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Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement

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ClinicalTrials.gov Identifier: NCT01240902
Recruitment Status : Active, not recruiting
First Posted : November 15, 2010
Results First Posted : June 8, 2015
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
Medtronic Cardiovascular

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Severe Aortic Stenosis
Interventions Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
Device: Surgical Aortic Valve Replacement (SAVR)
Enrollment 1453
Recruitment Details Between Feb 17, 2011 and Aug 23, 2013, 656 subjects were enrolled into the CoreValve US Pivotal Trial Extreme Risk study at 41 of the 43 activated centers in the United States. Between February 2, 2011 and July 23, 2013, 797 subjects were enrolled into the CoreValve US Pivotal Trial High Risk study at 45 centers in the United States.
Pre-assignment Details The first 3 successfully enrolled and implanted iliofemoral subjects at each implanting site, inclusive of both the High Risk Surgical and Extreme Risk patient populations were considered roll-in subjects, and were automatically assigned to undergo Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI).
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI) High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Period Title: Overall Study
Started 500 156 395 402
Completed 289 77 295 237
Not Completed 211 79 100 165
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR Total
Hide Arm/Group Description Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI) High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR) Total of all reporting groups
Overall Number of Baseline Participants 489 150 391 359 1389
Hide Baseline Analysis Population Description
Participant Population= As Treated (AT) cohort. The AT cohort consisted of all Intent to Treat (ITT) subjects with an attempted implant procedure.
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 489 participants 150 participants 391 participants 359 participants 1389 participants
83.2  (8.7) 81.3  (7.4) 83.2  (7.1) 83.3  (6.4) 83.0  (7.6)
[1]
Measure Description: Participant Population= Consisted of all subjects with an attempted implant procedure.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 489 participants 150 participants 391 participants 359 participants 1389 participants
Female
255
  52.1%
82
  54.7%
184
  47.1%
171
  47.6%
692
  49.8%
Male
234
  47.9%
68
  45.3%
207
  52.9%
188
  52.4%
697
  50.2%
[1]
Measure Description: Participant Population= Consisted of all subjects with an attempted implant procedure.
Race/Ethnicity, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 489 participants 150 participants 391 participants 359 participants 1389 participants
American Indian or Alaska Native 0 0 0 1 1
Asian 2 1 0 1 4
Native Hawaiian or Other Pacific Islander 0 0 0 0 0
Black or African American 19 5 3 11 38
White 468 143 387 343 1341
More than one race 0 0 0 0 0
Unknown or Not Reported 0 1 1 2 4
[1]
Measure Description: Participant Population= Consisted of all subjects with an attempted implant procedure.
Body Surface Area   [1] 
Mean (Standard Deviation)
Unit of measure:  M^2
Number Analyzed 489 participants 150 participants 391 participants 359 participants 1389 participants
1.8  (0.3) 1.8  (0.2) 1.8  (0.2) 1.9  (0.2) 1.8  (0.2)
[1]
Measure Description: Participant Population= Consisted of all subjects with an attempted implant procedure.
NYHA Classification   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 489 participants 150 participants 391 participants 359 participants 1389 participants
NYHA I 0 0 0 0 0
NYHA II 40 12 57 47 156
NYHA III 313 98 255 250 916
NYHA IV 136 40 79 62 317
[1]
Measure Description:

New York Heart Association (NYHA) Classification:

Class I: Subjects with cardiac disease but without resulting limitations of physical activity.

Class I: Subjects with cardiac disease resulting in slight limitation of physical activity.

Class III: Subjects with cardiac disease resulting in marked limitation of physical activity.

Class IV: Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort.

Society of Thoracic Surgeons (STS) Risk Score   [1] 
Mean (Standard Deviation)
Unit of measure:  % risk of mortality or morbidity
Number Analyzed 489 participants 150 participants 391 participants 359 participants 1389 participants
10.3  (5.5) 10.7  (5.7) 7.3  (3.0) 7.5  (3.3) 8.8  (4.7)
[1]
Measure Description: The Society of Thoracic Surgeons (STS) risk model predicts the risk of operative mortality and morbidity after adult cardiac surgery on the basis of patient demographic and clinical variables. After information has been entered on a given case, the online STS risk calculator provides a risk percentage for each of the outcomes. The risk percentage estimates the chance of a specific outcome for a patient with the indicated risk factors. A higher score indicates a higher risk. A lower score indicates a lower risk.
Logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE)   [1] 
Mean (Standard Deviation)
Unit of measure:  %
Number Analyzed 489 participants 150 participants 391 participants 359 participants 1389 participants
22.6  (17.1) 22.9  (15.9) 17.7  (13.0) 18.8  (13.2) 20.3  (15.1)
[1]
Measure Description: The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is a method of calculating predicted operative mortality for patients undergoing cardiac surgery. If a risk factor is present, a weight/number is assigned. The weights are added to give an approximate percent of predicted mortality. A higher score indicates a higher risk. A lower score indicates a lower risk.
1.Primary Outcome
Title Extreme Risk: All-cause Death or Major Stroke; High Risk Surgical: All-cause Mortality
Hide Description All-cause Death or Major Stroke (Extreme Risk- Medtronic CoreValve® System); All-cause Mortality (High Risk Surgical- Medtronic CoreValve® System vs. Surgical Valve)
Time Frame 1 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Measure Type: Number
Unit of Measure: percentage of participants, Kaplan-Meier
26.0 39.3 14.1 18.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Extreme Risk: TAVI Iliofemoral
Comments TAVR with the Medtronic CoreValve System meets the Performance Goal in the 12 month rate of all-cause mortality or major stroke H0: = πMCS TAVI ≥ 43.0% HA: = πMCS TAVI < 43.0% In the above expressions πMCS TAVI denotes the rate of all-cause mortality or major stroke during a fixed follow-up of 1 year.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method z-test, 1 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Kaplan-Meier
Estimated Value 26.0
Confidence Interval (2-Sided) 95%
22.3 to 30.1
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.0
Estimation Comments Kaplan-Meier Event Rate Greenwood Standard Error
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Extreme Risk: TAVI Non-Iliofemoral
Comments No performance goal created, only descriptive statistics are provided.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Kaplan-Meier
Estimated Value 39.3
Parameter Dispersion
Type: Standard Error of the Mean
Value: 4.0
Estimation Comments Kaplan-Meier Event Rate Greenwood Standard Error
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection High Risk: TAVI
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The 12 month all-cause mortality estimated rate was 20% for each group with a noninferiority margin of 7.5 percentage points. Assuming a 1:1 ratio in the treatment assignments, we estimated that a total of 355 patients were required in each group for the study to have power of 80% at a one-sided alpha level of 0.05. Accounting for a 10% loss to follow-up, we calculated that we would need to enroll 790 patients.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method z-test, 1 sided
Comments [Not Specified]
2.Secondary Outcome
Title Major Adverse Cardiovascular and Cerebrovascular Event (MACCE)
Hide Description

MACCE is defined as a composite of:

  • All Cause Mortality
  • Myocardial infarction (MI)
  • All Stroke
  • Reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve)
Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Measure Type: Number
Unit of Measure: percentage of participants, Kaplan-Meier
30 day 12.3 17.3 7.7 10.3
6 month 22.5 34.7 15.4 21.0
1 year 29.2 41.4 20.5 27.0
2 Year 42.3 51.0 29.7 38.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Risk: TAVI, High Risk: SAVR
Comments

Powered Secondary Hypothesis: TAVR with the Medtronic CoreValve System was superior to SAVR in binary rate of MACCE at 30 days or hospital discharge, whichever was longer:

H0: πMCS TAVR = πSAVR HA: πMCS TAVR < πSAVR In the above expression πMCS TAVR and πSAVR denoted rates of MACCE at 30 days or hospital discharge, whichever was longer.

