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
  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
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
  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.
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
  Hide 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). ]

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  
Number of 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). ]

Measure Type Primary
Measure Title Rate of Adjudicated Stroke or Systemic Embolism (SE) During the Intended Treatment Period
Measure Description Rate=Number of adjudicated stroke or SE events per 100 patient years. 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 "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. 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  
Number of Participants Analyzed  
[units: participants]
  9120     9081  
Rate of Adjudicated Stroke or Systemic Embolism (SE) During the Intended Treatment Period  
[units: Number of events per 100 patient years]
  1.27     1.60  


Statistical Analysis 1 for Rate of Adjudicated Stroke or Systemic Embolism (SE) During the Intended Treatment Period
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Cox Proportional Hazards Model
P Value [4] 0.0114
Hazard Ratio (HR) [5] 0.79
99% Confidence Interval ( 0.62 to 1.00 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  With 448 subjects with confirmed strokes or systemic emboli, study would have at least 90% power to meet both regulatory definitions of non-inferiority described in the following: (1) the non-inferiority (NI) of apixaban relative to warfarin was demonstrated if the upper bound of the two-sided 95% confidence interval (CI) for relative risk (RR) was less than 1.38; (2) the NI of apixaban relative to warfarin was demonstrated if the upper bound of the two-sided 99% CI for RR was less than 1.44.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Number of events required to achieve 90% power and meet criteria (1) is lower than number of events required to achieve 90% power and meet criteria (2). Study was sized to meet the more stringent criterion. With an average 2.1 years follow-up and assuming a stroke rate of 1.20 per hundred patient-years, ~18,000 randomized subjects allocated in a 1:1 ratio to apixaban or warfarin group would be needed to achieve the desired power. These calculations assumed an incidence of 1% loss to follow-up.
[3] Other relevant method information, such as adjustments or degrees of freedom:
 

Model included treatment group as a covariate; stratified by investigative site and prior warfarin/vitamin K antagonist status.

(experienced, naïve).

[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  2-sided P-value for superiority test
[5] Other relevant estimation information:
  apixaban / warfarin



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. ]

Measure Type Primary
Measure Title Number of Participants With Event of Major (International Society on Thrombosis and Hemostasis [ISTH]) Bleeding During Treatment Period
Measure Description ISTH Bleeding Criteria: Major bleeding=a bleeding event that was: clinically overt bleeding accompanied by a decrease in hemoglobin (Hgb) of 2 g/dL or more over a 24-hour period and/or a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least 1 of the following critical sites: intracranial, intraspinal, intraocular (within the corpus of the eye; a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, and retroperitoneal; bleeding that was fatal.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

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]
  9088     9052  
Number of Participants With Event of Major (International Society on Thrombosis and Hemostasis [ISTH]) Bleeding During Treatment Period  
[units: participants]
  327     462  

No statistical analysis provided for Number of Participants With Event of Major (International Society on Thrombosis and Hemostasis [ISTH]) Bleeding During Treatment Period



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. ]

Measure Type Primary
Measure Title Rate of Adjudicated Major (ISTH) Bleed Events During Treatment Period
Measure Description Rate=number of adjudicated major (ISTH) bleed events per 100 patient years. ISTH Bleeding Criteria: Major bleeding=a bleeding event that was: clinically overt bleeding accompanied by a decrease in hemoglobin (Hgb) of 2 g/dL or more and/or a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least 1 of the following sites: intracranial, intraspinal, intraocular (within the corpus of the eye; a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, and retroperitoneal; bleeding that was fatal.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

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]
  9088     9052  
Rate of Adjudicated Major (ISTH) Bleed Events During Treatment Period  
[units: Number of events  per 100 patient years]
  2.13     3.09  


Statistical Analysis 1 for Rate of Adjudicated Major (ISTH) Bleed Events During Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.69
95% Confidence Interval ( 0.60 to 0.80 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  4 key objectives were tested employing a closed, hierarchical testing procedure to conserve overall Type 1 error that was prespecified prior to the interim analysis. The significance level was adjusted for the formal interim test for superiority (the adjustment was small and did not impact the results). Overall type I error was preserved at ≤5%. (1) NI for the primary efficacy endpoint was assessed first (at NI margin=1.38 and one-sided α= 0.025; and at NI margin=1.44 and one-sided α= 0.005).
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Model included treatment group as a covariate; stratified by investigative site and prior warfarin/vitamin K antagonist status.
[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:
  apixaban / warfarin



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). ]

Measure Type Secondary
Measure Title Number of Participants With Events of All-Cause Death During the Intended Treatment Period
Measure Description Death was defined as all-cause mortality. All unobserved deaths were assumed to be cardiovascular in nature unless a non-cardiovascular cause could be clearly provided. Cardiovascular=deaths due to ischemic and hemorrhagic stroke, SE, myocardial infarction (MI), sudden death, heart failure, other cardiovascular, and unobserved deaths. Non-cardiovascular=all deaths due to a clearly documented non-cardiovascular cause (further classified into the categories: bleeding, study drug toxicity other than bleeding, malignancy, infection, trauma, and pulmonary causes of death).
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. 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  
Number of Participants Analyzed  
[units: participants]
  9120     9081  
Number of Participants With Events of All-Cause Death During the Intended Treatment Period  
[units: participants]
  603     669  

No statistical analysis provided for Number of Participants With Events of All-Cause Death During the Intended Treatment Period



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). ]

Measure Type Secondary
Measure Title Rate of Adjudicated All-Cause Death During the Intended Treatment Period
Measure Description All unobserved deaths were assumed to be cardiovascular in nature unless a non-cardiovascular cause could be clearly provided. Cardiovascular=deaths due to ischemic and hemorrhagic stroke, SE, MI, sudden death, heart failure, other cardiovascular, and unobserved deaths. Non-cardiovascular=all deaths due to a clearly documented non-cardiovascular cause (further classified into the categories: bleeding, study drug toxicity other than bleeding, malignancy, infection, trauma, and pulmonary causes of death).
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. 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  
Number of Participants Analyzed  
[units: participants]
  9120     9081  
Rate of Adjudicated All-Cause Death During the Intended Treatment Period  
[units: Number of events  per 100 patient years]
  3.52     3.94  


Statistical Analysis 1 for Rate of Adjudicated All-Cause Death During the Intended Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0465
Hazard Ratio (HR) [4] 0.89
95% Confidence Interval ( 0.80 to 1.00 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The 4 key objectives of the study were tested following a hierarchical testing strategy at a significance level adjusted for the formal interim test for superiority (the adjustment was small and did not impact the results). Overall type I error was preserved at ≤5%. (1) NI for the primary efficacy endpoint was assessed first (at NI margin=1.38 and one-sided α= 0.025; and at NI margin=1.44 and one-sided α= 0.005).
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Model included treatment group as a covariate; stratified by investigative site and prior warfarin/vitamin K antagonist status.
[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:
  apixaban / warfarin



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). ]

Measure Type Secondary
Measure Title Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), and Myocardial Infarction (MI) (as Individual Endpoints) During the Intended Treatment Period
Measure Description Diagnosis for an acute or evolving MI=elevation of creatine kinase-MB isoenzyme (CK-MB) or Troponin T or I ≥ 2 × the upper limit of normal (ULN), or if no CK-MB or troponin values are available, a total CK ≥ 2×ULN, or new, significant (≥0.04 s) Q waves in ≥2 contiguous leads. For descriptions of Stroke and SE, see Outcome Measure 1.
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. 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, or the efficacy cut-off date (30-Jan-2011). n=number of participants experiencing stated event.

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]
  9120     9081  
Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), and Myocardial Infarction (MI) (as Individual Endpoints) During the Intended Treatment Period  
[units: Number of events per 100 patient years]
   
Ischemic or Unspecified Stroke (n=162, 175)     0.97     1.05  
Hemorrhagic Stroke (n=40, 78)     0.24     0.47  
Systemic Embolism (n=15, 17)     0.09     0.10  
Myocardial Infarction (n=90, 102)     0.53     0.61  


Statistical Analysis 1 for Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), and Myocardial Infarction (MI) (as Individual Endpoints) During the Intended Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.4220
Hazard Ratio (HR) [4] 0.92
95% Confidence Interval ( 0.74 to 1.13 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Ischemic or Unspecified Stroke
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 2 for Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), and Myocardial Infarction (MI) (as Individual Endpoints) During the Intended Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0006
Hazard Ratio (HR) [4] 0.51
95% Confidence Interval ( 0.35 to 0.75 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Hemorrhagic Stroke
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 3 for Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), and Myocardial Infarction (MI) (as Individual Endpoints) During the Intended Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.7020
Hazard Ratio (HR) [4] 0.87
95% Confidence Interval ( 0.44 to 1.75 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Systemic Embolism
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 4 for Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), and Myocardial Infarction (MI) (as Individual Endpoints) During the Intended Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.3720
Hazard Ratio (HR) [4] 0.88
95% Confidence Interval ( 0.66 to 1.17 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Myocardial Infarction
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin



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). ]

Measure Type Secondary
Measure Title 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
Measure Description Diagnosis for an acute or evolving MI=elevation of CK-MB or Troponin T or I ≥ 2 × the ULN, or if no CK-MB or troponin values are available, a total CK ≥ 2×ULN, or new, significant (≥0.04 s) Q waves in ≥2 contiguous leads. For descriptions of Stroke and SE, see Outcome Measure 1. For description of ACD, see Outcome Measure 5.
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. Participants who didn't 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, or the efficacy cut-off date (30-Jan-2011). n= number of participants experiencing stated combination of events.

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]
  9120     9081  
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  
[units: Number of events per 100 patient years]
   
Stroke / SE / Major Bleeding (n=521, 666)     3.17     4.11  
Stroke / SE / All-Cause Death (ACD) (n=752, 837)     4.49     5.04  
Stroke / SE / Major Bleeding / ACD (n=1009, 1168)     6.13     7.20  
Stroke / SE / MI / ACD (n=810, 906)     4.85     5.49  
Ischemic or Unspecified Stroke / ACD (n=725, 796)     4.32     4.78  
Hemorrhagic Stroke / ACD (n=622, 703)     3.68     4.20  
SE / ACD (n=613, 679)     3.63     4.05  
MI / ACD (n=663, 740)     3.93     4.43  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.77
95% Confidence Interval ( 0.69 to 0.86 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Composite of Stroke / Systemic Embolism / Major Bleeding
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 2 for 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
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0192
Hazard Ratio (HR) [4] 0.89
95% Confidence Interval ( 0.81 to 0.98 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Composite of Stroke / Systemic Embolism / All-Cause Death
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 3 for 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
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0002
Hazard Ratio (HR) [4] 0.85
95% Confidence Interval ( 0.78 to 0.92 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Composite of Stroke / Systemic Embolism / Major Bleeding / All-Cause Death
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 4 for 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
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0107
Hazard Ratio (HR) [4] 0.88
95% Confidence Interval ( 0.80 to 0.97 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Composite of Stroke / Systemic Embolism / MI / All-Cause Death
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 5 for 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
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0432
Hazard Ratio (HR) [4] 0.90
95% Confidence Interval ( 0.82 to 1.00 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Composite of Ischemic or Unspecified Stroke / All-Cause Death
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 6 for 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
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0167
Hazard Ratio (HR) [4] 0.88
95% Confidence Interval ( 0.79 to 0.98 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Composite of Hemorrhagic Stroke / All-Cause Death
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 7 for 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
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0464
Hazard Ratio (HR) [4] 0.89
95% Confidence Interval ( 0.80 to 1.00 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Composite of Systemic Embolism / All-Cause Death
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 8 for 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
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0253
Hazard Ratio (HR) [4] 0.89
95% Confidence Interval ( 0.80 to 0.99 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Composite of Myocardial Infarction / All-Cause Death
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin



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). ]

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). ]

Measure Type Secondary
Measure Title Rate of Composite Stroke / Systemic Embolism / Major Bleeding in Warfarin/Vitamin K Antagonist (VKA) Naive Participants During the Intended Treatment Period
Measure Description No text entered.
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. Participants who did not experience an efficacy endpoint event were censored at the earlier of their death date, last contact date, 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  
Number of Participants Analyzed  
[units: participants]
  3912     3888  
Rate of Composite Stroke / Systemic Embolism / Major Bleeding in Warfarin/Vitamin K Antagonist (VKA) Naive Participants During the Intended Treatment Period  
[units: Number of events  per 100 patient years]
  3.21     4.06  


Statistical Analysis 1 for Rate of Composite Stroke / Systemic Embolism / Major Bleeding in Warfarin/Vitamin K Antagonist (VKA) Naive Participants During the Intended Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazards Model
P Value [3] 0.0098
Hazard Ratio (HR) [4] 0.80
95% Confidence Interval ( 0.67 to 0.95 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Composite Stroke/Systemic Embolism/Major Bleeding in Warfarin/Vitamin K Antagonist (VKA) Naive Participants
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin



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. ]

Measure Type Secondary
Measure Title Number of Participants With Events of Major or Clinically Relevant Nonmajor (CRNM) Bleed During Treatment Period
Measure Description Major bleeding=bleeding that is clinically overt and that either resulted in a decrease in hemoglobin of 2 g/dL or more over a 24-hour period, led to a transfusion of 2 or more units of packed red blood cells, occurred in a critical site, or led to death. CRNM bleeding=bleeding that is clinically overt, that satisfies none of the additional criteria required for the event to be adjudicated as a major bleeding event, that led to either hospital admission for bleeding, physician-guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

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]
  9088     9052  
Number of Participants With Events of Major or Clinically Relevant Nonmajor (CRNM) Bleed During Treatment Period  
[units: participants]
  613     877  

No statistical analysis provided for Number of Participants With Events of Major or Clinically Relevant Nonmajor (CRNM) Bleed During Treatment Period



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. ]

Measure Type Secondary
Measure Title Rate of Events of Major or Clinically Relevant Non-Major (CRNM) Bleed During Treatment Period
Measure Description Rate=number of major or CRNM bleed events per 100 patient years. Major=clinically overt and either 1) resulted in a decrease in hemoglobin of 2 g/dL or more over a 24-hour period, or 2) led to a transfusion of 2 or more units of packed red blood cells, or 3) occurred in a critical site, or 4) led to death. CRNM bleeding=clinically overt, but satisfied no additional criteria required to be adjudicated as a major bleeding event, and led to either 1) hospital admission for bleeding or 2) physician guided medical or surgical treatment for bleeding or 3) a change in antithrombotic therapy.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

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]
  9088     9052  
Rate of Events of Major or Clinically Relevant Non-Major (CRNM) Bleed During Treatment Period  
[units: number of events / 100 patient years]
  4.07     6.01  


Statistical Analysis 1 for Rate of Events of Major or Clinically Relevant Non-Major (CRNM) Bleed During Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazard Model
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.68
95% Confidence Interval ( 0.61 to 0.75 )
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin



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. ]

Measure Type Secondary
Measure Title Number of Participants With All Bleeding Events During Treatment Period
Measure Description All bleeding events include major bleeding, CRNM bleeding (see Outcome Measure 12 Description for definitions), plus events of minor bleeding and fatal bleeding. Minor bleeding: All acute clinically overt bleeding events not meeting the criteria for either major bleeding or clinically relevant non-major bleeding will be classified as minor bleeding. Fatal bleeding is defined as a bleeding event that the Clinical Events Committee determines is the primary cause of death or contributes directly to death.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

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]
  9088     9052  
Number of Participants With All Bleeding Events During Treatment Period  
[units: participants]
  2356     3060  

No statistical analysis provided for Number of Participants With All Bleeding Events During Treatment Period



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. ]

Measure Type Secondary
Measure Title Rate of All Bleeding Events During Treatment Period
Measure Description Rate=number of all bleeding events per 100 patient years. "All bleeding events" include major bleeding, CRNM bleeding (see Outcome Measure 12 Description for definitions), plus events of minor bleeding and fatal bleeding. Minor bleeding: All acute clinically overt bleeding events not meeting the criteria for either major bleeding or clinically relevant non-major bleeding will be classified as minor bleeding. Fatal bleeding is defined as a bleeding event that the Clinical Events Committee determines is the primary cause of death or contributes directly to death.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

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]
  9088     9052  
Rate of All Bleeding Events During Treatment Period  
[units: number of events per 100 patient years]
  18.08     25.82  


Statistical Analysis 1 for Rate of All Bleeding Events During Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazard Model
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.71
95% Confidence Interval ( 0.68 to 0.75 )
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin



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. ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Adverse Events (AEs), Bleeding AEs, Serious Adverse Events (SAEs), Discontinuations Due to AEs, or Deaths During the Treatment Period
Measure Description AE: all SAEs or AEs with onset from first dose through 2 days (AEs) or 30 days (SAEs) after the last dose of blinded study drug (BSD). SAE: all SAEs with onset from first dose through 30 days after the last dose of BSD. Bleeding AE: all serious or non-serious bleeding-related AEs with onset from first dose through 2 days after the last dose of BSD. Discontinuations due to AE: all SAEs or AEs with onset from first dose of BSD and with action taken=drug discontinued. Deaths: all deaths occurring from first dose through 30 days after the last dose of BSD.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

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]
  9088     9052  
Number of Participants With Adverse Events (AEs), Bleeding AEs, Serious Adverse Events (SAEs), Discontinuations Due to AEs, or Deaths During the Treatment Period  
[units: participants]
   
AE     7406     7521  
SAE     3182     3302  
Bleeding AE     2288     2961  
Discontinuations due to AE     688     758  
Deaths     429     468  

No statistical analysis provided for Number of Participants With Adverse Events (AEs), Bleeding AEs, Serious Adverse Events (SAEs), Discontinuations Due to AEs, or Deaths During the Treatment Period



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. ]

Measure Type Other Pre-specified
Measure Title Rate of Adjudicated Bleeding Endpoints Per Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) During the Treatment Period
Measure Description Rate=number of adjudicated GUSTO bleeding events per 100 patient years. GUSTO Bleeding Criteria: GUSTO severe (or life-threatening) bleeding: either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention. GUSTO moderate bleeding: bleeding that requires blood transfusion but does not result in hemodynamic compromise.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study. n=number of participants experiencing events.

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]
  9088     9052  
Rate of Adjudicated Bleeding Endpoints Per Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) During the Treatment Period  
[units: Number of events  per 100 patient years]
   
Severe (n=80, 172))     0.52     1.13  
Severe or Moderate (n=199, 328)     1.29     2.18  


Statistical Analysis 1 for Rate of Adjudicated Bleeding Endpoints Per Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) During the Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazard Model
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.46
95% Confidence Interval ( 0.35 to 0.60 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Severe GUSTO bleeding events
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 2 for Rate of Adjudicated Bleeding Endpoints Per Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) During the Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazard Model
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.60
95% Confidence Interval ( 0.50 to 0.71 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Severe or Moderate GUSTO bleeding events
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin



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. ]

Measure Type Other Pre-specified
Measure Title Rate of Adjudicated Bleeding Endpoints Per Thrombolysis in Myocardial Infarction (TIMI) During the Treatment Period
Measure Description Rate=number of adjudicated TIMI bleeding events per 100 patient years. TIMI Bleeding Criteria: Major bleeding=Intracranial bleeding and/or clinically overt bleeding associated with ≥5 gm/dL fall in Hgb or 15% fall in hematocrit (Hct) from baseline, accounting for transfusions. Minor bleeding=Clinically overt bleeding associated with ≥3 gm/dL fall in Hgb or a ≥10% fall in Hct from baseline, accounting for transfusions.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study. n=number of participants experiencing events.

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]
  9088     9052  
Rate of Adjudicated Bleeding Endpoints Per Thrombolysis in Myocardial Infarction (TIMI) During the Treatment Period  
[units: Number of events  per 100 patient years]
   
Major (n=148, 256)     0.96     1.69  
Major or Minor (n=239, 370)     1.55     2.46  


Statistical Analysis 1 for Rate of Adjudicated Bleeding Endpoints Per Thrombolysis in Myocardial Infarction (TIMI) During the Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazard Model
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.57
95% Confidence Interval ( 0.46 to 0.70 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Major TIMI bleeding event
[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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin

Statistical Analysis 2 for Rate of Adjudicated Bleeding Endpoints Per Thrombolysis in Myocardial Infarction (TIMI) During the Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazard Model
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.63
95% Confidence Interval ( 0.54 to 0.75 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Major or Minor TIMI bleeding criteria
[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:
  apixaban / warfarin



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. ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Net-Clinical Benefit During Treatment Period
Measure Description Net-Clinical Benefit = Composite of stroke, systemic embolism and ISTH major bleeding.
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

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]
  9088     9052  
Number of Participants With Net-Clinical Benefit During Treatment Period  
[units: participants]
  459     608  

No statistical analysis provided for Number of Participants With Net-Clinical Benefit During Treatment Period



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. ]

Measure Type Other Pre-specified
Measure Title Rate of Net-Clinical Benefit During Treatment Period
Measure Description Rate=number of events of net-clinical benefit per 100 patient years. Net-Clinical Benefit = Composite of stroke, systemic embolism and ISTH major bleeding
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.  
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.
Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

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]
  9088     9052  
Rate of Net-Clinical Benefit During Treatment Period  
[units: Number of events per 100 patient years]
  3.01     4.09  


Statistical Analysis 1 for Rate of Net-Clinical Benefit During Treatment Period
Groups [1] All groups
Method [2] Cox Proportional Hazard Model
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.74
95% Confidence Interval ( 0.65 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:
  nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
[4] Other relevant estimation information:
  apixaban / warfarin




  Serious Adverse Events


  Other Adverse Events
  Hide Other Adverse Events

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
  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
No text entered.


  More Information