Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation (ENVISAGE-TAVI AF)

Atrial Fibrillation Clinical Trial

Official title:

Edoxaban Versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation (TAVI) - in Atrial Fibrillation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02943785
• Other study ID #: DU176B-C-U4001
• Secondary ID: 2016-003930-26
• Status: Completed
• Phase: Phase 3
• Start date: March 21, 2017
• Est. completion date: February 28, 2021

Study information

• Verified date: March 2022
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

When the upper chambers of a person's heart receive or generate irregular electrical signals, it causes abnormal rhythm in the heartbeat. This is called atrial fibrillation.

Atrial fibrillation goes along with blood clots that may cause mainly strokes and less often other diseases, such as a heart attack. Some patients with atrial fibrillation have other heart disease, such as heart valves that may need to be replaced using catheters.

Often doctors give patients drugs that reduce those blood clots. These are either vitamin K antagonist (VKA) or direct anticoagulants, such as edoxaban. In these patients, it is unclear which of the drugs is better for reducing stroke without increasing severe bleedings.

Description:

Use of Edoxaban in patients with atrial fibrillation (AF) and indication to chronic oral anticoagulation (OAC) after transcatheter aortic valve implantation (TAVI)

Objective:

• To assess the effect of Edoxaban versus vitamin K antagonist (VKA) on net adverse clinical events (NACE), i.e., the composite of all-cause death, myocardial infarction (MI), ischemic stroke, systemic thromboembolism (SEE), valve thrombosis, and major bleeding (International Society on Thrombosis and Haemostasis [ISTH] definition).

• To assess the effect of Edoxaban versus VKA on major bleeding (ISTH definition).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1426
• Est. completion date: February 28, 2021
• Est. primary completion date: February 28, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Meets protocol-specified criteria for qualification and contraception

• Is willing and able to comply with any restrictions related food, drink and medications

• Voluntarily consents to participate and provides written informed consent prior to any protocol-specific procedures

Exclusion Criteria:

• Has history or current use of over-the-counter medications, dietary supplements, or drugs (including nicotine and alcohol) outside protocol-specified parameters

• Has signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise:

1. the safety or well-being of the participant or study staff

2. the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding)

3. the analysis of results

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Drug:
• Edoxaban-based Regimen
15 mg, 30 mg and 60 mg film coated tablet for oral use (with anti-platelet therapy pre-declared at randomization if prescribed)
• VKA-based Regimen
Dosed at International Normalized Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in the country location (with anti-platelet therapy pre-declared at randomization if prescribed).

