Timing of anticoagulation after acute ischemic stroke in patients with atrial fibrillation

  • Author / Creator
    Alrohimi, Anas M
  • Patients with atrial fibrillation (AF) and ischemic stroke are at high risk for stroke recurrence. Early anticoagulation may reduce the risk of recurrent events but is usually avoided due to the risk of hemorrhagic transformation (HT). The risk of HT is based on historical data from an older generation of anticoagulants. Recently, four direct oral anticoagulants (DOACs) have demonstrated a lower risk of intracranial hemorrhagic complications compared to older anticoagulants. However, in the pivotal phase III DOAC trials, AF patients were excluded within 7-30 days of an acute ischemic stroke (or up to 6 months for severe/disabling strokes). In patients with AF-related ischemic stroke, we aimed 1) To assess the safety of early DOAC initiation, 2) To identify clinical, imaging and RNA transcript predictors of HT, and 3) To determine the current practices on the timing of DOAC initiation.
    Chapter 1 reviews the risk of recurrent ischemic stroke and HT in patients with AF, pathophysiology, classification, predictors, natural history and outcomes of HT, and discusses the studies of early anticoagulation after AF-related ischemic stroke.
    Chapter 2 is a prospective study of patients with AF treated with dabigatran within 14 days of transient ischemic attack (TIA)/ minor ischemic stroke. Our results demonstrated that early dabigatran treatment did not precipitate symptomatic HT after minor stroke, and recurrent ischemic stroke as an outcome may be more common and important than HT.
    Chapter 3 is a prospective study of patients with AF treated with apixaban within 14 days of TIA/ ischemic stroke regardless of the size and severity. We found that early apixaban treatment did not precipitate symptomatic HT after stroke. All HT identified on neuroimaging were asymptomatic. Recurrent ischemic events were clinically symptomatic.
    Chapter 4 is a design for a randomized controlled trial (RCT) with an associated registry, which has actually begun at University of Alberta Hospital. A sample size of 150 patients with AF-related ischemic stroke is planned to be randomized 2:1 within five days of symptom onset to early (≤5 days, n=100) or delayed (6-14 days, n=50) edoxaban initiation. By conducting this RCT, we aimed to demonstrate the safety of edoxaban initiation within five days of AF-related stroke, and establish clinical, imaging and RNA transcript predictors of HT.
    Chapter 5 is an international electronic survey with practice-related demographic and clinical questions related to the timing of DOAC initiation. Our results showed that decisions related to the timing of DOAC initiation varied globally and the variability in clinical practice will continue until RCTs are completed.
    Chapter 6 is a pooled analysis of six studies of DOAC initiation within 14 days of ischemic stroke. Our analysis revealed that DOAC initiation within 48 hours after ischemic stroke was not associated with increased incident HT risk and that recurrent ischemic events were common and associated with poor outcomes.
    Chapter 7 is an interim analysis of the RCT that is described in chapter 4. We demonstrated that initiating edoxaban within five days of ischemic stroke onset was not associated with an increased risk of symptomatic or incident radiographic HT.
    By using clinical and systematic brain imaging data at baseline and following DOAC initiation, this thesis demonstrates that early DOAC initiation after ischemic stroke is not associated with an increased risk of HT. Baseline asymptomatic HT is associated with larger infarct volumes, and DOAC initiation does not appear to increase the risk of symptomatic HT. Incident radiographic HT on follow-up imaging could represent the natural history in the evolution of the infarct and does not appear to independently influence the functional outcomes. This may suggest that incident radiographic HT may be a useful objective performance criterion if systematic serial post-randomization imaging is included in the design. Finally, this thesis reveals that recurrent ischemic events are common, clinically symptomatic, and appear to affect functional outcomes. This observation suggests that recurrent ischemic stroke will be the more common clinical outcomes of interest in the RCTs; however, risk of symptomatic HT remains an important consideration as even a slight increase in frequency may outweigh any benefits of early anticoagulation. This thesis supports the need for further trials of DOAC timing after AF-related stroke, and our data might be useful for designing and calculating sample size requirements for future trials.

  • Subjects / Keywords
  • Graduation date
    Spring 2023
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.