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

Atrial Fibrillation Clinical Trial

— ENTRUST-AF-PCI  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02866175
• Other study ID #: DSE-EDO-01-15-EU
• Secondary ID: 2016-002683-14
• Status: Completed
• Phase: Phase 3
• Start date: February 24, 2017
• Est. completion date: June 6, 2019

Study information

• Verified date: April 2020
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1506
• Est. completion date: June 6, 2019
• Est. primary completion date: June 6, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Drug:
• Edoxaban
Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects
• Clopidogrel
Clopidogrel 75 mg once-daily
• Prasugrel
prasugrel 5mg or 10 mg once-daily
• Ticagrelor
ticagrelor 90 mg twice-daily
• Vitamin K antagonist
VKA once-daily dosing for target international normalized ratio between 2.0 and 3.0, inclusive

Locations

Country	Name	City	State
Austria	Medizinische Universitaetsklinik Graz	Graz
Austria	University Hospital Innsbruck	Innsbruck
Austria	Krankenhaus Hietzing	Wien
Austria	Wilhelminenspital	Wien
Belgium	ASZ Aalst	Aalst
Belgium	Imelda Ziekenhuis	Bonheiden
Belgium	AZ St Jan	Brugge
Belgium	Hopital Erasme	Brussel
Belgium	University Hospital Antwerp	Edegem
Belgium	Virga Jesse Jessa hospital	Hasselt
Belgium	AZ Delta	Roeselare
France	University Hospital of Angers	Angers
France	Hopital Cote Basque	Bayonne
France	Chru Jean Minjoz	Besancon
France	Metropole Savoie Hospital	Chambery
France	Centre Hospitalier Sud Francilien	Corbeil Essonnes Cedex
France	Hospital Henri Mondor	Creteil
France	CHU de Nice	Nice
France	Hôpital Bichat - Claude Bernard	Paris cedex 8
France	Hôpital Rangueil, Service Cancérologie	Toulouse
France	Clinique Vauban	Valenciennes
Germany	University Hospital Aachen	Aachen
Germany	Universitäts-Herzzentrum Freiburg • Bad Krozingen	Bad Krozingen
Germany	Kerckhoff Klinik	Bad Nauheim
Germany	Charité Benjamin Franklin	Berlin
Germany	Charité, Campus Virchow-Klinikum - Medizinische Klinik mit Schwerpunkt Kardiologie	Berlin
Germany	Vivantes Klinikum im Friedrichshaim	Berlin
Germany	Staedtische Kliniken Bielefeld	Bielefeld
Germany	GFO Kliniken Bonn - St.-Marien-Hospital	Bonn
Germany	Universitätsklinikum Bonn - Medizinische Klinik II - Innere Medizin (Kardiologie, Angiologie und Pneumologie)	Bonn
Germany	Klinikum Coburg Med. Klinik Kardiologie, Angiologie, Pneumologie	Coburg
Germany	St. Johannes- Hospital	Dortmund
Germany	Heinrich-Heine-Universität Düsseldorf - Universitätsklinikum Düsseldorf (UKD) Klinik für Kardiologie, Pneumologie und Angiologie	Düsseldorf
Germany	Universitaetsklinikum Freiburg Klinik für Kardiologie und Angiologie I	Freiburg
Germany	Universitäres Herzzentrum Hamburg GmbH (UHZ)	Hamburg
Germany	Universitätsklinikum Heidelberg Klinik für Kardiologie, Angiologie und Pneumologie (Innere Medizin III)	Heidelberg
Germany	Universitätsklinikum des Saarlandes Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin	Homburg
Germany	Universitätsklinikum Jena Klinik für Innere Medizin I, Kardiologie, Angiologie, Pneumologie, Internistische Intensivmedizin	Jena
Germany	Herzzentrum Leipzig - Universitätsklinik Klinik für Innere Medizin/Kardiologie	Leipzig
Germany	Klinikum Ludwigshafen	Ludwigshafen
Germany	Städtisches Klinikum Lüneburg	Lüneburg
Germany	Kliniken Maria Hilf GmbH	Mönchengladbach
Germany	Klinik Dr. Müller GmbH & Co. KG, Peter Osypka Herzzentrum	München
