Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation

Ischemic Stroke Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02042534
• Other study ID #: LMI-2013-1013
• Status: Completed
• Phase: Phase 2
• First received: January 17, 2014
• Last updated: July 20, 2016
• Start date: January 2014
• Est. completion date: December 2015

Study information

• Verified date: July 2016
• Source: Asan Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Korea: Ministry of Food and Drug Safety
• Study type: Interventional

Clinical Trial 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.

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 196
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 19 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Atrial Fibrillation
• Cerebral Infarction
• Ischemia
• Ischemic Attack, Transient
• Ischemic Stroke
• Stroke
• Transient Ischemic Attack

Intervention

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.
• 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.

Locations

Country	Name	City	State
Korea, Republic of	Asan Medical Center	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Asan Medical Center	Bayer

Country where clinical trial is conducted

Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of MRI-defined intracranial bleeding and recurrent ischemic lesion	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	Yes
Secondary	The number of patients with Intracranial bleeding	Intracranial bleeding confirmed by relevant neuroimagings	at 1 month	Yes
Secondary	The number of patients with recurrent ischemic lesion	Recurrent ischemic lesion confirmed by relevant neuroimagings	at 1 month	No
Secondary	Length of hospitalization	Time to event will be calculated	at 1month	No
Secondary	modified Rankin Score		at 1 month	No