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Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study (The APEX Study) (APEX)

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ClinicalTrials.gov Identifier: NCT01583218
Recruitment Status : Completed
First Posted : April 23, 2012
Results First Posted : September 20, 2017
Last Update Posted : September 26, 2018
Sponsor:
Information provided by (Responsible Party):
Portola Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition Venous Thromboembolism (VTE)
Interventions Drug: Betrixaban
Drug: Enoxaparin
Enrollment 7513
Recruitment Details First patient was enrolled on 3/29/2012 and last patient completed the study on 1/15/2016. Patients meeting the inclusion and none of the exclusion criteria at screening were randomized 1:1 to either the betrixaban or enoxaparin treatment group.
Pre-assignment Details To maintain the blind, patients either received betrixaban capsules for 35 to 42 days and daily subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days, or received daily SQ injections of enoxaparin for 10 ± 4 days and betrixaban placebo capsules for 35 to 42 days.
Arm/Group Title Betrixaban Enoxaparin
Hide Arm/Group Description Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
Period Title: Overall Study
Started 3759 3754
Completed 3470 3471
Not Completed 289 283
Reason Not Completed
Withdrawal by Subject             43             29
Death             206             211
Lost to Follow-up             11             17
Adverse event or serious adverse event             3             3
Patient /Family decision             3             0
Cannot contact patient directly             1             2
SOURCE DOCUMENT/COORDINATOR MISSING             0             2
Patient did not wish to attend visits             0             1
Patient randomized but not dosed             17             16
Patient was assessed via phone in person             1             0
Patient deemed ineligible after random             2             0
Patient was early terminated from study             0             1
Patient was randomized due to mistake             1             0
THE SUBJECT MOVED TO ANOTHER PROVINCE             0             1
Withdraw of consent on day of random             1             0
Arm/Group Title Betrixaban Enoxaparin Total
Hide Arm/Group Description Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days Total of all reporting groups
Overall Number of Baseline Participants 3759 3754 7513
Hide Baseline Analysis Population Description
All randomized subjects
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3759 participants 3754 participants 7513 participants
76.6  (8.46) 76.2  (8.31) 76.4  (8.39)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3759 participants 3754 participants 7513 participants
<75 years
1184
  31.5%
1237
  33.0%
2421
  32.2%
>=75 years
2575
  68.5%
2517
  67.0%
5092
  67.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3759 participants 3754 participants 7513 participants
Female
2054
  54.6%
2034
  54.2%
4088
  54.4%
Male
1705
  45.4%
1720
  45.8%
3425
  45.6%
1.Primary Outcome
Title Modified Intent-to-Treat (mITT) Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic Deep Vein Thrombosis (DVT), Non-fatal Pulmonary Emboli (PE), VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3
Hide Description mITT Cohort 1: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, venous thromboembolism (VTE) related death adjudicated by a blinded independent Clinical Events Committee (CEC) between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1).
Time Frame mITT Cohort 1: Between randomization and Day 47 (max)
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 1 (participants with baseline D-dimer ≥ 2 x upper limit normal (ULN) as determined by the local lab) of the mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
Arm/Group Title Betrixaban Enoxaparin
Hide Arm/Group Description:
Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days
Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
Overall Number of Participants Analyzed 2314 2313
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
5.70
(4.76 to 6.65)
7.18
(6.12 to 8.23)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Betrixaban, Enoxaparin
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.038
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Risk Reduction (RRR)
Estimated Value 0.209
Confidence Interval (2-Sided) 95%
0.013 to 0.366
Estimation Comments [Not Specified]
2.Primary Outcome
Title mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3
Hide Description mITT Cohort 2: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1).
Time Frame mITT Cohort 2: Between randomization and Day 47 (max)
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 (encompasses "both" participants over 75 and participants with baseline D-dimer ≥ 2 x ULN as determined by the local lab) of the mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
Arm/Group Title Betrixaban Enoxaparin
Hide Arm/Group Description:
Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days
Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
Overall Number of Participants Analyzed 3407 3391
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
4.70
(3.99 to 5.41)
6.02
(5.22 to 6.82)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Betrixaban, Enoxaparin
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.018
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Risk Reduction (RRR)
Estimated Value 0.216
Confidence Interval (2-Sided) 95%
0.041 to 0.359
Estimation Comments [Not Specified]
3.Primary Outcome
Title mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3
Hide Description mITT: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1).
Time Frame mITT: Between randomization and Day 47 (max)
Hide Outcome Measure Data
Hide Analysis Population Description
The mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
Arm/Group Title Betrixaban Enoxaparin
Hide Arm/Group Description:
Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days
Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
Overall Number of Participants Analyzed 3721 3720
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
4.43
(3.77 to 5.10)
5.99
(5.23 to 6.76)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Betrixaban, Enoxaparin
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Risk Reduction (RRR)
Estimated Value 0.254
Confidence Interval (2-Sided) 95%
0.092 to 0.387
Estimation Comments [Not Specified]
4.Primary Outcome
Title Percentage of Participants Experiencing Major Bleeding Through Seven Days After Discontinuation of All Study Medication
Hide Description Percentage of participants experiencing at least one major bleeding adjudicated by a blinded independent CEC between randomization (day 1) and up to seven days after discontinuation of all study medication.
Time Frame Between randomization and Day 49 (max)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population which consisted of all participants who had taken at least one dose of study drug.
Arm/Group Title Betrixaban Enoxaparin
Hide Arm/Group Description:
Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days
Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
Overall Number of Participants Analyzed 3716 3716
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
0.67
(0.41 to 0.94)
0.57
(0.32 to 0.81)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Betrixaban, Enoxaparin
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.554
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
5.Secondary Outcome
Title mITT Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3
Hide Description mITT Cohort 1: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1).
Time Frame mITT Cohort 1: Between randomization and Day 42 (max)
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 1 (participants with baseline D-dimer ≥ 2 x ULN as determined by the local lab) of the mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
Arm/Group Title Betrixaban Enoxaparin
Hide Arm/Group Description:
Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days
Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
Overall Number of Participants Analyzed 2314 2313
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
1.30
(0.84 to 1.76)
1.90
(1.35 to 2.46)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Betrixaban, Enoxaparin
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.092
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Risk Reduction (RRR)
Estimated Value 0.326
Confidence Interval (2-Sided) 95%
-0.069 to 0.576
Estimation Comments [Not Specified]
6.Secondary Outcome
Title mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3
Hide Description mITT Cohort 2: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1).
Time Frame mITT Cohort 2: Between randomization and Day 42 (max)
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 (encompasses "both" participants over 75 and participants with baseline D-dimer ≥ 2 x ULN as determined by the local lab) of the mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
Arm/Group Title Betrixaban Enoxaparin
Hide Arm/Group Description:
Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days
Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
Overall Number of Participants Analyzed 3407 3391
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
1.03
(0.69 to 1.37)
1.45
(1.04 to 1.85)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Betrixaban, Enoxaparin
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.11
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Risk Reduction (RRR)
Estimated Value 0.295
Confidence Interval (2-Sided) 95%
-0.085 to 0.542
Estimation Comments [Not Specified]
7.Secondary Outcome
Title mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3
Hide Description mITT: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1).
Time Frame mITT: Between randomization and Day 42 (max)
Hide Outcome Measure Data
Hide Analysis Population Description
The mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
Arm/Group Title Betrixaban Enoxaparin
Hide Arm/Group Description:
Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days
Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
Overall Number of Participants Analyzed 3721 3720
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
0.94
(0.63 to 1.25)
1.45
(1.07 to 1.84)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Betrixaban, Enoxaparin
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.039
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Risk Reduction (RRR)
Estimated Value 0.358
Confidence Interval (2-Sided) 95%
0.020 to 0.580
Estimation Comments [Not Specified]
Time Frame From first dose date (including) till the end of study
Adverse Event Reporting Description The number of patients at risk by study arm in the Adverse Events Results is based on Safety population, defined as patients who were randomized and received at least one dose of study drug. It leads to 3716 safety subjects in Betrixaban arm and 3716 in Enoxaprin arm which corresponds to the number of patients at risk in Adverse Events Results.
 
Arm/Group Title Betrixaban Enoxaparin
Hide Arm/Group Description Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
All-Cause Mortality
Betrixaban Enoxaparin
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Betrixaban Enoxaparin
Affected / at Risk (%) Affected / at Risk (%)
Total   657/3716 (17.68%)   615/3716 (16.55%) 
Blood and lymphatic system disorders     
Anaemia   8/3716 (0.22%)  4/3716 (0.11%) 
Iron deficiency anaemia   1/3716 (0.03%)  1/3716 (0.03%) 
Thrombocytopenia   1/3716 (0.03%)  1/3716 (0.03%) 
Coagulopathy   1/3716 (0.03%)  0/3716 (0.00%) 
Haemorrhagic anaemia   1/3716 (0.03%)  0/3716 (0.00%) 
Polycythaemia   0/3716 (0.00%)  1/3716 (0.03%) 
Spontaneous haematoma   1/3716 (0.03%)  0/3716 (0.00%) 
Cardiac disorders     
Cardiac failure   83/3716 (2.23%)  66/3716 (1.78%) 
Atrial fibrillation   11/3716 (0.30%)  23/3716 (0.62%) 
Cardiac failure congestive   10/3716 (0.27%)  15/3716 (0.40%) 
Cardiac failure acute   10/3716 (0.27%)  12/3716 (0.32%) 
Cardiac failure chronic   13/3716 (0.35%)  9/3716 (0.24%) 
Acute myocardial infarction   6/3716 (0.16%)  12/3716 (0.32%) 
Myocardial infarction   7/3716 (0.19%)  10/3716 (0.27%) 
Cardiogenic shock   9/3716 (0.24%)  6/3716 (0.16%) 
Cardiac arrest   7/3716 (0.19%)  5/3716 (0.13%) 
Coronary artery disease   8/3716 (0.22%)  3/3716 (0.08%) 
Angina unstable   3/3716 (0.08%)  7/3716 (0.19%) 
Acute coronary syndrome   6/3716 (0.16%)  3/3716 (0.08%) 
Atrioventricular block complete   5/3716 (0.13%)  3/3716 (0.08%) 
Myocardial ischaemia   2/3716 (0.05%)  6/3716 (0.16%) 
Angina pectoris   5/3716 (0.13%)  0/3716 (0.00%) 
Cardio-respiratory arrest   3/3716 (0.08%)  2/3716 (0.05%) 
Cardiopulmonary failure   1/3716 (0.03%)  4/3716 (0.11%) 
Ventricular tachycardia   4/3716 (0.11%)  1/3716 (0.03%) 
Coronary artery insufficiency   2/3716 (0.05%)  2/3716 (0.05%) 
Atrioventricular block   1/3716 (0.03%)  2/3716 (0.05%) 
Cardiovascular disorder   1/3716 (0.03%)  2/3716 (0.05%) 
Cardiovascular insufficiency   0/3716 (0.00%)  3/3716 (0.08%) 
Ventricular fibrillation   1/3716 (0.03%)  2/3716 (0.05%) 
Atrial flutter   0/3716 (0.00%)  2/3716 (0.05%) 
Atrioventricular block second degree   1/3716 (0.03%)  1/3716 (0.03%) 
Bradycardia   2/3716 (0.05%)  0/3716 (0.00%) 
Cardiomyopathy   1/3716 (0.03%)  1/3716 (0.03%) 
Cor pulmonale   1/3716 (0.03%)  1/3716 (0.03%) 
Pericardial effusion   1/3716 (0.03%)  1/3716 (0.03%) 
Sick sinus syndrome   1/3716 (0.03%)  1/3716 (0.03%) 
Supraventricular tachycardia   2/3716 (0.05%)  0/3716 (0.00%) 
Acute left ventricular failure   0/3716 (0.00%)  1/3716 (0.03%) 
Aortic valve incompetence   0/3716 (0.00%)  1/3716 (0.03%) 
Aortic valve stenosis   0/3716 (0.00%)  1/3716 (0.03%) 
Cardiac ventricular thrombosis   1/3716 (0.03%)  0/3716 (0.00%) 
Congestive cardiomyopathy   0/3716 (0.00%)  1/3716 (0.03%) 
Coronary artery stenosis   0/3716 (0.00%)  1/3716 (0.03%) 
Ischaemic cardiomyopathy   1/3716 (0.03%)  0/3716 (0.00%) 
Mitral valve incompetence   0/3716 (0.00%)  1/3716 (0.03%) 
Pericardial haemorrhage   1/3716 (0.03%)  0/3716 (0.00%) 
Sinoatrial block   0/3716 (0.00%)  1/3716 (0.03%) 
Stress cardiomyopathy   0/3716 (0.00%)  1/3716 (0.03%) 
Tricuspid valve incompetence   1/3716 (0.03%)  0/3716 (0.00%) 
Trifascicular block   1/3716 (0.03%)  0/3716 (0.00%) 
Ventricular extrasystoles   1/3716 (0.03%)  0/3716 (0.00%) 
Ventricular hypokinesia   0/3716 (0.00%)  1/3716 (0.03%) 
Ear and labyrinth disorders     
Vertigo   1/3716 (0.03%)  1/3716 (0.03%) 
Endocrine disorders     
Goitre   1/3716 (0.03%)  0/3716 (0.00%) 
Hypoparathyroidism   0/3716 (0.00%)  1/3716 (0.03%) 
Eye disorders     
Conjunctival haemorrhage   1/3716 (0.03%)  1/3716 (0.03%) 
Diabetic retinopathy   0/3716 (0.00%)  1/3716 (0.03%) 
Retinal haemorrhage   0/3716 (0.00%)  1/3716 (0.03%) 
Gastrointestinal disorders     
Gastrointestinal haemorrhage   18/3716 (0.48%)  5/3716 (0.13%) 
Rectal haemorrhage   15/3716 (0.40%)  3/3716 (0.08%) 
Abdominal pain   2/3716 (0.05%)  3/3716 (0.08%) 
Gastric ulcer haemorrhage   3/3716 (0.08%)  2/3716 (0.05%) 
Intestinal obstruction   1/3716 (0.03%)  4/3716 (0.11%) 
Haemorrhoidal haemorrhage   1/3716 (0.03%)  3/3716 (0.08%) 
Vomiting   0/3716 (0.00%)  4/3716 (0.11%) 
Colitis   0/3716 (0.00%)  3/3716 (0.08%) 
Diarrhoea   1/3716 (0.03%)  2/3716 (0.05%) 
Duodenal ulcer haemorrhage   2/3716 (0.05%)  1/3716 (0.03%) 
Upper gastrointestinal haemorrhage   1/3716 (0.03%)  2/3716 (0.05%) 
Gastric haemorrhage   2/3716 (0.05%)  0/3716 (0.00%) 
Gastric ulcer   2/3716 (0.05%)  0/3716 (0.00%) 
Gingival bleeding   1/3716 (0.03%)  1/3716 (0.03%) 
Intestinal haemorrhage   0/3716 (0.00%)  2/3716 (0.05%) 
Intestinal ischaemia   2/3716 (0.05%)  0/3716 (0.00%) 
Melaena   1/3716 (0.03%)  1/3716 (0.03%) 
Pharyngo-oesophageal diverticulum   1/3716 (0.03%)  1/3716 (0.03%) 
Abdominal strangulated hernia   1/3716 (0.03%)  0/3716 (0.00%) 
Abdominal wall haematoma   1/3716 (0.03%)  0/3716 (0.00%) 
Acute abdomen   0/3716 (0.00%)  1/3716 (0.03%) 
Constipation   1/3716 (0.03%)  0/3716 (0.00%) 
Duodenal ulcer   1/3716 (0.03%)  0/3716 (0.00%) 
Faecaloma   0/3716 (0.00%)  1/3716 (0.03%) 
Gastric ulcer perforation   0/3716 (0.00%)  1/3716 (0.03%) 
Gastroduodenal haemorrhage   1/3716 (0.03%)  0/3716 (0.00%) 
Gastrointestinal disorder   1/3716 (0.03%)  0/3716 (0.00%) 
Gastrointestinal necrosis   0/3716 (0.00%)  1/3716 (0.03%) 
Gastrointestinal polyp haemorrhage   1/3716 (0.03%)  0/3716 (0.00%) 
Intestinal perforation   0/3716 (0.00%)  1/3716 (0.03%) 
Large intestinal haemorrhage   1/3716 (0.03%)  0/3716 (0.00%) 
Lower gastrointestinal haemorrhage   1/3716 (0.03%)  0/3716 (0.00%) 
Mechanical ileus   0/3716 (0.00%)  1/3716 (0.03%) 
Nausea   0/3716 (0.00%)  1/3716 (0.03%) 
Pancreatitis   0/3716 (0.00%)  1/3716 (0.03%) 
Pancreatitis acute   1/3716 (0.03%)  0/3716 (0.00%) 
Peptic ulcer haemorrhage   0/3716 (0.00%)  1/3716 (0.03%) 
Volvulus   0/3716 (0.00%)  1/3716 (0.03%) 
General disorders     
Death   9/3716 (0.24%)  16/3716 (0.43%) 
Sudden cardiac death   6/3716 (0.16%)  5/3716 (0.13%) 
Multi-organ failure   3/3716 (0.08%)  6/3716 (0.16%) 
General physical health deterioration   6/3716 (0.16%)  2/3716 (0.05%) 
Sudden death   3/3716 (0.08%)  3/3716 (0.08%) 
Non-cardiac chest pain   2/3716 (0.05%)  1/3716 (0.03%) 
Pyrexia   3/3716 (0.08%)  0/3716 (0.00%) 
Cardiac death   1/3716 (0.03%)  1/3716 (0.03%) 
Chest pain   1/3716 (0.03%)  1/3716 (0.03%) 
Fatigue   1/3716 (0.03%)  1/3716 (0.03%) 
Asthenia   0/3716 (0.00%)  1/3716 (0.03%) 
Catheter site haemorrhage   0/3716 (0.00%)  1/3716 (0.03%) 
Condition aggravated   1/3716 (0.03%)  0/3716 (0.00%) 
Device malfunction   1/3716 (0.03%)  0/3716 (0.00%) 
Discomfort   0/3716 (0.00%)  1/3716 (0.03%) 
Fibrosis   1/3716 (0.03%)  0/3716 (0.00%) 
Generalised oedema   0/3716 (0.00%)  1/3716 (0.03%) 
Hyperthermia   1/3716 (0.03%)  0/3716 (0.00%) 
Impaired healing   1/3716 (0.03%)  0/3716 (0.00%) 
Injection site haemorrhage   0/3716 (0.00%)  1/3716 (0.03%) 
Necrosis   1/3716 (0.03%)  0/3716 (0.00%) 
Oedema peripheral   1/3716 (0.03%)  0/3716 (0.00%) 
Puncture site haemorrhage   0/3716 (0.00%)  1/3716 (0.03%) 
Ulcer   1/3716 (0.03%)  0/3716 (0.00%) 
Hepatobiliary disorders     
Cholecystitis   4/3716 (0.11%)  0/3716 (0.00%) 
Bile duct stone   2/3716 (0.05%)  0/3716 (0.00%) 
Cholecystitis acute   2/3716 (0.05%)  0/3716 (0.00%) 
Cholecystitis chronic   2/3716 (0.05%)  0/3716 (0.00%) 
Cholangitis   0/3716 (0.00%)  1/3716 (0.03%) 
Cholelithiasis   1/3716 (0.03%)  0/3716 (0.00%) 
Hepatitis   1/3716 (0.03%)  0/3716 (0.00%) 
Hepatocellular injury   1/3716 (0.03%)  0/3716 (0.00%) 
Ischaemic hepatitis   0/3716 (0.00%)  1/3716 (0.03%) 
Portal vein thrombosis   1/3716 (0.03%)  0/3716 (0.00%) 
Immune system disorders     
Drug hypersensitivity   1/3716 (0.03%)  1/3716 (0.03%) 
Anaphylactic reaction   0/3716 (0.00%)  1/3716 (0.03%) 
Hypersensitivity   0/3716 (0.00%)  1/3716 (0.03%) 
Infections and infestations     
Pneumonia   46/3716 (1.24%)  64/3716 (1.72%) 
Urinary tract infection   13/3716 (0.35%)  11/3716 (0.30%) 
Sepsis   13/3716 (0.35%)  7/3716 (0.19%) 
Septic shock   7/3716 (0.19%)  8/3716 (0.22%) 
Cellulitis   3/3716 (0.08%)  7/3716 (0.19%) 
Bronchitis   1/3716 (0.03%)  6/3716 (0.16%) 
Respiratory tract infection   4/3716 (0.11%)  3/3716 (0.08%) 
Erysipelas   4/3716 (0.11%)  2/3716 (0.05%) 
Gastroenteritis   4/3716 (0.11%)  0/3716 (0.00%) 
Bronchopneumonia   2/3716 (0.05%)  1/3716 (0.03%) 
Clostridium difficile colitis   1/3716 (0.03%)  2/3716 (0.05%) 
Endocarditis   1/3716 (0.03%)  2/3716 (0.05%) 
Infected skin ulcer   2/3716 (0.05%)  1/3716 (0.03%) 
Lobar pneumonia   1/3716 (0.03%)  2/3716 (0.05%) 
Pyelonephritis   2/3716 (0.05%)  1/3716 (0.03%) 
Pyelonephritis acute   1/3716 (0.03%)  2/3716 (0.05%) 
Wound infection   2/3716 (0.05%)  1/3716 (0.03%) 
Appendicitis   1/3716 (0.03%)  1/3716 (0.03%) 
Clostridium colitis   0/3716 (0.00%)  2/3716 (0.05%) 
Infection   2/3716 (0.05%)  0/3716 (0.00%) 
Osteomyelitis   2/3716 (0.05%)  0/3716 (0.00%) 
Pseudomembranous colitis   2/3716 (0.05%)  0/3716 (0.00%) 
Pulmonary sepsis   2/3716 (0.05%)  0/3716 (0.00%) 
Pulmonary tuberculosis   2/3716 (0.05%)  0/3716 (0.00%) 
Tracheobronchitis   1/3716 (0.03%)  1/3716 (0.03%) 
Urosepsis   1/3716 (0.03%)  1/3716 (0.03%) 
Abscess bacterial   0/3716 (0.00%)  1/3716 (0.03%) 
Appendicitis perforated   1/3716 (0.03%)  0/3716 (0.00%) 
Arthritis bacterial   0/3716 (0.00%)  1/3716 (0.03%) 
Atypical pneumonia   0/3716 (0.00%)  1/3716 (0.03%) 
Bacteraemia   1/3716 (0.03%)  0/3716 (0.00%) 
Bone abscess   1/3716 (0.03%)  0/3716 (0.00%) 
Bronchitis bacterial   1/3716 (0.03%)  0/3716 (0.00%) 
Clostridial infection   0/3716 (0.00%)  1/3716 (0.03%) 
Clostridium difficile infection   0/3716 (0.00%)  1/3716 (0.03%) 
Cystitis   1/3716 (0.03%)  0/3716 (0.00%) 
Device related infection   1/3716 (0.03%)  0/3716 (0.00%) 
Diverticulitis   0/3716 (0.00%)  1/3716 (0.03%) 
Empyema   1/3716 (0.03%)  0/3716 (0.00%) 
Endocarditis bacterial   0/3716 (0.00%)  1/3716 (0.03%) 
Enterococcal infection   1/3716 (0.03%)  0/3716 (0.00%) 
Epididymitis   1/3716 (0.03%)  0/3716 (0.00%) 
Escherichia bacteraemia   1/3716 (0.03%)  0/3716 (0.00%) 
Febrile infection   1/3716 (0.03%)  0/3716 (0.00%) 
Gallbladder empyema   0/3716 (0.00%)  1/3716 (0.03%) 
Gastrointestinal bacterial infection   0/3716 (0.00%)  1/3716 (0.03%) 
Infectious pleural effusion   0/3716 (0.00%)  1/3716 (0.03%) 
Infective exacerbation of chronic obstructive airways   0/3716 (0.00%)  1/3716 (0.03%) 
Influenza   1/3716 (0.03%)  0/3716 (0.00%) 
Intervertebral discitis   0/3716 (0.00%)  1/3716 (0.03%) 
Localised infection   0/3716 (0.00%)  1/3716 (0.03%) 
Mastoiditis   1/3716 (0.03%)  0/3716 (0.00%) 
Nosocomial infection   0/3716 (0.00%)  1/3716 (0.03%) 
Oral candidiasis   0/3716 (0.00%)  1/3716 (0.03%) 
Pneumonia staphylococcal   1/3716 (0.03%)  0/3716 (0.00%) 
Pneumonia streptococcal   1/3716 (0.03%)  0/3716 (0.00%) 
Pseudomonal sepsis   0/3716 (0.00%)  1/3716 (0.03%) 
Pseudomonas infection   0/3716 (0.00%)  1/3716 (0.03%) 
Psoas abscess   1/3716 (0.03%)  0/3716 (0.00%) 
Pyelocystitis   0/3716 (0.00%)  1/3716 (0.03%) 
Sinusitis   0/3716 (0.00%)  1/3716 (0.03%) 
Skin infection   1/3716 (0.03%)  0/3716 (0.00%) 
Soft tissue infection   0/3716 (0.00%)  1/3716 (0.03%) 
Staphylococcal sepsis   0/3716 (0.00%)  1/3716 (0.03%) 
Subcutaneous abscess   0/3716 (0.00%)  1/3716 (0.03%) 
Upper respiratory tract infection   0/3716 (0.00%)  1/3716 (0.03%) 
Viral upper respiratory tract infection   1/3716 (0.03%)  0/3716 (0.00%) 
Injury, poisoning and procedural complications     
Hip fracture   1/3716 (0.03%)  3/3716 (0.08%) 
Fall   3/3716 (0.08%)  0/3716 (0.00%) 
Rib fracture   0/3716 (0.00%)  3/3716 (0.08%) 
Cervical vertebral fracture   1/3716 (0.03%)  1/3716 (0.03%) 
Contusion   1/3716 (0.03%)  1/3716 (0.03%) 
Head injury   1/3716 (0.03%)  1/3716 (0.03%) 
Lumbar vertebral fracture   2/3716 (0.05%)  0/3716 (0.00%) 
Accident   0/3716 (0.00%)  1/3716 (0.03%) 
Accidental overdose   0/3716 (0.00%)  1/3716 (0.03%) 
Concussion   1/3716 (0.03%)  0/3716 (0.00%) 
Femur fracture   1/3716 (0.03%)  0/3716 (0.00%) 
Humerus fracture   1/3716 (0.03%)  0/3716 (0.00%) 
Iatrogenic injury   0/3716 (0.00%)  1/3716 (0.03%) 
Joint dislocation   1/3716 (0.03%)  0/3716 (0.00%) 
Patella fracture   1/3716 (0.03%)  0/3716 (0.00%) 
Pneumothorax traumatic   0/3716 (0.00%)  1/3716 (0.03%) 
Post procedural haemorrhage   0/3716 (0.00%)  1/3716 (0.03%) 
Procedural haemorrhage   1/3716 (0.03%)  0/3716 (0.00%) 
Pubis fracture   0/3716 (0.00%)  1/3716 (0.03%) 
Skin injury   1/3716 (0.03%)  0/3716 (0.00%) 
Spinal compression fracture   1/3716 (0.03%)  0/3716 (0.00%) 
Spinal cord injury   1/3716 (0.03%)  0/3716 (0.00%) 
Subdural haematoma   0/3716 (0.00%)  1/3716 (0.03%) 
Tendon rupture   1/3716 (0.03%)  0/3716 (0.00%) 
Traumatic fracture   1/3716 (0.03%)  0/3716 (0.00%) 
Traumatic haematoma   1/3716 (0.03%)  0/3716 (0.00%) 
Upper limb fracture   1/3716 (0.03%)  0/3716 (0.00%) 
Investigations     
Hepatic enzyme increased   2/3716 (0.05%)  5/3716 (0.13%) 
Aspiration bronchial   2/3716 (0.05%)  1/3716 (0.03%) 
Alanine aminotransferase increased   1/3716 (0.03%)  1/3716 (0.03%) 
General physical condition abnormal   1/3716 (0.03%)  1/3716 (0.03%) 
Blood alkaline phosphatase increased   1/3716 (0.03%)  0/3716 (0.00%) 
Blood creatinine increased   1/3716 (0.03%)  0/3716 (0.00%) 
Blood urea increased   1/3716 (0.03%)  0/3716 (0.00%) 
Blood urine present   1/3716 (0.03%)  0/3716 (0.00%) 
Catheterisation cardiac   0/3716 (0.00%)  1/3716 (0.03%) 
Transaminases increased   1/3716 (0.03%)  0/3716 (0.00%) 
Metabolism and nutrition disorders     
Type 2 diabetes mellitus   1/3716 (0.03%)  3/3716 (0.08%) 
Dehydration   1/3716 (0.03%)  2/3716 (0.05%) 
Diabetes mellitus   0/3716 (0.00%)  2/3716 (0.05%) 
Gout   1/3716 (0.03%)  1/3716 (0.03%) 
Hypokalaemia   2/3716 (0.05%)  0/3716 (0.00%) 
Hyponatraemia   1/3716 (0.03%)  1/3716 (0.03%) 
Failure to thrive   0/3716 (0.00%)  1/3716 (0.03%) 
Hypercalcaemia   1/3716 (0.03%)  0/3716 (0.00%) 
Hyperglycaemia   0/3716 (0.00%)  1/3716 (0.03%) 
Hyperkalaemia   0/3716 (0.00%)  1/3716 (0.03%) 
Hypernatraemia   0/3716 (0.00%)  1/3716 (0.03%) 
Hyperphosphataemia   0/3716 (0.00%)  1/3716 (0.03%) 
Hypoglycaemia   1/3716 (0.03%)  0/3716 (0.00%) 
Hypovolaemia   0/3716 (0.00%)  1/3716 (0.03%) 
Type 1 diabetes mellitus   1/3716 (0.03%)  0/3716 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthritis   2/3716 (0.05%)  0/3716 (0.00%) 
Musculoskeletal chest pain   1/3716 (0.03%)  1/3716 (0.03%) 
Arthralgia   1/3716 (0.03%)  0/3716 (0.00%) 
Cervical spinal stenosis   1/3716 (0.03%)  0/3716 (0.00%) 
Chondrocalcinosis   1/3716 (0.03%)  0/3716 (0.00%) 
Coccydynia   1/3716 (0.03%)  0/3716 (0.00%) 
Intervertebral disc degeneration   1/3716 (0.03%)  0/3716 (0.00%) 
Intervertebral disc disorder   1/3716 (0.03%)  0/3716 (0.00%) 
Intervertebral disc protrusion   0/3716 (0.00%)  1/3716 (0.03%) 
Osteoarthritis   0/3716 (0.00%)  1/3716 (0.03%) 
Osteochondrosis   1/3716 (0.03%)  0/3716 (0.00%) 
Polymyositis   0/3716 (0.00%)  1/3716 (0.03%) 
Scleroderma   0/3716 (0.00%)  1/3716 (0.03%) 
Synovial cyst   1/3716 (0.03%)  0/3716 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung neoplasm malignant   10/3716 (0.27%)  8/3716 (0.22%) 
Cervix carcinoma   2/3716 (0.05%)  1/3716 (0.03%) 
Metastases to central nervous system   3/3716 (0.08%)  0/3716 (0.00%) 
Adenocarcinoma of colon   2/3716 (0.05%)  0/3716 (0.00%) 
Gastric cancer   1/3716 (0.03%)  1/3716 (0.03%) 
Metastatic neoplasm   2/3716 (0.05%)  0/3716 (0.00%) 
Ovarian cancer   2/3716 (0.05%)  0/3716 (0.00%) 
Rectal cancer   2/3716 (0.05%)  0/3716 (0.00%) 
Adenocarcinoma   0/3716 (0.00%)  1/3716 (0.03%) 
Brain neoplasm   1/3716 (0.03%)  0/3716 (0.00%) 
Breast cancer metastatic   1/3716 (0.03%)  0/3716 (0.00%) 
Bronchial carcinoma   1/3716 (0.03%)  0/3716 (0.00%) 
Chronic lymphocytic leukaemia   1/3716 (0.03%)  0/3716 (0.00%) 
Colon cancer   0/3716 (0.00%)  1/3716 (0.03%) 
Colorectal adenocarcinoma   0/3716 (0.00%)  1/3716 (0.03%) 
Colorectal cancer   1/3716 (0.03%)  0/3716 (0.00%) 
Gastrointestinal stromal tumour   1/3716 (0.03%)  0/3716 (0.00%) 
Leukaemia   1/3716 (0.03%)  0/3716 (0.00%) 
Lung carcinoma cell type unspecified stage IV   1/3716 (0.03%)  0/3716 (0.00%) 
Malignant pleural effusion   0/3716 (0.00%)  1/3716 (0.03%) 
Meningioma   1/3716 (0.03%)  0/3716 (0.00%) 
Metastases to bone   0/3716 (0.00%)  1/3716 (0.03%) 
Metastases to liver   1/3716 (0.03%)  0/3716 (0.00%) 
Metastases to peritoneum   1/3716 (0.03%)  0/3716 (0.00%) 
Metastasis   0/3716 (0.00%)  1/3716 (0.03%) 
Myeloid leukaemia   1/3716 (0.03%)  0/3716 (0.00%) 
Neoplasm malignant   0/3716 (0.00%)  1/3716 (0.03%) 
Non-Hodgkin's lymphoma   0/3716 (0.00%)  1/3716 (0.03%) 
Oesophageal carcinoma   0/3716 (0.00%)  1/3716 (0.03%) 
Pancreatic carcinoma metastatic   1/3716 (0.03%)  0/3716 (0.00%) 
Plasma cell myeloma   1/3716 (0.03%)  0/3716 (0.00%) 
Plasmacytoma   1/3716 (0.03%)  0/3716 (0.00%) 
Pleural mesothelioma   0/3716 (0.00%)  1/3716 (0.03%) 
Rectosigmoid cancer   1/3716 (0.03%)  0/3716 (0.00%) 
Small cell lung cancer   1/3716 (0.03%)  0/3716 (0.00%) 
Throat cancer   1/3716 (0.03%)  0/3716 (0.00%) 
Transitional cell carcinoma   0/3716 (0.00%)  1/3716 (0.03%) 
Vulval cancer   1/3716 (0.03%)  0/3716 (0.00%) 
Nervous system disorders     
Ischaemic stroke   19/3716 (0.51%)  35/3716 (0.94%) 
Brain oedema   8/3716 (0.22%)  10/3716 (0.27%) 
Cerebrovascular accident   7/3716 (0.19%)  6/3716 (0.16%) 
Syncope   4/3716 (0.11%)  4/3716 (0.11%) 
Cerebral infarction   3/3716 (0.08%)  3/3716 (0.08%) 
Transient ischaemic attack   2/3716 (0.05%)  4/3716 (0.11%) 
Convulsion   2/3716 (0.05%)  3/3716 (0.08%) 
Loss of consciousness   4/3716 (0.11%)  1/3716 (0.03%) 
Haemorrhagic stroke   1/3716 (0.03%)  2/3716 (0.05%) 
Subarachnoid haemorrhage   1/3716 (0.03%)  2/3716 (0.05%) 
Coma   2/3716 (0.05%)  0/3716 (0.00%) 
Dizziness   1/3716 (0.03%)  1/3716 (0.03%) 
Encephalopathy   0/3716 (0.00%)  2/3716 (0.05%) 
Epilepsy   1/3716 (0.03%)  1/3716 (0.03%) 
Haemorrhagic transformation stroke   0/3716 (0.00%)  2/3716 (0.05%) 
Sciatica   1/3716 (0.03%)  1/3716 (0.03%) 
Carotid artery stenosis   0/3716 (0.00%)  1/3716 (0.03%) 
Cerebellar infarction   0/3716 (0.00%)  1/3716 (0.03%) 
Cerebral haemorrhage   0/3716 (0.00%)  1/3716 (0.03%) 
Cerebral ischaemia   0/3716 (0.00%)  1/3716 (0.03%) 
Hydrocephalus   1/3716 (0.03%)  0/3716 (0.00%) 
Hypoglycaemic coma   1/3716 (0.03%)  0/3716 (0.00%) 
Intraventricular haemorrhage   0/3716 (0.00%)  1/3716 (0.03%) 
Nervous system disorder   1/3716 (0.03%)  0/3716 (0.00%) 
Neuroglycopenia   1/3716 (0.03%)  0/3716 (0.00%) 
Neurological decompensation   0/3716 (0.00%)  1/3716 (0.03%) 
Paralysis flaccid   1/3716 (0.03%)  0/3716 (0.00%) 
Polyneuropathy   0/3716 (0.00%)  1/3716 (0.03%) 
Presyncope   0/3716 (0.00%)  1/3716 (0.03%) 
Unresponsive to stimuli   1/3716 (0.03%)  0/3716 (0.00%) 
Psychiatric disorders     
Confusional state   2/3716 (0.05%)  0/3716 (0.00%) 
Depression   0/3716 (0.00%)  2/3716 (0.05%) 
Anxiety   1/3716 (0.03%)  0/3716 (0.00%) 
Delirium   0/3716 (0.00%)  1/3716 (0.03%) 
Major depression   1/3716 (0.03%)  0/3716 (0.00%) 
Mental disorder   1/3716 (0.03%)  0/3716 (0.00%) 
Renal and urinary disorders     
Renal failure   10/3716 (0.27%)  15/3716 (0.40%) 
Renal failure acute   12/3716 (0.32%)  11/3716 (0.30%) 
Haematuria   17/3716 (0.46%)  5/3716 (0.13%) 
Renal failure chronic   8/3716 (0.22%)  4/3716 (0.11%) 
Haemorrhage urinary tract   2/3716 (0.05%)  1/3716 (0.03%) 
Renal impairment   3/3716 (0.08%)  0/3716 (0.00%) 
Acute prerenal failure   1/3716 (0.03%)  1/3716 (0.03%) 
Urinary retention   1/3716 (0.03%)  1/3716 (0.03%) 
Cystitis haemorrhagic   0/3716 (0.00%)  1/3716 (0.03%) 
Glomerulonephritis rapidly progressive   1/3716 (0.03%)  0/3716 (0.00%) 
Nephropathy   0/3716 (0.00%)  1/3716 (0.03%) 
Renal colic   1/3716 (0.03%)  0/3716 (0.00%) 
Urethral haemorrhage   1/3716 (0.03%)  0/3716 (0.00%) 
Reproductive system and breast disorders     
Benign prostatic hyperplasia   1/3716 (0.03%)  0/3716 (0.00%) 
Cervix haemorrhage uterine   1/3716 (0.03%)  0/3716 (0.00%) 
Genital haemorrhage   1/3716 (0.03%)  0/3716 (0.00%) 
Vaginal haemorrhage   1/3716 (0.03%)  0/3716 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease   38/3716 (1.02%)  43/3716 (1.16%) 
Respiratory failure   30/3716 (0.81%)  17/3716 (0.46%) 
Pulmonary embolism   11/3716 (0.30%)  26/3716 (0.70%) 
Acute respiratory failure   13/3716 (0.35%)  9/3716 (0.24%) 
Epistaxis   10/3716 (0.27%)  5/3716 (0.13%) 
Pulmonary oedema   6/3716 (0.16%)  4/3716 (0.11%) 
Pulmonary fibrosis   3/3716 (0.08%)  5/3716 (0.13%) 
Pleural effusion   2/3716 (0.05%)  5/3716 (0.13%) 
Asthma   3/3716 (0.08%)  3/3716 (0.08%) 
Dyspnoea   6/3716 (0.16%)  0/3716 (0.00%) 
Pneumothorax   3/3716 (0.08%)  3/3716 (0.08%) 
Acute pulmonary oedema   3/3716 (0.08%)  1/3716 (0.03%) 
Pneumonia aspiration   2/3716 (0.05%)  2/3716 (0.05%) 
Chronic respiratory failure   1/3716 (0.03%)  2/3716 (0.05%) 
Haemoptysis   2/3716 (0.05%)  1/3716 (0.03%) 
Respiratory distress   2/3716 (0.05%)  1/3716 (0.03%) 
Bronchiectasis   1/3716 (0.03%)  1/3716 (0.03%) 
Bronchitis chronic   1/3716 (0.03%)  1/3716 (0.03%) 
Bronchospasm   0/3716 (0.00%)  2/3716 (0.05%) 
Haemothorax   1/3716 (0.03%)  1/3716 (0.03%) 
Hypoxia   1/3716 (0.03%)  1/3716 (0.03%) 
Interstitial lung disease   0/3716 (0.00%)  2/3716 (0.05%) 
Lung disorder   0/3716 (0.00%)  2/3716 (0.05%) 
Pulmonary hypertension   1/3716 (0.03%)  1/3716 (0.03%) 
Respiratory arrest   0/3716 (0.00%)  2/3716 (0.05%) 
Sleep apnoea syndrome   1/3716 (0.03%)  1/3716 (0.03%) 
Acute respiratory distress syndrome   0/3716 (0.00%)  1/3716 (0.03%) 
Alveolitis allergic   0/3716 (0.00%)  1/3716 (0.03%) 
Bronchial obstruction   0/3716 (0.00%)  1/3716 (0.03%) 
Chylothorax   0/3716 (0.00%)  1/3716 (0.03%) 
Emphysema   1/3716 (0.03%)  0/3716 (0.00%) 
Paranasal cyst   0/3716 (0.00%)  1/3716 (0.03%) 
Pneumonitis   1/3716 (0.03%)  0/3716 (0.00%) 
Pneumothorax spontaneous   1/3716 (0.03%)  0/3716 (0.00%) 
Pulmonary haemorrhage   0/3716 (0.00%)  1/3716 (0.03%) 
Skin and subcutaneous tissue disorders     
Skin ulcer   3/3716 (0.08%)  1/3716 (0.03%) 
Decubitus ulcer   0/3716 (0.00%)  2/3716 (0.05%) 
Acute generalised exanthematous pustulosis   0/3716 (0.00%)  1/3716 (0.03%) 
Dermatitis bullous   0/3716 (0.00%)  1/3716 (0.03%) 
Ecchymosis   0/3716 (0.00%)  1/3716 (0.03%) 
Pemphigoid   1/3716 (0.03%)  0/3716 (0.00%) 
Petechiae   0/3716 (0.00%)  1/3716 (0.03%) 
Skin disorder   0/3716 (0.00%)  1/3716 (0.03%) 
Social circumstances     
Activities of daily living impaired   0/3716 (0.00%)  1/3716 (0.03%) 
