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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2015 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: May 17, 2015
Last verified: May 2015

September 4, 2013
May 17, 2015
May 2015
April 2019   (final data collection date for primary outcome measure)
  • 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.
Composite of ischemic stroke and systemic embolism [ Time Frame: event driven duration - mean follow-up time anticipated: 3 years ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01938248 on ClinicalTrials.gov Archive Site
  • 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
Major bleeding [ Time Frame: event driven duration - mean follow-up time anticipated: 3 years ] [ Designated as safety issue: Yes ]
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.
Not Provided
Not Provided
 
Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation
Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation

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.

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.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
  • Atrial Fibrillation
  • Stroke
  • 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
  • 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
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
4000
July 2019
April 2019   (final data collection date for primary outcome measure)

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)
Both
18 Years and older
No
Contact: Heather Beresh, M.Sc 905-527-4322 ext 40351 heather.beresh@phri.ca
Contact: Toni Newman 905-527-4322 ext 40633 toni.newman@phri.ca
Canada
 
NCT01938248
ARTESiA, 2014-001397-33
Yes
Jeff Healey, Population Health Research Institute
Population Health Research Institute
  • Bristol-Myers Squibb
  • Pfizer
  • Medtronic
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
Population Health Research Institute
May 2015

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