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Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation (TripleAXEL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02042534
Recruitment Status : Completed
First Posted : January 23, 2014
Results First Posted : February 8, 2017
Last Update Posted : February 8, 2017
Information provided by (Responsible Party):
Sun U. Kwon, Asan Medical Center

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.

Condition or disease Intervention/treatment Phase
Ischemic Stroke Transient Ischemic Attack Drug: Rivaroxaban Drug: Warfarin Phase 2

Detailed Description:
Primary endpoint: Composite of MRI-defined intracranial bleeding and recurrent ischemic lesion within 1 month after randomization (rivaroxaban vs conventional warfarin)

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 195 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : January 2014
Actual Primary Completion Date : December 2015
Actual Study Completion Date : December 2015

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: 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.
Drug: 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.

Other Name: Xarelto

Active Comparator: 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].
Drug: 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 ( Investigators will manage anticoagulation with warfarin per routine clinical care.

Primary Outcome Measures :
  1. Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging [ Time Frame: 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 Outcome Measures :
  1. The Number of Patients With Intracranial Bleeding [ Time Frame: at 1 month ]
    Intracranial bleeding confirmed by relevant neuroimagings

  2. The Number of Patients With Recurrent Ischemic Lesion [ Time Frame: at 1 month ]
    Recurrent ischemic lesion confirmed by relevant neuroimagings

  3. Length of Hospitalization [ Time Frame: at 1month ]
    Time to event will be calculated

  4. Number of Participants With Modified Rankin Score of 0 or 1 at Week 4 [ Time Frame: 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

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts 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 (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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02042534

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Korea, Republic of
Asan Medical Center
Seoul, Korea, Republic of, 138-736
Sponsors and Collaborators
Asan Medical Center
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Principal Investigator: Sun Uck Kwon, PhD. Asan Medical Center
Principal Investigator: Keun-Sik Hong, PhD InjeUniversityIlsanPaikHospital
Principal Investigator: Young Jae Kim, PhD Ewha Womans University Mokdong Hospital
Principal Investigator: Yang Ha Hwang, PhD Kyungpook National University Hospital
Principal Investigator: Jaekwan Cha, PhD Dong-A University Hospital
Principal Investigator: Woo-Keun Seo, PhD Korea University Guro Hospital
Principal Investigator: Eung-Gyu Kim, PhD InjeUniversityBusanPaikHospital
Principal Investigator: Byung-Woo Yoon, PhD Seoul National University Hospital
Principal Investigator: Kyung-Ho Yu, PhD Hallym University Medical Center
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Sun U. Kwon, Professor, Asan Medical Center Identifier: NCT02042534    
Other Study ID Numbers: LMI-2013-1013
First Posted: January 23, 2014    Key Record Dates
Results First Posted: February 8, 2017
Last Update Posted: February 8, 2017
Last Verified: December 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Sun U. Kwon, Asan Medical Center:
Additional relevant MeSH terms:
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Cerebral Infarction
Ischemic Attack, Transient
Atrial Fibrillation
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Arrhythmias, Cardiac
Heart Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia
Factor Xa Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action