initiation within and beyond 48 h post-AIS. METHODS: A pooled analysis of DOAC initiation within 14 days of AIS or transient ischemic attack (TIA) was conducted with six studies (four prospective open label treatment, blinded outcome studies and two randomized trials; NCT02295826 and NCT02283294). The primary endpoint was incident radiographic HT on follow-up imaging (days 7-30). Secondary endpoints included symptomatic HT, new parenchymal hemorrhage, recurrent ischemic events, extracranial hemorrhage, study period mortality, and follow-up modified Rankin Scale score. The results were reported as odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI). RESULTS: We evaluated 509 patients; median infarct volume was 1.5 (0.1-7.8) ml, and median National Institutes of Health Stroke Scale was 2 (0-3). Incident radiographic HT was seen on follow-up scan in 34 (6.8%) patients. DOAC initiation within 48 h from index event was not associated with incident HT (adjusted OR 0.67, [0.30-1.50] P = 0.32). No patients developed symptomatic HT. Conversely, 31 (6.1%) patients developed recurrent ischemic events, 64% of which occurred within 14 days. Initiating a DOAC within 48 h of onset was associated with similar recurrent ischemic event rates compared with those in which treatment was delayed (HR: 0.42, [0.17-1.008] P = 0.052). In contrast to HT, recurrent ischemic events were associated with poor functional outcomes (OR = 6.8, [2.84-16.24], p < 0.001). CONCLUSIONS: In this pooled analysis, initiation of DOAC within 48 h post-stroke was not associated with increased incident risk of HT, and none developed symptomatic HT. The analysis was underpowered to determine the effect of early DOAC use upon recurrent ischemic events.

Web Browsing: High-Speed Diagnosis and Treatment of Carotid Artery Web.

Background: Although carotid artery web (CaW) was initially described in 1973 as a potential etiology of ischemic stroke, it still remains underrecognized. Because CaW is a membrane affixed perpendicularly from the carotid wall that projects out into the lumen above the bifurcation, it typically is not stenotic, and hence, utilizing only 1 vessel imaging modality during conventional stroke workup may instead lead to a diagnosis of ESUS: embolic stroke of undetermined source. The term ESUS was created in 2014 by researchers to define a subset of cryptogenic, nonlacunar (embolic-appearing) strokes without clear cardiac or vascular cause. Purpose: In this review, we describe how, after multiple evaluations of vessels, CaW was diagnosed in relatively young patients (age 39-47 years old, without significant vascular risk factors) in whom otherwise were considered embolic stroke of undetermined source. This observation dovetails with the accompanying Neurohospitalist article entitled, "Delayed Thrombus Formation on Carotid Web and Its Medical and Endovascular Management for Secondary Stroke Prevention." Research Design: Not applicable. Case review. Results/Conclusion: This report demonstrates the futility of antiplatelet therapy for a young patient with CaW-related stroke. Based on these collective experiences and review of the literature, we postulate that: (1) multiple vascular imaging modalities during stroke workup may result in a CaW diagnosis instead of ESUS; (2) young stroke patients without traditional vascular risk factors are candidates for this "web browsing" of extended imaging of vessels; and (3) carotid artery stenting (CAS) or carotid endarterectomy (CEA) may be preferred as first-line over medical therapy alone (ie, antiplatelet or anticoagulation) because CEA/CAS addresses the stroke etiology, CaW, definitively.

Middle Cerebral Artery Duplication: A Near Miss for Stroke Thrombectomy.

Middle cerebral artery (MCA) duplication is a rare anatomical arrangement where an anomalous MCA arises from the distal end of the internal carotid artery. If occluded, a duplicated MCA can present with significant deficits comparable to an occlusion of the M2 vessel without obvious findings on vessel imaging via computed tomography angiography (CTA) or magnetic resonance angiography. A female in her 30s with no past medical history presented with suspected acute stroke 8 hours after last known normal-featuring new-onset right-sided weakness, facial droop, and slurred speech, which corresponds to a National Institutes of Health Stroke Scale score of 13. Head CTA was interpreted as preserved patency of intracranial vessels. CT perfusion was suggestive of a large area of penumbra. Emergent cerebral angiography demonstrated MCA duplication on the left side with proximal occlusion of the M1 branch supplying the traditional M2 territory. Mechanical thrombectomy achieved grade TICI 2b reperfusion. Throughout her hospital stay, her aphasia started to resolve, and the patient was discharged to inpatient rehabilitation. This case presents a diagnostic challenge and learning point in identifying similar patients in the future. We suggest the clinician, given a high clinical suspicion for large vessel occlusion, even if CTA is negative, to continue with CT perfusion to not miss stroke in patients with MCA duplication. If CT perfusion shows substantial deficit in an MCA distribution, one must consider that the patient may have an MCA duplication.

Untreated Stroke as Collateral Damage of COVID-19: "Time Is Brain" Versus "Stay at Home".

For decades, neurologists have been advocating that anyone with acute focal deficits report immediately to the closest hospital's emergency room. Major advancements in the hyperacute diagnosis and treatment of stroke have justified our call-to-action slogan of "Time is Brain"-faster therapy leads to superior outcomes. However, this mantra has been recently usurped by the catchphrase "Stay at Home" during the coronavirus disease 2019 (COVID-19) pandemic. Fewer patients are presenting to hospitals with acute stroke; our census is down. Presumably the etiology of this phenomenon is either strict "social distancing" that some people may misperceive to exclude even emergent situations, or fears of contracting the virus while hospitalized. In this Short Report, we describe the year-over-year drop in stroke volume (ischemic and hemorrhagic both) coinciding with a paradoxical rise in acute reperfusion therapies at our university hospital. These data imply that stroke patients with mild/moderate symptoms are most likely staying home, and not receiving urgent therapies, and correspondingly, only the most severely disabled stroke patients are ultimately seeking and receiving help. We must remind our patients and the general public that our services are essential and available, as stroke still remains a medical emergency, and carries a likely higher overall mortality risk than COVID-19. As neurologists, we also must be vigilant for the atypical presentations and varied etiologies of stroke associated with COVID-19 as well.

A Case Report of Extensive Cerebral Venous Sinus Thrombosis as a Presenting Sign of Relapsing Nephrotic Syndrome.

Nephrotic syndrome is defined by three characteristic features including proteinuria of >3 g in 24 hours, hypoalbuminemia of less than 3 g/dL, and peripheral edema. Multiple nephropathies can result in nephrotic syndrome. Most commonly, minimal change disease is seen in children under the age of 10, while adults are more commonly found to have membranous nephropathy. Hypercoagulability and thrombotic sequela can be seen in nephrotic syndrome, regardless of underlying etiology, and thrombosis is most commonly seen in deep veins of the lower extremities and renal veins. Our case identifies an adult with previously diagnosed and treated for minimal change disease who presented with weight gain, peripheral edema, foamy urine, headache but no neurologic deficits. The patient was found to have near to complete occlusion of the entire superior sagittal sinus, near complete occlusion of the left transverse and sigmoid sinuses, and nonocclusive thrombus in the right sigmoid sinus. She was treated with heparin and IV steroids then transitioned to warfarin and PO steroids, respectively, with resolution of symptoms. This case report emphasizes on the importance of recognizing CVST as a potential complication of nephrotic syndrome at both initial presentation and relapse.

Predictors of Atrial Fibrillation in Patients With Cryptogenic Stroke.

BACKGROUND AND PURPOSE: Many patients diagnosed with cryptogenic stroke or transient ischemic attack are subsequently found to have atrial fibrillation (AF) on outpatient cardiac telemetry monitoring. Identification of predictive factors for the detection of AF could assist with patient selection to increase the yield of telemetry and hasten initiation of appropriate secondary stroke prevention. METHODS: This was a retrospective cross-sectional study of patients diagnosed with cryptogenic stroke at a comprehensive stroke center and referred for at least 21 days of prolonged outpatient telemetry. Telemetry reports and data from the patient's stroke hospitalization, including imaging studies, electrocardiogram (EKG), echocardiogram, vital signs, and laboratory data, were reviewed. RESULTS: Ten percent of the 121 patients included in the study were diagnosed with AF based on outpatient telemetry. There was a strong association between presence of premature atrial contractions (PACs) on admission EKG and subsequent detection of AF (P = .004). Large left atrial diameter on echocardiogram was correlated with AF detection in males (P = .024). However, there was no association between AF and other echocardiographic measurements. Thyroid-stimulating hormone (TSH) levels were significantly higher in patients with cryptogenic stroke having AF (P = .008), with a TSH greater than 4.20 mIU/L predictive of detection of AF (P < .001). CONCLUSIONS: Atrial fibrillation was found by outpatient monitoring in a notable percentage of patients with cryptogenic stroke. Predictors of occult AF in our study population included PACs and higher TSH levels. Although an association between low TSH and AF has been well established, our results suggest that high TSH may be a predictive factor as well.

Protocol for AREST: Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation-A Randomized Controlled Trial of Early Anticoagulation After Acute Ischemic Stroke in Atrial Fibrillation.

Background: Optimal timing to initiate anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF) is currently unknown. Compared to other stroke etiologies, AF typically provokes larger infarct volumes and greater concern of hemorrhagic transformation, so seminal randomized trials waited weeks to months to begin anticoagulation after initial stroke. Subsequent data are limited and non-randomized. Guidelines suggest anticoagulation initiation windows between 3 and 14 days post-stroke, with Class IIa recommendations, and level of evidence B in the USA and C in Europe. Aims: This open-label, parallel-group, multi-center, randomized controlled trial AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) is designed to evaluate the safety and efficacy of early anticoagulation, based on stroke size, secondary prevention of ischemic stroke, and risks of subsequent hemorrhagic transformation. Methods: Subjects are randomly assigned in a 1:1 ratio to receive early apixaban at day 0-3 for transient ischemic attack (TIA), 3-5 for small-sized AIS (<1.5 cm), and 7-9 for medium-sized AIS (1.5 cm or greater but less than a full cortical territory), or warfarin at 1 week post-TIA or 2 weeks post-stroke. Large AISs are excluded. Study Outcomes: Primary: recurrent ischemic stroke, TIA, and fatal stroke; secondary: intracranial hemorrhage (ICH); hemorrhagic transformation (HT) of ischemic stroke; cerebral microbleeds (CMBs); neurologic disability [e.g., modified Rankin Scores (mRS), National Institutes of Health Stroke Scale (NIHSS), Stroke Specific Quality of Life scale (SS-QOL)]; and cardiac biomarkers [e.g., AF burden, transthoracic echo (TTE)/transesophageal echo (TEE) abnormalities]. Sample Size Estimates: Enrollment goal was 120 for 80% power (two-sided type I error rate of 0.05) to detect an absolute risk reduction of 16.5% postulated to occur with apixaban in the primary composite outcome of fatal stroke/recurrent ischemic stroke/TIA within 180 days. Enrollment was suspended at 91 subjects in 2019 after a focused guideline update recommended direct oral anticoagulants (DOACs) over warfarin in AF, excepting valvular disease (Class I, level of evidence A). Discussion: AREST will offer randomized controlled trial data about timeliness and safety of anticoagulation in AIS patients with AF. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02283294.