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

Participant Flow

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
Arm/Group Description	Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...
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

Baseline Characteristics

Arm/Group Title		Betrixaban	Enoxaparin	Total
Arm/Group Description		Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...	Total of all reporting groups
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
Baseline Analysis Population Description		...
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%

Outcome Measures

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
Description	mITT Cohort 1: Percentage of participants experiencing either symptoma...
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)

Outcome Measure Data

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
Arm/Group Description:	Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...
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)

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
Description	mITT Cohort 2: Percentage of participants experiencing either symptoma...
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)

Outcome Measure Data

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
Arm/Group Description:	Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...
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)

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
Description	mITT: Percentage of participants experiencing either symptomatic DVT, ...
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)

Outcome Measure Data

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
Arm/Group Description:	Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...
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)

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
Description	Percentage of participants experiencing at least one major bleeding ad...
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)

Outcome Measure Data

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
Arm/Group Description:	Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...
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)

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
Description	mITT Cohort 1: Percentage of participants experiencing either symptoma...
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)

Outcome Measure Data

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
Arm/Group Description:	Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...
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)

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
Description	mITT Cohort 2: Percentage of participants experiencing either symptoma...
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)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Betrixaban	Enoxaparin
Arm/Group Description:	Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...
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)

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
Description	mITT: Percentage of participants experiencing either symptomatic DVT, ...
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)

Outcome Measure Data

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
Arm/Group Description:	Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...
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)

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]

Adverse Events

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
Arm/Group Description	Daily oral (PO) betrixaban capsules...	Daily subcutaneous (SQ) injections ...
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	--/--	--/--
Serious Adverse Events 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
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

Limitations and Caveats

[Not Specified]

More Information

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):

Yee MK, Gibson CM, Nafee T, Kerneis M, Daaboul Y, Korjian S, Chi G, AlKhalfan F, Hernandez AF, Hull RD, Cohen AT, Goldhaber SZ. Characterization of Major and Clinically Relevant Non-Major Bleeds in the APEX Trial. TH Open. 2019 Apr 17;3(2):e103-e108. doi: 10.1055/s-0039-1685496. eCollection 2019 Apr.

Guy H, Laskier V, Fisher M, Bucior I, Deitelzweig S, Cohen AT. Budget impact analysis of betrixaban for venous thromboembolism prophylaxis in nonsurgical patients with acute medical illness in the United Kingdom. Expert Rev Pharmacoecon Outcomes Res. 2020 Jun;20(3):259-267. doi: 10.1080/14737167.2019.1629905. Epub 2019 Jun 19.

Chi G, Gibson CM, Kalayci A, Cohen AT, Hernandez AF, Hull RD, Kahe F, Jafarizade M, Sharfaei S, Liu Y, Harrington RA, Goldhaber SZ. Extended-duration betrixaban versus shorter-duration enoxaparin for venous thromboembolism prophylaxis in critically ill medical patients: an APEX trial substudy. Intensive Care Med. 2019 Apr;45(4):477-487. doi: 10.1007/s00134-019-05565-6. Epub 2019 Feb 18.

Kalayci A, Gibson CM, Chi G, Yee MK, Korjian S, Datta S, Nafee T, Gurin M, Haroian N, Qamar I, Hull RD, Hernandez AF, Cohen AT, Harrington RA, Goldhaber SZ. Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial. Thromb Haemost. 2018 Dec;118(12):2046-2052. doi: 10.1055/s-0038-1675606. Epub 2018 Nov 12.

Chi G, Gibson CM, Liu Y, Hernandez AF, Hull RD, Cohen AT, Harrington RA, Goldhaber SZ. Inverse relationship of serum albumin to the risk of venous thromboembolism among acutely ill hospitalized patients: Analysis from the APEX trial. Am J Hematol. 2019 Jan;94(1):21-28. doi: 10.1002/ajh.25296. Epub 2018 Oct 17.

Chi G, Goldhaber SZ, Hull RD, Hernandez AF, Kerneis M, Al Khalfan F, Cohen AT, Harrington RA, Gibson CM. Thrombus Burden of Deep Vein Thrombosis and Its Association with Thromboprophylaxis and D-Dimer Measurement: Insights from the APEX Trial. Thromb Haemost. 2017 Dec;117(12):2389-2395. doi: 10.1160/TH17-08-0538. Epub 2017 Dec 6.

Yee MK, Nafee T, Daaboul Y, Korjian S, AlKhalfan F, Kerneis M, Wiest C, Goldhaber SZ, Hernandez AF, Hull RD, Cohen AT, Harrington RA, Gibson CM. Increased benefit of betrixaban among patients with a history of venous thromboembolism: a post-hoc analysis of the APEX trial. J Thromb Thrombolysis. 2018 Jan;45(1):1-8. doi: 10.1007/s11239-017-1583-0.

Chi G, Januzzi JL, Korjian S, Daaboul Y, Goldhaber SZ, Hernandez AF, Hull RD, Gold A, Cohen AT, Harrington RA, Gibson CM. N-terminal pro-B-type natriuretic peptide and the risk of stroke among patients hospitalized with acute heart failure: an APEX trial substudy. J Thromb Thrombolysis. 2017 Nov;44(4):457-465. doi: 10.1007/s11239-017-1552-7.

Arbetter DF, Jain P, Yee MK, Michalak N, Hernandez AF, Hull RD, Goldhaber SZ, Harrington RA, Gold A, Cohen AT, Gibson CM. Competing risk analysis in a large cardiovascular clinical trial: An APEX substudy. Pharm Stat. 2017 Nov;16(6):445-450. doi: 10.1002/pst.1823. Epub 2017 Aug 24.

Chi G, Goldhaber SZ, Kittelson JM, Turpie AGG, Hernandez AF, Hull RD, Gold A, Curnutte JT, Cohen AT, Harrington RA, Gibson CM. Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis. J Thromb Haemost. 2017 Oct;15(10):1913-1922. doi: 10.1111/jth.13783. Epub 2017 Sep 4.

Gibson CM, Korjian S, Chi G, Daaboul Y, Jain P, Arbetter D, Goldhaber SZ, Hull R, Hernandez AF, Lopes RD, Gold A, Cohen AT, Harrington RA; APEX Investigators. Comparison of Fatal or Irreversible Events With Extended-Duration Betrixaban Versus Standard Dose Enoxaparin in Acutely Ill Medical Patients: An APEX Trial Substudy. J Am Heart Assoc. 2017 Jul 11;6(7). pii: e006015. doi: 10.1161/JAHA.117.006015.

Gibson CM, Goldhaber SZ, Cohen AT, Nafee T, Hernandez AF, Hull R, Korjian S, Daaboul Y, Chi G, Yee M, Harrington RA. When academic research organizations and clinical research organizations disagree: Processes to minimize discrepancies prior to unblinding of randomized trials. Am Heart J. 2017 Jul;189:1-8. doi: 10.1016/j.ahj.2017.03.018. Epub 2017 Mar 31.

Marszalek J, Mehrsefat S, Chi G. The risk of stroke among acutely ill hospitalized medical patients: lessons from recent trials on extended-duration thromboprophylaxis. Expert Rev Hematol. 2017 Aug;10(8):679-684. doi: 10.1080/17474086.2017.1343662. Epub 2017 Jun 21.

Gibson CM, Chi G, Halaby R, Korjian S, Daaboul Y, Jain P, Arbetter D, Goldhaber SZ, Hull R, Hernandez AF, Gold A, Bandman O, Harrington RA, Cohen AT; APEX Investigators. Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients: An APEX Trial Substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Circulation. 2017 Feb 14;135(7):648-655. doi: 10.1161/CIRCULATIONAHA.116.025427. Epub 2016 Nov 14.

Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 2016 Aug 11;375(6):534-44. doi: 10.1056/NEJMoa1601747. Epub 2016 May 27.

Cohen AT, Harrington R, Goldhaber SZ, Hull R, Gibson CM, Hernandez AF, Kitt MM, Lorenz TJ. The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. Am Heart J. 2014 Mar;167(3):335-41. doi: 10.1016/j.ahj.2013.11.006. Epub 2013 Dec 10.

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

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