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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified November 2014 by Population Health Research Institute
Sponsor:
Collaborators:
Bristol-Myers Squibb
Pfizer
Medtronic
Information provided by (Responsible Party):
Jeff Healey, Population Health Research Institute
ClinicalTrials.gov Identifier:
NCT01938248
First received: September 4, 2013
Last updated: November 4, 2014
Last verified: November 2014
  Purpose

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.


Condition Intervention Phase
Atrial Fibrillation
Stroke
Drug: Apixaban
Drug: aspirin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation

Resource links provided by NLM:


Further study details as provided by Population Health Research Institute:

Primary Outcome Measures:
  • Composite of ischemic stroke and systemic embolism [ Time Frame: event driven, duration of follow-up - mean follow-up time anticipated: 3 years ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: Yes ]

    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.


Secondary Outcome Measures:
  • Ischemic Stroke [ Time Frame: Duration of Follow-up ] [ Designated as safety issue: No ]
  • Myocardial Infarction [ Time Frame: Duration of follow-up ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
  • All-cause Death [ Time Frame: Duration of follow-up ] [ Designated as safety issue: No ]
  • Composite of stroke, MI, SE and death [ Time Frame: Duration of follow-up ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Composite of stroke, myocardial infarction, systemic embolism, all-cause death and major bleeding


Estimated Enrollment: 4000
Study Start Date: February 2015
Estimated Study Completion Date: March 2019
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Control
Aspirin 81 mg once daily
Drug: aspirin
aspirin 81 mg once daily
Other Names:
  • ASA
  • acetylsalicylic acid
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)
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

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 (Atrial rate > 175/min if an atrial lead is present), but no single episode > 24 hours in duration. SCAF requires electrogram confirmation (at least one episode) unless ≥ 6 hours in duration
  3. Age > 18 years
  4. CHA2DS2-VASc score of ≥ 4

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01938248

Contacts
Contact: Heather Beresh, M.Sc 905-527-4322 ext 40351 heather.beresh@phri.ca
Contact: Alina Dragomir, M.D. 905-527-4322 ext 40630 alina.dragomir@phri.ca

Sponsors and Collaborators
Population Health Research Institute
Bristol-Myers Squibb
Pfizer
Medtronic
Investigators
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
  More Information

No publications provided

Responsible Party: Jeff Healey, Principal Investigator, Population Health Research Institute
ClinicalTrials.gov Identifier: NCT01938248     History of Changes
Other Study ID Numbers: ARTESiA, 2014-001397-33
Study First Received: September 4, 2013
Last Updated: November 4, 2014
Health Authority: Canada: Canadian Institutes of Health Research
Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Population Health Research Institute:
Pacemaker, Artificial
Defibrillators, Implantable
Atrial Fibrillation
Stroke Risk

Additional relevant MeSH terms:
Atrial Fibrillation
Thromboembolism
Arrhythmias, Cardiac
Cardiovascular Diseases
Embolism and Thrombosis
Heart Diseases
Pathologic Processes
Thrombosis
Vascular Diseases
Aspirin
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antipyretics
Antirheumatic Agents
Cardiovascular Agents
Central Nervous System Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Fibrin Modulating Agents
Fibrinolytic Agents
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Platelet Aggregation Inhibitors
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014