ENTRUST-AF-PCI: Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

• Sponsor: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02866175
• Collaborator: (none)
• Enrollment: 1,506
• Locations: 200
• Arms: 2
• Actual Duration (Months): 27.3
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

There are insufficient data on the safety and efficacy of edoxaban plus antiplatelet therapy in subjects with atrial fibrillation (AF) following percutaneous intervention (PCI) with stenting. This study is designed to evaluate the safety and to explore the efficacy of an edoxaban-based antithrombotic regimen versus a vitamin K antagonist (VKA)-based antithrombotic regimen in subjects with AF following PCI with stent placement. Bleeding is a central safety outcome in cardiovascular clinical trials, especially for antithrombotic strategies and invasive procedures.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: Edoxaban; Drug: Clopidogrel; Drug: Prasugrel; Drug: Ticagrelor; Drug: Vitamin K antagonist	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1506 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Evaluation of the Safety and Efficacy of an Edoxaban-based Compared to a Vitamin K Antagonist-based Antithrombotic Regimen in Subjects With Atrial Fibrillation Following Successful Percutaneous Coronary Intervention (PCI) With Stent Placement.
• Actual Study Start Date: Feb 24, 2017
• Actual Primary Completion Date: Jun 6, 2019
• Actual Study Completion Date: Jun 6, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Edoxaban Regimen Participants will be randomized to receive edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) used.	Drug: Edoxaban; Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects; Other Names: Savaysa ; Drug: Clopidogrel; Clopidogrel 75 mg once-daily; Other Names: Plavix ; Drug: Prasugrel; prasugrel 5mg or 10 mg once-daily; Other Names: Effient ; Drug: Ticagrelor; ticagrelor 90 mg twice-daily
Active Comparator: Vitamin K Antagonist Regimen Participants will be randomized to receive VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.	Drug: Clopidogrel; Clopidogrel 75 mg once-daily; Other Names: Plavix ; Drug: Prasugrel; prasugrel 5mg or 10 mg once-daily; Other Names: Effient ; Drug: Ticagrelor; ticagrelor 90 mg twice-daily; Drug: Vitamin K antagonist; VKA once-daily dosing for target international normalized ratio between 2.0 and 3.0, inclusive

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adjudicated Major or Clinically Relevant Non-major Bleeding As First Event Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [Day 1 to 12 months postdose]

   Participants' first major or clinically relevant non-major bleeding (MCRB) events were reported. International Society on Thrombosis and Hemostasis (ISTH) defined bleeding events included: MCRB, major bleeding, including fatal bleeding (intracranial and non-intracranial), symptomatic intracranial hemorrhage, symptomatic bleeding in a critical area or organ, and clinically overt and causing ≥2.0 g/dL adjusted hemoglobin loss, clinically relevant non-major (CRNM) bleeding, minor bleedings, any bleeding (defined as the composite of major, CRNM, and minor bleeding), life-threatening bleeding, provoked (spontaneous, instrumental/traumatic, unknown) bleeding, and spontaneous bleeding.

Secondary Outcome Measures

1. Number of Participants With Adjudicated Major, Clinically Relevant Non-major and Minor Bleeding (All Events) Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist-Based Regimen [Day 1 to 12 months postdose]

   All major, clinically relevant non-major and minor bleeding are reported for the secondary outcome. Participants may have experiences more than 1 bleeding event, all occurrences are reported. Participants with International Society on Thrombosis and Hemostasis (ISTH) defined bleeding events included: major or clinically relevant non-major bleeding (MCRB), major bleeding, including fatal bleeding (intracranial and non-intracranial), symptomatic intracranial hemorrhage, symptomatic bleeding in a critical area or organ, and clinically overt and causing ≥2.0 g/dL adjusted hemoglobin loss, clinically relevant non-major (CRNM) bleeding, minor bleedings, any bleeding (defined as the composite of major, CRNM, and minor bleeding), life-threatening bleeding, provoked (spontaneous, instrumental/traumatic, unknown) bleeding, and spontaneous bleeding.

2. Number of Participants With Adjudicated Major, Minor, and Minimal Bleeding by Thrombolysis in Myocardial Infarction (TIMI) Definition Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [Day 1 to 12 months postdose]

   Thrombolysis in Myocardial Infarction (TIMI) defined bleeding events included: Major bleeding (including fatal bleeding and non-fatal bleeding [fulfilling the TIMI major bleeding definition], major or minor bleeding, minor bleeding, minimal bleeding, and any bleeding (defined as composite of major, minor, and minimal bleeding)

3. Number of Participants With Bleeding Academic Research Consortium (BARC) Type 1, 2, 3, and 5 Bleeding According to the BARC Definitions Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [Day 1 to 12 months postdose]

   Bleeding Academic Research Consortium (BARC) bleeding events included: Bleeding (defined by BARC type 3 or 5), bleeding (defined by BARC type 2, 3, or 5), and any bleeding (defined as the composite of BARC type 1, 2, 3, or 5), where increases in BARC type indicate worse outcome. Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consultation; Type 2: any overt, actionable sign of hemorrhage that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, medical intervention, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation; Type 3: Overt bleeding plus hemoglobin drop of 3 to ≤5 g/dL (3a), ≥5 g/dl (3b), and intracranial hemorrhage (3c) Type 5: Fatal bleeding

4. Number of Participants With Main Efficacy Endpoints For the Overall Study Period Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [Day 1 to 12 months postdose]

   The main efficacy endpoints were defined as the composite of cardiovascular death (ARC), stroke (protocol defined), systemic embolic event (SEE), myocardial infarction (MI), or definite stent thrombosis.

5. Number of Participants With Treatment-emergent Adverse Events (TEAEs) Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [Day 1 to 30 days after the last dose]

   Treatment-emergent adverse events (TEAEs) in >1.0% of participants were defined as events which started on or after first dose of the assigned study drug (edoxaban and VKA) or started prior to but then worsened after the first dose of the assigned study drug.

6. Number of Participants With Study Drug-related Treatment-emergent Adverse Events (TEAEs) Experienced by 2 or More Participants Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen [Day 1 to 30 days after the last dose]

   Study drug-related treatment-emergent adverse events (TEAEs) (experienced by 2 or more participants) were defined as events which started on or after first dose of the assigned study drug (edoxaban and VKA) or started prior to but then worsened after the first dose of the assigned study drug and were found to be related to treatment by the Investigator.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Oral anticoagulant (OAC) indication for atrial fibrillation for a period of at least 12 months following successful PCI with stenting.

Eligibility is assessed 4 hours after sheath removal and within 5 days after successful PCI with stent placement. If a staged PCI is planned, eligibility is assessed after completion of the last stage.

Successful PCI definition:

The success of a PCI procedure is defined by 2 interrelated components: angiographic findings, procedural / clinical outcomes as detailed below:

Angiographic Success A minimum stenosis diameter of < 20% (as visually assessed by angiography - residual blockage or stenosis reduced to less than 20% of the artery's diameter).

Sufficient enlargement of the lumen at the target site to improve coronary artery blood flow with final thrombolysis in myocardial infarction (TIMI) flow grade 3 (visually assessed by angiography), without occlusion of a significant side branch, flow-limiting dissection, distal embolization, or angiographic thrombus.

Procedural Success No major in-hospital clinical complications(e.g. ongoing International Society on Thrombosis and Haemostasis [ISTH] major or clinical relevant non-major procedural bleeding at the time of randomization, stroke, emergency coronary artery bypass graft [CABG]).

In summary, a clinically successful PCI requires both anatomic and procedural success along with relief of signs and/or symptoms of myocardial ischemia at the time of randomization.

Exclusion Criteria:

• Bleeding risks or systemic conditions

• Known bleeding diathesis, including but not limited to,

1. Uncontrolled active bleeding, encompassing both ISTH major and clinically relevant non-major bleeding, preceding randomization.

Lesion or condition, if considered to be a significant risk for major bleeding. This may include but is not limited to: unresolved gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding (e.g. malignancies with metastasis), recent unresolved brain or spinal injury, recent brain, spinal or ophthalmic surgery, any intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms (of more than 3.5 cm) or major intraspinal or intracerebral vascular abnormalities.

1. Medication-related

• International normalized ratio (INR) > 2.5 (the participant can be reconsidered at a later time, but within 5 days of sheath removal).

• Contraindication to edoxaban, VKA, acetylsalicylic acid (ASA) and/or P2Y12 antagonists;

• Concomitant treatment with other antithrombotic agents, fibrinolytic therapy and chronic nonsteroidal anti-inflammatory drugs (NSAIDs).

Concomitant conditions and therapies

• Critically ill or hemodynamically unstable subjects (at the time of randomization) including:

1. cardiogenic shock or acute decompensated heart failure, with the requirement for vasopressor agents or inotropic support or mechanical support to support circulation

2. respiratory failure requiring endotracheal intubation and mechanical ventilation.

• Any prior mechanical valvular prosthesis;

• Planned coronary or vascular intervention or major surgery within 12 months; Randomization must be deferred to the last stage in a multistep, multivessel PCI procedure;

• Moderate or severe mitral stenosis;

• Ischemic stroke within 2 weeks prior to randomization;

• Uncontrolled severe hypertension with a systolic blood pressure (BP) ≥180 mmHg and/or diastolic BP ≥ 120 mmHg;

• End stage renal disease (ESRD) (CrCL < 15 mL/min or on dialysis);

• Known abnormal liver function prior to randomization (including hepatic disease or biochemical evidence of significant liver derangement known prior to randomization).

Other exclusion criteria

• Any of the following abnormal local laboratory results prior to randomization:

1. Platelet count < 50 x10^9/L

2. Hemoglobin < 8 mg/dL

• Unable to provide written Informed Consent;

• Female participants of childbearing potential without using highly effective contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilised, or has not had a hysterectomy at least three months prior to the start of this study). Females taking oral contraceptives should have been on therapy for at least three months. Adequate contraceptives include: Combined (estrogen and progestogen containing) oral, intravaginal, transdermal, hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence;

• Pregnant or breast-feeding participants;

• Assessment that the participant is not likely to comply with the study procedures or have complete follow-up;

• Participating in another clinical trial that potentially interferes with the current study;

• Previous randomization in this study;

• Active on prescription drug abuse and addiction; abuse of illicit substances (i.e. marijuana, cocaine, methamphetamine, heroin) and alcohol abuses during the last 12 months according to the judgement of the investigator;

• Life expectancy < 12 months.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medizinische Universitaetsklinik Graz	Graz		Austria	8036
2	University Hospital Innsbruck	Innsbruck		Austria	6020
3	Krankenhaus Hietzing	Wien		Austria	1130
4	Wilhelminenspital	Wien		Austria	1160
5	ASZ Aalst	Aalst		Belgium	9300
6	Imelda Ziekenhuis	Bonheiden		Belgium	2820
7	AZ St Jan	Brugge		Belgium	8000
8	Hopital Erasme	Brussel		Belgium	1070
9	University Hospital Antwerp	Edegem		Belgium	2650
10	Virga Jesse Jessa hospital	Hasselt		Belgium	3500
11	AZ Delta	Roeselare		Belgium	8800
12	University Hospital of Angers	Angers		France	49933
13	Hopital Cote Basque	Bayonne		France	64100
14	Chru Jean Minjoz	Besancon		France	25030
15	Metropole Savoie Hospital	Chambery		France	73000
16	Centre Hospitalier Sud Francilien	Corbeil Essonnes Cedex		France	91106
17	Hospital Henri Mondor	Creteil		France	94000
18	CHU de Nice	Nice		France	6001
19	Hôpital Bichat - Claude Bernard	Paris cedex 8		France	75877
20	Hôpital Rangueil, Service Cancérologie	Toulouse		France	31400
21	Clinique Vauban	Valenciennes		France	59300
22	University Hospital Aachen	Aachen		Germany	52074
23	Universitäts-Herzzentrum Freiburg • Bad Krozingen	Bad Krozingen		Germany	79189
24	Kerckhoff Klinik	Bad Nauheim		Germany	61231
25	Vivantes Klinikum im Friedrichshaim	Berlin		Germany	10249
26	Charité Benjamin Franklin	Berlin		Germany	12203
27	Charité, Campus Virchow-Klinikum - Medizinische Klinik mit Schwerpunkt Kardiologie	Berlin		Germany	13353
28	Staedtische Kliniken Bielefeld	Bielefeld		Germany	33604
29	GFO Kliniken Bonn - St.-Marien-Hospital	Bonn		Germany	53115
30	Universitätsklinikum Bonn - Medizinische Klinik II - Innere Medizin (Kardiologie, Angiologie und Pneumologie)	Bonn		Germany	53127
31	Klinikum Coburg Med. Klinik Kardiologie, Angiologie, Pneumologie	Coburg		Germany	96450
32	St. Johannes- Hospital	Dortmund		Germany	44137
33	Heinrich-Heine-Universität Düsseldorf - Universitätsklinikum Düsseldorf (UKD) Klinik für Kardiologie, Pneumologie und Angiologie	Düsseldorf		Germany	40225
34	Universitaetsklinikum Freiburg Klinik für Kardiologie und Angiologie I	Freiburg		Germany	79106
35	Universitäres Herzzentrum Hamburg GmbH (UHZ)	Hamburg		Germany	20246
36	Universitätsklinikum Heidelberg Klinik für Kardiologie, Angiologie und Pneumologie (Innere Medizin III)	Heidelberg		Germany	69120
37	Universitätsklinikum des Saarlandes Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin	Homburg		Germany	66421
38	Universitätsklinikum Jena Klinik für Innere Medizin I, Kardiologie, Angiologie, Pneumologie, Internistische Intensivmedizin	Jena		Germany	7747
39	Herzzentrum Leipzig - Universitätsklinik Klinik für Innere Medizin/Kardiologie	Leipzig		Germany	4289
40	Klinikum Ludwigshafen	Ludwigshafen		Germany	67063
41	Städtisches Klinikum Lüneburg	Lüneburg		Germany	21339
42	Kliniken Maria Hilf GmbH	Mönchengladbach		Germany	41063
43	Klinik Dr. Müller GmbH & Co. KG, Peter Osypka Herzzentrum	München		Germany	81379
44	Universitätsklinikum Münster - Department für Kardiologie und Angiologie	Münster		Germany	48149
45	St. Vincenz-Krankenhaus Paderborn - Medizinische Klinik II	Paderborn		Germany	33098
46	Universitätsmedizin Rostock	Rostock		Germany	18057
47	Universitäts Klinikum Tübingen	Tübingen		Germany	72076
48	Herzklinik Ulm	Ulm		Germany	89077
49	Universitätsklinik Ulm - Zentrum für Innere Medizin - Klinik für Innere Medizin II	Ulm		Germany	89081
50	Schwarzwald-Baar Klinikum - Kliniken Villingen-Schwenningen - Innere Medizin III: Kardiologie und Intensivmedizin	Villingen-Schwenningen		Germany	78052
51	St. Josefs-Hospital - Medizinische Klinik I, Kardiologie	Wiesbaden		Germany	65189
52	HELIOS Klinikum Wuppertal - Herzzentrum	Wuppertal		Germany	42117
53	Állami Szívkórház	Balatonfüred		Hungary	8230
54	Budai Irgalmasrendi Kht.	Budapest		Hungary	1023
55	Gottsegen György Országos Kardiológiai Intézet	Budapest		Hungary	1096
56	Bajcsy-Zsilinszky Kórház és Rendelőintézet	Budapest		Hungary	1106
57	Magyar Honvédség Egészségügyi Központ	Budapest		Hungary	1134
58	Debreceni Egyetem Klinikai Központ	Debrecen		Hungary	4032
59	Békés Megyei Központi Kórház	Gyula		Hungary	5700
60	Petz Aladar Megyei Oktato Korhaz	Győr		Hungary	9023
61	Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház, Jósa András Oktatókórház	Nyíregyháza		Hungary	4400
62	Pécsi Tudományegyetem	Pécs		Hungary	7624
63	Szegedi Tudományegyetem	Szeged		Hungary	6725
64	Fejér Megyei Szent György Egyetemi Oktató Kórház	Székesfehérvár		Hungary	8000
65	Ospedale San Donato- ASL 8 Arezzo	Arezzo		Italy	52100
66	Policlinico di Bari	Bari		Italy	70124
67	Ospedale Maggiore C.A. Pizzardi -OR - Laboratorio di Cardiologia Interventistica	Bologna		Italy	40133
68	AOU Materdomini, Magna Graecia University	Catanzaro		Italy	88100
69	ASL2 Chieti - SS Maria Annunziata	Chieti		Italy	66100
70	A.S.O.S. Croce e Carle Cuneo	Cuneo		Italy	12100
71	AOU Sant'Anna	Ferrara		Italy	44124
72	Ospedale Careggi	Firenze		Italy	50134
73	Ospedali Riuniti di Foggia	Foggia		Italy	71122
74	Ospedale Alessandro Manzoni-Azienda Ospedaliera di Lecco	Lecco		Italy	23900
75	Asst Fatebenefratelli-Sacco	Milano		Italy	20157
76	AOU Policlinico di Modena	Modena		Italy	41124
77	University Hospital Federico II	Napoli		Italy	80131
78	Padova University Hospital	Padova		Italy	35128
79	Azienda Ospedaliero-Universitaria di Parma	Parma		Italy	43126
80	Ospedale degli Infermi	Rimini		Italy	47923
81	Ospedale degli Infermi di Rivoli	Rivoli		Italy	10098
82	Policlinico Agostino Gemelli	Roma		Italy	00168
83	S.Camillo Forlanini - Ospedale S.Camillo Reparto di Emodinamica	Rome		Italy	00152
84	Bolognini Hospital Seriate	Seriate		Italy	24068
85	"Santa Maria" University Hospital - Azienda Ospedaliera Santa Maria Di Terni	Terni		Italy	05100
86	U.O. Cardiologia Ospedale Borgo Trento	Verona		Italy	37126
87	Pusan National University Hospital	Busan		Korea, Republic of	49241
88	Daegu Catholic University Hospital	Daegu		Korea, Republic of	42472
89	Chonnam National University Hospital	Gwangju		Korea, Republic of	61469
90	Inje Univ. Ilsan Paik Hospital	Gyeonggi-do		Korea, Republic of	10380
91	The Catholic University of Korea St.Vincent's Hospital	Gyeonggi-do		Korea, Republic of	16247
92	Hallym University Sacred Heart Hospital	Gyeonggi-do		Korea, Republic of	431796
93	Inha University Hospital	Incheon		Korea, Republic of	400-711
94	Chonbuk National University Hospital	Jeonju		Korea, Republic of	561-712
95	Seoul National University Bundang Hospital	Seongnam		Korea, Republic of	136-200
96	Seoul National University Hospital	Seoul		Korea, Republic of	03080
97	Severance Hospital	Seoul		Korea, Republic of	03722
98	Samsung Medical Centre	Seoul		Korea, Republic of	06351
99	SEOUL St.Maria	Seoul		Korea, Republic of	06591
100	Boramae Medical Center	Seoul		Korea, Republic of	07061
101	Korea University Guro Hospital	Seoul		Korea, Republic of	08308
102	Korea University Anam Hospital	Seoul		Korea, Republic of	136705
103	Lithuanian University of Health Sciences hospital	Kaunas		Lithuania	50009
104	Klaipeda Seamen's Hospital	Klaipėda		Lithuania	92288
105	Vilnius University Hospital "Santariskiu Clinic"	Vilnius		Lithuania	08661
106	Republican Siauliai Hospital	Šiauliai		Lithuania	76231
107	St Antonius Hospital	Nieuwegein		Netherlands	3435 CM
108	Radboud university medical center	Nijmegen		Netherlands	6525 GA
109	Maasstad Hospital	Rotterdam		Netherlands	3079 DZ
110	MC Haaglanden	The Hague		Netherlands	2512 VA
111	II Oddział Kardiologiczny, Polsko-Amerykanskie Kliniki Serca	Bielsko-Biala		Poland	43-316
112	MCSN AHoP	Chrzanów		Poland	32-500
113	III Oddział Kardiologii Inwazyjnej, Angiologii i Elektrokardiologii Polsko-Amerykanskie Kliniki Serca	Dąbrowa Górnicza		Poland	41-300
114	Krakowski Szpital Specjalistyczny im. Jana Pawła II, Oddział Kliniczny Kardiologii Interwencyjnej z Pododdziałem Intenyswengo Nadzoru Kardiologicznego	Kraków		Poland	31-302
115	AHP IV DEP K-Kozle	Kędzierzyn-Koźle		Poland	47-200
116	Nyskie Centrum Sercowo-Naczyniowe, Polsko-Amerykanskie Kliniki Serca	Nysa		Poland	48-300
117	Clin-Medica OMC sp. z o.o. s.k.	Skierniewice		Poland	96-100
118	X Oddział Kardiologii Inwazyjnej, Elektrofizjologii i Elektrostymulacji Polsko-Amerykanskie Kliniki Serca	Tychy		Poland	43-100
119	Instytut Kardiologii im. Prymasa Tysiąclecia Stefana Kardynała Wyszyńskiego; Klinika Kardiologii i Angiologii Interwencyjnej	Warsaw		Poland	04-628
120	Instytut Kardiologii im. Prymasa Tysiaclecia Kardynala Stefana Wyszynskiego, Klinika Choroby Wieńcowej i Strukturalnych Chorób Serca	Warszawa		Poland	04-628
121	Nzoz Salus	Łódź		Poland	91-302
122	Hospital Garcia de Orta, EPE	Almada		Portugal	2805-267
123	Centro Hospitalar de Lisboa Ocidental, EPE - Hospital de Santa Cruz	Carnaxide		Portugal	2790-134
124	Centro Hospitalar e Universitário de Coimbra, EPE	Coimbra		Portugal	3000-075
125	Centro Hospitalar e Universitário de Coimbra, EPE - Hospital dos Covões	Coimbra		Portugal	3041 801
126	Centro Hospitalar de Lisboa Central, EPE - Hospital Santa Marta	Lisboa		Portugal	1169-024
127	Centro Hospitalar de Lisboa Norte, EPE - Hospital de Santa Maria	Lisboa		Portugal	1649-035
128	Emergency County Hospital Baia Mare	Baia Mare		Romania	430031
129	"Prof. C.C. Iliescu" Emergency Institute for Cardiovascular Diseases	Bucharest		Romania	022328
130	University Hospital of Bucharest	Bucharest		Romania	050098
131	Saint John Emergency Hospital	Bucharest		Romania	42122
132	Oradea Emergency County Clinical Hospital	Oradea		Romania	410169
133	Institutul de Boli Cardiovasculare Timisoara	Timişoara		Romania	300310
134	Emergency Institute of Cardiovascular Diseases and Transplantation	Târgu-Mureş		Romania	540136
135	Clinical Center of Serbia	Belgrade		Serbia	11000
136	Clinical Hospital Center -Zvezdara	Belgrade		Serbia	11000
137	Institute of CV Diseases Clinical Center of Serbia	Belgrade		Serbia	11000
138	Clinical Center Kragujevac	Kragujevac		Serbia	34000
139	Institute of Cardiovascular Diseases of Vojvodina	Sremska Kamenica		Serbia	21204
140	General University Hospital of Alicante	Alicante		Spain	3010
141	Hospital Universitari Germans Trias i Pujol	Badalona		Spain	8916
142	Complejo Hospitalario Universitario de Granada	Granada		Spain	18014
143	Bellvitge University Hospital	L'Hospitalet de Llobregat		Spain	8907
144	Complejo Asistencial Universitario de León	León		Spain	24071
145	Hospital Ramon y Cajal	Madrid		Spain	28034
146	Clinica Universitaria San Carlos	Madrid		Spain	28040
147	Hospital La Paz, Madrid	Madrid		Spain	28046
148	Hospital Universitario 12 de Octubre	Madrid		Spain	280471
149	Hospital Universitario Puerta de Hierro	Madrid		Spain	28222
150	Hospital Universitario Virgen de la Arrixaca	Murcia		Spain	30120
151	Hospital Universitario Virgen de La Victoria	Málaga		Spain	29010
152	Hospital Universitario de Salamanca	Salamanca		Spain	37007
153	Hospital Universitari i Politècnic La Fe	Valencia		Spain	46026
154	Hospital Clínico Universitario de Valladolid	Valladolid		Spain	47005
155	Hospital Álvaro Cunqueiro	Vigo		Spain	36312
156	HFR Freiburg - Kantonsspital Kardiologie	Fribourg		Switzerland	1700
157	Cardiocentro Ticino	Lugano		Switzerland	6900
158	Hsinchu Mackay Memorial Hospital (HMMH)	Hsinchu		Taiwan	30071
159	Kaohsiung medical University Chung-Ho Memorial Hospital (KMUH)	Kaohsiung		Taiwan	807
160	E-DA Hospital	Kaohsiung		Taiwan	824
161	Far Eastern Memorial Hospital (FEMH)	New Taipei City		Taiwan	220
162	China Medical University Hospital (CMUH)	Taichung		Taiwan	404
163	Chi-Mei Medical Center (CMMC)	Tainan		Taiwan	704
164	National Cheng Kung University Hospital	Tainan		Taiwan	704
165	Cheng Hsin General Hospital	Taipei		Taiwan	112
166	Taipei Veterans General Hospital	Taipei		Taiwan	112
167	Chang-Gung Memorial Hospital	Taoyuan		Taiwan	333
168	Cherkasy regional cardiological center	Cherkasy		Ukraine	18009
169	Chernihiv City Hospital #2	Chernihiv		Ukraine	14034
170	Chernivtsi Regional Clinical Cardiology Dispensary	Chernivtsi		Ukraine	58013
171	CI "Dnipropetrovsk Joint Emergency Hospital"	Dnipropetrovsk		Ukraine	49006
172	Communal Institution Dnepropetrovsk Regional Diagnostic Center	Dnipro		Ukraine	49060
173	Ivano-Frankivsk Central City Clinical Hospital	Ivano-Frankivs'k		Ukraine	76018
174	L.T. Malaya Therapy National Institute of the National Academy of medical science of Ukraine	Kharkiv		Ukraine	61039
175	Communal Health Care Institution "Regional Clinical Hospital - Center of Emergency Medical Care and Disaster Medicine"	Kharkiv		Ukraine	61058
176	Kharkiv City Clinical Hospital #8	Kharkiv		Ukraine	61178
177	Kharkiv Railway Clinical Hospital N1 of Brance "Health Center" of the Public joint stock company "Ukrainian Railway"	Kharkov		Ukraine	61000
178	Khmelnytskyy regional hospital	Khmel'nyts'kyy		Ukraine	29000
179	Insititute of Heart of MoH Ukraine	Kyiv		Ukraine	02660
180	Kyiv City Clinical Hospital#5	Kyiv		Ukraine	03115
181	State Institution 'National Scientific Central Institute of Cardiology named after MD Strazhesko'	Kyiv		Ukraine	03151
182	Kyiv City Clinical Hospital 4	Kyiv		Ukraine	04112
183	Oleksandrivska Kiyv City Clinical Hospital	Kyiv		Ukraine	1601
184	Communal Institution of Kyiv Regional Rada	Kyiv		Ukraine	4107
185	Lviv Regional State Clinical Treatment and Diagnostic Cardiology Center	L'viv		Ukraine	79015
186	Lutsk City Hospital	Luts'k		Ukraine	43024
187	Nikolaev Regional Clinical Hospital	Nikolayev		Ukraine	54003
188	Odessa Regional Hospital, Cardiosurgery Center	Odessa		Ukraine	65025
189	Communal Institution Rivne Regional Clinical Hospital	Rivne		Ukraine	33007
190	Communal Institution of Sumy Regional Rada	Sumy		Ukraine	40031
191	Transcarpathian Regional Clinical Cardiology Clinic	Uzhhorod		Ukraine	88018
192	Communal Institution "Vinnytsia Regional Diagnostic Center of cardiovascular disease"	Vinnytsya		Ukraine	21000
193	Vinnytsya Regional Clinical Hospital n.a. Pyrogov	Vinnytsya		Ukraine	21000
194	Zaporizhzhia Regional cardiology dispensary	Zaporizhzhia		Ukraine	69000
195	Blackpool Victoria Hospital	Blackpool	Lancashire	United Kingdom	FY3 8NR
196	University Hospital of Wales	Cardiff		United Kingdom	CF14 4XW
197	Golden Jubilee Hospital	Clydebank		United Kingdom	G81 4DY
198	Royal Infirmary of Edinburgh	Edinburgh		United Kingdom	EH16 4SA
199	Altnagelvin Area Hospital	Londonderry		United Kingdom	BT47 6SB
200	Southern Health and Social Care Trust	Portadown		United Kingdom	BT63 5QQ

