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

NCT01938248 | Completed Phase 4 DMC

• 2 other identifiers: ARTESiA2014-001397-33
• Study Type: interventional
• Target: 4,012
• Locations: 13 countries
• Sites: 130

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.

Conditions

Atrial Fibrillation; Stroke

Keywords

Pacemaker, Artificial; Defibrillators, Implantable; Atrial Fibrillation; Stroke Risk

Outcome Measures

Primary Outcomes (2)

• Composite of ischemic stroke and systemic embolism

  Definition of stroke: 1. Rapid onset\* of a focal/global neurological deficit 2. 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. 3. No other readily identifiable non-stroke cause for the clinical presentation 4. 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: 1. Fatal bleeding, and/or 2. 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 3. 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 Outcomes (6)

• Ischemic Stroke

  Duration of Follow-up

• 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

  Duration of follow-up

Study Arms (2)

Control

ACTIVE COMPARATOR

Aspirin 81 mg once daily

Drug: aspirin

Intervention

EXPERIMENTAL

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

Interventions

Apixaban DRUG

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)

Also known as: Eliquis

Intervention

aspirin DRUG

aspirin 81 mg once daily

Also known as: ASA, acetylsalicylic acid

Control

Eligibility Criteria

• Age: 55 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (130)

Cardiovascular Associates of Mesa, PC

Mesa, Arizona, 85206, United States

Location

St. Vincent Heart Clinic

Little Rock, Arkansas, 72205, United States

Location

Cardiovascular Associates of Marin and San Francisco Medical

Larkspur, California, 94939, United States

Location

Aurora Denver Cardiology Associates

Aurora, Colorado, 80012, United States

Location

Naples Interventional Cardiac Electrophysiology

Naples, Florida, 34102, United States

Location

Langhorne Cardiology Consultants, Inc.

Pensacola, Florida, 32501, United States

Location

One Health Cardiology, Owensboro Health, Inc.

Owensboro, Kentucky, 42304, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Sparrow Clinical Research Institute

Lansing, Michigan, 48912, United States

Location

Michigan Heart

Ypsilanti, Michigan, 48197, United States

Location

University of Missouri Health System

Columbia, Missouri, 65212, United States

Location

St. Louis Heart and Vascular

St Louis, Missouri, 63136, United States

Location

Glacier View Cardiology

Kalispell, Montana, 59901, United States

Location

The Cooper Health System

Camden, New Jersey, 08103, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

The Valley Hospital

Ridgewood, New Jersey, 07450, United States

Location

St. Peter's Health Partners Medical Association, PC

Albany, New York, 12205, United States

Location

Carolinas Healthcare System

Charlotte, North Carolina, 28203, United States

Location

WakeMed

Raleigh, North Carolina, 27610, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Pennsylvania State University

Hershey, Pennsylvania, 17033, United States

Location

Research Institute of LG Health / Penn Medicine

Lancaster, Pennsylvania, 17602, United States

Location

Virginia Heart

Falls Church, Virginia, 22042, United States

Location

Onze Lieve Vrouw Ziekenhuis

Aalst, 9300, Belgium

Location

Vivalia CSL St. Joseph

Arlon, 6700, Belgium

Location

Clinique Saint Jean-Brussels

Brussels, 1000, Belgium

Location

Grand Hopital de Charleroi

Gilly, 6060, Belgium

Location

AZ Groeninge

Kortrijk, 8500, Belgium

Location

University Hospitals Leuven

Leuven, 3000, Belgium

Location

CHC Saint Joseph

Liège, 4000, Belgium

Location

CHR de la Citadelle

Liège, 4000, Belgium

Location

AZ Delta

Roeselare, 8800, Belgium

Location

CHU Dinant-Godinne

Yvoir, 5530, Belgium

Location

University of Calgary Foothills Hospital

Calgary, Alberta, T2N 2T9, Canada

Location

Royal Alexandra Hospital

Edmonton, Alberta, T5H 3V9, Canada

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 2B7, Canada

Location

Grey Nuns Hospital

Edmonton, Alberta, T6L 5X8, Canada

Location

Heart Rhythm Research Office - St. Paul's Hospital

Vancouver, British Columbia, V6E 1M7, Canada

Location

Victoria Cardiac Arrhythmia Trials, Inc.

Victoria, British Columbia, V8T 1Z4, Canada

Location

St. Boniface Hospital

Winnepeg, Manitoba, R2H 2A6, Canada

Location

Capital District Health Authority

Halifax, Nova Scotia, Canada

Location

Health Sciences North

Greater Sudbury, Ontario, P3E 5J1, Canada

Location

Hamilton General Hospital

Hamilton, Ontario, L8L 2X2, Canada

Location

St. Mary's General Hospital

Kitchener, Ontario, N2M 1B2, Canada

Location

London Health Sciences Centre

London, Ontario, Canada

Location

Southlake Regional Health Centre

Newmarket, Ontario, Canada

Location

Oakville Cardiologists

Oakville, Ontario, Canada

Location

University of Ottawa Heart Institute

Ottawa, Ontario, Canada

Location

St. Michael's Hospital

Toronto, Ontario, Canada

Location

Sunnybrook Hospital

Toronto, Ontario, Canada

Location

Institute Universitaire de Cardiologie and de Pneumonologie

Laval, Quebec, Canada

Location

McGill University Health Centre

Montreal, Quebec, H3G 1A4, Canada

Location

CHUM - Hotel Dieu

Montreal, Quebec, Canada

Location

Hopital Sacre-Coeur de Montreal

Montreal, Quebec, Canada

Location

Montreal Heart Institute

Montreal, Quebec, Canada

Location

CHUS - Sherbrooke

Sherbrooke, Quebec, Canada

Location

Ciusss McQ

Trois-Rivières, Quebec, G8Z 3R9, Canada

Location

IKEM Institute for Clinical and Experimental Medicine

Prague, 14021, Czechia

Location

Hilleroed Hospital

Hilleroed, North Zealand, 3400, Denmark

Location

Sygehus Sonderjylland

Aabenraa, 6200, Denmark

Location

Aalborg University Hospital, Dept of Cardiology

Aalborg, 9000, Denmark

Location

Aarhus Unniversity Hospital, Skejby

Aarhus, DK-8200, Denmark

Location

Gentofte Hospital

Hellerup, 2900, Denmark

Location

Odense University Hospital

Odense, 5000, Denmark

Location

Hjertemedicinsk Forskning, RH Viborg, HEM

Viborg, 8800, Denmark

Location

Johann Wolfgang Goethe University Hospital Frankfurt

Frankfurt am Main, Hesse, 60590, Germany

Location

Katholisches Klinikum Mainz

Mainz, Rhineland-Palatinate, 55131, Germany

Location

Universitatsklinikum des Saarlandes

Homburg/Saar, Saarland, 66421, Germany

Location

MVZ am Kuchwald GmbH

Chemnitz, Saxony, 09113, Germany

Location

Zentrum fur klinische Prufungen in der Facharztzentrum Dresd

Dresden, Saxony, 01099, Germany

Location

University Medicine Gottingen

Göttingen, 37075, Germany

Location

Asklepios Klinik Barmbek

Hamburg, 22291, Germany

Location

Universitaetsklinikum Tuebingen, Kardiologie

Tübingen, 72076, Germany

Location

Allami Szivkorhaz Balatonfured

Balatonfüred, Veszprém megye, 8230, Hungary

Location

Magyar Honvedseg Egeszsegugyi Kozpont

Budapest, 1134, Hungary

Location

Semmelweis University

Budapest, H-1122, Hungary

Location

Ospedale Sant'Anna

San Fermo Della Batt, Como, 22020, Italy

Location

Cardiologia-A.O. Desio e Vimercate - Presisio di Vimercat

Vimercate, Monza Brianza MB, 20871, Italy

Location

Hospital Santa Maria Della Pieta

Nola, Napoli, 80035, Italy

Location

AOU Ospedali Riuniti

Ancona, 60126, Italy

Location

Ospedale Maggiore, Cardiologia Dept.

Bologna, 40133, Italy

Location

S.Orsola-Malpighi

Bologna, 40138, Italy

Location

Bolzano Regional Hospital, Dept of Cardiology

Bolzano, 39100, Italy

Location

Azienda Ospedaliero-Univeritaria Di Modena-Policlinico

Modena, 41124, Italy

Location

Ospedale G.B. Grassi

Rome, 00122, Italy

Location

University and Hospital of Trieste

Trieste, 34129, Italy

Location

Gelre Ziekenhuis

Zutphen, Gelderland, 7207 AE, Netherlands

Location

Atrium Orbis Heerlen

Heerlen, Limburg, 6419 PC, Netherlands

Location

Amphia Hospital Breda

Breda, North Brabant, 4818 CK, Netherlands

Location

Ziekenhuis Tjongerschans

Heerenveen, Provincie Friesland, 8441 PW, Netherlands

Location

Ikazia Ziekenhuis

Rotterdam, South Holland, 3083 AN, Netherlands

Location

BovenIJ Ziekenhuis

Amsterdam, 1034 CS, Netherlands

Location

Hospital Rijnstate

Arnhem, 6815 AD, Netherlands

Location

Deventer Hospital, Cardiology Research

Deventer, 7416 SE, Netherlands

Location

Hospital Gelderse Vallei

Ede, 6721 JT, Netherlands

Location

Treant Hospital Department Cardiology

Emmen, 7824 AA, Netherlands

Location

Admiraal de Ruyter Ziekenhuis

Goes, 4462 RA, Netherlands

Location

Treant Hospital - Bethseda, Hoogeveen

Hoogeveen, 7909 AA, Netherlands

Location

Bravis Ziekenhuis, locatie Roosendaal

Roosendaal, 4708 AE, Netherlands

Location

(ETZ) Elisabeth Tweesteden Hospital

Tilburg, 5022 GC, Netherlands

Location

Máxima Medisch Centrum

Veldhoven, 5504 DB, Netherlands

Location

Barum Hospital, Vestre Viken

Drammen, Buskerud, 3004, Norway

Location

Oslo University Hospital - Ulleval

Oslo, 0450, Norway

Location

Hospital Clinico Santiago de Compostela

Santiago de Composte, A Coruna, 15706, Spain

Location

Rafael Mendez Universitary Hospital

Lorca, Murcia, 30800, Spain

Location

Complexo Hospitalario Universitario A Coruna

A Coruña, 15006, Spain

Location

Hospital General Universitario de Alicante

Alicante, 03010, Spain

Location

Hospital Del Mar

Barcelona, 8003, Spain

Location

Hospital Juan Ramon Jimenez

Huelva, 21005, Spain

Location

Hospital Clinico San Carlos, Unidad De Arritmias

Madrid, 28040, Spain

Location

Hospital Universitario Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

Hospital Puerta de Hierro Majadahonda

Majadahonda, 28222, Spain

Location

Agencia Sanitaria Costa del Sol- Hospital Costa del Sol

Marbella, 29603, Spain

Location

Clinica Universidad de Navarra

Pamplona, 31008, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, 46010, Spain

Location

Hospital Clínico Universitario de Valladolid

Valladolid, 47003, Spain

Location

University Hospital Basel

Basel, Canton of Basel-City, 4031, Switzerland

Location

Kantonsspital St Gallen

Sankt Gallen, Canton of St. Gallen, 9007, Switzerland

Location

CHUV

Lausanne, Canton of Vaud, 1011, Switzerland

Location

Hopital Fribourgeois, site de Fribourg

Fribourg, 1708, Switzerland

Location

University Hospital of Geneva

Geneva, 1211, Switzerland

Location

Dorset County Hospital NHS Foundation Trust

Dorchester, Dorset, DT12JY, United Kingdom

Location

Hampshire Hospitals (NHS Foundation Trust)

Basingstoke, Hampshire, RG24 9NA, United Kingdom

Location

Portsmouth Hospitals NHS Trust

Portsmouth, Hampshire, PO6 3LY, United Kingdom

Location

Royal Alexandra Hospital

Paisley, Renfrewshire, PA29PN, United Kingdom

Location

Shrewsbury & Telford Hospital NHS

Shropshire, West Midlands, TF1 6TF, United Kingdom

Location

Blackpool Teaching Hospitals NHS Foundation Trust

Blackpool, FY3 8NR, United Kingdom

Location

Queen Elizabeth University Hospital

Glasgow, G51 4TF, United Kingdom

Location

Liverpool Heart and Chest Hospital

Liverpool, L14 3PE, United Kingdom

Location

Freeman Hospital

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (5)

• Siegal DM, Sticherling C, Healey JS, McIntyre WF, Christensen LS, Parkash R, Vanassche T, Conen D, Gold M, Granger CB, Nielsen JC, Carrier M, Wojdyla DM, Erath JW, Rivard L, Kutyifa V, Wright DJ, Lopes RD. Major Bleeding With Apixaban vs Aspirin: A Subanalysis of the ARTESiA Randomized Clinical Trial. JAMA Cardiol. 2025 Dec 1;10(12):1305-1314. doi: 10.1001/jamacardio.2025.4151.

  PMID: 41222953 DERIVED

• Shoamanesh A, Field TS, Coutts SB, Sharma M, Gladstone D, Hart RG, Boriani G, Wright DJ, Sticherling C, Birnie DH, Gold MR, Erath JW, Kutyifa V, Mian R, Benz AP, Granger CB, McIntyre WF, Connolly SJ, Nielsen JC, Alings M, Rivard L, Lopes RD, Healey JS; ARTESiA study investigators. Apixaban versus aspirin for stroke prevention in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack: subgroup analysis of the ARTESiA randomised controlled trial. Lancet Neurol. 2025 Feb;24(2):140-151. doi: 10.1016/S1474-4422(24)00475-7.

  PMID: 39862882 DERIVED

• McIntyre WF, Benz AP, Healey JS, Connolly SJ, Yang M, Lee SF, Field TS, Alings M, Benezet-Mazuecos J, Boriani G, Nielsen JC, Gold MR, Pergolini F, Glotzer TV, Granger CB, Lopes RD. Risk of Stroke or Systemic Embolism According to Baseline Frequency and Duration of Subclinical Atrial Fibrillation: Insights From the ARTESiA Trial. Circulation. 2024 Nov 26;150(22):1747-1755. doi: 10.1161/CIRCULATIONAHA.124.069903. Epub 2024 Sep 4.

  PMID: 39229707 DERIVED

• Lopes RD, Granger CB, Wojdyla DM, McIntyre WF, Alings M, Mani T, Ramasundarahettige C, Rivard L, Atar D, Birnie DH, Boriani G, Amit G, Leong-Sit P, Rinne C, Duray GZ, Gold MR, Hohnloser SH, Kutyifa V, Benezet-Mazuecos J, Cosedis Nielsen J, Sticherling C, Benz AP, Linde C, Kautzner J, Mabo P, Mairesse GH, Connolly SJ, Healey JS. Apixaban vs Aspirin According to CHA2DS2-VASc Score in Subclinical Atrial Fibrillation: Insights From ARTESiA. J Am Coll Cardiol. 2024 Jul 23;84(4):354-364. doi: 10.1016/j.jacc.2024.05.002. Epub 2024 May 19.

  PMID: 39019530 DERIVED

• Healey JS, Lopes RD, Granger CB, Alings M, Rivard L, McIntyre WF, Atar D, Birnie DH, Boriani G, Camm AJ, Conen D, Erath JW, Gold MR, Hohnloser SH, Ip J, Kautzner J, Kutyifa V, Linde C, Mabo P, Mairesse G, Benezet Mazuecos J, Cosedis Nielsen J, Philippon F, Proietti M, Sticherling C, Wong JA, Wright DJ, Zarraga IG, Coutts SB, Kaplan A, Pombo M, Ayala-Paredes F, Xu L, Simek K, Nevills S, Mian R, Connolly SJ; ARTESIA Investigators. Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation. N Engl J Med. 2024 Jan 11;390(2):107-117. doi: 10.1056/NEJMoa2310234. Epub 2023 Nov 12.

  PMID: 37952132 DERIVED

MeSH Terms

Conditions

Atrial Fibrillation; Stroke

Interventions

apixaban; Aspirin

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Jeff Healey, M.D.

  Population Health Research Institute

  PRINCIPAL INVESTIGATOR

• Stuart Connolly, M.D.

  Population Health Research Institute

  STUDY CHAIR

• Marco Alings, M.D.

  Working Group Cardiovascular Research Netherlands

  PRINCIPAL INVESTIGATOR

• Renato Lopes, M.D.

  Duke Clinical Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 4, 2013
• First Posted: September 10, 2013
• Study Start: May 1, 2015
• Primary Completion: October 27, 2023
• Study Completion: November 3, 2023
• Last Updated: November 15, 2023

Record last verified: 2023-11

Locations

ES (13); CH (5); NL (15); CA (24); US (23); DK (7); CZ (1); HU (3); DE (8); IT (10); BE (10); NO (2); GB (9)