Locations

Country	Name	City	State
Austria	Medizinische Universitaet Graz	Graz
Austria	Clinic Wels-Grieskirchen GmbH	Grieskirchen
Austria	Universitaetsklinik fuer Innere Medizin III	Innsbruck
Austria	Klinikum Klagenfurt am Worthersee	Klagenfurt
Austria	Krankenhaus Hietzing mit Neurologischem Zentrum Rosenhugel	Vienna
Austria	Universitätsklinik für Innere Medizin II	Vienna
Austria	Wilhelminenspital	Wien
Belgium	ASZ Aalst - Aalst campus	Aalst
Belgium	ZNA - Stuivenberg Ziekenhuis Netwerk Antwerpen	Antwerpen
Belgium	Hospital Erasme	Brussels
Belgium	UZA - Universtiair Ziekenhuis Antwerpen	Edegem
Belgium	ZOL Genk, Campus Sint-Jan	Genk
Belgium	Jessa Ziekenhuis- Campus Virga Jessa	Hasselt
Belgium	CHU de Liege	Liège
Belgium	AZ Delta Roeselare	Roeselare
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Hamilton General Hospital	Hamilton
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Montreal Heart Institute	Montréal	Quebec
Canada	Newmarket Cardiac Surgery Research Incorporated	Newmarket	Ontario
Canada	Universitè Laval	Québec
Canada	Horizon Health Network	Saint John
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University Health Network	Toronto	Ontario
France	CHU d'Angers	Angers
France	Clinique Saint Augustin	Bordeaux
France	Hopital Henri Mondor	Créteil
France	Institut Coeur Poumon - CHRU de Lille	Lille
France	CHU Arnaud de Villeneuve	Montpellier
France	Clinique du Millenaire Service de Cardiologie Interventionelle	Montpellier
France	Hopital Bichat	Paris
France	Institut Mutualiste Montsouris	Paris
France	CHU de Bordeaux Hopital du Haut Leveque	Pessac
France	CHU de Rouen	Rouen
France	Clinique Saint-Hilaire	Rouen
France	Nouvel Hopital Civil	Strasbourg
France	Clinique Pasteur / GCVI	Toulouse
Germany	Kerckhoff-Klinik	Bad Nauheim
Germany	Herz und Gefaess Klinik	Bad Neustadt An Der Saale
Germany	Segeberger Kliniken	Bad Segeberg
Germany	Charite Universitatsmedizin Berlin	Berlin
Germany	Immanuel Klinikum Bernau Herzzentrum Brandenburg	Berlin
Germany	Gesundheit Nord gGmbH	Bremen
Germany	Klinikum der Stadt Ludwigshafen	Dortmund
Germany	St. Johannes - Hospital	Dortmund
Germany	Heart Center Dresden, University Clinic Technical University Dresden	Dresden
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Elisabeth Krankenhaus Essen Klinik fur Kardiologie und Angiologie	Essen
Germany	Klinikum Fulda gAG	Fulda
Germany	Universitatsklinikum Halle (Saale)	Halle
Germany	Asklepios St. Georg Abteilung fuer Kardiologie	Hamburg
Germany	Heidelberg University Hospital	Heidelberg
Germany	Universitaetsklinik Schleswig-Holstein Campus Kiel	Kiel
Germany	MediClin Herzzentrum Lahr/Baden	Lahr
Germany	Herzzentrum Leipzig	Leipzig
Germany	Universitatsmedizin Mainz, Zentrum fur Kardiologie	Mainz
Germany	Klinikum rechts der Isar der Technischen Universitat Munchen	Muenchen
Germany	Deutsches Herzzentrum Munchen	München
Germany	Universitatsklinikum Essen, Klinik fur Kardiologie	München
Germany	Klinikum Oldenburg AöR	Oldenburg
Germany	Uniklinikum Regensburg, Med II	Regensburg
Germany	Krankenhaus der Barmherzigen	Trier
Germany	Universitaetsklinikum Tuebingen Medizinische Klinik, Abteilung III	Tuebingen
Germany	Universitatsklinikum Ulm	Ulm
Germany	Helios Herzzentrum Wuppertal	Wuppertal
Germany	Universitatsklinikum Wurzburg	Würzburg
Italy	Ospedali Riuniti Torrette Di Ancona	Ancona
Italy	Policlinico Sant'Orsola-Malpighi	Bologna
Italy	ASST Spedali Civili di Brescia-UO Cardiologia	Brescia
Italy	AOU Policlinico Vittorio Emanuele	Catania
Italy	Magna Graecia University	Catanzaro
Italy	Ospedale S. Croce e Carle	Cuneo
Italy	Citta di Lecce Hospital	Lecce
Italy	Azienda Socio Sanitaria Territoriale di Lecco	Lecco
Italy	ASST Ovest Milanese - Presidio Ospedallero di Legnana	Legnano
Italy	Fondazione Toscana Gabriele Monasterio	Massa
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	Centro Cardiologico Monzino IRCCS	Milano
Italy	Ospedale San Raffaele	Milano
Italy	A.A Dei Colli Monaldi UOC Cardiologia Interventistica	Napoli
Italy	Clinica Mediterranea	Napoli
Italy	Azienda Ospedaliera di Padova	Padova
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	IRCCS Policlinico San Matteo	Pavia
Italy	Centro Cuore Morgagni	Pedara
Italy	Azienda Ospedaliero-Universitaria Pisana	Pisa
Italy	IRCCS-ASMN Reggio Emilia	Reggio Emilia
Italy	AO San Camillo Forlanini	Rome
Italy	AOU Careggi, Interventistica Cardiologica Strutturale	Rome
Italy	Azienda Ospedaliero-Universitaria Policlinico Umberto I	Rome
Italy	Ospedale Sant'Andrea - U.O.S. Emodinamica Cardiologia Interventistica	Rome
Italy	Istituto Clinico Humanitas	Rozzano
Italy	AOU S.Giovanni Di Dio e Ruggi D'Aragona	Salerno
Italy	IRCCS Policlinico San Donato	San Donato Milanese
Italy	UOC Emodinamica III	Siena
Italy	Azienda Ospedaliera Integrata di Verona	Verona
Japan	Osaka City University Hospital	Abeno Ward	Osaka
Japan	Toyohashi Heart Center	Aichi
Japan	Tsukuba Medical Center Hospital	Amakubo	Ibaraki
Japan	New Tokyo Hospital	Chiba
Japan	Tokai University Hospital	Isehara	Kanagawa
Japan	Shonan Kamakura General Hospital	Kanagawa
Japan	St. Marianna University School of Medicine Hospital	Kawasaki	Kanagawa
Japan	Kishiwada Tokushukai Hospital	Kishiwada	Osaka
Japan	Kokura Memorial Hospital	Kitakyushu	Fukuoka
Japan	Iwate Medical University Hospital	Morioka	Iwate Prefecture
Japan	Ogaki Municipal Hospital	Ogaki	Gifu
Japan	Sapporo Higashi Tokushukai Hospital	Sapporo	Hokkaido
Japan	Sendai Kousei Hospital	Sendai	Miyagi
Japan	Keio University Hospital	Shinjuku City	Tokyo
Japan	Teikyo University Hospital	Tokyo	Itabashi
Japan	Toyama University Hospital	Toyama
Japan	Nagoya Heart Center	Toyohashi	Aichi
Japan	Saiseikai Yokohamashi Tobu Hospital	Yokohama	Kanagawa
Korea, Republic of	Asan Medical Center	Seoul	Songpa-gu
Korea, Republic of	Korean University Anam Hospital	Seoul	Seongbuk-gu
Korea, Republic of	Seoul National University Hospital	Seoul	Jongno-gu
Korea, Republic of	Seoul St. Mary's Hospital	Seoul	Seocho-gu
Korea, Republic of	Yonsei University Severance Hospital	Seoul	Seodaemun-gu
Netherlands	Academic Medical Center	Amsterdam
Netherlands	HagaZiekenhuis	Den Haag
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Medisch Centrum Leeuwarden	Leeuwarden
Netherlands	Erasmus Medical Center	Rotterdam
Poland	Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok
Poland	University Clinical Centre in Gdansk	Gdansk
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu	Poznan
Spain	Complexo hospitalario universitario de Santiago de Compostela	A Coruña
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Universitari Germans Trias I Pujol	Badalona	Barcelona
Spain	Hospital Clinico y Provincial de Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario Donostia	Donostia	Gipuzkoa
Spain	Complejo Asistencial de Granada	Grenada
Spain	Complexo Hospitalario Universitario de A Coruna	La Coruña
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital La Luz QuironSalud	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario La Princesa	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Málaga
Spain	Hospital Virgen de la Arrixaca	Murcia
Spain	Hospital Universitario Central de Asturias	Oviedo	Asturias
Spain	Valdecilla Hospital	Santander
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitario Virgen Macarena	Sevilla	Andalucia
Spain	Hospital Clinico de Valencia	Valencia
Spain	Hospital Clinico Universitario de Valladolid	Valladolid
Spain	Hospital Universitario Alvaro Cunqueiro	Vigo
Switzerland	Universitatsspital Basel	Basel
Switzerland	Bern University Hospital	Bern
Switzerland	Hopitaux Universitaires de Geneve	Geneve
Switzerland	Cardiocentro Ticino	Lugano
United Kingdom	BSUH, Cardiac Research Unit	Brighton	England
United Kingdom	Papworth Hospital NHS Foundation Trust	Cambridge	England
United Kingdom	University Hospital of Wales, Heath Park	Cardiff	Wales
United Kingdom	Royal Edinburgh Infirmary	Edinburgh	England
United Kingdom	University Hospitals of Leicester NHS Trust	Leicester
United Kingdom	Guys St Thomas Hospital	London	England
United Kingdom	Trent Cardiac Centre	Nottingham	England
United Kingdom	Oxford University Hospitals, John Radcliffe Hospital	Oxford	England
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Northern General Hospital	Sheffield	England
