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

Stroke Clinical Trial

— ARTESiA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01938248
• Other study ID #: ARTESiA
• Secondary ID: 2014-001397-33
• Status: Completed
• Phase: Phase 4
• Start date: May 2015
• Est. completion date: November 3, 2023

Study information

• Verified date: November 2023
• Source: Population Health Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4012
• Est. completion date: November 3, 2023
• Est. primary completion date: October 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Atrial Fibrillation
• Embolism
• Stroke
• Thromboembolism

Intervention

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)
• aspirin
aspirin 81 mg once daily

Locations

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

Sponsors (5)

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

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Ischemic Stroke		Duration of Follow-up
Secondary	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 intervention; OR; Pathological findings of an acute myocardial infarction	Duration of follow-up
Secondary	Cardiovascular Death		Duration of follow-up
Secondary	All-cause Death		Duration of follow-up
Secondary	Composite of stroke, MI, SE and death	Composite of stroke, myocardial infarction, systemic embolism and all-cause death	Duration of follow-up
Secondary	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