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

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

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.

Study Overview

• Status: Completed
• Conditions: Ischemic Stroke; Transient Ischemic Attack
• Intervention / Treatment: Drug: Rivaroxaban; Drug: Warfarin

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 195
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 (http://www.warfarindosing.org/Source/InitialDose.aspx). Investigators will manage anticoagulation with warfarin per routine clinical care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	1 month after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Patients With Intracranial Bleeding	Intracranial bleeding confirmed by relevant neuroimagings	at 1 month
The Number of Patients With Recurrent Ischemic Lesion	Recurrent ischemic lesion confirmed by relevant neuroimagings	at 1 month
Length of Hospitalization	Time to event will be calculated	at 1month
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	at 1 month

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Collaborators: Bayer
• Investigators: 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 and helpful links

General Publications

• 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.
• 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. Erratum In: Int J Stroke. 2016 Jul;11(5):NP63.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: January 17, 2014
• First Submitted That Met QC Criteria: January 20, 2014
• First Posted (Estimate): January 23, 2014

Study Record Updates

• Last Update Posted (Estimate): February 8, 2017
• Last Update Submitted That Met QC Criteria: December 14, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: stroke; TIA
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arrhythmias, Cardiac; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Ischemic Attack, Transient; Atrial Fibrillation; Cerebral Infarction; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Warfarin
• Other Study ID Numbers: LMI-2013-1013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED