Study Design, Setting, and Population: This was a retrospective, observational single-site cohort study conducted at Northwestern Memorial Hospital. Patients were included if they were ≥18 years old, admitted to Northwestern Memorial Hospital between January 1, 2022 to December 31, 2022, had a diagnosis of AIS not secondary to AF during their admission, and had an indication for therapeutic anticoagulation other than AF. Patients were excluded if they met any of the following exclusion criteria: 1) Anticoagulation not initiated within 14 days of AIS, 2) Presence of a ventricular assist device, 3) Receipt of decompressive craniotomy during the admission, 4) AIS etiology warranting immediate anticoagulation (e.g. vertebral artery dissection), 5) Decision to transition to hospice or comfort-focused care during the admission, or 6) Pregnancy, incarceration, or enrollment in a clinical trial during the study time period.
This study was approved by the Northwestern University Institutional Review Board and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.
Data Collection: A preliminary informatics report identified patients admitted within the defined time frame who met initial inclusion criteria; patients were then manually screened for exclusion criteria. For patients who met full inclusion criteria, data for baseline characteristics and primary and secondary outcomes were manually collected via chart review. Data were stored in a Research Electronic Data Capture database.
Outcomes and Clinical Definitions: Patients were counted within the early anticoagulation cohort if therapeutic anticoagulation was initiated within ≤4 days of the index ischemic stroke and the late cohort if initiated within 5-14 days, extrapolated from previously reported thresholds in the AF-related AIS literature and guidelines [2,7,8]. The primary outcome was a composite of major bleeding events while on therapeutic anticoagulation, defined as ICH or major extracranial bleeding within 30 days of the index event. The main secondary outcome was a composite of major bleeding events while on therapeutic anticoagulation, recurrent AIS, systemic embolism, and all-cause mortality within 30 days of the index event. Other outcomes, assessed at 30 days of the index event unless otherwise indicated, included individual components of the composite outcomes and time to occurrence for each initial event, clinically relevant non-major bleeding while on therapeutic anticoagulation and time to first non-major bleeding event, and modified Rankin Scale (mRS) at discharge, when available.
Diagnosis of index AIS was determined based on chart review of neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]) documented within the electronic health record (EHR), with the date of the first image confirming AIS counted as the date of AIS onset. AIS etiologies were determined by review of clinical documentation; two reviewers independently assigned a correlating Trial of Org 10172 in Acute Stroke Treatment (TOAST) category, with discrepancies resolved via a third reviewer [10]. Recurrent AIS was defined as new acute infarcts or worsening infarct burden confirmed on neuroimaging, occurring >24 hours after the index AIS. Systemic embolism was defined as acute vascular occlusion of any extremity or organ confirmed by imaging.
ICHs, including hemorrhagic transformation of the index stroke, were counted toward the outcome if they were defined on neuroimaging and occurred while on therapeutic anticoagulation as defined below. For patients who experienced hemorrhagic transformation prior to receiving anticoagulation, ICHs were only counted towards the outcome if neuroimaging confirmed a new or expanding ICH after initiation of anticoagulation. Major extracranial bleeding was defined per International Society for Thrombosis and Hemostasis (ISTH) criteria: Fatal bleeding; and/or symptomatic bleeding in a critical area or organ; and/or bleeding causing a fall in hemoglobin levels of >/=1.24 mmol/L or leading to a transfusion of >/=2 units of whole blood or red cells) [11]. Clinically relevant non-major bleeding was also defined per ISTH criteria: Hemorrhage that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria: 1) requiring medical intervention by a healthcare professional, 2) leading to hospitalization or increased level of care, or 3) prompting a face-to-face evaluation) [11]. Patients were considered to be on therapeutic anticoagulation after at least 1 dose of therapeutic enoxaparin or a direct-acting oral anticoagulant (DOAC), after international normalized ratio (INR) was within therapeutic range for warfarin, or after activated partial thromboplastin time (aPTT) or anti-factor Xa (anti-Xa) was within therapeutic range for heparin infusion.
The mRS score at discharge was determined by review of discharge summaries within the EHR. Only documented mRS scores, when available, were counted toward the outcome; no mRS scores were retrospectively calculated by the members of this study.
Stroke Characterization on Neuroimaging: A neurologist reviewed initial neuroimaging of the index AIS to determine infarct volume and supratentorial versus infratentorial involvement. If both CT and MRI imaging were available, MRI imaging was utilized. If multiple MRIs were available, the first post-AIS MRI was utilized. Infarct volumes <1 mL were not quantitatively assessed, but infarct volumes ≥1 mL were measured with the ellipsoid formula ABC/2. This formula was used to calculate the largest infarct volume visualized on imaging. Slices of the lesion with a volume greater than 75% were multiplied by 1. For slices with a lesion volume between 25% and 75%, the slice thickness was multiplied by 0.5. Slices with volume less than 25% of the largest lesion volume were not counted in the z axis [12].
Statistical Analysis: Data were summarized using means and standard deviations for parametric continuous data, medians and interquartile ranges (IQRs) for ordinal or non-parametric continuous data, and frequencies and percentages for nominal data. Baseline characteristics and outcomes were compared between cohorts using the student T-test for parametric continuous data, the Mann-Whitney U test for non-parametric continuous data or ordinal data, and Chi-square or Fisher’s exact tests for categorical data. p values ≤ 0.05 were considered statistically significant. All analyses were performed using SPSS version 29.0 software.