Sponsors and Collaborators

• Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company

Investigators

• Study Chair: Pascal Vranckx, MD, Hartcentrum Hasselt
• Study Chair: Andreas Gotte, Prof., MD, Medizinische Klinik II

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 28, 2017

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
• ClinicalTrials.gov Identifier: NCT02866175
• Other Study ID Numbers: DSE-EDO-01-15-EU; 2016-002683-14
• First Posted: Aug 15, 2016
• Last Update Posted: May 6, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company: percutaneous intervention; vitamin K antagonist
• Additional relevant MeSH terms: Atrial Fibrillation; Vitamin K; Edoxaban; Clopidogrel; Ticagrelor; Prasugrel Hydrochloride

Study Results

Participant Flow

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

Arm/Group Title	Edoxaban Regimen	Vitamin K Antagonist Regimen
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).	Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.
Period Title: Overall Study
STARTED	751	755
COMPLETED	616	580
NOT COMPLETED	135	175

Baseline Characteristics

Arm/Group Title	Edoxaban Regimen	Vitamin K Antagonist Regimen	Total
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).	Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.	Total of all reporting groups
Overall Participants	751	755	1506
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	226 30.1%	202 26.8%	428 28.4%
>=65 years	525 69.9%	553 73.2%	1078 71.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.4 (9.74)	70.1 (9.51)	69.7 (9.63)
Sex: Female, Male (Count of Participants)
Female	194 25.8%	192 25.4%	386 25.6%
Male	557 74.2%	563 74.6%	1120 74.4%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Romania	17 2.3%	22 2.9%	39 2.6%
Hungary	49 6.5%	54 7.2%	103 6.8%
Ukraine	169 22.5%	175 23.2%	344 22.8%
United Kingdom	6 0.8%	9 1.2%	15 1%
Portugal	12 1.6%	12 1.6%	24 1.6%
Switzerland	2 0.3%	5 0.7%	7 0.5%
Spain	58 7.7%	57 7.5%	115 7.6%
Austria	18 2.4%	8 1.1%	26 1.7%
Netherlands	3 0.4%	7 0.9%	10 0.7%
South Korea	50 6.7%	41 5.4%	91 6%
Belgium	43 5.7%	37 4.9%	80 5.3%
Taiwan	32 4.3%	46 6.1%	78 5.2%
Poland	74 9.9%	66 8.7%	140 9.3%
Italy	69 9.2%	84 11.1%	153 10.2%
France	21 2.8%	20 2.6%	41 2.7%
Lithuania	24 3.2%	21 2.8%	45 3%
Serbia	17 2.3%	11 1.5%	28 1.9%
Germany	87 11.6%	80 10.6%	167 11.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adjudicated Major or Clinically Relevant Non-major Bleeding As First Event Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
Description	Participants' first major or clinically relevant non-major bleeding (MCRB) events were reported. International Society on Thrombosis and Hemostasis (ISTH) defined bleeding events included: MCRB, major bleeding, including fatal bleeding (intracranial and non-intracranial), symptomatic intracranial hemorrhage, symptomatic bleeding in a critical area or organ, and clinically overt and causing ≥2.0 g/dL adjusted hemoglobin loss, clinically relevant non-major (CRNM) bleeding, minor bleedings, any bleeding (defined as the composite of major, CRNM, and minor bleeding), life-threatening bleeding, provoked (spontaneous, instrumental/traumatic, unknown) bleeding, and spontaneous bleeding.
Time Frame	Day 1 to 12 months postdose

Outcome Measure Data

Analysis Population Description

First major or clinically relevant non-major bleeding was assessed in the Intent-to-Treat Analysis Set.

