Clinical trial NCT01938248: Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation
Official title: Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Atrial Fibrillation
Stroke
Keywords: Pacemaker, Artificial
Defibrillators, Implantable
Atrial Fibrillation
Stroke Risk
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: Pfizer
name: Medtronic
name: Canadian Institutes of Health Research (CIHR)
First posted: 2013-09-10
Enrollment: 4012
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Composite of ischemic stroke and systemic embolism
timeFrame: event driven, duration of follow-up - mean follow-up time anticipated: 3 years
measure: Major Bleed
timeFrame: duration of follow-up
Secondary outcomes:
measure: Ischemic Stroke
timeFrame: Duration of Follow-up
measure: Myocardial Infarction
timeFrame: Duration of follow-up
measure: Cardiovascular Death
timeFrame: Duration of follow-up
measure: All-cause Death
timeFrame: Duration of follow-up
measure: Composite of stroke, MI, SE and death
timeFrame: Duration of follow-up
measure: Composite of stroke, MI, SE, death and major bleeding
timeFrame: Duration of follow-up
Other outcomes:
Locations:
city: Mesa
country: United States
facility: Cardiovascular Associates of Mesa, PC
state: Arizona
city: Little Rock
country: United States
facility: St. Vincent Heart Clinic
state: Arkansas
city: Larkspur
country: United States
facility: Cardiovascular Associates of Marin and San Francisco Medical
state: California
city: Aurora
country: United States
facility: Aurora Denver Cardiology Associates
state: Colorado
city: Naples
country: United States
facility: Naples Interventional Cardiac Electrophysiology
state: Florida
city: Pensacola
country: United States
facility: Langhorne Cardiology Consultants, Inc.
state: Florida
city: Owensboro
country: United States
facility: One Health Cardiology, Owensboro Health, Inc.
state: Kentucky
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Lansing
country: United States
facility: Sparrow Clinical Research Institute
state: Michigan
city: Ypsilanti
country: United States
facility: Michigan Heart
state: Michigan
city: Columbia
country: United States
facility: University of Missouri Health System
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis Heart and Vascular
state: Missouri
city: Kalispell
country: United States
facility: Glacier View Cardiology
state: Montana
city: Camden
country: United States
facility: The Cooper Health System
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Ridgewood
country: United States
facility: The Valley Hospital
state: New Jersey
city: Albany
country: United States
facility: St. Peter's Health Partners Medical Association, PC
state: New York
city: Charlotte
country: United States
facility: Carolinas Healthcare System
state: North Carolina
city: Raleigh
country: United States
facility: WakeMed
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Hershey
country: United States
facility: Pennsylvania State University
state: Pennsylvania
city: Lancaster
country: United States
facility: Research Institute of LG Health / Penn Medicine
state: Pennsylvania
city: Falls Church
country: United States
facility: Virginia Heart
state: Virginia
city: Aalst
country: Belgium
facility: Onze Lieve Vrouw Ziekenhuis
city: Arlon
country: Belgium
facility: Vivalia CSL St. Joseph
city: Brussels
country: Belgium
facility: Clinique Saint Jean-Brussels
city: Gilly
country: Belgium
facility: Grand Hopital de Charleroi
city: Kortrijk
country: Belgium
facility: AZ Groeninge
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Liege
country: Belgium
facility: CHC Saint Joseph
city: Liège
country: Belgium
facility: CHR de la Citadelle
city: Roeselare
country: Belgium
facility: AZ Delta
city: Yvoir
country: Belgium
facility: CHU Dinant-Godinne
city: Calgary
country: Canada
facility: University of Calgary Foothills Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Grey Nuns Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Heart Rhythm Research Office - St. Paul's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Victoria Cardiac Arrhythmia Trials, Inc.
state: British Columbia
city: Winnepeg
country: Canada
facility: St. Boniface Hospital
state: Manitoba
city: Halifax
country: Canada
facility: Capital District Health Authority
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Kitchener
country: Canada
facility: St. Mary's General Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Newmarket
country: Canada
facility: Southlake Regional Health Centre
state: Ontario
city: Oakville
country: Canada
facility: Oakville Cardiologists
state: Ontario
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute
state: Ontario
city: Sudbury
country: Canada
facility: Health Sciences North
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Hospital
state: Ontario
city: Laval
country: Canada
facility: Institute Universitaire de Cardiologie and de Pneumonologie
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hotel Dieu
state: Quebec
city: Montreal
country: Canada
facility: Hopital Sacre-Coeur de Montreal
state: Quebec
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Sherbrooke
country: Canada
facility: CHUS - Sherbrooke
state: Quebec
city: Trois-Rivières
country: Canada
facility: Ciusss McQ
state: Quebec
city: Prague
country: Czechia
facility: IKEM Institute for Clinical and Experimental Medicine
city: Hilleroed
country: Denmark
facility: Hilleroed Hospital
state: North Zealand
city: Aabenraa
country: Denmark
facility: Sygehus Sonderjylland
city: Aalborg
country: Denmark
facility: Aalborg University Hospital, Dept of Cardiology
city: Aarhus
country: Denmark
facility: Aarhus Unniversity Hospital, Skejby
city: Hellerup
country: Denmark
facility: Gentofte Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Viborg
country: Denmark
facility: Hjertemedicinsk Forskning, RH Viborg, HEM
city: Frankfurt
country: Germany
facility: Johann Wolfgang Goethe University Hospital Frankfurt
state: Hesse
city: Mainz
country: Germany
facility: Katholisches Klinikum Mainz
state: Rheinland-Pfalz
city: Homburg/Saar
country: Germany
facility: Universitatsklinikum des Saarlandes
state: Saarland
city: Chemnitz
country: Germany
facility: MVZ am Kuchwald GmbH
state: Saxony
city: Dresden
country: Germany
facility: Zentrum fur klinische Prufungen in der Facharztzentrum Dresd
state: Saxony
city: Gottingen
country: Germany
facility: University Medicine Gottingen
city: Hamburg
country: Germany
facility: Asklepios Klinik Barmbek
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen, Kardiologie
city: Balatonfured
country: Hungary
facility: Allami Szivkorhaz Balatonfured
state: Veszprem
city: Budapest
country: Hungary
facility: Magyar Honvedseg Egeszsegugyi Kozpont
city: Budapest
country: Hungary
facility: Semmelweis University
city: San Fermo Della Batt
country: Italy
facility: Ospedale Sant'Anna
state: Como
city: Vimercate
country: Italy
facility: Cardiologia-A.O. Desio e Vimercate - Presisio di Vimercat
state: Monza Brianza MB
city: Nola
country: Italy
facility: Hospital Santa Maria Della Pieta
state: Napoli
city: Ancona
country: Italy
facility: AOU Ospedali Riuniti
city: Bologna
country: Italy
facility: Ospedale Maggiore, Cardiologia Dept.
