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

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02943785
• Collaborator: Chiltern International Inc. (Industry)
• Enrollment: 1,426
• Locations: 230
• Arms: 2
• Actual Duration (Months): 47.3
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: Edoxaban-based Regimen; Drug: VKA-based Regimen	Phase 3

Detailed 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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 1426 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Mar 21, 2017
• Actual Primary Completion Date: Feb 28, 2021
• Actual Study Completion Date: Feb 28, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Edoxaban-based Regimen Edoxaban-based regimen 60 mg and 30 mg film coated tablet for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing must follow the locally approved label.	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); Other Names: Savaysa Lixiana
Active Comparator: VKA-based Regimen VKA-based regimen oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator will monitor the patient and adjust the VKA dose to maintain the dose within target.	Drug: 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).

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA [Baseline through study completion, up to 36 months post-dose]

   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].

2. Number of Participants Who Experienced Major Bleeding (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA [Baseline through study completion, up to 36 months post-dose]

   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.

Secondary Outcome Measures

1. Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on TIMI Criteria in Participants Taking Edoxaban vs VKA [Baseline through study completion, up to 36 months post-dose]

   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.

2. 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 [Baseline through study completion, up to 36 months post-dose]

   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

3. Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on GUSTO Criteria in Participants Taking Edoxaban vs VKA [Baseline through study completion, up to 36 months post-dose]

   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.

4. Number of Participants Who Experienced Major Adverse Cardiac Events (MACE) in Participants Taking Edoxaban vs VKA (Adjudicated Data) [Baseline through study completion, up to 36 months post-dose]

   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.

5. Number of Participants Who Experienced Major Adverse Cardiac and Cerebrovascular Events (MACCE) in Participants Taking Edoxaban vs VKA (Adjudicated Data) [Baseline through study completion, up to 36 months post-dose]

   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

6. Number of Participants Who Experienced a Composite of Adverse Events in Participants Taking Edoxaban vs VKA (Adjudicated Data) [Baseline through study completion, up to 36 months post-dose]

   A composite of clinical adverse events included cardiovascular death, MI ischemic stroke, SEE, valve thrombosis, and major bleeding as defined by ISTH criteria.

7. Number of Participants Who Experienced Stroke Events (Ischemic, Hemorrhagic, Undetermined) in Participants Taking Edoxaban vs VKA (Adjudicated Data) [Baseline through study completion, up to 36 months post-dose]

   Stroke events are categorized as any stroke, fatal stroke, and non-fatal stroke.

8. Number of Participants Who Experienced Systemic Embolic Events in Participants Taking Edoxaban vs VKA (Adjudicated Data) [Baseline through study completion, up to 36 months post-dose]

   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).

9. Number of Participants Who Experienced Myocardial Infarctions (MI) in Participants Taking Edoxaban vs VKA (Adjudicated Data) [Baseline through study completion, up to 36 months post-dose]

   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.

10. Number of Participants Who Experienced Valve Thrombosis in Participants Taking Edoxaban vs VKA (Adjudicated Data) [Baseline through study completion, up to 36 months post-dose]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	University of Arizona Sarver Heart Center	Tucson	Arizona	United States	85724
3	Arkansas Site Management Services	Little Rock	Arkansas	United States	72211
4	Loma Linda University Medical Center	Loma Linda	California	United States	92354
5	Cedar-Sinai Heart Institute	Los Angeles	California	United States	90048
6	UCLA Cardiovascular Center	Los Angeles	California	United States	90095
7	University of California - San Francisco	San Francisco	California	United States	94143
8	Santa Barbara Cottage Hospital	Santa Barbara	California	United States	93105-4365
9	Medstar Washington Hospital Center	Washington	District of Columbia	United States	20010
10	Medical Facility Associates	Washington	District of Columbia	United States	20037
11	Cardiology Associate Research	Daytona Beach	Florida	United States	32117
12	International Research Partners, LLC.	Doral	Florida	United States	33166
13	Memorial Healthcare Systems	Hollywood	Florida	United States	33021
14	UF Health Jacksonville	Jacksonville	Florida	United States	32209
15	Watson Clinic Center for Research	Lakeland	Florida	United States	33805
16	Tallahassee Research Institute, Inc.	Tallahassee	Florida	United States	32308
17	Rush University Medical Center	Chicago	Illinois	United States	60612
18	Carle Foundation Hospital	Urbana	Illinois	United States	61801
19	St. Vincent Heart Center	Indianapolis	Indiana	United States	77030
20	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
21	Maine Medical Center	Scarborough	Maine	United States	04074-7133
22	Washington Adventist Hospital	Takoma Park	Maryland	United States	20912
23	Baystate Health	Springfield	Massachusetts	United States	01199
24	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts	United States	01655
25	Sparrow Clinical Research Institute	Lansing	Michigan	United States	48912
26	MidMichigan Medical Center Midland	Midland	Michigan	United States	48670
27	Michigan Heart, St. Joseph Mercy Health System	Ypsilanti	Michigan	United States	48197
28	Essentia Health	Duluth	Minnesota	United States	55805
29	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
30	HealthEast Medical Research Institute	Saint Paul	Minnesota	United States	55104
31	Jackson Heart Clinic	Jackson	Mississippi	United States	39216
32	Clinical Investigators LLC	Saint Louis	Missouri	United States	63119
33	Renown Regional Medical Center	Reno	Nevada	United States	89502
34	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
35	The Valley Hospital	Paramus	New Jersey	United States	07652
36	New Mexico Heart Institute	Albuquerque	New Mexico	United States	87102
37	NY Presbyterian - Brooklyn Methodist Hospital	Brooklyn	New York	United States	11215
38	St. Francis Hospital	East Hills	New York	United States	11548
39	St. Joseph's Physicians	East Syracuse	New York	United States	13057
40	Rochester General Hospital	Geneva	New York	United States	14456
41	Northshore Community Hospital	Manhasset	New York	United States	11030
42	Mt. Sinai Hospital	New York	New York	United States	10029
43	Stony Brook University Medical Center	Stony Brook	New York	United States	11794-8167
44	Moses H. Cone Memorial Hospital Operating Corporation d/b/a Cone Health	Greensboro	North Carolina	United States	27401
45	East Carolina Heart Institute	Greenville	North Carolina	United States	27834
46	Promedica Toledo Hospital	Toledo	Ohio	United States	43615
47	Oklahoma Heart Hospital Research Foundation	Oklahoma City	Oklahoma	United States	73120
48	Southern Oregon Cardiology	Medford	Oregon	United States	97504
49	Providence Heart and Vascular Institute	Portland	Oregon	United States	97225
50	St. Luke's University Health Network	Bethlehem	Pennsylvania	United States	18015
51	Doylestown Health Cardiothoracic Surgery	Doylestown	Pennsylvania	United States	18901
52	Penn State Health, Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
53	Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
54	Pinnacle Health	Wormleysburg	Pennsylvania	United States	17043
55	WellSpan York Hospital	York	Pennsylvania	United States	17403
56	Black Hills Cardiovascular Research	Rapid City	South Dakota	United States	57701
57	SCRI - Centennial Medical Center	Nashville	Tennessee	United States	37203
58	Seton Heart Institute	Austin	Texas	United States	78745
59	Houston Methodist Research Institute	Houston	Texas	United States	77030
60	University of Texas Health Science Center Houston	Houston	Texas	United States	77030
61	Legacy Heart Center	Plano	Texas	United States	75024
62	Inova Heart and Vascular Institute	Falls Church	Virginia	United States	22042
63	Virginia Mason Medical Center	Seattle	Washington	United States	98101
64	Providence Sacred Heart Medical Research Center	Spokane	Washington	United States	99208
65	CAMC Memorial Hospital	Charleston	West Virginia	United States	25404
66	Aurora St. Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
67	Medizinische Universitaet Graz	Graz		Austria	8036
68	Clinic Wels-Grieskirchen GmbH	Grieskirchen		Austria	4710
69	Universitaetsklinik fuer Innere Medizin III	Innsbruck		Austria	6020
70	Klinikum Klagenfurt am Worthersee	Klagenfurt		Austria	9020
71	Universitätsklinik für Innere Medizin II	Vienna		Austria	1090
72	Krankenhaus Hietzing mit Neurologischem Zentrum Rosenhugel	Vienna		Austria	1130
73	Wilhelminenspital	Wien		Austria	1060
74	ASZ Aalst - Aalst campus	Aalst		Belgium	9300
75	ZNA - Stuivenberg Ziekenhuis Netwerk Antwerpen	Antwerpen		Belgium	2060
76	Hospital Erasme	Brussels		Belgium	B-1070
77	UZA - Universtiair Ziekenhuis Antwerpen	Edegem		Belgium	2650
78	ZOL Genk, Campus Sint-Jan	Genk		Belgium	3600
79	Jessa Ziekenhuis- Campus Virga Jessa	Hasselt		Belgium	3500
80	CHU de Liege	Liège		Belgium	B-4000
81	AZ Delta Roeselare	Roeselare		Belgium	8800
82	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2R7
83	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
84	London Health Sciences Centre	London	Ontario	Canada	N6A 5W9
85	Newmarket Cardiac Surgery Research Incorporated	Newmarket	Ontario	Canada	L3Y 3S9
86	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
87	University Health Network	Toronto	Ontario	Canada	M5G 2C4
88	Montreal Heart Institute	Montréal	Quebec	Canada	H1T 1C8
89	Hamilton General Hospital	Hamilton		Canada	L8L 2X2
90	Universitè Laval	Québec		Canada	G1V 4G5
91	Horizon Health Network	Saint John		Canada	E2L4L2
92	CHU d'Angers	Angers		France
93	Clinique Saint Augustin	Bordeaux		France	33074
94	Hopital Henri Mondor	Créteil		France	94000
95	Institut Coeur Poumon - CHRU de Lille	Lille		France	59000
96	CHU Arnaud de Villeneuve	Montpellier		France	34295
97	Clinique du Millenaire Service de Cardiologie Interventionelle	Montpellier		France	34960
98	Institut Mutualiste Montsouris	Paris		France	75014
99	Hopital Bichat	Paris		France	75877
100	CHU de Bordeaux Hopital du Haut Leveque	Pessac		France	33604
101	CHU de Rouen	Rouen		France	76000
102	Clinique Saint-Hilaire	Rouen		France	76000
103	Nouvel Hopital Civil	Strasbourg		France	67091
104	Clinique Pasteur / GCVI	Toulouse		France	31300
105	Kerckhoff-Klinik	Bad Nauheim		Germany	61231
106	Herz und Gefaess Klinik	Bad Neustadt An Der Saale		Germany	97616
107	Segeberger Kliniken	Bad Segeberg		Germany	23795
108	Charite Universitatsmedizin Berlin	Berlin		Germany	12200
109	Immanuel Klinikum Bernau Herzzentrum Brandenburg	Berlin		Germany	16321
110	Gesundheit Nord gGmbH	Bremen		Germany	28277
111	Klinikum der Stadt Ludwigshafen	Dortmund		Germany	44137
112	St. Johannes - Hospital	Dortmund		Germany	44137
113	Heart Center Dresden, University Clinic Technical University Dresden	Dresden		Germany	01307
114	Universitätsklinikum Düsseldorf	Düsseldorf		Germany	40225
115	Elisabeth Krankenhaus Essen Klinik fur Kardiologie und Angiologie	Essen		Germany	45138
116	Klinikum Fulda gAG	Fulda		Germany	36043
117	Universitatsklinikum Halle (Saale)	Halle		Germany	06120
118	Asklepios St. Georg Abteilung fuer Kardiologie	Hamburg		Germany	20099
119	Heidelberg University Hospital	Heidelberg		Germany	69120
120	Universitaetsklinik Schleswig-Holstein Campus Kiel	Kiel		Germany	24105
121	MediClin Herzzentrum Lahr/Baden	Lahr		Germany	77933
122	Herzzentrum Leipzig	Leipzig		Germany	4289
123	Universitatsmedizin Mainz, Zentrum fur Kardiologie	Mainz		Germany	55131
124	Klinikum rechts der Isar der Technischen Universitat Munchen	Muenchen		Germany	81675
125	Deutsches Herzzentrum Munchen	München		Germany	80636
126	Universitatsklinikum Essen, Klinik fur Kardiologie	München		Germany	81379
127	Klinikum Oldenburg AöR	Oldenburg		Germany	26133
128	Uniklinikum Regensburg, Med II	Regensburg		Germany	93042
129	Krankenhaus der Barmherzigen	Trier		Germany	54292
130	Universitaetsklinikum Tuebingen Medizinische Klinik, Abteilung III	Tuebingen		Germany	72076
131	Universitatsklinikum Ulm	Ulm		Germany	89081
132	Helios Herzzentrum Wuppertal	Wuppertal		Germany	42117
133	Universitatsklinikum Wurzburg	Würzburg		Germany	97080
134	Ospedali Riuniti Torrette Di Ancona	Ancona		Italy	60030
135	Policlinico Sant'Orsola-Malpighi	Bologna		Italy	40138
136	ASST Spedali Civili di Brescia-UO Cardiologia	Brescia		Italy	25123
137	AOU Policlinico Vittorio Emanuele	Catania		Italy	95123
138	Magna Graecia University	Catanzaro		Italy	88100
139	Ospedale S. Croce e Carle	Cuneo		Italy	12100
140	Citta di Lecce Hospital	Lecce		Italy	73100
141	Azienda Socio Sanitaria Territoriale di Lecco	Lecco		Italy	23900
142	ASST Ovest Milanese - Presidio Ospedallero di Legnana	Legnano		Italy	20025
143	Fondazione Toscana Gabriele Monasterio	Massa		Italy	54100
144	Ospedale San Raffaele	Milano		Italy	20132
145	Centro Cardiologico Monzino IRCCS	Milano		Italy	20138
146	ASST Grande Ospedale Metropolitano Niguarda	Milano		Italy	20162
147	Clinica Mediterranea	Napoli		Italy	80122
148	A.A Dei Colli Monaldi UOC Cardiologia Interventistica	Napoli		Italy	80131
149	Azienda Ospedaliera di Padova	Padova		Italy	35121
150	Fondazione IRCCS Policlinico San Matteo	Pavia		Italy	27100
151	IRCCS Policlinico San Matteo	Pavia		Italy	27100
152	Centro Cuore Morgagni	Pedara		Italy	95030
153	Azienda Ospedaliero-Universitaria Pisana	Pisa		Italy	56124
154	IRCCS-ASMN Reggio Emilia	Reggio Emilia		Italy	42123
155	AO San Camillo Forlanini	Rome		Italy	00152
156	Azienda Ospedaliero-Universitaria Policlinico Umberto I	Rome		Italy	00161
157	AOU Careggi, Interventistica Cardiologica Strutturale	Rome		Italy	00187
158	Ospedale Sant'Andrea - U.O.S. Emodinamica Cardiologia Interventistica	Rome		Italy	00189
159	Istituto Clinico Humanitas	Rozzano		Italy	20089
160	AOU S.Giovanni Di Dio e Ruggi D'Aragona	Salerno		Italy	84133
161	IRCCS Policlinico San Donato	San Donato Milanese		Italy
162	UOC Emodinamica III	Siena		Italy	53100
163	Azienda Ospedaliera Integrata di Verona	Verona		Italy	37126
164	Nagoya Heart Center	Toyohashi	Aichi	Japan	441-8530
165	Kokura Memorial Hospital	Kitakyushu	Fukuoka	Japan	802-8555
166	Ogaki Municipal Hospital	Ōgaki	Gifu	Japan	503-0864
167	Sapporo Higashi Tokushukai Hospital	Sapporo	Hokkaido	Japan	065-0033
168	Tsukuba Medical Center Hospital	Amakubo	Ibaraki	Japan	305-8558
169	Teikyo University Hospital	Tokyo	Itabashi	Japan	173-0003
170	Iwate Medical University Hospital	Morioka	Iwate Prefecture	Japan	020-8505
171	Tokai University Hospital	Isehara	Kanagawa	Japan	259-1193
172	St. Marianna University School of Medicine Hospital	Kawasaki	Kanagawa	Japan	216-0015
173	Saiseikai Yokohamashi Tobu Hospital	Yokohama	Kanagawa	Japan	230-8765
174	Sendai Kousei Hospital	Sendai	Miyagi	Japan	980-0873
175	Osaka City University Hospital	Abeno Ward	Osaka	Japan	545-8586
176	Kishiwada Tokushukai Hospital	Kishiwada	Osaka	Japan	596-0042
177	Keio University Hospital	Shinjuku City	Tokyo	Japan	160-0016
178	Toyohashi Heart Center	Aichi		Japan	441-8530
179	New Tokyo Hospital	Chiba		Japan	270-2232
180	Shonan Kamakura General Hospital	Kanagawa		Japan	247-0072
181	Toyama University Hospital	Toyama		Japan	930-0194
182	Seoul National University Hospital	Seoul	Jongno-gu	Korea, Republic of
183	Seoul St. Mary's Hospital	Seoul	Seocho-gu	Korea, Republic of	06591
184	Yonsei University Severance Hospital	Seoul	Seodaemun-gu	Korea, Republic of
185	Korean University Anam Hospital	Seoul	Seongbuk-gu	Korea, Republic of	02841
186	Asan Medical Center	Seoul	Songpa-gu	Korea, Republic of
187	Academic Medical Center	Amsterdam		Netherlands	1105 AZ
188	HagaZiekenhuis	Den Haag		Netherlands	2504 LN
189	University Medical Center Groningen	Groningen		Netherlands	9713 GZ
190	Medisch Centrum Leeuwarden	Leeuwarden		Netherlands	8934 AD
191	Erasmus Medical Center	Rotterdam		Netherlands	3015 CN
192	Uniwersytecki Szpital Kliniczny w Bialymstoku	Białystok		Poland	15-276
193	University Clinical Centre in Gdańsk	Gdańsk		Poland	80-952
194	Szpital Kliniczny Przemienienia Pańskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu	Poznań		Poland	61-848
195	Hospital Universitario Virgen Macarena	Sevilla	Andalucia	Spain	41009
196	Hospital Universitario Central de Asturias	Oviedo	Asturias	Spain	33011
197	Hospital Universitari Germans Trias I Pujol	Badalona	Barcelona	Spain	08916
198	Hospital Universitario Donostia	Donostia	Gipuzkoa	Spain	20014
199	Complexo hospitalario universitario de Santiago de Compostela	A Coruña		Spain	15706
200	Hospital General Universitario de Alicante	Alicante		Spain	03540
201	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
202	Hospital Clinico y Provincial de Barcelona	Barcelona		Spain	08036
203	Complejo Asistencial de Granada	Grenada		Spain	18014
204	Complexo Hospitalario Universitario de A Coruna	La Coruña		Spain	15006
205	Hospital La Luz QuironSalud	Madrid		Spain	28003
206	Hospital Universitario La Princesa	Madrid		Spain	28006
207	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
208	Hospital Clinico San Carlos	Madrid		Spain	28040
209	Hospital Universitario La Paz	Madrid		Spain	28046
210	Hospital Virgen de la Arrixaca	Murcia		Spain	31020
211	Hospital Universitario Virgen de la Victoria	Málaga		Spain	29010
212	Valdecilla Hospital	Santander		Spain	39008
213	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
214	Hospital Clinico de Valencia	Valencia		Spain	46010
215	Hospital Clinico Universitario de Valladolid	Valladolid		Spain	47003
216	Hospital Universitario Alvaro Cunqueiro	Vigo		Spain	36312
217	Universitatsspital Basel	Basel		Switzerland	4031
218	Bern University Hospital	Bern		Switzerland	3010
219	Hopitaux Universitaires de Geneve	Geneve		Switzerland	1205
220	Cardiocentro Ticino	Lugano		Switzerland	6900
221	BSUH, Cardiac Research Unit	Brighton	England	United Kingdom	BN2 5BE
222	Papworth Hospital NHS Foundation Trust	Cambridge	England	United Kingdom	CB23 3RE
223	Royal Edinburgh Infirmary	Edinburgh	England	United Kingdom	EH16 4SA
224	Guys St Thomas Hospital	London	England	United Kingdom	SE1 7EH
225	Trent Cardiac Centre	Nottingham	England	United Kingdom	NG5 1PB
226	Oxford University Hospitals, John Radcliffe Hospital	Oxford	England	United Kingdom	OX3 9DU
227	Northern General Hospital	Sheffield	England	United Kingdom	S5 7AU
228	University Hospital of Wales, Heath Park	Cardiff	Wales	United Kingdom	CF14 4XW
229	University Hospitals of Leicester NHS Trust	Leicester		United Kingdom	LE3 9QP
230	Derriford Hospital	Plymouth		United Kingdom	PL6 8DH

