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

• ClinicalTrials.gov Identifier: NCT00496769
• Recruitment Status: Completed
• First Posted: July 4, 2007
• Results First Posted: November 14, 2013
• Last Update Posted: June 15, 2018
• Sponsor: Bristol-Myers Squibb
• Collaborator: Pfizer
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: July 2, 2007
• First Posted Date: July 4, 2007
• Results First Submitted Date: August 1, 2013
• Results First Posted Date: November 14, 2013
• Last Update Posted Date: June 15, 2018
• Actual Study Start Date: August 31, 2007
• Actual Primary Completion Date: November 30, 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 16, 2018)

Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period [ Time Frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) ]

Event rate=percent of participants with an event divided by the total participants in the arm. Intended-treatment period=date of randomization to the efficacy cutoff date, which was to be the date on which at least 226 unrefuted original primary efficacy events occurred (date revised to May 28, 2010 following cessation of study for superior efficacy.)

• Original Primary Outcome Measures (submitted: July 2, 2007): To determine if apixaban 5 mg BID (2.5 mg BID in selected patients) is superior to ASA (81 to 324 mg QD) for preventing the composite outcome of stroke or systemic embolism in patients with atrial fibrillation and at least one additional risk factor [ Time Frame: Time to first occurrence ]

Current Secondary Outcome Measures (submitted: May 16, 2018)

• Event Rate for the Composite of Stroke of Any Type, Systemic Embolism, Myocardial Infarction, or Vascular Death During the Double-blind Treatment Period [ Time Frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) ]
  Event rate=percent of participants with an event divided by the total participants in the arm.
• Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death [ Time Frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) ]
  Event rate=percent of participants with an event divided by the total participants in the arm.
• Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period [ Time Frame: First dose of study drug (Day 1) to the earlier of a patient's discontinuation of double-blind study drug or the attainment of at least 226 primary efficacy events up to May 28, 2010 ]
  Event rate=percent of participants with an event divided by the total participants in the arm.
• Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period [ Time Frame: Day 1 to first bleeding event up to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) ]
  Event rate=percent of participants with an event divided by the total participants in the arm.
• Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome [ Time Frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug ]
  AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
• Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality [ Time Frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug ]
  BL=baseline, LLN=lower limit of normal, ULN=upper limit of normal. Hemoglobin (g/dL), low: BL>2 or value ≤8; hematocrit(%), low: <0.75*BL; erythrocytes (*10^6 cells/μL), low: <0.75*BL; platelet count (*10^9 cells/L),low: <100*10^9 cells/L; leukocytes (*10^3 cells/μL), low if <0.8*BL and BL<LLN or <LLN and BL >ULN or <0.75*LLN when BL is missing or LLN ≤BL≤ ULN, high if >1.2*BL and BL>ULN or >ULN when BL and BL<LLN or >1.25*ULN when BL is missing or LLN≤BL≤ULN; neutrophils (absolute), low: <1.0*10^3 cells/μL; eosinophils (absolute), high: >0.750*10^3 cells/μL; basophils (absolute), high: >0.4*10^3 cells/μL; monocytes (absolute), high: 2*10^3 cells/μL; lymphocytes (absolute), low if <0.75*10^3 cells/μL, high if >7.50*10^3 cells/μL; ALP (U/L), high: 2*ULN; AST (U/L), high: 3*ULN; AST (U/L), high: 3*ULN; bilirubin, total (mg/dL), high: >2*ULN; bilirubin, direct (mg/dL), high: 1.5*ULN; BUN (mg/dL), high:>2*ULN; creatinine (mg/dL), high: >1.5*ULN.
• Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued) [ Time Frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug ]
  LLN=lower limit of normal; ULN=upper limit of normal; BL=baseline. Sodium, serum (mEq/L):low if <0.95*BL and BL<LLN or <LLN and BL>ULN or <0.95*LLN when BL missing or LLN ≤BL≤ULN, high if >1.05*BL and BL>ULN or >ULN and BL<LLN or >1.05*ULN when BL missing or LLN≤BL≤ULN; potassium(mEq/L):low if <0.90*BL and BL<LLN or <LLN and BL>ULN or <0.90*LLN if BL missing or LLN≤BL≤ULN, high if >1.10*BL and BL>ULN or>ULN and BL<LLN or >1.10*ULN when BL missing or LLN≤BL≤ULN; chloride(mEq/L):low if <0.90*BL and BL<LLN or <LLN and BL>ULN or <0.90*LLN if BL missing or LLN≤BL ≤ULN, high if >1.10*BL and BL>ULN or >ULN and BL<LLN or >1.10* ULN if BL missing or LLN≤BL≤ULN; calcium(mg/dL):low if <0.75*BL and BL<LLN or <LLN and BL>ULN or <0.80*LLN if BL missing or LLN≤BL≤ULN, high if >1.25*BL and BL>ULN or >ULN if BL<LLN or >1.20*ULN if BL missing or LLN≤BL≤ULN ; bicarbonate(mEq/L):low if <0.75*BL when BL<LLN or <LLN when BL>ULN or <0.75*LLN if BL missing or LLN≤BL≤ULN, high if >1.25*BL when BL>ULN or >ULN
• Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued) [ Time Frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug ]
  ULN=upper limit of normal; LLN=lower limit of normal; BL=baseline. Creatine kinase (U/L), high:>5*ULN; protein, total(g/L):low if <0.90*BL when BL<LLN or <LLN when B >ULN or <0.90*LLN when BL is missing or LLN≤BL≤ULN, high if >1.10*BL if BL>ULN or >ULN when BL<LLN or >1.10*ULN if BL missing or LLN≤BL≤ULN.Protein,total(g/L): low if <0.90*BL if BL<LLN or <LLN if BL>ULN or <0.90*LLN if BL missing or LLN≤BL≤ULN, high if >1.10*BL if BL>ULN or >ULN if BL<LLN or >1.10*ULN if BL or LLN≤BL≤ULN; glucose, serum fasting (mg/dL): low if <0.8*BL if BL<LLN or <LLN when BL>ULN or <0.8*LLN when BL missing or LLN≤BL≤ULN, high if >2*BL when BL>ULN or >ULN when BL<LLN or >1.5*ULN if BL missing or LLN≤BL≤ULN; uric acid (mg/dL), high: >2*BL and BL>ULN or>1.5*ULN when BL missing or BL≤ULN; glucose, urine, high; protein, urine, high; blood, urine, high; leukocyte esterase, urine, high; RBC count, urine (Hpf), high; WBC count, urine (Hpf), high: ≥2 if BL=missing,=0 or =0.5 or if ≥3 if BL=1, or if ≥4 and BL≥2.

• Original Secondary Outcome Measures (submitted: July 2, 2007): To determine, in the same patients, if apixaban is superior to ASA for prevention of the composite outcome of: Stroke, systemic embolism, myocardial infarction or vascular death (major vascular events) [ Time Frame: Time to first occurrence ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase III Study of Apixaban in Patients With Atrial Fibrillation
• Official Title: Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment: A Randomized Double-blind Trial
• Brief Summary: The purpose of this clinical research study is to determine whether apixaban is more effective than acetylsalicylic acid in the prevention of strokes associated with patients with atrial fibrillation. The safety of this treatment will also be studied.
• Detailed Description: An optional Long-term Open-label Extension Phase of treatment with apixaban will be provided for qualifying participants following the conclusion of the double-blind phase
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Condition: Atrial Fibrillation

Intervention

• Drug: Apixaban
  Tablets, oral, 5 mg (2.5 mg in patients meeting any 2 of the following criteria: 80 years of age and older, weight of 60 kilograms or less, and a serum creatinine level of 1.5 mg/dL or higher), twice daily, up to 156 weeks
  Other Name: BMS-562247
• Drug: Acetylsalicylic acid
  Tablets, oral, 81-324 mg, once daily, up to 156 weeks

Study Arms

• Experimental: Apixaban
  Intervention: Drug: Apixaban
• Active Comparator: Acetylasalicylic acid
  Intervention: Drug: Acetylsalicylic acid

Publications *

• Bhagirath VC, Eikelboom JW, Hirsh J, Coppens M, Ginsberg J, Vanassche T, Yuan F, Chan N, Yusuf S, Connolly SJ. Apixaban-Calibrated Anti-FXa Activity in Relation to Outcome Events and Clinical Characteristics in Patients with Atrial Fibrillation: Results from the AVERROES Trial. TH Open. 2017 Dec 12;1(2):e139-e145. doi: 10.1055/s-0037-1613679. eCollection 2017 Jul.
• Ng KH, Shestakovska O, Connolly SJ, Eikelboom JW, Avezum A, Diaz R, Lanas F, Yusuf S, Hart RG. Efficacy and safety of apixaban compared with aspirin in the elderly: a subgroup analysis from the AVERROES trial. Age Ageing. 2016 Jan;45(1):77-83. doi: 10.1093/ageing/afv156. Epub 2015 Nov 19.
• Hohnloser SH, Shestakovska O, Eikelboom J, Franzosi MG, Tan RS, Zhu J, Yusuf S, Connolly SJ. The effects of apixaban on hospitalizations in patients with different types of atrial fibrillation: insights from the AVERROES trial. Eur Heart J. 2013 Sep;34(35):2752-9. doi: 10.1093/eurheartj/eht292. Epub 2013 Jul 25.
• 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. doi: 10.1016/S1474-4422(12)70017-0. 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. doi: 10.1056/NEJMoa1007432. Epub 2011 Feb 10.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 22, 2013): 6421
• Original Estimated Enrollment (submitted: July 2, 2007): 5600
• Actual Study Completion Date: May 25, 2017
• Actual Primary Completion Date: November 30, 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Male and female
• Age of 50 years or older
• Permanent, paroxysmal, or persistent atrial fibrillation (at screening or within 6 months prior to enrollment) documented by 12-lead electrocardiogram)

• At least 1 of the following risk factors for stroke:

  • Prior stroke or transient ischemic attack
  • Age of 75 years or older
  • Arterial hypertension on treatment
  • Diabetes mellitus
  • Heart failure (New York Health Authority Class 2 or greater at time of enrollment)
  • Left ventricular ejection fraction of 35% or less, documented within 6 months of enrollment
  • Peripheral arterial disease (previous arterial revascularization, limb or foot amputation, or current intermittent claudication with ankle-arm systolic blood pressure ratio <0.9)

• Not currently receiving vitamin K antagonist therapy for 1 of the following reasons:

  • Previous vitamin K antagonist therapy demonstrated as unsuitable and discontinued
  • Vitamin K antagonist therapy not previously used but expected unsuitable

Key Exclusion Criteria:

• Women who are pregnant or breast feeding
• Women of child bearing potential 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, such as thyrotoxicosis or pericarditis
• Valvular disease requiring surgery
• Planned ablation procedure for atrial fibrillation to be performed within 3 months
• Conditions other than atrial fibrillation that require chronic anticoagulation (such as, prosthetic mechanical heart valve, venous thromboembolism)

• Patients with serious bleeding in the last 6 months or at high risk for bleeding, including but not limited to those with:

  • Active peptic ulcer disease
  • Platelet count <100,000/mm^3 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 comorbid condition with life expectancy <1 year
• Severe renal insufficiency; any patient with a serum creatinine level >2.5 mg/dL or a calculated creatinine clearance <25 mL/min is excluded
• Alanine transaminase or aspartate aminotransferase levels >2 times upper limit of normal (ULN) or a total bilirubin level >1.5 times ULN (unless an alternative causative factor [such as Gilbert's syndrome] is identified)
• Allergy or adverse reaction to acetylsalicylic acid
• Required treatment with a thienopyridine (clopidogrel or ticlopidine)
• Prisoners or participants 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 for a psychiatric or physical illness

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, India, Indonesia, Israel, Italy, Korea, Republic of, Malaysia, Mexico, Norway, Philippines, Poland, Russian Federation, Singapore, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic, Hungary, Netherlands

Administrative Information

• NCT Number: NCT00496769
• Other Study ID Numbers: CV185-048
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Bristol-Myers Squibb
• Study Sponsor: Bristol-Myers Squibb
• Collaborators: Pfizer

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: May 2018