Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF-PCI)
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|ClinicalTrials.gov Identifier: NCT02866175|
Recruitment Status : Completed
First Posted : August 15, 2016
Results First Posted : May 6, 2020
Last Update Posted : May 6, 2020
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|Condition or disease||Intervention/treatment||Phase|
|Atrial Fibrillation||Drug: Edoxaban Drug: Clopidogrel Drug: Prasugrel Drug: Ticagrelor Drug: Vitamin K antagonist||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||1506 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Evaluation of the Safety and Efficacy of an Edoxaban-based Compared to a Vitamin K Antagonist-based Antithrombotic Regimen in Subjects With Atrial Fibrillation Following Successful Percutaneous Coronary Intervention (PCI) With Stent Placement.|
|Actual Study Start Date :||February 24, 2017|
|Actual Primary Completion Date :||June 6, 2019|
|Actual Study Completion Date :||June 6, 2019|
Experimental: Edoxaban Regimen
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.
Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects
Other Name: Savaysa
Clopidogrel 75 mg once-daily
Other Name: Plavix
prasugrel 5mg or 10 mg once-daily
Other Name: Effient
ticagrelor 90 mg twice-daily
Active Comparator: Vitamin K Antagonist Regimen
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.
Clopidogrel 75 mg once-daily
Other Name: Plavix
prasugrel 5mg or 10 mg once-daily
Other Name: Effient
ticagrelor 90 mg twice-daily
Drug: Vitamin K antagonist
VKA once-daily dosing for target international normalized ratio between 2.0 and 3.0, inclusive
- Number of Participants With Adjudicated Major or Clinically Relevant Non-major Bleeding As First Event Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [ Time Frame: Day 1 to 12 months postdose ]Participants' first major or clinically relevant non-major bleeding (MCRB) events were reported. International Society on Thrombosis and Hemostasis (ISTH) defined bleeding events included: MCRB, major bleeding, including fatal bleeding (intracranial and non-intracranial), symptomatic intracranial hemorrhage, symptomatic bleeding in a critical area or organ, and clinically overt and causing ≥2.0 g/dL adjusted hemoglobin loss, clinically relevant non-major (CRNM) bleeding, minor bleedings, any bleeding (defined as the composite of major, CRNM, and minor bleeding), life-threatening bleeding, provoked (spontaneous, instrumental/traumatic, unknown) bleeding, and spontaneous bleeding.
- Number of Participants With Adjudicated Major, Clinically Relevant Non-major and Minor Bleeding (All Events) Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist-Based Regimen [ Time Frame: Day 1 to 12 months postdose ]All major, clinically relevant non-major and minor bleeding are reported for the secondary outcome. Participants may have experiences more than 1 bleeding event, all occurrences are reported. Participants with International Society on Thrombosis and Hemostasis (ISTH) defined bleeding events included: major or clinically relevant non-major bleeding (MCRB), major bleeding, including fatal bleeding (intracranial and non-intracranial), symptomatic intracranial hemorrhage, symptomatic bleeding in a critical area or organ, and clinically overt and causing ≥2.0 g/dL adjusted hemoglobin loss, clinically relevant non-major (CRNM) bleeding, minor bleedings, any bleeding (defined as the composite of major, CRNM, and minor bleeding), life-threatening bleeding, provoked (spontaneous, instrumental/traumatic, unknown) bleeding, and spontaneous bleeding.
- Number of Participants With Adjudicated Major, Minor, and Minimal Bleeding by Thrombolysis in Myocardial Infarction (TIMI) Definition Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [ Time Frame: Day 1 to 12 months postdose ]Thrombolysis in Myocardial Infarction (TIMI) defined bleeding events included: Major bleeding (including fatal bleeding and non-fatal bleeding [fulfilling the TIMI major bleeding definition], major or minor bleeding, minor bleeding, minimal bleeding, and any bleeding (defined as composite of major, minor, and minimal bleeding)
- Number of Participants With Bleeding Academic Research Consortium (BARC) Type 1, 2, 3, and 5 Bleeding According to the BARC Definitions Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [ Time Frame: Day 1 to 12 months postdose ]
Bleeding Academic Research Consortium (BARC) bleeding events included: Bleeding (defined by BARC type 3 or 5), bleeding (defined by BARC type 2, 3, or 5), and any bleeding (defined as the composite of BARC type 1, 2, 3, or 5), where increases in BARC type indicate worse outcome.
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consultation; Type 2: any overt, actionable sign of hemorrhage that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, medical intervention, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation; Type 3: Overt bleeding plus hemoglobin drop of 3 to ≤5 g/dL (3a), ≥5 g/dl (3b), and intracranial hemorrhage (3c) Type 5: Fatal bleeding
- Number of Participants With Main Efficacy Endpoints For the Overall Study Period Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [ Time Frame: Day 1 to 12 months postdose ]The main efficacy endpoints were defined as the composite of cardiovascular death (ARC), stroke (protocol defined), systemic embolic event (SEE), myocardial infarction (MI), or definite stent thrombosis.
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [ Time Frame: Day 1 to 30 days after the last dose ]Treatment-emergent adverse events (TEAEs) in >1.0% of participants were defined as events which started on or after first dose of the assigned study drug (edoxaban and VKA) or started prior to but then worsened after the first dose of the assigned study drug.
- Number of Participants With Study Drug-related Treatment-emergent Adverse Events (TEAEs) Experienced by 2 or More Participants Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [ Time Frame: Day 1 to 30 days after the last dose ]Study drug-related treatment-emergent adverse events (TEAEs) (experienced by 2 or more participants) were defined as events which started on or after first dose of the assigned study drug (edoxaban and VKA) or started prior to but then worsened after the first dose of the assigned study drug and were found to be related to treatment by the Investigator.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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.
- Bleeding risks or systemic conditions
Known bleeding diathesis, including but not limited to,
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.
- 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:
- cardiogenic shock or acute decompensated heart failure, with the requirement for vasopressor agents or inotropic support or mechanical support to support circulation
- 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:
- Platelet count < 50 x10^9/L
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02866175
|Study Chair:||Pascal Vranckx, MD||Hartcentrum Hasselt|
|Study Chair:||Andreas Gotte, Prof., MD||Medizinische Klinik II|
Documents provided by Daiichi Sankyo, Inc. ( Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company ):
|Responsible Party:||Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company|
|Other Study ID Numbers:||
2016-002683-14 ( EudraCT Number )
|First Posted:||August 15, 2016 Key Record Dates|
|Results First Posted:||May 6, 2020|
|Last Update Posted:||May 6, 2020|
|Last Verified:||April 2020|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/|
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
|Time Frame:||Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.|
|Access Criteria:||Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.|
|Studies a U.S. FDA-regulated Drug Product:||No|
|Studies a U.S. FDA-regulated Device Product:||No|
|Product Manufactured in and Exported from the U.S.:||No|
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