Sponsors and Collaborators

• Daiichi Sankyo, Inc.
• Chiltern International Inc.

Investigators

• Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 29, 2019

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT02943785
• Other Study ID Numbers: DU176B-C-U4001; 2016-003930-26
• First Posted: Oct 25, 2016
• Last Update Posted: Mar 24, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daiichi Sankyo, Inc.: Transcatheter Aortic Valve Implantation -- TAVI; Anticoagulation; Atrial Fibrillation; ENVISAGE-TAVI-AF
• Additional relevant MeSH terms: Atrial Fibrillation; Edoxaban

Study Results

Participant Flow

Recruitment Details	A total of 1426 participants who met all inclusion criteria and no exclusion criteria were randomized to treatment at 173 clinic sites in Europe, Asia, and North America.
Pre-assignment Detail	Participants in the study underwent successful transcatheter aortic valve implantation (TAVI) and had a pre-existing atrial fibrillation (AF) or new onset AF.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Period Title: Overall Study
STARTED	713	713
COMPLETED	431	350
NOT COMPLETED	282	363

Baseline Characteristics

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)	Total
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.	Total of all reporting groups
Overall Participants	713	713	1426
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	82.1 (5.4)	82.1 (5.5)	82.1 (5.5)
Age, Customized (Count of Participants)
<65 years	5 0.7%	5 0.7%	10 0.7%
≥65 to <75 years	53 7.4%	55 7.7%	108 7.6%
≥75 to <80 years	131 18.4%	122 17.1%	253 17.7%
≥80 to <85 years	289 40.5%	298 41.8%	587 41.2%
≥85 to <90 years	191 26.8%	183 25.7%	374 26.2%
≥90 years	44 6.2%	50 7%	94 6.6%
Sex: Female, Male (Count of Participants)
Female	347 48.7%	331 46.4%	678 47.5%
Male	366 51.3%	382 53.6%	748 52.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	92 12.9%	89 12.5%	181 12.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 0.1%	4 0.6%	5 0.4%
White	593 83.2%	594 83.3%	1187 83.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	27 3.8%	26 3.6%	53 3.7%
Region of Enrollment (participants) [Number]
United States	77 10.8%	77 10.8%	154 10.8%
Japan	82 11.5%	77 10.8%	159 11.2%
United Kingdom	7 1%	10 1.4%	17 1.2%
Switzerland	17 2.4%	17 2.4%	34 2.4%
Spain	172 24.1%	172 24.1%	344 24.1%
Canada	8 1.1%	6 0.8%	14 1%
Austria	30 4.2%	32 4.5%	62 4.3%
Netherlands	28 3.9%	27 3.8%	55 3.9%
South Korea	9 1.3%	10 1.4%	19 1.3%
Belgium	17 2.4%	17 2.4%	34 2.4%
Poland	10 1.4%	10 1.4%	20 1.4%
Italy	65 9.1%	67 9.4%	132 9.3%
France	22 3.1%	24 3.4%	46 3.2%
Germany	169 23.7%	167 23.4%	336 23.6%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	74.6 (17.9)	76.0 (17.3)	75.3 (17.6)
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.5 (5.7)	27.9 (5.4)	27.7 (5.5)
Creatinine Clearance (Cockcroft-Gault formula) (mL/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min]	57.9 (24.0)	58.6 (24.3)	58.2 (24.1)
Hypertension (Count of Participants)
Count of Participants [Participants]	647 90.7%	657 92.1%	1304 91.4%
Diabetes mellitus (Count of Participants)
Count of Participants [Participants]	270 37.9%	257 36%	527 37%
Congestive heart failure (Count of Participants)
Congestive heart failure	591 82.9%	619 86.8%	1210 84.9%
NYHA class III or IV status	314 44%	328 46%	642 45%
Mitral valve disease (Count of Participants)
Count of Participants [Participants]	57 8%	60 8.4%	117 8.2%
History of stroke or transient ischemic attack (Count of Participants)
Count of Participants [Participants]	123 17.3%	116 16.3%	239 16.8%
Coronary artery disease (Count of Participants)
History of coronary artery disease	293 41.1%	297 41.7%	590 41.4%
Prior coronary bypass surgery	67 9.4%	60 8.4%	127 8.9%
Prior percutaneous coronary intervention	176 24.7%	192 26.9%	368 25.8%
Prior myocardial infarction	97 13.6%	101 14.2%	198 13.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA
Description	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].
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

Net adverse clinical events were assessed in the Intent-to-Treat (ITT) Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Count of Participants [Participants]	170 23.8%	157 22%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban, Vitamin K Antagonist (VKA)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The two-sided p-value (Noninferiority) was based on the noninferiority margin of 1.38.
Statistical Test of Hypothesis	p-Value	0.0141
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Number of Participants Who Experienced Major Bleeding (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA
Description	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.
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

Bleeding events were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Count of Participants [Participants]	98 13.7%	68 9.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban, Vitamin K Antagonist (VKA)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The two-sided p-value (Noninferiority) was based on the noninferiority margin of 1.38.
Statistical Test of Hypothesis	p-Value	0.9267
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.40
	Confidence Interval	(2-Sided) 95%; 1.03 to 1.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on TIMI Criteria in Participants Taking Edoxaban vs VKA
Description	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.
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

Net adverse clinical events were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Composite endpoint NACE (TIMI)	154 21.6%	141 19.8%
Composite of major and minor bleeding (TIMI)	72 10.1%	42 5.9%

4. Secondary Outcome

Title	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
Description	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
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

Net adverse clinical events were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Composite endpoint NACE (BARC Type 3 or 5)	164 23%	151 21.2%
Major bleeding (BARC Type 3 or 5)	89 12.5%	57 8%

5. Secondary Outcome

Title	Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on GUSTO Criteria in Participants Taking Edoxaban vs VKA
Description	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.
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

Net adverse clinical events were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Composite endpoint NACE (GUSTO)	160 22.4%	146 20.5%
Severe or life threatening and moderate bleeding (GUSTO)	82 11.5%	51 7.2%

6. Secondary Outcome

Title	Number of Participants Who Experienced Major Adverse Cardiac Events (MACE) in Participants Taking Edoxaban vs VKA (Adjudicated Data)
Description	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.
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

MACE were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Count of Participants [Participants]	61 8.6%	53 7.4%

7. Secondary Outcome

Title	Number of Participants Who Experienced Major Adverse Cardiac and Cerebrovascular Events (MACCE) in Participants Taking Edoxaban vs VKA (Adjudicated Data)
Description	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
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

MACE were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Count of Participants [Participants]	86 12.1%	80 11.2%

8. Secondary Outcome

Title	Number of Participants Who Experienced a Composite of Adverse Events in Participants Taking Edoxaban vs VKA (Adjudicated Data)
Description	A composite of clinical adverse events included cardiovascular death, MI ischemic stroke, SEE, valve thrombosis, and major bleeding as defined by ISTH criteria.
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

A composite of adverse events was assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Count of Participants [Participants]	151 21.2%	123 17.3%

9. Secondary Outcome

Title	Number of Participants Who Experienced Stroke Events (Ischemic, Hemorrhagic, Undetermined) in Participants Taking Edoxaban vs VKA (Adjudicated Data)
Description	Stroke events are categorized as any stroke, fatal stroke, and non-fatal stroke.
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

Stroke events were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Any stroke (ischemic, hemorrhagic, or undetermined)	29 4.1%	35 4.9%
Fatal stroke (ischemic, hemorrhagic, or undetermined)	4 0.6%	3 0.4%
Non-fatal stroke (ischemic, hemorrhagic, or undetermined)	25 3.5%	32 4.5%

10. Secondary Outcome

Title	Number of Participants Who Experienced Systemic Embolic Events in Participants Taking Edoxaban vs VKA (Adjudicated Data)
Description	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).
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

Systemic embolic events (SEE) were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Count of Participants [Participants]	2 0.3%	3 0.4%

11. Secondary Outcome

Title	Number of Participants Who Experienced Myocardial Infarctions (MI) in Participants Taking Edoxaban vs VKA (Adjudicated Data)
Description	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.
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

Myocardial infarctions were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Count of Participants [Participants]	12 1.7%	7 1%

12. Secondary Outcome

Title	Number of Participants Who Experienced Valve Thrombosis in Participants Taking Edoxaban vs VKA (Adjudicated Data)
Description	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.
Time Frame	Baseline through study completion, up to 36 months post-dose

Outcome Measure Data

Analysis Population Description

Valve thrombosis were assessed in the ITT Analysis Set.

Arm/Group Title	Edoxaban	Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablets for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.	Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
Measure Participants	713	713
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	Treatment-emergent adverse events were collected from the Safety Analysis Set from baseline up 4 weeks post-discontinuation of study treatment or through study completion, up to 36 months post-dose.
Adverse Event Reporting Description	Treatment-emergent adverse events are defined as events which start on or after any first dose of the assigned study medication regimen or started prior to but then worsened after any first dose of the assigned study medication regimen.
Arm/Group Title	Edoxaban		Vitamin K Antagonist (VKA)
Arm/Group Description	Participants randomized to receive the Edoxaban-based regimen which included 60 mg and 30 mg film coated tablet for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing followed the locally approved label.		Participants randomized to receive the VKA-based regimen which included oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator monitored the patient and adjusted the VKA dose to maintain the dose within target.
All Cause Mortality
	Edoxaban		Vitamin K Antagonist (VKA)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	83/693 (12%)		78/684 (11.4%)
Serious Adverse Events
	Edoxaban		Vitamin K Antagonist (VKA)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	388/693 (56%)		372/684 (54.4%)
Blood and lymphatic system disorders
Anemia	31/693 (4.5%)		11/684 (1.6%)
Blood loss anaemia	5/693 (0.7%)		1/684 (0.1%)
Iron deficiency anaemia	3/693 (0.4%)		3/684 (0.4%)
Thrombocytopenia	0/693 (0%)		6/684 (0.9%)
Anaemia folate deficiency	2/693 (0.3%)		0/684 (0%)
Hypochromic anaemia	2/693 (0.3%)		0/684 (0%)
Normocytic anaemia	2/693 (0.3%)		0/684 (0%)
Coagulopathy	0/693 (0%)		1/684 (0.1%)
Heparin-induced thrombocytopenia	0/693 (0%)		1/684 (0.1%)
Leukocytosis	1/693 (0.1%)		0/684 (0%)
Lymphadenopathy mediastinal	1/693 (0.1%)		0/684 (0%)
Microcytic anaemia	1/693 (0.1%)		0/684 (0%)
Nephrogenic anaemia	1/693 (0.1%)		0/684 (0%)
Normochromic anaemia	1/693 (0.1%)		0/684 (0%)
Normochromic normocytic anaemia	1/693 (0.1%)		0/684 (0%)
Pancytopenia	0/693 (0%)		1/684 (0.1%)
Splenic infarction	1/693 (0.1%)		0/684 (0%)
Spontaneous haematoma	0/693 (0%)		1/684 (0.1%)
Cardiac disorders
Cardiac failure	57/693 (8.2%)		64/684 (9.4%)
Atrial fibrillation	17/693 (2.5%)		18/684 (2.6%)
Cardiac failure congestive	23/693 (3.3%)		12/684 (1.8%)
Cardiac failure acute	8/693 (1.2%)		11/684 (1.6%)
Atrioventricular block complete	9/693 (1.3%)		6/684 (0.9%)
Mitral valve incompetence	6/693 (0.9%)		8/684 (1.2%)
Bradycardia	6/693 (0.9%)		3/684 (0.4%)
Cardiac arrest	2/693 (0.3%)		7/684 (1%)
Atrial flutter	6/693 (0.9%)		1/684 (0.1%)
Acute myocardial infarction	4/693 (0.6%)		2/684 (0.3%)
Angina pectoris	2/693 (0.3%)		4/684 (0.6%)
Sinus node dysfunction	4/693 (0.6%)		2/684 (0.3%)
Pericardial effusion	4/693 (0.6%)		1/684 (0.1%)
Tachyarrhythmia	2/693 (0.3%)		3/684 (0.4%)
Atrioventricular block	3/693 (0.4%)		1/684 (0.1%)
Cardio-respiratory arrest	0/693 (0%)		4/684 (0.6%)
Ventricular tachycardia	2/693 (0.3%)		2/684 (0.3%)
Bundle branch block left	2/693 (0.3%)		1/684 (0.1%)
Cardiac failure chronic	1/693 (0.1%)		2/684 (0.3%)
Coronary artery disease	3/693 (0.4%)		0/684 (0%)
Aortic valve stenosis	2/693 (0.3%)		0/684 (0%)
Arrhythmia	1/693 (0.1%)		1/684 (0.1%)
Cardiac asthma	1/693 (0.1%)		1/684 (0.1%)
Cardiac tamponade	1/693 (0.1%)		1/684 (0.1%)
Cardiopulmonary failure	2/693 (0.3%)		0/684 (0%)
Left ventricular failure	2/693 (0.3%)		0/684 (0%)
Myocardial infarction	0/693 (0%)		2/684 (0.3%)
Sinus arrest	1/693 (0.1%)		1/684 (0.1%)
Acute coronary syndrome	1/693 (0.1%)		0/684 (0%)
Acute left ventricular failure	1/693 (0.1%)		0/684 (0%)
Angina unstable	0/693 (0%)		1/684 (0.1%)
Aortic valve disease	0/693 (0%)		1/684 (0.1%)
Aortic valve incompetence	0/693 (0%)		1/684 (0.1%)
Atrial tachycardia	1/693 (0.1%)		0/684 (0%)
Atrioventricular block first degree	0/693 (0%)		1/684 (0.1%)
Atrioventricular block second degree	1/693 (0.1%)		0/684 (0%)
Bifascicular block	1/693 (0.1%)		0/684 (0%)
Bradyarrhythmia	1/693 (0.1%)		0/684 (0%)
Cardiogenic shock	0/693 (0%)		1/684 (0.1%)
Cardiorenal syndrome	0/693 (0%)		1/684 (0.1%)
Chronic left ventricular failure	0/693 (0%)		1/684 (0.1%)
Conduction disorder	1/693 (0.1%)		0/684 (0%)
Cor pulmonale	0/693 (0%)		1/684 (0.1%)
Coronary artery stenosis	0/693 (0%)		1/684 (0.1%)
Intracardiac thrombus	1/693 (0.1%)		0/684 (0%)
Ischaemic cardiomyopathy	1/693 (0.1%)		0/684 (0%)
Mitral valve disease	0/693 (0%)		1/684 (0.1%)
Pericarditis	1/693 (0.1%)		0/684 (0%)
Prosthetic cardiac valve thrombosis	1/693 (0.1%)		0/684 (0%)
Right ventricular failure	0/693 (0%)		1/684 (0.1%)
Stress cardiomyopathy	1/693 (0.1%)		0/684 (0%)
Supraventricular tachycardia	1/693 (0.1%)		0/684 (0%)
Ventricular dysfunction	0/693 (0%)		1/684 (0.1%)
Ventricular extrasystoles	1/693 (0.1%)		0/684 (0%)
Ear and labyrinth disorders
Tympanic membrane perforation	1/693 (0.1%)		0/684 (0%)
Vestibular disorder	0/693 (0%)		1/684 (0.1%)
Vestibular paroxysmia	1/693 (0.1%)		0/684 (0%)
Endocrine disorders
Hyperthyroidism	0/693 (0%)		1/684 (0.1%)
Eye disorders
Cataract	2/693 (0.3%)		1/684 (0.1%)
Retinal artery occlusion	2/693 (0.3%)		1/684 (0.1%)
Amaurosis fugax	0/693 (0%)		1/684 (0.1%)
Choroidal detachment	1/693 (0.1%)		0/684 (0%)
Retinal haemorrhage	0/693 (0%)		1/684 (0.1%)
Vitreous detachment	1/693 (0.1%)		0/684 (0%)
Gastrointestinal disorders
Lower gastrointestinal haemorrhage	16/693 (2.3%)		7/684 (1%)
Upper gastrointestinal haemorrhage	8/693 (1.2%)		4/684 (0.6%)
Diarrhoea	7/693 (1%)		1/684 (0.1%)
Gastrointestinal haemorrhage	5/693 (0.7%)		3/684 (0.4%)
Inguinal hernia	2/693 (0.3%)		6/684 (0.9%)
Rectal haemorrhage	4/693 (0.6%)		2/684 (0.3%)
Abdominal pain	1/693 (0.1%)		2/684 (0.3%)
Anal haemorrhage	3/693 (0.4%)		0/684 (0%)
Intestinal ischaemia	1/693 (0.1%)		2/684 (0.3%)
Intestinal obstruction	2/693 (0.3%)		1/684 (0.1%)
Melaena	3/693 (0.4%)		0/684 (0%)
Constipation	1/693 (0.1%)		1/684 (0.1%)
Diverticulum intestinal hemorrhagic	2/693 (0.3%)		0/684 (0%)
Gastric ulcer	1/693 (0.1%)		1/684 (0.1%)
Vomiting	0/693 (0%)		2/684 (0.3%)
Abdominal hernia	0/693 (0%)		1/684 (0.1%)
Anal fissure	1/693 (0.1%)		0/684 (0%)
Chronic gastritis	1/693 (0.1%)		0/684 (0%)
Colitis	1/693 (0.1%)		0/684 (0%)
Diverticulum intestinal	1/693 (0.1%)		0/684 (0%)
Enterocele	1/693 (0.1%)		0/684 (0%)
Gastric haemorrhage	0/693 (0%)		1/684 (0.1%)
Gastric perforation	0/693 (0%)		1/684 (0.1%)
Gastric polyps	0/693 (0%)		1/684 (0.1%)
Gastric ulcer haemorrhage	0/693 (0%)		1/684 (0.1%)
Gastritis	1/693 (0.1%)		0/684 (0%)
Gastroduodenal ulcer	1/693 (0.1%)		0/684 (0%)
Gastrointestinal disorder	1/693 (0.1%)		0/684 (0%)
Haematemesis	1/693 (0.1%)		0/684 (0%)
Haematochezia	1/693 (0.1%)		0/684 (0%)
Haemorrhoids	1/693 (0.1%)		0/684 (0%)
Ileus	0/693 (0%)		1/684 (0.1%)
Intestinal haemorrhage	1/693 (0.1%)		0/684 (0%)
Intestinal polyp	1/693 (0.1%)		0/684 (0%)
Mallory-Weiss syndrome	1/693 (0.1%)		0/684 (0%)
Mechanical ileus	0/693 (0%)		1/684 (0.1%)
Oesophageal ulcer	1/693 (0.1%)		0/684 (0%)
Pancreatic failure	1/693 (0.1%)		0/684 (0%)
Pancreatitis	0/693 (0%)		1/684 (0.1%)
Pancreatitis acute	0/693 (0%)		1/684 (0.1%)
Pancreatitis necrotising	0/693 (0%)		1/684 (0.1%)
Subileus	0/693 (0%)		1/684 (0.1%)
Ulcerative duodenitis	0/693 (0%)		1/684 (0.1%)
Umbilical hernia	1/693 (0.1%)		0/684 (0%)
General disorders
Death	8/693 (1.2%)		3/684 (0.4%)
General physical health deterioration	3/693 (0.4%)		6/684 (0.9%)
Asthenia	4/693 (0.6%)		4/684 (0.6%)
Multiple organ dysfunction syndrome	5/693 (0.7%)		2/684 (0.3%)
Non-cardiac chest pain	4/693 (0.6%)		2/684 (0.3%)
Sudden death	4/693 (0.6%)		2/684 (0.3%)
Impaired healing	1/693 (0.1%)		2/684 (0.3%)
Pyrexia	3/693 (0.4%)		0/684 (0%)
Malaise	1/693 (0.1%)		1/684 (0.1%)
Oedema peripheral	1/693 (0.1%)		1/684 (0.1%)
Pacemaker generated arrhythmia	2/693 (0.3%)		0/684 (0%)
Chest discomfort	0/693 (0%)		1/684 (0.1%)
Chest pain	0/693 (0%)		1/684 (0.1%)
Fatigue	0/693 (0%)		1/684 (0.1%)
Injection site haematoma	0/693 (0%)		1/684 (0.1%)
Peripheral swelling	0/693 (0%)		1/684 (0.1%)
Stent-graft endoleak	0/693 (0%)		1/684 (0.1%)
Sudden cardiac death	0/693 (0%)		1/684 (0.1%)
Systemic inflammatory response syndrome	1/693 (0.1%)		0/684 (0%)
Heart rate irregular	0/693 (0%)		1/684 (0.1%)
Hepatic enzyme increased	1/693 (0.1%)		0/684 (0%)
Inflammatory marker increased	1/693 (0.1%)		0/684 (0%)
Myocardial necrosis marker increased	0/693 (0%)		1/684 (0.1%)
Weight increased	0/693 (0%)		1/684 (0.1%)
Hepatobiliary disorders
Bile duct stone	4/693 (0.6%)		2/684 (0.3%)
Cholelithiasis	2/693 (0.3%)		2/684 (0.3%)
Cholangitis	2/693 (0.3%)		0/684 (0%)
Cholangitis acute	0/693 (0%)		2/684 (0.3%)
Cholecystitis	1/693 (0.1%)		0/684 (0%)
Hepatic function abnormal	0/693 (0%)		1/684 (0.1%)
Immune system disorders
Anaphylatic shock	1/693 (0.1%)		0/684 (0%)
Infections and infestations
Pneumonia	39/693 (5.6%)		37/684 (5.4%)
Urinary tract infection	21/693 (3%)		17/684 (2.5%)
Endocarditis	14/693 (2%)		7/684 (1%)
Respiratory tract infection	7/693 (1%)		13/684 (1.9%)
Sepsis	6/693 (0.9%)		7/684 (1%)
Bronchitis	4/693 (0.6%)		5/684 (0.7%)
COVID-19	2/693 (0.3%)		6/684 (0.9%)
Septic shock	5/693 (0.7%)		3/684 (0.4%)
Urosepsis	6/693 (0.9%)		2/684 (0.3%)
Cellulitis	3/693 (0.4%)		4/684 (0.6%)
Gastroenteritis	3/693 (0.4%)		3/684 (0.4%)
Bacteraemia	2/693 (0.3%)		3/684 (0.4%)
COVID-19 pneumonia	1/693 (0.1%)		4/684 (0.6%)
Influenza	4/693 (0.6%)		1/684 (0.1%)
Enterococcal sepsis	2/693 (0.3%)		2/684 (0.3%)
Lower respiratory tract infection	3/693 (0.4%)		1/684 (0.1%)
Appendicitis	0/693 (0%)		3/684 (0.4%)
Cystitis	3/693 (0.4%)		0/684 (0%)
Erysipelas	3/693 (0.4%)		0/684 (0%)
Infection	1/693 (0.1%)		2/684 (0.3%)
Intervertebral discitis	1/693 (0.1%)		2/684 (0.3%)
Staphylococcal bacteraemia	2/693 (0.3%)		1/684 (0.1%)
Staphylococcal sepsis	2/693 (0.3%)		1/684 (0.1%)
Streptococcal endocarditis	3/693 (0.4%)		0/684 (0%)
Clostridium difficile infection	1/693 (0.1%)		1/684 (0.1%)
Endocarditis staphylococcal	1/693 (0.1%)		1/684 (0.1%)
Enterococcal bacteraemia	1/693 (0.1%)		1/684 (0.1%)
Enterococcal infection	0/693 (0%)		2/684 (0.3%)
Epididymitis	1/693 (0.1%)		1/684 (0.1%)
Escherichia sepsis	2/693 (0.3%)		0/684 (0%)
Gangrene	1/693 (0.1%)		1/684 (0.1%)
Herpes zoster	2/693 (0.3%)		0/684 (0%)
Klebsiella infection	1/693 (0.1%)		1/684 (0.1%)
Pulmonary sepsis	1/693 (0.1%)		1/684 (0.1%)
Pyelonephritis	1/693 (0.1%)		1/684 (0.1%)
Streptococcal bacteraemia	1/693 (0.1%)		1/684 (0.1%)
Abscess soft tissue	1/693 (0.1%)		0/684 (0%)
Acinetobacter bacteraemia	1/693 (0.1%)		0/684 (0%)
Alveolar osteitis	1/693 (0.1%)		0/684 (0%)
Anal abscess	0/693 (0%)		1/684 (0.1%)
Aspergilloma	0/693 (0%)		1/684 (0.1%)
Bacterial sepsis	1/693 (0.1%)		0/684 (0%)
Citrobacter sepsis	1/693 (0.1%)		0/684 (0%)
Clostridium difficile colitis	0/693 (0%)		1/684 (0.1%)
Cystitis klebsiella	1/693 (0.1%)		0/684 (0%)
Device-related sepsis	1/693 (0.1%)		0/684 (0%)
Diverticulitis	1/693 (0.1%)		0/684 (0%)
Endocarditis enterococcal	1/693 (0.1%)		0/684 (0%)
Escherichia bacteraemia	1/693 (0.1%)		0/684 (0%)
Escherichia infection	1/693 (0.1%)		0/684 (0%)
Escherichia urinary tract infection	1/693 (0.1%)		0/684 (0%)
Fracture infection	1/693 (0.1%)		0/684 (0%)
Fungal tracheitis	0/693 (0%)		1/684 (0.1%)
Gastric infection	0/693 (0%)		1/684 (0.1%)
Groin infection	0/693 (0%)		1/684 (0.1%)
Herpes zoster oticus	1/693 (0.1%)		0/684 (0%)
Infected lymphocele	0/693 (0%)		1/684 (0.1%)
Infective aneurysm	0/693 (0%)		1/684 (0.1%)
Klebsiella bacteraemia	1/693 (0.1%)		0/684 (0%)
Klebsiella sepsis	0/693 (0%)		1/684 (0.1%)
Medical device site infection	0/693 (0%)		1/684 (0.1%)
Mycotic corneal ulcer	1/693 (0.1%)		0/684 (0%)
Nosocomial infection	1/693 (0.1%)		0/684 (0%)
Oesophageal candidiasis	0/693 (0%)		1/684 (0.1%)
Osteomyelitis	0/693 (0%)		1/684 (0.1%)
Peritonitis	0/693 (0%)		1/684 (0.1%)
Pneumococcal bacteraemia	0/693 (0%)		1/684 (0.1%)
Pneumococcal sepsis	1/693 (0.1%)		0/684 (0%)
Pneumonia pneumococcal	0/693 (0%)		1/684 (0.1%)
Pneumonia streptococcal	0/693 (0%)		1/684 (0.1%)
Postoperative wound infection	0/693 (0%)		1/684 (0.1%)
Pseudomonal sepsis	0/693 (0%)		1/684 (0.1%)
Pyelonephritis acute	0/693 (0%)		1/684 (0.1%)
Respiratory tract infection viral	1/693 (0.1%)		0/684 (0%)
Rhinovirus infection	1/693 (0.1%)		0/684 (0%)
Salmonellosis	0/693 (0%)		1/684 (0.1%)
Sinusitis	0/693 (0%)		1/684 (0.1%)
Streptococcal sepsis	1/693 (0.1%)		0/684 (0%)
Upper respiratory tract infection	0/693 (0%)		1/684 (0.1%)
Viral infection	1/693 (0.1%)		0/684 (0%)
Wound infection	1/693 (0.1%)		0/684 (0%)
Injury, poisoning and procedural complications
Vascular pseudoaneurysm	6/693 (0.9%)		8/684 (1.2%)
Fall	9/693 (1.3%)		4/684 (0.6%)
Femur fracture	5/693 (0.7%)		6/684 (0.9%)
Subdural haematoma	3/693 (0.4%)		5/684 (0.7%)
Femoral neck fracture	4/693 (0.6%)		3/684 (0.4%)
Head injury	3/693 (0.4%)		3/684 (0.4%)
Hip fracture	2/693 (0.3%)		4/684 (0.6%)
Pelvic fracture	2/693 (0.3%)		4/684 (0.6%)
Humerus fracture	2/693 (0.3%)		3/684 (0.4%)
Post procedural haemorrhage	0/693 (0%)		4/684 (0.6%)
Spinal compression fracture	2/693 (0.3%)		2/684 (0.3%)
Traumatic intracranial haemorrhage	2/693 (0.3%)		2/684 (0.3%)
Anaemia postoperative	0/693 (0%)		3/684 (0.4%)
Ankle fracture	2/693 (0.3%)		1/684 (0.1%)
Cervical vertebral fracture	3/693 (0.4%)		0/684 (0%)
Overdose	0/693 (0%)		3/684 (0.4%)
Fibula fracture	1/693 (0.1%)		1/684 (0.1%)
Lumbar vertebral fracture	1/693 (0.1%)		1/684 (0.1%)
Radius fracture	2/693 (0.3%)		0/684 (0%)
Skin laceration	1/693 (0.1%)		1/684 (0.1%)
Subcutaneous haematoma	0/693 (0%)		2/684 (0.3%)
Toxicity to various agents	1/693 (0.1%)		1/684 (0.1%)
Vascular access site pseduoaneurysm	1/693 (0.1%)		1/684 (0.1%)
Acetabulum fracture	0/693 (0%)		1/684 (0.1%)
Bone contusion	1/693 (0.1%)		0/684 (0%)
Chest injury	1/693 (0.1%)		0/684 (0%)
Clavicle fracture	0/693 (0%)		1/684 (0.1%)
Colon injury	1/693 (0.1%)		0/684 (0%)
Concussion	1/693 (0.1%)		0/684 (0%)
Contusion	0/693 (0%)		1/684 (0.1%)
Craniocerebral injury	1/693 (0.1%)		0/684 (0%)
Extradural haematoma	0/693 (0%)		1/684 (0.1%)
Face injury	0/693 (0%)		1/684 (0.1%)
Facial bones fracture	1/693 (0.1%)		0/684 (0%)
Foreign body in gastrointestinal tract	1/693 (0.1%)		0/684 (0%)
Fracture	0/693 (0%)		1/684 (0.1%)
Fractured sacrum	1/693 (0.1%)		0/684 (0%)
Hand fracture	0/693 (0%)		1/684 (0.1%)
Heat illness	1/693 (0.1%)		0/684 (0%)
Heat stroke	0/693 (0%)		1/684 (0.1%)
Joint dislocation	1/693 (0.1%)		0/684 (0%)
Open globe injury	1/693 (0.1%)		0/684 (0%)
Patella fracture	0/693 (0%)		1/684 (0.1%)
Post procedural complication	0/693 (0%)		1/684 (0.1%)
Post procedural fever	1/693 (0.1%)		0/684 (0%)
Post procedural haematoma	1/693 (0.1%)		0/684 (0%)
Postoperative delirium	0/693 (0%)		1/684 (0.1%)
Rib fracture	0/693 (0%)		1/684 (0.1%)
Road traffic accident	1/693 (0.1%)		0/684 (0%)
Seroma	0/693 (0%)		1/684 (0.1%)
Tendon rupture	1/693 (0.1%)		0/684 (0%)
Tibia fracture	0/693 (0%)		1/684 (0.1%)
Vascular access site haematoma	0/693 (0%)		1/684 (0.1%)
Wound	0/693 (0%)		1/684 (0.1%)
Wound dehiscence	1/693 (0.1%)		0/684 (0%)
Wound haemorrhage	0/693 (0%)		1/684 (0.1%)
Wrist fracture	0/693 (0%)		1/684 (0.1%)
Investigations
International normalised ratio increased	1/693 (0.1%)		5/684 (0.7%)
Haemoglobin decreased	2/693 (0.3%)		0/684 (0%)
Troponin increased	1/693 (0.1%)		1/684 (0.1%)
Anticoagulation drug level above therapeutic	0/693 (0%)		1/684 (0.1%)
Blood lactic acid increased	1/693 (0.1%)		0/684 (0%)
Coronavirus test positive	1/693 (0.1%)		0/684 (0%)
Ejection fraction decreased	0/693 (0%)		1/684 (0.1%)
General physical condition normal	0/693 (0%)		1/684 (0.1%)
Metabolism and nutrition disorders
Dehydration	3/693 (0.4%)		3/684 (0.4%)
Hyponatraemia	1/693 (0.1%)		3/684 (0.4%)
Fluid overload	2/693 (0.3%)		1/684 (0.1%)
Hypokalaemia	1/693 (0.1%)		2/684 (0.3%)
Cachexia	1/693 (0.1%)		1/684 (0.1%)
Decreased appetite	1/693 (0.1%)		1/684 (0.1%)
Hypoglycaemia	1/693 (0.1%)		1/684 (0.1%)
Malnutrition	0/693 (0%)		2/684 (0.3%)
Metabolic acidosis	1/693 (0.1%)		1/684 (0.1%)
Acidosis	0/693 (0%)		1/684 (0.1%)
Diabetes mellitus inadequate control	0/693 (0%)		1/684 (0.1%)
Diabetic metabolic decompensation	1/693 (0.1%)		0/684 (0%)
Fluid retention	1/693 (0.1%)		0/684 (0%)
Fructose intolerance	1/693 (0.1%)		0/684 (0%)
Gout	0/693 (0%)		1/684 (0.1%)
Hyperglycaemia	0/693 (0%)		1/684 (0.1%)
Hyperkalaemia	0/693 (0%)		1/684 (0.1%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	5/693 (0.7%)		3/684 (0.4%)
Haemarthrosis	0/693 (0%)		3/684 (0.4%)
Pain in extremity	0/693 (0%)		3/684 (0.4%)
Arthralgia	1/693 (0.1%)		1/684 (0.1%)
Arthritis	2/693 (0.3%)		0/684 (0%)
Back pain	1/693 (0.1%)		1/684 (0.1%)
Muscular weakness	1/693 (0.1%)		1/684 (0.1%)
Osteonecrosis	1/693 (0.1%)		1/684 (0.1%)
Arthropathy	1/693 (0.1%)		0/684 (0%)
Bursitis	1/693 (0.1%)		0/684 (0%)
Chest wall haematoma	0/693 (0%)		1/684 (0.1%)
Chondrocalcinosis pyrophosphate	0/693 (0%)		1/684 (0.1%)
Haematoma muscle	1/693 (0.1%)		0/684 (0%)
Osteonecrosis of jaw	1/693 (0.1%)		0/684 (0%)
Polymyalgia rheumatica	1/693 (0.1%)		0/684 (0%)
Rheumatoid arthritis	0/693 (0%)		1/684 (0.1%)
Rotator cuff syndrome	1/693 (0.1%)		0/684 (0%)
Soft tissue disorder	1/693 (0.1%)		0/684 (0%)
Spinal osteoarthritis	1/693 (0.1%)		0/684 (0%)
Spinal stenosis	1/693 (0.1%)		0/684 (0%)
Tendonitis	1/693 (0.1%)		0/684 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	2/693 (0.3%)		1/684 (0.1%)
Prostate cancer	2/693 (0.3%)		1/684 (0.1%)
Adenocarcinoma of colon	2/693 (0.3%)		0/684 (0%)
Basal cell carcinoma	2/693 (0.3%)		0/684 (0%)
Bladder cancer	1/693 (0.1%)		1/684 (0.1%)
Neoplasm malignant	1/693 (0.1%)		1/684 (0.1%)
Squamous cell carcinoma of skin	2/693 (0.3%)		0/684 (0%)
Acute leukaemia	0/693 (0%)		1/684 (0.1%)
Adenocarcinoma gastric	1/693 (0.1%)		0/684 (0%)
Anogenital warts	0/693 (0%)		1/684 (0.1%)
Breast cancer	0/693 (0%)		1/684 (0.1%)
Cholangiocarcinoma	1/693 (0.1%)		0/684 (0%)
Chronic lymphocytic leukaemia	0/693 (0%)		1/684 (0.1%)
Chronic myelomonocytic leukaemia	1/693 (0.1%)		0/684 (0%)
Gastrointestinal tract adenoma	0/693 (0%)		1/684 (0.1%)
Hepatocellular carcinoma	0/693 (0%)		1/684 (0.1%)
Leukaemia	0/693 (0%)		1/684 (0.1%)
Lung neoplasm	0/693 (0%)		1/684 (0.1%)
Lung neoplasm malignant	1/693 (0.1%)		0/684 (0%)
Lymphoma	1/693 (0.1%)		0/684 (0%)
Malignant melanoma	1/693 (0.1%)		0/684 (0%)
Malignant pleural effusion	0/693 (0%)		1/684 (0.1%)
Metastases to central nervous system	1/693 (0.1%)		0/684 (0%)
Metastases to pelvis	0/693 (0%)		1/684 (0.1%)
Myeloproliferative neoplasm	0/693 (0%)		1/684 (0.1%)
Neoplasm prostate	0/693 (0%)		1/684 (0.1%)
Neoplasm skin	0/693 (0%)		1/684 (0.1%)
Neuroendocrine carcinoma of the skin	0/693 (0%)		1/684 (0.1%)
Oesophageal adenocarcinoma	0/693 (0%)		1/684 (0.1%)
Papillary thyroid cancer	0/693 (0%)		1/684 (0.1%)
Prostate cancer metastatic	0/693 (0%)		1/684 (0.1%)
Rectal adenocarcinoma	0/693 (0%)		1/684 (0.1%)
Rectal cancer	1/693 (0.1%)		0/684 (0%)
Refractory cytopenia with unilineage dysplasia	1/693 (0.1%)		0/684 (0%)
Transitional cell carcinoma	1/693 (0.1%)		0/684 (0%)
Ureteric cancer	1/693 (0.1%)		0/684 (0%)
Nervous system disorders
Syncope	13/693 (1.9%)		12/684 (1.8%)
Ischaemic stroke	9/693 (1.3%)		10/684 (1.5%)
Transient ischaemic attack	7/693 (1%)		8/684 (1.2%)
Dizziness	6/693 (0.9%)		5/684 (0.7%)
Cerebral haemorrhage	5/693 (0.7%)		1/684 (0.1%)
Cerebral infarction	2/693 (0.3%)		4/684 (0.6%)
Embolic stroke	4/693 (0.6%)		1/684 (0.1%)
Cognitive disorder	3/693 (0.4%)		1/684 (0.1%)
Haemorrhage intracranial	1/693 (0.1%)		3/684 (0.4%)
Haemorrhage stroke	1/693 (0.1%)		3/684 (0.4%)
Chorea	2/693 (0.3%)		1/684 (0.1%)
Epilepsy	3/693 (0.4%)		0/684 (0%)
Loss of consciousness	3/693 (0.4%)		0/684 (0%)
Presyncope	1/693 (0.1%)		2/684 (0.3%)
Cerebral ischaemia	2/693 (0.3%)		0/684 (0%)
Cerebrovascular accident	0/693 (0%)		2/684 (0.3%)
Dementia	1/693 (0.1%)		1/684 (0.1%)
Embolic cerebral infarction	1/693 (0.1%)		1/684 (0.1%)
Lacunar infarction	2/693 (0.3%)		0/684 (0%)
Subarachnoid haemorrhage	1/693 (0.1%)		1/684 (0.1%)
Altered state of consciousness	0/693 (0%)		1/684 (0.1%)
Amnesia	0/693 (0%)		1/684 (0.1%)
Carotid artery stenosis	1/693 (0.1%)		0/684 (0%)
Carpal tunnel syndrome	1/693 (0.1%)		0/684 (0%)
Central nervous system lesion	1/693 (0.1%)		0/684 (0%)
Cerebellar infarction	0/693 (0%)		1/684 (0.1%)
Cerebral microangiopathy	0/693 (0%)		1/684 (0.1%)
Cerebrovascular disorder	0/693 (0%)		1/684 (0.1%)
Choreoathetosis	1/693 (0.1%)		0/684 (0%)
Cubital tunnel syndrome	1/693 (0.1%)		0/684 (0%)
Dementia Alzheimer's type	0/693 (0%)		1/684 (0.1%)
Dysaesthesia	0/693 (0%)		1/684 (0.1%)
Dysarthria	1/693 (0.1%)		0/684 (0%)
Generalised tonic-clonic seizure	1/693 (0.1%)		0/684 (0%)
Headache	0/693 (0%)		1/684 (0.1%)
Hypertensive encephalopathy	1/693 (0.1%)		0/684 (0%)
Intraventricular haemorrhage	1/693 (0.1%)		0/684 (0%)
Lacunar stroke	0/693 (0%)		1/684 (0.1%)
Metabolic encephalopathy	1/693 (0.1%)		0/684 (0%)
Paraesthesia	1/693 (0.1%)		0/684 (0%)
Parkinson's disease	1/693 (0.1%)		0/684 (0%)
Partial seizures	0/693 (0%)		1/684 (0.1%)
Sciatica	0/693 (0%)		1/684 (0.1%)
Seizure	1/693 (0.1%)		0/684 (0%)
Status epileticus	1/693 (0.1%)		0/684 (0%)
Vascular encephalopathy	1/693 (0.1%)		0/684 (0%)
Product Issues
Device leakage	3/693 (0.4%)		0/684 (0%)
Device malfunction	1/693 (0.1%)		1/684 (0.1%)
Device power source issue	0/693 (0%)		1/684 (0.1%)
Psychiatric disorders
Confusional state	4/693 (0.6%)		1/684 (0.1%)
Anxiety	1/693 (0.1%)		0/684 (0%)
Depression	0/693 (0%)		1/684 (0.1%)
Drug dependence	0/693 (0%)		1/684 (0.1%)
Mental status changes	0/693 (0%)		1/684 (0.1%)
Stress	0/693 (0%)		1/684 (0.1%)
Renal and urinary disorders
Acute kidney injury	18/693 (2.6%)		17/684 (2.5%)
Haematuria	11/693 (1.6%)		3/684 (0.4%)
Chronic kidney disease	1/693 (0.1%)		5/684 (0.7%)
Renal failure	4/693 (0.6%)		2/684 (0.3%)
Urinary retention	4/693 (0.6%)		0/684 (0%)
End stage renal disease	0/693 (0%)		2/684 (0.3%)
Nephrolithiasis	1/693 (0.1%)		1/684 (0.1%)
Renal impairment	1/693 (0.1%)		1/684 (0.1%)
Calculus bladder	1/693 (0.1%)		0/684 (0%)
Renal haematoma	1/693 (0.1%)		0/684 (0%)
Renal infarct	1/693 (0.1%)		0/684 (0%)
Ureterolithiasis	0/693 (0%)		1/684 (0.1%)
Urethral haemorrhage	1/693 (0.1%)		0/684 (0%)
Urethral stenosis	0/693 (0%)		1/684 (0.1%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/693 (0.1%)		1/684 (0.1%)
Female genital tract fistula	1/693 (0.1%)		0/684 (0%)
Pelvic haematoma	1/693 (0.1%)		0/684 (0%)
Prostatitis	1/693 (0.1%)		0/684 (0%)
Rectocele	1/693 (0.1%)		0/684 (0%)
Vaginal haemorrhage	1/693 (0.1%)		0/684 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	11/693 (1.6%)		8/684 (1.2%)
Respiratory failure	7/693 (1%)		8/684 (1.2%)
Chronic obstructive pulmonary disease	5/693 (0.7%)		7/684 (1%)
Epistaxis	7/693 (1%)		3/684 (0.4%)
Acute pulmonary oedema	5/693 (0.7%)		3/684 (0.4%)
Pleural effusion	5/693 (0.7%)		3/684 (0.4%)
Pneumonia aspiration	2/693 (0.3%)		2/684 (0.3%)
Pulmonary oedema	2/693 (0.3%)		2/684 (0.3%)
Acute respiratory failure	3/693 (0.4%)		0/684 (0%)
Asthma	1/693 (0.1%)		2/684 (0.3%)
Pulmonary hypertension	1/693 (0.1%)		2/684 (0.3%)
Haemoptysis	1/693 (0.1%)		1/684 (0.1%)
Hypoxia	1/693 (0.1%)		1/684 (0.1%)
Pulmonary fibrosis	1/693 (0.1%)		1/684 (0.1%)
Aspiration	0/693 (0%)		1/684 (0.1%)
Atelectasis	0/693 (0%)		1/684 (0.1%)
Bronchial hyperreactivity	1/693 (0.1%)		0/684 (0%)
Dyspnoea exertional	1/693 (0.1%)		0/684 (0%)
Emphysema	0/693 (0%)		1/684 (0.1%)
Haemothorax	1/693 (0.1%)		0/684 (0%)
Interstitial lung disease	1/693 (0.1%)		0/684 (0%)
Pharyngeal haematoma	1/693 (0.1%)		0/684 (0%)
Pharyngeal haemorrhage	1/693 (0.1%)		0/684 (0%)
Pickwickian syndrome	0/693 (0%)		1/684 (0.1%)
Pneumothorax	1/693 (0.1%)		0/684 (0%)
Respiratory acidosis	1/693 (0.1%)		0/684 (0%)
Respiratory distress	1/693 (0.1%)		0/684 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	1/693 (0.1%)		3/684 (0.4%)
Diabetic foot	2/693 (0.3%)		0/684 (0%)
Dermal cyst	1/693 (0.1%)		0/684 (0%)
Rash	1/693 (0.1%)		0/684 (0%)
Skin ulcer haemorrhage	0/693 (0%)		1/684 (0.1%)
Vascular disorders
Peripheral arterial occlusive disease	7/693 (1%)		5/684 (0.7%)
Haematoma	2/693 (0.3%)		9/684 (1.3%)
Hypertensive crisis	8/693 (1.2%)		1/684 (0.1%)
Orthostatic hypotension	3/693 (0.4%)		1/684 (0.1%)
Hypertension	2/693 (0.3%)		1/684 (0.1%)
Aortic dissection	2/693 (0.3%)		0/684 (0%)
Circulatory collapse	0/693 (0%)		2/684 (0.3%)
Hypotension	2/693 (0.3%)		0/684 (0%)
Iliac artery stenosis	2/693 (0.3%)		0/684 (0%)
Peripheral ischaemia	0/693 (0%)		2/684 (0.3%)
Phlebitis	1/693 (0.1%)		1/684 (0.1%)
Aortic aneurysm	1/693 (0.1%)		0/684 (0%)
Aortic occlusion	1/693 (0.1%)		0/684 (0%)
Aortic perforation	1/693 (0.1%)		0/684 (0%)
Aortic thrombosis	1/693 (0.1%)		0/684 (0%)
Arterial haemorrhage	1/693 (0.1%)		0/684 (0%)
Arterial occlusive disease	0/693 (0%)		1/684 (0.1%)
Arteriovenous fistula	0/693 (0%)		1/684 (0.1%)
Blue toe syndrome	1/693 (0.1%)		0/684 (0%)
Diabetic vascular disorder	0/693 (0%)		1/684 (0.1%)
Extremity necrosis	1/693 (0.1%)		0/684 (0%)
Femoral artery embolism	0/693 (0%)		1/684 (0.1%)
Haemorrhage	0/693 (0%)		1/684 (0.1%)
Hypovolaemic shock	0/693 (0%)		1/684 (0.1%)
Peripheral artery aneurysm	1/693 (0.1%)		0/684 (0%)
Peripheral artery thrombosis	0/693 (0%)		1/684 (0.1%)
Peripheral embolism	0/693 (0%)		1/684 (0.1%)
Peripheral vascular disorder	1/693 (0.1%)		0/684 (0%)
Peripheral venous disease	0/693 (0%)		1/684 (0.1%)
Shock haemorrhagic	0/693 (0%)		1/684 (0.1%)
Subclavian vein thrombosis	1/693 (0.1%)		0/684 (0%)
Varicose vein	1/693 (0.1%)		0/684 (0%)
Other (Not Including Serious) Adverse Events
	Edoxaban		Vitamin K Antagonist (VKA)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	522/693 (75.3%)		429/684 (62.7%)
Blood and lymphatic system disorders
Anaemia	62/693 (8.9%)		40/684 (5.8%)
Cardiac disorders
Cardiac failure	78/693 (11.3%)		85/684 (12.4%)
Atrial fibrillation	23/693 (3.3%)		36/684 (5.3%)
Infections and infestations
Urinary tract infection	63/693 (9.1%)		45/684 (6.6%)
Pneumonia	45/693 (6.5%)		43/684 (6.3%)
Injury, poisoning and procedural complications
Fall	35/693 (5.1%)		23/684 (3.4%)
Nervous system disorders
Dizziness	47/693 (6.8%)		33/684 (4.8%)
Renal and urinary disorders
Haematuria	40/693 (5.8%)		18/684 (2.6%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	64/693 (9.2%)		30/684 (4.4%)
Dyspnoea	39/693 (5.6%)		35/684 (5.1%)
Vascular disorders
Haematoma	26/693 (3.8%)		41/684 (6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.