Adding Antiplatelet During Edoxaban Treatment in Stroke Patients With Non-valvular Atrial Fibrillation (ADD-ON)

• Conditions: Acute Ischemic Stroke; Intracranial Atherosclerosis; Atrial Fibrillation; Antiplatelet; Extracranial Atherosclerosis; Coronary Artery Atherosclerosis; Peripheral Artery Stenosis; Anticoagulant
• Interventions: Drug: Edoxaban Monotherapy

• Registration Number: NCT04010955
• Lead Sponsor: Asan Medical Center

Brief Summary

This study aims to compare the effectiveness and safety regarding treatment with standard anticoagulant only or adding antiplatelet to anticoagulant in patients with non-valvular atrial fibrillation and significant atherosclerosis including extracranial, intracranial, coronary or peripheral artery.

Detailed Description

Although there is a significant increase in the risk of cerebral infarction in the presence of atrial fibrillation, it is difficult to say that all cerebral infarctions occurring in patients with atrial fibrillation are caused by atrial fibrillation. Carotid stenosis is found in 1/4 of patients with atrial fibrillation, which increases the risk of cerebral infarction. Additional antiplatelet therapy to standard anticoagulation therapy should be considered in some patients. To date, the best medical treatment for prevention of cerebral infarction in patients with atrial fibrillation and accompanying atherosclerosis has not been evaluated yet.

Edoxaban reduced bleeding complication compared to warfarin in patients with atrial fibrillation. In addition, the ENGAGE AF TIMI-48 study showed a tendency to reduce cerebral infarction (p for interaction = 0.08) when administered in combination with one antiplatelet agent and edoxaban. The administration of antiplatelet agents may be due to patients had accompanying myocardial infarction or cerebral infarction. This group is also thought to have a high risk of bleeding due to high HAS-BLED scores. Nonetheless, there was a similar degree of bleeding in patients receiving additional antiplatelet agents. There was also less bleeding in the warfarin arm than in the use of additional antiplatelet agents. (Major bleeding: 0.19 vs 0.24% / yr; intracranial hemorrhage: 0.43 vs 0.57% / yr)

Thus, Edoxaban have good clinical trial results in combination with antiplatelet agents in atrial fibrillation with atherosclerosis compared to other NOACs(new oral anticoagulants). It is also considered to be suitable for combination therapy with antiplatelet agents because of its advantages in different bleeding compared to other warfarin. However, there is no evidence to suggest that Edoxaban alone or in combination with additional antiplatelet agents is better for stroke patients with atrial fibrillation and significant arteriosclerosis.

Study Timeline

• Study First Submitted: 2019-06-24
• Study First Submitted QC: 2019-07-03
• Study First Posted: 2019-07-08
• Status Verified: 2019-10
• Study Start: 2019-10-01
• Last Update Submitted: 2019-10-10
• Last Update Posted: 2019-10-14
• Primary Completion: 2023-08-31
• Study Completion: 2024-02-28

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 1200

Inclusion Criteria

1. Patients with acute cerebral infarction or transient ischemic attack within 14 days of symptom onset based on Last Known Normal Time.

2. Patients with non-valvular atrial fibrillation including paroxysmal atrial fibrillation which is eligible for treatment with Edoxaban.

3. Patients with significant atherosclerosis confirmed by imaging tests on the cerebral arteries, coronary arteries, or peripheral arteries and suitable for the use of antiplatelet agents.

   • Significant intracranial internal stenosis confirmed by CTA or MRA
   • A history of coronary artery disease, meaningful findings from CTA or CAG Arterial stenosis
   • Peripheral arterial disease (Ankle-Brachial Index, ABI <0.9, significant stenosis found in lower limb ultrasonography

3. Men and women over 20 years old 4) Patients who voluntarily agreed to register the registry

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Exclusion Criteria

1. Patients with chronic renal failure (GFR <30 ml / min) or severe liver damage
2. patients requiring warfarin medication due to prosthetic valve replacement
3. patients with internal bleeding (active internal bleeding)
4. bleeding diathesis
5. History of acute myocardial infarction or received coronary artery procedure within 6 months before screening
6. Patients who have received or are scheduled to undergo carotid stenting within 1 year
7. Currently, two or more antiplatelet agents are required due to arteriosclerosis.
8. Patients whose survival period is expected to be less than 12 months due to serious diseases such as terminal cancer or liver failure
9. Patients who are scheduled for invasive surgery with possible uncontrolled bleeding, including major surgery
10. Women who are pregnant or lactating, do not have contraception during the study
11. A person who is found to be unsuitable for participation in the study due to the clinical laboratory test results or other reasons

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Edoxaban and antiplatelet combination	Edoxaban Monotherapy	edoxaban plus additional antiplatelet therapy in long term stroke prevention. However, transient cessation of antiplatelet therapy will be allowed at the discretion of duty physicians.
Edoxaban Monotherapy	Edoxaban Monotherapy	edoxaban monotherapy without additional antiplatelet therapy in long term stroke prevention. However, transient additional antiplatelet therapy will be allowed at the discretion of duty physicians.

Primary Outcome Measures

Name	Time	Method
MACE (major adverse cardiac event)	18 months	Duration for first occurrence of major cardiovascular events after patient registration: ischemic stroke, hemorrhagic stroke, myocardial infarction, vascular death

Secondary Outcome Measures

Name	Time	Method
Stroke	18 months	Duration for first occurrence of stroke (ischemic and hemorrhagic) after patient registration
Acute Myocardial Infarction	18 months	Duration for first occurrence of acute myocardial infarction after patient registration
Hemorrhagic stroke	18 months	Duration for first occurrence of hemorrhagic stroke after patient registration
Major bleeding	18 months	Duration for occurrence of major bleeding based on ISTH( International Society on Thrombosis and Haemostasis) after patient registration
Vascular death	18 months	Duration for first occurrence of vascular death after patient registration
Ischemic stroke	18 months	Duration for first occurrence of ischemic stroke after patient registration
Net clinical benefit based on reduction in major adverse cardiac event compared to major bleeding events	18 months	Net clinical benefit based on reduction in major adverse cardiac event compared to major bleeding events

Trial Locations

Locations (1)

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of