Assumptions:

1:1 treatment allocation ratio One-sided alpha=0.025 SAVR = 20.0% MCS TAVI = 12.1% Power = >80%

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1033
Comments Hierarchical test item #5, MACCE at 30 days or hospital discharge; whichever was longer. K-M rates TAVR 8.21%, SAVR 10.93%, Difference -2.73%, Standard Error 2.16%, and Upper 95% CI 1.5%.
Method Kaplan-Meier Point Estimate
Comments Using Greenwood formula
3.Secondary Outcome
Title The Occurrence of Individual MACCE Components
Hide Description

Individual MACCE Components Include:

  • All Cause Mortality
  • MI
  • All stroke
  • Reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve)
Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Measure Type: Number
Unit of Measure: percentage of participants, Kaplan-Meier
30 day All Cause Mortality 8.4 11.3 3.3 4.5
30 day MI 1.2 2.1 0.8 0.8
30 day Stroke 4.0 8.8 4.9 6.2
30 day Reintervention 1.1 0.0 0.8 0.0
6 month All Cause Mortality 18.6 28.7 9.0 14.0
6 month MI 1.5 2.1 1.6 1.1
6 month Stroke 5.2 12.0 7.3 9.9
6 month Reintervention 1.5 0.0 1.0 0.0
1 year All Cause Mortality 24.3 36.0 14.1 18.9
1 year MI 2.0 2.1 1.9 1.5
1 year Stroke 7.0 13.0 8.7 12.5
1 year Reintervention 1.8 1.0 2.2 0.0
2 year All Cause Mortality 36.6 44.9 22.2 28.6
2 year MI 2.8 3.2 1.9 2.3
2 year Stroke 8.6 16.1 10.9 16.6
2 year Reintervention 1.8 1.0 2.5 0.4
4.Secondary Outcome
Title Major Adverse Events (MAEs)
Hide Description

MAEs Include:

  • MACCE
  • Acute Kidney Injury
  • Cardiac Tamponade
  • Prosthetic Valve Dysfunction
  • Cardiogenic Shock
  • Valve Endocarditis
  • Life-Threatening, Disabling or Major Bleeding
  • Major Vascular Complication
  • Cardiac Perforation
  • Device Migration/Valve Embolism
Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Measure Type: Number
Unit of Measure: percentage of participants, Kaplan-Meier
30 day 54.2 69.3 52.4 50.2
6 month 60.5 76.0 58.6 76.4
1 year 63.4 80.0 60.1 59.8
2 year 71.3 84.0 66.4 66.8
5.Secondary Outcome
Title Conduction Disturbance Requiring Permanent Pacemaker Implantation
Hide Description [Not Specified]
Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Measure Type: Number
Unit of Measure: percentage of participants, Kaplan-Meier
30 day 21.6 16.4 20.0 7.1
6 month 24.4 20.5 21.9 9.9
1 year 26.4 21.5 22.5 11.6
2 year 28.8 22.6 25.8 12.8
6.Secondary Outcome
Title Change in NYHA Class
Hide Description

Change from baseline (continuous variable). A positive number corresponds to NYHA worsening; a negative number corresponds to NYHA improvement.

New York Heart Association (NYHA) Classification:

Class I: Subjects with cardiac disease but without resulting limitations of physical activity.

Class I: Subjects with cardiac disease resulting in slight limitation of physical activity.

Class III: Subjects with cardiac disease resulting in marked limitation of physical activity.

Class IV: Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort.

Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Mean (Standard Deviation)
Unit of Measure: average classification level change
30 day -1.3  (0.9) -1.0  (0.8) -1.3  (0.8) -1.0  (0.9)
6 month -1.6  (0.9) -1.4  (0.8) -1.5  (0.8) -1.4  (0.8)
1 year -1.6  (0.9) -1.4  (0.8) -1.5  (0.8) -1.5  (0.8)
2 year -1.6  (0.8) -1.4  (0.7) -1.5  (0.8) -1.5  (0.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Extreme Risk: TAVI Iliofemoral
Comments Change in NYHA classification from baseline to 1 year from secondary objective #5. The paired t-test will be used to test the null hypothesis that the mean paired difference is zero versus the two-sided alternative that the mean is not zero.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical test item #3, change from baseline to 1 year.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -1.6
Parameter Dispersion
Type: Standard Deviation
Value: 0.9
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection High Risk: TAVI, High Risk: SAVR
Comments

Change in NYHA classification from baseline to 1 year: TAVR vs. SAVR from secondary objective #5. The one-sided two-sample t-test was used to test non-inferiority at a level 0.05 the hypotheses:

H0: µ MCS TAVR ≤ µ SAVR -0.375 HA: µ MCS TAVR > µ SAVR -0.375 In the above expression µ MCS TAVR and µ SAVR denoted the mean number of classification improvements in NYHA from baseline to 1 year.

Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority margin= 0.375. For subjects with NYHA categories at both baseline and 1 year visit, the NYHA classification improvements were calculated as NYHAbaseline – NYHA1year.
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical test item #3, change from baseline to 1 year.
Method t-test, 1 sided
Comments [Not Specified]
7.Secondary Outcome
Title Change in Distance Walked During 6-Minute Walk Test (6MWT)
Hide Description Change in distance walked during 6MWT from baseline
Time Frame 30 day, 1 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Mean (Standard Deviation)
Unit of Measure: meters
30 day 19.6  (109.1) 13.3  (110.0) 25.8  (105.5) -6.9  (89.8)
1 year 13.9  (140.4) 22.2  (136.2) 27.0  (114.3) 24.0  (111.8)
8.Secondary Outcome
Title Ratio of Days Alive Out of Hospital Versus Total Days Alive
Hide Description [Not Specified]
Time Frame 1 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Mean (Standard Deviation)
Unit of Measure: ratio of days alive and out of hospital
0.86  (0.28) 0.81  (0.31) 0.92  (0.20) 0.89  (0.23)
9.Secondary Outcome
Title Quality of Life (QoL) Change
Hide Description

QoL summary score change from baseline using the following measures:

  • Kansas City Cardiomyopathy Questionnaire (KCCQ): Quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
  • 12 Item Short Form Health Survey (SF-12): Measures functional health and well-being. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
  • European QoL (EQ-5D): Measures 5 domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that can be converted to utilities using an algorithm. Utilities range from 0 to 1, with 1 representing perfect health, and 0 corresponding to the worst imaginable health state.
Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Mean (Standard Deviation)
Unit of Measure: units on a scale
30 day KCCQ- Overall 24.2  (28.9) 7.9  (33.5) 19.0  (29.4) 4.3  (28.1)
30 day KCCQ- Clinical 20.2  (28.0) 6.8  (32.0) 14.7  (28.6) 2.7  (27.1)
30 day SF-12-Physical 5.9  (10.4) 1.9  (10.4) 4.9  (10.2) -0.0  (10.1)
30 day SF-12-Mental 3.7  (14.2) -1.7  (16.2) 2.6  (13.1) -2.5  (13.4)
30 day EQ-5D 0.09  (0.29) 0.00  (0.30) 0.04  (0.24) -0.07  (0.26)
6 month KCCQ-Overall 27.4  (27.0) 23.1  (28.3) 24.8  (26.9) 22.9  (26.4)
6 month KCCQ- Clinical 22.2  (26.1) 17.5  (26.6) 18.6  (25.7) 17.7  (25.7)
6 month SF-12-Physical 5.2  (11.3) 4.5  (8.9) 6.3  (11.0) 6.2  (9.9)
6 month SF-12-Mental 4.6  (13.6) 4.4  (13.8) 4.6  (11.8) 2.6  (13.1)
6 month EQ-5D 0.09  (0.22) 0.05  (0.21) 0.05  (0.22) 0.04  (0.17)
1 year KCCQ-Overall 27.9  (27.1) 21.9  (26.8) 23.2  (25.4) 21.8  (26.5)
1 year KCCQ- Clinical 20.8  (26.8) 18.1  (24.9) 16.7  (25.5) 15.2  (26.0)
1 year SF-12-Physical 5.5  (10.8) 4.6  (10.0) 6.0  (11.5) 5.3  (10.3)
1 year SF-12-Mental 5.2  (13.7) 2.4  (14.3) 4.5  (11.8) 3.2  (12.1)
1 year EQ-5D 0.06  (0.25) 0.05  (0.25) 0.04  (0.19) 0.01  (0.19)
2 year KCCQ - Overall 25.2  (27.2) 14.9  (29.5) 22.2  (26.5) 18.7  (25.6)
2 year KCCQ - Clinical 18.8  (26.1) 11.6  (26.9) 14.6  (26.0) 12.6  (25.8)
2 year SF-12 - Physical 4.0  (11.2) 1.9  (11.9) 5.0  (12.1) 4.3  (10.2)
2 year SF-12 - Mental 3.8  (15.3) 2.2  (14.8) 3.6  (13.0) 1.7  (13.0)
2 year EQ-5D 0.04  (0.25) 0.03  (0.26) -0.01  (0.24) -0.01  (0.21)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Extreme Risk: TAVI Iliofemoral
Comments Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 1 year from secondary objective #8. The paired t-test will be used to test the null hypothesis that the mean paired difference is zero versus the two-sided alternative that the mean is not zero.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical test item #4
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection High Risk: TAVI, High Risk: SAVR
Comments

Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 1 year: TAVR vs. SAVR from secondary objective #8. The one-sided two-sample t-test was used to test non-inferiority at a level 0.05 the hypotheses:

H0: µ MCS TAVR ≤ µ SAVR -5 HA: µ MCS TAVR > µ SAVR -5 In the above expression µ MCS TAVR and µ SAVR denoted the mean improvements in the KCCQ score from baseline to 1 year.

Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority margin 5
Statistical Test of Hypothesis P-Value 0.0063
Comments Hierarchical test item #4
Method t-test, 1 sided
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection High Risk: TAVI, High Risk: SAVR
Comments

Change in SF-12 Physical Summary Scale from baseline to 30 days: TAVR vs. SAVR from secondary objective #8. The two-sided two-sample t-test was used to test at a level 0.05 the hypotheses:

H0: µ MCS TAVR = µ SAVR HA: µ MCS TAVR ≠ µ SAVR In the above expression µ MCS TAVR and µ SAVR denoted the mean improvements in the SF-12 Physical Summary Scale from baseline to 30 days.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical test item #6. Item #5 failed, therefore, item #6 also fails. Nominal p- value provided.
Method t-test, 2 sided
Comments [Not Specified]
10.Secondary Outcome
Title Echocardiographic Assessment of Valve Performance
Hide Description

Using the following measures:

- Effective Orifice Area (EOA)

Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with a valve implanted.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 486 148 390 354
Mean (Standard Deviation)
Unit of Measure: cm^2
30 day EOA 1.86  (0.56) 1.82  (0.64) 1.94  (0.56) 1.60  (0.51)
6 month EOA 1.88  (0.55) 1.85  (0.51) 1.91  (0.53) 1.56  (0.49)
1 year EOA 1.88  (0.54) 1.85  (0.51) 1.91  (0.52) 1.57  (0.49)
2 year EOA 1.86  (0.55) 1.83  (0.58) 1.87  (0.48) 1.51  (0.43)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Extreme Risk: TAVI Iliofemoral
Comments

EOA:

Change in effective orifice area from Baseline to 1 year from secondary objective #9. The paired t-test will be used to test the null hypothesis that the mean paired difference is zero versus the two-sided alternative that the mean is not zero.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical test item #2
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection High Risk: TAVI, High Risk: SAVR
Comments

EOA:

Change in effective orifice area from Baseline to 1 year: TAVR vs.SAVR from secondary objective #9. The one-sided two-sample t-test was used to test non-inferiority at a level 0.05 the hypotheses:

H0: µ MCS TAVR ≤ µ SAVR -0.375 HA: µ MCS TAVR > µ SAVR -0.375 In the above expression µ MCS TAVR and µ SAVR denoted the mean improvements in effective orifice area from Baseline to 1 year measured in cm2.

Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority margin 0.375
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical test item #2
Method t-test, 1 sided
Comments [Not Specified]
11.Secondary Outcome
Title Echocardiographic Assessment of Valve Performance
Hide Description

Using the following measures:

- Transvalvular Mean Gradient

Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with a valve implanted.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 486 148 390 354
Mean (Standard Deviation)
Unit of Measure: mmHg
30 day Mean Gradient 8.68  (4.16) 9.74  (5.82) 8.88  (3.86) 11.72  (5.70)
6 month Mean Gradient 9.10  (3.89) 9.42  (5.60) 9.08  (4.08) 12.12  (6.31)
1 year Mean Gradient 8.86  (4.09) 9.46  (5.65) 9.09  (3.49) 12.44  (7.36)
2 year Mean Gradient 8.70  (4.22) 9.24  (5.35) 8.47  (3.76) 12.05  (6.32)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Extreme Risk: TAVI Iliofemoral
Comments

Transvalvular Mean Gradient:

Change in transvalvular mean gradient from baseline to 1 year from secondary objective #9. The paired t-test will be used to test the null hypothesis that the mean paired difference is zero versus the two-sided alternative that the mean is not zero.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical test item #1
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection High Risk: TAVI, High Risk: SAVR
Comments

Transvalvular Mean Gradient:

Change in transvalvular mean gradient from baseline to 1 year: TAVR vs.SAVR from secondary objective #9. The one-sided two-sample t-test was used to test non-inferiority at a level of 0.05 the hypotheses: H0: μ MCS TAVR ≤ μ SAVR -15 HA: μ MCS TAVR > μ SAVR -15 In the above expression μ MCS TAVR and μ SAVR denoted the mean improvements in mean gradient from Baseline to 1 year measured in mmHg.

Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority margin 15
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical test item #1
Method t-test, 1 sided
Comments [Not Specified]
12.Secondary Outcome
Title Echocardiographic Assessment of Valve Performance
Hide Description

Using the following measure:

- Degree of Aortic Valve Regurgitation (Transvalvular and Paravalvular)

Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with a valve implanted.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 486 148 390 354
Measure Type: Number
Unit of Measure: percentage of participants
30 day Total Aortic Regurgitation- None 9.1 19.0 12.2 65.0
30 day Total Aortic Regurgitation- Trivial 32.7 33.9 41.4 23.0
30 day Total Aortic Regurgitation- Mild 43.0 34.7 36.4 10.7
30 day Total Aortic Regurgitation- Moderate 14.1 10.7 8.1 1.3
30 day Total Aortic Regurgitation- Severe 1.2 1.7 1.9 0.0
6 month Total Aortic Regurgitation- None 19.9 33.3 21.6 60.6
6 month Total Aortic Regurgitation- Trivial 33.5 27.1 37.2 28.0
6 month Total Aortic Regurgitation- Mild 36.5 35.4 29.7 9.8
6 month Total Aortic Regurgitation- Moderate 9.8 4.2 10.0 1.6
6 month Total Aortic Regurgitation- Severe 0.3 0.0 1.6 0.0
1 year Total Aortic Regurgitation- None 21.5 39.0 28.3 68.1
1 year Total Aortic Regurgitation- Trivial 40.6 36.6 35.7 21.7
1 year Total Aortic Regurgitation- Mild 31.5 20.7 29.0 8.8
1 year Total Aortic Regurgitation- Moderate 6.4 2.4 6.7 0.9
1 year Total Aortic Regurgitation- Severe 0.0 1.2 0.3 0.4
2 year Total Aortic Regurgitation - None 31.0 35.3 32.8 58.5
2 year Total Aortic Regurgitation - Trivial 26.3 36.8 27.0 27.3
2 year Total Aortic Regurgitation - Mild 36.1 23.5 32.0 13.1
2 year Total Aortic Regurgitation - Moderate 6.7 4.4 6.6 1.1
2 year Total Aortic Regurgitation - Severe 0.0 0.0 1.6 0.0
13.Secondary Outcome
Title Aortic Valve Hospitalizations
Hide Description [Not Specified]
Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Measure Type: Number
Unit of Measure: percentage of participants, Kaplan-Meier
30 day 6.7 8.7 3.9 5.2
6 month 16.4 18.3 13.4 9.0
1 year 21.9 21.2 16.5 14.0
2 year 29.5 27.2 24.2 18.2
14.Secondary Outcome
Title Cardiovascular Deaths and Valve Related Deaths
Hide Description [Not Specified]
Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Measure Type: Number
Unit of Measure: percentage of participants, Kaplan-Meier
30 day Cardiovascular Deaths 8.4 11.3 3.3 4.5
30 Day Valve Related Deaths 2.5 2.8 2.3 0.6
6 month Cardiovascular Deaths 15.0 23.6 7.4 10.5
6 month Valve Related Deaths 4.1 4.5 3.6 1.8
1 year Cardiovascular Deaths 18.3 28.7 10.6 12.9
1 year Valve Related Deaths 5.1 5.4 5.6 2.2
2 year Cardiovascular Deaths 26.2 35.1 15.4 19.4
2 year Valve Related Deaths 6.2 7.5 6.8 4.2
15.Secondary Outcome
Title Strokes and Transient Ischemic Attacks (TIAs)
Hide Description Strokes (of any severity) and TIAs
Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Measure Type: Number
Unit of Measure: percentage of participants, Kaplan-Meier
30 day 4.6 10.2 5.7 6.5
6 month 6.0 14.3 8.4 10.8
1 year 8.1 15.2 10.3 14.1
2 year 10.1 19.5 13.2 17.8
16.Secondary Outcome
Title Index Procedure Related MAEs
Hide Description [Not Specified]
Time Frame Procedure
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Measure Type: Number
Unit of Measure: percentage of participants
53.5 68.9 52.6 49.9
17.Secondary Outcome
Title Length of Index Procedure Hospital Stay
Hide Description [Not Specified]
Time Frame Number of days from admission to discharge
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with an attempted implant procedure.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 489 150 391 359
Mean (Standard Deviation)
Unit of Measure: days
9.2  (8.1) 11.2  (8.9) 8.0  (6.8) 12.5  (10.7)
18.Secondary Outcome
Title Device Success
Hide Description

Medtronic CoreValve® System subjects only.

Defined as:

  • Successful vascular access, delivery and deployment of the device, and successful retrieval of the delivery system,
  • Correct position of the device in the proper anatomical location (placement in the annulus with no impedance on device function),
  • Intended performance of the prosthetic valve (aortic valve area > 1.2 cm2 for 26, 29 and 31mm valves, ≥ 0.9 cm2 for 23mm valve (by echocardiography using the continuity equation) and mean aortic valve gradient < 20 mmHg or peak velocity < 3 m/sec, without moderate or severe prosthetic valve aortic regurgitation)
  • Only one valve implanted in the proper anatomical location
Time Frame Number of days from admission to discharge
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with a TAVR index procedure who were evaluable for device success.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 468 141 378 0
Measure Type: Number
Unit of Measure: percentage of participants
84.6 88.7 86.8
19.Secondary Outcome
Title Procedural Success
Hide Description

Medtronic CoreValve® System subjects only.

Defined as device success and absence of in-hospital MACCE.

Time Frame Number of days from admission to discharge
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with a TAVR index procedure who were evaluable for procedural success.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 476 142 384 0
Measure Type: Number
Unit of Measure: percentage of participants
77.5 77.5 81.3
20.Secondary Outcome
Title Prosthetic Valve Dysfunction (PVD)
Hide Description

PVD was defined according to VARC I using the Core Lab Echocardiography assessments including aortic regurgitation (AR) and aortic stenosis (AS) evaluations. Total AR reported as moderate or severe was considered PVD. AS was defined as significant stenosis and considered PVD if one of the following was met:

  • Peak velocity >4 m/s
  • Mean gradient >35 mmHg
  • EOA < 0.8 cm2
  • TVIV1 / TVIV2 < 0.25
Time Frame 30 day, 6 month, 1 year, 2 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participant Population= Consisted of all subjects with a valve implanted.
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description:
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access
Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access
High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
Overall Number of Participants Analyzed 486 148 390 354
Measure Type: Number
Unit of Measure: percentage of participants
30 day Aortic Stenosis 2.3 6.1 3.1 4.8
30 day Aortic Regurgitation 23.5 16.9 13.6 1.7
6 month Aortic Stenosis 3.1 6.1 3.8 6.5
6 month Aortic Regurgitation 26.1 18.2 17.2 2.3
1 year Aortic Stenosis 3.5 6.1 4.9 8.2
1 year Aortic Regurgitation 27.0 19.6 17.9 2.8
2 year Aortic Stenosis 3.9 6.8 5.4 9.3
2 year Aortic Regurgitation 27.8 19.6 19.7 2.8
Time Frame Adverse events (AEs) were collected from study enrollment to study closure, up to 5 years. Adverse event data are currently available and reported for up to 1 year
Adverse Event Reporting Description All new or worsening AEs were collected through12 months.
 
