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Trial record 1 of 3 for:    23388003 [PUBMED-IDS]
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Venous Thromboembolic Event (VTE) Prophylaxis in Medically Ill Patients (MAGELLAN)

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ClinicalTrials.gov Identifier: NCT00571649
Recruitment Status : Completed
First Posted : December 12, 2007
Results First Posted : June 27, 2012
Last Update Posted : September 15, 2016
Sponsor:
Collaborator:
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Information provided by (Responsible Party):
Bayer

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
Interventions Drug: Rivaroxaban (Xarelto, BAY59-7939)
Drug: Enoxaparin
Drug: Rivaroxaban placebo
Drug: Enoxaparin placebo
Enrollment 8101

Recruitment Details First patient first visit date: 04 DEC 2007; last patient last visit date 24 NOV 2010. Primary completion date: 12 AUG 2010. Participants were aged ≥40 years, hospitalized for an acute medical illness, and at risk of Venous Thromboembolism (VTE) (with heart failure, cancer, ischemic stroke, infection or inflammation, or respiratory insufficiency)
Pre-assignment Details A total of 8428 participants were screened; 327 failed. 8101 were randomized. 7998 (98.7%) were in the Safety Analysis Set (SAF), i.e. received study medication. 6024 (74.4%) were in the modified Intent to Treat (at Day 35) group (valid for SAF with adequate assessment of venous thromboembolism). A total of 6005 (74.1%) completed study.
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days during treatment period Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days during treatment period
Period Title: Treatment Period
Started 4050 4051
Participants Received Treatment 3997 4001
Day 10 3454 3499
Day 35 3033 3115
Completed 2958 3047
Not Completed 1092 1004
Reason Not Completed
Adverse Event             438             385
Clinical endpoint reached             50             56
Withdrawal by Subject             285             255
Death             76             59
Physician Decision             8             9
Lost to Follow-up             43             41
Non-compliant with study medication             88             89
Patient convenience             11             13
Protocol Violation             90             92
Technical problems             3             5
Period Title: Follow-up Period
Started 3583 [1] 3635 [1]
Completed 3038 [2] 3107 [2]
Not Completed 545 528
Reason Not Completed
Adverse Event             46             40
Clinical endpoint reached             5             2
Withdrawal by Subject             119             115
Death             132             133
Physician Decision             7             13
Lost to Follow-up             95             92
Patient convenience             136             121
Protocol Violation             5             12
[1]
Participants were required to enter follow-up even if treatment period not completed.
[2]
Began day after last dose study drug; ended on Day 90 (+/- 7 days) .
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin Total
Hide Arm/Group Description Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days (SAF population) Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days (SAF population) Total of all reporting groups
Overall Number of Baseline Participants 3997 4001 7998
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3997 participants 4001 participants 7998 participants
69.2  (11.9) 69.2  (11.7) 69.2  (11.8)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3997 participants 4001 participants 7998 participants
< 65 years 1323 1363 2686
65 to < 75 years 1144 1090 2234
>= 75 years 1530 1548 3078
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3997 participants 4001 participants 7998 participants
Female
1774
  44.4%
1898
  47.4%
3672
  45.9%
Male
2223
  55.6%
2103
  52.6%
4326
  54.1%
Race  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3997 participants 4001 participants 7998 participants
White 2749 2744 5493
Black 89 92 181
Asian 793 794 1587
Native American 12 12 24
Hispanic 69 70 139
Uncodable 106 112 218
Unknown 1 0 1
Missing 178 177 355
Reason for hospitalization   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3997 participants 4001 participants 7998 participants
Heart failure (NYHA Class III or NYHA Class IV) 1292 1301 2593
Active cancer 294 290 584
Acute ischemic stroke 691 692 1383
Acute Infectious and Inflammatory Diseases 1904 1876 3780
Acute infectious disease 1826 1801 3627
Acute inflammatory or rheumatic disease 150 149 299
Acute respiratory insufficiency 1085 1151 2236
[1]
Measure Description: Participants may have more than one acute condition as hospitalization reason. Acute medical illnesses included heart failure (New York Heart Association [NYHA] Class III [marked limitation of physical activity] or NYHA Class IV [inability to carry out any physical activity without discomfort)] active cancer, acute ischemic stroke, acute infectious and inflammatory diseases (including acute rheumatic diseases), acute respiratory insufficiency.
1.Primary Outcome
Title Percentage of Participants With Composite Endpoint of Venous Thromboembolism [VTE] (Any Deep Vein Thrombosis [DVT], Non Fatal Pulmonary Embolism [PE]) and VTE-related Death up to Day 35 + 6 Days
Hide Description A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time Frame Up to Day 35 + 6 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
modified Intent-to-Treat (mITT) Day 35: participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 35
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 2967 3057
Measure Type: Number
Unit of Measure: Percentage of participants
4.4 5.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin
Comments A sample size of 2876 valid patients per group was estimated to obtain a joint power of at least 90% for both primary endpoints (91.4% for superiority) with 4% event rate at day 35 for comparator and 40% relative risk reduction.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0211
Comments Hochberg procedure: A 2-sided p-value of less than 0.05 would be considered significant, if the 1-sided p-value of the other primary efficacy outcome measure was less than 0.025, elsewise a p-value of less than 0.025 would be considered significant.
Method Cochran-Mantel-Haenszel
Comments Weighted relative risks were calculated using asymptotic methods, with weights based upon sample sizes per strata (geographic region).
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.771
Confidence Interval 95%
0.618 to 0.962
Estimation Comments [Not Specified]
2.Primary Outcome
Title Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days
Hide Description A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time Frame Up to Day 10 + 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per Protocol (PP) Day 10: participant was valid for the safety analysis, had an adequate assessment of VTE up to Day 10 not later than 48 hours after stop of study drug, met inclusion criteria, and had no major protocol deviations.
