A Phase 2 interventional study of Rivaroxaban and Warfarin in Ischemic Stroke and Transient Ischemic Attack, sponsored by Asan Medical Center. Completed at 1 site in Korea, Republic of. Open to participants aged 19 Years and older. Per ClinicalTrials.gov, last updated 2017-02-08.
Sponsored by Asan Medical Center · Phase 2, Interventional, and Treatment
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.
Primary endpoint: Composite of MRI-defined intracranial bleeding and recurrent ischemic lesion within 1 month after randomization (rivaroxaban vs conventional warfarin)
7,286 studies on the registry are indexed under Stroke; 2,007 are open to participants now.
This study's enrollment of 195 is above the median of 50 across 5,369 interventional studies indexed under Stroke.
Browse Stroke studies →Asan Medical Center is the lead sponsor of 562 studies on the registry; 71 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria: All of below
Exclusion Criteria: Any of below
Prior history of symptomatic intracranial bleeding
: patients with asymptomatic bleedings or microbleedings on MRI are eligible for inclusion
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
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.
Drug: Rivaroxaban
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 \[2.0 - 3.0\].
Drug: Warfarin
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.
Also known as: Xarelto
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.
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
The Number of Patients With Intracranial Bleeding
Intracranial bleeding confirmed by relevant neuroimagings
Time frame: at 1 month
The Number of Patients With Recurrent Ischemic Lesion
Recurrent ischemic lesion confirmed by relevant neuroimagings
Time frame: at 1 month
Length of Hospitalization
Time to event will be calculated
Time frame: at 1month
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
| Milestone | Rivaroxaban | Warfarin |
|---|---|---|
| Started | 101 | 94 |
| Completed | 101 | 94 |
| Not completed | 0 | 0 |
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
| Participants | Rivaroxaban | Warfarin |
|---|---|---|
| Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging | 47 | 48 |
Intracranial bleeding confirmed by relevant neuroimagings
| Participants | Rivaroxaban | Warfarin |
|---|---|---|
| The Number of Patients With Intracranial Bleeding | 30 | 25 |
Recurrent ischemic lesion confirmed by relevant neuroimagings
| Participants | Rivaroxaban | Warfarin |
|---|---|---|
| The Number of Patients With Recurrent Ischemic Lesion | 28 | 31 |
Time to event will be calculated
| days | Rivaroxaban | Warfarin |
|---|---|---|
| Length of Hospitalization | 4.6 ± 3.9 | 5.6 ± 4.3 |
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
| participants | Rivaroxaban | Warfarin |
|---|---|---|
| Number of Participants With Modified Rankin Score of 0 or 1 at Week 4 | 79 | 64 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Rivaroxaban | — | 6/98 (6.1%) | 46/98 (46.9%) |
| Warfarin | — | 5/90 (5.6%) | 51/90 (56.7%) |
| Event | Rivaroxaban | Warfarin |
|---|---|---|
| Vertigo positionalEar and labyrinth disorders | 0/98 | 1/90 |
| Laboratory test abnormalInvestigations | 0/98 | 1/90 |
| ArthritisMusculoskeletal and connective tissue disorders | 0/98 | 1/90 |
| Cerebral infarctionNervous system disorders | 1/98 | 1/90 |
| Pulmonary hypertensionRespiratory, thoracic and mediastinal disorders | 0/98 | 1/90 |
| Atrial fibrillationCardiac disorders | 1/98 | 0/90 |
| Gastrooesophageal reflux diseaseGastrointestinal disorders | 1/98 | 0/90 |
| Large intestine polypGastrointestinal disorders | 1/98 | 0/90 |
| International normalised ratio increasedInvestigations | 1/98 | 0/90 |
| Stroke in evolutionNervous system disorders | 1/98 | 0/90 |
| Event | Rivaroxaban | Warfarin |
|---|---|---|
| OthersSocial circumstances | 24/98 | 12/90 |
| DizzinessNervous system disorders | 3/98 | 8/90 |
| ConstipationGastrointestinal disorders | 4/98 | 6/90 |
| International normalised ratio increasedInvestigations | 1/98 | 6/90 |
| Musculoskeletal painMusculoskeletal and connective tissue disorders | 2/98 | 4/90 |
| HypertensionVascular disorders | 4/98 | 0/90 |
| Decreased appetiteMetabolism and nutrition disorders | 0/98 | 3/90 |
| DepressionPsychiatric disorders | 1/98 | 3/90 |
| NauseaGastrointestinal disorders | 3/98 | 1/90 |
| NasopharyngitisInfections and infestations | 0/98 | 2/90 |
Modified Intention-to-treat analysis : The subject who is measured for the primary end point with IP is administered more than at least once after randomization
| Age, Continuous(years) | Rivaroxaban | Warfarin | Total |
|---|---|---|---|
| Mean | 70.2 ± 10.1 | 70.6 ± 10.9 | 70.4 ± 10.4 |
| Gender(Participants) | Rivaroxaban | Warfarin | Total |
|---|---|---|---|
| Female | 40 | 36 | 76 |
| Male | 55 | 52 | 107 |
| Body Mass Index(kg/㎡) | Rivaroxaban | Warfarin | Total |
|---|---|---|---|
| Mean | 24.4 ± 3.3 | 23.6 ± 3.1 | 24.0 ± 3.2 |
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Asan Medical Center