Arm/Group Title Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Hide Arm/Group Description Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI) High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)
All-Cause Mortality
Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Extreme Risk: TAVI Iliofemoral Extreme Risk: TAVI Non-Iliofemoral High Risk: TAVI High Risk: SAVR
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   452/489 (92.43%)      142/150 (94.67%)      346/390 (88.72%)      324/357 (90.76%)    
Blood and lymphatic system disorders         
Anaemia Deficiencies  1  2/489 (0.41%)  2 0/150 (0.00%)  0 2/390 (0.51%)  2 0/357 (0.00%)  0
Anaemias Due To Chronic Disorders  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Anaemias Haemolytic Immune  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Anaemias Nec  1  140/489 (28.63%)  170 70/150 (46.67%)  75 106/390 (27.18%)  132 151/357 (42.30%)  173
Coagulopathies  1  2/489 (0.41%)  3 2/150 (1.33%)  2 1/390 (0.26%)  1 4/357 (1.12%)  4
Eosinophilic Disorders  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Haematological Disorders  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Leukocytoses Nec  1  5/489 (1.02%)  5 1/150 (0.67%)  1 3/390 (0.77%)  3 4/357 (1.12%)  4
Marrow Depression And Hypoplastic Anaemias  1  1/489 (0.20%)  1 1/150 (0.67%)  1 2/390 (0.51%)  2 1/357 (0.28%)  1
Thrombocytopenias  1  11/489 (2.25%)  11 4/150 (2.67%)  4 8/390 (2.05%)  8 22/357 (6.16%)  22
Cardiac disorders         
Aortic Valvular Disorders  1  44/489 (9.00%)  45 12/150 (8.00%)  12 42/390 (10.77%)  42 10/357 (2.80%)  12
Cardiac Conduction Disorders  1  106/489 (21.68%)  109 24/150 (16.00%)  27 79/390 (20.26%)  85 18/357 (5.04%)  19
Cardiac Disorders Nec  1  9/489 (1.84%)  9 3/150 (2.00%)  3 7/390 (1.79%)  9 7/357 (1.96%)  7
Cardiac Signs And Symptoms Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 4/357 (1.12%)  4
Cardiac Valve Disorders Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Cardiomyopathies  1  1/489 (0.20%)  1 0/150 (0.00%)  0 4/390 (1.03%)  4 1/357 (0.28%)  1
Coronary Artery Disorders Nec  1  6/489 (1.23%)  6 4/150 (2.67%)  4 9/390 (2.31%)  9 4/357 (1.12%)  4
Heart Failures Nec  1  117/489 (23.93%)  186 29/150 (19.33%)  43 69/390 (17.69%)  95 62/357 (17.37%)  85
Ischaemic Coronary Artery Disorders  1  28/489 (5.73%)  30 8/150 (5.33%)  8 15/390 (3.85%)  17 12/357 (3.36%)  15
Mitral Valvular Disorders  1  9/489 (1.84%)  9 5/150 (3.33%)  5 3/390 (0.77%)  3 5/357 (1.40%)  5
Myocardial Disorders Nec  1  2/489 (0.41%)  2 0/150 (0.00%)  0 1/390 (0.26%)  1 2/357 (0.56%)  2
Noninfectious Pericarditis  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 1/357 (0.28%)  1
Pericardial Disorders Nec  1  5/489 (1.02%)  7 4/150 (2.67%)  4 5/390 (1.28%)  5 10/357 (2.80%)  10
Rate And Rhythm Disorders Nec  1  28/489 (5.73%)  29 6/150 (4.00%)  6 16/390 (4.10%)  18 19/357 (5.32%)  19
Right Ventricular Failures  1  3/489 (0.61%)  4 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Supraventricular Arrhythmias  1  65/489 (13.29%)  79 17/150 (11.33%)  22 43/390 (11.03%)  46 69/357 (19.33%)  80
Tricuspid Valvular Disorders  1  2/489 (0.41%)  2 3/150 (2.00%)  3 0/390 (0.00%)  0 2/357 (0.56%)  2
Ventricular Arrhythmias And Cardiac Arrest  1  48/489 (9.82%)  59 26/150 (17.33%)  30 27/390 (6.92%)  29 27/357 (7.56%)  27
Congenital, familial and genetic disorders         
Cardiac Septal Defects Congenital  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Coagulation Disorders Congenital  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Male Reproductive Tract Disorders Congenital  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Vascular Anomalies Congenital Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Ear and labyrinth disorders         
Hearing Losses  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Ear Disorders Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Inner Ear Signs And Symptoms  1  0/489 (0.00%)  0 1/150 (0.67%)  1 1/390 (0.26%)  1 0/357 (0.00%)  0
Endocrine disorders         
Thyroid Neoplasms  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Eye disorders         
Blindness (Excl Colour Blindness)  1  1/489 (0.20%)  1 1/150 (0.67%)  1 2/390 (0.51%)  2 0/357 (0.00%)  0
Cataract Conditions  1  2/489 (0.41%)  2 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Corneal Infections, Oedemas And Inflammations  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Lacrimal Disorders  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Retinal Bleeding And Vascular Disorders (Excl Retinopathy)  1  2/489 (0.41%)  2 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Retinal Structural Change, Deposit And Degeneration  1  1/489 (0.20%)  2 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Retinal, Choroid And Vitreous Infections And Inflammations  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Visual Disorders Nec  1  2/489 (0.41%)  2 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Gastrointestinal disorders         
Abdominal Wall Conditions Nec  1  1/489 (0.20%)  2 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Acute And Chronic Pancreatitis  1  4/489 (0.82%)  4 0/150 (0.00%)  0 2/390 (0.51%)  2 1/357 (0.28%)  1
Anal And Rectal Ulcers And Perforation  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Benign Neoplasms Gastrointestinal (Excl Oral Cavity)  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Colitis (Excl Infective)  1  2/489 (0.41%)  2 2/150 (1.33%)  2 0/390 (0.00%)  0 4/357 (1.12%)  4
Diaphragmatic Hernias  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Diarrhoea (Excl Infective)  1  4/489 (0.82%)  4 3/150 (2.00%)  3 3/390 (0.77%)  3 2/357 (0.56%)  2
Diverticula  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 2/357 (0.56%)  2
Duodenal And Small Intestinal Stenosis And Obstruction  1  2/489 (0.41%)  2 3/150 (2.00%)  3 2/390 (0.51%)  2 3/357 (0.84%)  3
Duodenal Ulcers And Perforation  1  0/489 (0.00%)  0 0/150 (0.00%)  0 2/390 (0.51%)  2 1/357 (0.28%)  1
Dyspeptic Signs And Symptoms  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Faecal Abnormalities Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 1/357 (0.28%)  1
Flatulence, Bloating And Distension  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Gastric And Oesophageal Haemorrhages  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Gastric Ulcers And Perforation  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 3/357 (0.84%)  3
Gastritis (Excl Infective)  1  3/489 (0.61%)  3 1/150 (0.67%)  1 2/390 (0.51%)  2 2/357 (0.56%)  2
Gastrointestinal And Abdominal Pains (Excl Oral And Throat)  1  13/489 (2.66%)  15 4/150 (2.67%)  4 3/390 (0.77%)  3 2/357 (0.56%)  2
Gastrointestinal Atonic And Hypomotility Disorders Nec  1  3/489 (0.61%)  3 1/150 (0.67%)  1 3/390 (0.77%)  4 1/357 (0.28%)  1
Gastrointestinal Fistulae  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Gastrointestinal Necrosis And Gangrene (Excl Gangrenous Hernia)  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Gastrointestinal Disorders Nec  1  2/489 (0.41%)  2 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Gastrointestinal Signs And Symptoms Nec  1  15/489 (3.07%)  15 7/150 (4.67%)  7 7/390 (1.79%)  7 12/357 (3.36%)  13
Gastrointestinal Spastic And Hypermotility Disorders  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Gastrointestinal Stenosis And Obstruction Nec  1  5/489 (1.02%)  5 1/150 (0.67%)  1 3/390 (0.77%)  3 3/357 (0.84%)  3
Gastrointestinal Ulcers And Perforation, Site Unspecified  1  1/489 (0.20%)  1 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Gastrointestinal Vascular Occlusion And Infarction  1  3/489 (0.61%)  3 1/150 (0.67%)  1 0/390 (0.00%)  0 1/357 (0.28%)  1
Haemorrhoids And Gastrointestinal Varices (Excl Oesophageal)  1  0/489 (0.00%)  0 1/150 (0.67%)  1 1/390 (0.26%)  1 0/357 (0.00%)  0
Inguinal Hernias  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Intestinal Haemorrhages  1  4/489 (0.82%)  4 1/150 (0.67%)  1 5/390 (1.28%)  5 4/357 (1.12%)  4
Intestinal Ulcers And Perforation Nec  1  3/489 (0.61%)  3 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Nausea And Vomiting Symptoms  1  2/489 (0.41%)  2 1/150 (0.67%)  2 3/390 (0.77%)  5 5/357 (1.40%)  5
Non-Site Specific Gastrointestinal Haemorrhages  1  35/489 (7.16%)  40 18/150 (12.00%)  20 27/390 (6.92%)  29 16/357 (4.48%)  17
Oesophageal Stenosis And Obstruction  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Oesophageal Ulcers And Perforation  1  2/489 (0.41%)  2 0/150 (0.00%)  0 3/390 (0.77%)  3 1/357 (0.28%)  1
Oesophagitis (Excl Infective)  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Oral Soft Tissue Pain And Paraesthesia  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Pancreatic Neoplasms  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Peritoneal And Retroperitoneal Disorders  1  1/489 (0.20%)  2 2/150 (1.33%)  2 0/390 (0.00%)  0 2/357 (0.56%)  2
Peritoneal And Retroperitoneal Haemorrhages  1  5/489 (1.02%)  5 1/150 (0.67%)  1 2/390 (0.51%)  2 1/357 (0.28%)  1
Umbilical Hernias  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Hepatic Fibrosis And Cirrhosis  1  3/489 (0.61%)  3 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Clostridia Infections  1  9/489 (1.84%)  9 2/150 (1.33%)  2 6/390 (1.54%)  7 6/357 (1.68%)  6
General disorders         
Administration Site Reactions Nec  1  1/489 (0.20%)  1 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Asthenic Conditions  1  11/489 (2.25%)  12 3/150 (2.00%)  3 9/390 (2.31%)  10 9/357 (2.52%)  9
Body Temperature Altered  1  2/489 (0.41%)  2 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Cardiac Complications Associated With Device  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Complications Associated With Device Nec  1  4/489 (0.82%)  4 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Death And Sudden Death  1  10/489 (2.04%)  10 5/150 (3.33%)  5 6/390 (1.54%)  6 3/357 (0.84%)  3
Device Issues Nec  1  40/489 (8.18%)  40 7/150 (4.67%)  7 28/390 (7.18%)  30 2/357 (0.56%)  2
Device Malfunction Events Nec  1  1/489 (0.20%)  1 1/150 (0.67%)  1 5/390 (1.28%)  5 5/357 (1.40%)  5
Febrile Disorders  1  3/489 (0.61%)  3 2/150 (1.33%)  2 7/390 (1.79%)  7 6/357 (1.68%)  6
Feelings And Sensations Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Gait Disturbances  1  0/489 (0.00%)  0 0/150 (0.00%)  0 3/390 (0.77%)  3 0/357 (0.00%)  0
General Signs And Symptoms Nec  1  7/489 (1.43%)  7 2/150 (1.33%)  2 4/390 (1.03%)  4 5/357 (1.40%)  5
Healing Abnormal Nec  1  2/489 (0.41%)  2 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Hernias Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Implant And Catheter Site Reactions  1  3/489 (0.61%)  3 0/150 (0.00%)  0 2/390 (0.51%)  2 0/357 (0.00%)  0
Inflammations  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Injection Site Reactions  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Mass Conditions Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Oedema Nec  1  6/489 (1.23%)  7 1/150 (0.67%)  1 6/390 (1.54%)  7 6/357 (1.68%)  6
Pain And Discomfort Nec  1  26/489 (5.32%)  33 9/150 (6.00%)  11 23/390 (5.90%)  29 19/357 (5.32%)  22
Product Physical Issues  1  1/489 (0.20%)  1 0/150 (0.00%)  0 2/390 (0.51%)  2 0/357 (0.00%)  0
Therapeutic And Nontherapeutic Responses  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Withdrawal And Rebound Effects  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Hepatobiliary disorders         
Bile Duct Infections And Inflammations  1  1/489 (0.20%)  1 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Cholecystitis And Cholelithiasis  1  3/489 (0.61%)  3 1/150 (0.67%)  1 4/390 (1.03%)  4 1/357 (0.28%)  1
Hepatic And Hepatobiliary Disorders Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Hepatic Failure And Associated Disorders  1  3/489 (0.61%)  3 0/150 (0.00%)  0 1/390 (0.26%)  1 3/357 (0.84%)  3
Hepatocellular Damage And Hepatitis Nec  1  5/489 (1.02%)  5 0/150 (0.00%)  0 0/390 (0.00%)  0 2/357 (0.56%)  2
Immune system disorders         
Anaphylactic Responses  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Infections and infestations         
Abdominal And Gastrointestinal Infections  1  6/489 (1.23%)  8 1/150 (0.67%)  1 4/390 (1.03%)  4 4/357 (1.12%)  4
Atypical Mycobacterial Infections  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Bacterial Infections Nec  1  22/489 (4.50%)  25 6/150 (4.00%)  6 15/390 (3.85%)  20 12/357 (3.36%)  12
Bone And Joint Infections  1  1/489 (0.20%)  1 1/150 (0.67%)  1 0/390 (0.00%)  0 1/357 (0.28%)  1
Candida Infections  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Cardiac Infections  1  6/489 (1.23%)  7 1/150 (0.67%)  1 1/390 (0.26%)  1 3/357 (0.84%)  3
Central Nervous System And Spinal Infections  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Ear Infections  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Enterobacter Infections  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 2/357 (0.56%)  2
Enterococcal Infections  1  4/489 (0.82%)  5 0/150 (0.00%)  0 0/390 (0.00%)  0 2/357 (0.56%)  2
Escherichia Infections  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Fungal Infections Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Haemophilus Infections  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Herpes Viral Infections  1  0/489 (0.00%)  0 2/150 (1.33%)  2 2/390 (0.51%)  2 0/357 (0.00%)  0
Infections Nec  1  8/489 (1.64%)  8 2/150 (1.33%)  2 6/390 (1.54%)  6 8/357 (2.24%)  8
Infectious Transmissions  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Influenza Viral Infections  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Klebsiella Infections  1  1/489 (0.20%)  1 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Lower Respiratory Tract And Lung Infections  1  74/489 (15.13%)  95 25/150 (16.67%)  26 44/390 (11.28%)  48 36/357 (10.08%)  43
Pseudomonal Infections  1  1/489 (0.20%)  2 1/150 (0.67%)  1 1/390 (0.26%)  1 2/357 (0.56%)  2
Sepsis, Bacteraemia, Viraemia And Fungaemia Nec  1  32/489 (6.54%)  35 17/150 (11.33%)  18 32/390 (8.21%)  38 29/357 (8.12%)  36
Staphylococcal Infections  1  3/489 (0.61%)  3 4/150 (2.67%)  4 3/390 (0.77%)  3 3/357 (0.84%)  4
Streptococcal Infections  1  2/489 (0.41%)  2 3/150 (2.00%)  3 2/390 (0.51%)  2 0/357 (0.00%)  0
Upper Respiratory Tract Infections  1  1/489 (0.20%)  1 2/150 (1.33%)  2 2/390 (0.51%)  2 0/357 (0.00%)  0
Urinary Tract Infections  1  28/489 (5.73%)  32 9/150 (6.00%)  11 21/390 (5.38%)  21 20/357 (5.60%)  22
Vascular Infections  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Viral Infections Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Injury, poisoning and procedural complications         
Anaesthetic Complications  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Cardiac And Vascular Procedural Complications  1  16/489 (3.27%)  17 3/150 (2.00%)  4 7/390 (1.79%)  7 3/357 (0.84%)  3
Cardiovascular Injuries  1  3/489 (0.61%)  3 2/150 (1.33%)  2 0/390 (0.00%)  0 2/357 (0.56%)  2
Cerebral Injuries Nec  1  0/489 (0.00%)  0 2/150 (1.33%)  2 5/390 (1.28%)  5 2/357 (0.56%)  2
Chest And Lung Injuries Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Fractures And Dislocations Nec  1  0/489 (0.00%)  0 2/150 (1.33%)  3 1/390 (0.26%)  1 3/357 (0.84%)  3
Gastrointestinal And Hepatobiliary Procedural Complications  1  1/489 (0.20%)  1 1/150 (0.67%)  1 0/390 (0.00%)  0 2/357 (0.56%)  2
Limb Injuries Nec (Incl Traumatic Amputation)  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Lower Limb Fractures And Dislocations  1  18/489 (3.68%)  19 1/150 (0.67%)  1 9/390 (2.31%)  10 10/357 (2.80%)  12
Non-Site Specific Injuries Nec  1  13/489 (2.66%)  13 4/150 (2.67%)  4 14/390 (3.59%)  16 6/357 (1.68%)  6
Non-Site Specific Procedural Complications  1  25/489 (5.11%)  27 6/150 (4.00%)  6 25/390 (6.41%)  26 28/357 (7.84%)  29
Pelvic Fractures And Dislocations  1  4/489 (0.82%)  4 2/150 (1.33%)  2 2/390 (0.51%)  2 1/357 (0.28%)  1
Poisoning And Toxicity  1  2/489 (0.41%)  2 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Radiation Injuries  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Reproductive System And Breast Injuries  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Respiratory Tract And Thoracic Cavity Procedural Complications  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 3/357 (0.84%)  3
Site Specific Injuries Nec  1  1/489 (0.20%)  1 1/150 (0.67%)  1 3/390 (0.77%)  3 1/357 (0.28%)  1
Skin Injuries Nec  1  10/489 (2.04%)  11 1/150 (0.67%)  1 5/390 (1.28%)  5 5/357 (1.40%)  5
Skin Procedural Complications  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Skull Fractures, Facial Bone Fractures And Dislocations  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Spinal Fractures And Dislocations  1  6/489 (1.23%)  7 1/150 (0.67%)  1 5/390 (1.28%)  8 2/357 (0.56%)  2
Thoracic Cage Fractures And Dislocations  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Transfusion Related Complications  1  0/489 (0.00%)  0 1/150 (0.67%)  1 1/390 (0.26%)  1 1/357 (0.28%)  1
Upper Limb Fractures And Dislocations  1  10/489 (2.04%)  11 0/150 (0.00%)  0 2/390 (0.51%)  2 5/357 (1.40%)  6
Investigations         
Bacteria Identification And Serology (Excl Mycobacteria)  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Blood Counts Nec  1  2/489 (0.41%)  2 2/150 (1.33%)  2 1/390 (0.26%)  1 0/357 (0.00%)  0
Blood Gas And Acid Base Analyses  1  0/489 (0.00%)  0 0/150 (0.00%)  0 3/390 (0.77%)  3 0/357 (0.00%)  0
Carbohydrate Tolerance Analyses (Incl Diabetes)  1  2/489 (0.41%)  2 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Cardiac Function Diagnostic Procedures  1  2/489 (0.41%)  2 3/150 (2.00%)  3 0/390 (0.00%)  0 6/357 (1.68%)  6
Coagulation And Bleeding Analyses  1  5/489 (1.02%)  5 2/150 (1.33%)  2 6/390 (1.54%)  6 6/357 (1.68%)  7
Ecg Investigations  1  1/489 (0.20%)  1 0/150 (0.00%)  0 2/390 (0.51%)  2 0/357 (0.00%)  0
Liver Function Analyses  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Metabolism Tests Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 1/357 (0.28%)  1
Microbiology And Serology Tests Nec  1  2/489 (0.41%)  2 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Mineral And Electrolyte Analyses  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Physical Examination Procedures  1  1/489 (0.20%)  1 0/150 (0.00%)  0 2/390 (0.51%)  2 2/357 (0.56%)  2
Platelet Analyses  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Protein Analyses Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Red Blood Cell Analyses  1  13/489 (2.66%)  13 4/150 (2.67%)  4 10/390 (2.56%)  10 11/357 (3.08%)  11
Renal Function Analyses  1  4/489 (0.82%)  4 1/150 (0.67%)  1 2/390 (0.51%)  2 1/357 (0.28%)  1
Respiratory Tract And Thoracic Imaging Procedures  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Skeletal And Cardiac Muscle Analyses  1  4/489 (0.82%)  4 2/150 (1.33%)  2 1/390 (0.26%)  1 5/357 (1.40%)  5
Tissue Enzyme Analyses Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Urinalysis Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Urinary Tract Function Analyses Nec  1  3/489 (0.61%)  3 2/150 (1.33%)  2 0/390 (0.00%)  0 3/357 (0.84%)  3
Vascular Tests Nec (Incl Blood Pressure)  1  3/489 (0.61%)  3 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
White Blood Cell Analyses  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Metabolism and nutrition disorders         
Appetite Disorders  1  1/489 (0.20%)  1 1/150 (0.67%)  1 1/390 (0.26%)  1 2/357 (0.56%)  2
Calcium Metabolism Disorders  1  2/489 (0.41%)  2 1/150 (0.67%)  1 2/390 (0.51%)  2 1/357 (0.28%)  2
Diabetes Mellitus (Incl Subtypes)  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Diabetic Complications Dermal  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Diabetic Complications Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Disorders Of Purine Metabolism  1  3/489 (0.61%)  3 0/150 (0.00%)  0 2/390 (0.51%)  2 0/357 (0.00%)  0
Electrolyte Imbalance Nec  1  5/489 (1.02%)  5 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
General Nutritional Disorders Nec  1  18/489 (3.68%)  20 7/150 (4.67%)  7 4/390 (1.03%)  4 15/357 (4.20%)  16
Hyperglycaemic Conditions Nec  1  4/489 (0.82%)  4 1/150 (0.67%)  1 3/390 (0.77%)  3 6/357 (1.68%)  6
Hypoglycaemic Conditions Nec  1  4/489 (0.82%)  4 5/150 (3.33%)  5 3/390 (0.77%)  3 4/357 (1.12%)  4
Magnesium Metabolism Disorders  1  0/489 (0.00%)  0 1/150 (0.67%)  1 1/390 (0.26%)  1 0/357 (0.00%)  0
Metabolic Acidoses (Excl Diabetic Acidoses)  1  3/489 (0.61%)  3 3/150 (2.00%)  4 1/390 (0.26%)  1 4/357 (1.12%)  4
Metabolic Alkaloses  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Mixed Acid-Base Disorders  1  2/489 (0.41%)  2 0/150 (0.00%)  0 3/390 (0.77%)  3 0/357 (0.00%)  0
Potassium Imbalance  1  14/489 (2.86%)  15 2/150 (1.33%)  2 8/390 (2.05%)  8 5/357 (1.40%)  6
Protein Metabolism Disorders Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 1/390 (0.26%)  1 0/357 (0.00%)  0
Sodium Imbalance  1  8/489 (1.64%)  10 2/150 (1.33%)  3 5/390 (1.28%)  5 5/357 (1.40%)  5
Total Fluid Volume Decreased  1  15/489 (3.07%)  15 8/150 (5.33%)  8 8/390 (2.05%)  9 14/357 (3.92%)  15
Total Fluid Volume Increased  1  12/489 (2.45%)  13 1/150 (0.67%)  1 7/390 (1.79%)  7 11/357 (3.08%)  12
Musculoskeletal and connective tissue disorders         
Arthropathies Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 2/390 (0.51%)  2 1/357 (0.28%)  1
Bone Disorders Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Bone Related Signs And Symptoms  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Joint Related Signs And Symptoms  1  2/489 (0.41%)  2 1/150 (0.67%)  1 3/390 (0.77%)  3 1/357 (0.28%)  1
Metabolic Bone Disorders  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Muscle Weakness Conditions  1  1/489 (0.20%)  1 3/150 (2.00%)  3 0/390 (0.00%)  0 3/357 (0.84%)  3
Musculoskeletal And Connective Tissue Pain And Discomfort  1  8/489 (1.64%)  9 1/150 (0.67%)  1 13/390 (3.33%)  15 7/357 (1.96%)  7
Musculoskeletal And Connective Tissue Signs And Symptoms Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Myopathies  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 3/357 (0.84%)  3
Osteoarthropathies  1  0/489 (0.00%)  0 2/150 (1.33%)  3 3/390 (0.77%)  4 1/357 (0.28%)  1
Spine And Neck Deformities  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
B-Cell Lymphomas Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 2/390 (0.51%)  2 0/357 (0.00%)  0
Bladder Neoplasms Malignant  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Breast And Nipple Neoplasms Malignant  1  1/489 (0.20%)  1 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Colonic Neoplasms Malignant  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Gastric Neoplasms Malignant  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Gastrointestinal Neoplasms Malignancy Unspecified Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Hepatic Neoplasms Malignant  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Leukaemias Acute Myeloid  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Multiple Myelomas  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 1/357 (0.28%)  1
Myelodysplastic Syndromes  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Neoplasms Malignant Site Unspecified Nec  1  3/489 (0.61%)  3 0/150 (0.00%)  0 2/390 (0.51%)  2 2/357 (0.56%)  2
Neuromas  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Pancreatic Neoplasms Malignant (Excl Islet Cell And Carcinoid)  1  0/489 (0.00%)  0 0/150 (0.00%)  0 2/390 (0.51%)  2 0/357 (0.00%)  0
Pharyngeal And Laryngeal Neoplasms Benign  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Prostatic Neoplasms Malignant  1  3/489 (0.61%)  3 1/150 (0.67%)  1 0/390 (0.00%)  0 1/357 (0.28%)  1
Renal Neoplasms Malignant  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Respiratory Tract And Pleural Neoplasms Malignant Cell Type Unspecified Nec  1  0/489 (0.00%)  0 2/150 (1.33%)  2 1/390 (0.26%)  1 0/357 (0.00%)  0
Skin Neoplasms Malignant And Unspecified (Excl Melanoma)  1  2/489 (0.41%)  2 1/150 (0.67%)  1 2/390 (0.51%)  2 2/357 (0.56%)  2
Thyroid Neoplasms Malignant  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Nervous system disorders         
Acute Polyneuropathies  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Central Nervous System Haemorrhages And Cerebrovascular Accidents  1  28/489 (5.73%)  28 14/150 (9.33%)  14 26/390 (6.67%)  30 32/357 (8.96%)  35
Central Nervous System Vascular Disorders Nec  1  2/489 (0.41%)  2 0/150 (0.00%)  0 3/390 (0.77%)  3 0/357 (0.00%)  0
Cerebellar Coordination And Balance Disturbances  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Coma States  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Cortical Dysfunction Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Dementia (Excl Alzheimer's Type)  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Disturbances In Consciousness Nec  1  9/489 (1.84%)  9 4/150 (2.67%)  5 14/390 (3.59%)  15 7/357 (1.96%)  8
Dyskinesias And Movement Disorders Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Encephalopathies Nec  1  14/489 (2.86%)  14 0/150 (0.00%)  0 4/390 (1.03%)  4 5/357 (1.40%)  5
Encephalopathies Toxic And Metabolic  1  8/489 (1.64%)  11 0/150 (0.00%)  0 3/390 (0.77%)  3 2/357 (0.56%)  2
Headaches Nec  1  0/489 (0.00%)  0 2/150 (1.33%)  2 1/390 (0.26%)  1 0/357 (0.00%)  0
Hydrocephalic Conditions  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Increased Intracranial Pressure Disorders  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Lumbar Spinal Cord And Nerve Root Disorders  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Memory Loss (Excl Dementia)  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Migraine Headaches  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Mononeuropathies  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 2/357 (0.56%)  2
Nervous System Disorders Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Neurological Signs And Symptoms Nec  1  7/489 (1.43%)  8 8/150 (5.33%)  8 2/390 (0.51%)  2 11/357 (3.08%)  11
Neuromuscular Junction Dysfunction  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Paralysis And Paresis (Excl Cranial Nerve)  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 2/357 (0.56%)  2
Peripheral Neuropathies Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Seizures And Seizure Disorders Nec  1  3/489 (0.61%)  3 3/150 (2.00%)  4 1/390 (0.26%)  1 10/357 (2.80%)  10
Sensory Abnormalities Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Speech And Language Abnormalities  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Transient Cerebrovascular Events  1  7/489 (1.43%)  8 1/150 (0.67%)  1 6/390 (1.54%)  6 2/357 (0.56%)  2
Tremor (Excl Congenital)  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Vagus Nerve Disorders  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Psychiatric disorders         
Anxiety Symptoms  1  0/489 (0.00%)  0 0/150 (0.00%)  0 2/390 (0.51%)  2 0/357 (0.00%)  0
Behaviour And Socialisation Disturbances  1  0/489 (0.00%)  0 0/150 (0.00%)  0 0/390 (0.00%)  0 1/357 (0.28%)  1
Confusion And Disorientation  1  6/489 (1.23%)  6 1/150 (0.67%)  1 8/390 (2.05%)  9 4/357 (1.12%)  4
Deliria  1  3/489 (0.61%)  3 1/150 (0.67%)  1 4/390 (1.03%)  4 1/357 (0.28%)  1
Depressive Disorders  1  3/489 (0.61%)  3 0/150 (0.00%)  0 2/390 (0.51%)  2 2/357 (0.56%)  2
Mental Disorders Nec  1  13/489 (2.66%)  13 3/150 (2.00%)  4 4/390 (1.03%)  4 14/357 (3.92%)  14
Perception Disturbances  1  0/489 (0.00%)  0 1/150 (0.67%)  1 2/390 (0.51%)  2 0/357 (0.00%)  0
Suicidal And Self-Injurious Behaviour  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Renal and urinary disorders         
Bladder And Urethral Symptoms  1  7/489 (1.43%)  7 8/150 (5.33%)  9 8/390 (2.05%)  9 9/357 (2.52%)  11
Bladder Disorders Nec  1  1/489 (0.20%)  1 3/150 (2.00%)  3 0/390 (0.00%)  0 2/357 (0.56%)  2
Genital And Urinary Tract Disorders Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Nephritis Nec  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Nephropathies And Tubular Disorders Nec  1  1/489 (0.20%)  1 1/150 (0.67%)  1 1/390 (0.26%)  1 1/357 (0.28%)  1
Renal Disorders Nec  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 1/357 (0.28%)  1
Renal Failure And Impairment  1  90/489 (18.40%)  108 31/150 (20.67%)  43 38/390 (9.74%)  42 58/357 (16.25%)  66
Renal Failure Complications  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Renal Lithiasis  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Renal Obstructive Disorders  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 1/357 (0.28%)  1
Renal Vascular And Ischaemic Conditions  1  2/489 (0.41%)  2 1/150 (0.67%)  1 1/390 (0.26%)  1 2/357 (0.56%)  2
Ureteric Disorders Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Urinary Abnormalities  1  10/489 (2.04%)  13 1/150 (0.67%)  1 8/390 (2.05%)  8 6/357 (1.68%)  11
Reproductive system and breast disorders         
Breast Disorders Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Pelvic Prolapse Conditions  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Prostatic Neoplasms And Hypertrophy  1  1/489 (0.20%)  1 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Reproductive Tract Disorders Nec (Excl Neoplasms)  1  1/489 (0.20%)  1 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Scrotal Disorders Nec  1  2/489 (0.41%)  2 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Vulvovaginal Disorders Nec  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Breathing Abnormalities  1  26/489 (5.32%)  27 21/150 (14.00%)  29 30/390 (7.69%)  33 26/357 (7.28%)  31
Bronchial Conditions Nec  1  1/489 (0.20%)  1 1/150 (0.67%)  1 1/390 (0.26%)  1 0/357 (0.00%)  0
Bronchospasm And Obstruction  1  25/489 (5.11%)  28 16/150 (10.67%)  21 13/390 (3.33%)  15 8/357 (2.24%)  9
Conditions Associated With Abnormal Gas Exchange  1  7/489 (1.43%)  7 1/150 (0.67%)  1 6/390 (1.54%)  6 6/357 (1.68%)  6
Coughing And Associated Symptoms  1  2/489 (0.41%)  2 1/150 (0.67%)  1 5/390 (1.28%)  6 0/357 (0.00%)  0
Diaphragmatic Disorders  1  0/489 (0.00%)  0 2/150 (1.33%)  2 0/390 (0.00%)  0 0/357 (0.00%)  0
Laryngeal And Adjacent Sites Disorders Nec (Excl Infections And Neoplasms)  1  0/489 (0.00%)  0 1/150 (0.67%)  1 0/390 (0.00%)  0 0/357 (0.00%)  0
Laryngeal Spasm, Oedema And Obstruction  1  0/489 (0.00%)  0 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Lower Respiratory Tract Inflammatory And Immunologic Conditions  1  8/489 (1.64%)  9 6/150 (4.00%)  6 7/390 (1.79%)  7 8/357 (2.24%)  8
Lower Respiratory Tract Signs And Symptoms  1  2/489 (0.41%)  2 0/150 (0.00%)  0 0/390 (0.00%)  0 0/357 (0.00%)  0
Mediastinal Disorders  1  0/489 (0.00%)  0 2/150 (1.33%)  2 1/390 (0.26%)  1 3/357 (0.84%)  3
Nasal Disorders Nec  1  4/489 (0.82%)  5 1/150 (0.67%)  1 5/390 (1.28%)  5 1/357 (0.28%)  1
Parenchymal Lung Disorders Nec  1  6/489 (1.23%)  6 3/150 (2.00%)  3 3/390 (0.77%)  3 4/357 (1.12%)  4
Pharyngeal Disorders (Excl Infections And Neoplasms)  1  1/489 (0.20%)  1 0/150 (0.00%)  0 1/390 (0.26%)  1 0/357 (0.00%)  0
Pneumothorax And Pleural Effusions Nec  1  54/489 (11.04%)  74 26/150 (17.33%)  36 29/390 (7.44%)  39 67/357 (18.77%)  86
Pulmonary Hypertensions  1  2/489 (0.41%)  2 1/150 (0.67%)  1 5/390 (1.28%)  5 0/357 (0.00%)  0
Pulmonary Oedemas  1