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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Stroke, Atrial Fibrillation

Intervention / Treatment
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* Drug: Apixaban
* Drug: aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Permanent pacemaker or defibrillator (with or without resynchronization) or insertable cardiac monitor capable of detecting SCAF 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. Age ≥ 55 years 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: Clinical atrial fibrillation documented by surface ECG (12 lead ECG, Telemetry, Holter) lasting ≥ 6 minutes, with or without clinical symptoms Mechanical valve prosthesis, deep vein thrombosis, recent pulmonary embolism or other condition requiring treatment with an anticoagulant Contra-indication to apixaban or aspirin: Allergy to aspirin or apixaban 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) 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) Moderate to severe hepatic impairment Ongoing need for combination therapy with aspirin and clopidogrel (or other combination of two platelet inhibitors) 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) Ongoing need for strong dual inducers of CYP 3A4 or P-glycoprotein (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) Received an investigational drug in the past 30 days Participants considered by the investigator to be unsuitable for the study for any of the following reasons: Not agreeable for treatment with either aspirin or apixaban or anticipated to have poor compliance on study drug treatment Unwilling to attend study follow-up visits Life expectancy less than the expected duration of the trial2 years due to concomitant disease 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)

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>Aspirin 81 mg once daily | Drug: aspirin<br>* aspirin 81 mg once daily<br>* Other names: acetylsalicylic acid;|
| Experimental: Intervention<br>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<br>* 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)<br>* Other names: Eliquis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ischemic Stroke |  | Duration of Follow-up | 
| 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 | 
| Cardiovascular Death |  | Duration of follow-up | 
| All-cause Death |  | Duration of follow-up | 
| Composite of stroke, MI, SE and death | Composite of stroke, myocardial infarction, systemic embolism and all-cause death | Duration of follow-up | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pacemaker, Artificial, Defibrillators, Implantable, Atrial Fibrillation, Stroke Risk