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

NCT03433235 | Completed Phase 2

• 1 other identifier: AMC 2018-0033
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Ischemic Stroke

Outcome Measures

Primary Outcomes (1)

• recurrent ischemic strokes

  The incidence rate of symptomatic or asymptomatic recurrent ischemic strokes on DWI

  at Day 10-14

Secondary Outcomes (5)

• Recurrent ischemic lesions

  until Day 10-14

• Clinical neurological deterioration

  until Day 10-14

• recanalization (full or partial) of occluded vessels

  at Day 10-14

• intracranial hemorrhages

  at Day 10-14

• Functional status

  at 3 months

Study Arms (2)

Early edoxaban initiation group

EXPERIMENTAL

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

Conventional edoxaban initiation group

ACTIVE COMPARATOR

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

Drug: Edoxaban

Interventions

Edoxaban DRUG

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

Also known as: Lixiana

Conventional edoxaban initiation group; Early edoxaban initiation group

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Jong Sung Kim: lead
• Kyung Hee University Hospital: collaborator
• Soon Chun Hyang University: collaborator
• Dong-A University Hospital: collaborator

Study Sites (1)

Asan Medical Center

Seoul, South Korea

Location

Related Publications (12)

• Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, D'Agostino RB. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996 Oct;27(10):1760-4. doi: 10.1161/01.str.27.10.1760.

  PMID: 8841325 BACKGROUND

• Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW Jr, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013 Mar;44(3):870-947. doi: 10.1161/STR.0b013e318284056a. Epub 2013 Jan 31.

  PMID: 23370205 BACKGROUND

• Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013 Jul;34(27):2094-106. doi: 10.1093/eurheartj/eht134. Epub 2013 Apr 26.

  PMID: 23625209 BACKGROUND

• Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P; ESC Scientific Document Group. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: Executive summary. Eur Heart J. 2017 Jul 14;38(27):2137-2149. doi: 10.1093/eurheartj/ehw058.

  PMID: 27282612 BACKGROUND

• Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.

  PMID: 24251359 BACKGROUND

• Schulman S. New oral anticoagulant agents - general features and outcomes in subsets of patients. Thromb Haemost. 2014 Apr 1;111(4):575-82. doi: 10.1160/TH13-09-0803. Epub 2014 Jan 23.

  PMID: 24452881 BACKGROUND

• Kang DW, Han MK, Kim HJ, Sohn H, Kim BJ, Kwon SU, Kim JS, Warach S. Silent new ischemic lesions after index stroke and the risk of future clinical recurrent stroke. Neurology. 2016 Jan 19;86(3):277-85. doi: 10.1212/WNL.0000000000002289. Epub 2015 Dec 18.

  PMID: 26683639 BACKGROUND

• Lee EJ, Kang DW, Warach S. Silent New Brain Lesions: Innocent Bystander or Guilty Party? J Stroke. 2016 Jan;18(1):38-49. doi: 10.5853/jos.2015.01410. Epub 2015 Oct 15.

  PMID: 26467195 BACKGROUND

• Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998 Oct 17;352(9136):1245-51. doi: 10.1016/s0140-6736(98)08020-9.

  PMID: 9788453 BACKGROUND

• Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.

  PMID: 15842354 BACKGROUND

• Duchin K, Duggal A, Atiee GJ, Kidokoro M, Takatani T, Shipitofsky NL, He L, Zhang G, Kakkar T. An Open-Label Crossover Study of the Pharmacokinetics of the 60-mg Edoxaban Tablet Crushed and Administered Either by a Nasogastric Tube or in Apple Puree in Healthy Adults. Clin Pharmacokinet. 2018 Feb;57(2):221-228. doi: 10.1007/s40262-017-0554-0.

  PMID: 28512699 BACKGROUND

• Seiffge DJ, Traenka C, Polymeris A, Hert L, Peters N, Lyrer P, Engelter ST, Bonati LH, De Marchis GM. Early start of DOAC after ischemic stroke: Risk of intracranial hemorrhage and recurrent events. Neurology. 2016 Nov 1;87(18):1856-1862. doi: 10.1212/WNL.0000000000003283. Epub 2016 Sep 30.

  PMID: 27694266 BACKGROUND

MeSH Terms

Conditions

Ischemic Stroke

Interventions

edoxaban

Condition Hierarchy (Ancestors)

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

Study Officials

• Jong Sung Kim, M.D.,Ph D.

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: February 8, 2018
• First Posted: February 14, 2018
• Study Start: June 19, 2018
• Primary Completion: April 14, 2020
• Study Completion: July 2, 2020
• Last Updated: December 11, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)