Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation
Condition: Ischemic Stroke; Transient Ischemic Attack
MeSH terms: Stroke; Ischemic Stroke; Cerebral Infarction; Ischemic Attack, Transient; Atrial Fibrillation; Ischemia
Intervention: Rivaroxaban; Warfarin
Intervention description: Rivaroxaban group receive oral rivaroxaban 10 mg once daily for 5 consecutive days, followed by 20 mg or 15 mg in patients with a calculated creatinine clearance of 30-49 ml/min.
The dosage of rivaroxaban is leveraged from results of ROCKET-AF trial, where 20 mg of rivaroxaban was shown to offer balanced efficacy and safety.; To harmonize the warfarin regimen across the sites, fixed algorithm was used in dose calculation, both loading and maintenance, and age, sex, ethnicity, race, weight, height, smoking history, presence of liver disease, indication, baseline INR, target INR and concomitant medication were considered as cofactors (http://www.warfarindosing.org/Source/InitialDose.aspx). Investigators will manage anticoagulation with warfarin per routine clinical care.
Intervention MeSH terms: Warfarin; Rivaroxaban
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 195.0
Sex: All
Minimum age: 19 Years
Healthy volunteers: No
Keywords: stroke; TIA

Summary:

      Rationale Acute ischemic stroke due to atrial fibrillation (AF) carries a high risk for early
      recurrence. In acute stage, guidelines recommend aspirin, but do not recommend
      anticoagulation due to the increased risk of intracranial bleeding. Since, aspirin has a
      limited efficacy of preventing recurrent stroke in AF, expert consensus suggests early
      anticoagulation in non-severe stroke with AF. The current practice for acute ischemic stroke
      patients with AF is delayed warfarin administration with aspirin use for non-minor stroke or
      immediate warfarin administration (sometimes with heparin bridging) for minor stroke.
      However, conventional anticoagulation with warfarin in acute ischemic stroke with AF has the
      following limitations: 1) risk of intracranial bleeding particularly in acute stage, 2)
      delayed action and transient paradoxical thrombogenic tendency due to the inhibition of
      protein C, resulting in the risk of early recurrent embolic stroke, and 3) prolongation of
      hospitalization waiting for full anticoagulation. In contrast, as compared to warfarin,
      rivaroxaban is advantageous for reduced risk of intracranial bleeding and immediate
      anticoagulation efficacy.

      Goal The current trial will examine whether early initiation (within 5 days from stroke
      onset) of rivaroxaban as compared to conventional warfarin would reduce intracranial
      bleeding, recurrent embolic stroke, and hospital stay in patients with acute ischemic stroke
      due to AF.
    

Eligibility criteria:

        Inclusion Criteria: All of below

          -  Acute ischemic stroke or TIA presumed to be cardioembolic origin (within 5 days from
             stroke onset) with mild severity: infarct size on DWI less than 1/3 of MCA territory,
             1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere

          -  Atrial fibrillation including paroxysmal atrial fibrillation: atrial fibrillation must
             be documented by ECG evidence (e.g., 12-lead ECG, rhythm strip, Holter, pacemaker
             interrogation) within 30 days before randomization. This could be obtained from a
             notation in the subject's record (e.g., medical chart, hospital discharge summary).

          -  Age ≥19 years

          -  Informed consent

        Exclusion Criteria: Any of below

          -  Chronic renal failure (GFR less than 30ml/min) or severe hepatic impairment

          -  Significant hemorrhagic transformation (parenchymal hematoma type I or II by the ECASS
             definition)

          -  Stroke mechanism of presumed small vessel occlusion: single small subcortical infarct
             in the perforating artery territory

          -  Large hemispheric or cerebellar infarction; larger than 1/3 of MCA territory, 1/2 of
             ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere

          -  Mechanical valve requiring warfarin therapy

          -  Active internal bleeding

          -  Prior history of symptomatic intracranial bleeding

             : patients with asymptomatic bleedings or microbleedings on MRI are eligible for
             inclusion

          -  Major surgery or major trauma within 30 days that might be associated with increased
             bleeding risk

          -  Clinically significant gastrointestinal bleeding within 6 months

          -  Intravenous tissue plasminogen activator use or mechanical embolectomy within 48 hours
             plus 'significant hemorrhagic transformation as described above (exclusion criteria
             2)' or 'large hemispheric infarction or cerebellar infarction as described above
             (exclusion criteria 4)'

             : patients achieving successful reperfusion without hemorrhage nor large infarction
             are eligible for enrollment

          -  Severe anemia: hemoglobin <10 g/dL

          -  Bleeding diathesis; thrombocytopenia (<90,000/µL, prolonged PT (INR>1.7)

          -  Sustained uncontrolled hypertension: SBP >180 mmHg or DBP >100 mmHg

          -  Severe devastating illness, such terminal cancer, hepatic failure; therefore, the
             participants have a life expectancy less than 6 months.

          -  Planned invasive procedure with potential for uncontrolled bleeding, including major
             surgery