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

Phase 4

Completed

• Conditions: Atrial Fibrillation; Stroke
• Interventions: Drug: Apixaban; Drug: aspirin

• Registration Number: NCT01938248
• Lead Sponsor: Population Health Research Institute

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 Timeline

• Study First Submitted: 2013-09-04
• Study First Submitted QC: 2013-09-04
• Study First Posted: 2013-09-10
• Study Start: 2015-05
• Primary Completion: 2023-10-27
• Status Verified: 2023-11
• Study Completion: 2023-11-03
• Last Update Submitted: 2023-11-14
• Last Update Posted: 2023-11-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 4012

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intervention	Apixaban	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)
Control	aspirin	Aspirin 81 mg once daily

Primary Outcome Measures

Name	Time	Method
Composite of ischemic stroke and systemic embolism	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	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.

Secondary Outcome Measures

Name	Time	Method
Cardiovascular Death	Duration of follow-up
Myocardial Infarction	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
All-cause Death	Duration of follow-up
Composite of stroke, MI, SE and death	Duration of follow-up	Composite of stroke, myocardial infarction, systemic embolism and all-cause death
Composite of stroke, MI, SE, death and major bleeding	Duration of follow-up	Composite of stroke, myocardial infarction, systemic embolism, all-cause death and major bleeding
Ischemic Stroke	Duration of Follow-up

Trial Locations

Locations (129)

Cardiovascular Associates of Mesa, PC; 🇺🇸 Mesa, Arizona, United States

St. Vincent Heart Clinic; 🇺🇸 Little Rock, Arkansas, United States

Cardiovascular Associates of Marin and San Francisco Medical; 🇺🇸 Larkspur, California, United States

Aurora Denver Cardiology Associates; 🇺🇸 Aurora, Colorado, United States

Naples Interventional Cardiac Electrophysiology; 🇺🇸 Naples, Florida, United States

Langhorne Cardiology Consultants, Inc.; 🇺🇸 Pensacola, Florida, United States

One Health Cardiology, Owensboro Health, Inc.; 🇺🇸 Owensboro, Kentucky, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

Sparrow Clinical Research Institute; 🇺🇸 Lansing, Michigan, United States

Michigan Heart; 🇺🇸 Ypsilanti, Michigan, United States

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