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CompletedNCT00496769AVERROESUpdated Jun 15, 2018Results posted

A Phase III Study of Apixaban in Patients With Atrial Fibrillation

A Phase 3 interventional study of Apixaban and Acetylsalicylic acid in Atrial Fibrillation, sponsored by Bristol-Myers Squibb. Completed at 503 sites in 36 countries. Open to participants aged 50 Years and older. Per ClinicalTrials.gov, last updated 2018-06-15.

Sponsored by Bristol-Myers Squibb · Phase 3, Interventional, and Prevention

Phase
Phase 3
Study type
Interventional
Enrollment
6,421
Allocation
Randomized
Ages
50 Years and older
Sex
All
01

Study 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.

Read the 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

02

Conditions studied

  • Atrial Fibrillation

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03

In context

Atrial Fibrillation

3,870 studies on the registry are indexed under Atrial Fibrillation; 924 are open to participants now.

This study's enrollment of 6,421 is above the median of 144 across 2,380 interventional studies indexed under Atrial Fibrillation.

Browse Atrial Fibrillation studies →

Lead sponsor

Bristol-Myers Squibb is the lead sponsor of 1,538 studies on the registry; 116 are open to participants now.

Of its 429 completed or terminated interventional studies of FDA-regulated products, 223 (52%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
50 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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
05

Study design

Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
6,421 participants (actual)

Study arms

  • Experimental
    Apixaban

    Drug: Apixaban

  • Active comparator
    Acetylasalicylic acid

    Drug: Acetylsalicylic acid

Interventions

  • DrugApixaban

    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

    Also known as: BMS-562247

  • DrugAcetylsalicylic acid

    Tablets, oral, 81-324 mg, once daily, up to 156 weeks

06

What researchers measure

Primary outcomes

  1. Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period

    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.)

    Time frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)

Secondary outcomes

  1. Event Rate for the Composite of Stroke of Any Type, Systemic Embolism, Myocardial Infarction, or Vascular Death During the Double-blind Treatment Period

    Event rate=percent of participants with an event divided by the total participants in the arm.

    Time frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)

  2. Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death

    Event rate=percent of participants with an event divided by the total participants in the arm.

    Time frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)

  3. Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period

    Event rate=percent of participants with an event divided by the total participants in the arm.

    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

  4. Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period

    Event rate=percent of participants with an event divided by the total participants in the arm.

    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)

  5. Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome

    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.

    Time frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug

  6. Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality

    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.

    Time frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug

  7. Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)

    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

    Time frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug

  8. Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)

    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.

    Time frame: First dose of study drug (Day 1) to 30 days after last dose of blinded study drug

07

Results

Posted Nov 14, 2013
Limitations and caveats
On May 28, 2010, after a planned interim analysis for efficacy, the Data Monitoring Committee recommended early termination due to apixaban's superior efficacy over ASA, with an acceptable safety profile. The open-label phase is ongoing.

Participant flow

Double Blind
Participant flow — Double Blind
MilestoneApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyOpen Label Apixaban
Started280727910
Received treatment279827080
Completed224921420
Not completed5586490
Withdrew: >=1 reason assigned per patient5586490
Open Label
Participant flow — Open Label
MilestoneApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyOpen Label Apixaban
Started003275
Completed002264
Not completed001011
Withdrew: >=1 reason assigned per patient001011

Outcome measures

PrimaryEvent Rate of Stroke/Systemic Embolism During the Intended-treatment Period

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.)

Time frame:
Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)
Reported as:
Number · Percentage of events
Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period
Percentage of eventsApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once Daily
Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period1.623.63
Statistical analysis
  • Apixaban, 2.5 or 5 mg Twice Daily vs Acetylsalicylic Acid, 81-324 mg Once Daily · Log Rank · p = <0.00001 · Hazard ratio (hr): 0.45 · 95% CI 0.32 to 0.62
SecondaryEvent Rate for the Composite of Stroke of Any Type, Systemic Embolism, Myocardial Infarction, or Vascular Death During the Double-blind Treatment Period

Event rate=percent of participants with an event divided by the total participants in the arm.

Time frame:
Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)
Reported as:
Number · Percentage of events per year
Event Rate for the Composite of Stroke of Any Type, Systemic Embolism, Myocardial Infarction, or Vascular Death During the Double-blind Treatment Period
Percentage of events per yearApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once Daily
Event Rate for the Composite of Stroke of Any Type, Systemic Embolism, Myocardial Infarction, or Vascular Death During the Double-blind Treatment Period4.216.35
Statistical analysis
  • Apixaban, 2.5 or 5 mg Twice Daily vs Acetylsalicylic Acid, 81-324 mg Once Daily · Log Rank · p = 0.00026 · Hazard ratio (hr): 0.66 · 95% CI 0.53 to 0.83Vascular death
SecondaryEvent Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death

Event rate=percent of participants with an event divided by the total participants in the arm.

Time frame:
Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)
Reported as:
Number · Percentage of events per year
Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death
Percentage of events per yearApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once Daily
All-cause death (n=111, 140)3.514.42
Net clinical benefit (n=163, 220)5.237.13
Vascular death (n=84, 96)2.653.03
Statistical analysis
  • Apixaban, 2.5 or 5 mg Twice Daily vs Acetylsalicylic Acid, 81-324 mg Once Daily · Log Rank · p = 0.06782 · Hazard ratio (hr): 0.79 · 95% CI 0.62 to 1.02All-cause death
  • Apixaban, 2.5 or 5 mg Twice Daily vs Acetylsalicylic Acid, 81-324 mg Once Daily · Log Rank · p = 0.00280 · Hazard ratio (hr): 0.73 · 95% CI 0.60 to 0.90Composite endpoint of major vascular events and major bleeding-net clinical benefit
  • Apixaban, 2.5 or 5 mg Twice Daily vs Acetylsalicylic Acid, 81-324 mg Once Daily · Log Rank · p = 0.36586 · Hazard ratio (hr): 0.87 · 95% CI 0.65 to 1.17Vascular death
SecondaryEvent Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period

Event rate=percent of participants with an event divided by the total participants in the arm.

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
Reported as:
Number · Percentage of events per year
Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period
Percentage of events per yearApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once Daily
Major bleeding1.410.92
Major or CRNM bleeding4.463.24
All bleeding10.858.32
Statistical analysis
  • Apixaban, 2.5 or 5 mg Twice Daily vs Acetylsalicylic Acid, 81-324 mg Once Daily · Log Rank · p = 0.0716 · Hazard ratio (hr): 1.54 · 95% CI 0.96 to 2.45Major bleeding
  • Apixaban, 2.5 or 5 mg Twice Daily vs Acetylsalicylic Acid, 81-324 mg Once Daily · Log Rank · p = 0.0017 · Hazard ratio (hr): 1.30 · 95% CI 1.10 to 1.53All bleeding
  • Apixaban, 2.5 or 5 mg Twice Daily vs Acetylsalicylic Acid, 81-324 mg Once Daily · Log Rank · p = 0.0144 · Hazard ratio (hr): 1.38 · 95% CI 1.07 to 1.78Major or CNRM bleeding
SecondaryRate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period

Event rate=percent of participants with an event divided by the total participants in the arm.

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)
Reported as:
Number · Percentage of events per year
Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period
Percentage of events per yearApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once Daily
Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period10.858.32
Statistical analysis
  • Apixaban, 2.5 or 5 mg Twice Daily vs Acetylsalicylic Acid, 81-324 mg Once Daily · Log Rank · p = 0.0017 · Hazard ratio (hr): 1.30 · 95% CI 1.10 to 1.53
SecondaryNumber of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome

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.

Time frame:
First dose of study drug (Day 1) to 30 days after last dose of blinded study drug
Reported as:
Number · Participants
Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome
ParticipantsApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once Daily
AEs18331925
SAEs657804
Bleeding AEs281259
Discontinuations due to AE266362
Deaths91115
SecondaryNumber of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality

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.

Time frame:
First dose of study drug (Day 1) to 30 days after last dose of blinded study drug
Reported as:
Number · Participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality
ParticipantsApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once Daily
Hemoglobin, low (n=1956, 1893)131120
Hemoglobin, high (n=1956, 1893)00
Hematocrit, low (n=1728, 1687)139
Hematocrit, high (n=1728, 1687)00
Erythrocytes, low (n=1728, 1687)1212
Erythrocytes, high (n=1728, 1687)00
Platelet count, low (n=2148, 2098)710
Platelet count, high (n=2148, 2098)00
Leukocytes, low (n=1738, 1698)1214
Leukocytes, high (n=1738, 1698)1418
Neutrophils (absolute), low (n=2170, 2138)21
Neutrophils (absolute), high (n=2170, 2138)00
Eosinophils (absolute), low (n=2170, 2138)00
Eosinophils (absolute), high (n=2170, 2138)4868
Basophils (absolute), low (n=2170, 2138)00
Basophils (absolute), high (n=2170, 2138)00
Monocytes (absolute), low (n=2170, 2138)00
Monocytes (absolute), high (n=2170, 2138)02
Lymphocytes (absolute), low (n=2170, 2138)5262
Lymphocytes (absolute), high (n=2170, 2138)45
Alkaline phosphatase (ALP), low (n=2781, 2758)00
ALP, high (n=2781, 2758)3427
Aspartate phosphatase (AST), low (n=2779, 2753)00
AST, high (n=2779, 2753)2833
Alanine aminotransferase (ALT), low (n=2779, 2753)00
ALT, high (n=2779, 2753)2331
Bilirubin (total), low (n=2781, 2758)00
Bilirubin (total), high (n=2781, 2758)3043
Bilirubin (direct), low (n=2773, 2750)00
Bilirubin (direct), high (n=2773, 2750)241248
Blood urea nitrogen (BUN), low (n=2201, 2172)00
BUN, high (n=2201, 2172)4250
Creatinine, low (n=2209, 2178)00
Creatinine, high (n=2209, 2178)6771
SecondaryNumber of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)

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

Time frame:
First dose of study drug (Day 1) to 30 days after last dose of blinded study drug
Reported as:
Number · Participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)
ParticipantsApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once Daily
Sodium (serum), low (n=1768, 1740)26
Sodium (serum), high (n=1768, 1740)12
Potassium (serum), low (n=1763, 1737)68
Potassium (serum), high (n=1763, 1737)2028
Chloride (serum), low (n=1768, 1740)03
Chloride (serum), high (n=1768, 1740)01
Calcium (total), low (n=106, 109)00
Calcium (total), high (n=106, 109)00
Bicarbonate, low (n=1664, 1619)00
Bicarbonate, high (n=1664, 1619)00
SecondaryNumber of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)

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.

Time frame:
First dose of study drug (Day 1) to 30 days after last dose of blinded study drug
Reported as:
Number · Participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)
ParticipantsApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once Daily
Creatine kinase, low (n=2780, 2758)00
Creatine kinase, high (n=2780, 2758)1325
Protein (total), low (n=103, 109)00
Protein (total), high (n=103, 109)00
Uric acid, low (n=386, 390)00
Uric acid, high (n=386, 390)10
Glucose (urine), low (n=2, 3)00
Glucose (urine), high (n=2, 3)01
Protein (urine), low (n=3, 5)00
Protein (urine), high (n=3, 5)11
Blood (urine), low (n=3, 5)00
Blood (urine), high (n=3, 5)10
Leukocyte esterase (urine), low (n=3,5)00
Leukocyte esterase (urine), high (n=3,5)00
Red blood cells (RBC) (urine), low (n=2,2)00
RBC (urine), high (n=2,2)10
White blood cells (urine), low (n=2,2)00
WBC (urine), high (n=2,2)00

Adverse events

Collected over From first dose to last dose plus 30 days (assessed up to May 2017, approximately 95 months). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Apixaban, 2.5 or 5 mg Twice Daily111/2,798 (4%)657/2,798 (23.5%)207/2,798 (7.4%)
Acetylsalicylic Acid, 81-324 mg Once Daily140/2,780 (5%)804/2,780 (28.9%)267/2,780 (9.6%)
Open Label Apixaban286/3,275 (8.7%)1,228/3,275 (37.5%)180/3,275 (5.5%)
Most frequent serious events
Showing 10 of 931
Most frequent serious events
EventApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyOpen Label Apixaban
Cardiac failureCardiac disorders60/279876/2780116/3275
Atrial fibrillationCardiac disorders72/279870/2780113/3275
PneumoniaInfections and infestations37/279855/278099/3275
Ischaemic strokeNervous system disorders19/279846/278022/3275
Cardiac failure congestiveCardiac disorders39/279828/278053/3275
Cerebrovascular accidentNervous system disorders16/279840/278015/3275
DeathGeneral disorders14/27989/278038/3275
Transient ischaemic attackNervous system disorders10/279829/278013/3275
Sudden deathGeneral disorders9/279812/278032/3275
Chest painGeneral disorders16/279824/278028/3275
Most frequent other events
Most frequent other events
EventApixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyOpen Label Apixaban
DizzinessNervous system disorders109/2798144/2780132/3275
DyspnoeaRespiratory, thoracic and mediastinal disorders109/2798141/2780164/3275

Baseline characteristics

Age, Continuous
Age, Continuous(years)Apixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyTotal
Mean69.7 ± 9.4470.0 ± 9.7169.9 ± 9.58
Age, Customized
Age, Customized(Participants)Apixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyTotal
< 65 years8558651720
>=65 but <75 years10499381987
>=75 years9039881891
Sex: Female, Male
Sex: Female, Male(Participants)Apixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyTotal
Female114711742321
Male166016173277
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Apixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyTotal
American Indian or Alaska Native6612
Asian5415441085
Native Hawaiian or Other Pacific Islander314
Black or African American102636
White222121784399
Other263662
Number of Participants by Number of Risk Factors for Stroke
Number of Participants by Number of Risk Factors for Stroke(Participants)Apixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyTotal
1 or fewer108510772162
2 or more172217143436
Number of Participants With Risk Factors for Stroke
Number of Participants With Risk Factors for Stroke(Participants)Apixaban, 2.5 or 5 mg Twice DailyAcetylsalicylic Acid, 81-324 mg Once DailyTotal
Age of 75 years or older9039881891
Prior stroke or transient ischemic attack390374764
Heart failure (NYHA class ≥2) or LVEF ≤35%9619261887
Diabetes mellitus5365591095
Hypertension requiring pharmacologic treatment240824294837
Peripheral artery disease6678144
08

Study locations

503 sites
  • Mobile Heart Specialists, Pc
    Mobile, Alabama 36608, United States
  • Southwest Heart
    Tucson, Arizona 85710, United States
  • Cardiology Consultants Of Orange County Med. Group Inc
    Anaheim, California 92801, United States
  • Kaiser Permanente Medical Center, West Los Angeles
    Los Angeles, California 90034, United States
  • Desert Med Grp Inc, Dba Desert Oasis Healthcare Med Group
    Palm Springs, California 92262, United States
  • Yogesh K. Paliwal Md
    Pomona, California 91767, United States
  • San Diego Managed Care Group
    Poway, California 92064, United States
  • University Of California, San Diego
    San Diego, California 92103, United States
  • Santa Rosa Cardiology
    Santa Rosa, California 95405, United States
  • North County Internal Medicine
    Vista, California 92083, United States
  • Cardiology Associates Of New Haven,Pc
    Guilford, Connecticut 06437, United States
  • Stamford Therapeutics Consortium
    Stamford, Connecticut 06905, United States
  • Bay Pines Va Healthcare System
    Bay Pines, Florida 33744, United States
  • Research Alliance, Inc.
    Clearwater, Florida 33756, United States
  • The Heart & Vascular Institute Of Florida
    Clearwater, Florida 33756, United States
  • Kim A. Klancke, Md
    Daytona Beach, Florida 32114, United States
  • The Heart Group Pl
    Fort Myers, Florida 33908, United States
  • Baptist Heart Specialists
    Jacksonville Beach, Florida 32250, United States
  • St. Vincent'S Ambulatory Care, Inc
    Jacksonville, Florida 32204, United States
  • Michael F. Lesser, Md, Facc Osler Medical Inc.
    Melbourne, Florida 32901, United States
  • Cardiovascular Center Of Sarasota
    Sarasota, Florida 34239, United States
  • The Broward Heart Group, Pa
    Tamarac, Florida 33321, United States
  • Southeast Regional Research Group
    Columbus, Georgia 31904, United States
  • Southeast Regional Research Group
    Savannah, Georgia 31406, United States
  • Fox Valley Clinical Research Center, Llc
    Aurora, Illinois 60504, United States
  • North Chicago Va Medical Center
    North Chicago, Illinois 60064, United States
  • Indiana Heart Physicians, Inc.
    Indianapolis, Indiana 46237, United States
  • The Care Group, Llc
    Indianapolis, Indiana 46290, United States
  • Hutchinson Clinic, Pa
    Hutchinson, Kansas 67502, United States
  • Dr. Jeffrey Chen
    Lafayette, Louisiana 70506, United States
  • Peninsula Cardiology Associates, P.A.
    Salisbury, Maryland 21804, United States
  • Pentucket Medical Associates
    Haverhill, Massachusetts 01830, United States
  • Great Lakes Heart Center Of Alpena
    Alpena, Michigan 49707, United States
  • Henry Ford Hospital K-15
    Detroit, Michigan 48202, United States
  • Michigan Heart And Vascular Specialists
    Petoskey, Michigan 49770, United States
  • Academic Cardiology Associates
    Rochester Hills, Michigan 48307, United States
  • Tupelo Neurology Clinic, Pa
    Tupelo, Mississippi 38801, United States
  • Missouri Cardiovascular Specialists
    Columbia, Missouri 65201, United States
  • University Of Missouri
    Columbia, Missouri 65212, United States
  • Glacier View Cardiology, Pc
    Kalispell, Montana 59901, United States
  • Hunterdon Cardiovascular Associates
    Flemington, New Jersey 08822, United States
  • Capital Cardiology Associates
    Albany, New York 12211, United States
  • Nyu Hudson Valley Cardiology
    Cortlandt Manor, New York 10567, United States
  • Long Island Heart Associates
    Mineola, New York 11501, United States
  • Dr William Kufs
    Saratoga Springs, New York 12866, United States
  • Capital Cardiology Associates
    Troy, New York 12180, United States
  • Terry V. Arnold, Md
    Lexington, North Carolina 27293, United States
  • Pinehurst Medical Clinic, Inc
    Pinehurst, North Carolina 28374, United States
  • Sanford Cardiology
    Sanford, North Carolina 27330, United States
  • Ira R. Friedlander, M.D.
    Canton, Ohio 44710, United States
  • Davis Heart & Lung Research Institute
    Columbus, Ohio 43210, United States
  • Integris Cardiovascular Physicians
    Oklahoma City, Oklahoma 73112, United States
  • South Oklahoma Heart Research
    Oklahoma City, Oklahoma 73135, United States
  • Oregon Medical Group - Clinical Research
    Eugene, Oregon 97401, United States
  • Hillsboro Cardiology Pc
    Hillsboro, Oregon 97123, United States
  • The Portland Clinic, Llp
    Portland, Oregon 97205, United States
  • Comprehensive Cardiology Consultants
    Langhorne, Pennsylvania 19047, United States
  • Grand View - Lehigh Valley Health Services
    Sellersville, Pennsylvania 18960, United States
  • West Chester Cardiology
    West Chester, Pennsylvania 19380, United States
  • Cardiology Consultants Of Philadelphia
    Yardley, Pennsylvania 19067, United States
  • Lowcountry Medical Group, Llc
    Beaufort, South Carolina 29906, United States
  • Medical University Of South Carolina
    Charleston, South Carolina 29425, United States
  • Internal Medicine Of Greer
    Greer, South Carolina 29650, United States
  • Knoxville Heart Group
    Knoxville, Tennessee 37916, United States
  • Sentara York Clinical Research
    Norfolk, Virginia 23510, United States
  • Roanoke Heart Institute, Plc
    Roanoke, Virginia 24014, United States
  • Salem Veterans Administration Medical Center
    Salem, Virginia 24153, United States
  • Walla Walla Clinic
    Walla Walla, Washington 99362, United States
  • Marshfield Clinic
    Marshfield, Wisconsin 54449, United States
  • Local Institution
    Adrogue, Buenos Aires 1846, Argentina
  • Local Institution
    Autonoma Buenos Aires, Buenos Aires C1119ACN, Argentina
  • Local Institution
    Bahia Blanca, Buenos Aires B8000FTD, Argentina
  • Local Institution
    Coronel Suarez, Buenos Aires B7540GHD, Argentina
  • Local Institution
    Haedo, Buenos Aires B1706AJU, Argentina
  • Local Institution
    La Plata, Buenos Aires B1900AXI, Argentina
  • Local Institution
    La Plata, Buenos Aires B1902COS, Argentina
  • Local Institution
    Mar Del Plata, Buenos Aires B7600FZN, Argentina
  • Local Institution
    Merlo, Buenos Aires B1722COV, Argentina
  • Local Institution
    Ramos Mejia, Buenos Aires B1704ETD, Argentina
  • Local Institution
    San Francisco, Cordoba X2400MHC, Argentina
  • Local Institution
    San Salvador De Jujuy, Jujuy Y4600ABF, Argentina
  • Local Institution
    Zarate, Provincia Buenos Aires B2800DGH, Argentina
  • Local Institution
    Rosario, Santa FE 2000, Argentina
  • Local Institution
    Rosario, Santa FE S2000CVB, Argentina
  • Local Institution
    Rosario, Santa FE S2001ODA, Argentina
  • Local Institution
    San Miguel De Tucuman, Tucuman T4000ICL, Argentina
  • Local Institution
    San Miguel De Tucuman, Tucuman T4000JCU, Argentina
  • Local Institution
    Buenos Aires, 1221, Argentina
  • Local Institution
    Cordoba, 5000, Argentina
  • Local Institution
    Cordoba, 5016, Argentina
  • Local Institution
    Cordoba, X5000AAX, Argentina
  • Local Institution
    Cordoba, X5000EPU, Argentina
  • Local Institution
    Cordoba, X5000EVQ, Argentina
  • Local Institution
    Cordoba, X5009BSN, Argentina
  • Local Institution
    Corrientes, 3400, Argentina
  • Local Institution
    Salta, A4406CLA, Argentina
  • Local Institution
    Santa Fe, 3000, Argentina
  • Local Institution
    Coffs Harbour, New South Wales 2450, Australia
  • Local Institution
    Concord, New South Wales 2139, Australia
  • Local Institution
    Gosford, New South Wales 2250, Australia

Showing the first 100 of 503 sites across 36 countries.

09

References and documents

Publications

  • Jamieson MJ, Byon W, Dettloff RW, Crawford M, Gargalovic PS, Merali SJ, Onorato J, Quintero AJ, Russ C. Apixaban Use in Obese Patients: A Review of the Pharmacokinetic, Interventional, and Observational Study Data. Am J Cardiovasc Drugs. 2022 Nov;22(6):615-631. doi: 10.1007/s40256-022-00524-x. Epub 2022 May 16. PubMed 35570249 ↗
  • Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD008834. doi: 10.1002/14651858.CD008834.pub4. PubMed 35224730 ↗
  • 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. PubMed 31249919 ↗
  • 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. PubMed 26590293 ↗
  • 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. PubMed 23892201 ↗
  • 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. PubMed 23390125 ↗
  • 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. PubMed 23033347 ↗
  • 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. PubMed 22305462 ↗
  • 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. PubMed 21309657 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 15, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00496769
Lead sponsor
Bristol-Myers Squibb
Collaborators
Pfizer
Responsible party
Sponsor
First posted
Jul 4, 2007
Start date
Aug 31, 2007
Primary completion
Nov 30, 2010
Completion
May 25, 2017
Results posted
Nov 14, 2013
Last update
Jun 15, 2018

Study contacts

Bristol-Myers Squibb
study director · Bristol-Myers Squibb

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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