Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation

NCT02042534 | Completed Phase 2 Results DMC

• 1 other identifier: LMI-2013-1013
• Study Type: interventional
• Target: 195
• Locations: 1 country
• Sites: 1

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.

Conditions

Ischemic Stroke; Transient Ischemic Attack

Keywords

stroke; TIA

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• The Number of Patients With Intracranial Bleeding

  at 1 month

• The Number of Patients With Recurrent Ischemic Lesion

  at 1 month

• Length of Hospitalization

  at 1month

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

  at 1 month

Study Arms (2)

Rivaroxaban

EXPERIMENTAL

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

Warfarin

ACTIVE COMPARATOR

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

Interventions

Rivaroxaban DRUG

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.

Also known as: Xarelto

Rivaroxaban

Warfarin DRUG

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.

Warfarin

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Major surgery or major trauma within 30 days that might be associated with increased bleeding risk
• Clinically significant gastrointestinal bleeding within 6 months
• : 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

Sponsors & Collaborators

• Asan Medical Center: lead
• Bayer: collaborator

Study Sites (1)

Asan Medical Center

Seoul, 138-736, South Korea

Location

Related Publications (2)

• 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.

  PMID: 28892526 DERIVED

• 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.

  PMID: 25346499 DERIVED

MeSH Terms

Conditions

Ischemic Stroke; Ischemic Attack, Transient; Stroke

Interventions

Rivaroxaban; Warfarin

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Brain Ischemia

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Sun U. Kwon, MD, PhD, Prof
• Organization: Asan Medical Center, University of Ulsan

sukwon@amc.seoul.kr

82-2-3010-3960

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 17, 2014
• First Posted: January 23, 2014
• Study Start: January 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: February 8, 2017
• Results First Posted: February 8, 2017

Record last verified: 2016-12

Locations

KR (1)