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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  
Number of Participants  
[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  
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
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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.  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  
Number of 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
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Time Frame No text entered.
Additional Description Treated population (includes all patients who received at least 1 dose of study drug.)

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Warfarin No text entered.
Apixaban No text entered.

Other Adverse Events
    Warfarin     Apixaban  
Total, other (not including serious) adverse events      
# participants affected / at risk     3876/9088     4071/9052  
Gastrointestinal disorders      
Diarrhoea † 1    
# participants affected / at risk     580/9088 (6.38%)     581/9052 (6.42%)  
General disorders      
Oedema peripheral † 1    
# participants affected / at risk     607/9088 (6.68%)     661/9052 (7.30%)  
Infections and infestations      
Urinary tract infection † 1    
# participants affected / at risk     471/9088 (5.18%)     501/9052 (5.53%)  
Nasopharyngitis † 1    
# participants affected / at risk     763/9088 (8.40%)     779/9052 (8.61%)  
Bronchitis † 1    
# participants affected / at risk     473/9088 (5.20%)     493/9052 (5.45%)  
Injury, poisoning and procedural complications      
Contusion † 1    
# participants affected / at risk     299/9088 (3.29%)     479/9052 (5.29%)  
Musculoskeletal and connective tissue disorders      
Back pain † 1    
# participants affected / at risk     428/9088 (4.71%)     502/9052 (5.55%)  
Arthralgia † 1    
# participants affected / at risk     444/9088 (4.89%)     462/9052 (5.10%)  
Nervous system disorders      
Headache † 1    
# participants affected / at risk     480/9088 (5.28%)     485/9052 (5.36%)  
Dizziness † 1    
# participants affected / at risk     654/9088 (7.20%)     702/9052 (7.76%)  
Respiratory, thoracic and mediastinal disorders      
Cough † 1    
# participants affected / at risk     493/9088 (5.42%)     505/9052 (5.58%)  
Dyspnoea † 1    
# participants affected / at risk     583/9088 (6.42%)     633/9052 (6.99%)  
Epistaxis † 1    
# participants affected / at risk     547/9088 (6.02%)     666/9052 (7.36%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 14.0



  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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