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

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.

Study Overview

• Status: Completed
• Conditions: Stroke; Atrial Fibrillation
• Intervention / Treatment: Drug: aspirin; Drug: Apixaban

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 Type: Interventional
• Enrollment (Actual): 4012
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Permanent pacemaker or defibrillator (with or without resynchronization) or insertable cardiac monitor capable of detecting SCAF
2. 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.
3. Age ≥ 55 years
4. 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:

1. Clinical atrial fibrillation documented by surface ECG (12 lead ECG, Telemetry, Holter) lasting ≥ 6 minutes, with or without clinical symptoms
2. Mechanical valve prosthesis, deep vein thrombosis, recent pulmonary embolism or other condition requiring treatment with an anticoagulant

3. Contra-indication to apixaban or aspirin:

   1. Allergy to aspirin or apixaban
   2. 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)
   3. 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)
   4. Moderate to severe hepatic impairment
   5. Ongoing need for combination therapy with aspirin and clopidogrel (or other combination of two platelet inhibitors)
   6. 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)
   7. Ongoing need for strong dual inducers of CYP 3A4 or P-glycoprotein (e.g., rifampin, carbamazepine, phenytoin, St. John's wort)
4. Received an investigational drug in the past 30 days

5. Participants considered by the investigator to be unsuitable for the study for any of the following reasons:

   1. Not agreeable for treatment with either aspirin or apixaban or anticipated to have poor compliance on study drug treatment
   2. Unwilling to attend study follow-up visits
   3. Life expectancy less than the expected duration of the trial2 years due to concomitant disease
6. 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of ischemic stroke and systemic embolism	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	event driven, duration of follow-up - mean follow-up time anticipated: 3 years
Major Bleed	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.	duration of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ischemic Stroke		Duration of Follow-up
Myocardial Infarction	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 interventionOR; Pathological findings of an acute myocardial infarction	Duration of follow-up
Cardiovascular Death		Duration of follow-up
All-cause Death		Duration of follow-up
Composite of stroke, MI, SE and death	Composite of stroke, myocardial infarction, systemic embolism and all-cause death	Duration of follow-up
Composite of stroke, MI, SE, death and major bleeding	Composite of stroke, myocardial infarction, systemic embolism, all-cause death and major bleeding	Duration of follow-up

Collaborators and Investigators

• Sponsor: Population Health Research Institute
• Collaborators: Bristol-Myers Squibb; Pfizer; Canadian Institutes of Health Research (CIHR); Medtronic
• Investigators: Principal Investigator: Jeff Healey, M.D., Population Health Research Institute; Principal Investigator: Marco Alings, M.D., Working Group Cardiovascular Research Netherlands; Study Chair: Stuart Connolly, M.D., Population Health Research Institute; Principal Investigator: Renato Lopes, M.D., Duke Clinical Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2015
• Primary Completion (Actual): October 27, 2023
• Study Completion (Actual): November 3, 2023

Study Registration Dates

• First Submitted: September 4, 2013
• First Submitted That Met QC Criteria: September 4, 2013
• First Posted (Estimated): September 10, 2013

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Defibrillators, Implantable; Stroke Risk; Pacemaker, Artificial
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Arrhythmias, Cardiac; Embolism; Atrial Fibrillation; Thromboembolism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Apixaban
• Other Study ID Numbers: ARTESiA; 2014-001397-33 (EudraCT Number)