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 2938 2993
Measure Type: Number
Unit of Measure: Percentage of participants
2.7 2.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin
Comments A sample size of 2876 valid patients per group was estimated to obtain a joint power of at least 90% for both primary endpoints (98.6% power for non-inferiority) with 1.8% event rate at day 10 for comparator and 35% relative risk reduction.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Rivaroxaban would be considered at least as effective as the comparator if the upper limit of the CI (Confidence Interval) was less than 1.5
Statistical Test of Hypothesis P-Value 0.0025
Comments Hochberg procedure: A 1-sided p-value of less than 0.025 would be considered significant, if the 2-sided p-value of the other primary efficacy outcome measure was less than 0.05, elsewise a p-value of less than 0.0125 would be considered significant.
Method Cochran-Mantel-Haenszel
Comments Weighted relative risks were calculated using asymptotic methods, with weights based upon sample sizes per strata (geographic region).
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.968
Confidence Interval 95%
0.713 to 1.314
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and All-cause Mortality up to Day 35 + 6 Days
Hide Description A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and death (VTE-related and not VTE-related).
Time Frame Up to Day 35 + 6 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
modified Intent-to-Treat (mITT) Day 35 (participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 35) expanded to include participants who had an assessment of all deaths, including not VTE-related
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 3096 3169
Measure Type: Number
Unit of Measure: Percentage of participants
8.6 9.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3758
Comments Test hierarchy: A p-value of less than 0.05 would be considered significant, if the tests for the two primary efficacy outcome measures were significant.
Method Cochran-Mantel-Haenszel
Comments Weighted relative risks were calculated using asymptotic methods, with weights based upon sample sizes per strata (geographic region).
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.931
Confidence Interval 95%
0.795 to 1.091
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days Per mITT Population
Hide Description A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time Frame Up to Day 10 + 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
modified Intent-to-Treat (mITT) Day 10: participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 10
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 3232 3271
Measure Type: Number
Unit of Measure: Percentage of participants
3.0 3.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9473
Comments Test hierarchy: A p-value of less than 0.05 would be considered significant, if the tests for the 2 primary efficacy outcomes and for “Composite endpoint of VTE (any DVT, non fatal PE) and all-cause mortality up to Day 35 + 6 days” were significant.
Method Cochran-Mantel-Haenszel
Comments Weighted relative risks were calculated using asymptotic methods, with weights based upon sample sizes per strata (geographic region).
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.991
Confidence Interval 95%
0.753 to 1.304
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Participants With VTE Combined With All-cause Mortality up to Day 10 + 5 Days
Hide Description A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and death (VTE-related and not VTE-related).
Time Frame Up to Day 10 + 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
modified Intent-to-Treat (mITT) Day 10 (participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 10) expanded to include participants who had an assessment of all deaths, including not VTE-related
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 3281 3310
Measure Type: Number
Unit of Measure: Percentage of participants
4.8 4.5
6.Secondary Outcome
Title Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90
Hide Description Symptomatic VTE (non-fatal PE and DVT in lower extremity), including and excluding VTE-related death (PE and PE cannot be excluded) up to Days 10, 35, and 90
Time Frame At Day 10 + 5 days, at Day 35 + 6 days, and at Day 90 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population: Participant had at least one dose of study drug.
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 3997 4001
Measure Type: Number
Unit of Measure: Percentage of participants
symptomatic VTE (incl. VTE-related death)-Day 10 0.7 0.6
symptomatic VTE (non fatal)-Day 10 0.5 0.3
symptomatic VTE (incl. VTE-related death)-Day 35 1.0 1.4
symptomatic VTE (non fatal)-Day 35 0.6 0.7
symptomatic VTE (incl. VTE-related death)-Day 90 1.7 1.9
symptomatic VTE (non fatal)-Day 90 0.7 0.9
7.Secondary Outcome
Title Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 35 + 6 Days
Hide Description Net clinical benefit is a composite of the primary efficacy endpoint (asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death) plus major and clinically relevant non-major bleeding events.
Time Frame Up to Day 35 + 6 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
modified Intent-to-Treat (mITT) Day 35 (participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 35) expanded to include participants with major and clinically relevant bleeding events.
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 3042 3082
Measure Type: Number
Unit of Measure: Percentage of participants
9.4 7.8
8.Secondary Outcome
Title Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 10 + 5 Days
Hide Description Net clinical benefit is a composite of the primary efficacy endpoint (asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death) plus major and clinically relevant non-major bleeding events
Time Frame Up to Day 10 + 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants valid for safety analysis, with adequate assessment of VTE (to Day 10 within 48 hours of study drug), met inclusion criteria, and no major protocol deviations; expanded to include participants who had major bleeding or clinically relevant non-major bleeding events and met all criteria for PP except valid assessment of thromboembolism.
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 2950 3007
Measure Type: Number
Unit of Measure: Percentage of participants
4.5 3.9
9.Secondary Outcome
Title Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90
Hide Description Major vascular events included cardiovascular death, acute myocardial infarction (MI), or acute ischemic stroke. Participants may have had a vascular event in more than one category.
Time Frame At Day 10 + 5 days, at Day 35 + 6 days, and at Day 90 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population: Participant had at least one dose of study drug.
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 3997 4001
Measure Type: Number
Unit of Measure: Percentage of participants
Any event-Day 10 1.0 1.0
Ischemic stroke-Day 10 0.3 0.3
Acute MI-Day 10 0.5 0.4
Death (cardiovascular)-Day 10 0.4 0.4
Any event-Day 35 1.8 1.6
Ischemic stroke-Day 35 0.5 0.5
Acute MI-Day 35 0.6 0.5
Death (cardiovascular)-Day 35 0.9 0.8
Any event-Day 90 2.8 2.8
Ischemic stroke-Day 90 0.8 1.1
Acute MI-Day 90 0.9 0.7
Death (cardiovascular)-Day 90 1.4 1.4
10.Secondary Outcome
Title Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days
Hide Description The components of the composite endpoint include asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time Frame Up to Day 35 + 6 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
modified Intent-to-Treat (mITT) Day 35: participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 35
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 2967 3057
Measure Type: Number
Unit of Measure: Percentage of participants
Symptomatic non-fatal PE 0.3 0.5
Symptomatic DVT in lower extremity 0.4 0.5
Asymptomatic proximal DVT in lower extremity 3.5 4.4
VTE related death 0.6 1.0
11.Secondary Outcome
Title Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days
Hide Description The components of the composite endpoint include asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time Frame Up to Day 10 + 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per Protocol Day 10: participant was valid for the safety analysis, had an adequate assessment of VTE up to Day 10 not later than 48 hours after stop of study drug, met inclusion criteria, and had no major protocol deviations
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 2938 2993
Measure Type: Number
Unit of Measure: Percentage of participants
Symptomatic non-fatal PE 0.2 0.1
Symptomatic DVT in lower extremity 0.2 0.2
Asymptomatic proximal DVT in lower extremity 2.4 2.4
VTE related death 0.1 0.2
12.Secondary Outcome
Title Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days
Hide Description All deaths, including VTE-related deaths, cardiovascular deaths, and other deaths.
Time Frame Up to Day 90 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population: Participant had at least one dose of study drug.
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 3997 4001
Measure Type: Number
Unit of Measure: Percentage of participants
Any event 6.7 6.2
Death (cardiovascular) 1.4 1.4
Death (other) 4.3 3.7
VTE related death 1.0 1.1
13.Secondary Outcome
Title Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Intake of Any Study Medication (Day 35 + 6 Days)
Hide Description Major bleeding events were defined as events leading to >=2 g/dL fall in hemoglobin; or transfusion of >= 2 units of packed RBCs (Red blood cells) or whole blood; or leading to death. Non-major bleeding events were defined as overt bleeding not meeting the criteria of major bleeding
Time Frame Up to Day 35 + 6 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population: Participant had at least one dose of study drug.
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 3997 4001
Measure Type: Number
Unit of Measure: Percentage of participants
4.1 1.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin
Comments There was no sample size estimation as this was not planed as confirmatory analysis
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 2-sided p-value. No adjustment for multiple testing.
Method Cochran-Mantel-Haenszel
Comments Weighted relative risks were calculated using asymptotic methods, with weights based upon sample sizes per strata (geographic region).
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 2.455
Confidence Interval (2-Sided) 95%
1.854 to 3.251
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Application of a Study Medication Syringe (Day 10 + 5 Days)
Hide Description Major bleeding events were defined as events leading to >=2 g/dL fall in hemoglobin or transfusion of >=2 units of packed RBCs or whole blood or leading to death. Non-major bleeding events were defined as overt bleeding not meeting the criteria of major bleeding.
Time Frame Up to Day 10 + 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population: Participant had at least one dose of study drug.
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description:
Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
Overall Number of Participants Analyzed 3997 4001
Measure Type: Number
Unit of Measure: Percentage of participants
2.8 1.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin
Comments There was no sample size estimation as this was not planed as confirmatory analysis
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 2-sided p-value. No adjustment for multiple testing.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 2.272
Confidence Interval (2-Sided) 95%
1.628 to 3.171
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Hide Arm/Group Description Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days
All-Cause Mortality
Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Rivaroxaban (Xarelto, BAY59-7939) Enoxaparin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1034/3997 (25.87%)      976/4001 (24.39%)    
Blood and lymphatic system disorders     
Agranulocytosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Anaemia * 1  18/3997 (0.45%)  20 13/4001 (0.32%)  13
Coagulopathy * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Disseminated intravascular coagulation * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  2
Febrile neutropenia * 1  4/3997 (0.10%)  5 3/4001 (0.07%)  4
Leukocytosis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Leukopenia * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Lymphadenopathy * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Neutropenia * 1  0/3997 (0.00%)  0 3/4001 (0.07%)  3
Normochromic normocytic anaemia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pancytopenia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Thrombocytopenia * 1  13/3997 (0.33%)  13 9/4001 (0.22%)  9
Anaemia of malignant disease * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Haemorrhagic anaemia * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Heparin-induced thrombocytopenia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Cardiac disorders     
Acute myocardial infarction * 1  30/3997 (0.75%)  31 28/4001 (0.70%)  29
Angina pectoris * 1  1/3997 (0.03%)  1 4/4001 (0.10%)  4
Angina unstable * 1  6/3997 (0.15%)  7 6/4001 (0.15%)  6
Aortic valve incompetence * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Aortic valve stenosis * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Arrhythmia * 1  2/3997 (0.05%)  2 6/4001 (0.15%)  6
Arteriosclerosis coronary artery * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Atrial fibrillation * 1  23/3997 (0.58%)  23 22/4001 (0.55%)  24
Atrial flutter * 1  5/3997 (0.13%)  5 2/4001 (0.05%)  2
Atrial tachycardia * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Atrioventricular block * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Atrioventricular block complete * 1  3/3997 (0.08%)  3 5/4001 (0.12%)  5
Bradycardia * 1  1/3997 (0.03%)  1 4/4001 (0.10%)  4
Cardiac arrest * 1  12/3997 (0.30%)  13 11/4001 (0.27%)  12
Cardiac failure * 1  76/3997 (1.90%)  84 76/4001 (1.90%)  81
Cardiac failure acute * 1  11/3997 (0.28%)  12 25/4001 (0.62%)  28
Cardiac failure chronic * 1  10/3997 (0.25%)  10 10/4001 (0.25%)  11
Cardiac failure congestive * 1  31/3997 (0.78%)  37 31/4001 (0.77%)  38
Cardiac hypertrophy * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Cardio-respiratory arrest * 1  11/3997 (0.28%)  11 12/4001 (0.30%)  12
Cardiogenic shock * 1  6/3997 (0.15%)  6 4/4001 (0.10%)  4
Cardiomegaly * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Cardiomyopathy * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Cardiovascular disorder * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  2
Cor pulmonale * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Cor pulmonale chronic * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Coronary artery disease * 1  12/3997 (0.30%)  13 7/4001 (0.17%)  8
Coronary artery occlusion * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Coronary artery stenosis * 1  1/3997 (0.03%)  1 3/4001 (0.07%)  3
Left ventricular failure * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  2
Myocardial infarction * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Myocardial ischaemia * 1  3/3997 (0.08%)  3 6/4001 (0.15%)  6
Palpitations * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pericardial effusion * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Pericardial haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Pericarditis * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Right ventricular failure * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Sick sinus syndrome * 1  2/3997 (0.05%)  2 3/4001 (0.07%)  3
Sinus arrest * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Sinus bradycardia * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Supraventricular tachycardia * 1  3/3997 (0.08%)  3 1/4001 (0.02%)  1
Trifascicular block * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Ventricular fibrillation * 1  4/3997 (0.10%)  6 3/4001 (0.07%)  3
Ventricular tachycardia * 1  7/3997 (0.18%)  8 1/4001 (0.02%)  2
Intracardiac thrombus * 1  1/3997 (0.03%)  1 3/4001 (0.07%)  3
Atrial thrombosis * 1  4/3997 (0.10%)  4 0/4001 (0.00%)  0
Ischaemic cardiomyopathy * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Tachyarrhythmia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Left ventricular dysfunction * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Bradyarrhythmia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Electromechanical dissociation * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Cardiopulmonary failure * 1  5/3997 (0.13%)  5 8/4001 (0.20%)  8
Acute coronary syndrome * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  2
Haemorrhage coronary artery * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Congestive cardiomyopathy * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Cardiac perforation * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Right ventricular dysfunction * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Mitral valve disease * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Cardiac fibrillation * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Rheumatic heart disease * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Acute left ventricular failure * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Supraventricular tachyarrhythmia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Cardiovascular insufficiency * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Chronotropic incompetence * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Atrioventricular dissociation * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Congenital, familial and genetic disorders     
Atrial septal defect * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Gastrointestinal angiodysplasia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Pyloric stenosis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Myotonic dystrophy * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Ear and labyrinth disorders     
Ear haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Vertigo * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  2
Eye disorders     
Cataract * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Conjunctival haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Diabetic retinopathy * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Eye haemorrhage * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Eye pain * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Glaucoma * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Keratitis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Macular degeneration * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Macular oedema * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Optic atrophy * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Periorbital oedema * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Pupils unequal * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Retinopathy hypertensive * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Vision blurred * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Vitreous haemorrhage * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Entropion * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain * 1  6/3997 (0.15%)  7 4/4001 (0.10%)  5
Abdominal pain upper * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  2
Acute abdomen * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Ascites * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Colitis * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Colitis ischaemic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Colonic polyp * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Constipation * 1  2/3997 (0.05%)  2 3/4001 (0.07%)  3
Diarrhoea * 1  5/3997 (0.13%)  6 10/4001 (0.25%)  11
Diarrhoea haemorrhagic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Diverticulum * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Diverticulum intestinal * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Diverticulum intestinal haemorrhagic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Duodenal ulcer * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Duodenal ulcer haemorrhage * 1  3/3997 (0.08%)  3 1/4001 (0.02%)  1
Duodenal ulcer perforation * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Dyspepsia * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Dysphagia * 1  0/3997 (0.00%)  0 3/4001 (0.07%)  3
Enteritis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Enterocolitis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Femoral hernia, obstructive * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Gastric haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Gastric ulcer * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Gastric ulcer haemorrhage * 1  2/3997 (0.05%)  2 3/4001 (0.07%)  3
Gastric ulcer perforation * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Gastritis * 1  3/3997 (0.08%)  3 0/4001 (0.00%)  0
Gastrooesophageal reflux disease * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Gastroduodenal ulcer * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Gastrointestinal haemorrhage * 1  12/3997 (0.30%)  12 7/4001 (0.17%)  8
Gastrointestinal perforation * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Gingival bleeding * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Haematemesis * 1  3/3997 (0.08%)  3 4/4001 (0.10%)  4
Haematochezia * 1  4/3997 (0.10%)  4 1/4001 (0.02%)  1
Ileus * 1  6/3997 (0.15%)  6 0/4001 (0.00%)  0
Ileus paralytic * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Impaired gastric emptying * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  2
Inguinal hernia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Intestinal infarction * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Intestinal ischaemia * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Intestinal obstruction * 1  5/3997 (0.13%)  5 3/4001 (0.07%)  3
Large intestinal ulcer * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Mallory-Weiss syndrome * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Melaena * 1  6/3997 (0.15%)  6 3/4001 (0.07%)  3
Mesenteric artery stenosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Mouth haemorrhage * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Nausea * 1  3/3997 (0.08%)  3 5/4001 (0.12%)  7
Oesophageal haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Oesophageal spasm * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Oesophageal stenosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Oesophageal ulcer * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Oesophageal varices haemorrhage * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pancreatitis * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Pancreatitis acute * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Pancreatitis chronic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Peritoneal haemorrhage * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Peritonitis * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Proctalgia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Rectal haemorrhage * 1  4/3997 (0.10%)  4 4/4001 (0.10%)  5
Reflux oesophagitis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Retroperitoneal haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Small intestinal obstruction * 1  1/3997 (0.03%)  1 3/4001 (0.07%)  3
Thrombosis mesenteric vessel * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Upper gastrointestinal haemorrhage * 1  4/3997 (0.10%)  4 2/4001 (0.05%)  2
Vomiting * 1  7/3997 (0.18%)  7 4/4001 (0.10%)  5
Oesophagitis ulcerative * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Anal haemorrhage * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Lower gastrointestinal haemorrhage * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  3
