Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

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.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02866175

Acronym

ENTRUST-AF-PCI

Enrollment

1506

Registered

2016-08-15

Start date

2017-02-24

Completion date

2019-06-06

Last updated

2020-05-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Atrial Fibrillation

Keywords

percutaneous intervention, vitamin K antagonist

Brief summary

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.

Interventions

DRUGEdoxaban

Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects

DRUGClopidogrel

Clopidogrel 75 mg once-daily

DRUGPrasugrel

prasugrel 5mg or 10 mg once-daily

DRUGTicagrelor

ticagrelor 90 mg twice-daily

DRUGVitamin K antagonist

VKA once-daily dosing for target international normalized ratio between 2.0 and 3.0, inclusive

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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

Design outcomes

Primary

Measure	Time frame	Description
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	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.

Secondary

Measure	Time frame	Description
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	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	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 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	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 Treatment-emergent Adverse Events (TEAEs) Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen	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	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.
Number of Participants With Main Efficacy Endpoints For the Overall Study Period Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen	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.

Countries

Austria, Belgium, France, Germany, Hungary, Italy, Lithuania, Netherlands, Poland, Portugal, Romania, Serbia, South Korea, Spain, Switzerland, Taiwan, Ukraine, United Kingdom

Participant flow

Recruitment details

A total of 1506 participants who met all inclusion criteria and no exclusion criteria were enrolled in the study; 1486 participants received treatment. A total of 20 participants (5 Edoxaban and 15 Vitamin K Antagonist) did not receive treatment.

Participants by arm

Arm	Count
Edoxaban Regimen Participants who were randomized to 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).	751
Vitamin K Antagonist Regimen Participants who were randomized to VKA in combination with 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) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.	755
Total	1,506

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	56	54
Overall Study	Death	30	23
Overall Study	Did not receive treatment	5	15
Overall Study	Lack of Efficacy	0	1
Overall Study	Lost to Follow-up	2	0
Overall Study	Other	7	14
Overall Study	Physician Decision	3	15
Overall Study	Progressive disease	1	1
Overall Study	Withdrawal by Subject	31	52

Baseline characteristics

Characteristic	Edoxaban Regimen	Vitamin K Antagonist Regimen	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	525 Participants	553 Participants	1078 Participants
Age, Categorical Between 18 and 65 years	226 Participants	202 Participants	428 Participants
Age, Continuous	69.4 years STANDARD_DEVIATION 9.74	70.1 years STANDARD_DEVIATION 9.51	69.7 years STANDARD_DEVIATION 9.63
Race and Ethnicity Not Collected	—	—	0 Participants
Region of Enrollment Austria	18 participants	8 participants	26 participants
Region of Enrollment Belgium	43 participants	37 participants	80 participants
Region of Enrollment France	21 participants	20 participants	41 participants
Region of Enrollment Germany	87 participants	80 participants	167 participants
Region of Enrollment Hungary	49 participants	54 participants	103 participants
Region of Enrollment Italy	69 participants	84 participants	153 participants
Region of Enrollment Lithuania	24 participants	21 participants	45 participants
Region of Enrollment Netherlands	3 participants	7 participants	10 participants
Region of Enrollment Poland	74 participants	66 participants	140 participants
Region of Enrollment Portugal	12 participants	12 participants	24 participants
Region of Enrollment Romania	17 participants	22 participants	39 participants
Region of Enrollment Serbia	17 participants	11 participants	28 participants
Region of Enrollment South Korea	50 participants	41 participants	91 participants
Region of Enrollment Spain	58 participants	57 participants	115 participants
Region of Enrollment Switzerland	2 participants	5 participants	7 participants
Region of Enrollment Taiwan	32 participants	46 participants	78 participants
Region of Enrollment Ukraine	169 participants	175 participants	344 participants
Region of Enrollment United Kingdom	6 participants	9 participants	15 participants
Sex: Female, Male Female	194 Participants	192 Participants	386 Participants
Sex: Female, Male Male	557 Participants	563 Participants	1120 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	46 / 746	37 / 740
other Total, other adverse events	457 / 746	447 / 740
serious Total, serious adverse events	176 / 746	175 / 740

Outcome results

Primary

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

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.