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

• ClinicalTrials.gov Identifier: NCT02042534
• Recruitment Status: Completed
• First Posted: January 23, 2014
• Results First Posted: February 8, 2017
• Last Update Posted: February 8, 2017
• Sponsor: Asan Medical Center
• Collaborator: Bayer
• Information provided by (Responsible Party): Sun U. Kwon, Asan Medical Center

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.

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)

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

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

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

Contacts and Locations

Locations

Korea, Republic of

Asan Medical Center

Seoul, Korea, Republic of, 138-736

Sponsors and Collaborators

Asan Medical Center

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Sun U. Kwon, Professor, Asan Medical Center
• ClinicalTrials.gov Identifier: NCT02042534
• Other Study ID Numbers: LMI-2013-1013
• First Posted: January 23, 2014
• 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:

stroke; TIA

Additional relevant MeSH terms:

Stroke; Ischemic Stroke; Cerebral Infarction; Ischemic Attack, Transient; Atrial Fibrillation; Ischemia; 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; Infarction; Necrosis; Warfarin; Rivaroxaban; Anticoagulants; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action