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

Medtronic CoreValve® Continued Access Study

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 very high risk and high risk for aortic valve surgery.

Study Overview

• Status: Completed
• Conditions: Severe Aortic Stenosis
• Intervention / Treatment: Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)

• Study Type: Interventional
• Enrollment (Actual): 2777
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner Good Samaritan
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California University Hospital
    • Los Angeles, California, United States, 90072
      • Kaiser Permanente - Los Angeles Medical Center
    • Mountain View, California, United States, 94040
      • El Camino Hospital
    • Palo Alto, California, United States, 94304
      • VA Palo Alto Health Care System
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center / Georgetown Hospital
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Health System / Jackson Memorial Hospital
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Saint Joseph's Hospital of Atlanta
    • Atlanta, Georgia, United States, 30309
      • Piedmont Heart Institute
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • St. Vincent Heart Center of Indiana
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Iowa Heart Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Hospital
  • Louisiana
    • Houma, Louisiana, United States, 70360
      • Cardiovascular Institute of the South/Terrebonne General
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health Systems
    • Detroit, Michigan, United States, 48236
      • St. John Hospital and Medical Center
    • Detroit, Michigan, United States, 48201
      • Detroit Medical Center Cardiovascular Institute
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Hospitals
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Morristown Memorial Hospital
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital/ Long Island Jewish Hospital
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • New York, New York, United States, 10029
      • The Mount Sinai Medical Center
    • New York, New York, United States, 10075
      • Lenox Hill Hospital
    • Roslyn, New York, United States, 11576
      • St. Francis Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University - Baptist Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals - Case Medical Center
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Medical Center - The Richard M. Ross Heart Hospital
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Harrisburg, Pennsylvania, United States, 17043
      • Pinnacle Health
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75226
      • Baylor Heart and Vascular Hospital
    • Houston, Texas, United States, 77030
      • Texas Heart Institute at St. Luke's Episcopal Hospital
    • Houston, Texas, United States, 77030
      • The Methodist Hospital - The Methodist DeBakey Heart & Vascular Center
  • Vermont
    • Burlington, Vermont, United States, 05458
      • University of Vermont Medical Center
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital
  • Washington
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • St. Luke's Medical Center - Aurora Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. High Risk: Subject must have co-morbidities 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.

   OR

   Extreme Risk: Subject must have co-morbidities 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.

2. 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
3. Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater.
4. 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.
5. The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits.

Exclusion Criteria:

Clinical

1. Evidence of an acute myocardial infarction ≤ 30 days before the intended treatment.
2. Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to the MCS TAVI procedure including bare metal and drug eluting stents.
3. Blood dyscrasias as defined: leukopenia (WBC < 1000mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy.
4. Untreated clinically significant coronary artery disease requiring revascularization.
5. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support.
6. Need for emergency surgery for any reason.
7. Severe ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20% as measured by resting echocardiogram.
8. Recent (within 6 months) cerebrovascular accident (CVA) or transient ischemic attack (TIA).
9. End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min.
10. Active GI bleeding that would preclude anticoagulation.

11. A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated:

    • Aspirin
    • Heparin (HIT/HITTS) and bivalirudin
    • Nitinol (titanium or nickel)
    • Ticlopidine and clopidogrel
    • Contrast media
12. Ongoing sepsis, including active endocarditis.
13. Subject refuses a blood transfusion.
14. Life expectancy < 12 months due to associated non-cardiac co-morbid conditions.
15. Other medical, social, or psychological conditions that in the opinion of an Investigator precludes the subject from appropriate consent.
16. 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).
17. Currently participating in an investigational drug or another device trial.

18. Symptomatic carotid or vertebral artery disease.

    Anatomical

19. High Risk:Native aortic annulus size < 20 mm or > 29 mm per the baseline diagnostic imaging (until 23mm valve enrollment completion/closure in the CoreValve® US Pivotal Trial-High Risk Cohort)

    OR

    Extreme Risk: Native aortic annulus size < 18 mm or > 29 mm per the baseline diagnostic imaging. (High risk and extreme risk upon 23mm valve enrollment completion/closure in the CoreValve® US Pivotal Trial-High Risk Cohort)

20. Pre-existing prosthetic heart valve any position.
21. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation (3-4+)).
22. Moderate to severe (3-4+) or severe (4+) mitral or severe (4+) tricuspid regurgitation.
23. Moderate to severe mitral stenosis.
24. Hypertrophic obstructive cardiomyopathy.
25. Echocardiographic evidence of new or untreated intracardiac mass, thrombus or vegetation.
26. Severe basal septal hypertrophy with an outflow gradient.
27. 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).
28. Ascending aorta diameter >43 mm if the aortic annulus diameter is 23-29 mm; ascending aortic 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 (Extreme Risk only until 23 mm valve enrollment completion/closure in the CoreValve® US Pivotal Trial-High Risk Cohort).
29. Congenital bicuspid or unicuspid valve verified by echocardiography.

30. Sinus of valsalva anatomy that would prevent adequate coronary perfusion.

    Vascular

31. Transarterial access not able to accommodate an 18Fr sheath.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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)
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)
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extreme Risk: All-cause Death or Major Stroke; High Risk Surgical: All-cause Mortality	All-cause Death or Major Stroke (Extreme Risk- Medtronic CoreValve® System); All-cause Mortality (High Risk Surgical- Medtronic CoreValve® System vs. Surgical Valve)	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Index Procedure Related MAEs		Procedure
Length of Index Procedure Hospital Stay		Number of days from admission to discharge
Major Adverse Cardiovascular and Cerebrovascular Event (MACCE)	MACCE is defined as a composite of: All-Cause Death; 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)	30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
The Occurrence of Individual MACCE Components	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)	30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
Major Adverse Events (MAEs)	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	30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
Conduction Disturbance Requiring Permanent Pacemaker Implantation		30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
Change From Baseline in NYHA Class	Change from baseline (continuous variable). A positive number corresponds to NYHA worsening; a negative number corresponds to NYHA improvement. 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.	Baseline to 30 days, baseline to 6 months, baseline to 1 year. The 2-5 year outcome data will be reported once data set is complete.
Change From Baseline in Distance Walked During 6-Minute Walk Test (6MWT)	Change in distance walked during 6MWT from baseline	Baseline to 30 days, baseline to 1 year
Ratio of Days Alive Out of Hospital at 365 Days Post Procedure Versus Total Days Alive		1 year
Quality of Life (QoL) Change	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.	30 day, 6 month, 1 year. The 2-5 year outcome data will be reported once data set is complete.
Echocardiographic Assessment of Valve Performance	Using the following measure: • Effective Orifice Area (EOA) analyzed overall per Extreme Risk or High Risk. Iliofemoral access and non-iliofemoral access are not reported separate because this is a valve performance measurement.	30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
Echocardiographic Assessment of Valve Performance	Using the following measure: • Transvalvular Mean Gradient analyzed overall per Extreme Risk or High Risk. Iliofemoral access and non-iliofemoral access are not reported separate because this is a valve performance measurement.	30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
Echocardiographic Assessment of Valve Performance	Using the following measure: - Degree of Aortic Valve Regurgitation (Transvalvular and Paravalvular) analyzed overall per Extreme Risk or High Risk. Iliofemoral access and non-iliofemoral access are not reported separate because this is a valve performance measurement.	30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
Aortic Valve Hospitalizations		30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
Cardiovascular Deaths and Valve-Related Deaths		30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
Strokes and Transient Ischemic Attacks (TIAs)	Strokes (of any severity) and TIAs	30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.
Device Success	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	Number of days from admission to discharge
Procedural Success	Defined as device success and absence of in-hospital MACCE.	Number of days from admission to discharge
Prosthetic Valve Dysfunction (PVD)	PVD was defined according to VARC using the site reported 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	30 day, 6 months, and 1 year. The 2-5 year outcome data will be reported once data set is complete.

Collaborators and Investigators

• Sponsor: Medtronic Cardiovascular
• Investigators: Principal Investigator: David H Adams, MD, Icahn School Of Medicine At Mount Sinai

Publications and helpful links

General Publications

• Pineda AM, Kevin Harrison J, Kleiman NS, Reardon MJ, Conte JV, O'Hair DP, Chetcuti SJ, Huang J, Yakubov SJ, Popma JJ, Beohar N. Clinical impact of baseline chronic kidney disease in patients undergoing transcatheter or surgical aortic valve replacement. Catheter Cardiovasc Interv. 2019 Mar 1;93(4):740-748. doi: 10.1002/ccd.27928. Epub 2018 Oct 20.
• Kleiman NS, Maini BJ, Reardon MJ, Conte J, Katz S, Rajagopal V, Kauten J, Hartman A, McKay R, Hagberg R, Huang J, Popma J; CoreValve Investigators. Neurological Events Following Transcatheter Aortic Valve Replacement and Their Predictors: A Report From the CoreValve Trials. Circ Cardiovasc Interv. 2016 Sep;9(9):e003551. doi: 10.1161/CIRCINTERVENTIONS.115.003551. Erratum In: Circ Cardiovasc Interv. 2016 Nov;9(11):
• Butala NM, Song Y, Shen C, Cohen DJ, Yeh RW. Effect of intensive versus limited monitoring on clinical trial conduct and outcomes: A randomized trial. Am Heart J. 2022 Jan;243:77-86. doi: 10.1016/j.ahj.2021.09.002. Epub 2021 Sep 14.

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2012
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 18, 2019

Study Registration Dates

• First Submitted: February 3, 2012
• First Submitted That Met QC Criteria: February 8, 2012
• First Posted (Estimate): February 10, 2012

Study Record Updates

• Last Update Posted (Actual): October 25, 2022
• Last Update Submitted That Met QC Criteria: October 21, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Aortic Valve Replacement; Valvular Heart Disease; High Risk; Severe Aortic Stenosis; Critical Aortic Stenosis; Extreme Risk
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis; Constriction, Pathologic
• Other Study ID Numbers: 10037989DOC REV 1C