Arm/Group Title	Edoxaban Regimen	Vitamin K Antagonist Regimen
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).	Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration).
Measure Participants	751	755
Composite MCRB	128 17%	152 20.1%
Major bleeding	39 5.2%	44 5.8%
Clinically relevant non-major bleeding	89 11.9%	108 14.3%

2. Secondary Outcome

Title	Number of Participants With Adjudicated Major, Clinically Relevant Non-major and Minor Bleeding (All Events) Defined by International Society on Thrombosis and Haemostasis Following Edoxaban-based Regimen Compared With Vitamin K Antagonist-Based Regimen
Description	All major, clinically relevant non-major and minor bleeding are reported for the secondary outcome. Participants may have experiences more than 1 bleeding event, all occurrences are reported. Participants with International Society on Thrombosis and Hemostasis (ISTH) defined bleeding events included: major or clinically relevant non-major bleeding (MCRB), major bleeding, including fatal bleeding (intracranial and non-intracranial), symptomatic intracranial hemorrhage, symptomatic bleeding in a critical area or organ, and clinically overt and causing ≥2.0 g/dL adjusted hemoglobin loss, clinically relevant non-major (CRNM) bleeding, minor bleedings, any bleeding (defined as the composite of major, CRNM, and minor bleeding), life-threatening bleeding, provoked (spontaneous, instrumental/traumatic, unknown) bleeding, and spontaneous bleeding.
Time Frame	Day 1 to 12 months postdose

Outcome Measure Data

Analysis Population Description

All major, clinically relevant non-major, and minor bleeding events were assessed in the Intent-to-Treat Analysis Set.

Arm/Group Title	Edoxaban Regimen	Vitamin K Antagonist Regimen
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).	Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration).
Measure Participants	751	755
Major bleeding	45 6%	48 6.4%
Clinically relevant non-major bleeding	97 12.9%	114 15.1%
Minor bleeding	116 15.4%	125 16.6%
Symptomatic intracranial hemorrhage	4 0.5%	9 1.2%
Fatal major bleeding	1 0.1%	7 0.9%
Fatal intracranial hemorrhage	0 0%	4 0.5%
Life-threatening bleeding	5 0.7%	8 1.1%
Spontaneous bleeding	184 24.5%	210 27.8%

3. Secondary Outcome

Title	Number of Participants With Adjudicated Major, Minor, and Minimal Bleeding by Thrombolysis in Myocardial Infarction (TIMI) Definition Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
Description	Thrombolysis in Myocardial Infarction (TIMI) defined bleeding events included: Major bleeding (including fatal bleeding and non-fatal bleeding [fulfilling the TIMI major bleeding definition], major or minor bleeding, minor bleeding, minimal bleeding, and any bleeding (defined as composite of major, minor, and minimal bleeding)
Time Frame	Day 1 to 12 months postdose

Outcome Measure Data

Analysis Population Description

Major, minor, and minimal bleeding was assessed in the Intent-to-Treat Analysis Set.

Arm/Group Title	Edoxaban Regimen	Vitamin K Antagonist Regimen
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).	Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration).
Measure Participants	751	755
Major bleeding	15 2%	24 3.2%
Fatal bleeding	1 0.1%	4 0.5%
Major or minor bleeding	124 16.5%	144 19.1%
Minor bleeding	113 15%	126 16.7%
Minimal bleeding	117 15.6%	131 17.4%

4. Secondary Outcome

Title	Number of Participants With Bleeding Academic Research Consortium (BARC) Type 1, 2, 3, and 5 Bleeding According to the BARC Definitions Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
Description	Bleeding Academic Research Consortium (BARC) bleeding events included: Bleeding (defined by BARC type 3 or 5), bleeding (defined by BARC type 2, 3, or 5), and any bleeding (defined as the composite of BARC type 1, 2, 3, or 5), where increases in BARC type indicate worse outcome. Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consultation; Type 2: any overt, actionable sign of hemorrhage that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, medical intervention, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation; Type 3: Overt bleeding plus hemoglobin drop of 3 to ≤5 g/dL (3a), ≥5 g/dl (3b), and intracranial hemorrhage (3c) Type 5: Fatal bleeding
Time Frame	Day 1 to 12 months postdose

Outcome Measure Data

Analysis Population Description

BARC type 1, 2, 3, and 5 bleeding was assessed in the Intent-to-Treat Analysis Set.

Arm/Group Title	Edoxaban Regimen	Vitamin K Antagonist Regimen
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).	Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration).
Measure Participants	751	755
Bleeding (BARC Type 3 or 5)	36 4.8%	42 5.6%
Bleeding (BARC Type 2, 3, or 5)	124 16.5%	144 19.1%
Bleeding (BARC Type 1, 2, 3, or 5)	207 27.6%	242 32.1%

5. Secondary Outcome

Title	Number of Participants With Main Efficacy Endpoints For the Overall Study Period Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
Description	The main efficacy endpoints were defined as the composite of cardiovascular death (ARC), stroke (protocol defined), systemic embolic event (SEE), myocardial infarction (MI), or definite stent thrombosis.
Time Frame	Day 1 to 12 months postdose

Outcome Measure Data

Analysis Population Description

Efficacy endpoints were assessed in the Intent-to-Treat Analysis Set.

Arm/Group Title	Edoxaban Regimen	Vitamin K Antagonist Regimen
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).	Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration.
Measure Participants	751	755
Composite MEE event	49 6.5%	46 6.1%
Cardiovascular death (ARC)	10 1.3%	12 1.6%
Stroke (Protocol definition)	10 1.3%	11 1.5%
Systemic Embolic Event	0 0%	0 0%
Myocardial infarction	22 2.9%	18 2.4%
Definite stent thrombosis	7 0.9%	5 0.7%

6. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
Description	Treatment-emergent adverse events (TEAEs) in >1.0% of participants were defined as events which started on or after first dose of the assigned study drug (edoxaban and VKA) or started prior to but then worsened after the first dose of the assigned study drug.
Time Frame	Day 1 to 30 days after the last dose

Outcome Measure Data

Analysis Population Description

Safety events were assessed in the Safety Analysis Set.

Arm/Group Title	Edoxaban Regimen	Vitamin K Antagonist Regimen
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).	Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration).
Measure Participants	746	740
Any TEAE	457 60.9%	447 59.2%
Infections and Infestations	145 19.3%	140 18.5%
Nasopharyngitis	25 3.3%	22 2.9%
Pneumonia	20 2.7%	22 2.9%
Bronchitis	19 2.5%	20 2.6%
Urinary tract infection	14 1.9%	19 2.5%
Respiratory tract infection	12 1.6%	15 2%
Influenza	10 1.3%	7 0.9%
Cardiac Disorders	136 18.1%	134 17.7%
Cardiac failure	40 5.3%	47 6.2%
Atrial fibrillation	39 5.2%	41 5.4%
Bradycardia	10 1.3%	7 0.9%
Cardiac failure congestive	8 1.1%	8 1.1%
Ventricular extrasystoles	7 0.9%	8 1.1%
Tachycardia	11 1.5%	3 0.4%
General Disorders & Administration Site Condition	113 15%	98 13%
Non-cardiac chest pain	30 4%	24 3.2%
Oedema peripheral	31 4.1%	22 2.9%
Asthenia	21 2.8%	14 1.9%
Chest pain	7 0.9%	11 1.5%
Fatigue	11 1.5%	6 0.8%
Gastrointestinal Disorders	110 14.6%	83 11%
Diarrhoea	23 3.1%	19 2.5%
Constipation	11 1.5%	7 0.9%
Abdominal pain upper	6 0.8%	10 1.3%
Gastritis	9 1.2%	5 0.7%
Nausea	8 1.1%	5 0.7%
Dyspepsia	8 1.1%	3 0.4%
Respiratory,Thoracic, and Mediastinal Disorders	87 11.6%	72 9.5%
Dyspnoea	22 2.9%	26 3.4%
Cough	21 2.8%	11 1.5%
Dyspnoea exertional	18 2.4%	5 0.7%
Chronic obstructive pulmonary disease	6 0.8%	10 1.3%
Musculoskeletal and Connective Tissue Disorders	69 9.2%	83 11%
Back pain	14 1.9%	14 1.9%
Arthralgia	11 1.5%	12 1.6%
Pain in extremity	5 0.7%	13 1.7%
Myalgia	8 1.1%	8 1.1%
Osteoarthritis	9 1.2%	5 0.7%
Investigations	70 9.3%	79 10.5%
Blood creatinine increased	15 2%	13 1.7%
Alanine aminotransferase increased	8 1.1%	13 1.7%
Blood pressure increased	12 1.6%	8 1.1%
Creatinine renal clearance decreased	12 1.6%	7 0.9%
Aspartate aminotransferase increased	7 0.9%	11 1.5%
International normalised ratio increased	0 0%	12 1.6%
Nervous System Disorders	83 11.1%	65 8.6%
Dizziness	30 4%	22 2.9%
Headache	19 2.5%	12 1.6%
Syncope	8 1.1%	6 0.8%
Vascular Disorders	55 7.3%	62 8.2%
Hypertension	23 3.1%	23 3%
Hypotension	14 1.9%	14 1.9%
Hypertensive crisis	11 1.5%	8 1.1%
Renal and Urinary Disorders	49 6.5%	55 7.3%
Renal failure	11 1.5%	12 1.6%
Acute kidney injury	8 1.1%	13 1.7%
Renal impairment	7 0.9%	8 1.1%
Injury, Poisoning, and Procedural Complications	44 5.9%	44 5.8%
Fall	8 1.1%	12 1.6%
Skin and Subcutaneous Tissue Disorders	55 7.3%	33 4.4%
Pruritus	12 1.6%	7 0.9%
Rash	10 1.3%	9 1.2%
Metabolism and Nutrition Disorders	42 5.6%	42 5.6%
Gout	11 1.5%	4 0.5%
Blood and Lymphatic System Disorders	41 5.5%	35 4.6%
Anaemia	19 2.5%	20 2.6%
Psychiatric Disorder	23 3.1%	20 2.6%
Insomnia	8 1.1%	8 1.1%
Ear and Labyrinth Disorders	12 1.6%	16 2.1%
Vertigo	8 1.1%	5 0.7%

7. Secondary Outcome

Title	Number of Participants With Study Drug-related Treatment-emergent Adverse Events (TEAEs) Experienced by 2 or More Participants Following Edoxaban-based Regimen Compared With Vitamin K Antagonist (VKA)-Based Regimen
Description	Study drug-related treatment-emergent adverse events (TEAEs) (experienced by 2 or more participants) were defined as events which started on or after first dose of the assigned study drug (edoxaban and VKA) or started prior to but then worsened after the first dose of the assigned study drug and were found to be related to treatment by the Investigator.
Time Frame	Day 1 to 30 days after the last dose

Outcome Measure Data

Analysis Population Description

Safety events were assessed in the Safety Analysis Set.

Arm/Group Title	Edoxaban Regimen	Vitamin K Antagonist Regimen
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).	Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration).
Measure Participants	746	740
Any Related TEAE	57 7.6%	48 6.4%
Blood and Lymphatic System Disorders	12 1.6%	11 1.5%
Anaemia	9 1.2%	7 0.9%
Haemorrhagic anaemia	0 0%	2 0.3%
Normochromic normocytic anaemia	2 0.3%	0 0%
Investigations	7 0.9%	16 2.1%
International normalised ratio increased	0 0%	12 1.6%
Blood creatinine increased	3 0.4%	1 0.1%
Creatinine renal clearance decreased	2 0.3%	2 0.3%
Haemoglobin decreased	2 0.3%	0 0%
Gastrointestinal Disorders	12 1.6%	4 0.5%
Abdominal pain upper	3 0.4%	1 0.1%
Dyspepsia	3 0.4%	1 0.1%
Nausea	2 0.3%	0 0%
Skin and Subcutaneous Tissue Disorders	6 0.8%	5 0.7%
Pruritus	2 0.3%	1 0.1%
Rash	1 0.1%	2 0.3%
Injury, Poisoning, and Procedural Complications	1 0.1%	7 0.9%
Overdose	0 0%	4 0.5%
Contusion	1 0.1%	1 0.1%
General Disorders & Administration Site Conditions	6 0.8%	1 0.1%
Death	3 0.4%	0 0%
Renal and Urinary Disorders	2 0.3%	2 0.3%
Chronic kidney disease	1 0.1%	1 0.1%
Renal failure	1 0.1%	1 0.1%
Nervous System Disorders	3 0.4%	0 0%
Dizziness	2 0.3%	0 0%