United States	New Mexico Heart Institute	Albuquerque	New Mexico
United States	Seton Heart Institute	Austin	Texas
United States	St. Luke's University Health Network	Bethlehem	Pennsylvania
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	NY Presbyterian - Brooklyn Methodist Hospital	Brooklyn	New York
United States	CAMC Memorial Hospital	Charleston	West Virginia
United States	Rush University Medical Center	Chicago	Illinois
United States	Cardiology Associate Research	Daytona Beach	Florida
United States	International Research Partners, LLC.	Doral	Florida
United States	Doylestown Health Cardiothoracic Surgery	Doylestown	Pennsylvania
United States	Essentia Health	Duluth	Minnesota
United States	St. Francis Hospital	East Hills	New York
United States	St. Joseph's Physicians	East Syracuse	New York
United States	Inova Heart and Vascular Institute	Falls Church	Virginia
United States	Rochester General Hospital	Geneva	New York
United States	Moses H. Cone Memorial Hospital Operating Corporation d/b/a Cone Health	Greensboro	North Carolina
United States	East Carolina Heart Institute	Greenville	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Penn State Health, Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Memorial Healthcare Systems	Hollywood	Florida
United States	Houston Methodist Research Institute	Houston	Texas
United States	University of Texas Health Science Center Houston	Houston	Texas
United States	St. Vincent Heart Center	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Jackson Heart Clinic	Jackson	Mississippi
United States	UF Health Jacksonville	Jacksonville	Florida
United States	Watson Clinic Center for Research	Lakeland	Florida
United States	Sparrow Clinical Research Institute	Lansing	Michigan
United States	Arkansas Site Management Services	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Cedar-Sinai Heart Institute	Los Angeles	California
United States	UCLA Cardiovascular Center	Los Angeles	California
United States	Northshore Community Hospital	Manhasset	New York
United States	Southern Oregon Cardiology	Medford	Oregon
United States	MidMichigan Medical Center Midland	Midland	Michigan
United States	Aurora St. Luke's Medical Center	Milwaukee	Wisconsin
United States	SCRI - Centennial Medical Center	Nashville	Tennessee
United States	Mt. Sinai Hospital	New York	New York
United States	Oklahoma Heart Hospital Research Foundation	Oklahoma City	Oklahoma
United States	The Valley Hospital	Paramus	New Jersey
United States	Legacy Heart Center	Plano	Texas
United States	Providence Heart and Vascular Institute	Portland	Oregon
United States	Black Hills Cardiovascular Research	Rapid City	South Dakota
United States	Renown Regional Medical Center	Reno	Nevada
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Clinical Investigators LLC	Saint Louis	Missouri
United States	HealthEast Medical Research Institute	Saint Paul	Minnesota
United States	University of California - San Francisco	San Francisco	California
United States	Santa Barbara Cottage Hospital	Santa Barbara	California
United States	Maine Medical Center	Scarborough	Maine
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Providence Sacred Heart Medical Research Center	Spokane	Washington
United States	Baystate Health	Springfield	Massachusetts
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Washington Adventist Hospital	Takoma Park	Maryland
United States	Tallahassee Research Institute, Inc.	Tallahassee	Florida
United States	Promedica Toledo Hospital	Toledo	Ohio
United States	University of Arizona Sarver Heart Center	Tucson	Arizona
United States	Carle Foundation Hospital	Urbana	Illinois
United States	Medical Facility Associates	Washington	District of Columbia
United States	Medstar Washington Hospital Center	Washington	District of Columbia
United States	Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts
United States	Pinnacle Health	Wormleysburg	Pennsylvania
United States	WellSpan York Hospital	York	Pennsylvania
United States	Michigan Heart, St. Joseph Mercy Health System	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.	Chiltern International Inc.

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA	The composite endpoint net adverse clinical events (NACE) included all-cause death, myocardial infarction (MI), ischemic stroke, systemic embolic events (SEE), valve thrombosis, and major bleeding per definition of the International Society on Thrombosis and Haemostasis (ISTH].	Baseline through study completion, up to 36 months post-dose
Primary	Number of Participants Who Experienced Major Bleeding (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA	ISTH Bleeding Criteria for Major Bleeding are defined as clinically overt bleeding that is associated with: a fall in hemoglobin of 2 g/dL (1.24 mmol/L) or more, or a transfusion of 2 or more units of whole blood or packed red blood cells, or symptomatic bleeding into a critical site or organ such as intracranial, intraspinal, intraocular, retroperitoneal, pericardial, intra-articular, or intramuscular with compartment syndrome, or a fatal outcome.	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on TIMI Criteria in Participants Taking Edoxaban vs VKA	The composite endpoint of net adverse event clinical events (NACE) included all-cause death, myocardial infarction (MI), ischemic stroke, systemic embolic events (SEE), valve thrombosis, and major bleeding based on Thrombolysis in Myocardial Infarction (TIMI) criteria. Bleeding by TIMI criteria was defined as the following: (1) Major, any intracranial hemorrhage or any clinically overt bleeding, (including bleeding evident in imaging studies) associated with a fall of hemoglobin (Hb) of = 5g/dL or fatal bleeding and (2) Minor, any clinically overt bleeding associated with a fall in Hb = 3g/dL but < 5 g/dL.	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on BARC Type 3 or 5 Criteria in Participants Taking Edoxaban vs VKA	The composite endpoint of net adverse event clinical events (NACE) included all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding based on Bleeding Academic Research Consortium (BARC) Type 3 or 5 criteria. Major bleeding by BARC criteria was defined as Type 3: clinical, laboratory, and/or imaging evidence of bleeding with provider responses; Type 3a: any transfusion with overt bleeding; overt bleeding plus Hb drop of 3 to < 5 g/dL; Type 3b: overt bleeding plus Hb drop = 5 g/dL; cardiac tamponade; bleeding requiring surgical intervention; bleeding requiring intravenous vasoactive drugs; Type 3c: intracranial hemorrhage; subcategories confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision; Type 5: fatal bleeding; Type 5a: probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious; Type 5b: definite fatal bleeding; overt bleeding or autopsy or imaging confirmation	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on GUSTO Criteria in Participants Taking Edoxaban vs VKA	The composite endpoint of net adverse event clinical events (NACE) included all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding based on Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO). GUSTO criteria was defined as the following: severe or life threatening: intracerebral hemorrhage or resulting in substantial hemodynamic compromise requiring treatment and moderate: requiring blood transfusion but not resulting in hemodynamic compromise.	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced Major Adverse Cardiac Events (MACE) in Participants Taking Edoxaban vs VKA (Adjudicated Data)	Major adverse cardiac events (MACE) is defined as the composite of all-cause death (excluding adjudicated non-cardiac death), MI, or repeat coronary revascularization of the target lesion.	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced Major Adverse Cardiac and Cerebrovascular Events (MACCE) in Participants Taking Edoxaban vs VKA (Adjudicated Data)	Major adverse cardiac and cerebrovascular events (MACCE) is defined as the composite of all-cause death (excluding adjudicated non-cardiac death), MI, stroke (ischemic, hemorrhagic, or undetermined), or repeat coronary revascularization of the target lesion	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced a Composite of Adverse Events in Participants Taking Edoxaban vs VKA (Adjudicated Data)	A composite of clinical adverse events included cardiovascular death, MI ischemic stroke, SEE, valve thrombosis, and major bleeding as defined by ISTH criteria.	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced Stroke Events (Ischemic, Hemorrhagic, Undetermined) in Participants Taking Edoxaban vs VKA (Adjudicated Data)	Stroke events are categorized as any stroke, fatal stroke, and non-fatal stroke.	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced Systemic Embolic Events in Participants Taking Edoxaban vs VKA (Adjudicated Data)	Systemic thromboembolism [non-central nervous system] is defined as abrupt vascular insufficiency of an extremity or organ associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms, (e.g., trauma, atherosclerosis, instrumentation).	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced Myocardial Infarctions (MI) in Participants Taking Edoxaban vs VKA (Adjudicated Data)	Peri-procedural MI was defined as new ischemic symptoms or signs and elevated cardiac biomarkers within 72 hours after index procedure, consisting of at least one sample post-procedure with a peak value exceeding 15x as the upper reference limit (URL) for troponin or 5x for CK-MB. Spontaneous MI is defined as any one of the following: Detection of rise and/or fall of cardiac biomarkers with at least one value above the 99th percentile URL, together with the evidence of myocardial ischemia with at least one of the following: Symptoms of ischemia; ECG changes indicative of new ischemia; New pathological Q-waves in at least two contiguous leads; Imaging evidence of a new loss of viable myocardium or new wall motion abnormality; Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischemia, and accompanied by new ST elevation or new left bundle branch block, and/or evidence of fresh thrombus; Pathological findings of an acute MI.	Baseline through study completion, up to 36 months post-dose
Secondary	Number of Participants Who Experienced Valve Thrombosis in Participants Taking Edoxaban vs VKA (Adjudicated Data)	Valve thrombosis was defined as any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment.	Baseline through study completion, up to 36 months post-dose