Clinical trial NCT02042534: Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation
Official title: Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation: Acute Stroke With Xarelto to Reduce Intracranial Bleeding, Recurrent Embolic Stroke, and Hospital Stay, Phase 2, Conceptual Multicenter Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ischemic Stroke
Transient Ischemic Attack
Keywords: stroke
TIA
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2014-01-23
Enrollment: 195
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)

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

Primary outcomes:
measure: Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging
timeFrame: 1 month after randomization
Secondary outcomes:
measure: The Number of Patients With Intracranial Bleeding
timeFrame: at 1 month
measure: The Number of Patients With Recurrent Ischemic Lesion
timeFrame: at 1 month
measure: Length of Hospitalization
timeFrame: at 1month
measure: Number of Participants With Modified Rankin Score of 0 or 1 at Week 4
timeFrame: at 1 month
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
Study officials:
affiliation: Asan Medical Center
name: Sun Uck Kwon, PhD.
role: PRINCIPAL_INVESTIGATOR
affiliation: InjeUniversityIlsanPaikHospital
name: Keun-Sik Hong, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ewha Womans University Mokdong Hospital
name: Young Jae Kim, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kyungpook National University Hospital
name: Yang Ha Hwang, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dong-A University Hospital
name: Jaekwan Cha, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Korea University Guro Hospital
name: Woo-Keun Seo, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: InjeUniversityBusanPaikHospital
name: Eung-Gyu Kim, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seoul National University Hospital
name: Byung-Woo Yoon, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hallym University Medical Center
name: Kyung-Ho Yu, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hong KS, Kwon SU, Lee SH, Lee JS, Kim YJ, Song TJ, Kim YD, Park MS, Kim EG, Cha JK, Sung SM, Yoon BW, Bang OY, Seo WK, Hwang YH, Ahn SH, Kang DW, Kang HG, Yu KH; Phase 2 Exploratory Clinical Study to Assess the Effects of Xarelto (Rivaroxaban) Versus Warfarin on Ischemia, Bleeding, and Hospital Stay in Acute Cerebral Infarction Patients With Non-valvular Atrial Fibrillation (Triple AXEL) Study Group. Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation-Related Mild Ischemic Stroke: A Randomized Clinical Trial. JAMA Neurol. 2017 Oct 1;74(10):1206-1215. doi: 10.1001/jamaneurol.2017.2161.
citation: Hong KS, Choi YJ, Kwon SU; Triple AXEL Investigators. Rationale and design of Triple AXEL: trial for early anticoagulation in acute ischemic stroke patients with nonvalvular atrial fibrillation. Int J Stroke. 2015 Jan;10(1):128-33. doi: 10.1111/ijs.12386. Epub 2014 Oct 26.