Diabetic gastroparesis * 1  1/3997 (0.03%)  2 0/4001 (0.00%)  0
Internal hernia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Oedematous pancreatitis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Small intestinal haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Haemorrhoidal haemorrhage * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Varices oesophageal * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Hernial eventration * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Retroperitoneal haematoma * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Intestinal haemorrhage * 1  1/3997 (0.03%)  2 0/4001 (0.00%)  0
Abdominal hernia obstructive * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Diverticular perforation * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
General disorders     
Asthenia * 1  4/3997 (0.10%)  4 1/4001 (0.02%)  1
Chest pain * 1  10/3997 (0.25%)  10 16/4001 (0.40%)  18
Chills * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Death * 1  14/3997 (0.35%)  14 9/4001 (0.22%)  9
Fatigue * 1  2/3997 (0.05%)  2 3/4001 (0.07%)  3
Impaired healing * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Malaise * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Multi-organ failure * 1  8/3997 (0.20%)  8 5/4001 (0.12%)  5
Oedema * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Oedema peripheral * 1  2/3997 (0.05%)  2 5/4001 (0.12%)  6
Pain * 1  4/3997 (0.10%)  4 2/4001 (0.05%)  3
Pyrexia * 1  8/3997 (0.20%)  8 9/4001 (0.22%)  9
Sudden death * 1  8/3997 (0.20%)  8 5/4001 (0.12%)  5
Performance status decreased * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  3
Hernia pain * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Sudden cardiac death * 1  2/3997 (0.05%)  2 7/4001 (0.17%)  7
General physical health deterioration * 1  5/3997 (0.13%)  5 4/4001 (0.10%)  4
Puncture site haemorrhage * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Nodule * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Catheter site haematoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Ulcer haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Drug intolerance * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Unevaluable event * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Non-cardiac chest pain * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Implant site haematoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Device malfunction * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Device dislocation * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Device occlusion * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Disuse syndrome * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Device capturing issue * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Hepatobiliary disorders     
Acute hepatic failure * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Biliary colic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Cholecystitis * 1  1/3997 (0.03%)  1 3/4001 (0.07%)  4
Cholecystitis acute * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  2
Cholelithiasis * 1  2/3997 (0.05%)  2 4/4001 (0.10%)  4
Cholestasis * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Granulomatous liver disease * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Hepatic cirrhosis * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Hepatic congestion * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Hepatic failure * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Hepatic function abnormal * 1  7/3997 (0.18%)  7 5/4001 (0.12%)  5
Hepatic steatosis * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Hepatitis acute * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Hepatitis alcoholic * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Hepatitis toxic * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Hepatorenal syndrome * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Hyperbilirubinaemia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Ischaemic hepatitis * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Jaundice * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Cytolytic hepatitis * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Bile duct obstruction * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Haemobilia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Hepatic lesion * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Cryptogenic cirrhosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Liver injury * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Immune system disorders     
Amyloidosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Anaphylactic reaction * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Drug hypersensitivity * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Hypersensitivity * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Sarcoidosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Infections and infestations     
Abscess * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Acquired immunodeficiency syndrome * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Appendicitis * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Appendicitis perforated * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Bacteraemia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Bronchiectasis * 1  3/3997 (0.08%)  3 2/4001 (0.05%)  2
Bronchiolitis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Bronchitis * 1  18/3997 (0.45%)  18 4/4001 (0.10%)  4
Bronchopneumonia * 1  8/3997 (0.20%)  8 10/4001 (0.25%)  10
Cellulitis * 1  20/3997 (0.50%)  23 9/4001 (0.22%)  10
Cellulitis streptococcal * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Diarrhoea infectious * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Disseminated tuberculosis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Diverticulitis * 1  5/3997 (0.13%)  5 1/4001 (0.02%)  1
Empyema * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Endocarditis * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  3
Enteritis necroticans * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Enterococcal bacteraemia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Erysipelas * 1  4/3997 (0.10%)  4 2/4001 (0.05%)  2
Furuncle * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Gangrene * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  3
Gastroenteritis * 1  12/3997 (0.30%)  12 4/4001 (0.10%)  4
Gastroenteritis viral * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Gastrointestinal infection * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Hepatitis C * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Herpes zoster * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  2
Impetigo * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Infected skin ulcer * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Infection * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Liver abscess * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Lobar pneumonia * 1  4/3997 (0.10%)  4 1/4001 (0.02%)  1
Localised infection * 1  3/3997 (0.08%)  3 0/4001 (0.00%)  0
Lower respiratory tract infection * 1  4/3997 (0.10%)  4 3/4001 (0.07%)  3
Lung abscess * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Meningitis * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Necrotising fasciitis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Oesophageal candidiasis * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Oral candidiasis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Osteomyelitis * 1  4/3997 (0.10%)  4 1/4001 (0.02%)  1
Peridiverticular abscess * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Perinephric abscess * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Peritoneal abscess * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pneumonia * 1  74/3997 (1.85%)  78 76/4001 (1.90%)  78
Pneumonia klebsiella * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Pneumonia pneumococcal * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Pneumonia primary atypical * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Postoperative wound infection * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pseudomembranous colitis * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Pulmonary tuberculosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pyelonephritis * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Pyelonephritis acute * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Pyometra * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pyothorax * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Retroperitoneal abscess * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Salmonellosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Sepsis * 1  29/3997 (0.73%)  30 14/4001 (0.35%)  14
Septic shock * 1  15/3997 (0.38%)  16 18/4001 (0.45%)  20
Sinusitis * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Subcutaneous abscess * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Tuberculosis * 1  1/3997 (0.03%)  2 0/4001 (0.00%)  0
Upper respiratory tract infection * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Urinary tract infection * 1  17/3997 (0.43%)  20 13/4001 (0.32%)  14
Viral infection * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Viral upper respiratory tract infection * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Wound infection * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Urosepsis * 1  4/3997 (0.10%)  4 6/4001 (0.15%)  6
Abscess limb * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Staphylococcal bacteraemia * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Burn infection * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Haematoma infection * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Pulmonary sepsis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Bacterial sepsis * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Sepsis syndrome * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Psoas abscess * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Phlebitis infective * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Infective exacerbation of chronic obstructive airways disease * 1  10/3997 (0.25%)  10 12/4001 (0.30%)  12
Lung infection pseudomonal * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Abdominal sepsis * 1  3/3997 (0.08%)  3 0/4001 (0.00%)  0
Wound sepsis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Staphylococcal infection * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Tuberculosis liver * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Enterocolitis infectious * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Wound infection staphylococcal * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Implant site infection * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Intervertebral discitis * 1  1/3997 (0.03%)  2 0/4001 (0.00%)  0
Diabetic foot infection * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Abdominal abscess * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pneumonia bacterial * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Arthritis infective * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Lung infection * 1  2/3997 (0.05%)  2 4/4001 (0.10%)  4
Pneumonia fungal * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Bronchitis bacterial * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Respiratory tract infection * 1  10/3997 (0.25%)  12 6/4001 (0.15%)  6
Cholecystitis infective * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Infective spondylitis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Device related infection * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  2
Staphylococcal skin infection * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Post procedural infection * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
H1N1 influenza * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Device related sepsis * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Injury, poisoning and procedural complications     
Alcohol poisoning * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Ankle fracture * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Burns second degree * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Clavicle fracture * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Drug toxicity * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Eye penetration * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Fall * 1  5/3997 (0.13%)  5 3/4001 (0.07%)  3
Femoral neck fracture * 1  2/3997 (0.05%)  2 4/4001 (0.10%)  4
Femur fracture * 1  2/3997 (0.05%)  2 3/4001 (0.07%)  3
Foot fracture * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Head injury * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Hip fracture * 1  5/3997 (0.13%)  5 0/4001 (0.00%)  0
Humerus fracture * 1  4/3997 (0.10%)  4 2/4001 (0.05%)  2
Incisional hernia, obstructive * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Operative haemorrhage * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Overdose * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Periorbital haematoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pneumoconiosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Radius fracture * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Rib fracture * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Spinal compression fracture * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Spinal cord injury cervical * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Spinal fracture * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Subdural haematoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Subdural haemorrhage * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Therapeutic agent toxicity * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Tibia fracture * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Wound dehiscence * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Suture rupture * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Vascular graft occlusion * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Traumatic fracture * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Cervical vertebral fracture * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Lumbar vertebral fracture * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Contusion * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Post procedural haemorrhage * 1  4/3997 (0.10%)  4 1/4001 (0.02%)  1
Wound * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Traumatic haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Exposure to toxic agent * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Thermal burn * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Wound necrosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Multiple drug overdose * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Poisoning * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Chest injury * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Upper limb fracture * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Procedural pain * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Gastrointestinal stoma complication * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Procedural nausea * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Foreign body * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Investigations     
Alanine aminotransferase increased * 1  20/3997 (0.50%)  20 23/4001 (0.57%)  26
Arteriogram coronary * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Aspartate aminotransferase increased * 1  1/3997 (0.03%)  1 5/4001 (0.12%)  7
Biopsy lymph gland * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Blood bilirubin increased * 1  4/3997 (0.10%)  4 1/4001 (0.02%)  1
Blood creatinine increased * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Blood glucose abnormal * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Blood glucose decreased * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Blood glucose increased * 1  1/3997 (0.03%)  2 0/4001 (0.00%)  0
Creatinine renal clearance decreased * 1  4/3997 (0.10%)  4 3/4001 (0.07%)  3
Gamma-glutamyltransferase increased * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Haemoglobin decreased * 1  2/3997 (0.05%)  3 1/4001 (0.02%)  1
Immunoglobulins increased * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Liver function test abnormal * 1  8/3997 (0.20%)  8 5/4001 (0.12%)  5
Prothrombin time prolonged * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Weight decreased * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Aspiration bronchial * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Transaminases increased * 1  3/3997 (0.08%)  3 2/4001 (0.05%)  2
Blood alkaline phosphatase increased * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Hepatic enzyme increased * 1  10/3997 (0.25%)  10 11/4001 (0.27%)  11
Occult blood positive * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Coagulation test * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
False positive investigation result * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Metabolism and nutrition disorders     
