Ischemic Stroke, Transient Ischemic Attack
Conditions
Keywords
stroke, TIA
Brief 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.
Detailed description
Primary endpoint: Composite of MRI-defined intracranial bleeding and recurrent ischemic lesion within 1 month after randomization (rivaroxaban vs conventional warfarin)
Interventions
DRUGRivaroxaban
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.
DRUGWarfarin
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.
Sponsors
Bayer
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
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 (
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging | 1 month after randomization | Intracranial bleeding: symptomatic hemorrhage confirmed by CT or MRI or asymptomatic hemorrhage on follow-up GRE or SWI imaging at 1 month Recurrent ischemic lesion: symptomatic ischemic stroke confirmed by relevant neuroimagings or asymptomatic recurrent ischemic lesion on follow-up or FLAIR imaging at 1 month |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients With Intracranial Bleeding | at 1 month | Intracranial bleeding confirmed by relevant neuroimagings |
| The Number of Patients With Recurrent Ischemic Lesion | at 1 month | Recurrent ischemic lesion confirmed by relevant neuroimagings |
| Length of Hospitalization | at 1month | Time to event will be calculated |
| Number of Participants With Modified Rankin Score of 0 or 1 at Week 4 | at 1 month | modified Rankin Score 0 : No symptoms at all 1. : No significant disability despite symptoms; able to carry out all usual duties and activities 2. : Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3. : Moderate disability; requiring some help, but able to walk without assistance 4. : Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5. : Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6. : Dead |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban Rivaroxaban group for 1 month : initial 5 days after randomization rivaroxaban 10mg QD will be administered. Rivaroxaban 20mg QD, but 15mg in case of Cr CL will be administered for remaining 25 days.
Rivaroxaban: 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. | 95 |
| Warfarin Patients allocated to warfarin receive warfarin plus aspirin 100mg until INR value exceed 1.7 followed by warfarin monotherapy with target INR value of 2.5 \[2.0 - 3.0\].
Warfarin: 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. | 88 |
| Total | 183 |
Baseline characteristics
| Characteristic | Total | Rivaroxaban | Warfarin |
|---|---|---|---|
| Age, Continuous | 70.4 years STANDARD_DEVIATION 10.4 | 70.2 years STANDARD_DEVIATION 10.1 | 70.6 years STANDARD_DEVIATION 10.9 |
| Body Mass Index | 24.0 kg/㎡ STANDARD_DEVIATION 3.2 | 24.4 kg/㎡ STANDARD_DEVIATION 3.3 | 23.6 kg/㎡ STANDARD_DEVIATION 3.1 |
| Gender Female | 76 Participants | 40 Participants | 36 Participants |
| Gender Male | 107 Participants | 55 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 98 | 51 / 90 |
| serious Total, serious adverse events | 6 / 98 | 5 / 90 |
Outcome results
Primary
Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging
Intracranial bleeding: symptomatic hemorrhage confirmed by CT or MRI or asymptomatic hemorrhage on follow-up GRE or SWI imaging at 1 month Recurrent ischemic lesion: symptomatic ischemic stroke confirmed by relevant neuroimagings or asymptomatic recurrent ischemic lesion on follow-up or FLAIR imaging at 1 month
Time frame: 1 month after randomization
Population: * modified Intention to treat: 95 / 88 (Rivaroxaban/Warfarin)~* Per protocol: 93 / 87 (Rivaroxaban/Warfarin)~* Safety: 98 / 90 (Rivaroxaban/Warfarin)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging | 47 Participants |
| Warfarin | Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging | 48 Participants |
Secondary
Length of Hospitalization
Time to event will be calculated
Time frame: at 1month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban | Length of Hospitalization | 4.6 days | Standard Deviation 3.9 |
| Warfarin | Length of Hospitalization | 5.6 days | Standard Deviation 4.3 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Number of Participants With Modified Rankin Score of 0 or 1 at Week 4
modified Rankin Score 0 : No symptoms at all 1. : No significant disability despite symptoms; able to carry out all usual duties and activities 2. : Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3. : Moderate disability; requiring some help, but able to walk without assistance 4. : Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5. : Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6. : Dead
Time frame: at 1 month
Population: Modified ITT (mRS 0,1 at Week 4, n(%)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Number of Participants With Modified Rankin Score of 0 or 1 at Week 4 | 79 participants |
| Warfarin | Number of Participants With Modified Rankin Score of 0 or 1 at Week 4 | 64 participants |
p-value: 0.3301Cochran-Mantel-Haenszel
Secondary
The Number of Patients With Intracranial Bleeding
Intracranial bleeding confirmed by relevant neuroimagings
Time frame: at 1 month
Population: Modified ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | The Number of Patients With Intracranial Bleeding | 30 Participants |
| Warfarin | The Number of Patients With Intracranial Bleeding | 25 Participants |
p-value: 0.6765Chi-squared
Secondary
The Number of Patients With Recurrent Ischemic Lesion
Recurrent ischemic lesion confirmed by relevant neuroimagings
Time frame: at 1 month
Population: Modified ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | The Number of Patients With Recurrent Ischemic Lesion | 28 Participants |
| Warfarin | The Number of Patients With Recurrent Ischemic Lesion | 31 Participants |
p-value: 0.3753Chi-squared