Adverse Events

Time Frame	Adverse events were collected from Day 1 to 30 days after last dose, up to 2 years, 4 months.
Adverse Event Reporting Description	Adverse events were reported from the Safety Analysis Set (746 Edoxaban regimen; 740 Vitamin K Antagonist regimen).
Arm/Group Title	Edoxaban Regimen		Vitamin K Antagonist Regimen
Arm/Group Description	Participants who were randomized to Edoxaban 60 mg once-daily or 30 mg once-daily and clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used).		Participants who were randomized to VKA in combination with clopidogrel 75 mg once-daily (or in the presence of a documented clinical need prasugrel [5 mg or 10 mg once-daily] or ticagrelor [90 mg twice-daily] may be used) and aspirin (100 mg once-daily, for a minimum of 1 month and up to 12 months duration).
All Cause Mortality
	Edoxaban Regimen		Vitamin K Antagonist Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/746 (6.2%)		37/740 (5%)
Serious Adverse Events
	Edoxaban Regimen		Vitamin K Antagonist Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	176/746 (23.6%)		175/740 (23.6%)
Blood and lymphatic system disorders
Anaemia	4/746 (0.5%)		3/740 (0.4%)
Normochromic normocytic anaemia	2/746 (0.3%)		0/740 (0%)
Hypochromic anaemia	1/746 (0.1%)		0/740 (0%)
Immune thrombocytopenic purpura	0/746 (0%)		1/740 (0.1%)
Iron deficiency anaemia	1/746 (0.1%)		0/740 (0%)
Nephrogenic anaemia	1/746 (0.1%)		0/740 (0%)
Pancytopenia	1/746 (0.1%)		0/740 (0%)
Cardiac disorders
Cardiac failure	29/746 (3.9%)		35/740 (4.7%)
Atrial fibrillation	20/746 (2.7%)		14/740 (1.9%)
Cardiac failure congestive	6/746 (0.8%)		5/740 (0.7%)
Cardiac failure acute	2/746 (0.3%)		4/740 (0.5%)
Sinus node dysfunction	2/746 (0.3%)		3/740 (0.4%)
Atrial flutter	3/746 (0.4%)		1/740 (0.1%)
Cardiac failure chronic	3/746 (0.4%)		1/740 (0.1%)
Mitral valve incompetence	1/746 (0.1%)		3/740 (0.4%)
Aortic valve stenosis	2/746 (0.3%)		1/740 (0.1%)
Bradycardia	2/746 (0.3%)		1/740 (0.1%)
Tachycardia	2/746 (0.3%)		1/740 (0.1%)
Ventricular fibrillation	2/746 (0.3%)		1/740 (0.1%)
Ventricular tachycardia	3/746 (0.4%)		0/740 (0%)
Atrial tachycardia	2/746 (0.3%)		0/740 (0%)
Atrioventricular block second degree	0/746 (0%)		2/740 (0.3%)
Cardiac arrest	2/746 (0.3%)		0/740 (0%)
Cardio-respiratory arrest	2/746 (0.3%)		0/740 (0%)
Cardiogenic shock	2/746 (0.3%)		0/740 (0%)
Coronary artery disease	2/746 (0.3%)		0/740 (0%)
Coronary artery stenosis	1/746 (0.1%)		1/740 (0.1%)
Acute left ventricular failure	0/746 (0%)		1/740 (0.1%)
Adams-Stokes syndrome	1/746 (0.1%)		0/740 (0%)
Angina unstable	0/746 (0%)		1/740 (0.1%)
Atrioventricular block complete	0/746 (0%)		1/740 (0.1%)
Cardiac ventricular thrombosis	1/746 (0.1%)		0/740 (0%)
Cardiovascular insufficiency	0/746 (0%)		1/740 (0.1%)
Left ventricular dysfunction	0/746 (0%)		1/740 (0.1%)
Pulseless electrical activity	1/746 (0.1%)		0/740 (0%)
Sinus arrest	1/746 (0.1%)		0/740 (0%)
Tachyarrhythmia	0/746 (0%)		1/740 (0.1%)
Ventricular arrhythmia	0/746 (0%)		1/740 (0.1%)
Congenital, familial and genetic disorders
Phimosis	0/746 (0%)		1/740 (0.1%)
Endocrine disorders
Adrenal insufficiency	1/746 (0.1%)		0/740 (0%)
Eye disorders
Cataract	1/746 (0.1%)		1/740 (0.1%)
Iridocyclitis	1/746 (0.1%)		0/740 (0%)
Gastrointestinal disorders
Abdominal pain upper	1/746 (0.1%)		2/740 (0.3%)
Diarrhoea	2/746 (0.3%)		1/740 (0.1%)
Abdominal pain	2/746 (0.3%)		0/740 (0%)
Gastric ulcer	0/746 (0%)		2/740 (0.3%)
Inguinal hernia	0/746 (0%)		2/740 (0.3%)
Abdominal distension	1/746 (0.1%)		0/740 (0%)
Acute abdomen	1/746 (0.1%)		0/740 (0%)
Anal fissure	1/746 (0.1%)		0/740 (0%)
Anal stenosis	0/746 (0%)		1/740 (0.1%)
Colitis ulcerative	1/746 (0.1%)		0/740 (0%)
Crohn's disease	1/746 (0.1%)		0/740 (0%)
Dental cyst	0/746 (0%)		1/740 (0.1%)
Enterocolitis	1/746 (0.1%)		0/740 (0%)
Gastritis	1/746 (0.1%)		0/740 (0%)
Haemorrhoids	1/746 (0.1%)		0/740 (0%)
Large intestine perforation	0/746 (0%)		1/740 (0.1%)
Pancreatitis chronic	0/746 (0%)		1/740 (0.1%)
Rectal polyp	1/746 (0.1%)		0/740 (0%)
General disorders
Non-cardiac chest pain	6/746 (0.8%)		3/740 (0.4%)
Death	4/746 (0.5%)		3/740 (0.4%)
Sudden death	1/746 (0.1%)		3/740 (0.4%)
Chest pain	2/746 (0.3%)		1/740 (0.1%)
Vascular stent thrombosis	2/746 (0.3%)		1/740 (0.1%)
Asthenia	2/746 (0.3%)		0/740 (0%)
Vascular stent restenosis	2/746 (0.3%)		0/740 (0%)
Chest discomfort	0/746 (0%)		1/740 (0.1%)
Drowning	0/746 (0%)		1/740 (0.1%)
Hernia	0/746 (0%)		1/740 (0.1%)
Sudden cardiac death	1/746 (0.1%)		0/740 (0%)
Hepatobiliary disorders
Cholecystitis acute	3/746 (0.4%)		4/740 (0.5%)
Cholelithiasis	2/746 (0.3%)		0/740 (0%)
Biliary fistula	0/746 (0%)		1/740 (0.1%)
Cholecystitis	0/746 (0%)		1/740 (0.1%)
Hepatitis	0/746 (0%)		1/740 (0.1%)
Hepatorenal syndrome	1/746 (0.1%)		0/740 (0%)
Immune system disorders
Amyloidosis	1/746 (0.1%)		0/740 (0%)
Infections and infestations
Pneumonia	14/746 (1.9%)		13/740 (1.8%)
Urinary tract infection	3/746 (0.4%)		2/740 (0.3%)
Cellulitis	3/746 (0.4%)		1/740 (0.1%)
Septic shock	3/746 (0.4%)		1/740 (0.1%)
Appendicitis	1/746 (0.1%)		2/740 (0.3%)
Sepsis	2/746 (0.3%)		1/740 (0.1%)
Bronchitis	1/746 (0.1%)		1/740 (0.1%)
Erysipelas	1/746 (0.1%)		1/740 (0.1%)
Infective exacerbation of chronic obstructive airways disease	1/746 (0.1%)		1/740 (0.1%)
Respiratory tract infection	0/746 (0%)		2/740 (0.3%)
Aeromonas infection	0/746 (0%)		1/740 (0.1%)
Cholecystitis infective	0/746 (0%)		1/740 (0.1%)
Device-related infection	0/746 (0%)		1/740 (0.1%)
Gangrene	1/746 (0.1%)		0/740 (0%)
Gastroenteritis viral	1/746 (0.1%)		0/740 (0%)
Implant site infection	0/746 (0%)		1/740 (0.1%)
Infectious colitis	1/746 (0.1%)		0/740 (0%)
Influenza	1/746 (0.1%)		0/740 (0%)
Lower respiratory tract infection	0/746 (0%)		1/740 (0.1%)
Meningitis cryptococcal	1/746 (0.1%)		0/740 (0%)
Osteomyelitis	0/746 (0%)		1/740 (0.1%)
Peritoneal abscess	0/746 (0%)		1/740 (0.1%)
Postoperative wound infection	0/746 (0%)		1/740 (0.1%)
Sialoadenitis	0/746 (0%)		1/740 (0.1%)
Sinusitis	1/746 (0.1%)		0/740 (0%)
Streptococcal sepsis	1/746 (0.1%)		0/740 (0%)
Tracheobronchitis	0/746 (0%)		1/740 (0.1%)
Urosepsis	1/746 (0.1%)		0/740 (0%)
Wound infection	1/746 (0.1%)		0/740 (0%)
Injury, poisoning and procedural complications
Fall	0/746 (0%)		2/740 (0.3%)
Head injury	1/746 (0.1%)		1/740 (0.1%)
Hip fracture	1/746 (0.1%)		1/740 (0.1%)
Overdose	0/746 (0%)		2/740 (0.3%)
Arterial restenosis	1/746 (0.1%)		0/740 (0%)
Compression fracture	0/746 (0%)		1/740 (0.1%)
Concussion	1/746 (0.1%)		0/740 (0%)
Costal cartilage fracture	0/746 (0%)		1/740 (0.1%)
Femur fracture	0/746 (0%)		1/740 (0.1%)
Hand fracture	1/746 (0.1%)		0/740 (0%)
Humerus fracture	1/746 (0.1%)		0/740 (0%)
Limb injury	1/746 (0.1%)		0/740 (0%)
Product use issue	0/746 (0%)		1/740 (0.1%)
Rib fracture	1/746 (0.1%)		0/740 (0%)
Wound necrosis	0/746 (0%)		1/740 (0.1%)
Investigations
International normalised ratio increased	0/746 (0%)		3/740 (0.4%)
Metabolism and nutrition disorders
Diabetes mellitus	2/746 (0.3%)		2/740 (0.3%)
Decreased appetite	1/746 (0.1%)		0/740 (0%)
Diabetic metabolic decompensation	0/746 (0%)		1/740 (0.1%)