Abnormal loss of weight * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Cachexia * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Dehydration * 1  9/3997 (0.23%)  9 5/4001 (0.12%)  5
Diabetes mellitus * 1  2/3997 (0.05%)  2 3/4001 (0.07%)  3
Diabetes mellitus inadequate control * 1  3/3997 (0.08%)  3 1/4001 (0.02%)  1
Diabetic ketoacidosis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Fluid overload * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Hyperammonaemia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Hypercalcaemia * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Hyperglycaemia * 1  1/3997 (0.03%)  1 4/4001 (0.10%)  4
Hyperkalaemia * 1  2/3997 (0.05%)  2 3/4001 (0.07%)  3
Hyperosmolar state * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Hypoglycaemia * 1  3/3997 (0.08%)  3 7/4001 (0.17%)  7
Hypokalaemia * 1  0/3997 (0.00%)  0 3/4001 (0.07%)  3
Hyponatraemia * 1  4/3997 (0.10%)  5 4/4001 (0.10%)  4
Hypovolaemia * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Lactic acidosis * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Metabolic acidosis * 1  3/3997 (0.08%)  3 3/4001 (0.07%)  3
Diabetic foot * 1  3/3997 (0.08%)  3 4/4001 (0.10%)  4
Malnutrition * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Decreased appetite * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Back pain * 1  1/3997 (0.03%)  1 3/4001 (0.07%)  3
Gouty arthritis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Groin pain * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Lumbar spinal stenosis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Muscle haemorrhage * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Muscular weakness * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Musculoskeletal pain * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Myopathy * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Osteoarthritis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Osteonecrosis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Pain in extremity * 1  1/3997 (0.03%)  1 3/4001 (0.07%)  3
Pathological fracture * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Rhabdomyolysis * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Spinal column stenosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Systemic lupus erythematosus * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Tendon disorder * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Trismus * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Intervertebral disc protrusion * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adenocarcinoma * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Basal cell carcinoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Bile duct cancer * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Bladder cancer * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Bladder neoplasm * 1  2/3997 (0.05%)  3 0/4001 (0.00%)  0
Breast cancer * 1  2/3997 (0.05%)  3 4/4001 (0.10%)  4
Breast cancer in situ * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Breast neoplasm * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Bronchial carcinoma * 1  3/3997 (0.08%)  3 1/4001 (0.02%)  1
Cervix carcinoma * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Colon cancer * 1  5/3997 (0.13%)  5 3/4001 (0.07%)  3
Colorectal cancer stage IV * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Gastric cancer * 1  1/3997 (0.03%)  1 3/4001 (0.07%)  3
Hepatic neoplasm malignant * 1  3/3997 (0.08%)  3 0/4001 (0.00%)  0
Hodgkin's disease * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  3
Laryngeal cancer * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Lung adenocarcinoma * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Lung adenocarcinoma recurrent * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Lung carcinoma cell type unspecified stage IV * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Lung squamous cell carcinoma stage unspecified * 1  4/3997 (0.10%)  4 2/4001 (0.05%)  2
Lymphoma * 1  3/3997 (0.08%)  3 0/4001 (0.00%)  0
Malignant pleural effusion * 1  0/3997 (0.00%)  0 3/4001 (0.07%)  3
Mediastinum neoplasm * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Meningioma * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Mesothelioma malignant * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Metastases to adrenals * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Metastases to bone * 1  1/3997 (0.03%)  1 3/4001 (0.07%)  3
Metastases to liver * 1  6/3997 (0.15%)  6 3/4001 (0.07%)  3
Metastases to lung * 1  2/3997 (0.05%)  3 1/4001 (0.02%)  1
Metastases to lymph nodes * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Metastases to pleura * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Metastases to spine * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Metastatic malignant melanoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Metastatic pain * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Multiple myeloma * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Myeloproliferative disorder * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Neoplasm malignant * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Non-small cell lung cancer stage IV * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Oesophageal carcinoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Ovarian cancer * 1  1/3997 (0.03%)  1 4/4001 (0.10%)  4
Ovarian epithelial cancer metastatic * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Pancreatic carcinoma * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Pancreatic carcinoma metastatic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Plasmacytoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Prostate cancer metastatic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Rectal cancer recurrent * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Renal cancer * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Sarcoma * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Small cell lung cancer stage unspecified * 1  1/3997 (0.03%)  1 3/4001 (0.07%)  3
Tongue neoplasm malignant stage unspecified * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Uterine cancer * 1  3/3997 (0.08%)  3 0/4001 (0.00%)  0
Metastases to pancreas * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Tumour haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Lung cancer metastatic * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Myeloma recurrence * 1  1/3997 (0.03%)  2 0/4001 (0.00%)  0
Malignant neoplasm progression * 1  3/3997 (0.08%)  3 4/4001 (0.10%)  4
Metastases to peritoneum * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Metastases to meninges * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Colorectal cancer metastatic * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Small intestine carcinoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Anal cancer metastatic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Hepatic cancer metastatic * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Biliary cancer metastatic * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Colon cancer metastatic * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Ovarian cancer metastatic * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Cancer pain * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Lung neoplasm malignant * 1  16/3997 (0.40%)  18 11/4001 (0.27%)  11
Metastases to central nervous system * 1  4/3997 (0.10%)  4 3/4001 (0.07%)  3
Paraneoplastic syndrome * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Prostate cancer * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Brain neoplasm * 1  2/3997 (0.05%)  2 2/4001 (0.05%)  3
Colon neoplasm * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Metastatic neoplasm * 1  3/3997 (0.08%)  4 2/4001 (0.05%)  2
Nasopharyngeal cancer * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Neoplasm progression * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Paraproteinaemia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Pleural neoplasm * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Renal neoplasm * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Salivary gland neoplasm * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Non-small cell lung cancer * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Lung neoplasm * 1  4/3997 (0.10%)  5 1/4001 (0.02%)  1
Lung adenocarcinoma metastatic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Renal cell carcinoma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Sarcoma metastatic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Nervous system disorders     