Germany	Universitätsklinikum Münster - Department für Kardiologie und Angiologie	Münster
Germany	St. Vincenz-Krankenhaus Paderborn - Medizinische Klinik II	Paderborn
Germany	Universitätsmedizin Rostock	Rostock
Germany	Universitäts Klinikum Tübingen	Tübingen
Germany	Herzklinik Ulm	Ulm
Germany	Universitätsklinik Ulm - Zentrum für Innere Medizin - Klinik für Innere Medizin II	Ulm
Germany	Schwarzwald-Baar Klinikum - Kliniken Villingen-Schwenningen - Innere Medizin III: Kardiologie und Intensivmedizin	Villingen-Schwenningen
Germany	St. Josefs-Hospital - Medizinische Klinik I, Kardiologie	Wiesbaden
Germany	HELIOS Klinikum Wuppertal - Herzzentrum	Wuppertal
Hungary	Állami Szívkórház	Balatonfüred
Hungary	Bajcsy-Zsilinszky Kórház és Rendelointézet	Budapest
Hungary	Budai Irgalmasrendi Kht.	Budapest
Hungary	Gottsegen György Országos Kardiológiai Intézet	Budapest
Hungary	Magyar Honvédség Egészségügyi Központ	Budapest
Hungary	Debreceni Egyetem Klinikai Központ	Debrecen
Hungary	Petz Aladar Megyei Oktato Korhaz	Gyor
Hungary	Békés Megyei Központi Kórház	Gyula
Hungary	Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház, Jósa András Oktatókórház	Nyíregyháza
Hungary	Pécsi Tudományegyetem	Pécs
Hungary	Szegedi Tudományegyetem	Szeged
Hungary	Fejér Megyei Szent György Egyetemi Oktató Kórház	Székesfehérvár
Italy	Ospedale San Donato- ASL 8 Arezzo	Arezzo
Italy	Policlinico di Bari	Bari
Italy	Ospedale Maggiore C.A. Pizzardi -OR - Laboratorio di Cardiologia Interventistica	Bologna
Italy	AOU Materdomini, Magna Graecia University	Catanzaro
Italy	ASL2 Chieti - SS Maria Annunziata	Chieti
Italy	A.S.O.S. Croce e Carle Cuneo	Cuneo
Italy	AOU Sant'Anna	Ferrara
Italy	Ospedale Careggi	Firenze
Italy	Ospedali Riuniti di Foggia	Foggia
Italy	Ospedale Alessandro Manzoni-Azienda Ospedaliera di Lecco	Lecco
Italy	Asst Fatebenefratelli-Sacco	Milano
Italy	AOU Policlinico di Modena	Modena
Italy	University Hospital Federico II	Napoli
Italy	Padova University Hospital	Padova
Italy	Azienda Ospedaliero-Universitaria di Parma	Parma
Italy	Ospedale degli Infermi	Rimini
Italy	Ospedale degli Infermi di Rivoli	Rivoli
Italy	Policlinico Agostino Gemelli	Roma
Italy	S.Camillo Forlanini - Ospedale S.Camillo Reparto di Emodinamica	Rome
Italy	Bolognini Hospital Seriate	Seriate
Italy	"Santa Maria" University Hospital - Azienda Ospedaliera Santa Maria Di Terni	Terni
Italy	U.O. Cardiologia Ospedale Borgo Trento	Verona
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Daegu Catholic University Hospital	Daegu
Korea, Republic of	Chonnam National University Hospital	Gwangju
Korea, Republic of	Hallym University Sacred Heart Hospital	Gyeonggi-do
Korea, Republic of	Inje Univ. Ilsan Paik Hospital	Gyeonggi-do
Korea, Republic of	The Catholic University of Korea St.Vincent's Hospital	Gyeonggi-do
Korea, Republic of	Inha University Hospital	Incheon
Korea, Republic of	Chonbuk National University Hospital	Jeonju
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Boramae Medical Center	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Samsung Medical Centre	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	SEOUL St.Maria	Seoul
Korea, Republic of	Severance Hospital	Seoul
Lithuania	Republican Siauliai Hospital	Šiauliai
Lithuania	Lithuanian University of Health Sciences hospital	Kaunas
Lithuania	Klaipeda Seamen's Hospital	Klaipeda
Lithuania	Vilnius University Hospital "Santariskiu Clinic"	Vilnius
Netherlands	St Antonius Hospital	Nieuwegein
Netherlands	Radboud university medical center	Nijmegen
Netherlands	Maasstad Hospital	Rotterdam
Netherlands	MC Haaglanden	The Hague
Poland	II Oddzial Kardiologiczny, Polsko-Amerykanskie Kliniki Serca	Bielsko-Biala
Poland	MCSN AHoP	Chrzanów
Poland	III Oddzial Kardiologii Inwazyjnej, Angiologii i Elektrokardiologii Polsko-Amerykanskie Kliniki Serca	Dabrowa Górnicza
Poland	AHP IV DEP K-Kozle	Kedzierzyn-Kozle
Poland	Krakowski Szpital Specjalistyczny im. Jana Pawla II, Oddzial Kliniczny Kardiologii Interwencyjnej z Pododdzialem Intenyswengo Nadzoru Kardiologicznego	Kraków
Poland	Nzoz Salus	Lódz
Poland	Nyskie Centrum Sercowo-Naczyniowe, Polsko-Amerykanskie Kliniki Serca	Nysa
Poland	Clin-Medica OMC sp. z o.o. s.k.	Skierniewice
Poland	X Oddzial Kardiologii Inwazyjnej, Elektrofizjologii i Elektrostymulacji Polsko-Amerykanskie Kliniki Serca	Tychy
Poland	Instytut Kardiologii im. Prymasa Tysiaclecia Stefana Kardynala Wyszynskiego; Klinika Kardiologii i Angiologii Interwencyjnej	Warsaw
Poland	Instytut Kardiologii im. Prymasa Tysiaclecia Kardynala Stefana Wyszynskiego, Klinika Choroby Wiencowej i Strukturalnych Chorób Serca	Warszawa
Portugal	Hospital Garcia de Orta, EPE	Almada
Portugal	Centro Hospitalar de Lisboa Ocidental, EPE - Hospital de Santa Cruz	Carnaxide
Portugal	Centro Hospitalar e Universitário de Coimbra, EPE	Coimbra
Portugal	Centro Hospitalar e Universitário de Coimbra, EPE - Hospital dos Covões	Coimbra
Portugal	Centro Hospitalar de Lisboa Central, EPE - Hospital Santa Marta	Lisboa
Portugal	Centro Hospitalar de Lisboa Norte, EPE - Hospital de Santa Maria	Lisboa
Romania	Emergency County Hospital Baia Mare	Baia Mare
Romania	"Prof. C.C. Iliescu" Emergency Institute for Cardiovascular Diseases	Bucharest
Romania	Saint John Emergency Hospital	Bucharest
Romania	University Hospital of Bucharest	Bucharest
Romania	Oradea Emergency County Clinical Hospital	Oradea
Romania	Emergency Institute of Cardiovascular Diseases and Transplantation	Târgu-Mures
Romania	Institutul de Boli Cardiovasculare Timisoara	Timisoara
Serbia	Clinical Center of Serbia	Belgrade
Serbia	Clinical Hospital Center -Zvezdara	Belgrade
Serbia	Institute of CV Diseases Clinical Center of Serbia	Belgrade
Serbia	Clinical Center Kragujevac	Kragujevac
Serbia	Institute of Cardiovascular Diseases of Vojvodina	Sremska Kamenica
Spain	General University Hospital of Alicante	Alicante
Spain	Hospital Universitari Germans Trias i Pujol	Badalona
Spain	Complejo Hospitalario Universitario de Granada	Granada
Spain	Bellvitge University Hospital	L'Hospitalet de Llobregat
Spain	Complejo Asistencial Universitario de León	León
Spain	Clinica Universitaria San Carlos	Madrid
Spain	Hospital La Paz, Madrid	Madrid
Spain	Hospital Ramon y Cajal	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Puerta de Hierro	Madrid
Spain	Hospital Universitario Virgen de La Victoria	Málaga
Spain	Hospital Universitario Virgen de la Arrixaca	Murcia
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitari i Politècnic La Fe	Valencia
Spain	Hospital Clínico Universitario de Valladolid	Valladolid
Spain	Hospital Álvaro Cunqueiro	Vigo
Switzerland	HFR Freiburg - Kantonsspital Kardiologie	Fribourg
Switzerland	Cardiocentro Ticino	Lugano
Taiwan	Hsinchu Mackay Memorial Hospital (HMMH)	Hsinchu
Taiwan	E-DA Hospital	Kaohsiung
Taiwan	Kaohsiung medical University Chung-Ho Memorial Hospital (KMUH)	Kaohsiung
Taiwan	Far Eastern Memorial Hospital (FEMH)	New Taipei City
Taiwan	China Medical University Hospital (CMUH)	Taichung
Taiwan	Chi-Mei Medical Center (CMMC)	Tainan
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Cheng Hsin General Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang-Gung Memorial Hospital	Taoyuan
Ukraine	Cherkasy regional cardiological center	Cherkasy
Ukraine	Chernihiv City Hospital #2	Chernihiv
Ukraine	Chernivtsi Regional Clinical Cardiology Dispensary	Chernivtsi
Ukraine	Communal Institution Dnepropetrovsk Regional Diagnostic Center	Dnipro
Ukraine	CI "Dnipropetrovsk Joint Emergency Hospital"	Dnipropetrovsk
Ukraine	Ivano-Frankivsk Central City Clinical Hospital	Ivano-Frankivs'k
Ukraine	Communal Health Care Institution "Regional Clinical Hospital - Center of Emergency Medical Care and Disaster Medicine"	Kharkiv
Ukraine	Kharkiv City Clinical Hospital #8	Kharkiv
Ukraine	L.T. Malaya Therapy National Institute of the National Academy of medical science of Ukraine	Kharkiv
Ukraine	Kharkiv Railway Clinical Hospital N1 of Brance "Health Center" of the Public joint stock company "Ukrainian Railway"	Kharkov
Ukraine	Khmelnytskyy regional hospital	Khmel'nyts'kyy
Ukraine	Communal Institution of Kyiv Regional Rada	Kyiv
Ukraine	Insititute of Heart of MoH Ukraine	Kyiv
Ukraine	Kyiv City Clinical Hospital 4	Kyiv
Ukraine	Kyiv City Clinical Hospital#5	Kyiv
Ukraine	Oleksandrivska Kiyv City Clinical Hospital	Kyiv
Ukraine	State Institution 'National Scientific Central Institute of Cardiology named after MD Strazhesko'	Kyiv
Ukraine	Lviv Regional State Clinical Treatment and Diagnostic Cardiology Center	L'viv
Ukraine	Lutsk City Hospital	Luts'k
Ukraine	Nikolaev Regional Clinical Hospital	Nikolayev
Ukraine	Odessa Regional Hospital, Cardiosurgery Center	Odessa
Ukraine	Communal Institution Rivne Regional Clinical Hospital	Rivne
Ukraine	Communal Institution of Sumy Regional Rada	Sumy
Ukraine	Transcarpathian Regional Clinical Cardiology Clinic	Uzhhorod
Ukraine	Communal Institution "Vinnytsia Regional Diagnostic Center of cardiovascular disease"	Vinnytsya
Ukraine	Vinnytsya Regional Clinical Hospital n.a. Pyrogov	Vinnytsya
Ukraine	Zaporizhzhia Regional cardiology dispensary	Zaporizhzhia
United Kingdom	Blackpool Victoria Hospital	Blackpool	Lancashire
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Golden Jubilee Hospital	Clydebank
United Kingdom	Royal Infirmary of Edinburgh	Edinburgh
United Kingdom	Altnagelvin Area Hospital	Londonderry
United Kingdom	Southern Health and Social Care Trust	Portadown

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Day 1 to 12 months postdose
Secondary	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	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.	Day 1 to 12 months postdose
Secondary	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	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)	Day 1 to 12 months postdose
Secondary	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	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	Day 1 to 12 months postdose
Secondary	Number of Participants With Main Efficacy Endpoints For the Overall Study Period Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen	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.	Day 1 to 12 months postdose
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen	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.	Day 1 to 30 days after the last dose
Secondary	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	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.	Day 1 to 30 days after the last dose