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

• Sponsor: Medtronic Cardiovascular
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Extreme Risk: TAVI Iliofemoral	Extreme Risk: TAVI Non-Iliofemoral	High Risk: TAVI	High Risk: SAVR	Total
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
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.

Outcome Measures

1. Primary Outcome

Title	Extreme Risk: All-cause Death or Major Stroke; High Risk Surgical: All-cause Mortality
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

Outcome Measure Data

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
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

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

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

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)
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

Outcome Measure Data

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
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

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
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

Outcome Measure Data

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
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)
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

Outcome Measure Data

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
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
Description	[Not Specified]
Time Frame	30 day, 6 month, 1 year, 2 year

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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)

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]

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)
Description	Change in distance walked during 6MWT from baseline
Time Frame	30 day, 1 year

Outcome Measure Data

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
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
Description	[Not Specified]
Time Frame	1 year

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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)

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]

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]

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
Description	Using the following measures: - Effective Orifice Area (EOA)
Time Frame	30 day, 6 month, 1 year, 2 year

Outcome Measure Data

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
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)

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]

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
Description	Using the following measures: - Transvalvular Mean Gradient
Time Frame	30 day, 6 month, 1 year, 2 year

Outcome Measure Data

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
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)

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]

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
Description	Using the following measure: - Degree of Aortic Valve Regurgitation (Transvalvular and Paravalvular)
Time Frame	30 day, 6 month, 1 year, 2 year

Outcome Measure Data

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
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
Description	[Not Specified]
Time Frame	30 day, 6 month, 1 year, 2 year

Outcome Measure Data

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
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
Description	[Not Specified]
Time Frame	30 day, 6 month, 1 year, 2 year

Outcome Measure Data

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
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)
Description	Strokes (of any severity) and TIAs
Time Frame	30 day, 6 month, 1 year, 2 year

Outcome Measure Data

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
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
Description	[Not Specified]
Time Frame	Procedure

Outcome Measure Data

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
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
Description	[Not Specified]
Time Frame	Number of days from admission to discharge

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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)
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

Outcome Measure Data

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
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

Adverse Events

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
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	--/--		--/--		--/--		--/--
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