Early Administration of Edoxaban After Acute Ischemic Stroke in Patients With Non-valvular Atrial Fibrillation

Sponsor

Jong Sung Kim (Other)

Overall Status

Completed

CT.gov ID

NCT03433235

Collaborator

Kyung Hee University Hospital (Other), Soon Chun Hyang University (Other), Dong-A University Hospital (Other)

Enrollment

Location

Arms

24.4

Actual Duration (Months)

2.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The investigators hypothesize that earlier initiation of edoxaban in AF-related stroke patients may significantly reduce the early recurrence of ischemic stroke, compared with conventional strategy of anticoagulation following 1-3-6-12 rule. To expedite the verification of the hypothesis, the investigators are planning to use diffusion weighted imaging (DWI), which has been reported to be a surrogate to predict both short-term and long-term prognosis after stroke, to detect the recurrent ischemic events. Because data on the early anticoagulation in patients with AF-related stroke are limited, the investigators decided to perform a pilot study before establishing an appropriate clinical trial protocol. This study will help estimate the efficacy and safety of early administration of edoxaban, and determine the sample size of a following clinical trial. To ensure the safety in this pilot exploration, the investigators will not include patients with severe ischemic strokes, who are often prone to experience hemorrhagic transformation in the acute post-stroke period.

Condition or Disease	Intervention/Treatment	Phase
Acute Ischemic Stroke	Drug: Edoxaban	Phase 2

Detailed Description

In patients with ischemic stroke and atrial fibrillation (AF), the risk of stroke recurrence is high, especially shortly after the event. Because AF-related strokes are usually larger in their size and more fatal than other types of ischemic stroke, it is important to prevent recurrent cardioembolic strokes with adequate secondary prevention. However, as damaged brain tissues and vessels are prone to bleed, early anticoagulation may be harmful.

For this reason, urgent anticoagulation has not been recommended in stroke patients with AF, and the appropriate time point to start anticoagulation remains controversial. Guideline recommends 1-3-6-12 rule* in initiating anticoagulation. However, this rule is not derived from a scientifically proven study results. Furthermore, although the risk of intracranial hemorrhage may be reduced to some extent with this strategy, the risk of early recurrence of embolic stroke may outweigh the potential benefit of delayed anticoagulation.

Edoxaban, which selectively blocks factor Xa, has a lower risk of hemorrhage, but with a similar efficacy in preventing ischemic events in patients with AF compared with warfarin. Even compared with the other factor Xa inhibitors, it is considered to have a lower risk of bleeding. Therefore, edoxaban may be safely given in the early phase in patients with stroke associated with AF, while not significantly increasing the risk of hemorrhages.

Study Design

Study Type:

Interventional

Actual Enrollment :

68 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Early Administration of Edoxaban After Acute Ischemic Stroke in Patients With Non-valvular Atrial Fibrillation: a Randomized, Multi-center, Parallel-group Trial (PILOT)

Actual Study Start Date :

Jun 19, 2018

Actual Primary Completion Date :

Apr 14, 2020

Actual Study Completion Date :

Jul 2, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early edoxaban initiation group Low dose of edoxaban (15 or 30 mg) once daily from Day 2, then standard dose of edoxaban (30 or 60 mg) according to '3-6' rule.	Drug: Edoxaban 1-3-6-12 rule* Anticoagulation in patients with acute ischemic stroke and atrial fibrillation can be initiated from the following days after stroke event. After 1 day: transient ischemic attacks After 3 days: mild ischemic strokes (NIHSS <8) After 6 days: moderate ischemic strokes (NIHSS 8-16) After 12 days: severe ischemic strokes (NIHSS >16) - NIHSS: National Institute of Health Stroke Scales Other Names: Lixiana
Active Comparator: Conventional edoxaban initiation group No antithrombotic treatment† -- then standard dose of edoxaban (30 or 60 mg) according to '3-6' rule.	Drug: Edoxaban 1-3-6-12 rule* Anticoagulation in patients with acute ischemic stroke and atrial fibrillation can be initiated from the following days after stroke event. After 1 day: transient ischemic attacks After 3 days: mild ischemic strokes (NIHSS <8) After 6 days: moderate ischemic strokes (NIHSS 8-16) After 12 days: severe ischemic strokes (NIHSS >16) - NIHSS: National Institute of Health Stroke Scales Other Names: Lixiana

Arm

Intervention/Treatment

Experimental: Early edoxaban initiation group

Low dose of edoxaban (15 or 30 mg) once daily from Day 2, then standard dose of edoxaban (30 or 60 mg) according to '3-6' rule.

