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Trial record 1 of 2 for:    NCT01938248
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Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA)

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ClinicalTrials.gov Identifier: NCT01938248
Recruitment Status : Recruiting
First Posted : September 10, 2013
Last Update Posted : September 16, 2020
Sponsor:
Collaborators:
Bristol-Myers Squibb
Pfizer
Medtronic
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Jeff Healey, Population Health Research Institute

Tracking Information
First Submitted Date  ICMJE September 4, 2013
First Posted Date  ICMJE September 10, 2013
Last Update Posted Date September 16, 2020
Actual Study Start Date  ICMJE May 2015
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 4, 2014)
  • Composite of ischemic stroke and systemic embolism [ Time Frame: event driven, duration of follow-up - mean follow-up time anticipated: 3 years ]
    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
  • Major Bleed [ Time Frame: duration of follow-up ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 4, 2013)
Composite of ischemic stroke and systemic embolism [ Time Frame: event driven duration - mean follow-up time anticipated: 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2014)
  • Ischemic Stroke [ Time Frame: Duration of Follow-up ]
  • Myocardial Infarction [ Time Frame: Duration of follow-up ]
    MI definition:
    1. 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
    2. Pathological findings of an acute myocardial infarction
  • Cardiovascular Death [ Time Frame: Duration of follow-up ]
  • All-cause Death [ Time Frame: Duration of follow-up ]
  • Composite of stroke, MI, SE and death [ Time Frame: Duration of follow-up ]
    Composite of stroke, myocardial infarction, systemic embolism and all-cause death
  • Composite of stroke, MI, SE, death and major bleeding [ Time Frame: Duration of follow-up ]
    Composite of stroke, myocardial infarction, systemic embolism, all-cause death and major bleeding
Original Secondary Outcome Measures  ICMJE
 (submitted: September 4, 2013)
Major bleeding [ Time Frame: event driven duration - mean follow-up time anticipated: 3 years ]
Major bleeding defined as: bleeding into a critical organ, requiring surgery, associated with at least a 2 g/dL drop in hemoglobin or requiring the transfusion of at least 2 units of packed red blood cells.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation
Official Title  ICMJE Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Atrial Fibrillation
  • Stroke
Intervention  ICMJE
  • 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 Name: Eliquis
  • Drug: aspirin
    aspirin 81 mg once daily
    Other Names:
    • ASA
    • acetylsalicylic acid
Study Arms  ICMJE
  • Active Comparator: Control
    Aspirin 81 mg once daily
    Intervention: Drug: aspirin
  • 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)
    Intervention: Drug: Apixaban
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 4, 2013)
4000
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 55 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kim Simek 905-527-4322 ext 40524 kim.simek@phri.ca
Contact: Heather Beresh 905-527-4322 ext 40351 heather.beresh@phri.ca
Listed Location Countries  ICMJE Belgium,   Canada,   Czechia,   Denmark,   Germany,   Hungary,   Italy,   Netherlands,   Norway,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01938248
Other Study ID Numbers  ICMJE ARTESiA
2014-001397-33 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jeff Healey, Population Health Research Institute
Study Sponsor  ICMJE Population Health Research Institute
Collaborators  ICMJE
  • Bristol-Myers Squibb
  • Pfizer
  • Medtronic
  • Canadian Institutes of Health Research (CIHR)
Investigators  ICMJE
Principal Investigator: Jeff Healey, M.D. Population Health Research Institute
Study Chair: Stuart Connolly, M.D. Population Health Research Institute
Principal Investigator: Marco Alings, M.D. Working Group Cardiovascular Research Netherlands
Principal Investigator: Renato Lopes, M.D. Duke Clinical Research Institute
PRS Account Population Health Research Institute
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP