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 (Industry)

Overall Status

Completed

CT.gov ID

NCT01240902

Collaborator

(none)

1,453

Enrollment

Locations

Arms

101.1

Actual Duration (Months)

32.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the safety and efficacy of the Medtronic CoreValve® System in the treatment of symptomatic severe aortic stenosis in subjects who have a predicted high risk for aortic valve surgery and/or very high risk for aortic valve surgery.

Condition or Disease	Intervention/Treatment	Phase
Severe Aortic Stenosis	Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI) Device: Surgical Aortic Valve Replacement (SAVR)	N/A

Study Design

Study Type:

Interventional

Actual Enrollment :

1453 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Medtronic CoreValve® U.S. Pivotal Trial

Actual Study Start Date :

Dec 10, 2010

Actual Primary Completion Date :

Aug 1, 2014

Actual Study Completion Date :

May 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Extreme Risk: TAVI Iliofemoral Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access	Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI) Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
Experimental: Extreme Risk: TAVI Non-Iliofemoral Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access	Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI) Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
Experimental: High Risk: TAVI High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)	Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI) Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
Active Comparator: High Risk: SAVR High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR)	Device: Surgical Aortic Valve Replacement (SAVR) Surgical Aortic Valve Replacement (SAVR)

Outcome Measures

Primary Outcome Measures

Extreme Risk: All-cause Death or Major Stroke; High Risk Surgical: All-cause Mortality [1 year]
All-cause Death or Major Stroke (Extreme Risk- Medtronic CoreValve® System); All-cause Mortality (High Risk Surgical- Medtronic CoreValve® System vs. Surgical Valve)

Secondary Outcome Measures

Major Adverse Cardiovascular and Cerebrovascular Event (MACCE) [30 day, 6 month, 1 year, 2 year]
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)
The Occurrence of Individual MACCE Components [30 day, 6 month, 1 year, 2 year]
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)
Major Adverse Events (MAEs) [30 day, 6 month, 1 year, 2 year]
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
Conduction Disturbance Requiring Permanent Pacemaker Implantation [30 day, 6 month, 1 year, 2 year]
Change in NYHA Class [30 day, 6 month, 1 year, 2 year]
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.
Change in Distance Walked During 6-Minute Walk Test (6MWT) [30 day, 1 year]
Change in distance walked during 6MWT from baseline
Ratio of Days Alive Out of Hospital Versus Total Days Alive [1 year]
Quality of Life (QoL) Change [30 day, 6 month, 1 year, 2 year]
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.
Echocardiographic Assessment of Valve Performance [30 day, 6 month, 1 year, 2 year]
Using the following measures: - Effective Orifice Area (EOA)
Echocardiographic Assessment of Valve Performance [30 day, 6 month, 1 year, 2 year]
Using the following measures: - Transvalvular Mean Gradient
Echocardiographic Assessment of Valve Performance [30 day, 6 month, 1 year, 2 year]
Using the following measure: - Degree of Aortic Valve Regurgitation (Transvalvular and Paravalvular)
Aortic Valve Hospitalizations [30 day, 6 month, 1 year, 2 year]
Cardiovascular Deaths and Valve Related Deaths [30 day, 6 month, 1 year, 2 year]
Strokes and Transient Ischemic Attacks (TIAs) [30 day, 6 month, 1 year, 2 year]
Strokes (of any severity) and TIAs
Index Procedure Related MAEs [Procedure]
Length of Index Procedure Hospital Stay [Number of days from admission to discharge]
Device Success [Number of days from admission to discharge]
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
Procedural Success [Number of days from admission to discharge]
Medtronic CoreValve® System subjects only. Defined as device success and absence of in-hospital MACCE.
Prosthetic Valve Dysfunction (PVD) [30 day, 6 month, 1 year, 2 year]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Extreme Risk Only: Subject must have comorbidities such that one cardiologist and two cardiac surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or serious morbidity exceeds the probability of meaningful improvement. Specifically, the predicted operative risk of death or serious, irreversible morbidity is ≥ 50% at 30 days.
High Risk Surgical Only: Subject must have comorbidities such that one cardiologist and two cardiac surgeons agree that predicted risk of operative mortality is ≥15% (and predicted operative mortality or serious, irreversible morbidity risk of < 50%) at 30 days.
Subject has senile degenerative aortic valve stenosis with: mean gradient > 40 mmHg, or jet velocity greater than 4.0 m/sec by either resting or dobutamine stress echocardiogram, or simultaneous pressure recordings at cardiac catheterization (either resting or dobutamine stress), AND an initial aortic valve area of ≤ 0.8 cm2 (or aortic valve area index ≤ 0.5 cm2/m2) by resting echocardiogram or simultaneous pressure recordings at cardiac catheterization
Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater.
The subject or the subject's legal representative has been informed of the nature of the trial, agrees to its provisions and has provided written informed consent as approved by the IRB of the respective clinical site.
The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits.

Exclusion Criteria:

Clinical

Evidence of an acute myocardial infarction ≤ 30 days before the intended treatment.
Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to the intended treatment. (High Risk Surgical Only: Including bare metal stents. Additionally, any drug eluting stents placed within 6 months prior to the index procedure.)
Blood dyscrasias as defined: leukopenia (WBC < 1000mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy.
Untreated clinically significant coronary artery disease requiring revascularization.
Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support.
Need for emergency surgery for any reason.
Severe ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20% as measured by resting echocardiogram.
Recent (within 6 months) cerebrovascular accident (CVA) or transient ischemic attack (TIA).
End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min.
Active Gastrointestinal (GI) bleeding within the past 3 months.
A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated:
Aspirin
Heparin (HIT/HITTS)
Bivalirudin (Extreme Risk Only)
Nitinol (titanium or nickel)
Ticlopidine and clopidogrel
Contrast media
Ongoing sepsis, including active endocarditis.
Subject refuses a blood transfusion.
Life expectancy < 12 months due to associated non-cardiac co-morbid conditions.
Other medical, social, or psychological conditions that in the opinion of an Investigator precludes the subject from appropriate consent.
Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits).
Currently participating in an investigational drug or another device trial.
Symptomatic carotid or vertebral artery disease.
Subject has been offered surgical aortic valve replacement but declined. (High Risk Surgical Only)

Anatomical

Native aortic annulus size < 18 mm or > 29 mm per the baseline diagnostic imaging.
Pre-existing prosthetic heart valve any position.
Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation (3-4+)).
Moderate to severe (3-4+) or severe (4+) mitral or severe (4+) tricuspid regurgitation.
Moderate to severe mitral stenosis.
Hypertrophic obstructive cardiomyopathy.
New or untreated echocardiographic evidence of intracardiac mass, thrombus or vegetation.
Severe basal septal hypertrophy with an outflow gradient.
Aortic root angulation (angle between plane of aortic valve annulus and horizontal plane/vertebrae) > 70° (for femoral and left subclavian/axillary access) and > 30° (for right subclavian/axillary access).
Ascending aorta diameter > 43 mm if the aortic annulus diameter is 23-29 mm; ascending aorta diameter > 40 mm if the aortic annulus diameter is 20-23 mm; or an ascending aorta diameter > 34 mm if the aortic annulus diameter is 18-20 mm.
Congenital bicuspid or unicuspid valve verified by echocardiography.
Sinus of valsalva anatomy that would prevent adequate coronary perfusion.

Vascular

Transarterial access not able to accommodate an 18Fr sheath.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Good Samaritan	Phoenix	Arizona	United States	85006
2	Kaiser Permanente - Los Angeles Medical Center	Los Angeles	California	United States	90027
3	University of Southern California University Hospital	Los Angeles	California	United States	90033
4	El Camino Hospital	Mountain View	California	United States	94040
5	VA Palo Alto Health Care System	Palo Alto	California	United States	94304
6	Hartford Hospital	Hartford	Connecticut	United States	06102
7	Yale New Haven Hospital	New Haven	Connecticut	United States	06520
8	Washington Hospital Center / Georgetown Hospital	Washington	District of Columbia	United States	20010
9	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
10	University of Miami Health System / Jackson Memorial Hospital	Miami	Florida	United States	33136
11	Piedmont Heart Institute	Atlanta	Georgia	United States	30309
12	Saint Joseph's Hospital of Atlanta	Atlanta	Georgia	United States	30342
13	Loyola University Medical Center	Maywood	Illinois	United States	60153
14	St. Vincent Heart Center of Indiana	Indianapolis	Indiana	United States	46290
15	Iowa Heart Center	Des Moines	Iowa	United States	50314
16	University of Kansas Hospital	Kansas City	Kansas	United States	66160
17	Cardiovascular Institute of the South/ Terrebone General	Houma	Louisiana	United States	70360
18	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
19	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
20	University of Michigan Health Systems	Ann Arbor	Michigan	United States	48109
21	Detroit Medical Center Cardiovascular Institute	Detroit	Michigan	United States	48201
22	St. John Hospital and Medical Center	Detroit	Michigan	United States	48236
23	Spectrum Health Hospitals	Grand Rapids	Michigan	United States	49503
24	Morristown Memorial Hospital	Morristown	New Jersey	United States	07962
25	North Shore University Hospital/ Long Island Jewish Hospital	Manhasset	New York	United States	11030
26	NYU Langone Medical Center	New York	New York	United States	10016
27	The Mount Sinai Medical Center	New York	New York	United States	10029
28	Lenox Hill Hospital	New York	New York	United States	10075
29	St. Francis Hospital	Roslyn	New York	United States	11576
30	Duke University Medical Center	Durham	North Carolina	United States	27710
31	Wake Forest University - Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
32	University Hospitals - Case Medical Center	Cleveland	Ohio	United States	44106
33	The Ohio State University Medical Center - The Richard M. Ross Heart Hospital	Columbus	Ohio	United States	43210
34	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
35	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
36	Pinnacle Health	Harrisburg	Pennsylvania	United States	17043
37	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
38	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
39	Baylor Heart and Vascular Hospital	Dallas	Texas	United States	75226
40	Texas Heart Institute at St. Luke's Episcopal Hospital	Houston	Texas	United States	77030
41	The Methodist Hospital - The Methodist DeBakey Heart & Vascular Center	Houston	Texas	United States	77030
42	University of Vermont Medical Center	Burlington	Vermont	United States	05458
43	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
44	Providence Sacred Heart Medical Center	Spokane	Washington	United States	99204
45	St. Luke's Medical Center - Aurora Health Care	Milwaukee	Wisconsin	United States	53215

Sponsors and Collaborators

Medtronic Cardiovascular

Investigators

Principal Investigator: David H Adams, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Related Info

Publications

None provided.

Responsible Party:

Medtronic Cardiovascular

ClinicalTrials.gov Identifier:

NCT01240902

Other Study ID Numbers:

MCV-US-2009-01

First Posted:

Nov 15, 2010

Last Update Posted:

Jun 16, 2022

Last Verified:

May 1, 2022

Keywords provided by Medtronic Cardiovascular

Valvular Heart Disease

Critical Aortic Stenosis

Severe Aortic Stenosis

High Risk

Aortic Valve Replacement

Additional relevant MeSH terms:

Aortic Valve Stenosis

Constriction, Pathologic

Study Results

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 Detail	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 Participants	489	150	391	359	1389
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	83.2 (8.7)	81.3 (7.4)	83.2 (7.1)	83.3 (6.4)	83.0 (7.6)
Sex: Female, Male (Count of 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%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%	0 0%	0 0%	1 0.3%	1 0.1%
Asian	2 0.4%	1 0.7%	0 0%	1 0.3%	4 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	19 3.9%	5 3.3%	3 0.8%	11 3.1%	38 2.7%
White	468 95.7%	143 95.3%	387 99%	343 95.5%	1341 96.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 0.7%	1 0.3%	2 0.6%	4 0.3%
Body Surface Area (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.8 (0.3)	1.8 (0.2)	1.8 (0.2)	1.9 (0.2)	1.8 (0.2)
NYHA Classification (participants) [Number]
NYHA I	0 0%	0 0%	0 0%	0 0%	0 0%
NYHA II	40 8.2%	12 8%	57 14.6%	47 13.1%	156 11.2%
NYHA III	313 64%	98 65.3%	255 65.2%	250 69.6%	916 65.9%
NYHA IV	136 27.8%	40 26.7%	79 20.2%	62 17.3%	317 22.8%
Society of Thoracic Surgeons (STS) Risk Score (% risk of mortality or morbidity) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% risk of mortality or morbidity]	10.3 (5.5)	10.7 (5.7)	7.3 (3.0)	7.5 (3.3)	8.8 (4.7)
Logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	22.6 (17.1)	22.9 (15.9)	17.7 (13.0)	18.8 (13.2)	20.3 (15.1)

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)
Measure Participants	489	150	391	359
Number [percentage of participants, Kaplan-Meier]	26.0 5.3%	39.3 26.2%	14.1 3.6%	18.9 5.3%

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	z-test, 1 sided
	Comments

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	39.3
	Confidence Interval	(2-Sided) % to
	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
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	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
	Method	z-test, 1 sided
	Comments

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)
Measure Participants	489	150	391	359
30 day	12.3 2.5%	17.3 11.5%	7.7 2%	10.3 2.9%
6 month	22.5 4.6%	34.7 23.1%	15.4 3.9%	21.0 5.8%
1 year	29.2 6%	41.4 27.6%	20.5 5.2%	27.0 7.5%
2 Year	42.3 8.7%	51.0 34%	29.7 7.6%	38.6 10.8%

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 (legacy)
	Comments

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)
Measure Participants	489	150	391	359
30 day All Cause Mortality	8.4 1.7%	11.3 7.5%	3.3 0.8%	4.5 1.3%
30 day MI	1.2 0.2%	2.1 1.4%	0.8 0.2%	0.8 0.2%
30 day Stroke	4.0 0.8%	8.8 5.9%	4.9 1.3%	6.2 1.7%
30 day Reintervention	1.1 0.2%	0.0 0%	0.8 0.2%	0.0 0%
6 month All Cause Mortality	18.6 3.8%	28.7 19.1%	9.0 2.3%	14.0 3.9%
6 month MI	1.5 0.3%	2.1 1.4%	1.6 0.4%	1.1 0.3%
6 month Stroke	5.2 1.1%	12.0 8%	7.3 1.9%	9.9 2.8%
6 month Reintervention	1.5 0.3%	0.0 0%	1.0 0.3%	0.0 0%
1 year All Cause Mortality	24.3 5%	36.0 24%	14.1 3.6%	18.9 5.3%
1 year MI	2.0 0.4%	2.1 1.4%	1.9 0.5%	1.5 0.4%
1 year Stroke	7.0 1.4%	13.0 8.7%	8.7 2.2%	12.5 3.5%
1 year Reintervention	1.8 0.4%	1.0 0.7%	2.2 0.6%	0.0 0%
2 year All Cause Mortality	36.6 7.5%	44.9 29.9%	22.2 5.7%	28.6 8%
2 year MI	2.8 0.6%	3.2 2.1%	1.9 0.5%	2.3 0.6%
2 year Stroke	8.6 1.8%	16.1 10.7%	10.9 2.8%	16.6 4.6%
2 year Reintervention	1.8 0.4%	1.0 0.7%	2.5 0.6%	0.4 0.1%

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)
Measure Participants	489	150	391	359
30 day	54.2 11.1%	69.3 46.2%	52.4 13.4%	50.2 14%
6 month	60.5 12.4%	76.0 50.7%	58.6 15%	76.4 21.3%
1 year	63.4 13%	80.0 53.3%	60.1 15.4%	59.8 16.7%
2 year	71.3 14.6%	84.0 56%	66.4 17%	66.8 18.6%

5. Secondary Outcome

Title	Conduction Disturbance Requiring Permanent Pacemaker Implantation
Description
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)
Measure Participants	489	150	391	359
30 day	21.6 4.4%	16.4 10.9%	20.0 5.1%	7.1 2%
6 month	24.4 5%	20.5 13.7%	21.9 5.6%	9.9 2.8%
1 year	26.4 5.4%	21.5 14.3%	22.5 5.8%	11.6 3.2%
2 year	28.8 5.9%	22.6 15.1%	25.8 6.6%	12.8 3.6%

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)
Measure Participants	489	150	391	359
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 (legacy)
	Comments

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

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) % to
	Parameter Dispersion	Type: Standard Deviation Value: 0.9
	Estimation Comments

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 (legacy)
	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

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)
Measure Participants	489	150	391	359
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
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)
Measure Participants	489	150	391	359
Mean (Standard Deviation) [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)
Measure Participants	489	150	391	359
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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Hierarchical test item #4
	Method	t-test, 2 sided
	Comments

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 (legacy)
	Comments	Non-inferiority margin 5

Statistical Test of Hypothesis	p-Value	0.0063
	Comments	Hierarchical test item #4
	Method	t-test, 1 sided
	Comments

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 (legacy)
	Comments

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

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)
Measure Participants	486	148	390	354
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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Hierarchical test item #2
	Method	t-test, 2 sided
	Comments

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 (legacy)
	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

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)
Measure Participants	486	148	390	354
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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Hierarchical test item #1
	Method	t-test, 2 sided
	Comments

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 (legacy)
	Comments	Non-inferiority margin 15

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Hierarchical test item #1
	Method	t-test, 1 sided
	Comments

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)
Measure Participants	486	148	390	354
30 day Total Aortic Regurgitation- None	9.1 1.9%	19.0 12.7%	12.2 3.1%	65.0 18.1%
30 day Total Aortic Regurgitation- Trivial	32.7 6.7%	33.9 22.6%	41.4 10.6%	23.0 6.4%
30 day Total Aortic Regurgitation- Mild	43.0 8.8%	34.7 23.1%	36.4 9.3%	10.7 3%
30 day Total Aortic Regurgitation- Moderate	14.1 2.9%	10.7 7.1%	8.1 2.1%	1.3 0.4%
30 day Total Aortic Regurgitation- Severe	1.2 0.2%	1.7 1.1%	1.9 0.5%	0.0 0%
6 month Total Aortic Regurgitation- None	19.9 4.1%	33.3 22.2%	21.6 5.5%	60.6 16.9%
6 month Total Aortic Regurgitation- Trivial	33.5 6.9%	27.1 18.1%	37.2 9.5%	28.0 7.8%
6 month Total Aortic Regurgitation- Mild	36.5 7.5%	35.4 23.6%	29.7 7.6%	9.8 2.7%
6 month Total Aortic Regurgitation- Moderate	9.8 2%	4.2 2.8%	10.0 2.6%	1.6 0.4%
6 month Total Aortic Regurgitation- Severe	0.3 0.1%	0.0 0%	1.6 0.4%	0.0 0%
1 year Total Aortic Regurgitation- None	21.5 4.4%	39.0 26%	28.3 7.2%	68.1 19%
1 year Total Aortic Regurgitation- Trivial	40.6 8.3%	36.6 24.4%	35.7 9.1%	21.7 6%
1 year Total Aortic Regurgitation- Mild	31.5 6.4%	20.7 13.8%	29.0 7.4%	8.8 2.5%
1 year Total Aortic Regurgitation- Moderate	6.4 1.3%	2.4 1.6%	6.7 1.7%	0.9 0.3%
1 year Total Aortic Regurgitation- Severe	0.0 0%	1.2 0.8%	0.3 0.1%	0.4 0.1%
2 year Total Aortic Regurgitation - None	31.0 6.3%	35.3 23.5%	32.8 8.4%	58.5 16.3%
2 year Total Aortic Regurgitation - Trivial	26.3 5.4%	36.8 24.5%	27.0 6.9%	27.3 7.6%
2 year Total Aortic Regurgitation - Mild	36.1 7.4%	23.5 15.7%	32.0 8.2%	13.1 3.6%
2 year Total Aortic Regurgitation - Moderate	6.7 1.4%	4.4 2.9%	6.6 1.7%	1.1 0.3%
2 year Total Aortic Regurgitation - Severe	0.0 0%	0.0 0%	1.6 0.4%	0.0 0%

13. Secondary Outcome

Title	Aortic Valve Hospitalizations
Description
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)
Measure Participants	489	150	391	359
30 day	6.7 1.4%	8.7 5.8%	3.9 1%	5.2 1.4%
6 month	16.4 3.4%	18.3 12.2%	13.4 3.4%	9.0 2.5%
1 year	21.9 4.5%	21.2 14.1%	16.5 4.2%	14.0 3.9%
2 year	29.5 6%	27.2 18.1%	24.2 6.2%	18.2 5.1%

14. Secondary Outcome

Title	Cardiovascular Deaths and Valve Related Deaths
Description
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)
Measure Participants	489	150	391	359
30 day Cardiovascular Deaths	8.4 1.7%	11.3 7.5%	3.3 0.8%	4.5 1.3%
30 Day Valve Related Deaths	2.5 0.5%	2.8 1.9%	2.3 0.6%	0.6 0.2%
6 month Cardiovascular Deaths	15.0 3.1%	23.6 15.7%	7.4 1.9%	10.5 2.9%
6 month Valve Related Deaths	4.1 0.8%	4.5 3%	3.6 0.9%	1.8 0.5%
1 year Cardiovascular Deaths	18.3 3.7%	28.7 19.1%	10.6 2.7%	12.9 3.6%
1 year Valve Related Deaths	5.1 1%	5.4 3.6%	5.6 1.4%	2.2 0.6%
2 year Cardiovascular Deaths	26.2 5.4%	35.1 23.4%	15.4 3.9%	19.4 5.4%
2 year Valve Related Deaths	6.2 1.3%	7.5 5%	6.8 1.7%	4.2 1.2%

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)
Measure Participants	489	150	391	359
30 day	4.6 0.9%	10.2 6.8%	5.7 1.5%	6.5 1.8%
6 month	6.0 1.2%	14.3 9.5%	8.4 2.1%	10.8 3%
1 year	8.1 1.7%	15.2 10.1%	10.3 2.6%	14.1 3.9%
2 year	10.1 2.1%	19.5 13%	13.2 3.4%	17.8 5%

16. Secondary Outcome

Title	Index Procedure Related MAEs
Description
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)
Measure Participants	489	150	391	359
Number [percentage of participants]	53.5 10.9%	68.9 45.9%	52.6 13.5%	49.9 13.9%

17. Secondary Outcome

Title	Length of Index Procedure Hospital Stay
Description
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)
Measure Participants	489	150	391	359
Mean (Standard Deviation) [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)
Measure Participants	468	141	378	0
Number [percentage of participants]	84.6 17.3%	88.7 59.1%	86.8 22.2%

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)
Measure Participants	476	142	384	0
Number [percentage of participants]	77.5 15.8%	77.5 51.7%	81.3 20.8%

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)
Measure Participants	486	148	390	354
30 day Aortic Stenosis	2.3 0.5%	6.1 4.1%	3.1 0.8%	4.8 1.3%
30 day Aortic Regurgitation	23.5 4.8%	16.9 11.3%	13.6 3.5%	1.7 0.5%
6 month Aortic Stenosis	3.1 0.6%	6.1 4.1%	3.8 1%	6.5 1.8%
6 month Aortic Regurgitation	26.1 5.3%	18.2 12.1%	17.2 4.4%	2.3 0.6%
1 year Aortic Stenosis	3.5 0.7%	6.1 4.1%	4.9 1.3%	8.2 2.3%
1 year Aortic Regurgitation	27.0 5.5%	19.6 13.1%	17.9 4.6%	2.8 0.8%
2 year Aortic Stenosis	3.9 0.8%	6.8 4.5%	5.4 1.4%	9.3 2.6%
2 year Aortic Regurgitation	27.8 5.7%	19.6 13.1%	19.7 5%	2.8 0.8%

Adverse Events

	Extreme Risk: TAVI Iliofemoral		Extreme Risk: TAVI Non-Iliofemoral		High Risk: TAVI		High Risk: SAVR
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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
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 (92.4%)		142/150 (94.7%)		346/390 (88.7%)		324/357 (90.8%)
Blood and lymphatic system disorders
Anaemia Deficiencies	2/489 (0.4%)	2	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Anaemias Due To Chronic Disorders	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Anaemias Haemolytic Immune	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Anaemias Nec	140/489 (28.6%)	170	70/150 (46.7%)	75	106/390 (27.2%)	132	151/357 (42.3%)	173
Coagulopathies	2/489 (0.4%)	3	2/150 (1.3%)	2	1/390 (0.3%)	1	4/357 (1.1%)	4
Eosinophilic Disorders	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Haematological Disorders	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Leukocytoses Nec	5/489 (1%)	5	1/150 (0.7%)	1	3/390 (0.8%)	3	4/357 (1.1%)	4
Marrow Depression And Hypoplastic Anaemias	1/489 (0.2%)	1	1/150 (0.7%)	1	2/390 (0.5%)	2	1/357 (0.3%)	1
Thrombocytopenias	11/489 (2.2%)	11	4/150 (2.7%)	4	8/390 (2.1%)	8	22/357 (6.2%)	22
Cardiac disorders
Aortic Valvular Disorders	44/489 (9%)	45	12/150 (8%)	12	42/390 (10.8%)	42	10/357 (2.8%)	12
Cardiac Conduction Disorders	106/489 (21.7%)	109	24/150 (16%)	27	79/390 (20.3%)	85	18/357 (5%)	19
Cardiac Disorders Nec	9/489 (1.8%)	9	3/150 (2%)	3	7/390 (1.8%)	9	7/357 (2%)	7
Cardiac Signs And Symptoms Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	4/357 (1.1%)	4
Cardiac Valve Disorders Nec	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Cardiomyopathies	1/489 (0.2%)	1	0/150 (0%)	0	4/390 (1%)	4	1/357 (0.3%)	1
Coronary Artery Disorders Nec	6/489 (1.2%)	6	4/150 (2.7%)	4	9/390 (2.3%)	9	4/357 (1.1%)	4
Heart Failures Nec	117/489 (23.9%)	186	29/150 (19.3%)	43	69/390 (17.7%)	95	62/357 (17.4%)	85
Ischaemic Coronary Artery Disorders	28/489 (5.7%)	30	8/150 (5.3%)	8	15/390 (3.8%)	17	12/357 (3.4%)	15
Mitral Valvular Disorders	9/489 (1.8%)	9	5/150 (3.3%)	5	3/390 (0.8%)	3	5/357 (1.4%)	5
Myocardial Disorders Nec	2/489 (0.4%)	2	0/150 (0%)	0	1/390 (0.3%)	1	2/357 (0.6%)	2
Noninfectious Pericarditis	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	1/357 (0.3%)	1
Pericardial Disorders Nec	5/489 (1%)	7	4/150 (2.7%)	4	5/390 (1.3%)	5	10/357 (2.8%)	10
Rate And Rhythm Disorders Nec	28/489 (5.7%)	29	6/150 (4%)	6	16/390 (4.1%)	18	19/357 (5.3%)	19
Right Ventricular Failures	3/489 (0.6%)	4	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Supraventricular Arrhythmias	65/489 (13.3%)	79	17/150 (11.3%)	22	43/390 (11%)	46	69/357 (19.3%)	80
Tricuspid Valvular Disorders	2/489 (0.4%)	2	3/150 (2%)	3	0/390 (0%)	0	2/357 (0.6%)	2
Ventricular Arrhythmias And Cardiac Arrest	48/489 (9.8%)	59	26/150 (17.3%)	30	27/390 (6.9%)	29	27/357 (7.6%)	27
Congenital, familial and genetic disorders
Cardiac Septal Defects Congenital	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Coagulation Disorders Congenital	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Male Reproductive Tract Disorders Congenital	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Vascular Anomalies Congenital Nec	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Ear and labyrinth disorders
Hearing Losses	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Ear Disorders Nec	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Inner Ear Signs And Symptoms	0/489 (0%)	0	1/150 (0.7%)	1	1/390 (0.3%)	1	0/357 (0%)	0
Endocrine disorders
Thyroid Neoplasms	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Eye disorders
Blindness (Excl Colour Blindness)	1/489 (0.2%)	1	1/150 (0.7%)	1	2/390 (0.5%)	2	0/357 (0%)	0
Cataract Conditions	2/489 (0.4%)	2	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Corneal Infections, Oedemas And Inflammations	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Lacrimal Disorders	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Retinal Bleeding And Vascular Disorders (Excl Retinopathy)	2/489 (0.4%)	2	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Retinal Structural Change, Deposit And Degeneration	1/489 (0.2%)	2	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Retinal, Choroid And Vitreous Infections And Inflammations	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Visual Disorders Nec	2/489 (0.4%)	2	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Gastrointestinal disorders
Abdominal Wall Conditions Nec	1/489 (0.2%)	2	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Acute And Chronic Pancreatitis	4/489 (0.8%)	4	0/150 (0%)	0	2/390 (0.5%)	2	1/357 (0.3%)	1
Anal And Rectal Ulcers And Perforation	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Benign Neoplasms Gastrointestinal (Excl Oral Cavity)	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Colitis (Excl Infective)	2/489 (0.4%)	2	2/150 (1.3%)	2	0/390 (0%)	0	4/357 (1.1%)	4
Diaphragmatic Hernias	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Diarrhoea (Excl Infective)	4/489 (0.8%)	4	3/150 (2%)	3	3/390 (0.8%)	3	2/357 (0.6%)	2
Diverticula	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	2/357 (0.6%)	2
Duodenal And Small Intestinal Stenosis And Obstruction	2/489 (0.4%)	2	3/150 (2%)	3	2/390 (0.5%)	2	3/357 (0.8%)	3
Duodenal Ulcers And Perforation	0/489 (0%)	0	0/150 (0%)	0	2/390 (0.5%)	2	1/357 (0.3%)	1
Dyspeptic Signs And Symptoms	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Faecal Abnormalities Nec	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	1/357 (0.3%)	1
Flatulence, Bloating And Distension	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Gastric And Oesophageal Haemorrhages	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Gastric Ulcers And Perforation	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	3/357 (0.8%)	3
Gastritis (Excl Infective)	3/489 (0.6%)	3	1/150 (0.7%)	1	2/390 (0.5%)	2	2/357 (0.6%)	2
Gastrointestinal And Abdominal Pains (Excl Oral And Throat)	13/489 (2.7%)	15	4/150 (2.7%)	4	3/390 (0.8%)	3	2/357 (0.6%)	2
Gastrointestinal Atonic And Hypomotility Disorders Nec	3/489 (0.6%)	3	1/150 (0.7%)	1	3/390 (0.8%)	4	1/357 (0.3%)	1
Gastrointestinal Fistulae	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Gastrointestinal Necrosis And Gangrene (Excl Gangrenous Hernia)	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Gastrointestinal Disorders Nec	2/489 (0.4%)	2	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Gastrointestinal Signs And Symptoms Nec	15/489 (3.1%)	15	7/150 (4.7%)	7	7/390 (1.8%)	7	12/357 (3.4%)	13
Gastrointestinal Spastic And Hypermotility Disorders	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Gastrointestinal Stenosis And Obstruction Nec	5/489 (1%)	5	1/150 (0.7%)	1	3/390 (0.8%)	3	3/357 (0.8%)	3
Gastrointestinal Ulcers And Perforation, Site Unspecified	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Gastrointestinal Vascular Occlusion And Infarction	3/489 (0.6%)	3	1/150 (0.7%)	1	0/390 (0%)	0	1/357 (0.3%)	1
Haemorrhoids And Gastrointestinal Varices (Excl Oesophageal)	0/489 (0%)	0	1/150 (0.7%)	1	1/390 (0.3%)	1	0/357 (0%)	0
Inguinal Hernias	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Intestinal Haemorrhages	4/489 (0.8%)	4	1/150 (0.7%)	1	5/390 (1.3%)	5	4/357 (1.1%)	4
Intestinal Ulcers And Perforation Nec	3/489 (0.6%)	3	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Nausea And Vomiting Symptoms	2/489 (0.4%)	2	1/150 (0.7%)	2	3/390 (0.8%)	5	5/357 (1.4%)	5
Non-Site Specific Gastrointestinal Haemorrhages	35/489 (7.2%)	40	18/150 (12%)	20	27/390 (6.9%)	29	16/357 (4.5%)	17
Oesophageal Stenosis And Obstruction	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Oesophageal Ulcers And Perforation	2/489 (0.4%)	2	0/150 (0%)	0	3/390 (0.8%)	3	1/357 (0.3%)	1
Oesophagitis (Excl Infective)	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Oral Soft Tissue Pain And Paraesthesia	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Pancreatic Neoplasms	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Peritoneal And Retroperitoneal Disorders	1/489 (0.2%)	2	2/150 (1.3%)	2	0/390 (0%)	0	2/357 (0.6%)	2
Peritoneal And Retroperitoneal Haemorrhages	5/489 (1%)	5	1/150 (0.7%)	1	2/390 (0.5%)	2	1/357 (0.3%)	1
Umbilical Hernias	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Hepatic Fibrosis And Cirrhosis	3/489 (0.6%)	3	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Clostridia Infections	9/489 (1.8%)	9	2/150 (1.3%)	2	6/390 (1.5%)	7	6/357 (1.7%)	6
General disorders
Administration Site Reactions Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Asthenic Conditions	11/489 (2.2%)	12	3/150 (2%)	3	9/390 (2.3%)	10	9/357 (2.5%)	9
Body Temperature Altered	2/489 (0.4%)	2	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Cardiac Complications Associated With Device	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Complications Associated With Device Nec	4/489 (0.8%)	4	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Death And Sudden Death	10/489 (2%)	10	5/150 (3.3%)	5	6/390 (1.5%)	6	3/357 (0.8%)	3
Device Issues Nec	40/489 (8.2%)	40	7/150 (4.7%)	7	28/390 (7.2%)	30	2/357 (0.6%)	2
Device Malfunction Events Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	5/390 (1.3%)	5	5/357 (1.4%)	5
Febrile Disorders	3/489 (0.6%)	3	2/150 (1.3%)	2	7/390 (1.8%)	7	6/357 (1.7%)	6
Feelings And Sensations Nec	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Gait Disturbances	0/489 (0%)	0	0/150 (0%)	0	3/390 (0.8%)	3	0/357 (0%)	0
General Signs And Symptoms Nec	7/489 (1.4%)	7	2/150 (1.3%)	2	4/390 (1%)	4	5/357 (1.4%)	5
Healing Abnormal Nec	2/489 (0.4%)	2	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Hernias Nec	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Implant And Catheter Site Reactions	3/489 (0.6%)	3	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Inflammations	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Injection Site Reactions	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Mass Conditions Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Oedema Nec	6/489 (1.2%)	7	1/150 (0.7%)	1	6/390 (1.5%)	7	6/357 (1.7%)	6
Pain And Discomfort Nec	26/489 (5.3%)	33	9/150 (6%)	11	23/390 (5.9%)	29	19/357 (5.3%)	22
Product Physical Issues	1/489 (0.2%)	1	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Therapeutic And Nontherapeutic Responses	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Withdrawal And Rebound Effects	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Hepatobiliary disorders
Bile Duct Infections And Inflammations	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Cholecystitis And Cholelithiasis	3/489 (0.6%)	3	1/150 (0.7%)	1	4/390 (1%)	4	1/357 (0.3%)	1
Hepatic And Hepatobiliary Disorders Nec	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Hepatic Failure And Associated Disorders	3/489 (0.6%)	3	0/150 (0%)	0	1/390 (0.3%)	1	3/357 (0.8%)	3
Hepatocellular Damage And Hepatitis Nec	5/489 (1%)	5	0/150 (0%)	0	0/390 (0%)	0	2/357 (0.6%)	2
Immune system disorders
Anaphylactic Responses	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Infections and infestations
Abdominal And Gastrointestinal Infections	6/489 (1.2%)	8	1/150 (0.7%)	1	4/390 (1%)	4	4/357 (1.1%)	4
Atypical Mycobacterial Infections	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Bacterial Infections Nec	22/489 (4.5%)	25	6/150 (4%)	6	15/390 (3.8%)	20	12/357 (3.4%)	12
Bone And Joint Infections	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	1/357 (0.3%)	1
Candida Infections	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Cardiac Infections	6/489 (1.2%)	7	1/150 (0.7%)	1	1/390 (0.3%)	1	3/357 (0.8%)	3
Central Nervous System And Spinal Infections	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Ear Infections	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Enterobacter Infections	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	2/357 (0.6%)	2
Enterococcal Infections	4/489 (0.8%)	5	0/150 (0%)	0	0/390 (0%)	0	2/357 (0.6%)	2
Escherichia Infections	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Fungal Infections Nec	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Haemophilus Infections	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Herpes Viral Infections	0/489 (0%)	0	2/150 (1.3%)	2	2/390 (0.5%)	2	0/357 (0%)	0
Infections Nec	8/489 (1.6%)	8	2/150 (1.3%)	2	6/390 (1.5%)	6	8/357 (2.2%)	8
Infectious Transmissions	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Influenza Viral Infections	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Klebsiella Infections	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Lower Respiratory Tract And Lung Infections	74/489 (15.1%)	95	25/150 (16.7%)	26	44/390 (11.3%)	48	36/357 (10.1%)	43
Pseudomonal Infections	1/489 (0.2%)	2	1/150 (0.7%)	1	1/390 (0.3%)	1	2/357 (0.6%)	2
Sepsis, Bacteraemia, Viraemia And Fungaemia Nec	32/489 (6.5%)	35	17/150 (11.3%)	18	32/390 (8.2%)	38	29/357 (8.1%)	36
Staphylococcal Infections	3/489 (0.6%)	3	4/150 (2.7%)	4	3/390 (0.8%)	3	3/357 (0.8%)	4
Streptococcal Infections	2/489 (0.4%)	2	3/150 (2%)	3	2/390 (0.5%)	2	0/357 (0%)	0
Upper Respiratory Tract Infections	1/489 (0.2%)	1	2/150 (1.3%)	2	2/390 (0.5%)	2	0/357 (0%)	0
Urinary Tract Infections	28/489 (5.7%)	32	9/150 (6%)	11	21/390 (5.4%)	21	20/357 (5.6%)	22
Vascular Infections	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Viral Infections Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Injury, poisoning and procedural complications
Anaesthetic Complications	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Cardiac And Vascular Procedural Complications	16/489 (3.3%)	17	3/150 (2%)	4	7/390 (1.8%)	7	3/357 (0.8%)	3
Cardiovascular Injuries	3/489 (0.6%)	3	2/150 (1.3%)	2	0/390 (0%)	0	2/357 (0.6%)	2
Cerebral Injuries Nec	0/489 (0%)	0	2/150 (1.3%)	2	5/390 (1.3%)	5	2/357 (0.6%)	2
Chest And Lung Injuries Nec	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Fractures And Dislocations Nec	0/489 (0%)	0	2/150 (1.3%)	3	1/390 (0.3%)	1	3/357 (0.8%)	3
Gastrointestinal And Hepatobiliary Procedural Complications	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	2/357 (0.6%)	2
Limb Injuries Nec (Incl Traumatic Amputation)	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Lower Limb Fractures And Dislocations	18/489 (3.7%)	19	1/150 (0.7%)	1	9/390 (2.3%)	10	10/357 (2.8%)	12
Non-Site Specific Injuries Nec	13/489 (2.7%)	13	4/150 (2.7%)	4	14/390 (3.6%)	16	6/357 (1.7%)	6
Non-Site Specific Procedural Complications	25/489 (5.1%)	27	6/150 (4%)	6	25/390 (6.4%)	26	28/357 (7.8%)	29
Pelvic Fractures And Dislocations	4/489 (0.8%)	4	2/150 (1.3%)	2	2/390 (0.5%)	2	1/357 (0.3%)	1
Poisoning And Toxicity	2/489 (0.4%)	2	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Radiation Injuries	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Reproductive System And Breast Injuries	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Respiratory Tract And Thoracic Cavity Procedural Complications	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	3/357 (0.8%)	3
Site Specific Injuries Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	3/390 (0.8%)	3	1/357 (0.3%)	1
Skin Injuries Nec	10/489 (2%)	11	1/150 (0.7%)	1	5/390 (1.3%)	5	5/357 (1.4%)	5
Skin Procedural Complications	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Skull Fractures, Facial Bone Fractures And Dislocations	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Spinal Fractures And Dislocations	6/489 (1.2%)	7	1/150 (0.7%)	1	5/390 (1.3%)	8	2/357 (0.6%)	2
Thoracic Cage Fractures And Dislocations	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Transfusion Related Complications	0/489 (0%)	0	1/150 (0.7%)	1	1/390 (0.3%)	1	1/357 (0.3%)	1
Upper Limb Fractures And Dislocations	10/489 (2%)	11	0/150 (0%)	0	2/390 (0.5%)	2	5/357 (1.4%)	6
Investigations
Bacteria Identification And Serology (Excl Mycobacteria)	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Blood Counts Nec	2/489 (0.4%)	2	2/150 (1.3%)	2	1/390 (0.3%)	1	0/357 (0%)	0
Blood Gas And Acid Base Analyses	0/489 (0%)	0	0/150 (0%)	0	3/390 (0.8%)	3	0/357 (0%)	0
Carbohydrate Tolerance Analyses (Incl Diabetes)	2/489 (0.4%)	2	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Cardiac Function Diagnostic Procedures	2/489 (0.4%)	2	3/150 (2%)	3	0/390 (0%)	0	6/357 (1.7%)	6
Coagulation And Bleeding Analyses	5/489 (1%)	5	2/150 (1.3%)	2	6/390 (1.5%)	6	6/357 (1.7%)	7
Ecg Investigations	1/489 (0.2%)	1	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Liver Function Analyses	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Metabolism Tests Nec	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	1/357 (0.3%)	1
Microbiology And Serology Tests Nec	2/489 (0.4%)	2	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Mineral And Electrolyte Analyses	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Physical Examination Procedures	1/489 (0.2%)	1	0/150 (0%)	0	2/390 (0.5%)	2	2/357 (0.6%)	2
Platelet Analyses	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Protein Analyses Nec	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Red Blood Cell Analyses	13/489 (2.7%)	13	4/150 (2.7%)	4	10/390 (2.6%)	10	11/357 (3.1%)	11
Renal Function Analyses	4/489 (0.8%)	4	1/150 (0.7%)	1	2/390 (0.5%)	2	1/357 (0.3%)	1
Respiratory Tract And Thoracic Imaging Procedures	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Skeletal And Cardiac Muscle Analyses	4/489 (0.8%)	4	2/150 (1.3%)	2	1/390 (0.3%)	1	5/357 (1.4%)	5
Tissue Enzyme Analyses Nec	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Urinalysis Nec	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Urinary Tract Function Analyses Nec	3/489 (0.6%)	3	2/150 (1.3%)	2	0/390 (0%)	0	3/357 (0.8%)	3
Vascular Tests Nec (Incl Blood Pressure)	3/489 (0.6%)	3	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
White Blood Cell Analyses	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Metabolism and nutrition disorders
Appetite Disorders	1/489 (0.2%)	1	1/150 (0.7%)	1	1/390 (0.3%)	1	2/357 (0.6%)	2
Calcium Metabolism Disorders	2/489 (0.4%)	2	1/150 (0.7%)	1	2/390 (0.5%)	2	1/357 (0.3%)	2
Diabetes Mellitus (Incl Subtypes)	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Diabetic Complications Dermal	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Diabetic Complications Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Disorders Of Purine Metabolism	3/489 (0.6%)	3	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Electrolyte Imbalance Nec	5/489 (1%)	5	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
General Nutritional Disorders Nec	18/489 (3.7%)	20	7/150 (4.7%)	7	4/390 (1%)	4	15/357 (4.2%)	16
Hyperglycaemic Conditions Nec	4/489 (0.8%)	4	1/150 (0.7%)	1	3/390 (0.8%)	3	6/357 (1.7%)	6
Hypoglycaemic Conditions Nec	4/489 (0.8%)	4	5/150 (3.3%)	5	3/390 (0.8%)	3	4/357 (1.1%)	4
Magnesium Metabolism Disorders	0/489 (0%)	0	1/150 (0.7%)	1	1/390 (0.3%)	1	0/357 (0%)	0
Metabolic Acidoses (Excl Diabetic Acidoses)	3/489 (0.6%)	3	3/150 (2%)	4	1/390 (0.3%)	1	4/357 (1.1%)	4
Metabolic Alkaloses	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Mixed Acid-Base Disorders	2/489 (0.4%)	2	0/150 (0%)	0	3/390 (0.8%)	3	0/357 (0%)	0
Potassium Imbalance	14/489 (2.9%)	15	2/150 (1.3%)	2	8/390 (2.1%)	8	5/357 (1.4%)	6
Protein Metabolism Disorders Nec	0/489 (0%)	0	1/150 (0.7%)	1	1/390 (0.3%)	1	0/357 (0%)	0
Sodium Imbalance	8/489 (1.6%)	10	2/150 (1.3%)	3	5/390 (1.3%)	5	5/357 (1.4%)	5
Musculoskeletal and connective tissue disorders
Arthropathies Nec	0/489 (0%)	0	1/150 (0.7%)	1	2/390 (0.5%)	2	1/357 (0.3%)	1
Bone Disorders Nec	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Bone Related Signs And Symptoms	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Joint Related Signs And Symptoms	2/489 (0.4%)	2	1/150 (0.7%)	1	3/390 (0.8%)	3	1/357 (0.3%)	1
Metabolic Bone Disorders	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Muscle Weakness Conditions	1/489 (0.2%)	1	3/150 (2%)	3	0/390 (0%)	0	3/357 (0.8%)	3
Musculoskeletal And Connective Tissue Pain And Discomfort	8/489 (1.6%)	9	1/150 (0.7%)	1	13/390 (3.3%)	15	7/357 (2%)	7
Musculoskeletal And Connective Tissue Signs And Symptoms Nec	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Myopathies	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	3/357 (0.8%)	3
Osteoarthropathies	0/489 (0%)	0	2/150 (1.3%)	3	3/390 (0.8%)	4	1/357 (0.3%)	1
Spine And Neck Deformities	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-Cell Lymphomas Nec	0/489 (0%)	0	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Bladder Neoplasms Malignant	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Breast And Nipple Neoplasms Malignant	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Colonic Neoplasms Malignant	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Gastric Neoplasms Malignant	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Gastrointestinal Neoplasms Malignancy Unspecified Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Hepatic Neoplasms Malignant	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Leukaemias Acute Myeloid	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Multiple Myelomas	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	1/357 (0.3%)	1
Myelodysplastic Syndromes	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Neoplasms Malignant Site Unspecified Nec	3/489 (0.6%)	3	0/150 (0%)	0	2/390 (0.5%)	2	2/357 (0.6%)	2
Neuromas	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Pancreatic Neoplasms Malignant (Excl Islet Cell And Carcinoid)	0/489 (0%)	0	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Pharyngeal And Laryngeal Neoplasms Benign	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Prostatic Neoplasms Malignant	3/489 (0.6%)	3	1/150 (0.7%)	1	0/390 (0%)	0	1/357 (0.3%)	1
Renal Neoplasms Malignant	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Respiratory Tract And Pleural Neoplasms Malignant Cell Type Unspecified Nec	0/489 (0%)	0	2/150 (1.3%)	2	1/390 (0.3%)	1	0/357 (0%)	0
Skin Neoplasms Malignant And Unspecified (Excl Melanoma)	2/489 (0.4%)	2	1/150 (0.7%)	1	2/390 (0.5%)	2	2/357 (0.6%)	2
Thyroid Neoplasms Malignant	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Nervous system disorders
Acute Polyneuropathies	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Central Nervous System Haemorrhages And Cerebrovascular Accidents	28/489 (5.7%)	28	14/150 (9.3%)	14	26/390 (6.7%)	30	32/357 (9%)	35
Central Nervous System Vascular Disorders Nec	2/489 (0.4%)	2	0/150 (0%)	0	3/390 (0.8%)	3	0/357 (0%)	0
Cerebellar Coordination And Balance Disturbances	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Coma States	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Cortical Dysfunction Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Dementia (Excl Alzheimer's Type)	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Disturbances In Consciousness Nec	9/489 (1.8%)	9	4/150 (2.7%)	5	14/390 (3.6%)	15	7/357 (2%)	8
Dyskinesias And Movement Disorders Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Encephalopathies Nec	14/489 (2.9%)	14	0/150 (0%)	0	4/390 (1%)	4	5/357 (1.4%)	5
Encephalopathies Toxic And Metabolic	8/489 (1.6%)	11	0/150 (0%)	0	3/390 (0.8%)	3	2/357 (0.6%)	2
Headaches Nec	0/489 (0%)	0	2/150 (1.3%)	2	1/390 (0.3%)	1	0/357 (0%)	0
Hydrocephalic Conditions	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Increased Intracranial Pressure Disorders	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Lumbar Spinal Cord And Nerve Root Disorders	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Memory Loss (Excl Dementia)	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Migraine Headaches	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Mononeuropathies	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	2/357 (0.6%)	2
Nervous System Disorders Nec	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Neurological Signs And Symptoms Nec	7/489 (1.4%)	8	8/150 (5.3%)	8	2/390 (0.5%)	2	11/357 (3.1%)	11
Neuromuscular Junction Dysfunction	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Paralysis And Paresis (Excl Cranial Nerve)	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	2/357 (0.6%)	2
Peripheral Neuropathies Nec	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Seizures And Seizure Disorders Nec	3/489 (0.6%)	3	3/150 (2%)	4	1/390 (0.3%)	1	10/357 (2.8%)	10
Sensory Abnormalities Nec	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Speech And Language Abnormalities	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Transient Cerebrovascular Events	7/489 (1.4%)	8	1/150 (0.7%)	1	6/390 (1.5%)	6	2/357 (0.6%)	2
Tremor (Excl Congenital)	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Vagus Nerve Disorders	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Psychiatric disorders
Anxiety Symptoms	0/489 (0%)	0	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Behaviour And Socialisation Disturbances	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Confusion And Disorientation	6/489 (1.2%)	6	1/150 (0.7%)	1	8/390 (2.1%)	9	4/357 (1.1%)	4
Deliria	3/489 (0.6%)	3	1/150 (0.7%)	1	4/390 (1%)	4	1/357 (0.3%)	1
Depressive Disorders	3/489 (0.6%)	3	0/150 (0%)	0	2/390 (0.5%)	2	2/357 (0.6%)	2
Mental Disorders Nec	13/489 (2.7%)	13	3/150 (2%)	4	4/390 (1%)	4	14/357 (3.9%)	14
Perception Disturbances	0/489 (0%)	0	1/150 (0.7%)	1	2/390 (0.5%)	2	0/357 (0%)	0
Suicidal And Self-Injurious Behaviour	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Renal and urinary disorders
Bladder And Urethral Symptoms	7/489 (1.4%)	7	8/150 (5.3%)	9	8/390 (2.1%)	9	9/357 (2.5%)	11
Bladder Disorders Nec	1/489 (0.2%)	1	3/150 (2%)	3	0/390 (0%)	0	2/357 (0.6%)	2
Genital And Urinary Tract Disorders Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Nephritis Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Nephropathies And Tubular Disorders Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	1/390 (0.3%)	1	1/357 (0.3%)	1
Renal Disorders Nec	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	1/357 (0.3%)	1
Renal Failure And Impairment	90/489 (18.4%)	108	31/150 (20.7%)	43	38/390 (9.7%)	42	58/357 (16.2%)	66
Renal Failure Complications	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Renal Lithiasis	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Renal Obstructive Disorders	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	1/357 (0.3%)	1
Renal Vascular And Ischaemic Conditions	2/489 (0.4%)	2	1/150 (0.7%)	1	1/390 (0.3%)	1	2/357 (0.6%)	2
Ureteric Disorders Nec	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Urinary Abnormalities	10/489 (2%)	13	1/150 (0.7%)	1	8/390 (2.1%)	8	6/357 (1.7%)	11
Reproductive system and breast disorders
Breast Disorders Nec	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Pelvic Prolapse Conditions	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Prostatic Neoplasms And Hypertrophy	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Reproductive Tract Disorders Nec (Excl Neoplasms)	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Scrotal Disorders Nec	2/489 (0.4%)	2	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Vulvovaginal Disorders Nec	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Respiratory, thoracic and mediastinal disorders
Breathing Abnormalities	26/489 (5.3%)	27	21/150 (14%)	29	30/390 (7.7%)	33	26/357 (7.3%)	31
Bronchial Conditions Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	1/390 (0.3%)	1	0/357 (0%)	0
Bronchospasm And Obstruction	25/489 (5.1%)	28	16/150 (10.7%)	21	13/390 (3.3%)	15	8/357 (2.2%)	9
Conditions Associated With Abnormal Gas Exchange	7/489 (1.4%)	7	1/150 (0.7%)	1	6/390 (1.5%)	6	6/357 (1.7%)	6
Coughing And Associated Symptoms	2/489 (0.4%)	2	1/150 (0.7%)	1	5/390 (1.3%)	6	0/357 (0%)	0
Diaphragmatic Disorders	0/489 (0%)	0	2/150 (1.3%)	2	0/390 (0%)	0	0/357 (0%)	0
Laryngeal And Adjacent Sites Disorders Nec (Excl Infections And Neoplasms)	0/489 (0%)	0	1/150 (0.7%)	1	0/390 (0%)	0	0/357 (0%)	0
Laryngeal Spasm, Oedema And Obstruction	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Lower Respiratory Tract Inflammatory And Immunologic Conditions	8/489 (1.6%)	9	6/150 (4%)	6	7/390 (1.8%)	7	8/357 (2.2%)	8
Lower Respiratory Tract Signs And Symptoms	2/489 (0.4%)	2	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Mediastinal Disorders	0/489 (0%)	0	2/150 (1.3%)	2	1/390 (0.3%)	1	3/357 (0.8%)	3
Nasal Disorders Nec	4/489 (0.8%)	5	1/150 (0.7%)	1	5/390 (1.3%)	5	1/357 (0.3%)	1
Parenchymal Lung Disorders Nec	6/489 (1.2%)	6	3/150 (2%)	3	3/390 (0.8%)	3	4/357 (1.1%)	4
Pharyngeal Disorders (Excl Infections And Neoplasms)	1/489 (0.2%)	1	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Pneumothorax And Pleural Effusions Nec	54/489 (11%)	74	26/150 (17.3%)	36	29/390 (7.4%)	39	67/357 (18.8%)	86
Pulmonary Hypertensions	2/489 (0.4%)	2	1/150 (0.7%)	1	5/390 (1.3%)	5	0/357 (0%)	0
Pulmonary Oedemas	23/489 (4.7%)	24	3/150 (2%)	3	9/390 (2.3%)	9	10/357 (2.8%)	10
Pulmonary Thrombotic And Embolic Conditions	7/489 (1.4%)	7	1/150 (0.7%)	1	1/390 (0.3%)	1	0/357 (0%)	0
Respiratory Failures (Excl Neonatal)	54/489 (11%)	62	28/150 (18.7%)	29	36/390 (9.2%)	40	54/357 (15.1%)	68
Respiratory Tract Disorders Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	3/390 (0.8%)	3	2/357 (0.6%)	2
Tracheal Disorders (Excl Infections And Neoplasms)	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Upper Respiratory Tract Signs And Symptoms	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Skin and subcutaneous tissue disorders
Bullous Conditions	0/489 (0%)	0	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Dermal And Epidermal Conditions Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	1/357 (0.3%)	1
Dermatitis And Eczema	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	2/357 (0.6%)	2
Dermatitis Ascribed To Specific Agent	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Purpura And Related Conditions	2/489 (0.4%)	2	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Rashes, Eruptions And Exanthems Nec	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Skin And Subcutaneous Tissue Ulcerations	3/489 (0.6%)	3	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Skin Haemorrhages	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Skin Injuries And Mechanical Dermatoses	2/489 (0.4%)	3	1/150 (0.7%)	1	6/390 (1.5%)	6	4/357 (1.1%)	4
Skin Preneoplastic Conditions Nec	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Social circumstances
Housing Circumstances	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Surgical and medical procedures
Cardiac Device Therapeutic Procedures	1/489 (0.2%)	1	1/150 (0.7%)	1	1/390 (0.3%)	1	0/357 (0%)	0
Corneal And Scleral Therapeutic Procedures	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Fracture Treatments (Excl Skull And Spine)	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Hernia Repairs	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Joint Therapeutic Procedures	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Lens Therapeutic Procedures	0/489 (0%)	0	0/150 (0%)	0	2/390 (0.5%)	2	0/357 (0%)	0
Limb Therapeutic Procedures	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Muscle Therapeutic Procedures	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Prophylactic Procedures Nec	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Renal Therapeutic Procedures	0/489 (0%)	0	0/150 (0%)	0	1/390 (0.3%)	1	0/357 (0%)	0
Therapeutic Procedures Nec	9/489 (1.8%)	9	0/150 (0%)	0	3/390 (0.8%)	3	2/357 (0.6%)	2
Tracheal Therapeutic Procedures	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Ureteric Therapeutic Procedures	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Vascular disorders
Accelerated And Malignant Hypertension	2/489 (0.4%)	2	2/150 (1.3%)	2	0/390 (0%)	0	1/357 (0.3%)	1
Aneurysms And Dissections Non-Site Specific	0/489 (0%)	0	5/150 (3.3%)	5	0/390 (0%)	0	0/357 (0%)	0
Aortic Aneurysms And Dissections	4/489 (0.8%)	4	3/150 (2%)	3	1/390 (0.3%)	1	5/357 (1.4%)	5
Aortic Necrosis And Vascular Insufficiency	0/489 (0%)	0	0/150 (0%)	0	0/390 (0%)	0	1/357 (0.3%)	1
Arterial And Aortic Injuries	2/489 (0.4%)	2	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Blood Pressure Disorders Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	0/390 (0%)	0	2/357 (0.6%)	2
Circulatory Collapse And Shock	6/489 (1.2%)	7	2/150 (1.3%)	2	2/390 (0.5%)	2	4/357 (1.1%)	4
Haemorrhages Nec	20/489 (4.1%)	24	13/150 (8.7%)	13	19/390 (4.9%)	19	10/357 (2.8%)	11
Lymphangiopathies	2/489 (0.4%)	2	0/150 (0%)	0	2/390 (0.5%)	3	0/357 (0%)	0
Lymphoedemas	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Non-Site Specific Embolism And Thrombosis	6/489 (1.2%)	7	1/150 (0.7%)	1	1/390 (0.3%)	1	2/357 (0.6%)	2
Non-Site Specific Necrosis And Vascular Insufficiency Nec	3/489 (0.6%)	3	2/150 (1.3%)	2	3/390 (0.8%)	3	3/357 (0.8%)	3
Non-Site Specific Vascular Disorders Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	2/390 (0.5%)	2	0/357 (0%)	0
Peripheral Aneurysms And Dissections	5/489 (1%)	5	0/150 (0%)	0	9/390 (2.3%)	9	1/357 (0.3%)	1
Peripheral Embolism And Thrombosis	21/489 (4.3%)	22	5/150 (3.3%)	5	7/390 (1.8%)	7	5/357 (1.4%)	6
Peripheral Vascular Disorders Nec	1/489 (0.2%)	1	1/150 (0.7%)	1	2/390 (0.5%)	3	0/357 (0%)	0
Peripheral Vasoconstriction, Necrosis And Vascular Insufficiency	16/489 (3.3%)	18	2/150 (1.3%)	2	12/390 (3.1%)	12	2/357 (0.6%)	3
Site Specific Vascular Disorders Nec	3/489 (0.6%)	3	1/150 (0.7%)	1	0/390 (0%)	0	6/357 (1.7%)	7
Varicose Veins Non-Site Specific	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Vascular Hypertensive Disorders Nec	11/489 (2.2%)	11	3/150 (2%)	3	14/390 (3.6%)	15	7/357 (2%)	7
Vascular Hypotensive Disorders	52/489 (10.6%)	54	15/150 (10%)	15	21/390 (5.4%)	23	38/357 (10.6%)	40
Vascular Malformations And Acquired Anomalies	1/489 (0.2%)	1	0/150 (0%)	0	0/390 (0%)	0	0/357 (0%)	0
Other (Not Including 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	440/489 (90%)		139/150 (92.7%)		355/390 (91%)		320/357 (89.6%)
Blood and lymphatic system disorders
Anaemias Nec	90/489 (18.4%)	98	27/150 (18%)	28	76/390 (19.5%)	77	69/357 (19.3%)	78
Leukocytoses Nec	38/489 (7.8%)	42	18/150 (12%)	19	25/390 (6.4%)	26	46/357 (12.9%)	49
Thrombocytopenias	68/489 (13.9%)	73	32/150 (21.3%)	33	61/390 (15.6%)	64	90/357 (25.2%)	95
Cardiac disorders
Cardiac Conduction Disorders	114/489 (23.3%)	137	32/150 (21.3%)	37	80/390 (20.5%)	100	54/357 (15.1%)	68
Heart Failures Nec	30/489 (6.1%)	32	9/150 (6%)	9	20/390 (5.1%)	22	21/357 (5.9%)	24
Rate And Rhythm Disorders Nec	29/489 (5.9%)	30	12/150 (8%)	13	21/390 (5.4%)	22	30/357 (8.4%)	31
Supraventricular Arrhythmias	60/489 (12.3%)	66	36/150 (24%)	42	59/390 (15.1%)	69	80/357 (22.4%)	91
Ventricular Arrhythmias And Cardiac Arrest	31/489 (6.3%)	33	8/150 (5.3%)	10	22/390 (5.6%)	22	9/357 (2.5%)	9
Gastrointestinal disorders
Gastrointestinal Atonic And Hypomotility Disorders Nec	36/489 (7.4%)	37	12/150 (8%)	12	22/390 (5.6%)	22	24/357 (6.7%)	24
Nausea And Vomiting Symptoms	26/489 (5.3%)	33	7/150 (4.7%)	7	23/390 (5.9%)	25	16/357 (4.5%)	21
General disorders
Febrile Disorders	36/489 (7.4%)	39	7/150 (4.7%)	8	16/390 (4.1%)	16	16/357 (4.5%)	16
Oedema Nec	44/489 (9%)	48	16/150 (10.7%)	18	34/390 (8.7%)	35	26/357 (7.3%)	31
Pain And Discomfort Nec	30/489 (6.1%)	34	9/150 (6%)	10	26/390 (6.7%)	30	30/357 (8.4%)	33
Infections and infestations
Lower Respiratory Tract And Lung Infections	26/489 (5.3%)	26	16/150 (10.7%)	16	18/390 (4.6%)	19	21/357 (5.9%)	23
Urinary Tract Infections	75/489 (15.3%)	80	28/150 (18.7%)	34	51/390 (13.1%)	59	58/357 (16.2%)	67
Injury, poisoning and procedural complications
Non-Site Specific Injuries Nec	25/489 (5.1%)	26	2/150 (1.3%)	2	21/390 (5.4%)	23	11/357 (3.1%)	15
Non-Site Specific Procedural Complications	21/489 (4.3%)	23	6/150 (4%)	6	20/390 (5.1%)	21	29/357 (8.1%)	29
Investigations
Skeletal And Cardiac Muscle Analyses	16/489 (3.3%)	16	7/150 (4.7%)	7	15/390 (3.8%)	15	19/357 (5.3%)	19
Metabolism and nutrition disorders
Hyperglycaemic Conditions Nec	22/489 (4.5%)	22	6/150 (4%)	6	19/390 (4.9%)	19	29/357 (8.1%)	30
Magnesium Metabolism Disorders	17/489 (3.5%)	17	9/150 (6%)	10	6/390 (1.5%)	6	9/357 (2.5%)	9
Potassium Imbalance	56/489 (11.5%)	63	16/150 (10.7%)	25	36/390 (9.2%)	38	33/357 (9.2%)	37
Sodium Imbalance	25/489 (5.1%)	26	10/150 (6.7%)	13	22/390 (5.6%)	22	28/357 (7.8%)	29
Musculoskeletal and connective tissue disorders
Musculoskeletal And Connective Tissue Pain And Discomfort	34/489 (7%)	42	16/150 (10.7%)	19	34/390 (8.7%)	39	22/357 (6.2%)	22
Nervous system disorders
Neurological Signs And Symptoms Nec	18/489 (3.7%)	20	2/150 (1.3%)	2	21/390 (5.4%)	22	17/357 (4.8%)	21
Psychiatric disorders
Anxiety Symptoms	25/489 (5.1%)	25	6/150 (4%)	6	14/390 (3.6%)	14	14/357 (3.9%)	14
Confusion And Disorientation	32/489 (6.5%)	34	13/150 (8.7%)	14	24/390 (6.2%)	25	23/357 (6.4%)	25
Renal and urinary disorders
Renal Failure And Impairment	67/489 (13.7%)	78	16/150 (10.7%)	20	40/390 (10.3%)	43	44/357 (12.3%)	51
Reproductive system and breast disorders
Pneumothorax And Pleural Effusions Nec	76/489 (15.5%)	82	30/150 (20%)	32	52/390 (13.3%)	58	91/357 (25.5%)	105
Respiratory, thoracic and mediastinal disorders
Breathing Abnormalities	26/489 (5.3%)	26	8/150 (5.3%)	8	27/390 (6.9%)	29	14/357 (3.9%)	16
Bronchospasm And Obstruction	7/489 (1.4%)	7	10/150 (6.7%)	11	4/390 (1%)	5	10/357 (2.8%)	10
Conditions Associated With Abnormal Gas Exchange	12/489 (2.5%)	12	8/150 (5.3%)	11	11/390 (2.8%)	12	11/357 (3.1%)	11
Parenchymal Lung Disorders Nec	35/489 (7.2%)	35	10/150 (6.7%)	10	23/390 (5.9%)	23	41/357 (11.5%)	41
Pulmonary Oedemas	29/489 (5.9%)	29	5/150 (3.3%)	5	20/390 (5.1%)	20	26/357 (7.3%)	27
Vascular disorders
Haemorrhages Nec	34/489 (7%)	35	4/150 (2.7%)	4	26/390 (6.7%)	26	9/357 (2.5%)	9
Vascular Hypertensive Disorders Nec	45/489 (9.2%)	49	20/150 (13.3%)	20	46/390 (11.8%)	55	37/357 (10.4%)	40
Vascular Hypotensive Disorders	68/489 (13.9%)	73	18/150 (12%)	21	40/390 (10.3%)	41	40/357 (11.2%)	43

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Results Point of Contact

Name/Title	Hatice Bilgic Lim
Organization	Medtronic, Inc.
Phone
Email	rs.medtroniccardiovascularclinicaltrials@medtronic.com

Responsible Party:

Medtronic Cardiovascular

ClinicalTrials.gov Identifier:

NCT01240902

Other Study ID Numbers:

MCV-US-2009-01

First Posted:

Nov 15, 2010

Last Update Posted:

Jun 16, 2022

Last Verified:

May 1, 2022

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

Study Details

Study Description

Brief Summary

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

More Information

Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact