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

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


  Outcome Measures
  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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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 
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
  Hide Serious Adverse Events

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

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

Serious Adverse Events
    Warfarin   Apixaban
Total, serious adverse events     
# participants affected / at risk   3182/9088 (35.01%)   3302/9052 (36.48%) 
Blood and lymphatic system disorders     
Bicytopenia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Haemorrhagic disorder † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Leukocytosis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Lymphadenitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Disseminated intravascular coagulation † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Hypocoagulable state † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Idiopathic thrombocytopenic purpura † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Lymphadenopathy † 1     
# participants affected / at risk   3/9088 (0.03%)   1/9052 (0.01%) 
Autoimmune thrombocytopenia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Eosinophilia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Microcytic anaemia † 1     
# participants affected / at risk   0/9088 (0.00%)   3/9052 (0.03%) 
Splenic cyst † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Spontaneous haematoma † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Thrombocytopenia † 1     
# participants affected / at risk   5/9088 (0.06%)   7/9052 (0.08%) 
Anaemia of chronic disease † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Leukopenia † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Thrombocytopenic purpura † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Anaemia † 1     
# participants affected / at risk   48/9088 (0.53%)   43/9052 (0.48%) 
Anaemia of malignant disease † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Anaemia vitamin B12 deficiency † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Bone marrow oedema † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Coagulopathy † 1     
# participants affected / at risk   4/9088 (0.04%)   6/9052 (0.07%) 
Haemolytic anaemia † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Haemorrhagic anaemia † 1     
# participants affected / at risk   5/9088 (0.06%)   3/9052 (0.03%) 
Hypochromic anaemia † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Iron deficiency anaemia † 1     
# participants affected / at risk   5/9088 (0.06%)   9/9052 (0.10%) 
Pancytopenia † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Febrile neutropenia † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Cardiac disorders     
Acute coronary syndrome † 1     
# participants affected / at risk   20/9088 (0.22%)   16/9052 (0.18%) 
Aortic valve incompetence † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Atrial fibrillation † 1     
# participants affected / at risk   301/9088 (3.31%)   287/9052 (3.17%) 
Cardiac fibrillation † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Cardiopulmonary failure † 1     
# participants affected / at risk   6/9088 (0.07%)   4/9052 (0.04%) 
Cor pulmonale † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Ischaemic cardiomyopathy † 1     
# participants affected / at risk   8/9088 (0.09%)   1/9052 (0.01%) 
Left ventricular failure † 1     
# participants affected / at risk   7/9088 (0.08%)   9/9052 (0.10%) 
Mitral valve stenosis † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Nodal rhythm † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Sinus bradycardia † 1     
# participants affected / at risk   6/9088 (0.07%)   3/9052 (0.03%) 
Bundle branch block left † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Cardiomegaly † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Cardiovascular insufficiency † 1     
# participants affected / at risk   0/9088 (0.00%)   4/9052 (0.04%) 
Intracardiac thrombus † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Myocardial infarction † 1     
# participants affected / at risk   80/9088 (0.88%)   63/9052 (0.70%) 
Sinus arrest † 1     
# participants affected / at risk   4/9088 (0.04%)   1/9052 (0.01%) 
Angina unstable † 1     
# participants affected / at risk   112/9088 (1.23%)   87/9052 (0.96%) 
Atrial thrombosis † 1     
# participants affected / at risk   4/9088 (0.04%)   2/9052 (0.02%) 
Bradyarrhythmia † 1     
# participants affected / at risk   9/9088 (0.10%)   3/9052 (0.03%) 
Cardiac valve disease † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Cyanosis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Extrasystoles † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Left ventricular dysfunction † 1     
# participants affected / at risk   4/9088 (0.04%)   4/9052 (0.04%) 
Mitral valve disease † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Myocarditis † 1     
# participants affected / at risk   3/9088 (0.03%)   0/9052 (0.00%) 
Restrictive cardiomyopathy † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Right ventricular failure † 1     
# participants affected / at risk   5/9088 (0.06%)   2/9052 (0.02%) 
Ventricular arrhythmia † 1     
# participants affected / at risk   2/9088 (0.02%)   4/9052 (0.04%) 
Ventricular fibrillation † 1     
# participants affected / at risk   9/9088 (0.10%)   12/9052 (0.13%) 
Angina pectoris † 1     
# participants affected / at risk   49/9088 (0.54%)   39/9052 (0.43%) 
Aortic valve stenosis † 1     
# participants affected / at risk   7/9088 (0.08%)   1/9052 (0.01%) 
Atrioventricular block † 1     
# participants affected / at risk   5/9088 (0.06%)   3/9052 (0.03%) 
Atrioventricular block first degree † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Cardiac disorder † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Cardio-respiratory arrest † 1     
# participants affected / at risk   8/9088 (0.09%)   8/9052 (0.09%) 
Cardiogenic shock † 1     
# participants affected / at risk   9/9088 (0.10%)   7/9052 (0.08%) 
Coronary artery dissection † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Myocardial ischaemia † 1     
# participants affected / at risk   17/9088 (0.19%)   17/9052 (0.19%) 
Ventricular extrasystoles † 1     
# participants affected / at risk   0/9088 (0.00%)   3/9052 (0.03%) 
Atrial tachycardia † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Cardiac amyloidosis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Cardiac failure chronic † 1     
# participants affected / at risk   16/9088 (0.18%)   23/9052 (0.25%) 
Cardiac failure congestive † 1     
# participants affected / at risk   171/9088 (1.88%)   175/9052 (1.93%) 
Cardiomyopathy † 1     
# participants affected / at risk   6/9088 (0.07%)   7/9052 (0.08%) 
Congestive cardiomyopathy † 1     
# participants affected / at risk   8/9088 (0.09%)   8/9052 (0.09%) 
Heart valve stenosis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Hypertensive cardiomyopathy † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Nodal arrhythmia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Prinzmetal angina † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Stress cardiomyopathy † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Supraventricular extrasystoles † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Arrhythmia † 1     
# participants affected / at risk   2/9088 (0.02%)   12/9052 (0.13%) 
Atrioventricular block complete † 1     
# participants affected / at risk   7/9088 (0.08%)   12/9052 (0.13%) 
Chronotropic incompetence † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Conduction disorder † 1     
# participants affected / at risk   2/9088 (0.02%)   4/9052 (0.04%) 
Diastolic dysfunction † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Mitral valve prolapse † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Sinus tachycardia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Supraventricular tachycardia † 1     
# participants affected / at risk   6/9088 (0.07%)   4/9052 (0.04%) 
Tricuspid valve incompetence † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Ventricular tachycardia † 1     
# participants affected / at risk   27/9088 (0.30%)   31/9052 (0.34%) 
Acute myocardial infarction † 1     
# participants affected / at risk   44/9088 (0.48%)   44/9052 (0.49%) 
Adams-Stokes syndrome † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Aortic valve disease † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Arteriosclerosis coronary artery † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Atrial flutter † 1     
# participants affected / at risk   29/9088 (0.32%)   35/9052 (0.39%) 
Bradycardia † 1     
# participants affected / at risk   32/9088 (0.35%)   43/9052 (0.48%) 
Cardiac asthma † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Cardiac failure † 1     
# participants affected / at risk   310/9088 (3.41%)   301/9052 (3.33%) 
Coronary artery disease † 1     
# participants affected / at risk   60/9088 (0.66%)   61/9052 (0.67%) 
Heart valve incompetence † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Mitral valve incompetence † 1     
# participants affected / at risk   13/9088 (0.14%)   13/9052 (0.14%) 
Pericarditis † 1     
# participants affected / at risk   1/9088 (0.01%)   3/9052 (0.03%) 
Sick sinus syndrome † 1     
# participants affected / at risk   49/9088 (0.54%)   40/9052 (0.44%) 
Acute left ventricular failure † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Atrioventricular block second degree † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Cardiac arrest † 1     
# participants affected / at risk   27/9088 (0.30%)   28/9052 (0.31%) 
Cardiac failure acute † 1     
# participants affected / at risk   25/9088 (0.28%)   20/9052 (0.22%) 
Cardiac tamponade † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Chordae tendinae rupture † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Cor pulmonale acute † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Coronary artery insufficiency † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Coronary artery occlusion † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Coronary artery stenosis † 1     
# participants affected / at risk   4/9088 (0.04%)   6/9052 (0.07%) 
Hypertensive heart disease † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Palpitations † 1     
# participants affected / at risk   12/9088 (0.13%)   6/9052 (0.07%) 
Pericardial effusion † 1     
# participants affected / at risk   5/9088 (0.06%)   0/9052 (0.00%) 
Sinus arrhythmia † 1     
# participants affected / at risk   4/9088 (0.04%)   1/9052 (0.01%) 
Tachyarrhythmia † 1     
# participants affected / at risk   8/9088 (0.09%)   6/9052 (0.07%) 
Tachycardia † 1     
# participants affected / at risk   6/9088 (0.07%)   3/9052 (0.03%) 
Ventricular tachyarrhythmia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Congenital, familial and genetic disorders     
Gastrointestinal angiodysplasia † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Vitello-intestinal duct remnant † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Aplasia † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Gilbert's syndrome † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Phimosis † 1     
# participants affected / at risk   1/9088 (0.01%)   4/9052 (0.04%) 
Dermoid cyst † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Gastrointestinal angiodysplasia haemorrhagic † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Hydrocele † 1     
# participants affected / at risk   5/9088 (0.06%)   2/9052 (0.02%) 
Adenomatous polyposis coli † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Gastrointestinal arteriovenous malformation † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Thalassaemia beta † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Cystic lymphangioma † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Ear and labyrinth disorders     
Ear haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Tinnitus † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Tympanic membrane perforation † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Vertigo positional † 1     
# participants affected / at risk   1/9088 (0.01%)   4/9052 (0.04%) 
Vestibular disorder † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Sudden hearing loss † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Vertigo † 1     
# participants affected / at risk   21/9088 (0.23%)   13/9052 (0.14%) 
Cerumen impaction † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Endocrine disorders     
Thyroid mass † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Adrenal haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Basedow's disease † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Hyperthyroidism † 1     
# participants affected / at risk   3/9088 (0.03%)   4/9052 (0.04%) 
Inappropriate antidiuretic hormone secretion † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Hyperaldosteronism † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Primary hyperaldosteronism † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Hypothyroidism † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Goitre † 1     
# participants affected / at risk   3/9088 (0.03%)   0/9052 (0.00%) 
Eye disorders     
Cataract nuclear † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Diabetic retinopathy † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Diplopia † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Phacolytic glaucoma † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Retinal vascular occlusion † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Glaucoma † 1     
# participants affected / at risk   0/9088 (0.00%)   6/9052 (0.07%) 
Retinal vein thrombosis † 1     
# participants affected / at risk   4/9088 (0.04%)   0/9052 (0.00%) 
Vision blurred † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Amaurosis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Eye haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   3/9052 (0.03%) 
Eyelid ptosis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Macular degeneration † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Vitreous degeneration † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Vitreous haemorrhage † 1     
# participants affected / at risk   3/9088 (0.03%)   4/9052 (0.04%) 
Cataract † 1     
# participants affected / at risk   26/9088 (0.29%)   34/9052 (0.38%) 
Conjunctival haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Conjunctivitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Ocular vascular disorder † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Open angle glaucoma † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Retinal artery occlusion † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Angle closure glaucoma † 1     
# participants affected / at risk   3/9088 (0.03%)   0/9052 (0.00%) 
Aphakia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Chorioretinal disorder † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Eye disorder † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Macular oedema † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Retinal detachment † 1     
# participants affected / at risk   5/9088 (0.06%)   2/9052 (0.02%) 
Keratitis sclerosing † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Retinal haemorrhage † 1     
# participants affected / at risk   3/9088 (0.03%)   3/9052 (0.03%) 
Retinopathy † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Amaurosis fugax † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Dacryostenosis acquired † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Retinal vein occlusion † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Trichiasis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Ulcerative keratitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Gastrointestinal disorders     
Abdominal strangulated hernia † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Barrett's oesophagus † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Colitis ulcerative † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Cyclic vomiting syndrome † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Duodenal ulcer haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   6/9052 (0.07%) 
Gastric polyps † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Gastric ulcer † 1     
# participants affected / at risk   9/9088 (0.10%)   10/9052 (0.11%) 
Haematemesis † 1     
# participants affected / at risk   1/9088 (0.01%)   4/9052 (0.04%) 
Haemorrhagic erosive gastritis † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Ileus paralytic † 1     
# participants affected / at risk   0/9088 (0.00%)   3/9052 (0.03%) 
Inguinal hernia † 1     
# participants affected / at risk   20/9088 (0.22%)   29/9052 (0.32%) 
Intestinal infarction † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Large intestinal ulcer † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Lower gastrointestinal haemorrhage † 1     
# participants affected / at risk   12/9088 (0.13%)   12/9052 (0.13%) 
Oesophageal haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Oesophageal stenosis † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Oesophagitis ulcerative † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Pancreatic mass † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Pancreatitis chronic † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Rectal tenesmus † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Retroperitoneal haematoma † 1     
# participants affected / at risk   2/9088 (0.02%)   4/9052 (0.04%) 
Retroperitoneal haemorrhage † 1     
# participants affected / at risk   0/9088 (0.00%)   3/9052 (0.03%) 
Upper gastrointestinal haemorrhage † 1     
# participants affected / at risk   23/9088 (0.25%)   32/9052 (0.35%) 
Vomiting † 1     
# participants affected / at risk   6/9088 (0.07%)   3/9052 (0.03%) 
Abdominal pain lower † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Colitis ischaemic † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Duodenal ulcer perforation † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Dysphagia † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Gastritis † 1     
# participants affected / at risk   17/9088 (0.19%)   8/9052 (0.09%) 
Gastrointestinal ulcer haemorrhage † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Hiatus hernia † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Intestinal obstruction † 1     
# participants affected / at risk   3/9088 (0.03%)   9/9052 (0.10%) 
Large intestine perforation † 1     
# participants affected / at risk   4/9088 (0.04%)   1/9052 (0.01%) 
Lip haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Mallory-Weiss syndrome † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Mouth cyst † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Oesophageal disorder † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Pancreatitis acute † 1     
# participants affected / at risk   8/9088 (0.09%)   4/9052 (0.04%) 
Periodontitis † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Peritonitis † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Pneumatosis intestinalis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Pneumoperitoneum † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Polyp colorectal † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Rectal polyp † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Small intestinal perforation † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Tooth socket haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Abdominal mass † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Anal prolapse † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Anorectal disorder † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Appendiceal mucocoele † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Dental caries † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Diarrhoea † 1     
# participants affected / at risk   9/9088 (0.10%)   8/9052 (0.09%) 
Diverticulum intestinal † 1     
# participants affected / at risk   4/9088 (0.04%)   2/9052 (0.02%) 
Enteritis † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Gastric ulcer haemorrhage † 1     
# participants affected / at risk   13/9088 (0.14%)   12/9052 (0.13%) 
Gastritis erosive † 1     
# participants affected / at risk   5/9088 (0.06%)   9/9052 (0.10%) 
Gastritis haemorrhagic † 1     
# participants affected / at risk   5/9088 (0.06%)   7/9052 (0.08%) 
Gastroduodenal haemorrhage † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Gastroduodenal ulcer † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Gastrointestinal pain † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Gastrointestinal toxicity † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Intestinal ischaemia † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Intestinal polyp † 1     
# participants affected / at risk   1/9088 (0.01%)   3/9052 (0.03%) 
Jejunal perforation † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Large intestinal haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Pancreatitis † 1     
# participants affected / at risk   11/9088 (0.12%)   13/9052 (0.14%) 
Pancreatitis necrotising † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Peritoneal haemorrhage † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Retroperitoneal fibrosis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Tooth disorder † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Abdominal discomfort † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Abdominal wall disorder † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Ascites † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Diverticular perforation † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Gallstone ileus † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Gastric haemorrhage † 1     
# participants affected / at risk   5/9088 (0.06%)   6/9052 (0.07%) 
Gastrointestinal disorder † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Gastrointestinal necrosis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Haematochezia † 1     
# participants affected / at risk   4/9088 (0.04%)   7/9052 (0.08%) 
Haemorrhoids † 1     
# participants affected / at risk   6/9088 (0.07%)   9/9052 (0.10%) 
Ileus † 1     
# participants affected / at risk   4/9088 (0.04%)   5/9052 (0.06%) 
Impaired gastric emptying † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Oesophageal obstruction † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Oesophageal ulcer † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Oesophagitis haemorrhagic † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Peptic ulcer † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Umbilical hernia † 1     
# participants affected / at risk   1/9088 (0.01%)   8/9052 (0.09%) 
Anal fissure † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Anal skin tags † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Diarrhoea haemorrhagic † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Diverticulum † 1     
# participants affected / at risk   5/9088 (0.06%)   5/9052 (0.06%) 
Diverticulum intestinal haemorrhagic † 1     
# participants affected / at risk   2/9088 (0.02%)   6/9052 (0.07%) 
Faecaloma † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Faeces discoloured † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Gastrointestinal ulcer † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Haemorrhoidal haemorrhage † 1     
# participants affected / at risk   3/9088 (0.03%)   3/9052 (0.03%) 
Hernial eventration † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Inguinal hernia, obstructive † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Intestinal haemorrhage † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Large intestinal obstruction † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Peptic ulcer haemorrhage † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Rectal haemorrhage † 1     
# participants affected / at risk   19/9088 (0.21%)   19/9052 (0.21%) 
Subileus † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Abdominal pain † 1     
# participants affected / at risk   14/9088 (0.15%)   13/9052 (0.14%) 
Acquired oesophageal web † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Anal haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Colitis † 1     
# participants affected / at risk   4/9088 (0.04%)   2/9052 (0.02%) 
Constipation † 1     
# participants affected / at risk   9/9088 (0.10%)   3/9052 (0.03%) 
Femoral hernia, obstructive † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Gastric disorder † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Mouth haemorrhage † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Nausea † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Oesophageal spasm † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Pancreatic pseudocyst † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Umbilical hernia, obstructive † 1     
# participants affected / at risk   1/9088 (0.01%)   3/9052 (0.03%) 
Abdominal pain upper † 1     
# participants affected / at risk   9/9088 (0.10%)   3/9052 (0.03%) 
Abdominal wall haematoma † 1     
# participants affected / at risk   0/9088 (0.00%)   3/9052 (0.03%) 
Colonic obstruction † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Colonic polyp † 1     
# participants affected / at risk   11/9088 (0.12%)   12/9052 (0.13%) 
Epigastric discomfort † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Gastrointestinal erosion † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Gastrointestinal motility disorder † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Gastrointestinal perforation † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Gingival bleeding † 1     
# participants affected / at risk   2/9088 (0.02%)   3/9052 (0.03%) 
Intestinal polyp haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   3/9052 (0.03%) 
Oesophageal ulcer haemorrhage † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Small intestinal obstruction † 1     
# participants affected / at risk   8/9088 (0.09%)   13/9052 (0.14%) 
Volvulus † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Abdominal adhesions † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Abdominal hernia † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Anal fistula † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Duodenal ulcer † 1     
# participants affected / at risk   4/9088 (0.04%)   4/9052 (0.04%) 
Dyspepsia † 1     
# participants affected / at risk   4/9088 (0.04%)   2/9052 (0.02%) 
Gastroduodenitis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Gastrointestinal haemorrhage † 1     
# participants affected / at risk   47/9088 (0.52%)   48/9052 (0.53%) 
Gastrointestinal inflammation † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Gastrooesophageal reflux disease † 1     
# participants affected / at risk   3/9088 (0.03%)   3/9052 (0.03%) 
Ileitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Irritable bowel syndrome † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Malabsorption † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Melaena † 1     
# participants affected / at risk   11/9088 (0.12%)   9/9052 (0.10%) 
Oesophagitis † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Toothache † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
General disorders     
Catheter site haemorrhage † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Device battery issue † 1     
# participants affected / at risk   2/9088 (0.02%)   3/9052 (0.03%) 
Device failure † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Drowning † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Drug interaction † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
General physical health deterioration † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Implant site inflammation † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Bloody discharge † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Device dislocation † 1     
# participants affected / at risk   2/9088 (0.02%)   4/9052 (0.04%) 
Fatigue † 1     
# participants affected / at risk   4/9088 (0.04%)   4/9052 (0.04%) 
Medical device site reaction † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Non-cardiac chest pain † 1     
# participants affected / at risk   22/9088 (0.24%)   26/9052 (0.29%) 
Oedema † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Pyrexia † 1     
# participants affected / at risk   9/9088 (0.10%)   5/9052 (0.06%) 
Vessel puncture site haematoma † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Chest discomfort † 1     
# participants affected / at risk   4/9088 (0.04%)   2/9052 (0.02%) 
Fibrosis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Hernia † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Implant site reaction † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Multi-organ failure † 1     
# participants affected / at risk   5/9088 (0.06%)   5/9052 (0.06%) 
Sudden death † 1     
# participants affected / at risk   57/9088 (0.63%)   50/9052 (0.55%) 
Adverse drug reaction † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Device malfunction † 1     
# participants affected / at risk   11/9088 (0.12%)   6/9052 (0.07%) 
Hernia obstructive † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Mass † 1     
# participants affected / at risk   3/9088 (0.03%)   0/9052 (0.00%) 
Necrobiosis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Cardiac death † 1     
# participants affected / at risk   11/9088 (0.12%)   6/9052 (0.07%) 
Death † 1     
# participants affected / at risk   16/9088 (0.18%)   26/9052 (0.29%) 
Device lead damage † 1     
# participants affected / at risk   3/9088 (0.03%)   0/9052 (0.00%) 
Gait disturbance † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Generalised oedema † 1     
# participants affected / at risk   0/9088 (0.00%)   3/9052 (0.03%) 
Impaired healing † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Implant site thrombosis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Ischaemic ulcer † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Localised oedema † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Medical device complication † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Oedema peripheral † 1     
# participants affected / at risk   6/9088 (0.07%)   5/9052 (0.06%) 
Sudden cardiac death † 1     
# participants affected / at risk   30/9088 (0.33%)   18/9052 (0.20%) 
Chest pain † 1     
# participants affected / at risk   43/9088 (0.47%)   72/9052 (0.80%) 
Granuloma † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Infusion site haemorrhage † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Malaise † 1     
# participants affected / at risk   3/9088 (0.03%)   1/9052 (0.01%) 
Systemic inflammatory response syndrome † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Ulcer haemorrhage † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Vestibulitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Chills † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Cyst † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Influenza like illness † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Organ failure † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Pelvic mass † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Polyp † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Puncture site haemorrhage † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Accidental death † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Asthenia † 1     
# participants affected / at risk   12/9088 (0.13%)   8/9052 (0.09%) 
Cyst rupture † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Device capturing issue † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Device stimulation issue † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Exercise tolerance decreased † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Inflammation † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Hepatobiliary disorders     
Cholangitis acute † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Cholecystitis chronic † 1     
# participants affected / at risk   5/9088 (0.06%)   3/9052 (0.03%) 
Hyperbilirubinaemia † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Alcoholic liver disease † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Cholecystitis † 1     
# participants affected / at risk   19/9088 (0.21%)   19/9052 (0.21%) 
Hepatic function abnormal † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Acute hepatic failure † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Bile duct stone † 1     
# participants affected / at risk   4/9088 (0.04%)   5/9052 (0.06%) 
Chronic hepatitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Hepatic congestion † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Hepatic steatosis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Hepatitis acute † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Ischaemic hepatitis † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Biliary colic † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Cholecystitis acute † 1     
# participants affected / at risk   16/9088 (0.18%)   20/9052 (0.22%) 
Cholestasis † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Hepatitis toxic † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Cholangitis † 1     
# participants affected / at risk   5/9088 (0.06%)   4/9052 (0.04%) 
Hepatic cirrhosis † 1     
# participants affected / at risk   3/9088 (0.03%)   3/9052 (0.03%) 
Jaundice cholestatic † 1     
# participants affected / at risk   3/9088 (0.03%)   0/9052 (0.00%) 
Biliary dyskinesia † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Hepatic ischaemia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Hepatitis † 1     
# participants affected / at risk   0/9088 (0.00%)   5/9052 (0.06%) 
Cholelithiasis † 1     
# participants affected / at risk   24/9088 (0.26%)   16/9052 (0.18%) 
Gallbladder disorder † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Liver disorder † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Bile duct obstruction † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Hepatic failure † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Hydrocholecystis † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Jaundice † 1     
# participants affected / at risk   3/9088 (0.03%)   1/9052 (0.01%) 
Immune system disorders     
Hypersensitivity † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Amyloidosis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Anaphylactic reaction † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Anaphylactic shock † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Serum sickness † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Drug hypersensitivity † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Infections and infestations     
Abscess limb † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Acid fast bacilli infection † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Endocarditis † 1     
# participants affected / at risk   0/9088 (0.00%)   2/9052 (0.02%) 
Gangrene † 1     
# participants affected / at risk   5/9088 (0.06%)   0/9052 (0.00%) 
Haemorrhoid infection † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Herpes zoster infection neurological † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Incision site infection † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Infected epidermal cyst † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Intervertebral discitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Lobar pneumonia † 1     
# participants affected / at risk   16/9088 (0.18%)   12/9052 (0.13%) 
Oesophageal candidiasis † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Osteomyelitis † 1     
# participants affected / at risk   4/9088 (0.04%)   4/9052 (0.04%) 
Peritoneal abscess † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Pharyngeal abscess † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Pneumonia † 1     
# participants affected / at risk   202/9088 (2.22%)   231/9052 (2.55%) 
Postoperative wound infection † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Staphylococcal infection † 1     
# participants affected / at risk   3/9088 (0.03%)   1/9052 (0.01%) 
Streptococcal bacteraemia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Subdiaphragmatic abscess † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Typhoid fever † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Viral diarrhoea † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Abdominal wall abscess † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Breast cellulitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Bronchopneumonia † 1     
# participants affected / at risk   9/9088 (0.10%)   7/9052 (0.08%) 
Campylobacter gastroenteritis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Clostridium difficile colitis † 1     
# participants affected / at risk   3/9088 (0.03%)   5/9052 (0.06%) 
Device related infection † 1     
# participants affected / at risk   6/9088 (0.07%)   3/9052 (0.03%) 
Empyema † 1     
# participants affected / at risk   2/9088 (0.02%)   1/9052 (0.01%) 
Endometritis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Gastroenteritis Escherichia coli † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Gastroenteritis norovirus † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Gastrointestinal infection † 1     
# participants affected / at risk   2/9088 (0.02%)   0/9052 (0.00%) 
Implant site infection † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Liver abscess † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Malaria † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Mastitis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Necrotising fasciitis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Otitis media † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Perirectal abscess † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Pneumonia staphylococcal † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Respiratory tract infection † 1     
# participants affected / at risk   17/9088 (0.19%)   16/9052 (0.18%) 
Staphylococcal bacteraemia † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Staphylococcal skin infection † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Tracheobronchitis † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Urinary tract infection bacterial † 1     
# participants affected / at risk   1/9088 (0.01%)   2/9052 (0.02%) 
Vestibular neuronitis † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Appendicitis perforated † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Bronchitis haemophilus † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Bronchitis viral † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Diarrhoea infectious † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Endocarditis bacterial † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Enterococcal bacteraemia † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Erysipelas † 1     
# participants affected / at risk   12/9088 (0.13%)   15/9052 (0.17%) 
Injection site abscess † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Laryngitis † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Osteomyelitis chronic † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Post procedural cellulitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Pseudomonas infection † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Psoas abscess † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Sialoadenitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Tooth infection † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Tuberculosis † 1     
# participants affected / at risk   1/9088 (0.01%)   1/9052 (0.01%) 
Upper respiratory tract infection † 1     
# participants affected / at risk   5/9088 (0.06%)   11/9052 (0.12%) 
Urethritis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Weil's disease † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Abscess intestinal † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Appendicitis † 1     
# participants affected / at risk   13/9088 (0.14%)   9/9052 (0.10%) 
Bacterial infection † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Bronchiolitis † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Cystitis † 1     
# participants affected / at risk   3/9088 (0.03%)   2/9052 (0.02%) 
Dysentery † 1     
# participants affected / at risk   0/9088 (0.00%)   1/9052 (0.01%) 
Ear infection † 1     
# participants affected / at risk   1/9088 (0.01%)   0/9052 (0.00%) 
Gastroenteritis viral † 1     
# participants affected / at risk   3/9088 (0.03%)   5/9052 (0.06%) 
H1N1 influenza † 1     
# participants affected / at risk   2/9088 (0.02%)   2/9052 (0.02%) 
Infected bites