Optimal Antithrombotic Therapy in Ischemic Stroke Patients With Non-Valvular Atrial Fibrillation and Atherothrombosis (ATIS-NVAF)

The Purpose of this open-label randomized controlled multicenter trial is to evaluate the efficacy and safety of mono-drug therapy with oral anticoagulant compared to combination therapy with antiplatelet drug, in ischemic stroke patients with non-valvular atrial fibrillation and atherothrombosis.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke; Atrial Fibrillation; Atherothrombosis
• Intervention / Treatment: Drug: Oral Anticoagulant; Drug: Antiplatelet Drug

Detailed Description

The Purpose of this open-label randomized controlled multicenter trial is to evaluate the efficacy and safety of mono-drug therapy with oral anticoagulant compared to combination therapy with antiplatelet drug, in ischemic stroke patients with non-valvular atrial fibrillation and atherothrombosis. Target sample size is 400. The primary outcome is a composite endpoint of ischemic cardiovascular events (cardiovascular death, ischemic stroke, myocardial infarction, systemic embolism, ischemic events requiring urgent revascularization) and major bleeding defined by the International Society on Thrombosis and Haemostasis(ISTH) criteria within 2 years after randomization.

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Hiroshi Yamagami, MD; Phone Number: +81-6-6942-1331; Email: yamagami-brain@umin.ac.jp
• Study Contact Backup: Name: Shuhei Okazaki, MD; Phone Number: +81-6-6879-3576; Email: s-okazaki@umin.ac.jp

Study Locations

• Japan
  • Osaka, Japan, 540-0006
    • Recruiting
    • National Hospital Organization Osaka National Hospital
    • Contact: Hiroshi Yamagami, MD; Phone Number: +81-6-6942-1331; Email: yamagami-brain@umin.ac.jp
    • Contact: Shuhei Okazaki, MD; Phone Number: +81-6-6879-3576; Email: s-okazaki@umin.ac.jp
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0047
      • Recruiting
      • Kobe City Medical Center General Hospital
      • Contact: Nobuyuki Sakai, MD; Phone Number: 078-302-7537; Email: n.sakai@siren.ocn.ne.jp
      • Contact: Nobuyuki Ohara, MD; Phone Number: 078-302-7537; Email: nobuyuki.ohara@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with an acute ischemic stroke or TIA from 8 days and up to 360 days from the onset of symptoms
2. Age 20 or older
3. Patients with non-valvular atrial fibrillation (chronic or paroxysmal) who start or continue taking an oral anticoagulant

4. Patients who have one of the following atherothrombotic diseases

   1. A past history of ischemic heart disease (myocardial infarction, angina pectoris, coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI)
   2. A past history of peripheral artery disease (symptomatic peripheral arterial occlusive disease, lower extremity bypass surgery/angioplasty/stenting)
   3. Carotid artery stenosis (symptomatic or asymptomatic (=>50% diameter), a history of carotid artery stenting (CAS) or carotid endarterectomy (CEA))
   4. Intracranial artery stenosis (=>50% stenosis of the diameter of a major intracranial artery: intracranial internal carotid artery, anterior cerebral artery (ACA)-A1 and A2, middle cerebral artery (MCA)-M1 and M2, posterior cerebral artery (PCA)-P1 and P2, vertebral artery, and basilar artery; a history of intracranial stent placement or intracranial bypass surgery)
   5. A past history of atherothrombotic brain infarction, lacunar infarction, or branch atheromatous disease
5. Patients without severe disability (modified Rankin Scale score =<4)
6. Patients who can take oral medications
7. Patients who can receive follow-up survey
8. Provision of written informed consent either directly or by a suitable surrogate

Exclusion Criteria:

1. History of myocardial infarction or acute coronary syndrome within the past 12 months
2. Patients who underwent PCI with drug-eluting stents within the past 12 months or PCI with bare-metal stents within the past 3 months
3. Patients who underwent carotid artery stent placement, intracranial stent placement, or lower extremity stent placement within the past 3 months
4. History of symptomatic intracranial hemorrhage or gastrointestinal bleeding within the past 6 months
5. Hemorrhagic diathesis or blood coagulation disorders
6. Platelet counts <100,000 /mm3 at enrollment.
7. Severe anemia (hemoglobin <7 g/dL)
8. Severe renal failure (creatinine clearance =<15 mL/min) or undergoing chronic hemodialysis.
9. Severe liver dysfunction (Grade B or C of the Child-Pugh classification)
10. Patients with severe disability requires constant nursing care, bedridden (modified Rankin Scale score =5)
11. Pregnant or possibly pregnant women
12. Active cancer
13. Expectation of survival less than 2 years
14. Anticoagulant or antiplatelet is scheduled to be discontinued for more than 4 weeks during the follow-up period
15. Planned revascularization procedure during the follow-up period
16. Patients who are enrolled in other trials
17. Patients judged as inappropriate for this study by investigators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dual-therapy group; Dual-therapy group: single anticoagulant drug and single antiplatelet drug. The dosage is determined according to each drug's package insert in Japan. In patients treated with warfarin, the target international normalized ratio (INR) range of 2.0-3.0 for those <70 years and 1.6-2.6 for those =>70 years is recommended according to the Japanese guidelines.	Drug: Oral Anticoagulant; warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban; Drug: Antiplatelet Drug; aspirin, clopidogrel, prasugrel, ticlopidine, or cilostazol
Active Comparator: Single-therapy group; Single-therapy group: single anticoagulant drug. The dosage is determined according to each drug's package insert in Japan. In patients treated with warfarin, the target international normalized ratio (INR) range of 2.0-3.0 for those <70 years and 1.6-2.6 for those =>70 years is recommended according to the Japanese guidelines.	Drug: Oral Anticoagulant; warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint of ischemic cardiovascular events and major bleeding	One of the following ischemic cardiovascular events (cardiovascular death, ischemic stroke, myocardial infarction, systemic embolism, or ischemic events requiring urgent revascularization), or major bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria	2 years after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	All-cause mortality	2 years after randomization
Ischemic cardiovascular events	Ischemic cardiovascular events (cardiovascular death, ischemic stroke, myocardial infarction, systemic embolism, ischemic events requiring urgent revascularization)	2 years after randomization
All ischemic cardiovascular events including transient ischemia	All ischemic cardiovascular events including transient ischemia (cardiovascular death, ischemic stroke, transient ischemic attack (TIA), myocardial infarction, unstable angina pectoris, systemic embolism, progression of symptomatic peripheral artery disease, ischemic events requiring urgent revascularization)	2 years after randomization
Ischemic stroke	Ischemic stroke	2 years after randomization
Myocardial infarction and cardiovascular death	Myocardial infarction and cardiovascular death	2 years after randomization
major bleeding	major bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria	2 years after randomization
Intracranial hemorrhage	Intracranial hemorrhage	2 years after randomization

Collaborators and Investigators

• Sponsor: National Hospital Organization Osaka National Hospital
• Collaborators: Network for Clinical Stroke Trials; The BMS/Pfizer Japan Thrombosis Investigator Initiated Research Program
• Investigators: Principal Investigator: Hiroshi Yamagami, MD, National Hospital Organization Osaka National Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2017
• Primary Completion (Anticipated): April 30, 2022
• Study Completion (Anticipated): April 30, 2026

Study Registration Dates

• First Submitted: February 8, 2017
• First Submitted That Met QC Criteria: February 19, 2017
• First Posted (Actual): February 23, 2017

Study Record Updates

• Last Update Posted (Actual): October 12, 2020
• Last Update Submitted That Met QC Criteria: October 8, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: anticoagulant; antiplatelet
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arrhythmias, Cardiac; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Atrial Fibrillation; Cerebral Infarction; Anticoagulants; Platelet Aggregation Inhibitors
• Other Study ID Numbers: ATIS-NVAF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No