Research & Innovation

ENVISAGE-TAVI AF

Clinical Trials

SLUHN 2018-10

Edoxaban Versus Standard of Care and their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation – In Atrial Fibrillation

Physician & Study Coordinator

Study Coordinator

Susan Hahn

484-526-7825

susan.hahn2@sluhn.org

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Synopsis

Synopsis: The optimal antithrombotic (‘blood thinning’) therapy in patients with atrial fibrillation following Transcatheter Aortic Valve Implantation (a catheter based procedure where a new valve is placed in the location of your old and narrowed aortic valve) is unknown at this time. This research study will compare the relative effects of two therapies.

There are two main types of blood thinners- anticoagulants and antiplatelet drugs. Anticoagulants, such as edoxaban or vitamin-K antagonists (VKA) such as warfarin, and antiplatelet drugs, such as Acetyl Salicylic Acid (ASA) (e.g. aspirin) and the drugs called P2Y12 inhibitors (e.g., clopidogrel), which prevent platelets from clumping together to form a clot.

Anticoagulants are typically used in patients with atrial fibrillation, while a combination of antiplatelets such as aspirin and a P2Y12 inhibitor is used in patients following coronary artery stenting.

Edoxaban has been developed as an alternative to VKA and has already been approved for clinical use in European countries, the United States, Japan, Hong Kong, South Korea and Taiwan for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, high blood pressure, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack (TIA). It has been demonstrated that edoxaban is safer than VKA in its approved use.

In this study, edoxaban alone or in combination with aspirin and/or a P2Y12 inhibitor will be compared to a VKA alone or in combination with aspirin and/or a P2Y12 inhibitor. The treatments will be compared for safety with regard to bleeding and effectiveness with regard to thrombotic complications like stroke in patients who have atrial fibrillation AND have undergone a successful Transcatheter Aortic Valve Implantation (TAVI).

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Inclusion Criteria
  • Successful transfemoral TAVI (other access routes may only be used if they become standard of care in the countries participating in this study with a proven superior outcome and after written approval of this study’s Executive Committee [EC]) with any approved/marketed device; success is defined as:
    • Correct positioning of a single prosthetic heart valve into the proper anatomical location
    • Presence of all 3 conditions post TAVI
      • i. Mean aortic valve gradient <20 mmHg
      • ii. Peak transvalvular velocity <3.0 m/s
      • iii. 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 AF
    • New onset AF (e.g., > 30 seconds documented by ECG)
  • Provision of signed informed consent
  • Age ≥18 years

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Exclusion Criteria

Bleeding risks or systemic conditions

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

Procedure related

  • Serious unresolved periprocedural complications

Medication related

  • Any contraindication to either Edoxaban or VKA per local label; specifically USA patients 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 anti-inflammatory drugs (NSAIDs)
  • Requirement for DAPT at randomization that will be indicated for more than 4 weeks beyond randomization
  • Treatment with other investigational 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)
  • Valve replacement for native aortic valve insufficiency
  • Any scheduled or unscheduled catheter based interventional procedure during the index TAVI
  • Subjects with mechanical heart valves
  • Mitral valve stenosis Grade III-IV/IV
  • Active infective endocarditis
  • Major surgery within 30 days prior to randomization
  • Elective PCI within 7 days prior to randomization
  • ST-elevation myocardial infarction within 30 days prior to TAVI until randomization (non-ST-elevation myocardial infarction is no exclusion)
  • Endstage renal disease (creatinine clearance [CrCL] < 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 as defined as hypertension documented by BP which repeatedly measures 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)

Other exclusion criteria

  • Any of the following abnormal local laboratory results at the time of randomization:
    • Platelet count < 50 x 109/L
    • Hemoglobin < 8 g/dL (5 mmol/L at randomization, no ongoing bleeding, no transfusion of whole blood or red blood cells within 24 hours)
  • 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 trial
  • 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

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