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

Primary Purpose

Ischemic Stroke, Transient Ischemic Attack

Status

Completed

Phase

Phase 2

Locations

Korea, Republic of

Study Type

Interventional

Intervention

Rivaroxaban

Warfarin

About this trial

This is an interventional treatment trial for Ischemic Stroke focused on measuring stroke, TIA

Eligibility Criteria

19 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Asan Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Rivaroxaban

Warfarin

Arm Description

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.

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].

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

The Number of Patients With Intracranial Bleeding

Intracranial bleeding confirmed by relevant neuroimagings

The Number of Patients With Recurrent Ischemic Lesion

Recurrent ischemic lesion confirmed by relevant neuroimagings

Length of Hospitalization

Time to event will be calculated

Number of Participants With Modified Rankin Score of 0 or 1 at Week 4

modified Rankin Score 0 : No symptoms at all : No significant disability despite symptoms; able to carry out all usual duties and activities : Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance : Moderate disability; requiring some help, but able to walk without assistance : Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance : Severe disability; bedridden, incontinent and requiring constant nursing care and attention : Dead

Full Information

NCT ID

NCT02042534

First Posted

January 17, 2014

Last Updated

December 14, 2016

Sponsor

Asan Medical Center

Collaborators

Bayer

1. Study Identification

Unique Protocol Identification Number

NCT02042534

Brief Title

Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation

Acronym

TripleAXEL

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

2. Study Status

Record Verification Date

December 2016

Overall Recruitment Status

Completed

Study Start Date

January 2014 (undefined)

Primary Completion Date

December 2015 (Actual)

Study Completion Date

December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Asan Medical Center

Collaborators

Bayer

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ischemic Stroke, Transient Ischemic Attack

Keywords

stroke, TIA

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

195 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Rivaroxaban

Arm Type

Experimental

Arm Description

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.

Arm Title

Warfarin

Arm Type

Active Comparator

Arm Description

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].

Intervention Type

Drug

Intervention Name(s)

Rivaroxaban

Other Intervention Name(s)

Xarelto

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.

Intervention Type

Drug

Intervention Name(s)

Warfarin

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging

Description

Time Frame

1 month after randomization

Secondary Outcome Measure Information:

Title

The Number of Patients With Intracranial Bleeding

Description

Intracranial bleeding confirmed by relevant neuroimagings

Time Frame

at 1 month

Title

The Number of Patients With Recurrent Ischemic Lesion

Description

Recurrent ischemic lesion confirmed by relevant neuroimagings

Time Frame

at 1 month

Title

Length of Hospitalization

Description

Time to event will be calculated

Time Frame

at 1month

Title

Number of Participants With Modified Rankin Score of 0 or 1 at Week 4

Description

Time Frame

at 1 month

10. Eligibility

Sex

All

Minimum Age & Unit of Time

19 Years

Accepts Healthy Volunteers

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

Overall Study Officials: