Sub-Clinical Atrial Fibrillation Biomarker Study
Sub-Clinical Atrial Fibrillation Biomarker Study
This is a sub-study of the ARTESiA study registered as NCT01938248. This study is designed to
 validate biomarkers in subclinical atrial fibrillation and to determine if the prospective
 biomarker will be informative of the potential efficacy of treatment.
Atrial fibrillation (AF) is the most common cardiac rhythm disorder worldwide, and is gaining
 in prevalence. Currently, the treatment for atrial fibrillation is concentrated on patients
 with existing atrial fibrillation, and the reduction in risks of complications of stroke with
 anticoagulation. Furthermore, mechanical interventions such as atrial ablation procedures are
 fraught with inconsistent results. The availability of serum based biomarkers that can
 predict the early onset of atrial fibrillation, and also the ability to prognosticate risk,
 may help in the identification of patients at risk for AF complications early. This would
 also allow the identification of the patient population most suitable for the evaluation of
 possible future intervention strategies to prevent the onset of atrial fibrillation, and
 alter its natural history and complications.

 Currently the best biomarkers in predicting atrial fibrillation risk are in fact markers for
 heart failure - NTproBNP and high sensitivity troponin. These markers are independent from
 CHA2DS2-VASc score. While this is very helpful, these markers will not be able to distinguish
 these 2 conditions because heart failure and atrial fibrillation often co-exist. The
 investigator's Cardiovascular Biomarker Discovery and Translation team has been using deep
 proteomic analysis of both human tissues and reprogrammed human stem cells to identify novel
 candidate biomarkers. This has been very successfully applied to diastolic heart failure, and
 there are now several new markers for this condition that have been validated across 3
 populations. The investigators have several potential candidates for atrial fibrillation, but
 validation in the appropriate cohort, particularly those at the earliest risks of atrial
 fibrillation, will be most important.

 The ARTESiA study is an ideal study setting to perform the biomarker validation, as the
 parent trial will recruit patients with silent atrial fibrillation detected only by
 dual-chamber pacemakers, defibrillators or insertable cardiac monitors. This would constitute
 a potentially earlier stage atrial fibrillation patient cohort, with known subsequent risks
 in a prospective fashion. The prospective evaluation of approved medications of aspirin and
 apixaban will also be helpful to determine if the prospective biomarker will be informative
 of the potential efficacy of treatment, or be unchanged by the treatment modalities.
Inclusion Criteria:

 -  Permanent pacemaker or defibrillator (with or without resynchronization) or insertable
 cardiac monitor

 -  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

 -  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

 -  Must be from a participating Canadian recruitment centre

 -  Consent to participate in the ARTESiA parent study

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

 -  Allergy to aspirin or apixaban

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

 -  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)

 -  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 both CYP3A4 and P-glycoprotein (e.g., ketoconazole, itraconazole,
 ritonavir or clarithromycin)

 -  Ongoing need for strong inducers of both CYP3A4 and 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 2 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, abstinence or other method
 with less than 1% failure rate)