Efficacy and Safety of Edoxaban in Patients With Atrial Fibrillation and Mitral Stenosis

Study Overview
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Brief Summary
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This study aims to compare the efficacy and safety of the edoxaban and the warfarin in atrial fibrillation patients with mitral stenosis. The study design is a multicenter, randomized, open-label, investigator initiated phase 2 trial. The patients were randomly assigned to Edoxaban or Warfarin groups. Primary outcome was a composite of stroke and systemic arterial thromboembolism. The safety outcome was major bleeding.

Detailed Description
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Non-vitamin K antagonist oral anticoagulants (NOACs) are generally recommended as 1st line therapy for oral anticoagulant in patients with atrial fibrillation (AF). But, the efficacy and safety of NOAC in AF patients with prosthetic mechanical heart valves or moderate to severe mitral valve stenosis have not been proven, and the guidelines recommend vitamin K antagonist (VKA) administration to those patient groups. This trial aims to compare the efficacy and safety of the edoxaban and the warfarin in AF patients with moderate to severe mitral valve stenosis. Edoxaban in patients with aTrial fibrillation and MItral Stenosis (ERTEMIS) trial is a multicenter, randomized, open-label, investigator initiated phase 2 trial. The patients were randomly assigned to Edoxaban or Warfarin groups. The primary efficacy outcome is a composite of stroke and systemic arterial thromboembolism. The secondary efficacy outcomes are each component of the primary efficacy outcomes and death from any cause. The safety outcome was major bleeding.

Official Title
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A Randomized, Open, Phase 2 Study to Evaluate the Efficacy and Safety of Edoxaban in Patients With Atrial Fibrillation and Mitral Stenosis

Conditions
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Mitral Valve Stenosis, Atrial Fibrillation, Stroke, Systemic Embolism

Intervention / Treatment
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* Drug: Edoxaban
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria 18 < Age < 80 AF diagnosed by ECG at any time prior to enrollment Moderate or severe mitral valve stenosis diagnosed by echocardiography at any time prior to enrollment Exclusion criteria Refusal to consent Transient AF due to reversible cause (Postoperative, ongoing systemic inflammation, thyrotoxicosis) Patients undergoing mechanical valve replacement Coagulopathy Hepatic impairment with significant bleeding risk High bleeding risk due to following disease or condition diagnosed within 1 month prior to randomization GI ulcer or bleeding, Esophageal or gastric varix, Malignancy, Brain or cord injury, Surgery for brain, spinal cord, opthalmic, Intracranial hemorrhage, Arteriovenous malformation, Vascular aneurysms, Brain or spinal vascular disorder Stroke, Systemic arterial thromboembolism, Acute myocardial infarction diagnosed within 14 days prior to randomization End stage kidney disease (CrCL < 15mL/min) or Dialysis Severe hypertension Alcohol abuse or other psychiatric disease Epidural puncture or anesthesia Pulmonary thromboembolism with hemodynamical instability requiring thrombolysis or thrombectomy Pregnant or lactating women Allergy to edoxaban or warfarin Ongoing need for other anticoagulant or clarithromycin, rifampin) Participants for other trials within 1 month prior to enrollment Other patients to be inappropriate to participate in the trial determined by the investigator

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Edoxaban<br>Patients in the Edoxaban group take Edoxaban 60mg once daily. If any of the following conditions are present, take 30mg once daily. CrCl 15-50mL/min Body weight ≤ 60kg Concomitant use of P-glycoprotein inhibitor (Dronearone, Ciclosporine, Erythromycin or Ketoconazole) | Drug: Edoxaban<br>* Patients in the Edoxaban group take Edoxaban 60mg once daily. If any of the following conditions are present, take 30mg once daily. CrCl 15-50mL/min Body weight ≤ 60kg Concomitant use of P-glycoprotein inhibitor (Dronearone, Ciclosporine, Erythromycin or Ketoconazole)<br>|
| Active Comparator: Warfarin<br>Patients in the Warfarin group take Warfarin 2-10mg once daily, dose adjusted with the target INR 2-3. In the elderly or frail patients, a lower dose administration is allowed at the discretion of the investigator. | Drug: Warfarin<br>* Patients in the Warfarin group take Warfarin 2-10mg once daily, dose adjusted with the target INR 2-3. In the elderly or frail patients, a lower dose administration is allowed at the discretion of the investigator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of Stroke or Systemic arterial thromboembolism | The number of patients with the first occurrence of a stroke or systemic embolism during the study period | 15 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroke | The number of patients with the first occurrence of a stroke during the study period | 15 days after randomization | 
| Systemic embolism | The number of patients with the first occurrence of a systemic embolism during the study period | 15 days after randomization | 
| Death from any cause | The number of patients who died for any reason during the study period | 15 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Edoxaban, Warfarin, Stroke, Systemic embolism, Mitral Valve Stenosis, Atrial Fibrillation