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

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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Prevention
Conditions Atrial Fibrillation
Atrial Flutter
Interventions Drug: warfarin
Drug: apixaban
Enrollment 20976
Recruitment Details  
Pre-assignment Details 20998 participants were enrolled, and 18201 were randomized.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 9120 [1] 9081 [1]
Completed 6810 6588
Not Completed 2310 2493
Reason Not Completed
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
Arm/Group Title Apixaban Warfarin Total
Hide Arm/Group Description 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. 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 of all reporting groups
Overall Number of Baseline Participants 9120 9081 18201
Hide Baseline Analysis Population Description
Randomized participants
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9120 participants 9081 participants 18201 participants
69.1  (9.61) 69.0  (9.74) 69.1  (9.68)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
<65 years
2731
  29.9%
2740
  30.2%
5471
  30.1%
Between 65 and 75 years
3539
  38.8%
3513
  38.7%
7052
  38.7%
>=75 years
2850
  31.3%
2828
  31.1%
5678
  31.2%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
Female
3234
  35.5%
3182
  35.0%
6416
  35.3%
Male
5886
  64.5%
5899
  65.0%
11785
  64.7%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
White (European)
5440
  59.6%
5366
  59.1%
10806
  59.4%
White (Middle Eastern or North African)
59
   0.6%
66
   0.7%
125
   0.7%
White (Other White)
2037
  22.3%
2060
  22.7%
4097
  22.5%
White (Not Reported)
0
   0.0%
1
   0.0%
1
   0.0%
Black / African American
125
   1.4%
102
   1.1%
227
   1.2%
Asian (Asian Indian)
307
   3.4%
312
   3.4%
619
   3.4%
Asian (Chinese)
536
   5.9%
536
   5.9%
1072
   5.9%
Asian (Japanese)
164
   1.8%
180
   2.0%
344
   1.9%
Asian (Other Asian)
303
   3.3%
304
   3.3%
607
   3.3%
American Indian / Alaska Native
26
   0.3%
24
   0.3%
50
   0.3%
Native Hawaiian / Other Pacific Islander
2
   0.0%
2
   0.0%
4
   0.0%
Other
121
   1.3%
127
   1.4%
248
   1.4%
Not Reported
0
   0.0%
1
   0.0%
1
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
Hispanic / Latino
1808
  19.8%
1803
  19.9%
3611
  19.8%
Not Hispanic / Latino
7312
  80.2%
7276
  80.1%
14588
  80.1%
Not Reported
0
   0.0%
2
   0.0%
2
   0.0%
Female Age Category  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
<=50 years
81
   0.9%
88
   1.0%
169
   0.9%
>50 years
3153
  34.6%
3094
  34.1%
6247
  34.3%
not applicable (male)
5886
  64.5%
5899
  65.0%
11785
  64.7%
Apixaban/Matching Placebo Dose at Randomization  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
2.5 mg twice daily (BID)
428
   4.7%
403
   4.4%
831
   4.6%
5.0 mg BID
8692
  95.3%
8678
  95.6%
17370
  95.4%
Risk Factor at Enrollment: Age >= 75 Years  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
>=75 years
2850
  31.3%
2828
  31.1%
5678
  31.2%
<75 years
6270
  68.8%
6253
  68.9%
12523
  68.8%
Risk Factor at Enrollment: Prior Stroke  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
With prior stroke
1045
  11.5%
1082
  11.9%
2127
  11.7%
Prior stroke not a risk factor
8075
  88.5%
7999
  88.1%
16074
  88.3%
Risk Factor at Enrollment: Prior Transient Ischemic Attack (TIA)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
With prior TIA
603
   6.6%
654
   7.2%
1257
   6.9%
Prior TIA not a risk factor
8517
  93.4%
8427
  92.8%
16944
  93.1%
Risk Factor At Enrollment: Symptomatic Chronic Heart Failure (CHF)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
With symptomatic CHF
2784
  30.5%
2757
  30.4%
5541
  30.4%
Symptomatic CHF not a risk factor
6336
  69.5%
6324
  69.6%
12660
  69.6%
Risk Factor at Enrollment: Left Ventricle Ejection Fraction (LVEF) <=40%  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
With LVEF <=40%
1324
  14.5%
1301
  14.3%
2625
  14.4%
LVEF <=40% not a risk factor
7796
  85.5%
7780
  85.7%
15576
  85.6%
Number of Risk Factors  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
<= 1
3025
  33.2%
3000
  33.0%
6025
  33.1%
>= 2
6095
  66.8%
6081
  67.0%
12176
  66.9%
CHADS-2 Score at Enrollment   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9120 participants 9081 participants 18201 participants
Score of <= 1
3100
  34.0%
3083
  34.0%
6183
  34.0%
Score of 2
3262
  35.8%
3254
  35.8%
6516
  35.8%
Score of >= 3
2758
  30.2%
2744
  30.2%
5502
  30.2%
[1]
Measure Description: 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] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 9120 participants 9081 participants 18201 participants
2.1  (1.10) 2.1  (1.11) 2.1  (2.10)
[1]
Measure Description: 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).
1.Primary Outcome
Title Number of Participants With First Event of Ischemic/Unspecified Stroke, Hemorrhagic Stroke, or Systemic Embolism (SE) During the Intended Treatment Period
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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).
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9120 9081
Measure Type: Number
Unit of Measure: participants
Ischemic or Unspecified Stroke 159 173
Hemorrhagic Stroke 38 76
Systemic Embolism 15 16
2.Primary Outcome
Title Rate of Adjudicated Stroke or Systemic Embolism (SE) During the Intended Treatment Period
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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).
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9120 9081
Measure Type: Number
Unit of Measure: Number of events per 100 patient years
1.27 1.60
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments 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.
Type of Statistical Test Superiority
Comments 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. Non-inferiority for the primary efficacy endpoint will be assessed first. If non-inferiority (using a NI margin of 1.38) is demonstrated then, superiority for the primary efficacy endpoint will be tested
Statistical Test of Hypothesis P-Value 0.0114
Comments 2-sided P-value for superiority test
Method Cox Proportional Hazards Model
Comments Model included treatment group as a covariate; stratified by investigative site and prior warfarin/vitamin K antagonist status. (experienced, naïve).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
.66 to .95
Estimation Comments apixaban / warfarin
3.Secondary Outcome
Title Number of Participants With Event of Major (International Society on Thrombosis and Hemostasis [ISTH]) Bleeding During Treatment Period
Hide 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, 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: participants
327 462
4.Secondary Outcome
Title Rate of Adjudicated Major (ISTH) Bleed Events During Treatment Period
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: Number of events per 100 patient years
2.13 3.09
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments [Not Specified]
Type of Statistical Test Superiority
Comments

4 key objectives were tested using a closed testing procedure. NI for the primary efficacy will be tested 1st. If NI is demonstrated then

  1. superiority for the primary efficacy will be tested
  2. if superiority for the primary efficacy is

    1. not demonstrated, stop
    2. demonstrated, then superiority for MB will be tested
  3. if superiority for MB is

    1. not demonstrated, stop
    2. demonstrated, then superiority for all cause death will be tested All tests will be done at 1-sided α = 0.025
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Cox Proportional Hazards Model
Comments Model included treatment group as a covariate; stratified by investigative site and prior warfarin/vitamin K antagonist status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.69
Confidence Interval (2-Sided) 95%
0.60 to 0.80
Estimation Comments apixaban / warfarin
5.Secondary Outcome
Title Number of Participants With Events of All-Cause Death During the Intended Treatment Period
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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).
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9120 9081
Measure Type: Number
Unit of Measure: participants
603 669
6.Secondary Outcome
Title Rate of Adjudicated All-Cause Death During the Intended Treatment Period
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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).
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9120 9081
Measure Type: Number
Unit of Measure: Number of events per 100 patient years
3.52 3.94
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments

4 key objectives were tested using a closed testing procedure. NI for the primary efficacy will be tested 1st. If NI is demonstrated then

  1. superiority for the primary efficacy will be tested
  2. if superiority for the primary efficacy is

    1. not demonstrated, stop
    2. demonstrated, then superiority for MB will be tested
  3. if superiority for MB is

    1. not demonstrated, stop
    2. demonstrated, then superiority for all cause death will be tested All tests will be done at 1-sided α = 0.025
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0465
Comments [Not Specified]
Method Cox Proportional Hazards Model
Comments Model included treatment group as a covariate; stratified by investigative site and prior warfarin/vitamin K antagonist status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.80 to 1.00
Estimation Comments apixaban / warfarin
7.Secondary Outcome
Title Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), and Myocardial Infarction (MI) (as Individual Endpoints) During the Intended Treatment Period
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9120 9081
Measure Type: Number
Unit of Measure: 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
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Ischemic or Unspecified Stroke
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4220
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.74 to 1.13
Estimation Comments apixaban / warfarin
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Hemorrhagic Stroke
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.51
Confidence Interval (2-Sided) 95%
0.35 to 0.75
Estimation Comments apixaban / warfarin
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Systemic Embolism
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7020
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.44 to 1.75
Estimation Comments apixaban / warfarin
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Myocardial Infarction
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3720
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.66 to 1.17
Estimation Comments apixaban / warfarin
8.Secondary Outcome
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
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9120 9081
Measure Type: Number
Unit of Measure: 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
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Composite of Stroke / Systemic Embolism / Major Bleeding
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.77
Confidence Interval (2-Sided) 95%
0.69 to 0.86
Estimation Comments apixaban / warfarin
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Composite of Stroke / Systemic Embolism / All-Cause Death
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0192
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.81 to 0.98
Estimation Comments apixaban / warfarin
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Composite of Stroke / Systemic Embolism / Major Bleeding / All-Cause Death
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.78 to 0.92
Estimation Comments apixaban / warfarin
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Composite of Stroke / Systemic Embolism / MI / All-Cause Death
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0107
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.80 to 0.97
Estimation Comments apixaban / warfarin
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Composite of Ischemic or Unspecified Stroke / All-Cause Death
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0432
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.90
Confidence Interval (2-Sided) 95%
0.82 to 1.00
Estimation Comments apixaban / warfarin
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Composite of Hemorrhagic Stroke / All-Cause Death
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0167
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.79 to 0.98
Estimation Comments apixaban / warfarin
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Composite of Systemic Embolism / All-Cause Death
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0464
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.80 to 1.00
Estimation Comments apixaban / warfarin
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Composite of Myocardial Infarction / All-Cause Death
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0253
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.80 to 0.99
Estimation Comments apixaban / warfarin
9.Secondary Outcome
Title Number of Warfarin/Vitamin K Antagonist (VKA) Naive Participants With Composite Stroke / Systemic Embolism (SE) / Major Bleeding During the Intended Treatment Period
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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).
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 3912 3888
Measure Type: Number
Unit of Measure: participants
229 285
10.Secondary Outcome
Title Rate of Composite Stroke / Systemic Embolism / Major Bleeding in Warfarin/Vitamin K Antagonist (VKA) Naive Participants During the Intended Treatment Period
Hide Description [Not Specified]
Time Frame "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding).
Hide Outcome Measure Data
Hide Analysis Population Description
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).
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 3912 3888
Measure Type: Number
Unit of Measure: Number of events per 100 patient years
3.21 4.06
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Composite Stroke/Systemic Embolism/Major Bleeding in Warfarin/Vitamin K Antagonist (VKA) Naive Participants
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0098
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazards Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.67 to 0.95
Estimation Comments apixaban / warfarin
11.Secondary Outcome
Title Number of Participants With Events of Major or Clinically Relevant Nonmajor (CRNM) Bleed During Treatment Period
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: participants
613 877
12.Secondary Outcome
Title Rate of Events of Major or Clinically Relevant Non-Major (CRNM) Bleed During Treatment Period
Hide 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, 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: number of events / 100 patient years
4.07 6.01
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazard Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
0.61 to 0.75
Estimation Comments apixaban / warfarin
13.Secondary Outcome
Title Number of Participants With All Bleeding Events During Treatment Period
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: participants
2356 3060
14.Secondary Outcome
Title Rate of All Bleeding Events During Treatment Period
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: number of events per 100 patient years
18.08 25.82
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazard Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.68 to 0.75
Estimation Comments apixaban / warfarin
15.Other Pre-specified Outcome
Title Number of Participants With Adverse Events (AEs), Bleeding AEs, Serious Adverse Events (SAEs), Discontinuations Due to AEs, or Deaths During the Treatment Period
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: participants
AE 7406 7521
SAE 3182 3302
Bleeding AE 2288 2961
Discontinuations due to AE 688 758
Deaths 429 468
16.Other Pre-specified Outcome
Title Rate of Adjudicated Bleeding Endpoints Per Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) During the Treatment Period
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: 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
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Severe GUSTO bleeding events
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazard Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.46
Confidence Interval (2-Sided) 95%
0.35 to 0.60
Estimation Comments apixaban / warfarin
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Severe or Moderate GUSTO bleeding events
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazard Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
0.50 to 0.71
Estimation Comments apixaban / warfarin
17.Other Pre-specified Outcome
Title Rate of Adjudicated Bleeding Endpoints Per Thrombolysis in Myocardial Infarction (TIMI) During the Treatment Period
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: 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
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Major TIMI bleeding event
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazard Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.57
Confidence Interval (2-Sided) 95%
0.46 to 0.70
Estimation Comments apixaban / warfarin
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments Major or Minor TIMI bleeding criteria
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Cox Proportional Hazard Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.54 to 0.75
Estimation Comments apixaban / warfarin
18.Other Pre-specified Outcome
Title Number of Participants With Net-Clinical Benefit During Treatment Period
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: participants
459 608
19.Other Pre-specified Outcome
Title Rate of Net-Clinical Benefit During Treatment Period
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Apixaban Warfarin
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 9088 9052
Measure Type: Number
Unit of Measure: Number of events per 100 patient years
3.01 4.09
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments nominal two-sided p-value was associated with a test of H0: RR=1 vs H1: RR ≠ 1
Method Cox Proportional Hazard Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.65 to 0.83
Estimation Comments apixaban / warfarin
Time Frame [Not Specified]
Adverse Event Reporting Description Treated population (includes all patients who received at least 1 dose of study drug.)
 
Arm/Group Title Warfarin Apixaban
Hide Arm/Group Description [Not Specified] [Not Specified]
All-Cause Mortality
Warfarin Apixaban
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Warfarin Apixaban
Affected / at Risk (%) Affected / at Risk (%)
Total   3182/9088 (35.01%)   3302/9052 (36.48%) 
Blood and lymphatic system disorders     
Bicytopenia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Haemorrhagic disorder  1  1/9088 (0.01%)  0/9052 (0.00%) 
Leukocytosis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Lymphadenitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Disseminated intravascular coagulation  1  1/9088 (0.01%)  2/9052 (0.02%) 
Hypocoagulable state  1  0/9088 (0.00%)  1/9052 (0.01%) 
Idiopathic thrombocytopenic purpura  1  1/9088 (0.01%)  1/9052 (0.01%) 
Lymphadenopathy  1  3/9088 (0.03%)  1/9052 (0.01%) 
Autoimmune thrombocytopenia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Eosinophilia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Microcytic anaemia  1  0/9088 (0.00%)  3/9052 (0.03%) 
Splenic cyst  1  1/9088 (0.01%)  0/9052 (0.00%) 
Spontaneous haematoma  1  1/9088 (0.01%)  2/9052 (0.02%) 
Thrombocytopenia  1  5/9088 (0.06%)  7/9052 (0.08%) 
Anaemia of chronic disease  1  1/9088 (0.01%)  0/9052 (0.00%) 
Leukopenia  1  1/9088 (0.01%)  1/9052 (0.01%) 
Thrombocytopenic purpura  1  0/9088 (0.00%)  1/9052 (0.01%) 
Anaemia  1  48/9088 (0.53%)  43/9052 (0.48%) 
Anaemia of malignant disease  1  1/9088 (0.01%)  0/9052 (0.00%) 
Anaemia vitamin B12 deficiency  1  0/9088 (0.00%)  1/9052 (0.01%) 
Bone marrow oedema  1  0/9088 (0.00%)  1/9052 (0.01%) 
Coagulopathy  1  4/9088 (0.04%)  6/9052 (0.07%) 
Haemolytic anaemia  1  2/9088 (0.02%)  0/9052 (0.00%) 
Haemorrhagic anaemia  1  5/9088 (0.06%)  3/9052 (0.03%) 
Hypochromic anaemia  1  1/9088 (0.01%)  1/9052 (0.01%) 
Iron deficiency anaemia  1  5/9088 (0.06%)  9/9052 (0.10%) 
Pancytopenia  1  1/9088 (0.01%)  1/9052 (0.01%) 
Febrile neutropenia  1  2/9088 (0.02%)  0/9052 (0.00%) 
Cardiac disorders     
Acute coronary syndrome  1  20/9088 (0.22%)  16/9052 (0.18%) 
Aortic valve incompetence  1  1/9088 (0.01%)  0/9052 (0.00%) 
Atrial fibrillation  1  301/9088 (3.31%)  287/9052 (3.17%) 
Cardiac fibrillation  1  1/9088 (0.01%)  0/9052 (0.00%) 
Cardiopulmonary failure  1  6/9088 (0.07%)  4/9052 (0.04%) 
Cor pulmonale  1  2/9088 (0.02%)  0/9052 (0.00%) 
Ischaemic cardiomyopathy  1  8/9088 (0.09%)  1/9052 (0.01%) 
Left ventricular failure  1  7/9088 (0.08%)  9/9052 (0.10%) 
Mitral valve stenosis  1  1/9088 (0.01%)  2/9052 (0.02%) 
Nodal rhythm  1  1/9088 (0.01%)  0/9052 (0.00%) 
Sinus bradycardia  1  6/9088 (0.07%)  3/9052 (0.03%) 
Bundle branch block left  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cardiomegaly  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cardiovascular insufficiency  1  0/9088 (0.00%)  4/9052 (0.04%) 
Intracardiac thrombus  1  2/9088 (0.02%)  1/9052 (0.01%) 
Myocardial infarction  1  80/9088 (0.88%)  63/9052 (0.70%) 
Sinus arrest  1  4/9088 (0.04%)  1/9052 (0.01%) 
Angina unstable  1  112/9088 (1.23%)  87/9052 (0.96%) 
Atrial thrombosis  1  4/9088 (0.04%)  2/9052 (0.02%) 
Bradyarrhythmia  1  9/9088 (0.10%)  3/9052 (0.03%) 
Cardiac valve disease  1  2/9088 (0.02%)  0/9052 (0.00%) 
Cyanosis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Extrasystoles  1  1/9088 (0.01%)  0/9052 (0.00%) 
Left ventricular dysfunction  1  4/9088 (0.04%)  4/9052 (0.04%) 
Mitral valve disease  1  1/9088 (0.01%)  1/9052 (0.01%) 
Myocarditis  1  3/9088 (0.03%)  0/9052 (0.00%) 
Restrictive cardiomyopathy  1  0/9088 (0.00%)  1/9052 (0.01%) 
Right ventricular failure  1  5/9088 (0.06%)  2/9052 (0.02%) 
Ventricular arrhythmia  1  2/9088 (0.02%)  4/9052 (0.04%) 
Ventricular fibrillation  1  9/9088 (0.10%)  12/9052 (0.13%) 
Angina pectoris  1  49/9088 (0.54%)  39/9052 (0.43%) 
Aortic valve stenosis  1  7/9088 (0.08%)  1/9052 (0.01%) 
Atrioventricular block  1  5/9088 (0.06%)  3/9052 (0.03%) 
Atrioventricular block first degree  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cardiac disorder  1  2/9088 (0.02%)  0/9052 (0.00%) 
Cardio-respiratory arrest  1  8/9088 (0.09%)  8/9052 (0.09%) 
