Clinical Trials

Inclusion Criteria:

• Successful TAVI via transvascular access routes such as femoral, carotid, axillary, and subclavian arteries. Other access routes need prior approval per majority vote from 3 members of the Executive Committee (both Global Lead Investigators and the Daiichi Sankyo Medical Lead or his/her designee). Success is defined as:
  • Correct positioning of a single prosthetic heart valve into the proper anatomical location.
  • Presence of all 3 conditions post TAVI:
    • Mean aortic valve gradient < 20 mm Hg;
    • Peak transvalvular velocity < 3.0 m/s;
    • Aortic valve regurgitation of 2 or less.
  • No clinically overt stroke.
  • No uncontrolled bleeding at time of randomization.
• Indication for chronic OAC:
  • Documented pre-existing atrial fibriliation (AF);
  • New onset AF (e.g., > 30 seconds documented by ECG).
• Provision of signed informed consent.
• Age ≥ 18 years old.

Exclusion Criteria:

Bleeding risks or systemic conditions

• Conditions with a high risk of bleeding:
  • o This may include but is not limited to: active peptic ulcer with upper gastrointestinal bleeding within last 90 days prior to randomization, malignancy at high risk of bleeding, major intraspinal or intracerebral vascular abnormalities, recent unresolved brain or spinal injury, or spinal surgery (recent = within the last 90 days prior to randomization), any intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, or clinically relevant vascular aneurysms.
• Other known bleeding diathesis.
• Conditions that make it difficult for the subject to swallow the study medication.

Procedure related

• Serious unresolved periprocedural complications.

Medication related

• Any contraindication to EITHER Edoxaban OR VKA per local label; this includes hypersensitivity to the active ingredient or to any of the excipients, or any components of the study medications; specifically, USA subjects with a creatinine clearance of > 95 mL/min must be excluded.
• Concomitant treatment with other antithrombotic agents (ASA >100 mg/day, fibrinolytic therapy, or chronic (>4 days/week) use of nonsteroidal antiinflammatory drugs (NSAIDs)); however, NSAID patches are permitted.
• Requirement for dual antiplatelet therapy (DAPT) at randomization that will be indicated for more than 3 months beyond the first study dose of OAC.
• Treatment with other investigational (i.e., nonapproved) drugs or devices within 30 days before enrollment or planned use of investigational drugs or devices during the study.

Concomitant conditions and therapies

• Clinically overt stroke within the last 90 days before TAVI.
• Any scheduled drug or device based therapy during the treatment period that would eliminate the need for chronic oral anticoagulation (any other diagnostic or therapeutic procedure that is associated with temporary interruption of OAC is permitted).
• Any bail out catheter based on cardiac interventional procedure during the index TAVI (however, during the same session as TAVI (pre or post TAVI) scheduled PCI and angioplasty of the iliac/femoral arteries are permitted).
• Subjects with mechanical heart valves.
• Mitral valve stenosis Grade III-IV/IV (moderate to severe/severe); however, subjects with moderate mitral valve stenosis are allowed within the study.
• Active infective endocarditis.
• Major surgery within 30 days prior to randomization.
• ST-elevation myocardial infarction within 30 days prior to TAVI until randomization (non-STelevation myocardial infarction is no exclusion).
• End stage renal disease (creatinine clearance < 15 mL/min or dialysis) at randomization.
• Severe hepatic impairment or hepatic disease associated with coagulopathy (e.g., acute/chronic active hepatitis or cirrhosis, Child Pugh B, C).
• Uncontrolled severe hypertension documented by repeated BP of ≥170/100 mmHg, despite medical intervention.
• Respiratory failure requiring mechanical ventilation at time of randomization.
• Critically ill or hemodynamically unstable subjects at the time of randomization, (i.e., cardiogenic shock, acute heart failure, including the requirement for pharmacologic treatment or mechanical support to assist circulation).
• Active malignancy (requiring chemotherapy, radiation or surgery at the time of randomization) except for adequately treated non-melanoma skin cancer or other noninvasive or in situ neoplasms (e.g., cervical cancer in situ that has been successfully treated); anti-hormonal therapy is allowed.

Other exclusion criteria

• Any of the following abnormal local laboratory results at the time of randomization:
  • Platelet count < 50 x10^9/L;
  • Hemoglobin < 8 g/dL (5 mmol/L at randomization, no ongoing bleeding, no blood transfusion of whole blood or red blood cells within 24 hours); however, for subjects with a history of hemoglobin of no less than 7.5 g/dL while taking chronic OAC, the exclusion will be based on hemoglobin of <7.5 g/dL.
• Female subjects of childbearing potential without using highly effective methods of contraception (i.e., a method of contraception with a failure rate < 1% during the course of the study, including the follow up period). A female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilized, or has not had a hysterectomy at least three months prior to the start of this study.
• [Visit 1]). Females taking oral contraceptives should have been on that therapy for at least three months. Highly effective methods of contraception includes combined (estrogen and progestogen containing) oral, intravaginal or transdermal hormonal contraception associated with inhibition of ovulation; progestogen-only oral, injectable or implantable hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; along with barrier methods of contraception (male condom, female condom, cervical cap, diaphragm, contraceptive sponge).
• Pregnant or breast-feeding subjects.
• Assessment by the Investigator that the subject is not likely to comply with the study procedures or will complete follow-up.
• Current participation in another clinical study (unless the registry DOES NOT interfere with the evaluation of ENVISAGE-TAVI-AF as per this protocol. Before including such a subject, the Investigator shall discuss the situation with the Daiichi Medical Lead or his/her designee).
• Previous randomization in this study.
• Drug or alcohol dependence within the past 12 months prior to randomization as judged by the Investigator.
• Life expectancy less than 6 months beyond the targeted last visit.
• Subjects with antiphospholipid syndrome who are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies) with thrombosis.