Altered state of consciousness * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Amyotrophic lateral sclerosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Ataxia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Autonomic nervous system imbalance * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Carotid artery stenosis * 1  4/3997 (0.10%)  4 0/4001 (0.00%)  0
Cauda equina syndrome * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Cerebellar haemorrhage * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Cerebral atrophy * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Cerebral circulatory failure * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Cerebral haemorrhage * 1  4/3997 (0.10%)  4 2/4001 (0.05%)  2
Cerebral infarction * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Cerebral ischaemia * 1  3/3997 (0.08%)  3 1/4001 (0.02%)  1
Cerebrovascular accident * 1  5/3997 (0.13%)  5 1/4001 (0.02%)  1
Cervical myelopathy * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Coma * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Convulsion * 1  2/3997 (0.05%)  2 3/4001 (0.07%)  3
Dementia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Dementia Alzheimer's type * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Diabetic hyperglycaemic coma * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Dizziness * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Dysarthria * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Embolic stroke * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Encephalopathy * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Epilepsy * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Extrapyramidal disorder * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Grand mal convulsion * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Guillain-Barre syndrome * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Haemorrhage intracranial * 1  3/3997 (0.08%)  3 1/4001 (0.02%)  1
Haemorrhagic stroke * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Hemiparesis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Hepatic encephalopathy * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Hydrocephalus * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Hypoaesthesia * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Hypoglycaemic coma * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Intracranial aneurysm * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Lethargy * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Loss of consciousness * 1  3/3997 (0.08%)  3 1/4001 (0.02%)  1
Myoclonus * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Nerve compression * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Neuropathy peripheral * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Parkinsonism * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Peripheral sensory neuropathy * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Presyncope * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Radiculopathy * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Sciatica * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Somnolence * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Speech disorder * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Spinal cord compression * 1  4/3997 (0.10%)  4 0/4001 (0.00%)  0
Subarachnoid haemorrhage * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Syncope * 1  15/3997 (0.38%)  18 10/4001 (0.25%)  10
Tension headache * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Transient ischaemic attack * 1  4/3997 (0.10%)  4 10/4001 (0.25%)  10
Unresponsive to stimuli * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Carotid artery occlusion * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Psychomotor skills impaired * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Quadriparesis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
VIIth nerve paralysis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Lacunar infarction * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Haemorrhagic transformation stroke * 1  2/3997 (0.05%)  2 3/4001 (0.07%)  3
Vascular dementia * 1  1/3997 (0.03%)  1 2/4001 (0.05%)  2
Intracranial venous sinus thrombosis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Ischaemic stroke * 1  30/3997 (0.75%)  31 39/4001 (0.97%)  40
Partial seizures * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Parkinson's disease * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Metabolic encephalopathy * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Critical illness polyneuropathy * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Acute polyneuropathy * 1  1/3997 (0.03%)  3 0/4001 (0.00%)  0
Brain stem stroke * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Hypoxic-ischaemic encephalopathy * 1  3/3997 (0.08%)  3 0/4001 (0.00%)  0
Psychiatric disorders     
Anorexia nervosa * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Anxiety * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Completed suicide * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Confusional state * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Delirium * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Depression * 1  1/3997 (0.03%)  1 5/4001 (0.12%)  5
Disorientation * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Panic attack * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Somatisation disorder * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Suicide attempt * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Mental status changes * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Bipolar disorder * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Major depression * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  2
Mental disorder * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Psychotic disorder * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  2
Psychiatric decompensation * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Renal and urinary disorders     
Acute prerenal failure * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Anuria * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Azotaemia * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Calculus ureteric * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Calculus urinary * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  2
Cystitis haemorrhagic * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Haematuria * 1  9/3997 (0.23%)  9 7/4001 (0.17%)  7
Nephritis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Nephrolithiasis * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Nephrotic syndrome * 1  0/3997 (0.00%)  0 2/4001 (0.05%)  2
Obstructive uropathy * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Proteinuria * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Renal failure * 1  12/3997 (0.30%)  12 14/4001 (0.35%)  14
Renal failure acute * 1  31/3997 (0.78%)  32 16/4001 (0.40%)  16
Renal failure chronic * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Urinary bladder haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Urinary retention * 1  2/3997 (0.05%)  2 0/4001 (0.00%)  0
Cystitis glandularis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Urethral haemorrhage * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Renal impairment * 1  2/3997 (0.05%)  2 1/4001 (0.02%)  1
Pulmonary renal syndrome * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Reproductive system and breast disorders     
Benign prostatic hyperplasia * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Epididymitis * 1  1/3997 (0.03%)  1 1/4001 (0.02%)  1
Penile haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Prostatitis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Vaginal haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Postmenopausal haemorrhage * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Perineal fistula * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema * 1  8/3997 (0.20%)  8 5/4001 (0.12%)  5
Acute respiratory distress syndrome * 1  1/3997 (0.03%)  1 5/4001 (0.12%)  5
Acute respiratory failure * 1  35/3997 (0.88%)  37 12/4001 (0.30%)  13
Apnoeic attack * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Aspiration * 1  0/3997 (0.00%)  0 1/4001 (0.02%)  1
Asthma * 1  8/3997 (0.20%)  9 6/4001 (0.15%)  7
Atelectasis * 1  1/3997 (0.03%)  1 0/4001 (0.00%)  0
Bronchitis chronic * 1  3/3997 (0.08%)  3 2/4001 (0.05%)  2
Chronic obstructive pulmonary disease * 1