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

NCT ID: NCT01938248

Last Updated: 2023-11-15

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

4012 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-05-31

Study Completion Date

2023-11-03

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Atrial Fibrillation Stroke

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Control

Aspirin 81 mg once daily

Group Type ACTIVE_COMPARATOR

aspirin

Intervention Type DRUG

aspirin 81 mg once daily

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)

Group Type EXPERIMENTAL

Apixaban

Intervention Type 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)

Interventions

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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)

Intervention Type DRUG

aspirin

aspirin 81 mg once daily

Intervention Type DRUG

Other Intervention Names

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Eliquis ASA acetylsalicylic acid

Eligibility Criteria

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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)
Minimum Eligible Age

55 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Bristol-Myers Squibb

INDUSTRY

Sponsor Role collaborator

Pfizer

INDUSTRY

Sponsor Role collaborator

Medtronic

INDUSTRY

Sponsor Role collaborator

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role collaborator

Population Health Research Institute

OTHER

Sponsor Role lead

Responsible Party

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Jeff Healey

Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Jeff Healey, M.D.

Role: PRINCIPAL_INVESTIGATOR

Population Health Research Institute

Stuart Connolly, M.D.

Role: STUDY_CHAIR

Population Health Research Institute

Marco Alings, M.D.

Role: PRINCIPAL_INVESTIGATOR

Working Group Cardiovascular Research Netherlands

Renato Lopes, M.D.

Role: PRINCIPAL_INVESTIGATOR

Duke Clinical Research Institute

Locations

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Cardiovascular Associates of Mesa, PC

Mesa, Arizona, United States

Site Status

St. Vincent Heart Clinic

Little Rock, Arkansas, United States

Site Status

Cardiovascular Associates of Marin and San Francisco Medical

Larkspur, California, United States

Site Status

Aurora Denver Cardiology Associates

Aurora, Colorado, United States

Site Status

Naples Interventional Cardiac Electrophysiology

Naples, Florida, United States

Site Status

Langhorne Cardiology Consultants, Inc.

Pensacola, Florida, United States

Site Status

One Health Cardiology, Owensboro Health, Inc.

Owensboro, Kentucky, United States

Site Status

Tufts Medical Center

Boston, Massachusetts, United States

Site Status

Sparrow Clinical Research Institute

Lansing, Michigan, United States

Site Status

Michigan Heart

Ypsilanti, Michigan, United States

Site Status

University of Missouri Health System

Columbia, Missouri, United States

Site Status

St. Louis Heart and Vascular

St Louis, Missouri, United States

Site Status

Glacier View Cardiology

Kalispell, Montana, United States

Site Status

The Cooper Health System

Camden, New Jersey, United States

Site Status

Hackensack University Medical Center

Hackensack, New Jersey, United States

Site Status

The Valley Hospital

Ridgewood, New Jersey, United States

Site Status

St. Peter's Health Partners Medical Association, PC

Albany, New York, United States

Site Status

Carolinas Healthcare System

Charlotte, North Carolina, United States

Site Status

WakeMed

Raleigh, North Carolina, United States

Site Status

Cleveland Clinic

Cleveland, Ohio, United States

Site Status

Pennsylvania State University

Hershey, Pennsylvania, United States

Site Status

Research Institute of LG Health / Penn Medicine

Lancaster, Pennsylvania, United States

Site Status

Virginia Heart

Falls Church, Virginia, United States

Site Status

Onze Lieve Vrouw Ziekenhuis

Aalst, , Belgium

Site Status

Vivalia CSL St. Joseph

Arlon, , Belgium

Site Status

Clinique Saint Jean-Brussels

Brussels, , Belgium

Site Status

Grand Hopital de Charleroi

Gilly, , Belgium

Site Status

AZ Groeninge

Kortrijk, , Belgium

Site Status

University Hospitals Leuven

Leuven, , Belgium

Site Status

CHC Saint Joseph

Liège, , Belgium

Site Status

CHR de la Citadelle

Liège, , Belgium

Site Status

AZ Delta

Roeselare, , Belgium

Site Status

CHU Dinant-Godinne

Yvoir, , Belgium

Site Status

University of Calgary Foothills Hospital

Calgary, Alberta, Canada

Site Status

Royal Alexandra Hospital

Edmonton, Alberta, Canada

Site Status

University of Alberta Hospital

Edmonton, Alberta, Canada

Site Status

Grey Nuns Hospital

Edmonton, Alberta, Canada

Site Status

Heart Rhythm Research Office - St. Paul's Hospital

Vancouver, British Columbia, Canada

Site Status

Victoria Cardiac Arrhythmia Trials, Inc.

Victoria, British Columbia, Canada

Site Status

St. Boniface Hospital

Winnepeg, Manitoba, Canada

Site Status

Capital District Health Authority

Halifax, Nova Scotia, Canada

Site Status

Health Sciences North

Greater Sudbury, Ontario, Canada

Site Status

Hamilton General Hospital

Hamilton, Ontario, Canada

Site Status

St. Mary's General Hospital

Kitchener, Ontario, Canada

Site Status

London Health Sciences Centre

London, Ontario, Canada

Site Status

Southlake Regional Health Centre

Newmarket, Ontario, Canada

Site Status

Oakville Cardiologists

Oakville, Ontario, Canada

Site Status

University of Ottawa Heart Institute

Ottawa, Ontario, Canada

Site Status

St. Michael's Hospital

Toronto, Ontario, Canada

Site Status

Sunnybrook Hospital

Toronto, Ontario, Canada

Site Status

Institute Universitaire de Cardiologie and de Pneumonologie

Laval, Quebec, Canada

Site Status

McGill University Health Centre

Montreal, Quebec, Canada

Site Status

CHUM - Hotel Dieu

Montreal, Quebec, Canada

Site Status

Hopital Sacre-Coeur de Montreal

Montreal, Quebec, Canada

Site Status

Montreal Heart Institute

Montreal, Quebec, Canada

Site Status

CHUS - Sherbrooke

Sherbrooke, Quebec, Canada

Site Status

Ciusss McQ

Trois-Rivières, Quebec, Canada

Site Status

IKEM Institute for Clinical and Experimental Medicine

Prague, , Czechia

Site Status

Hilleroed Hospital

Hilleroed, North Zealand, Denmark

Site Status

Sygehus Sonderjylland

Aabenraa, , Denmark

Site Status

Aalborg University Hospital, Dept of Cardiology

Aalborg, , Denmark

Site Status

Aarhus Unniversity Hospital, Skejby

Aarhus, , Denmark

Site Status

Gentofte Hospital

Hellerup, , Denmark

Site Status

Odense University Hospital

Odense, , Denmark

Site Status

Hjertemedicinsk Forskning, RH Viborg, HEM

Viborg, , Denmark

Site Status

Johann Wolfgang Goethe University Hospital Frankfurt

Frankfurt am Main, Hesse, Germany

Site Status

Katholisches Klinikum Mainz

Mainz, Rhineland-Palatinate, Germany

Site Status

Universitatsklinikum des Saarlandes

Homburg/Saar, Saarland, Germany

Site Status

MVZ am Kuchwald GmbH

Chemnitz, Saxony, Germany

Site Status

Zentrum fur klinische Prufungen in der Facharztzentrum Dresd

Dresden, Saxony, Germany

Site Status

University Medicine Gottingen

Göttingen, , Germany

Site Status

Asklepios Klinik Barmbek

Hamburg, , Germany

Site Status

Universitaetsklinikum Tuebingen, Kardiologie

Tübingen, , Germany

Site Status

Allami Szivkorhaz Balatonfured

Balatonfüred, Veszprém megye, Hungary

Site Status

Magyar Honvedseg Egeszsegugyi Kozpont

Budapest, , Hungary

Site Status

Semmelweis University

Budapest, , Hungary

Site Status

Ospedale Sant'Anna

San Fermo Della Batt, Como, Italy

Site Status

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

Vimercate, Monza Brianza MB, Italy

Site Status

Hospital Santa Maria Della Pieta

Nola, Napoli, Italy

Site Status

AOU Ospedali Riuniti

Ancona, , Italy

Site Status

Ospedale Maggiore, Cardiologia Dept.

Bologna, , Italy

Site Status

S.Orsola-Malpighi

Bologna, , Italy

Site Status

Bolzano Regional Hospital, Dept of Cardiology

Bolzano, , Italy

Site Status

Azienda Ospedaliero-Univeritaria Di Modena-Policlinico

Modena, , Italy

Site Status

Ospedale G.B. Grassi

Rome, , Italy

Site Status

University and Hospital of Trieste

Trieste, , Italy

Site Status

Gelre Ziekenhuis

Zutphen, Gelderland, Netherlands

Site Status

Atrium Orbis Heerlen

Heerlen, Limburg, Netherlands

Site Status

Amphia Hospital Breda

Breda, North Brabant, Netherlands

Site Status

Ziekenhuis Tjongerschans

Heerenveen, Provincie Friesland, Netherlands

Site Status

Ikazia Ziekenhuis

Rotterdam, South Holland, Netherlands

Site Status

BovenIJ Ziekenhuis

Amsterdam, , Netherlands

Site Status

Hospital Rijnstate

Arnhem, , Netherlands

Site Status

Deventer Hospital, Cardiology Research

Deventer, , Netherlands

Site Status

Hospital Gelderse Vallei

Ede, , Netherlands

Site Status

Treant Hospital Department Cardiology

Emmen, , Netherlands

Site Status

Admiraal de Ruyter Ziekenhuis

Goes, , Netherlands

Site Status

Treant Hospital - Bethseda, Hoogeveen

Hoogeveen, , Netherlands

Site Status

Bravis Ziekenhuis, locatie Roosendaal

Roosendaal, , Netherlands

Site Status

(ETZ) Elisabeth Tweesteden Hospital

Tilburg, , Netherlands

Site Status

Máxima Medisch Centrum

Veldhoven, , Netherlands

Site Status

Barum Hospital, Vestre Viken

Drammen, Buskerud, Norway

Site Status

Oslo University Hospital - Ulleval

Oslo, , Norway

Site Status

Hospital Clinico Santiago de Compostela

Santiago de Composte, A Coruna, Spain

Site Status

Rafael Mendez Universitary Hospital

Lorca, Murcia, Spain

Site Status

Complexo Hospitalario Universitario A Coruna

A Coruña, , Spain

Site Status

Hospital General Universitario de Alicante

Alicante, , Spain

Site Status

Hospital Del Mar

Barcelona, , Spain

Site Status

Hospital Juan Ramon Jimenez

Huelva, , Spain

Site Status

Hospital Clinico San Carlos, Unidad De Arritmias

Madrid, , Spain

Site Status

Hospital Universitario Fundacion Jimenez Diaz

Madrid, , Spain

Site Status

Hospital Puerta de Hierro Majadahonda

Majadahonda, , Spain

Site Status

Agencia Sanitaria Costa del Sol- Hospital Costa del Sol

Marbella, , Spain

Site Status

Clinica Universidad de Navarra

Pamplona, , Spain

Site Status

Hospital Clinico Universitario de Valencia

Valencia, , Spain

Site Status

Hospital Clínico Universitario de Valladolid

Valladolid, , Spain

Site Status

University Hospital Basel

Basel, Canton of Basel-City, Switzerland

Site Status

Kantonsspital St Gallen

Sankt Gallen, Canton of St. Gallen, Switzerland

Site Status

CHUV

Lausanne, Canton of Vaud, Switzerland

Site Status

Hopital Fribourgeois, site de Fribourg

Fribourg, , Switzerland

Site Status

University Hospital of Geneva

Geneva, , Switzerland

Site Status

Dorset County Hospital NHS Foundation Trust

Dorchester, Dorset, United Kingdom

Site Status

Hampshire Hospitals (NHS Foundation Trust)

Basingstoke, Hampshire, United Kingdom

Site Status

Portsmouth Hospitals NHS Trust

Portsmouth, Hampshire, United Kingdom

Site Status

Royal Alexandra Hospital

Paisley, Renfrewshire, United Kingdom

Site Status

Shrewsbury & Telford Hospital NHS

Shropshire, West Midlands, United Kingdom

Site Status

Blackpool Teaching Hospitals NHS Foundation Trust

Blackpool, , United Kingdom

Site Status

Queen Elizabeth University Hospital

Glasgow, , United Kingdom

Site Status

Liverpool Heart and Chest Hospital

Liverpool, , United Kingdom

Site Status

Freeman Hospital

Newcastle upon Tyne, , United Kingdom

Site Status

Countries

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United States Belgium Canada Czechia Denmark Germany Hungary Italy Netherlands Norway Spain Switzerland United Kingdom

References

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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.

Reference Type DERIVED
PMID: 39862882 (View on PubMed)

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.

Reference Type DERIVED
PMID: 39229707 (View on PubMed)

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.

Reference Type DERIVED
PMID: 39019530 (View on PubMed)

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.

Reference Type DERIVED
PMID: 37952132 (View on PubMed)

Other Identifiers

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2014-001397-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ARTESiA

Identifier Type: -

Identifier Source: org_study_id

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