Hyponatraemia	0/746 (0%)		1/740 (0.1%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	2/746 (0.3%)		2/740 (0.3%)
Back pain	2/746 (0.3%)		1/740 (0.1%)
Intervertebral disc protusion	0/746 (0%)		3/740 (0.4%)
Arthralgia	1/746 (0.1%)		0/740 (0%)
Chondropathy	0/746 (0%)		1/740 (0.1%)
Joint swelling	0/746 (0%)		1/740 (0.1%)
Monarthritis	0/746 (0%)		1/740 (0.1%)
Musculoskeletal chest pain	0/746 (0%)		1/740 (0.1%)
Musculoskeletal discomfort	1/746 (0.1%)		0/740 (0%)
Neuropathic arthropathy	0/746 (0%)		1/740 (0.1%)
Pain in extremity	0/746 (0%)		1/740 (0.1%)
Rheumatic disorder	0/746 (0%)		1/740 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	2/746 (0.3%)		1/740 (0.1%)
Basal cell carcinoma	0/746 (0%)		2/740 (0.3%)
Adenocarcinoma gastric	0/746 (0%)		1/740 (0.1%)
Atypical fibroxanthoma	1/746 (0.1%)		0/740 (0%)
Bladder cancer	0/746 (0%)		1/740 (0.1%)
Bladder neoplasm	1/746 (0.1%)		0/740 (0%)
Fibrosarcoma	1/746 (0.1%)		0/740 (0%)
Hepatocellular carcinoma	1/746 (0.1%)		0/740 (0%)
Lung neoplasm malignant	1/746 (0.1%)		0/740 (0%)
Metastases to bone	1/746 (0.1%)		0/740 (0%)
Oesophageal carcinoma	1/746 (0.1%)		0/740 (0%)
Pancreatic neoplasm	0/746 (0%)		1/740 (0.1%)
Rectosigmoid cancer	1/746 (0.1%)		0/740 (0%)
Tongue neoplasm malignant stage unspecified	0/746 (0%)		1/740 (0.1%)
Nervous system disorders
Syncope	3/746 (0.4%)		0/740 (0%)
Sciatica	1/746 (0.1%)		1/740 (0.1%)
Brain oedema	0/746 (0%)		1/740 (0.1%)
Carotid artery stenosis	1/746 (0.1%)		0/740 (0%)
Cervicogenic headache	0/746 (0%)		1/740 (0.1%)
Cognitive disorder	0/746 (0%)		1/740 (0.1%)
Diabetic neuropathy	0/746 (0%)		1/740 (0.1%)
Dizziness	0/746 (0%)		1/740 (0.1%)
Monoparesis	1/746 (0.1%)		0/740 (0%)
Neuropathy peripheral	0/746 (0%)		1/740 (0.1%)
Seizure	0/746 (0%)		1/740 (0.1%)
Vertebrobasilar insufficiency	0/746 (0%)		1/740 (0.1%)
Product Issues
Device capturing issue	0/746 (0%)		1/740 (0.1%)
Psychiatric disorders
Confusional state	0/746 (0%)		2/740 (0.3%)
Suicide attempt	0/746 (0%)		1/740 (0.1%)
Renal and urinary disorders
Acute kidney injury	3/746 (0.4%)		7/740 (0.9%)
Renal failure	5/746 (0.7%)		2/740 (0.3%)
Nephrolithiasis	1/746 (0.1%)		1/740 (0.1%)
Calculus urethral	0/746 (0%)		1/740 (0.1%)
End stage renal disease	0/746 (0%)		1/740 (0.1%)
Prerenal failure	1/746 (0.1%)		0/740 (0%)
Renal artery stenosis	1/746 (0.1%)		0/740 (0%)
Renal impairment	0/746 (0%)		1/740 (0.1%)
Urethral stenosis	1/746 (0.1%)		0/740 (0%)
Urinary retention	1/746 (0.1%)		0/740 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	3/746 (0.4%)		1/740 (0.1%)
Prostatitis	2/746 (0.3%)		1/740 (0.1%)
Ovarian cyst	2/746 (0.3%)		0/740 (0%)
Cervical dysplasia	0/746 (0%)		1/740 (0.1%)
Spermatocele	0/746 (0%)		1/740 (0.1%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	5/746 (0.7%)		9/740 (1.2%)
Acute pulmonary oedema	2/746 (0.3%)		3/740 (0.4%)
Pulmonary oedema	3/746 (0.4%)		2/740 (0.3%)
Dyspnoea	2/746 (0.3%)		2/740 (0.3%)
Asthma	0/746 (0%)		3/740 (0.4%)
Respiratory failure	1/746 (0.1%)		2/740 (0.3%)
Pleural effusion	1/746 (0.1%)		1/740 (0.1%)
Pneumonitis	0/746 (0%)		2/740 (0.3%)
Respiratory arrest	0/746 (0%)		2/740 (0.3%)
Dyspnoea at rest	1/746 (0.1%)		0/740 (0%)
Dyspnoea exertional	1/746 (0.1%)		0/740 (0%)
Hydrothorax	1/746 (0.1%)		0/740 (0%)
Pneumothorax	1/746 (0.1%)		0/740 (0%)
Skin and subcutaneous tissue disorders
Diabetic foot	2/746 (0.3%)		0/740 (0%)
Cold sweat	0/746 (0%)		1/740 (0.1%)
Cutaneous lupus erythematosus	1/746 (0.1%)		0/740 (0%)
Pemphigoid	0/746 (0%)		1/740 (0.1%)
Psoriasis	1/746 (0.1%)		0/740 (0%)
Skin ulcer	0/746 (0%)		1/740 (0.1%)
Urticaria	1/746 (0.1%)		0/740 (0%)
Surgical and medical procedures
Coronary revascularisation	0/746 (0%)		1/740 (0.1%)
Vascular disorders
Hypertensive crisis	4/746 (0.5%)		3/740 (0.4%)
Hypertension	2/746 (0.3%)		1/740 (0.1%)
Peripheral arterial occlusive disease	1/746 (0.1%)		2/740 (0.3%)
Orthostatic hypotension	0/746 (0%)		2/740 (0.3%)
Aortic dissection	0/746 (0%)		1/740 (0.1%)
Extremity necrosis	0/746 (0%)		1/740 (0.1%)
Hypotension	0/746 (0%)		1/740 (0.1%)
Peripheral artery occlusion	0/746 (0%)		1/740 (0.1%)
Other (Not Including Serious) Adverse Events
	Edoxaban Regimen		Vitamin K Antagonist Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	457/746 (61.3%)		447/740 (60.4%)
Blood and lymphatic system disorders
Anaemia	19/746 (2.5%)		20/740 (2.7%)
Cardiac disorders
Cardiac failure	40/746 (5.4%)		47/740 (6.4%)
Atrial fibrillation	39/746 (5.2%)		41/740 (5.5%)
Bradycardia	10/746 (1.3%)		7/740 (0.9%)
Cardiac failure congestive	8/746 (1.1%)		8/740 (1.1%)
Ventricular extrasystoles	7/746 (0.9%)		8/740 (1.1%)
Tachycardia	11/746 (1.5%)		3/740 (0.4%)
Ear and labyrinth disorders
Vertigo	8/746 (1.1%)		5/740 (0.7%)
Gastrointestinal disorders
Diarrhoea	23/746 (3.1%)		19/740 (2.6%)
Constipation	11/746 (1.5%)		7/740 (0.9%)
Abdominal pain upper	6/746 (0.8%)		10/740 (1.4%)
Gastritis	9/746 (1.2%)		5/740 (0.7%)
Nausea	8/746 (1.1%)		5/740 (0.7%)
Dyspepsia	8/746 (1.1%)		3/740 (0.4%)
General disorders
Non-cardiac chest pain	30/746 (4%)		24/740 (3.2%)
Oedema peripheral	31/746 (4.2%)		22/740 (3%)
Asthenia	21/746 (2.8%)		14/740 (1.9%)
Chest pain	7/746 (0.9%)		11/740 (1.5%)
Fatigue	11/746 (1.5%)		6/740 (0.8%)
Infections and infestations
Nasopharyngitis	25/746 (3.4%)		22/740 (3%)
Pneumonia	20/746 (2.7%)		22/740 (3%)
Bronchitis	19/746 (2.5%)		20/740 (2.7%)
Urinary tract infection	14/746 (1.9%)		19/740 (2.6%)
Respiratory tract infection	12/746 (1.6%)		15/740 (2%)
Influenza	10/746 (1.3%)		7/740 (0.9%)
Injury, poisoning and procedural complications
Fall	8/746 (1.1%)		12/740 (1.6%)
Investigations
Blood creatinine increased	15/746 (2%)		13/740 (1.8%)
Alanine aminotransferase increased	8/746 (1.1%)		13/740 (1.8%)
Blood pressure increased	12/746 (1.6%)		8/740 (1.1%)
Creatinine renal clearance increased	12/746 (1.6%)		7/740 (0.9%)
Aspartate aminotransferase increased	7/746 (0.9%)		11/740 (1.5%)
International normalised ratio increased	0/746 (0%)		12/740 (1.6%)
Metabolism and nutrition disorders
Gout	11/746 (1.5%)		4/740 (0.5%)
Musculoskeletal and connective tissue disorders
Back pain	14/746 (1.9%)		14/740 (1.9%)
Arthralgia	11/746 (1.5%)		12/740 (1.6%)
Pain in extremity	5/746 (0.7%)		13/740 (1.8%)
Myalgia	8/746 (1.1%)		8/740 (1.1%)
Osteoarthritis	9/746 (1.2%)		5/740 (0.7%)
Nervous system disorders
Dizziness	30/746 (4%)		22/740 (3%)
Headache	19/746 (2.5%)		12/740 (1.6%)
Syncope	8/746 (1.1%)		6/740 (0.8%)
Psychiatric disorders
Insomnia	8/746 (1.1%)		8/740 (1.1%)
Renal and urinary disorders
Renal failure	11/746 (1.5%)		12/740 (1.6%)
Acute kidney injury	8/746 (1.1%)		13/740 (1.8%)
Renal impairment	7/746 (0.9%)		8/740 (1.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	22/746 (2.9%)		26/740 (3.5%)
Cough	21/746 (2.8%)		11/740 (1.5%)
Dyspnoea exertional	18/746 (2.4%)		5/740 (0.7%)
Chronic obstructive pulmonary disease	6/746 (0.8%)		10/740 (1.4%)
Skin and subcutaneous tissue disorders
Pruritus	12/746 (1.6%)		7/740 (0.9%)
Rash	10/746 (1.3%)		9/740 (1.2%)
Vascular disorders
Hypertension	23/746 (3.1%)		23/740 (3.1%)
Hypotension	14/746 (1.9%)		14/740 (1.9%)
Hypertensive crisis	11/746 (1.5%)		8/740 (1.1%)

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.