Surgical and medical procedures     
Coronary artery bypass   1/3716 (0.03%)  0/3716 (0.00%) 
Glaucoma surgery   1/3716 (0.03%)  0/3716 (0.00%) 
Hip arthroplasty   1/3716 (0.03%)  0/3716 (0.00%) 
Hospitalisation   1/3716 (0.03%)  0/3716 (0.00%) 
Hysterectomy   1/3716 (0.03%)  0/3716 (0.00%) 
Leg amputation   0/3716 (0.00%)  1/3716 (0.03%) 
Mitral valve repair   0/3716 (0.00%)  1/3716 (0.03%) 
Surgery   1/3716 (0.03%)  0/3716 (0.00%) 
Vascular disorders     
Deep vein thrombosis   16/3716 (0.43%)  38/3716 (1.02%) 
Hypotension   8/3716 (0.22%)  3/3716 (0.08%) 
Haematoma   5/3716 (0.13%)  1/3716 (0.03%) 
Peripheral arterial occlusive disease   1/3716 (0.03%)  2/3716 (0.05%) 
Peripheral ischaemia   1/3716 (0.03%)  2/3716 (0.05%) 
Aortic aneurysm   1/3716 (0.03%)  1/3716 (0.03%) 
Aortic dissection   1/3716 (0.03%)  1/3716 (0.03%) 
Aortic stenosis   2/3716 (0.05%)  0/3716 (0.00%) 
Arteriosclerosis   1/3716 (0.03%)  1/3716 (0.03%) 
Haemorrhage   2/3716 (0.05%)  0/3716 (0.00%) 
Haemorrhagic vasculitis   1/3716 (0.03%)  1/3716 (0.03%) 
Hypertensive crisis   1/3716 (0.03%)  1/3716 (0.03%) 
Venous thrombosis   0/3716 (0.00%)  2/3716 (0.05%) 
Aneurysm   0/3716 (0.00%)  1/3716 (0.03%) 
Angiopathy   1/3716 (0.03%)  0/3716 (0.00%) 
Arterial disorder   1/3716 (0.03%)  0/3716 (0.00%) 
Arterial stenosis   1/3716 (0.03%)  0/3716 (0.00%) 
Bleeding varicose vein   1/3716 (0.03%)  0/3716 (0.00%) 
Embolism arterial   1/3716 (0.03%)  0/3716 (0.00%) 
Essential hypertension   1/3716 (0.03%)  0/3716 (0.00%) 
Femoral artery aneurysm   0/3716 (0.00%)  1/3716 (0.03%) 
Hypertension   1/3716 (0.03%)  0/3716 (0.00%) 
Intra-abdominal haematoma   0/3716 (0.00%)  1/3716 (0.03%) 
Ischaemia   1/3716 (0.03%)  0/3716 (0.00%) 
Peripheral artery aneurysm   0/3716 (0.00%)  1/3716 (0.03%) 
Peripheral artery stenosis   1/3716 (0.03%)  0/3716 (0.00%) 
Peripheral vascular disorder   1/3716 (0.03%)  0/3716 (0.00%) 
Phlebitis superficial   0/3716 (0.00%)  1/3716 (0.03%) 
Shock haemorrhagic   0/3716 (0.00%)  1/3716 (0.03%) 
Venous thrombosis limb   0/3716 (0.00%)  1/3716 (0.03%) 
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Betrixaban Enoxaparin
Affected / at Risk (%) Affected / at Risk (%)
Total   879/3716 (23.65%)   779/3716 (20.96%) 
Blood and lymphatic system disorders     
Anaemia   44/3716 (1.18%)  29/3716 (0.78%) 
Cardiac disorders     
Atrial fibrillation   50/3716 (1.35%)  85/3716 (2.29%) 
Cardiac failure   48/3716 (1.29%)  32/3716 (0.86%) 
Mitral valve incompetence   41/3716 (1.10%)  49/3716 (1.32%) 
Tricuspid valve incompetence   38/3716 (1.02%)  41/3716 (1.10%) 
Gastrointestinal disorders     
Constipation   109/3716 (2.93%)  102/3716 (2.74%) 
Nausea   67/3716 (1.80%)  55/3716 (1.48%) 
Diarrhoea   63/3716 (1.70%)  59/3716 (1.59%) 
General disorders     
Oedema peripheral   39/3716 (1.05%)  19/3716 (0.51%) 
Infections and infestations     
Urinary tract infection   110/3716 (2.96%)  78/3716 (2.10%) 
Metabolism and nutrition disorders     
Hypokalaemia   91/3716 (2.45%)  84/3716 (2.26%) 
Nervous system disorders     
Headache   74/3716 (1.99%)  59/3716 (1.59%) 
Psychiatric disorders     
Insomnia   87/3716 (2.34%)  89/3716 (2.40%) 
Renal and urinary disorders     
Renal cyst   55/3716 (1.48%)  47/3716 (1.26%) 
Haematuria   46/3716 (1.24%)  23/3716 (0.62%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease   53/3716 (1.43%)  41/3716 (1.10%) 
Epistaxis   48/3716 (1.29%)  19/3716 (0.51%) 
Vascular disorders     
Hypertension   88/3716 (2.37%)  80/3716 (2.15%) 
Deep vein thrombosis   29/3716 (0.78%)  58/3716 (1.56%) 
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Due to multi centers, studies and countries this varies.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Head of Clinical Development
Organization: Portola Pharmaceuticals, Inc.
Phone: 650-246-7000
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Portola Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01583218    
Other Study ID Numbers: 11-019
First Submitted: April 16, 2012
First Posted: April 23, 2012
Results First Submitted: July 19, 2017
Results First Posted: September 20, 2017
Last Update Posted: September 26, 2018