Cardiogenic shock  1  9/9088 (0.10%)  7/9052 (0.08%) 
Coronary artery dissection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Myocardial ischaemia  1  17/9088 (0.19%)  17/9052 (0.19%) 
Ventricular extrasystoles  1  0/9088 (0.00%)  3/9052 (0.03%) 
Atrial tachycardia  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cardiac amyloidosis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cardiac failure chronic  1  16/9088 (0.18%)  23/9052 (0.25%) 
Cardiac failure congestive  1  171/9088 (1.88%)  175/9052 (1.93%) 
Cardiomyopathy  1  6/9088 (0.07%)  7/9052 (0.08%) 
Congestive cardiomyopathy  1  8/9088 (0.09%)  8/9052 (0.09%) 
Heart valve stenosis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Hypertensive cardiomyopathy  1  0/9088 (0.00%)  2/9052 (0.02%) 
Nodal arrhythmia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Prinzmetal angina  1  1/9088 (0.01%)  0/9052 (0.00%) 
Stress cardiomyopathy  1  1/9088 (0.01%)  0/9052 (0.00%) 
Supraventricular extrasystoles  1  2/9088 (0.02%)  0/9052 (0.00%) 
Arrhythmia  1  2/9088 (0.02%)  12/9052 (0.13%) 
Atrioventricular block complete  1  7/9088 (0.08%)  12/9052 (0.13%) 
Chronotropic incompetence  1  0/9088 (0.00%)  1/9052 (0.01%) 
Conduction disorder  1  2/9088 (0.02%)  4/9052 (0.04%) 
Diastolic dysfunction  1  0/9088 (0.00%)  1/9052 (0.01%) 
Mitral valve prolapse  1  1/9088 (0.01%)  0/9052 (0.00%) 
Sinus tachycardia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Supraventricular tachycardia  1  6/9088 (0.07%)  4/9052 (0.04%) 
Tricuspid valve incompetence  1  2/9088 (0.02%)  2/9052 (0.02%) 
Ventricular tachycardia  1  27/9088 (0.30%)  31/9052 (0.34%) 
Acute myocardial infarction  1  44/9088 (0.48%)  44/9052 (0.49%) 
Adams-Stokes syndrome  1  1/9088 (0.01%)  1/9052 (0.01%) 
Aortic valve disease  1  0/9088 (0.00%)  2/9052 (0.02%) 
Arteriosclerosis coronary artery  1  2/9088 (0.02%)  2/9052 (0.02%) 
Atrial flutter  1  29/9088 (0.32%)  35/9052 (0.39%) 
Bradycardia  1  32/9088 (0.35%)  43/9052 (0.48%) 
Cardiac asthma  1  1/9088 (0.01%)  0/9052 (0.00%) 
Cardiac failure  1  310/9088 (3.41%)  301/9052 (3.33%) 
Coronary artery disease  1  60/9088 (0.66%)  61/9052 (0.67%) 
Heart valve incompetence  1  1/9088 (0.01%)  0/9052 (0.00%) 
Mitral valve incompetence  1  13/9088 (0.14%)  13/9052 (0.14%) 
Pericarditis  1  1/9088 (0.01%)  3/9052 (0.03%) 
Sick sinus syndrome  1  49/9088 (0.54%)  40/9052 (0.44%) 
Acute left ventricular failure  1  2/9088 (0.02%)  2/9052 (0.02%) 
Atrioventricular block second degree  1  2/9088 (0.02%)  1/9052 (0.01%) 
Cardiac arrest  1  27/9088 (0.30%)  28/9052 (0.31%) 
Cardiac failure acute  1  25/9088 (0.28%)  20/9052 (0.22%) 
Cardiac tamponade  1  0/9088 (0.00%)  1/9052 (0.01%) 
Chordae tendinae rupture  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cor pulmonale acute  1  2/9088 (0.02%)  2/9052 (0.02%) 
Coronary artery insufficiency  1  2/9088 (0.02%)  2/9052 (0.02%) 
Coronary artery occlusion  1  2/9088 (0.02%)  2/9052 (0.02%) 
Coronary artery stenosis  1  4/9088 (0.04%)  6/9052 (0.07%) 
Hypertensive heart disease  1  2/9088 (0.02%)  2/9052 (0.02%) 
Palpitations  1  12/9088 (0.13%)  6/9052 (0.07%) 
Pericardial effusion  1  5/9088 (0.06%)  0/9052 (0.00%) 
Sinus arrhythmia  1  4/9088 (0.04%)  1/9052 (0.01%) 
Tachyarrhythmia  1  8/9088 (0.09%)  6/9052 (0.07%) 
Tachycardia  1  6/9088 (0.07%)  3/9052 (0.03%) 
Ventricular tachyarrhythmia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Congenital, familial and genetic disorders     
Gastrointestinal angiodysplasia  1  1/9088 (0.01%)  1/9052 (0.01%) 
Vitello-intestinal duct remnant  1  0/9088 (0.00%)  1/9052 (0.01%) 
Aplasia  1  0/9088 (0.00%)  1/9052 (0.01%) 
Gilbert's syndrome  1  1/9088 (0.01%)  0/9052 (0.00%) 
Phimosis  1  1/9088 (0.01%)  4/9052 (0.04%) 
Dermoid cyst  1  0/9088 (0.00%)  1/9052 (0.01%) 
Gastrointestinal angiodysplasia haemorrhagic  1  2/9088 (0.02%)  0/9052 (0.00%) 
Hydrocele  1  5/9088 (0.06%)  2/9052 (0.02%) 
Adenomatous polyposis coli  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gastrointestinal arteriovenous malformation  1  1/9088 (0.01%)  0/9052 (0.00%) 
Thalassaemia beta  1  1/9088 (0.01%)  0/9052 (0.00%) 
Cystic lymphangioma  1  1/9088 (0.01%)  0/9052 (0.00%) 
Ear and labyrinth disorders     
Ear haemorrhage  1  1/9088 (0.01%)  0/9052 (0.00%) 
Tinnitus  1  0/9088 (0.00%)  1/9052 (0.01%) 
Tympanic membrane perforation  1  1/9088 (0.01%)  0/9052 (0.00%) 
Vertigo positional  1  1/9088 (0.01%)  4/9052 (0.04%) 
Vestibular disorder  1  1/9088 (0.01%)  1/9052 (0.01%) 
Sudden hearing loss  1  0/9088 (0.00%)  1/9052 (0.01%) 
Vertigo  1  21/9088 (0.23%)  13/9052 (0.14%) 
Cerumen impaction  1  0/9088 (0.00%)  1/9052 (0.01%) 
Endocrine disorders     
Thyroid mass  1  0/9088 (0.00%)  1/9052 (0.01%) 
Adrenal haemorrhage  1  1/9088 (0.01%)  0/9052 (0.00%) 
Basedow's disease  1  1/9088 (0.01%)  1/9052 (0.01%) 
Hyperthyroidism  1  3/9088 (0.03%)  4/9052 (0.04%) 
Inappropriate antidiuretic hormone secretion  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hyperaldosteronism  1  1/9088 (0.01%)  0/9052 (0.00%) 
Primary hyperaldosteronism  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hypothyroidism  1  1/9088 (0.01%)  1/9052 (0.01%) 
Goitre  1  3/9088 (0.03%)  0/9052 (0.00%) 
Eye disorders     
Cataract nuclear  1  1/9088 (0.01%)  0/9052 (0.00%) 
Diabetic retinopathy  1  0/9088 (0.00%)  1/9052 (0.01%) 
Diplopia  1  0/9088 (0.00%)  1/9052 (0.01%) 
Phacolytic glaucoma  1  1/9088 (0.01%)  0/9052 (0.00%) 
Retinal vascular occlusion  1  1/9088 (0.01%)  0/9052 (0.00%) 
Glaucoma  1  0/9088 (0.00%)  6/9052 (0.07%) 
Retinal vein thrombosis  1  4/9088 (0.04%)  0/9052 (0.00%) 
Vision blurred  1  1/9088 (0.01%)  0/9052 (0.00%) 
Amaurosis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Eye haemorrhage  1  1/9088 (0.01%)  3/9052 (0.03%) 
Eyelid ptosis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Macular degeneration  1  0/9088 (0.00%)  1/9052 (0.01%) 
Vitreous degeneration  1  1/9088 (0.01%)  0/9052 (0.00%) 
Vitreous haemorrhage  1  3/9088 (0.03%)  4/9052 (0.04%) 
Cataract  1  26/9088 (0.29%)  34/9052 (0.38%) 
Conjunctival haemorrhage  1  1/9088 (0.01%)  1/9052 (0.01%) 
Conjunctivitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Ocular vascular disorder  1  1/9088 (0.01%)  0/9052 (0.00%) 
Open angle glaucoma  1  0/9088 (0.00%)  2/9052 (0.02%) 
Retinal artery occlusion  1  2/9088 (0.02%)  2/9052 (0.02%) 
Angle closure glaucoma  1  3/9088 (0.03%)  0/9052 (0.00%) 
Aphakia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Chorioretinal disorder  1  0/9088 (0.00%)  1/9052 (0.01%) 
Eye disorder  1  0/9088 (0.00%)  1/9052 (0.01%) 
Macular oedema  1  0/9088 (0.00%)  1/9052 (0.01%) 
Retinal detachment  1  5/9088 (0.06%)  2/9052 (0.02%) 
Keratitis sclerosing  1  1/9088 (0.01%)  0/9052 (0.00%) 
Retinal haemorrhage  1  3/9088 (0.03%)  3/9052 (0.03%) 
Retinopathy  1  0/9088 (0.00%)  1/9052 (0.01%) 
Amaurosis fugax  1  2/9088 (0.02%)  0/9052 (0.00%) 
Dacryostenosis acquired  1  0/9088 (0.00%)  1/9052 (0.01%) 
Retinal vein occlusion  1  0/9088 (0.00%)  1/9052 (0.01%) 
Trichiasis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Ulcerative keratitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gastrointestinal disorders     
Abdominal strangulated hernia  1  1/9088 (0.01%)  2/9052 (0.02%) 
Barrett's oesophagus  1  1/9088 (0.01%)  0/9052 (0.00%) 
Colitis ulcerative  1  1/9088 (0.01%)  1/9052 (0.01%) 
Cyclic vomiting syndrome  1  1/9088 (0.01%)  0/9052 (0.00%) 
Duodenal ulcer haemorrhage  1  1/9088 (0.01%)  6/9052 (0.07%) 
Gastric polyps  1  0/9088 (0.00%)  2/9052 (0.02%) 
Gastric ulcer  1  9/9088 (0.10%)  10/9052 (0.11%) 
Haematemesis  1  1/9088 (0.01%)  4/9052 (0.04%) 
Haemorrhagic erosive gastritis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Ileus paralytic  1  0/9088 (0.00%)  3/9052 (0.03%) 
Inguinal hernia  1  20/9088 (0.22%)  29/9052 (0.32%) 
Intestinal infarction  1  1/9088 (0.01%)  1/9052 (0.01%) 
Large intestinal ulcer  1  0/9088 (0.00%)  2/9052 (0.02%) 
Lower gastrointestinal haemorrhage  1  12/9088 (0.13%)  12/9052 (0.13%) 
Oesophageal haemorrhage  1  1/9088 (0.01%)  0/9052 (0.00%) 
Oesophageal stenosis  1  0/9088 (0.00%)  2/9052 (0.02%) 
Oesophagitis ulcerative  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pancreatic mass  1  0/9088 (0.00%)  1/9052 (0.01%) 
Pancreatitis chronic  1  1/9088 (0.01%)  1/9052 (0.01%) 
Rectal tenesmus  1  0/9088 (0.00%)  1/9052 (0.01%) 
Retroperitoneal haematoma  1  2/9088 (0.02%)  4/9052 (0.04%) 
Retroperitoneal haemorrhage  1  0/9088 (0.00%)  3/9052 (0.03%) 
Upper gastrointestinal haemorrhage  1  23/9088 (0.25%)  32/9052 (0.35%) 
Vomiting  1  6/9088 (0.07%)  3/9052 (0.03%) 
Abdominal pain lower  1  2/9088 (0.02%)  0/9052 (0.00%) 
Colitis ischaemic  1  3/9088 (0.03%)  2/9052 (0.02%) 
Duodenal ulcer perforation  1  1/9088 (0.01%)  1/9052 (0.01%) 
Dysphagia  1  1/9088 (0.01%)  1/9052 (0.01%) 
Gastritis  1  17/9088 (0.19%)  8/9052 (0.09%) 
Gastrointestinal ulcer haemorrhage  1  0/9088 (0.00%)  2/9052 (0.02%) 
Hiatus hernia  1  0/9088 (0.00%)  2/9052 (0.02%) 
Intestinal obstruction  1  3/9088 (0.03%)  9/9052 (0.10%) 
Large intestine perforation  1  4/9088 (0.04%)  1/9052 (0.01%) 
Lip haemorrhage  1  1/9088 (0.01%)  2/9052 (0.02%) 
Mallory-Weiss syndrome  1  1/9088 (0.01%)  2/9052 (0.02%) 
Mouth cyst  1  0/9088 (0.00%)  1/9052 (0.01%) 
Oesophageal disorder  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pancreatitis acute  1  8/9088 (0.09%)  4/9052 (0.04%) 
Periodontitis  1  2/9088 (0.02%)  1/9052 (0.01%) 
Peritonitis  1  2/9088 (0.02%)  2/9052 (0.02%) 
Pneumatosis intestinalis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pneumoperitoneum  1  0/9088 (0.00%)  1/9052 (0.01%) 
Polyp colorectal  1  1/9088 (0.01%)  0/9052 (0.00%) 
Rectal polyp  1  0/9088 (0.00%)  1/9052 (0.01%) 
Small intestinal perforation  1  1/9088 (0.01%)  0/9052 (0.00%) 
Tooth socket haemorrhage  1  1/9088 (0.01%)  0/9052 (0.00%) 
Abdominal mass  1  0/9088 (0.00%)  1/9052 (0.01%) 
Anal prolapse  1  1/9088 (0.01%)  0/9052 (0.00%) 
Anorectal disorder  1  1/9088 (0.01%)  0/9052 (0.00%) 
Appendiceal mucocoele  1  0/9088 (0.00%)  1/9052 (0.01%) 
Dental caries  1  1/9088 (0.01%)  1/9052 (0.01%) 
Diarrhoea  1  9/9088 (0.10%)  8/9052 (0.09%) 
Diverticulum intestinal  1  4/9088 (0.04%)  2/9052 (0.02%) 
Enteritis  1  0/9088 (0.00%)  2/9052 (0.02%) 
Gastric ulcer haemorrhage  1  13/9088 (0.14%)  12/9052 (0.13%) 
Gastritis erosive  1  5/9088 (0.06%)  9/9052 (0.10%) 
Gastritis haemorrhagic  1  5/9088 (0.06%)  7/9052 (0.08%) 
Gastroduodenal haemorrhage  1  0/9088 (0.00%)  1/9052 (0.01%) 
Gastroduodenal ulcer  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gastrointestinal pain  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gastrointestinal toxicity  1  1/9088 (0.01%)  0/9052 (0.00%) 
Intestinal ischaemia  1  3/9088 (0.03%)  2/9052 (0.02%) 
Intestinal polyp  1  1/9088 (0.01%)  3/9052 (0.03%) 
Jejunal perforation  1  0/9088 (0.00%)  1/9052 (0.01%) 
Large intestinal haemorrhage  1  1/9088 (0.01%)  1/9052 (0.01%) 
Pancreatitis  1  11/9088 (0.12%)  13/9052 (0.14%) 
Pancreatitis necrotising  1  1/9088 (0.01%)  0/9052 (0.00%) 
Peritoneal haemorrhage  1  2/9088 (0.02%)  2/9052 (0.02%) 
Retroperitoneal fibrosis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Tooth disorder  1  0/9088 (0.00%)  1/9052 (0.01%) 
Abdominal discomfort  1  0/9088 (0.00%)  1/9052 (0.01%) 
Abdominal wall disorder  1  1/9088 (0.01%)  0/9052 (0.00%) 
Ascites  1  3/9088 (0.03%)  2/9052 (0.02%) 
Diverticular perforation  1  1/9088 (0.01%)  1/9052 (0.01%) 
Gallstone ileus  1  0/9088 (0.00%)  1/9052 (0.01%) 
Gastric haemorrhage  1  5/9088 (0.06%)  6/9052 (0.07%) 
Gastrointestinal disorder  1  2/9088 (0.02%)  0/9052 (0.00%) 
Gastrointestinal necrosis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Haematochezia  1  4/9088 (0.04%)  7/9052 (0.08%) 
Haemorrhoids  1  6/9088 (0.07%)  9/9052 (0.10%) 
Ileus  1  4/9088 (0.04%)  5/9052 (0.06%) 
Impaired gastric emptying  1  0/9088 (0.00%)  2/9052 (0.02%) 
Oesophageal obstruction  1  0/9088 (0.00%)  1/9052 (0.01%) 
Oesophageal ulcer  1  0/9088 (0.00%)  1/9052 (0.01%) 
Oesophagitis haemorrhagic  1  1/9088 (0.01%)  0/9052 (0.00%) 
Peptic ulcer  1  1/9088 (0.01%)  1/9052 (0.01%) 
Umbilical hernia  1  1/9088 (0.01%)  8/9052 (0.09%) 
Anal fissure  1  1/9088 (0.01%)  1/9052 (0.01%) 
Anal skin tags  1  0/9088 (0.00%)  1/9052 (0.01%) 
Diarrhoea haemorrhagic  1  1/9088 (0.01%)  1/9052 (0.01%) 
Diverticulum  1  5/9088 (0.06%)  5/9052 (0.06%) 
Diverticulum intestinal haemorrhagic  1  2/9088 (0.02%)  6/9052 (0.07%) 
Faecaloma  1  1/9088 (0.01%)  1/9052 (0.01%) 
Faeces discoloured  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gastrointestinal ulcer  1  0/9088 (0.00%)  1/9052 (0.01%) 
Haemorrhoidal haemorrhage  1  3/9088 (0.03%)  3/9052 (0.03%) 
Hernial eventration  1  0/9088 (0.00%)  2/9052 (0.02%) 
Inguinal hernia, obstructive  1  3/9088 (0.03%)  2/9052 (0.02%) 
Intestinal haemorrhage  1  0/9088 (0.00%)  1/9052 (0.01%) 
Large intestinal obstruction  1  1/9088 (0.01%)  0/9052 (0.00%) 
Peptic ulcer haemorrhage  1  2/9088 (0.02%)  1/9052 (0.01%) 
Rectal haemorrhage  1  19/9088 (0.21%)  19/9052 (0.21%) 
Subileus  1  0/9088 (0.00%)  1/9052 (0.01%) 
Abdominal pain  1  14/9088 (0.15%)  13/9052 (0.14%) 
Acquired oesophageal web  1  0/9088 (0.00%)  1/9052 (0.01%) 
Anal haemorrhage  1  1/9088 (0.01%)  0/9052 (0.00%) 
Colitis  1  4/9088 (0.04%)  2/9052 (0.02%) 
Constipation  1  9/9088 (0.10%)  3/9052 (0.03%) 
Femoral hernia, obstructive  1  2/9088 (0.02%)  2/9052 (0.02%) 
Gastric disorder  1  1/9088 (0.01%)  1/9052 (0.01%) 
Mouth haemorrhage  1  2/9088 (0.02%)  1/9052 (0.01%) 
Nausea  1  1/9088 (0.01%)  1/9052 (0.01%) 
Oesophageal spasm  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pancreatic pseudocyst  1  0/9088 (0.00%)  1/9052 (0.01%) 
Umbilical hernia, obstructive  1  1/9088 (0.01%)  3/9052 (0.03%) 
Abdominal pain upper  1  9/9088 (0.10%)  3/9052 (0.03%) 
Abdominal wall haematoma  1  0/9088 (0.00%)  3/9052 (0.03%) 
Colonic obstruction  1  0/9088 (0.00%)  1/9052 (0.01%) 
Colonic polyp  1  11/9088 (0.12%)  12/9052 (0.13%) 
Epigastric discomfort  1  0/9088 (0.00%)  1/9052 (0.01%) 
Gastrointestinal erosion  1  0/9088 (0.00%)  2/9052 (0.02%) 
Gastrointestinal motility disorder  1  0/9088 (0.00%)  2/9052 (0.02%) 
Gastrointestinal perforation  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gingival bleeding  1  2/9088 (0.02%)  3/9052 (0.03%) 
Intestinal polyp haemorrhage  1  1/9088 (0.01%)  3/9052 (0.03%) 
Oesophageal ulcer haemorrhage  1  0/9088 (0.00%)  1/9052 (0.01%) 
Small intestinal obstruction  1  8/9088 (0.09%)  13/9052 (0.14%) 
Volvulus  1  2/9088 (0.02%)  1/9052 (0.01%) 
Abdominal adhesions  1  1/9088 (0.01%)  2/9052 (0.02%) 
Abdominal hernia  1  3/9088 (0.03%)  2/9052 (0.02%) 
Anal fistula  1  1/9088 (0.01%)  0/9052 (0.00%) 
Duodenal ulcer  1  4/9088 (0.04%)  4/9052 (0.04%) 
Dyspepsia  1  4/9088 (0.04%)  2/9052 (0.02%) 
Gastroduodenitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Gastrointestinal haemorrhage  1  47/9088 (0.52%)  48/9052 (0.53%) 
Gastrointestinal inflammation  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gastrooesophageal reflux disease  1  3/9088 (0.03%)  3/9052 (0.03%) 
Ileitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Irritable bowel syndrome  1  1/9088 (0.01%)  2/9052 (0.02%) 
Malabsorption  1  1/9088 (0.01%)  0/9052 (0.00%) 
Melaena  1  11/9088 (0.12%)  9/9052 (0.10%) 
Oesophagitis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Toothache  1  1/9088 (0.01%)  2/9052 (0.02%) 
General disorders     
Catheter site haemorrhage  1  0/9088 (0.00%)  1/9052 (0.01%) 
Device battery issue  1  2/9088 (0.02%)  3/9052 (0.03%) 
Device failure  1  3/9088 (0.03%)  2/9052 (0.02%) 
Drowning  1  0/9088 (0.00%)  1/9052 (0.01%) 
Drug interaction  1  1/9088 (0.01%)  0/9052 (0.00%) 
General physical health deterioration  1  1/9088 (0.01%)  2/9052 (0.02%) 
Implant site inflammation  1  0/9088 (0.00%)  1/9052 (0.01%) 
Bloody discharge  1  0/9088 (0.00%)  1/9052 (0.01%) 
Device dislocation  1  2/9088 (0.02%)  4/9052 (0.04%) 
Fatigue  1  4/9088 (0.04%)  4/9052 (0.04%) 
Medical device site reaction  1  1/9088 (0.01%)  0/9052 (0.00%) 
Non-cardiac chest pain  1  22/9088 (0.24%)  26/9052 (0.29%) 
Oedema  1  2/9088 (0.02%)  1/9052 (0.01%) 
Pyrexia  1  9/9088 (0.10%)  5/9052 (0.06%) 
Vessel puncture site haematoma  1  0/9088 (0.00%)  1/9052 (0.01%) 
Chest discomfort  1  4/9088 (0.04%)  2/9052 (0.02%) 
Fibrosis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hernia  1  2/9088 (0.02%)  1/9052 (0.01%) 
Implant site reaction  1  1/9088 (0.01%)  0/9052 (0.00%) 
Multi-organ failure  1  5/9088 (0.06%)  5/9052 (0.06%) 
Sudden death  1  57/9088 (0.63%)  50/9052 (0.55%) 
Adverse drug reaction  1  2/9088 (0.02%)  1/9052 (0.01%) 
Device malfunction  1  11/9088 (0.12%)  6/9052 (0.07%) 
Hernia obstructive  1  3/9088 (0.03%)  2/9052 (0.02%) 
Mass  1  3/9088 (0.03%)  0/9052 (0.00%) 
Necrobiosis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cardiac death  1  11/9088 (0.12%)  6/9052 (0.07%) 
Death  1  16/9088 (0.18%)  26/9052 (0.29%) 
Device lead damage  1  3/9088 (0.03%)  0/9052 (0.00%) 
Gait disturbance  1  1/9088 (0.01%)  2/9052 (0.02%) 
Generalised oedema  1  0/9088 (0.00%)  3/9052 (0.03%) 
Impaired healing  1  0/9088 (0.00%)  1/9052 (0.01%) 
Implant site thrombosis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Ischaemic ulcer  1  1/9088 (0.01%)  0/9052 (0.00%) 
Localised oedema  1  1/9088 (0.01%)  0/9052 (0.00%) 
Medical device complication  1  2/9088 (0.02%)  1/9052 (0.01%) 
Oedema peripheral  1  6/9088 (0.07%)  5/9052 (0.06%) 
Sudden cardiac death  1  30/9088 (0.33%)  18/9052 (0.20%) 
Chest pain  1  43/9088 (0.47%)  72/9052 (0.80%) 
Granuloma  1  1/9088 (0.01%)  1/9052 (0.01%) 
Infusion site haemorrhage  1  0/9088 (0.00%)  1/9052 (0.01%) 
Malaise  1  3/9088 (0.03%)  1/9052 (0.01%) 
Systemic inflammatory response syndrome  1  0/9088 (0.00%)  1/9052 (0.01%) 
Ulcer haemorrhage  1  1/9088 (0.01%)  1/9052 (0.01%) 
Vestibulitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Chills  1  1/9088 (0.01%)  0/9052 (0.00%) 
Cyst  1  0/9088 (0.00%)  1/9052 (0.01%) 
Influenza like illness  1  0/9088 (0.00%)  1/9052 (0.01%) 
Organ failure  1  0/9088 (0.00%)  1/9052 (0.01%) 
Pelvic mass  1  1/9088 (0.01%)  0/9052 (0.00%) 
Polyp  1  2/9088 (0.02%)  2/9052 (0.02%) 
Puncture site haemorrhage  1  0/9088 (0.00%)  1/9052 (0.01%) 
Accidental death  1  1/9088 (0.01%)  0/9052 (0.00%) 
Asthenia  1  12/9088 (0.13%)  8/9052 (0.09%) 
Cyst rupture  1  0/9088 (0.00%)  1/9052 (0.01%) 
Device capturing issue  1  0/9088 (0.00%)  1/9052 (0.01%) 
Device stimulation issue  1  1/9088 (0.01%)  0/9052 (0.00%) 
Exercise tolerance decreased  1  0/9088 (0.00%)  1/9052 (0.01%) 
Inflammation  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hepatobiliary disorders     
Cholangitis acute  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cholecystitis chronic  1  5/9088 (0.06%)  3/9052 (0.03%) 
Hyperbilirubinaemia  1  0/9088 (0.00%)  1/9052 (0.01%) 
Alcoholic liver disease  1  1/9088 (0.01%)  0/9052 (0.00%) 
Cholecystitis  1  19/9088 (0.21%)  19/9052 (0.21%) 
Hepatic function abnormal  1  0/9088 (0.00%)  1/9052 (0.01%) 
Acute hepatic failure  1  1/9088 (0.01%)  1/9052 (0.01%) 
Bile duct stone  1  4/9088 (0.04%)  5/9052 (0.06%) 
Chronic hepatitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hepatic congestion  1  2/9088 (0.02%)  2/9052 (0.02%) 
Hepatic steatosis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hepatitis acute  1  2/9088 (0.02%)  2/9052 (0.02%) 
Ischaemic hepatitis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Biliary colic  1  3/9088 (0.03%)  2/9052 (0.02%) 
Cholecystitis acute  1  16/9088 (0.18%)  20/9052 (0.22%) 
Cholestasis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Hepatitis toxic  1  1/9088 (0.01%)  1/9052 (0.01%) 
Cholangitis  1  5/9088 (0.06%)  4/9052 (0.04%) 
Hepatic cirrhosis  1  3/9088 (0.03%)  3/9052 (0.03%) 
Jaundice cholestatic  1  3/9088 (0.03%)  0/9052 (0.00%) 
Biliary dyskinesia  1  0/9088 (0.00%)  1/9052 (0.01%) 
Hepatic ischaemia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hepatitis  1  0/9088 (0.00%)  5/9052 (0.06%) 
Cholelithiasis  1  24/9088 (0.26%)  16/9052 (0.18%) 
Gallbladder disorder  1  0/9088 (0.00%)  1/9052 (0.01%) 
Liver disorder  1  2/9088 (0.02%)  1/9052 (0.01%) 
Bile duct obstruction  1  0/9088 (0.00%)  1/9052 (0.01%) 
Hepatic failure  1  1/9088 (0.01%)  2/9052 (0.02%) 
Hydrocholecystis  1  2/9088 (0.02%)  0/9052 (0.00%) 
Jaundice  1  3/9088 (0.03%)  1/9052 (0.01%) 
Immune system disorders     
Hypersensitivity  1  0/9088 (0.00%)  1/9052 (0.01%) 
Amyloidosis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Anaphylactic reaction  1  1/9088 (0.01%)  1/9052 (0.01%) 
Anaphylactic shock  1  1/9088 (0.01%)  0/9052 (0.00%) 
Serum sickness  1  0/9088 (0.00%)  1/9052 (0.01%) 
Drug hypersensitivity  1  1/9088 (0.01%)  1/9052 (0.01%) 
Infections and infestations     
Abscess limb  1  3/9088 (0.03%)  2/9052 (0.02%) 
Acid fast bacilli infection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Endocarditis  1  0/9088 (0.00%)  2/9052 (0.02%) 
Gangrene  1  5/9088 (0.06%)  0/9052 (0.00%) 
Haemorrhoid infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Herpes zoster infection neurological  1  1/9088 (0.01%)  0/9052 (0.00%) 
Incision site infection  1  1/9088 (0.01%)  2/9052 (0.02%) 
Infected epidermal cyst  1  1/9088 (0.01%)  0/9052 (0.00%) 
Intervertebral discitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Lobar pneumonia  1  16/9088 (0.18%)  12/9052 (0.13%) 
Oesophageal candidiasis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Osteomyelitis  1  4/9088 (0.04%)  4/9052 (0.04%) 
Peritoneal abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pharyngeal abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pneumonia  1  202/9088 (2.22%)  231/9052 (2.55%) 
Postoperative wound infection  1  3/9088 (0.03%)  2/9052 (0.02%) 
Staphylococcal infection  1  3/9088 (0.03%)  1/9052 (0.01%) 
Streptococcal bacteraemia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Subdiaphragmatic abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Typhoid fever  1  0/9088 (0.00%)  1/9052 (0.01%) 
Viral diarrhoea  1  1/9088 (0.01%)  0/9052 (0.00%) 
Abdominal wall abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Breast cellulitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Bronchopneumonia  1  9/9088 (0.10%)  7/9052 (0.08%) 
Campylobacter gastroenteritis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Clostridium difficile colitis  1  3/9088 (0.03%)  5/9052 (0.06%) 
Device related infection  1  6/9088 (0.07%)  3/9052 (0.03%) 
Empyema  1  2/9088 (0.02%)  1/9052 (0.01%) 
Endometritis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gastroenteritis Escherichia coli  1  0/9088 (0.00%)  1/9052 (0.01%) 
Gastroenteritis norovirus  1  2/9088 (0.02%)  0/9052 (0.00%) 
Gastrointestinal infection  1  2/9088 (0.02%)  0/9052 (0.00%) 
Implant site infection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Liver abscess  1  1/9088 (0.01%)  1/9052 (0.01%) 
Malaria  1  0/9088 (0.00%)  1/9052 (0.01%) 
Mastitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Necrotising fasciitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Otitis media  1  1/9088 (0.01%)  0/9052 (0.00%) 
Perirectal abscess  1  0/9088 (0.00%)  1/9052 (0.01%) 
Pneumonia staphylococcal  1  1/9088 (0.01%)  0/9052 (0.00%) 
Respiratory tract infection  1  17/9088 (0.19%)  16/9052 (0.18%) 
Staphylococcal bacteraemia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Staphylococcal skin infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Tracheobronchitis  1  1/9088 (0.01%)  2/9052 (0.02%) 
Urinary tract infection bacterial  1  1/9088 (0.01%)  2/9052 (0.02%) 
Vestibular neuronitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Appendicitis perforated  1  2/9088 (0.02%)  2/9052 (0.02%) 
Bronchitis haemophilus  1  0/9088 (0.00%)  1/9052 (0.01%) 
Bronchitis viral  1  1/9088 (0.01%)  1/9052 (0.01%) 
Diarrhoea infectious  1  0/9088 (0.00%)  1/9052 (0.01%) 
Endocarditis bacterial  1  1/9088 (0.01%)  1/9052 (0.01%) 
Enterococcal bacteraemia  1  1/9088 (0.01%)  1/9052 (0.01%) 
Erysipelas  1  12/9088 (0.13%)  15/9052 (0.17%) 
Injection site abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Laryngitis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Osteomyelitis chronic  1  0/9088 (0.00%)  1/9052 (0.01%) 
Post procedural cellulitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pseudomonas infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Psoas abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Sialoadenitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Tooth infection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Tuberculosis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Upper respiratory tract infection  1  5/9088 (0.06%)  11/9052 (0.12%) 
Urethritis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Weil's disease  1  0/9088 (0.00%)  1/9052 (0.01%) 
Abscess intestinal  1  0/9088 (0.00%)  1/9052 (0.01%) 
Appendicitis  1  13/9088 (0.14%)  9/9052 (0.10%) 
Bacterial infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Bronchiolitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Cystitis  1  3/9088 (0.03%)  2/9052 (0.02%) 
Dysentery  1  0/9088 (0.00%)  1/9052 (0.01%) 
Ear infection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gastroenteritis viral  1  3/9088 (0.03%)  5/9052 (0.06%) 
H1N1 influenza  1  2/9088 (0.02%)  2/9052 (0.02%) 
Infected bites  1  1/9088 (0.01%)  0/9052 (0.00%) 
Infection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Localised infection  1  2/9088 (0.02%)  3/9052 (0.03%) 
Lower respiratory tract infection  1  20/9088 (0.22%)  10/9052 (0.11%) 
Lung infection  1  8/9088 (0.09%)  11/9052 (0.12%) 
Mastoiditis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Peritoneal infection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pneumonia legionella  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pyelonephritis  1  8/9088 (0.09%)  1/9052 (0.01%) 
Scrotal abscess  1  0/9088 (0.00%)  1/9052 (0.01%) 
Sepsis  1  26/9088 (0.29%)  22/9052 (0.24%) 
Tooth abscess  1  3/9088 (0.03%)  3/9052 (0.03%) 
Abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Anal fistula infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Arthritis bacterial  1  6/9088 (0.07%)  3/9052 (0.03%) 
Arthritis infective  1  4/9088 (0.04%)  1/9052 (0.01%) 
Bacterial sepsis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cellulitis  1  44/9088 (0.48%)  60/9052 (0.66%) 
Cholecystitis infective  1  3/9088 (0.03%)  3/9052 (0.03%) 
Diabetic foot infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Endocarditis haemophilus  1  0/9088 (0.00%)  1/9052 (0.01%) 
Enteritis infectious  1  2/9088 (0.02%)  0/9052 (0.00%) 
Escherichia bacteraemia  1  2/9088 (0.02%)  0/9052 (0.00%) 
Escherichia urinary tract infection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Extradural abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Furuncle  1  0/9088 (0.00%)  1/9052 (0.01%) 
Gastroenteritis  1  30/9088 (0.33%)  21/9052 (0.23%) 
Klebsiella bacteraemia  1  0/9088 (0.00%)  1/9052 (0.01%) 
Labyrinthitis  1  2/9088 (0.02%)  0/9052 (0.00%) 
Lymphangitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Oral infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Perineal abscess  1  1/9088 (0.01%)  1/9052 (0.01%) 
Pilonidal cyst  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pneumonia pneumococcal  1  0/9088 (0.00%)  1/9052 (0.01%) 
Pneumonia primary atypical  1  1/9088 (0.01%)  1/9052 (0.01%) 
Pyelonephritis acute  1  3/9088 (0.03%)  3/9052 (0.03%) 
Pyelonephritis chronic  1  1/9088 (0.01%)  1/9052 (0.01%) 
Salmonellosis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Streptococcal infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Abdominal sepsis  1  0/9088 (0.00%)  2/9052 (0.02%) 
Bronchitis bacterial  1  0/9088 (0.00%)  2/9052 (0.02%) 
Chronic sinusitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Dacryocystitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Escherichia sepsis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Gastroenteritis shigella  1  0/9088 (0.00%)  1/9052 (0.01%) 
Hepatitis B  1  0/9088 (0.00%)  1/9052 (0.01%) 
Infected skin ulcer  1  2/9088 (0.02%)  2/9052 (0.02%) 
Influenza  1  5/9088 (0.06%)  11/9052 (0.12%) 
Joint abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Lung abscess  1  0/9088 (0.00%)  2/9052 (0.02%) 
Pharyngitis  1  3/9088 (0.03%)  0/9052 (0.00%) 
Respiratory tract infection bacterial  1  0/9088 (0.00%)  1/9052 (0.01%) 
Septic shock  1  5/9088 (0.06%)  7/9052 (0.08%) 
Sinobronchitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Sinusitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Skin infection  1  2/9088 (0.02%)  1/9052 (0.01%) 
Staphylococcal sepsis  1  3/9088 (0.03%)  0/9052 (0.00%) 
Subcutaneous abscess  1  1/9088 (0.01%)  1/9052 (0.01%) 
Superinfection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Urinary tract infection  1  60/9088 (0.66%)  48/9052 (0.53%) 
Uterine abscess  1  0/9088 (0.00%)  1/9052 (0.01%) 
Viral infection  1  3/9088 (0.03%)  3/9052 (0.03%) 
Wound infection  1  3/9088 (0.03%)  5/9052 (0.06%) 
Acute sinusitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Appendiceal abscess  1  0/9088 (0.00%)  1/9052 (0.01%) 
Brain abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Cellulitis of male external genital organ  1  1/9088 (0.01%)  1/9052 (0.01%) 
Clostridial infection  1  2/9088 (0.02%)  0/9052 (0.00%) 
Diverticulitis  1  13/9088 (0.14%)  12/9052 (0.13%) 
Haematoma infection  1  0/9088 (0.00%)  2/9052 (0.02%) 
Herpes virus infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Herpes zoster  1  4/9088 (0.04%)  1/9052 (0.01%) 
Incision site abscess  1  0/9088 (0.00%)  1/9052 (0.01%) 
Infected lymphocele  1  0/9088 (0.00%)  1/9052 (0.01%) 
Infected sebaceous cyst  1  0/9088 (0.00%)  1/9052 (0.01%) 
Meningitis bacterial  1  1/9088 (0.01%)  1/9052 (0.01%) 
Nosocomial infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Pneumococcal sepsis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Post procedural infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Pseudomembranous colitis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Respiratory tract infection viral  1  0/9088 (0.00%)  2/9052 (0.02%) 
Urosepsis  1  16/9088 (0.18%)  7/9052 (0.08%) 
Abdominal abscess  1  2/9088 (0.02%)  2/9052 (0.02%) 
Abdominal infection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Acarodermatitis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Anal abscess  1  2/9088 (0.02%)  3/9052 (0.03%) 
Bacteraemia  1  0/9088 (0.00%)  1/9052 (0.01%) 
Bronchitis  1  38/9088 (0.42%)  34/9052 (0.38%) 
Bursitis infective  1  0/9088 (0.00%)  3/9052 (0.03%) 
Candida sepsis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hantaviral infection  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hepatitis A  1  1/9088 (0.01%)  0/9052 (0.00%) 
Infective exacerbation of chronic obstructive airways disease  1  5/9088 (0.06%)  2/9052 (0.02%) 
Meningitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Nail infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Orchitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Otitis externa  1  1/9088 (0.01%)  0/9052 (0.00%) 
Perineal infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Pneumonia bacterial  1  3/9088 (0.03%)  2/9052 (0.02%) 
Pulmonary tuberculosis  1  1/9088 (0.01%)  0/9052 (0.00%) 
Pyelocystitis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Rectal abscess  1  1/9088 (0.01%)  0/9052 (0.00%) 
Respiratory syncytial virus infection  1  0/9088 (0.00%)  1/9052 (0.01%) 
Viraemia  1  1/9088 (0.01%)  0/9052 (0.00%) 
Injury, poisoning and procedural complications     
Accidental overdose  1  1/9088 (0.01%)  4/9052 (0.04%) 
Arterial injury  1  1/9088 (0.01%)  1/9052 (0.01%) 
Burns third degree  1  1/9088 (0.01%)  0/9052 (0.00%) 
Cartilage injury  1  0/9088 (0.00%)  1/9052 (0.01%) 
Cystitis radiation  1  1/9088 (0.01%)  0/9052 (0.00%) 
Hand fracture  1  0/9088 (0.00%)  2/9052 (0.02%) 
In-stent coronary artery restenosis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Ligament injury  1  0/9088 (0.00%)  2/9052 (0.02%) 
Periprosthetic fracture  1  1/9088 (0.01%)  0/9052 (0.00%) 
Post procedural haematuria  1  1/9088 (0.01%)  1/9052 (0.01%) 
Post-traumatic pain  1  1/9088 (0.01%)  0/9052 (0.00%) 
Respiratory fume inhalation disorder  1  1/9088 (0.01%)  1/9052 (0.01%) 
Skeletal injury  1  0/9088 (0.00%)  1/9052 (0.01%) 
Splenic injury  1  0/9088 (0.00%)  1/9052 (0.01%) 
Tooth fracture  1  0/9088 (0.00%)  1/9052 (0.01%) 
Toxicity to various agents  1  13/9088 (0.14%)  14/9052 (0.15%) 
Upper limb fracture  1  6/9088 (0.07%)  7/9052 (0.08%) 
Animal bite  1  1/9088 (0.01%)  0/9052 (0.00%) 
Contusion  1  2/9088 (0.02%)  5/9052 (0.06%) 
Foot fracture  1  4/9088 (0.04%)  0/9052 (0.00%) 
Gastrointestinal stoma complication  1  1/9088 (0.01%)  0/9052 (0.00%) 
Medication error  1  1/9088 (0.01%)  0/9052 (0.00%) 
Spinal column injury  1  1/9088 (0.01%)  0/9052 (0.00%) 
Spinal compression fracture  1  4/9088 (0.04%)  8/9052 (0.09%) 
Subcutaneous haematoma  1  1/9088 (0.01%)  5/9052 (0.06%) 
Synovial rupture  1  0/9088 (0.00%)  1/9052 (0.01%) 
Tendon rupture  1  2/9088 (0.02%)  0/9052 (0.00%) 
Traumatic arthropathy  1  1/9088 (0.01%)  0/9052 (0.00%) 
Traumatic haematoma  1  3/9088 (0.03%)  1/9052 (0.01%) 
Traumatic lung injury  1  0/9088 (0.00%)  2/9052 (0.02%) 
Adrenal haematoma  1  0/9088 (0.00%)  1/9052 (0.01%) 
Arterial restenosis  1  1/9088 (0.01%)  1/9052 (0.01%) 
Facial bones fracture  1  1/9088 (0.01%)  2/9052 (0.02%) 
Fall  1  24/9088 (0.26%)  30/9052 (0.33%) 
Open fracture  1  0/9088 (0.00%)  1/9052 (0.01%) 
Operative haemorrhage  1  2/9088 (0.02%)  0/9052 (0.00%) 
Procedural pain  1  0/9088 (0.00%)  1/9052 (0.01%) 
Snake bite  1  0/9088 (0.00%)  1/9052 (0.01%) 
Splenic rupture  1  0/9088 (0.00%)  2/9052 (0.02%) 
Tibia fracture  1  5/9088 (0.06%)  3/9052 (0.03%) 
Acetabulum fracture  1  1/9088 (0.01%)  0/9052 (0.00%) 
Ankle fracture  1  9/9088 (0.10%)  9/9052 (0.10%) 
Carbon monoxide poisoning  1  1/9088 (0.01%)  0/9052 (0.00%) 
Chest injury  1  1/9088 (0.01%)  3/9052 (0.03%) 
Clavicle fracture  1  0/9088 (0.00%)  5/9052 (0.06%) 
Femoral neck fracture  1  9/9088 (0.10%)  4/9052 (0.04%) 
Joint dislocation  1  5/9088 (0.06%)  6/9052 (0.07%) 
Joint sprain  1  2/9088 (0.02%)  1/9052 (0.01%) 
Muscle injury  1  0/9088 (0.00%)  2/9052 (0.02%) 
Overdose  1  26/9088 (0.29%)  40/9052 (0.44%) 
Pelvic fracture  1  4/9088 (0.04%)  2/9052 (0.02%) 
Post procedural complication  1  3/9088 (0.03%)  0/9052 (0.00%) 
Postoperative ileus  1  0/9088 (0.00%)  1/9052 (0.01%) 
Scapula fracture  1  0/9088 (0.00%)  1/9052 (0.01%) 
Skull fracture  1  0/9088 (0.00%)  3/9052 (0.03%) 
Subdural haematoma  1  7/9088 (0.08%)  27/9052 (0.30%) 
Thermal burn  1  1/9088 (0.01%)  1/9052 (0.01%) 
Traumatic haemorrhage  1  1/9088 (0.01%)  1/9052 (0.01%) 
Wrist fracture  1  4/9088 (0.04%)  2/9052 (0.02%) 
Anaemia postoperative  1  1/9088 (0.01%)  2/9052 (0.02%) 
Barotrauma  1  1/9088 (0.01%)  0/9052 (0.00%) 
Bone fissure  1  1/9088 (0.01%)  0/9052 (0.00%) 
Cervical vertebral fracture  1  0/9088 (0.00%)  3/9052 (0.03%) 
Drug administration error  1  1/9088 (0.01%)  0/9052 (0.00%) 
Eyeball rupture  1  1/9088 (0.01%)  0/9052 (0.00%) 
Femur fracture  1  11/9088 (0.12%)  16/9052 (0.18%) 
Hip fracture  1  19/9088 (0.21%)  28/9052 (0.31%) 
In-stent arterial restenosis  1  0/9088 (0.00%)  1/9052 (0.01%) 
Ligament rupture  1  0/9088 (0.00%)  1/9052 (0.01%) 
Lower limb fracture  1  2/9088 (0.02%)  4/9052 (0.04%) 
Patella fracture  1  4/9088 (0.04%)  1/9052 (0.01%) 
Post procedural haematoma  1  1/9088 (0.01%)  2/9052 (0.02%) 
Thoracic vertebral fracture  1  0/9088 (0.00%)  5/9052 (0.06%) 
Traumatic brain injury  1  3/9088 (0.03%)  3/9052 (0.03%) 
Traumatic renal injury  1  2/9088 (0.02%)  1/9052 (0.01%) 
Wound  1