ARTESiA: Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation

Sponsor

Population Health Research Institute (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01938248

Collaborator

Bristol-Myers Squibb (Industry), Pfizer (Industry), Medtronic (Industry), Canadian Institutes of Health Research (CIHR) (Other)

4,012

Enrollment

130

Locations

Arms

103

Anticipated Duration (Months)

30.9

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study aims to determine if treatment with apixaban, compared with aspirin, will reduce the risk of ischemic stroke and systemic embolism in patients with device-detected sub-clinical atrial fibrillation and additional risk factors for stroke.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation Stroke	Drug: Apixaban Drug: aspirin	Phase 4

Detailed Description

Device-detected sub-clinical atrial fibrillation (SCAF) is a new disorder that has been recognized since the availability of implantable devices capable of long term continuous heart rhythm monitoring. It is characterized by one or more runs of rapid atrial arrhythmia detected by the device without symptoms and without any clinical atrial fibrillation (AF) detected by the usual methods, (i.e. electrocardiogram, Holter monitor, etc.). In the ASSERT trial, SCAF was detected by a pacemaker or implantable cardioverter defibrillator (ICD) in nearly 40% of patients during 2 and a half years of follow up. The presence of SCAF increased stroke risk by 2.5-fold (1). The risk of stroke or systemic embolism among patients with SCAF and a CHADS2 score ≥ 4 was 2.75% per year. Oral anticoagulation is effective and safe for stroke prevention in patients with clinical atrial fibrillation, but it is unknown if the same risk benefit ratio exists for anticoagulation therapy in patients with SCAF (2;3). SCAF differs from clinical AF in being of shorter duration, being asymptomatic, and often have a more regular rhythm in the right atrium where it is typically detected. Data ASSERT suggest that the increase in stroke risk with SCAF may be less than the increase with clinical AF. Therefore opinion leaders have written that the role of oral anticoagulation for the treatment of SCAF is uncertain and that randomized trials of anticoagulation are needed (4;5). Recent surveys of pacemaker clinic practice indicate that only 25% of patients with SCAF are treated with oral anticoagulation (6;7). Thus there is clinical equipoise for a trial of oral anticoagulation compared to aspirin in higher risk patients with SCAF.

Apixaban is a Factor Xa inhibitor that is an effective and safe anticoagulant. It has been shown to have an excellent risk benefit profile for stroke prevention in clinical AF (14, 15). It is highly suitable to test if oral anticoagulation therapy will reduce the risk of stroke or systemic embolism in SCAF.

Patients will be randomized double-blind to receive apixaban or aspirin. Apixaban dose will be 5 mg twice daily (2.5 mg twice daily if 2 or more of: age > 80, weight ≤ 60 kg or serum creatinine ≥ 133 mmol/L). Those assigned to aspirin will receive a dose of 81 mg daily. The study will be event driven and will continue until 248 patients have experienced a primary outcome event.

Study Design

Study Type:

Interventional

Actual Enrollment :

4012 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation

Actual Study Start Date :

May 1, 2015

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Control Aspirin 81 mg once daily	Drug: aspirin aspirin 81 mg once daily Other Names: ASA acetylsalicylic acid
Experimental: Intervention Apixaban, 5 mg twice daily (or 2.5 mg twice daily if 2 or more of: age > 80, weight ≤ 60 kg or serum creatinine ≥ 133 mmol/L)	Drug: Apixaban apixaban at a dose of 5 mg twice daily (2.5 mg twice daily if 2 or more of: age > 80, weight ≤ 60 kg or serum creatinine ≥ 133 mmol/L) Other Names: Eliquis

Arm

Intervention/Treatment

Active Comparator: Control

Aspirin 81 mg once daily

Drug: aspirin

aspirin 81 mg once daily

Other Names:

ASA

acetylsalicylic acid

Experimental: Intervention

Apixaban, 5 mg twice daily (or 2.5 mg twice daily if 2 or more of: age > 80, weight ≤ 60 kg or serum creatinine ≥ 133 mmol/L)

Drug: Apixaban

apixaban at a dose of 5 mg twice daily (2.5 mg twice daily if 2 or more of: age > 80, weight ≤ 60 kg or serum creatinine ≥ 133 mmol/L)

Other Names:

Eliquis

Outcome Measures

Primary Outcome Measures

Composite of ischemic stroke and systemic embolism [event driven, duration of follow-up - mean follow-up time anticipated: 3 years]
Definition of stroke: Rapid onset* of a focal/global neurological deficit Duration of a focal/global neurological deficit ≥ 24 hours OR the neurological deficit results in death OR the neurological deficit is supported by clear evidence of cerebral infarction on diffusion-weighted MRI imaging. No other readily identifiable non-stroke cause for the clinical presentation Confirmation of the diagnosis by specialist evaluation or brain imaging procedure Definition of Systemic Embolism: Clinical signs and symptoms consistent with embolic arterial occlusion plus at least one of the following objective findings of arterial embolism: Surgical report indicating evidence of arterial embolism Pathological specimens related to embolism removal Imaging evidence consistent with arterial embolism Autopsy reports
Major Bleed [duration of follow-up]
The main safety outcome will be the occurrence of clinically overt major bleeding as defined by the ISTH criteria: Fatal bleeding, and/or Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or Bleeding causing a fall in hemoglobin level of 2 g/dL or more, or leading to transfusion of two or more units of whole blood or red cells.

Secondary Outcome Measures

Ischemic Stroke [Duration of Follow-up]
Myocardial Infarction [Duration of follow-up]
MI definition: Typical rise and gradual fall (troponin) or more rapid rise and fall (CKMB) of biochemical markers of myocardial necrosis with at least one of: a) ischemic symptoms; b) development of pathological Q-waves on the ECG; c) ECG changes indicative of ischemia; d) Coronary artery intervention OR Pathological findings of an acute myocardial infarction
Cardiovascular Death [Duration of follow-up]
All-cause Death [Duration of follow-up]
Composite of stroke, MI, SE and death [Duration of follow-up]
Composite of stroke, myocardial infarction, systemic embolism and all-cause death
Composite of stroke, MI, SE, death and major bleeding [Duration of follow-up]
Composite of stroke, myocardial infarction, systemic embolism, all-cause death and major bleeding

Eligibility Criteria

Criteria

Ages Eligible for Study:

55 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Permanent pacemaker or defibrillator (with or without resynchronization) or insertable cardiac monitor capable of detecting SCAF
At least one episode of SCAF ≥ 6 minutes in duration but no single episode > 24 hours in duration at any time prior to enrollment. Any atrial high rate episode with average

175 beats/min will be considered as SCAF. No distinction will be made between atrial fibrillation and atrial flutter. SCAF requires electrogram confirmation (at least one episode) unless ≥ 6 hours in duration.

Age ≥ 55 years
Risk Factor(s) for Stroke:

Previous stroke, TIA or systemic arterial embolism OR Age at least 75 OR Age 65-74 with at least 2 other risk factors OR Age 55-64 with at least 3 other risk factors

Other risk factors are:

hypertension
CHF
diabetes
vascular disease (i.e. CAD, PAD or Aortic Plaque)
female

Exclusion Criteria:

Clinical atrial fibrillation documented by surface ECG (12 lead ECG, Telemetry, Holter) lasting ≥ 6 minutes, with or without clinical symptoms
Mechanical valve prosthesis, deep vein thrombosis, recent pulmonary embolism or other condition requiring treatment with an anticoagulant
Contra-indication to apixaban or aspirin:
Allergy to aspirin or apixaban
Severe renal insufficiency (creatinine clearance must be calculated in all patients; any patient with either a serum creatinine > 2.5 mg/dL [221 µmol/L] or a calculated creatinine clearance < 25 ml/min is excluded)
Serious bleeding in the last 6 months or at high risk of bleeding (this includes, but is not limited to: prior intracranial hemorrhage, active peptic ulcer disease, platelet count < 50,000/mm3 or hemoglobin < 10 g/dL, recent stroke within past 10 days, documented hemorrhagic tendencies or blood dyscrasias)
Moderate to severe hepatic impairment
Ongoing need for combination therapy with aspirin and clopidogrel (or other combination of two platelet inhibitors)
Meets criteria for requiring lower dose of apixaban AND also has ongoing need for strong inhibitors of CYP 3A4 or P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir or clarithromycin)
Ongoing need for strong dual inducers of CYP 3A4 or P-glycoprotein (e.g., rifampin, carbamazepine, phenytoin, St. John's wort)
Received an investigational drug in the past 30 days
Participants considered by the investigator to be unsuitable for the study for any of the following reasons:
Not agreeable for treatment with either aspirin or apixaban or anticipated to have poor compliance on study drug treatment
Unwilling to attend study follow-up visits
Life expectancy less than the expected duration of the trial2 years due to concomitant disease
Women who are pregnant, breast-feeding or of child-bearing potential without an acceptable form of contraception in place (sterilization, hormonal contraceptives, intrauterine device, barrier methods or abstinence)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cardiovascular Associates of Mesa, PC	Mesa	Arizona	United States	85206
2	St. Vincent Heart Clinic	Little Rock	Arkansas	United States	72205
3	Cardiovascular Associates of Marin and San Francisco Medical	Larkspur	California	United States	94939
4	Aurora Denver Cardiology Associates	Aurora	Colorado	United States	80012
5	Naples Interventional Cardiac Electrophysiology	Naples	Florida	United States	34102
6	Langhorne Cardiology Consultants, Inc.	Pensacola	Florida	United States	32501
7	One Health Cardiology, Owensboro Health, Inc.	Owensboro	Kentucky	United States	42304
8	Tufts Medical Center	Boston	Massachusetts	United States	02111
9	Sparrow Clinical Research Institute	Lansing	Michigan	United States	48912
10	Michigan Heart	Ypsilanti	Michigan	United States	48197
11	University of Missouri Health System	Columbia	Missouri	United States	65212
12	St. Louis Heart and Vascular	Saint Louis	Missouri	United States	63136
13	Glacier View Cardiology	Kalispell	Montana	United States	59901
14	The Cooper Health System	Camden	New Jersey	United States	08103
15	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
16	The Valley Hospital	Ridgewood	New Jersey	United States	07450
17	St. Peter's Health Partners Medical Association, PC	Albany	New York	United States	12205
18	Carolinas Healthcare System	Charlotte	North Carolina	United States	28203
19	WakeMed	Raleigh	North Carolina	United States	27610
20	Cleveland Clinic	Cleveland	Ohio	United States	44195
21	Pennsylvania State University	Hershey	Pennsylvania	United States	17033
22	Research Institute of LG Health / Penn Medicine	Lancaster	Pennsylvania	United States	17602
23	Virginia Heart	Falls Church	Virginia	United States	22042
24	Onze Lieve Vrouw Ziekenhuis	Aalst		Belgium	9300
25	Vivalia CSL St. Joseph	Arlon		Belgium	6700
26	Clinique Saint Jean-Brussels	Brussels		Belgium	1000
27	Grand Hopital de Charleroi	Gilly		Belgium	6060
28	AZ Groeninge	Kortrijk		Belgium	8500
29	University Hospitals Leuven	Leuven		Belgium	3000
30	CHC Saint Joseph	Liege		Belgium	4000
31	CHR de la Citadelle	Liège		Belgium	4000
32	AZ Delta	Roeselare		Belgium	8800
33	CHU Dinant-Godinne	Yvoir		Belgium	5530
34	University of Calgary Foothills Hospital	Calgary	Alberta	Canada	T2N 2T9
35	Royal Alexandra Hospital	Edmonton	Alberta	Canada	T5H 3V9
36	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
37	Grey Nuns Hospital	Edmonton	Alberta	Canada	T6L 5X8
38	Heart Rhythm Research Office - St. Paul's Hospital	Vancouver	British Columbia	Canada	V6E 1M7
39	Victoria Cardiac Arrhythmia Trials, Inc.	Victoria	British Columbia	Canada	V8T 1Z4
40	St. Boniface Hospital	Winnepeg	Manitoba	Canada	R2H 2A6
41	Capital District Health Authority	Halifax	Nova Scotia	Canada
42	Hamilton General Hospital	Hamilton	Ontario	Canada	L8L 2X2
43	St. Mary's General Hospital	Kitchener	Ontario	Canada	N2M 1B2
44	London Health Sciences Centre	London	Ontario	Canada
45	Southlake Regional Health Centre	Newmarket	Ontario	Canada
46	Oakville Cardiologists	Oakville	Ontario	Canada
47	University of Ottawa Heart Institute	Ottawa	Ontario	Canada
48	Health Sciences North	Sudbury	Ontario	Canada	P3E 5J1
49	St. Michael's Hospital	Toronto	Ontario	Canada
50	Sunnybrook Hospital	Toronto	Ontario	Canada
51	Institute Universitaire de Cardiologie and de Pneumonologie	Laval	Quebec	Canada
52	McGill University Health Centre	Montreal	Quebec	Canada	H3G 1A4
53	CHUM - Hotel Dieu	Montreal	Quebec	Canada
54	Hopital Sacre-Coeur de Montreal	Montreal	Quebec	Canada
55	Montreal Heart Institute	Montreal	Quebec	Canada
56	CHUS - Sherbrooke	Sherbrooke	Quebec	Canada
57	Ciusss McQ	Trois-Rivières	Quebec	Canada	G8Z 3R9
58	IKEM Institute for Clinical and Experimental Medicine	Prague		Czechia	14021
59	Hilleroed Hospital	Hilleroed	North Zealand	Denmark	3400
60	Sygehus Sonderjylland	Aabenraa		Denmark	6200
61	Aalborg University Hospital, Dept of Cardiology	Aalborg		Denmark	9000
62	Aarhus Unniversity Hospital, Skejby	Aarhus		Denmark	DK-8200
63	Gentofte Hospital	Hellerup		Denmark	2900
64	Odense University Hospital	Odense		Denmark	5000
65	Hjertemedicinsk Forskning, RH Viborg, HEM	Viborg		Denmark	8800
66	Johann Wolfgang Goethe University Hospital Frankfurt	Frankfurt	Hesse	Germany	60590
67	Katholisches Klinikum Mainz	Mainz	Rheinland-Pfalz	Germany	55131
68	Universitatsklinikum des Saarlandes	Homburg/Saar	Saarland	Germany	66421
69	MVZ am Kuchwald GmbH	Chemnitz	Saxony	Germany	09113
70	Zentrum fur klinische Prufungen in der Facharztzentrum Dresd	Dresden	Saxony	Germany	01099
71	University Medicine Gottingen	Gottingen		Germany	37075
72	Asklepios Klinik Barmbek	Hamburg		Germany	22291
73	Universitaetsklinikum Tuebingen, Kardiologie	Tuebingen		Germany	72076
74	Allami Szivkorhaz Balatonfured	Balatonfured	Veszprem	Hungary	8230
75	Magyar Honvedseg Egeszsegugyi Kozpont	Budapest		Hungary	1134
76	Semmelweis University	Budapest		Hungary	H-1122
77	Ospedale Sant'Anna	San Fermo Della Batt	Como	Italy	22020
78	Cardiologia-A.O. Desio e Vimercate - Presisio di Vimercat	Vimercate	Monza Brianza MB	Italy	20871
79	Hospital Santa Maria Della Pieta	Nola	Napoli	Italy	80035
80	AOU Ospedali Riuniti	Ancona		Italy	60126
81	Ospedale Maggiore, Cardiologia Dept.	Bologna		Italy	40133
82	S.Orsola-Malpighi	Bologna		Italy	40138
83	Bolzano Regional Hospital, Dept of Cardiology	Bolzano		Italy	39100
84	Azienda Ospedaliero-Univeritaria Di Modena-Policlinico	Modena		Italy	41124
85	Ospedale G.B. Grassi	Rome		Italy	00122
86	University and Hospital of Trieste	Trieste		Italy	34129
87	Ziekenhuis Tjongerschans	Heerenveen	Friesland	Netherlands	8441 PW
88	Gelre Ziekenhuis	Zutphen	Gelderland	Netherlands	7207 AE
89	Atrium Orbis Heerlen	Heerlen	Limburg	Netherlands	6419 PC
90	Amphia Hospital Breda	Breda	Noord-Brabant	Netherlands	4818 CK
91	Ikazia Ziekenhuis	Rotterdam	Zuid-Holland	Netherlands	3083 AN
92	BovenIJ Ziekenhuis	Amsterdam		Netherlands	1034 CS
93	Hospital Rijnstate	Arnhem		Netherlands	6815 AD
94	Deventer Hospital, Cardiology Research	Deventer		Netherlands	7416 SE
95	Hospital Gelderse Vallei	Ede		Netherlands	6721 JT
96	Treant Hospital Department Cardiology	Emmen		Netherlands	7824 AA
97	Admiraal de Ruyter Ziekenhuis	Goes		Netherlands	4462 RA
98	Treant Hospital - Bethseda, Hoogeveen	Hoogeveen		Netherlands	7909 AA
99	Bravis Ziekenhuis, locatie Roosendaal	Roosendaal		Netherlands	4708 AE
100	(ETZ) Elisabeth Tweesteden Hospital	Tilburg		Netherlands	5022 GC
101	Máxima Medisch Centrum	Veldhoven		Netherlands	5504 DB
102	Barum Hospital, Vestre Viken	Drammen	Buskerud	Norway	3004
103	Oslo University Hospital - Ulleval	Oslo		Norway	0450
104	Hospital Clinico Santiago de Compostela	Santiago De Composte	A Coruna	Spain	15706
105	Rafael Mendez Universitary Hospital	Lorca	Murcia	Spain	30800
106	Complexo Hospitalario Universitario A Coruna	A Coruna		Spain	15006
107	Hospital General Universitario de Alicante	Alicante		Spain	03010
108	Hospital Del Mar	Barcelona		Spain	8003
109	Hospital Juan Ramon Jimenez	Huelva		Spain	21005
110	Hospital Clinico San Carlos, Unidad De Arritmias	Madrid		Spain	28040
111	Hospital Universitario Fundacion Jimenez Diaz	Madrid		Spain	28040
112	Hospital Puerta de Hierro Majadahonda	Majadahonda		Spain	28222
113	Agencia Sanitaria Costa del Sol- Hospital Costa del Sol	Marbella		Spain	29603
114	Clinica Universidad de Navarra	Pamplona		Spain	31008
115	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
116	Hospital Clínico Universitario de Valladolid	Valladolid		Spain	47003
117	University Hospital Basel	Basel	Basel-Stadt	Switzerland	4031
118	Kantonsspital St Gallen	St. Gallen	Saint Gallen	Switzerland	9007
119	CHUV	Lausanne	Vaud	Switzerland	1011
120	Hopital Fribourgeois, site de Fribourg	Fribourg		Switzerland	1708
121	University Hospital of Geneva	Geneva		Switzerland	1211
122	Dorset County Hospital NHS Foundation Trust	Dorchester	Dorset	United Kingdom	DT12JY
123	Hampshire Hospitals (NHS Foundation Trust)	Basingstoke	Hampshire	United Kingdom	RG24 9NA
124	Portsmouth Hospitals NHS Trust	Portsmouth	Hampshire	United Kingdom	PO6 3LY
125	Royal Alexandra Hospital	Paisley	Renfrewshire	United Kingdom	PA29PN
126	Shrewsbury & Telford Hospital NHS	Shropshire	West Midlands	United Kingdom	TF1 6TF
127	Blackpool Teaching Hospitals NHS Foundation Trust	Blackpool		United Kingdom	FY3 8NR
128	Queen Elizabeth University Hospital	Glasgow		United Kingdom	G51 4TF
129	Liverpool Heart and Chest Hospital	Liverpool		United Kingdom	L14 3PE
130	Freeman Hospital	Newcastle-upon-Tyne		United Kingdom	NE7 7DN

Sponsors and Collaborators

Population Health Research Institute
Bristol-Myers Squibb
Pfizer
Medtronic
Canadian Institutes of Health Research (CIHR)

Investigators

Principal Investigator: Jeff Healey, M.D., Population Health Research Institute
Study Chair: Stuart Connolly, M.D., Population Health Research Institute
Principal Investigator: Marco Alings, M.D., Working Group Cardiovascular Research Netherlands
Principal Investigator: Renato Lopes, M.D., Duke Clinical Research Institute