A Phase III Study of Apixaban in Patients With Atrial Fibrillation (AVERROES)

The purpose of this clinical research study is to learn if apixaban is more effective than Acetylsalicylic Acid (ASA) in preventing strokes associated with subjects who have atrial fibrillation. The safety of this treatment will also be studied.

Long-Term Open Label Extension: An optional Long-Term Open-Label Extension (LTOLE) of open-label treatment with apixaban following conclusion of the double-blind trial is provided for qualifying subjects

• Drug: Apixaban
  Tablets, Oral, 5 mg (2.5 mg in selected patients), BID, Up to 36 months/End of Study
  Other Name: BMS-562247
• Drug: Acetylsalicylic Acid (ASA)
  Tablets, Oral, 81 - 324 mg, QD, Up to 36 months/End of Study
• Drug: Apixaban
  Tablets, Oral, 5 mg (2.5 mg in selected patients), BID, Up to 36 months
  Other Name: BMS-562247

• Experimental: Apixaban
  (Double-Blind Phase)
  Intervention: Drug: Apixaban
• Placebo Comparator: Acetylasalicylic Acid (ASA)
  (Double-Blind Phase)
  Intervention: Drug: Acetylsalicylic Acid (ASA)
• Experimental: Apixaban (Long-Term Open-Label Extension)
  (Open Label Phase)
  Intervention: Drug: Apixaban

• Lip GY, Connolly S, Yusuf S, Shestakovska O, Flaker G, Hart R, Lanas F, Xavier D, Eikelboom J; ERROES Investigators. Modification of outcomes with aspirin or apixaban in relation to CHADS(2) and CHA(2)DS(2)-VASc scores in patients with atrial fibrillation: a secondary analysis of the AVERROES study. Circ Arrhythm Electrophysiol. 2013 Feb;6(1):31-8. doi: 10.1161/CIRCEP.112.975847. Epub 2013 Feb 6.
• Flaker GC, Eikelboom JW, Shestakovska O, Connolly SJ, Kaatz S, Budaj A, Husted S, Yusuf S, Lip GY, Hart RG. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial. Stroke. 2012 Dec;43(12):3291-7. doi: 10.1161/STROKEAHA.112.664144. Epub 2012 Oct 2.
• Diener HC, Eikelboom J, Connolly SJ, Joyner CD, Hart RG, Lip GY, O'Donnell M, Hohnloser SH, Hankey GJ, Shestakovska O, Yusuf S; AVERROES steering committee and investigators. Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol. 2012 Mar;11(3):225-31. Epub 2012 Feb 1.
• Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011 Mar 3;364(9):806-17. Epub 2011 Feb 10.

Inclusion Criteria:

• Permanent, paroxysmal or persistent atrial fibrillation documented by 12 lead ECG on the day of screening OR
• If not in atrial fibrillation at screening, atrial fibrillation must be documented in the 6 months prior to enrollment by 12 lead ECF, or as an episode at least 5 minutes in duration on a rhythm strip or Holter recording. Pacemaker or ICD electrogram recordings may be used to document AF but the duration of atrial fibrillation must be at least 30 minutes if this is the only documentation of AF

• Presence of at least one of the following risk factors for stroke:

  • Prior stroke or TIA
  • Age ≥ 75 years
  • Arterial hypertension on treatment
  • Diabetes mellitus
  • Heart failure. NYHA Class 2 or greater at time of enrollment
  • Left ventricular ejection fraction 35% or less, documented within 6 months of enrollment
  • Documented peripheral arterial disease (previous arterial revascularization, limb or foot amputation, or current intermittent claudication with ankle-arm systolic blood pressure ratio < 0.9)

  • The patient is not currently receiving vitamin K antagonist therapy for one of the following reasons:

    • Previous vitamin K antagonist therapy has been demonstrated to be unsuitable and its use has been discontinued (e.g., poor anticoagulant control, adverse events, need for other treatments that may interact with VKA, patient unable or unwilling to adhere to dose or INR monitoring instructions)
    • Vitamin K antagonist therapy has not been previously used but would be expected to be unsuitable (e.g., unlikely to comply with dosing or monitoring requirement, need for other treatments which may interact with VKA, unlikely to adhere to restrictions on alcohol, diet or non-prescription medications, risk of VKA therapy considered to outweigh the risk of stroke or systemic embolism, patient is unwilling to take VKA).
  • Men and women ≥ 50 years of age

Exclusion Criteria:

• Women who are pregnant or breast feeding
• Women of child bearing potential (WOCBP) who are unwilling to meet the study requirements for pregnancy testing or are unwilling or unable to use an acceptable method to avoid pregnancy.
• Atrial fibrillation due to reversible causes (e.g., thyrotoxicosis, pericarditis)
• Valvular disease requiring surgery
• Planned atrial fibrillation ablation procedure to be performed within 3 months
• Conditions other than atrial fibrillation that require chronic anticoagulation (e.g., prosthetic mechanical heart valve, venous thromboembolism

• Patient with serious bleeding in the last 6 months or at high risk of bleeding. This includes, but is not limited to:

  • Active peptic ulcer disease
  • Platelet count < 100,000/mm3 or hemoglobin < 10g/dL
  • Recent stroke (within 10 days)
  • Documented hemorrhagic tendencies or blood dyscrasias
  • Current alcohol or drug abuse, or psychosocial reasons that make study participation impractical
  • Severe co-morbid condition with life expectancy <1 year
  • Severe renal insufficiency (creatinine clearance must be calculated in all patients: any patient with either a serum creatinine > 2.5 mg/dL [221 umol/L] or a calculated creatinine clearance < 25 ml/min is excluded)
• ALT or AST > 2 times upper limit of normal or a total bilirubin > 1.5 times upper limit of normal (unless an alternative causative factor [e.g., Gilbert's syndrome] is identified)
• Allergy or adverse reaction to ASA
• See section 5.5.1 (Prohibited and/or Restricted Treatments) for therapies which are prohibited at study entry
• Required treatment with a thienopyridine (clopidogrel or ticlopidine; see also section 5.5.2.1 Acetylsalicylic acid (ASA) and Thienopyridines).
• Prisoners or subjects who are compulsory detained (involuntarily incarcerated)
• Use of an investigational drug or device within the past 30 days or prior randomization into an apixaban clinical study
• Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness