Principal Investigator: Benjamin Steinberg
Keywords: Implantable cardioverter-defibrillator , Cardiac resynchronization therapy , Apixaban , Aspirin , Pacemaker , Defibrillator , Stroke Risk , Atrial Fibrillation , Cardiovascular disease , Arrhythmia Department: Cardiovascular Medicine
IRB Number: 00106810 Co Investigator: Mihail Chelu
Specialty: Cardiology, Cardiology, Cardiology, Cardiology, Cardiology
Sub Specialties: Interventional Cardiology, General Cardiology, Cardiac Imaging, Cardiac Electrophysiology, Preventive Cardiology
Recruitment Status: Recruiting

Contact Information

Andy Rivera
ANDY.RIVERA@UTAH.EDU
8015850904

Simple Summary

To determine if the use of apixaban in patients with sub-clinical atrial fibrillation will reduce the incidence of stroke and systemic embolism compared to aspirin.

Detailed Description

Device-detected sub-clinical atrial fibrillation (SCAF) 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 was associated with increased stroke risk (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). Very few patients with SCAF were enrolled in the trials of anticoagulation in patients with AF. SCAF differs from clinical AF in being of shorter duration and, being asymptomatic. Data from ASSERT suggest that the increase in stroke risk with SCAF may be less than the increase with clinical AF. Thus although SCAF is a variant of AF, 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 systemicembolism 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 µmol/L). Those assigned to aspirin will receive a dose of 81 mg daily. The study will beevent driven and will continue until 248 patients have experienced a primary efficacy outcome event.

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 device detected 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

Definitions of "risk factors":

Stroke or TIA - Any clinical history of stroke (signs or symptoms ≥ 24 hours) or TIA (signs or symptoms < 24 hours) OR CT or MRI evidence of prior silent infarction (with or without symptoms)

Systemic Arterial Embolism - Any clinical history of systemic arterial embolism

Hypertension - Any history of hypertension requiring antihypertensive treatment OR two blood pressure readings > 140/90 (either value) on separate days taken after 5minutes rest and which would, in the opinion of the treating physician, require treatment with antihypertensive therapy

Heart Failure - Clinical heart failure diagnosed at any time OR a left ventricular ejection fraction < 50%

Diabetes - Known history of diabetes OR currently taking insulin or any oral diabetic medication OR HbA1c > 8% OR fasting blood sugar > 14 mmol/L

Vascular disease - Evidence of atherosclerosis on coronary angiogram, nuclear testing or stress testing; or evidence of aortic or peripheral arterial disease using ultrasound, CT or MRI imaging. Vascular disease need only be present, not necessarily flow-limiting or symptomatic.

 

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, recent (within past 6 months) deep vein thrombosis or pulmonary embolism or other condition requiring treatment with an anticoagulant

3. Allergy to aspirin or apixaban

4. Severe renal insufficiency (serum creatinine > 2.5 mg/dL [221 μmol/L] or a calculated creatinine clearance < 25 ml/min)

5. 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, clinically significant thrombocytopenia or anemia, recent stroke within past 10 days, documented hemorrhagic tendencies or blood dyscrasias)

6. Moderate to severe hepatic impairment

7. Ongoing need for combination therapy with aspirin and clopidogrel (or other combination of two platelet inhibitors)

8. Meets criteria for requiring lower dose of apixaban AND also has ongoing need for strong inhibitors of both CYP3A4 and P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir or clarithromycin)

9. Ongoing need for strong inducers of both CYP3A4 and P-glycoprotein (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort)

10. Received an investigational drug in the past 30 days

11. Participants considered by the investigator to be unsuitable for the study for any of the following reasons:

  -a. Not agreeable for treatment with either aspirin or apixaban or anticipated to have poor compliance on study drug treatment

  -b. Unwilling to attend study follow-up visits

  -c. Life expectancy less than 2 years due to concomitant disease

12. Women who are pregnant, breast-feeding or of child-bearing potential without an acceptable form of contraception in place (sterilization, abstinence or other method with less than 1% failure rate)

Participant Reimbursement

None