city: Bologna
country: Italy
facility: S.Orsola-Malpighi
city: Bolzano
country: Italy
facility: Bolzano Regional Hospital, Dept of Cardiology
city: Modena
country: Italy
facility: Azienda Ospedaliero-Univeritaria Di Modena-Policlinico
city: Rome
country: Italy
facility: Ospedale G.B. Grassi
city: Trieste
country: Italy
facility: University and Hospital of Trieste
city: Heerenveen
country: Netherlands
facility: Ziekenhuis Tjongerschans
state: Friesland
city: Zutphen
country: Netherlands
facility: Gelre Ziekenhuis
state: Gelderland
city: Heerlen
country: Netherlands
facility: Atrium Orbis Heerlen
state: Limburg
city: Breda
country: Netherlands
facility: Amphia Hospital Breda
state: Noord-Brabant
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
state: Zuid-Holland
city: Amsterdam
country: Netherlands
facility: BovenIJ Ziekenhuis
city: Arnhem
country: Netherlands
facility: Hospital Rijnstate
city: Deventer
country: Netherlands
facility: Deventer Hospital, Cardiology Research
city: Ede
country: Netherlands
facility: Hospital Gelderse Vallei
city: Emmen
country: Netherlands
facility: Treant Hospital Department Cardiology
city: Goes
country: Netherlands
facility: Admiraal de Ruyter Ziekenhuis
city: Hoogeveen
country: Netherlands
facility: Treant Hospital - Bethseda, Hoogeveen
city: Roosendaal
country: Netherlands
facility: Bravis Ziekenhuis, locatie Roosendaal
city: Tilburg
country: Netherlands
facility: (ETZ) Elisabeth Tweesteden Hospital
city: Veldhoven
country: Netherlands
facility: Máxima Medisch Centrum
city: Drammen
country: Norway
facility: Barum Hospital, Vestre Viken
state: Buskerud
city: Oslo
country: Norway
facility: Oslo University Hospital - Ulleval
city: Santiago De Composte
country: Spain
facility: Hospital Clinico Santiago de Compostela
state: A Coruna
city: Lorca
country: Spain
facility: Rafael Mendez Universitary Hospital
state: Murcia
city: A Coruna
country: Spain
facility: Complexo Hospitalario Universitario A Coruna
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: Hospital Del Mar
city: Huelva
country: Spain
facility: Hospital Juan Ramon Jimenez
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos, Unidad De Arritmias
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Majadahonda
country: Spain
facility: Hospital Puerta de Hierro Majadahonda
city: Marbella
country: Spain
facility: Agencia Sanitaria Costa del Sol- Hospital Costa del Sol
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valladolid
country: Spain
facility: Hospital Clínico Universitario de Valladolid
city: Basel
country: Switzerland
facility: University Hospital Basel
state: Basel-Stadt
city: St. Gallen
country: Switzerland
facility: Kantonsspital St Gallen
state: Saint Gallen
city: Lausanne
country: Switzerland
facility: CHUV
state: Vaud
city: Fribourg
country: Switzerland
facility: Hopital Fribourgeois, site de Fribourg
city: Geneva
country: Switzerland
facility: University Hospital of Geneva
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital NHS Foundation Trust
state: Dorset
city: Basingstoke
country: United Kingdom
facility: Hampshire Hospitals (NHS Foundation Trust)
state: Hampshire
city: Portsmouth
country: United Kingdom
facility: Portsmouth Hospitals NHS Trust
state: Hampshire
city: Paisley
country: United Kingdom
facility: Royal Alexandra Hospital
state: Renfrewshire
city: Shropshire
country: United Kingdom
facility: Shrewsbury & Telford Hospital NHS
state: West Midlands
city: Blackpool
country: United Kingdom
facility: Blackpool Teaching Hospitals NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Liverpool
country: United Kingdom
facility: Liverpool Heart and Chest Hospital
city: Newcastle-upon-Tyne
country: United Kingdom
facility: Freeman Hospital
Study officials:
affiliation: Population Health Research Institute
name: Jeff Healey, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Population Health Research Institute
name: Stuart Connolly, M.D.
role: STUDY_CHAIR
affiliation: Working Group Cardiovascular Research Netherlands
name: Marco Alings, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke Clinical Research Institute
name: Renato Lopes, M.D.
role: PRINCIPAL_INVESTIGATOR
References: