Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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: March 1, 2016
Last verified: March 2016
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
  Hide Participant Flow

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
  Hide Baseline Characteristics

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 
Overall Participants Analyzed 
[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
  Show All Outcome Measures

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) ]

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) ]

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) ]
  Hide Outcome Measure 3

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 
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 ]

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 ]

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 ]

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 ]

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 ]

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) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide 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.


  More Information