Drug: Edoxaban

1-3-6-12 rule* Anticoagulation in patients with acute ischemic stroke and atrial fibrillation can be initiated from the following days after stroke event. After 1 day: transient ischemic attacks After 3 days: mild ischemic strokes (NIHSS <8) After 6 days: moderate ischemic strokes (NIHSS 8-16) After 12 days: severe ischemic strokes (NIHSS >16) - NIHSS: National Institute of Health Stroke Scales

Other Names:

Lixiana

Active Comparator: Conventional edoxaban initiation group

No antithrombotic treatment† -- then standard dose of edoxaban (30 or 60 mg) according to '3-6' rule.

Drug: Edoxaban

Other Names:

Lixiana

Outcome Measures

Primary Outcome Measures

recurrent ischemic strokes [at Day 10-14]
The incidence rate of symptomatic or asymptomatic recurrent ischemic strokes on DWI

Secondary Outcome Measures

Recurrent ischemic lesions [until Day 10-14]
The incidence rate of recurrent ischemic lesions with significant clinical worsening (≥NIHSS 4) The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.
Clinical neurological deterioration [until Day 10-14]
The rate of clinical neurological deterioration, rapid worsening of an existing focal neurological deficit (≥ 24 hours) that is clinically judged by the investigator not to be attributable to non-ischemic etiology (≥NIHSS 2) The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.
recanalization (full or partial) of occluded vessels [at Day 10-14]
The rate of recanalization (full or partial) of occluded vessels on follow-up intracranial TOF
intracranial hemorrhages [at Day 10-14]
The incidence rate of intracranial hemorrhages on follow-up gradient echo (GRE)
Functional status [at 3 months]
Functional status (modified Rankin Scale [mRS]) The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms. - No significant disability. Able to carry out all usual activities, despite some symptoms. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. - Moderate disability. Requires some help, but able to walk unassisted. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. - Dead.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Acute ischemic strokes (< 48 h from symptom onset) showing ischemic lesions confirmed by DWI, which are attributable to atrial fibrillation
Evidence of persistent or paroxysmal atrial fibrillation (already known or newly detected)
Age ≥20 y
Patients who provided informed consent

Exclusion Criteria:

Transient ischemic attack with no DWI lesions or severe ischemic strokes (NIHSS >16)
Significant hemorrhagic transformation (parenchymal hematoma type I or type II by the ECASS definition or those accompanying with worsening of an existing focal neurological deficit [NIHSS ≥4])10 on baseline MRI
Mechanical heart valve, rheumatic heart valve disease, or any other conditions requiring strong anticoagulation such as vitamin K antagonist or heparin treatment
Concomitant significant atherosclerotic stenosis (>50%) in the proximal arteries, which are possibly responsible for stroke lesions
Recent (<3 months) history of cerebral bleeding
Active internal bleeding or clinically significant bleeding
Severe anemia (Hb <10 g/dL) or bleeding diathesis (platelet count <100,000/uL or PT-INR >1.7) (If there is no active bleeding sign, it is permitted to enroll Hb <9 g/dL , platelet count <70,000/uL)
Uncontrolled hypertension: persistent systolic pressure >180 mmHg or diastolic pressure >110 mmHg
Active, advanced medical diseases (liver, kidney, pulmonary disease or cancer) with a life expectancy <6 months
Renal impairment (CrCl <30 mL/min) or undergoing Hemodialysis (or Peritoneal Dialysis)
Treatment with a strong inducer of p-glycoprotein (carbamazepine, dexamethasone, doxorubicin, nefazodone, pentobarbital, phenobarbital, prazocin, rifampin, St.John's wort, tenofovir, tipranavir, trazodone, vinblastine)
Contraindication to MRI
Pregnancy, breast-feeding or having a plan to be pregnant
Participation in the other investigational drug trials simultaneously or within 3 months before the first administration of the study medication. Observational studies without an intervention (eg study medication) are allowed.
Any clinical conditions (eg abnormal lab tests) unsuitable for undergoing clinical trials at the discretion of the clinical investigators
Known hypersensitivity to the study drug (edoxaban), its ingredients, or formulation excipients
Patient with liver disease related to coagulation disorder and clinically significant bleeding risk
Severe Liver disease
Patient who has increase risk of bleeding due to the following disease

recent gastrointestinal ulcer history
carcinoma increased risk of bleeding
recent brain or spinal injury
recent brain, spinal or optical surgery histroy
esophageal varix
arteriovenous malformations
vascular aneurysms (over 3.5cm)
intra spinal or cerebral vascular disorder

Patient with other anticoagulants
intermitant or severe mitral stenosis
a pulmonary embolism patient who is hemodynamic unstabled or required thrombolytic therpy or pulmonary emnolectomy