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

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ClinicalTrials.gov Identifier: NCT00412984
Recruitment Status : Completed
First Posted : December 19, 2006
Results First Posted : April 29, 2013
Last Update Posted : July 3, 2018
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Prevention
Conditions: Atrial Fibrillation
Atrial Flutter
Interventions: Drug: warfarin
Drug: apixaban

  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
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

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]
Count of Participants
     
<65 years      2731  29.9%      2740  30.2%      5471  30.1% 
Between 65 and 75 years      3539  38.8%      3513  38.7%      7052  38.7% 
>=75 years      2850  31.3%      2828  31.1%      5678  31.2% 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      3234  35.5%      3182  35.0%      6416  35.3% 
Male      5886  64.5%      5899  65.0%      11785  64.7% 
Race/Ethnicity, Customized 
[Units: Participants]
Count of Participants
     
White (European)      5440  59.6%      5366  59.1%      10806  59.4% 
White (Middle Eastern or North African)      59   0.6%      66   0.7%      125   0.7% 
White (Other White)      2037  22.3%      2060  22.7%      4097  22.5% 
White (Not Reported)      0   0.0%      1   0.0%      1   0.0% 
Black / African American      125   1.4%      102   1.1%      227   1.2% 
Asian (Asian Indian)      307   3.4%      312   3.4%      619   3.4% 
Asian (Chinese)      536   5.9%      536   5.9%      1072   5.9% 
Asian (Japanese)      164   1.8%      180   2.0%      344   1.9% 
Asian (Other Asian)      303   3.3%      304   3.3%      607   3.3% 
American Indian / Alaska Native      26   0.3%      24   0.3%      50   0.3% 
Native Hawaiian / Other Pacific Islander      2   0.0%      2   0.0%      4   0.0% 
Other      121   1.3%      127   1.4%      248   1.4% 
Not Reported      0   0.0%      1   0.0%      1   0.0% 
Race/Ethnicity, Customized 
[Units: Participants]
Count of Participants
     
Hispanic / Latino      1808  19.8%      1803  19.9%      3611  19.8% 
Not Hispanic / Latino      7312  80.2%      7276  80.1%      14588  80.1% 
Not Reported      0   0.0%      2   0.0%      2   0.0% 
Female Age Category 
[Units: Participants]
Count of Participants
     
<=50 years      81   0.9%      88   1.0%      169   0.9% 
>50 years      3153  34.6%      3094  34.1%      6247  34.3% 
not applicable (male)      5886  64.5%      5899  65.0%      11785  64.7% 
Apixaban/Matching Placebo Dose at Randomization 
[Units: Participants]
Count of Participants
     
2.5 mg twice daily (BID)      428   4.7%      403   4.4%      831   4.6% 
5.0 mg BID      8692  95.3%      8678  95.6%      17370  95.4% 
Risk Factor at Enrollment: Age >= 75 Years 
[Units: Participants]
Count of Participants
     
>=75 years      2850  31.3%      2828  31.1%      5678  31.2% 
<75 years      6270  68.8%      6253  68.9%      12523  68.8% 
Risk Factor at Enrollment: Prior Stroke 
[Units: Participants]
Count of Participants
     
With prior stroke      1045  11.5%      1082  11.9%      2127  11.7% 
Prior stroke not a risk factor      8075  88.5%      7999  88.1%      16074  88.3% 
Risk Factor at Enrollment: Prior Transient Ischemic Attack (TIA) 
[Units: Participants]
Count of Participants
     
With prior TIA      603   6.6%      654   7.2%      1257   6.9% 
Prior TIA not a risk factor      8517  93.4%      8427  92.8%      16944  93.1% 
Risk Factor At Enrollment: Symptomatic Chronic Heart Failure (CHF) 
[Units: Participants]
Count of Participants
     
With symptomatic CHF      2784  30.5%      2757  30.4%      5541  30.4% 
Symptomatic CHF not a risk factor      6336  69.5%      6324  69.6%      12660  69.6% 
Risk Factor at Enrollment: Left Ventricle Ejection Fraction (LVEF) <=40% 
[Units: Participants]
Count of Participants
     
With LVEF <=40%      1324  14.5%      1301  14.3%      2625  14.4% 
LVEF <=40% not a risk factor      7796  85.5%      7780  85.7%      15576  85.6% 
Number of Risk Factors 
[Units: Participants]
Count of Participants
     
<= 1      3025  33.2%      3000  33.0%      6025  33.1% 
>= 2      6095  66.8%      6081  67.0%      12176  66.9% 
CHADS-2 Score at Enrollment [1] 
[Units: Participants]
Count of Participants
     
Score of <= 1      3100  34.0%      3083  34.0%      6183  34.0% 
Score of 2      3262  35.8%      3254  35.8%      6516  35.8% 
Score of >= 3      2758  30.2%      2744  30.2%      5502  30.2% 
[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

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). ]

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.  Secondary:   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.  Secondary:   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). ]

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

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
No text entered.


  More Information

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.


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


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):


Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00412984     History of Changes
Other Study ID Numbers: CV185-030
First Submitted: December 18, 2006
First Posted: December 19, 2006
Results First Submitted: January 25, 2013
Results First Posted: April 29, 2013
Last Update Posted: July 3, 2018