Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF-PCI)

Daiichi Sankyo

Status and phase: Completed; Phase 3

Conditions: Atrial Fibrillation

Treatments: Drug: Ticagrelor; Drug: Vitamin K antagonist; Drug: Edoxaban; Drug: Clopidogrel; Drug: Prasugrel

Study type: Interventional

Funder types: Industry

Identifiers

NCT02866175

DSE-EDO-01-15-EU

2016-002683-14 (EudraCT Number)

Details and patient eligibility

About

There are insufficient data on the safety and efficacy of edoxaban plus antiplatelet therapy in subjects with atrial fibrillation (AF) following percutaneous intervention (PCI) with stenting. This study is designed to evaluate the safety and to explore the efficacy of an edoxaban-based antithrombotic regimen versus a vitamin K antagonist (VKA)-based antithrombotic regimen in subjects with AF following PCI with stent placement. Bleeding is a central safety outcome in cardiovascular clinical trials, especially for antithrombotic strategies and invasive procedures.

Enrollment: 1,506 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Oral anticoagulant (OAC) indication for atrial fibrillation for a period of at least 12 months following successful PCI with stenting.

Eligibility is assessed 4 hours after sheath removal and within 5 days after successful PCI with stent placement. If a staged PCI is planned, eligibility is assessed after completion of the last stage.

Successful PCI definition:

The success of a PCI procedure is defined by 2 interrelated components: angiographic findings, procedural / clinical outcomes as detailed below:

Angiographic Success A minimum stenosis diameter of < 20% (as visually assessed by angiography - residual blockage or stenosis reduced to less than 20% of the artery's diameter).

Sufficient enlargement of the lumen at the target site to improve coronary artery blood flow with final thrombolysis in myocardial infarction (TIMI) flow grade 3 (visually assessed by angiography), without occlusion of a significant side branch, flow-limiting dissection, distal embolization, or angiographic thrombus.

Procedural Success No major in-hospital clinical complications(e.g. ongoing International Society on Thrombosis and Haemostasis [ISTH] major or clinical relevant non-major procedural bleeding at the time of randomization, stroke, emergency coronary artery bypass graft [CABG]).

In summary, a clinically successful PCI requires both anatomic and procedural success along with relief of signs and/or symptoms of myocardial ischemia at the time of randomization.

Exclusion criteria

• Bleeding risks or systemic conditions

• Known bleeding diathesis, including but not limited to,

  1. Uncontrolled active bleeding, encompassing both ISTH major and clinically relevant non-major bleeding, preceding randomization.

     Lesion or condition, if considered to be a significant risk for major bleeding. This may include but is not limited to: unresolved gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding (e.g. malignancies with metastasis), recent unresolved brain or spinal injury, recent brain, spinal or ophthalmic surgery, any intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms (of more than 3.5 cm) or major intraspinal or intracerebral vascular abnormalities.

  2. Medication-related

• International normalized ratio (INR) > 2.5 (the participant can be reconsidered at a later time, but within 5 days of sheath removal).

• Contraindication to edoxaban, VKA, acetylsalicylic acid (ASA) and/or P2Y12 antagonists;

• Concomitant treatment with other antithrombotic agents, fibrinolytic therapy and chronic nonsteroidal anti-inflammatory drugs (NSAIDs).

Concomitant conditions and therapies

• Critically ill or hemodynamically unstable subjects (at the time of randomization) including:

  1. cardiogenic shock or acute decompensated heart failure, with the requirement for vasopressor agents or inotropic support or mechanical support to support circulation
  2. respiratory failure requiring endotracheal intubation and mechanical ventilation.

• Any prior mechanical valvular prosthesis;

• Planned coronary or vascular intervention or major surgery within 12 months; Randomization must be deferred to the last stage in a multistep, multivessel PCI procedure;

• Moderate or severe mitral stenosis;

• Ischemic stroke within 2 weeks prior to randomization;

• Uncontrolled severe hypertension with a systolic blood pressure (BP) ≥180 mmHg and/or diastolic BP ≥ 120 mmHg;

• End stage renal disease (ESRD) (CrCL < 15 mL/min or on dialysis);

• Known abnormal liver function prior to randomization (including hepatic disease or biochemical evidence of significant liver derangement known prior to randomization).

Other exclusion criteria

• Any of the following abnormal local laboratory results prior to randomization:

  1. Platelet count < 50 x10^9/L
  2. Hemoglobin < 8 mg/dL

• Unable to provide written Informed Consent;

• Female participants of childbearing potential without using highly effective contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilised, or has not had a hysterectomy at least three months prior to the start of this study). Females taking oral contraceptives should have been on therapy for at least three months. Adequate contraceptives include: Combined (estrogen and progestogen containing) oral, intravaginal, transdermal, hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence;

• Pregnant or breast-feeding participants;

• Assessment that the participant is not likely to comply with the study procedures or have complete follow-up;

• Participating in another clinical trial that potentially interferes with the current study;

• Previous randomization in this study;

• Active on prescription drug abuse and addiction; abuse of illicit substances (i.e. marijuana, cocaine, methamphetamine, heroin) and alcohol abuses during the last 12 months according to the judgement of the investigator;

• Life expectancy < 12 months.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,506 participants in 2 patient groups

Edoxaban Regimen

Experimental group

Description:

Participants will be randomized to receive edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel \[5 mg or 10 mg once-daily\] or ticagrelor \[90 mg twice-daily\] may be used) used.

Treatment:

Drug: Prasugrel

Drug: Ticagrelor

Drug: Clopidogrel

Drug: Edoxaban

Vitamin K Antagonist Regimen

Active Comparator group

Description:

Participants will be randomized to receive VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel \[5mg or 10 mg once-daily\] or ticagrelor \[90 mg twice-daily\] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.

Treatment:

Drug: Prasugrel

Drug: Ticagrelor

Drug: Vitamin K antagonist

Drug: Clopidogrel