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Abstract: 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.

Abstract: Background: An admission blood pressure over 185/110 mm Hg is associated with increased risk of recombinant tissue plasminogen activator (r-tPA)-related hemorrhagic transformation (HT). Stroke guidelines recommend blood pressure (BP) above 185/110 mm Hg be lowered before r-tPA treatment. How high blood pressure increases blood brain barrier disruption and risk of HT remains poorly understood. We evaluated peripheral leukocyte activation in stroke patients in relation to elevated admission blood pressure and potential contribution to blood brain barrier disruption. To study whether differences in immune response between patients in both groups existed past admission, we also analyzed differential gene expression for these groups at 5 hours and 24 hours after stroke onset. Methods: Blood samples from acute ischemic stroke patients were collected within 3 hours (prior to treatment with thrombolytic), 5 hours and 24 hours of stroke onset. Patients were grouped by admission BP above 185/110 mm Hg (n=19) and BP below 185/110 mm Hg (n=47). Total blood RNA was assessed by whole genome microarray and differential gene expression for admission, 5 hour and 24-hour time points was analyzed by ANCOVA. Functional analysis of identified genes was performed. Correlation analysis was conducted to identify genes associated with systolic blood pressure (SBP). Results: Strokes with admission BP above 185/110 mm Hg had 226 genes differentially expressed at admission (within 3 hours of stroke onset) as compared to strokes with BP below 185/110 mm Hg (p < 0.05, fold change ≥ |1.2|). In the higher BP group, SBP remained significantly elevated at 5-hours (p < 0.05) and non-significantly elevated at 24 hours, whereas in the lower BP group, SBP stabilized at 5 hours. Therefore, we also evaluated differential gene expression between the higher and lower BP group at 5 hours and 24 hours post-stroke. At 5 hours, 923 genes were differentially expressed between the higher and lower BP groups and at 24 hours, 422 genes were differentially expressed by admission blood pressure (p < 0.05, fold change ≥ |1.2|). Key genes associated with BP above 185/110 mm Hg included EDN3 (Endothelin-3), MMP21 (Matrix metallopeptidase 21), MMP-25 (matrix metallopeptidase 25), MMP-28 (matrix metallopeptidase 28), TLR4 (toll-like receptor 4), AREG (amphiregulin), CAV-1 (caveolin 1) and CCR2 (Chemokine receptor 2). Key pathways were associated with adaptive immunity, IL-17 and TH17 signalling, TLR signalling and nitric oxide signalling. 99 genes linearly correlated with systolic blood pressure including CCR2 (r = -0.32, P = 0.0009), and AREG (r = 0.286, P = 0.024,) (r > |0.2|, p < 0.05). Conclusions: A blood pressure greater than 185/110 mm Hg is associated with differential immune activation in patients with acute ischemic stroke which persists for at least the first 24 hours after stroke. These differences may contribute to blood brain barrier disruption and risk of HT in acute stroke patients with very high admission blood pressure. Whether modulating immune activation could reduce blood brain barrier disruption and risk of HT requires further study.

Previous animal experiments have indicated that administration of fluoxetine and simvastatin at 20-26 hours post-stroke decreases the volume of ischemic infarcts. This experiment expanded on previous experiments by adding ascorbic acid to the post-stroke regimen, initiating simvastatin pre-stroke, and adding a third initiation time frame (48-54 hours). Male retired breeder Sprague-Dawley rats were on simvastatin for 7 days prior to stroke induction. Combined medications of 5 milligrams/kilogram of fluoxetine, 1 milligram/kilogram of simvastatin and 20 milligrams/kilogram of ascorbic acid were orally administered at 6-12 hours, 20-26 hours, or 48-54 hours, respectively, following stroke induction. Adult rats that were treated 20-26 hours post-stroke showed a decrease in infarct volume (15.67 ± 5.622 millimeters cubed, P=0.0098) compared to the control. The combination of simvastatin, fluoxetine and ascorbic acid decreased the relative risk (RR=0.3704 (95% confidence interval 0.0987 to 1.3905, p-value = 0.1411) of bleeding after ischemic stroke if initiated 20-26 hours after stroke induction in rats.