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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00496769
First received: July 2, 2007
Last updated: October 22, 2013
Last verified: October 2013
Results First Received: August 1, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Prevention
Condition: Atrial Fibrillation
Interventions: Drug: Apixaban
Drug: Acetylsalicylic acid

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total 6421 patients were enrolled in the study. Of these, 5598 were randomized (2807 to apixaban and 2791 to acetylsalicylic acid). Most (435) of the patients who were not randomized (823) no longer met study criteria. Of those randomized, 5578 received treatment (2798 with apixaban, and 2780 with acetylsalicylic acid).

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion

Participant Flow:   Overall Study
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
STARTED     2807 [1]   2791 [1]
Received Treatment     2798     2708  
COMPLETED     2249     2142  
NOT COMPLETED     558     649  
>=1 reason assigned per patient                 558                 649  
[1] Randomized



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion
Total Total of all reporting groups

Baseline Measures
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily     Total  
Number of Participants  
[units: participants]
  2807     2791     5598  
Age  
[units: years]
Mean ± Standard Deviation
  69.7  ± 9.44     70.0  ± 9.71     69.9  ± 9.58  
Age, Customized  
[units: Participants]
     
< 65 years     855     865     1720  
>=65 but <75 years     1049     938     1987  
>=75 years     903     988     1891  
Gender  
[units: participants]
     
Female     1147     1174     2321  
Male     1660     1617     3277  
Race/Ethnicity, Customized  
[units: participants]
     
American Indian or Alaska Native     6     6     12  
Asian     541     544     1085  
Native Hawaiian or Other Pacific Islander     3     1     4  
Black or African American     10     26     36  
White     2221     2178     4399  
Other     26     36     62  
Number of Participants by Number of Risk Factors for Stroke  
[units: Participants]
     
1 or fewer     1085     1077     2162  
2 or more     1722     1714     3436  
Number of Participants With Risk Factors for Stroke [1]
[units: Participants]
     
Age of 75 years or older     903     988     1891  
Prior stroke or transient ischemic attack     390     374     764  
Heart failure (NYHA class ≥2) or LVEF ≤35%     961     926     1887  
Diabetes mellitus     536     559     1095  
Hypertension requiring pharmacologic treatment     2408     2429     4837  
Peripheral artery disease     66     78     144  
[1] NYHA=New York Health Authority; LVEF=left ventricular ejection fraction



  Outcome Measures
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1.  Primary:   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) ]

Measure Type Primary
Measure Title Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period
Measure Description 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)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least 1 dose of study drug.

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion

Measured Values
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
Number of Participants Analyzed  
[units: participants]
  2807     2791  
Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period  
[units: Percentage of events]
  1.62     3.63  


Statistical Analysis 1 for Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.00001
Hazard Ratio (HR) [4] 0.45
95% Confidence Interval ( 0.32 to 0.62 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
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2.  Primary:   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) ]

Measure Type Primary
Measure Title Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period
Measure Description 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)  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least 1 dose of study drug.

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once, with dosage based on investigator discretion.

Measured Values
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
Number of Participants Analyzed  
[units: participants]
  2798     2780  
Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period  
[units: Percentage of events per year]
  10.85     8.32  


Statistical Analysis 1 for Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0017
Hazard Ratio (HR) [4] 1.30
95% Confidence Interval ( 1.10 to 1.53 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Event Rates of Major Vascular Events (Stroke/Systemic Embolism, Myocardial Infarction, Death) in the Intended-treatment Period   [ Time Frame: Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy) ]

Measure Type Secondary
Measure Title Event Rates of Major Vascular Events (Stroke/Systemic Embolism, Myocardial Infarction, Death) in the Intended-treatment Period
Measure Description 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)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least 1 dose of study drug

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once, with dosage based on investigator discretion.

Measured Values
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
Number of Participants Analyzed  
[units: participants]
  2807     2791  
Event Rates of Major Vascular Events (Stroke/Systemic Embolism, Myocardial Infarction, Death) in the Intended-treatment Period  
[units: Percentage of events per year]
  4.21     6.35  


Statistical Analysis 1 for Event Rates of Major Vascular Events (Stroke/Systemic Embolism, Myocardial Infarction, Death) in the Intended-treatment Period
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.00026
Hazard Ratio (HR) [4] 0.66
95% Confidence Interval ( 0.53 to 0.83 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   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 ]

Measure Type Secondary
Measure Title Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least 1 dose of study drug.

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion

Measured Values
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
Number of Participants Analyzed  
[units: participants]
  2798     2780  
Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period  
[units: Percentage of events per year]
   
Major bleeding     1.41     0.92  
Major or CRNM bleeding     4.46     3.24  
All bleeding     10.85     8.32  


Statistical Analysis 1 for Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0716
Hazard Ratio (HR) [4] 1.54
95% Confidence Interval ( 0.96 to 2.45 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Major bleeding

Statistical Analysis 2 for Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0144
Hazard Ratio (HR) [4] 1.38
95% Confidence Interval ( 1.07 to 1.78 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Major or CNRM bleeding

Statistical Analysis 3 for Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0017
Hazard Ratio (HR) [4] 1.30
95% Confidence Interval ( 1.10 to 1.53 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  All bleeding



5.  Secondary:   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 ]

Measure Type Secondary
Measure Title Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome
Measure Description 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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least 1 dose of study drug.

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once, with dosage based on investigator discretion

Measured Values
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
Number of Participants Analyzed  
[units: participants]
  2798     2780  
Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome  
[units: Participants]
   
AEs     1833     1925  
SAEs     657     804  
Bleeding AEs     281     259  
Discontinuations due to AE     266     362  
Deaths     91     115  

No statistical analysis provided for Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome



6.  Secondary:   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 ]

Measure Type Secondary
Measure Title Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality
Measure Description 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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least 1 dose of study drug. n=number evaluable

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once, with dosage based on investigator discretion.

Measured Values
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
Number of Participants Analyzed  
[units: participants]
  2798     2780  
Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality  
[units: Participants]
   
Hemoglobin, low (n=1956, 1893)     131     120  
Hemoglobin, high (n=1956, 1893)     0     0  
Hematocrit, low (n=1728, 1687)     13     9  
Hematocrit, high (n=1728, 1687)     0     0  
Erythrocytes, low (n=1728, 1687)     12     12  
Erythrocytes, high (n=1728, 1687)     0     0  
Platelet count, low (n=2148, 2098)     7     10  
Platelet count, high (n=2148, 2098)     0     0  
Leukocytes, low (n=1738, 1698)     12     14  
Leukocytes, high (n=1738, 1698)     14     18  
Neutrophils (absolute), low (n=2170, 2138)     2     1  
Neutrophils (absolute), high (n=2170, 2138)     0     0  
Eosinophils (absolute), low (n=2170, 2138)     0     0  
Eosinophils (absolute), high (n=2170, 2138)     48     68  
Basophils (absolute), low (n=2170, 2138)     0     0  
Basophils (absolute), high (n=2170, 2138)     0     0  
Monocytes (absolute), low (n=2170, 2138)     0     0  
Monocytes (absolute), high (n=2170, 2138)     0     2  
Lymphocytes (absolute), low (n=2170, 2138)     52     62  
Lymphocytes (absolute), high (n=2170, 2138)     4     5  
Alkaline phosphatase (ALP), low (n=2781, 2758)     0     0  
ALP, high (n=2781, 2758)     34     27  
Aspartate phosphatase (AST), low (n=2779, 2753)     0     0  
AST, high (n=2779, 2753)     28     33  
Alanine aminotransferase (ALT), low (n=2779, 2753)     0     0  
ALT, high (n=2779, 2753)     23     31  
Bilirubin (total), low (n=2781, 2758)     0     0  
Bilirubin (total), high (n=2781, 2758)     30     43  
Bilirubin (direct), low (n=2773, 2750)     0     0  
Bilirubin (direct), high (n=2773, 2750)     241     248  
Blood urea nitrogen (BUN), low (n=2201, 2172)     0     0  
BUN, high (n=2201, 2172)     42     50  
Creatinine, low (n=2209, 2178)     0     0  
Creatinine, high (n=2209, 2178)     67     71  

No statistical analysis provided for Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality



7.  Secondary:   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 ]

Measure Type Secondary
Measure Title Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)
Measure Description 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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least 1 dose of study drug. n=number evaluable

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once, with dosage based on investigator discretion.

Measured Values
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
Number of Participants Analyzed  
[units: participants]
  2798     2780  
Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)  
[units: Participants]
   
Sodium (serum), low (n=1768, 1740)     2     6  
Sodium (serum), high (n=1768, 1740)     1     2  
Potassium (serum), low (n=1763, 1737)     6     8  
Potassium (serum), high (n=1763, 1737)     20     28  
Chloride (serum), low (n=1768, 1740)     0     3  
Chloride (serum), high (n=1768, 1740)     0     1  
Calcium (total), low (n=106, 109)     0     0  
Calcium (total), high (n=106, 109)     0     0  
Bicarbonate, low (n=1664, 1619)     0     0  
Bicarbonate, high (n=1664, 1619)     0     0  

No statistical analysis provided for Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)



8.  Secondary:   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 ]

Measure Type Secondary
Measure Title Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)
Measure Description ULN=upper limit of normal; LLN=lower limit ofnormal; 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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least 1 dose of study drug. n=number evaluable

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once, with dosage based on investigator discretion.

Measured Values
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
Number of Participants Analyzed  
[units: participants]
  2798     2780  
Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)  
[units: Participants]
   
Creatine kinase, low (n=2780, 2758)     0     0  
Creatine kinase, high (n=2780, 2758)     13     25  
Protein (total), low (n=103, 109)     0     0  
Protein (total), high (n=103, 109)     0     0  
Uric acid, low (n=386, 390)     0     0  
Uric acid, high (n=386, 390)     1     0  
Glucose (urine), low (n=2, 3)     0     0  
Glucose (urine), high (n=2, 3)     0     1  
Protein (urine), low (n=3, 5)     0     0  
Protein (urine), high (n=3, 5)     1     1  
Blood (urine), low (n=3, 5)     0     0  
Blood (urine), high (n=3, 5)     1     0  
Leukocyte esterase (urine), low (n=3,5)     0     0  
Leukocyte esterase (urine), high (n=3,5)     0     0  
Red blood cells (RBC) (urine), low (n=2,2)     0     0  
RBC (urine), high (n=2,2)     1     0  
White blood cells (urine), low (n=2,2)     0     0  
WBC (urine), high (n=2,2)     0     0  

No statistical analysis provided for Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)



9.  Secondary:   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) ]

Measure Type Secondary
Measure Title Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death
Measure Description 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)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least 1 dose of study drug.

Reporting Groups
  Description
Apixaban, 2.5 or 5 mg Twice Daily Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria.
Acetylsalicylic Acid, 81-324 mg Once Daily Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion

Measured Values
    Apixaban, 2.5 or 5 mg Twice Daily     Acetylsalicylic Acid, 81-324 mg Once Daily  
Number of Participants Analyzed  
[units: participants]
  2807     2791  
Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death  
[units: Percentage of events per year]
   
All-cause death (n=111, 140)     3.51     4.42  
Net clinical benefit (n=163, 220)     5.23     7.13  
Vascular death (n=84, 96)     2.65     3.03  


Statistical Analysis 1 for Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.06782
Hazard Ratio (HR) [4] 0.79
95% Confidence Interval ( 0.62 to 1.02 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  All-cause death

Statistical Analysis 2 for Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.00280
Hazard Ratio (HR) [4] 0.73
95% Confidence Interval ( 0.60 to 0.90 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Composite endpoint of major vascular events and major bleeding-net clinical benefit

Statistical Analysis 3 for Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.36586
Hazard Ratio (HR) [4] 0.87
95% Confidence Interval ( 0.65 to 1.17 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Vascular death




  Serious Adverse Events


  Other Adverse Events


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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.  


Results Point of Contact:  
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided by Bristol-Myers Squibb

Publications automatically indexed to this study:


Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00496769     History of Changes
Other Study ID Numbers: CV185-048
Study First Received: July 2, 2007
Results First Received: August 1, 2013
Last Updated: October 22, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Brazil: National Health Surveillance Agency
Chile: Instituto de Salud Publica de Chile
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Mexico: Federal Commission for Sanitary Risks Protection
Austria: Agency for Health and Food Safety
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Denmark: Danish Medicines Agency
Finland: Finnish Medicines Agency
France: Ministry of Health
Germany: Ministry of Health
Greece: National Organization of Medicines
Israel: Ministry of Health
Italy: Ministry of Health
Norway: Ministry of Health and Social Affairs
Spain: Spanish Agency of Medicines
South Africa: Department of Health
Sweden: The National Board of Health and Welfare
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Czech Republic: Ministry of Health
Poland: Ministry of Health
Russia: Ministry of Health of the Russian Federation
Ukraine: Ministry of Health
Australia: Department of Health and Ageing Therapeutic Goods Administration
China: National Institute for the Control of Pharmaceutical and Biological Products
Hong Kong: Department of Health
India: Central Drugs Standard Control Organization
Indonesia: Ministry of Health
Korea: Food and Drug Administration
Malaysia: National Pharmaceutical Control Bureau
Philippines: Department of Health
Singapore: Ministry of Health
Taiwan: Department of Health