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Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00412984
First received: December 18, 2006
Last updated: September 27, 2013
Last verified: September 2013
Results First Received: January 25, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Prevention
Conditions: Atrial Fibrillation
Atrial Flutter
Interventions: Drug: warfarin
Drug: apixaban

  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
20998 participants were enrolled, and 18201 were randomized.

Reporting Groups
  Description
Apixaban Participants received apixaban and warfarin-placebo following randomization during a titration phase using a dosing algorithm for warfarin- placebo; apixaban was dosed at 5 mg twice daily (BID) [or 2.5 mg BID in select subjects]. Subsequent warfarin placebo doses were recommended based upon an algorithm using an encrypted, shammed International Normalized Ratio (INR) procedure to preserve the double blind; however, the final dosing decision rested with the investigator.
Warfarin Participants received apixaban-placebo and warfarin following randomization during a titration phase using a dosing algorithm for warfarin; apixaban-placebo was dosed at 5 mg twice daily (BID) [or 2.5 mg BID in select subjects]. Subsequent warfarin doses were recommended based upon an algorithm and encrypted INR testing to preserve the double blind; however, the final dosing decision rested with the investigator.

Participant Flow:   Overall Study
    Apixaban   Warfarin
STARTED   9120 [1]   9081 [1] 
COMPLETED   6810   6588 
NOT COMPLETED   2310   2493 
Death                331                349 
Adverse Event                679                738 
Withdrawal by Subject                921                989 
Lost to Follow-up                51                39 
Poor/Noncompliance                57                77 
Pregnancy                1                0 
Subject No Longer Meets Study Criteria                87                100 
Administrative Reason by Sponsor                11                8 
Physician Refused to Continue Treatment                81                89 
Other Reason                80                92 
Not Reported                11                12 
[1] Randomized participants



  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.
Randomized participants

Reporting Groups
  Description
Apixaban Participants received apixaban and warfarin-placebo following randomization during a titration phase using a dosing algorithm for warfarin- placebo; apixaban was dosed at 5 mg twice daily (BID) [or 2.5 mg BID in select subjects]. Subsequent warfarin placebo doses were recommended based upon an algorithm using an encrypted, shammed International Normalized Ratio (INR) procedure to preserve the double blind; however, the final dosing decision rested with the investigator.
Warfarin Participants received apixaban-placebo and warfarin following randomization during a titration phase using a dosing algorithm for warfarin; apixaban-placebo was dosed at 5 mg twice daily (BID) [or 2.5 mg BID in select subjects]. Subsequent warfarin doses were recommended based upon an algorithm and encrypted INR testing to preserve the double blind; however, the final dosing decision rested with the investigator.
Total Total of all reporting groups

Baseline Measures
   Apixaban   Warfarin   Total 
Overall Participants Analyzed 
[Units: Participants]
 9120   9081   18201 
Age 
[Units: Years]
Mean (Standard Deviation)
 69.1  (9.61)   69.0  (9.74)   69.1  (9.68) 
Age, Customized 
[Units: Participants]
     
<65 years   2731   2740   5471 
Between 65 and 75 years   3539   3513   7052 
>=75 years   2850   2828   5678 
Gender 
[Units: Participants]
     
Female   3234   3182   6416 
Male   5886   5899   11785 
Race/Ethnicity, Customized 
[Units: Participants]
     
White (European)   5440   5366   10806 
White (Middle Eastern or North African)   59   66   125 
White (Other White)   2037   2060   4097 
White (Not Reported)   0   1   1 
Black / African American   125   102   227 
Asian (Asian Indian)   307   312   619 
Asian (Chinese)   536   536   1072 
Asian (Japanese)   164   180   344 
Asian (Other Asian)   303   304   607 
American Indian / Alaska Native   26   24   50 
Native Hawaiian / Other Pacific Islander   2   2   4 
Other   121   127   248 
Not Reported   0   1   1 
Race/Ethnicity, Customized 
[Units: Participants]
     
Hispanic / Latino   1808   1803   3611 
Not Hispanic / Latino   7312   7276   14588 
Not Reported   0   2   2 
Female Age Category 
[Units: Participants]
     
<=50 years   81   88   169 
>50 years   3153   3094   6247 
not applicable (male)   5886   5899   11785 
Apixaban/Matching Placebo Dose at Randomization 
[Units: Participants]
     
2.5 mg twice daily (BID)   428   403   831 
5.0 mg BID   8692   8678   17370 
Risk Factor at Enrollment: Age >= 75 Years 
[Units: Participants]
     
>=75 years   2850   2828   5678 
<75 years   6270   6253   12523 
Risk Factor at Enrollment: Prior Stroke 
[Units: Participants]
     
With prior stroke   1045   1082   2127 
Prior stroke not a risk factor   8075   7999   16074 
Risk Factor at Enrollment: Prior Transient Ischemic Attack (TIA) 
[Units: Participants]
     
With prior TIA   603   654   1257 
Prior TIA not a risk factor   8517   8427   16944 
Risk Factor At Enrollment: Symptomatic Chronic Heart Failure (CHF) 
[Units: Participants]
     
With symptomatic CHF   2784   2757   5541 
Symptomatic CHF not a risk factor   6336   6324   12660 
Risk Factor at Enrollment: Left Ventricle Ejection Fraction (LVEF) <=40% 
[Units: Participants]
     
With LVEF <=40%   1324   1301   2625 
LVEF <=40% not a risk factor   7796   7780   15576 
Number of Risk Factors 
[Units: Participants]
     
<= 1   3025   3000   6025 
>= 2   6095   6081   12176 
CHADS-2 Score at Enrollment [1] 
[Units: Participants]
     
Score of <= 1   3100   3083   6183 
Score of 2   3262   3254   6516 
Score of >= 3   2758   2744   5502 
[1] The CHADS2 score is a clinical prediction rule for estimating the risk of stroke in patients with nonrheumatic atrial fibrillation (AF). A high CHADS2 score corresponds to a greater risk of stroke, while a low CHADS2 score corresponds to a lower risk of stroke (range 0 to 6). The CHADS2 score is determined by adding together the points that correspond to the 5 conditions that are present: 1 point each for congestive heart failure, hypertension, age ≥75 years, or diabetes mellitus; 2 points for prior stroke or transient ischemic attack (TIA).
Mean CHADS-2 Score at Enrollment [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 2.1  (1.10)   2.1  (1.11)   2.1  (2.10) 
[1] The CHADS2 score is a clinical prediction rule for estimating the risk of stroke in patients with nonrheumatic atrial fibrillation (AF). A high CHADS2 score corresponds to a greater risk of stroke, while a low CHADS2 score corresponds to a lower risk of stroke (range 0 to 6). The CHADS2 score is determined by adding together the points that correspond to the 5 conditions that are present: 1 point each for Congestive Heart Failure, Hypertension, Age ≥75 years, or Diabetes Mellitus; 2 points for prior stroke or transient ischemic attack (TIA).


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Participants With First Event of Ischemic/Unspecified Stroke, Hemorrhagic Stroke, or Systemic Embolism (SE) During the Intended Treatment Period   [ Time Frame: Time to first event in "Intended Treatment Period": started on day of randomization, ended at efficacy cut-off date (date target number of primary efficacy events [448] was expected to have occurred; set to 30-Jan-2011, prior to unblinding). ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title Number of Participants With First Event of Ischemic/Unspecified Stroke, Hemorrhagic Stroke, or Systemic Embolism (SE) During the Intended Treatment Period
Measure Description All suspected efficacy events were adjudicated by the Central Events Committee (CEC). Diagnosis of stroke=the nontraumatic focal neurological deficit lasting at least 24 hours, and includes ischemic stroke, hemorrhagic stroke, ischemic stroke with hemorrhagic conversion, stroke of uncertain type, and retinal ischemic event (embolism, infarction). Diagnosis of SE=clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries), supported by evidence of embolism from surgical specimens, autopsy, angiography, vascular imaging, or other objective testing.
Time Frame Time to first event in "Intended Treatment Period": started on day of randomization, ended at efficacy cut-off date (date target number of primary efficacy events [448] was expected to have occurred; set to 30-Jan-2011, prior to unblinding).  
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.
Intention to treat analysis, randomized participants. Participants who did not experience an efficacy endpoint event were censored at the earlier of their death date (when death is not part of the endpoint), last contact date (for subjects who withdrew consent to be followed up or were lost to follow-up) or the efficacy cut-off date (30-Jan-2011).

Reporting Groups
  Description
Apixaban Participants received apixaban and warfarin-placebo following randomization during a titration phase using a dosing algorithm for warfarin- placebo; apixaban was dosed at 5 mg twice daily (BID) [or 2.5 mg BID in select subjects]. Subsequent warfarin placebo doses were recommended based upon an algorithm using an encrypted, shammed International Normalized Ratio (INR) procedure to preserve the double blind; however, the final dosing decision rested with the investigator.
Warfarin Participants received apixaban-placebo and warfarin following randomization during a titration phase using a dosing algorithm for warfarin; apixaban-placebo was dosed at 5 mg twice daily (BID) [or 2.5 mg BID in select subjects]. Subsequent warfarin doses were recommended based upon an algorithm and encrypted INR testing to preserve the double blind; however, the final dosing decision rested with the investigator.

Measured Values
   Apixaban   Warfarin 
Participants Analyzed 
[Units: Participants]
 9120   9081 
Number of Participants With First Event of Ischemic/Unspecified Stroke, Hemorrhagic Stroke, or Systemic Embolism (SE) During the Intended Treatment Period 
[Units: Participants]
   
Ischemic or Unspecified Stroke   159   173 
Hemorrhagic Stroke   38   76 
Systemic Embolism   15   16 

No statistical analysis provided for Number of Participants With First Event of Ischemic/Unspecified Stroke, Hemorrhagic Stroke, or Systemic Embolism (SE) During the Intended Treatment Period



2.  Primary:   Rate of Adjudicated Stroke or Systemic Embolism (SE) During the Intended Treatment Period   [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]

3.  Primary:   Number of Participants With Event of Major (International Society on Thrombosis and Hemostasis [ISTH]) Bleeding During Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

4.  Primary:   Rate of Adjudicated Major (ISTH) Bleed Events During Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

5.  Secondary:   Number of Participants With Events of All-Cause Death During the Intended Treatment Period   [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]

6.  Secondary:   Rate of Adjudicated All-Cause Death During the Intended Treatment Period   [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]

7.  Secondary:   Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), and Myocardial Infarction (MI) (as Individual Endpoints) During the Intended Treatment Period   [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]

8.  Secondary:   Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), Myocardial Infarction (MI) and All-Cause Death (ACD) (as Composite Endpoints) During the Intended Treatment Period   [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]

9.  Secondary:   Number of Warfarin/Vitamin K Antagonist (VKA) Naive Participants With Composite Stroke / Systemic Embolism (SE) / Major Bleeding During the Intended Treatment Period   [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]
  Hide Outcome Measure 9

Measure Type Secondary
Measure Title Number of Warfarin/Vitamin K Antagonist (VKA) Naive Participants With Composite Stroke / Systemic Embolism (SE) / Major Bleeding During the Intended Treatment Period
Measure Description For descriptions of Stroke and SE, see Outcome Measure 1. For description of Major bleeding, see Outcome Measure 3.
Time Frame "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding).  
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.
Intention to treat analysis, randomized participants who were Warfarin/Vitamin K Antagonist (VKA) naïve (a stratification variable, defined as receiving ≤30 consecutive days of prior warfarin/VKA treatment). Participants not experiencing efficacy endpoint event were censored at earlier of death, last contact, or efficacy cut-off date (30-Jan-2011).

Reporting Groups
  Description
Apixaban Participants received apixaban and warfarin-placebo following randomization during a titration phase using a dosing algorithm for warfarin- placebo; apixaban was dosed at 5 mg twice daily (BID) [or 2.5 mg BID in select subjects]. Subsequent warfarin placebo doses were recommended based upon an algorithm using an encrypted, shammed International Normalized Ratio (INR) procedure to preserve the double blind; however, the final dosing decision rested with the investigator.
Warfarin Participants received apixaban-placebo and warfarin following randomization during a titration phase using a dosing algorithm for warfarin; apixaban-placebo was dosed at 5 mg twice daily (BID) [or 2.5 mg BID in select subjects]. Subsequent warfarin doses were recommended based upon an algorithm and encrypted INR testing to preserve the double blind; however, the final dosing decision rested with the investigator.

Measured Values
   Apixaban   Warfarin 
Participants Analyzed 
[Units: Participants]
 3912   3888 
Number of Warfarin/Vitamin K Antagonist (VKA) Naive Participants With Composite Stroke / Systemic Embolism (SE) / Major Bleeding During the Intended Treatment Period 
[Units: Participants]
 229   285 

No statistical analysis provided for Number of Warfarin/Vitamin K Antagonist (VKA) Naive Participants With Composite Stroke / Systemic Embolism (SE) / Major Bleeding During the Intended Treatment Period



10.  Secondary:   Rate of Composite Stroke / Systemic Embolism / Major Bleeding in Warfarin/Vitamin K Antagonist (VKA) Naive Participants During the Intended Treatment Period   [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]

11.  Secondary:   Number of Participants With Events of Major or Clinically Relevant Nonmajor (CRNM) Bleed During Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

12.  Secondary:   Rate of Events of Major or Clinically Relevant Non-Major (CRNM) Bleed During Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

13.  Secondary:   Number of Participants With All Bleeding Events During Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

14.  Secondary:   Rate of All Bleeding Events During Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

15.  Other Pre-specified:   Number of Participants With Adverse Events (AEs), Bleeding AEs, Serious Adverse Events (SAEs), Discontinuations Due to AEs, or Deaths During the Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

16.  Other Pre-specified:   Rate of Adjudicated Bleeding Endpoints Per Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) During the Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

17.  Other Pre-specified:   Rate of Adjudicated Bleeding Endpoints Per Thrombolysis in Myocardial Infarction (TIMI) During the Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

18.  Other Pre-specified:   Number of Participants With Net-Clinical Benefit During Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]

19.  Other Pre-specified:   Rate of Net-Clinical Benefit During Treatment Period   [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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
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