The HeartWare™ Ventricular Assist System as Destination Therapy of Advanced Heart Failure: the ENDURANCE Trial (ENDURANCE)

A Prospective, Randomized, Controlled, Un-blinded, Multi-Center Clinical Trial to Evaluate the HeartWare™ Ventricular Assist System (VAS) for Destination Therapy of Advanced Heart Failure

The purpose of this study is to determine the safety and effectiveness of the HeartWare Ventricular Assist System in patients with chronic Stage D/ New York Heart Association (NYHA) Class IIIB/IV left ventricular failure who have received and failed optimal medical therapy, and who are ineligible for cardiac transplantation.

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure
• Intervention / Treatment: Device: Control LVAD; Device: HeartWare® VAS

Detailed Description

The HeartWare Ventricular Assist System (VAS) is intended for use in patients with chronic Stage D/NYHA Class IIIB/IV left ventricular failure who have received and failed optimal medical therapy and who are ineligible for cardiac transplantation. The ENDURANCE clinical study is a prospective, randomized, unblinded, multi-center, non-inferiority evaluation of the HeartWare® VAS versus a control group consisting of any FDA-approved Left Ventricular Assist Device (LVAD) approved for destination therapy. Patients are randomized to HeartWare® VAS or control LVAD in a 2:1 ratio. Each patient receiving the HeartWare® VAS or control LVAD is followed to the primary endpoint at 2 years, with a subsequent follow-up period extending to 5 years post implant.

• Study Type: Interventional
• Enrollment (Actual): 451
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • The University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital - Phoenix
  • California
    • Los Angeles, California, United States, 90033
      • The University of Southern California
    • San Diego, California, United States, 92123
      • Sharp Memorial
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Leprino
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida - Gainesville
    • Miami, Florida, United States, 33136
      • University of Miami/Jackson Memorial Hospital
    • Tampa, Florida, United States, 33606
      • Tampa Transplant Institute/Tampa General Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory Clinic Inc.
    • Atlanta, Georgia, United States, 30342
      • Saint Joseph Hospital of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Christ Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • IU Health Methodist
    • Indianapolis, Indiana, United States, 46260
      • Saint Vincent Health
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Jewish Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70115
      • John Ochsner Heart & Vascular Institute
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Hospital
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Abbott Northwestern
    • Rochester, Minnesota, United States, 55902
      • St. Mary's Hospital - Mayo
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University/Barnes-Jewish Hospital
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10032
      • New York Presbyterian Hospital/Columbia
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Presbyterian
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Dallas, Texas, United States, 75390
      • University of Texas - South Western
    • Houston, Texas, United States, 77030
      • The Methodist Hospital
    • Houston, Texas, United States, 77030
      • Texas Heart Institute
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Innova Heart and Vascular Institute Research - Cardiac Vascular & Thoracic Surgery Associates, PC
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Spokane, Washington, United States, 99204
      • Northwest Cardiothoracic &Transplant Surgeons
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Saint Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Must be ≥18 years of age at consent
2. Body Surface Area (BSA) ≥ 1.2 m2
3. Patients with advanced heart failure symptoms (New York Heart Association (NYHA) Class IIIB or IV) who are: (patient must meet one of the following) 3a. On optimal medical management, including dietary salt restriction and diuretics, for at least 45 out of the last 60 days and are failing to respond; or 3b. In NYHA Class III or NYHA Class IV heart failure for at least 14 days, and dependent on intra aortic balloon pump (IABP) for 7 days and/or inotropes for at least 14 days
4. Left ventricular ejection fraction ≤ 25%
5. LVAD implant is intended as destination therapy
6. Must be able to receive either the HeartWare® VAS or control LVAD
7. Female patients of childbearing potential must agree to use adequate contraceptive precautions for the duration of the study.
8. The patient or legally authorized representative has signed the informed consent form

Exclusion Criteria:

1. Body Mass Index (BMI) > 40
2. Existence of any ongoing mechanical circulatory support (MCS) other than an intra-aortic balloon pump (IABP)
3. Prior cardiac transplant.
4. History of confirmed, untreated abdominal or thoracic aortic aneurysm > 5 cm.
5. Cardiothoracic surgery within 30 days of randomization.
6. Acute myocardial infarction within 14 days of implant
7. Patients eligible for cardiac transplantation
8. On ventilator support for > 72 hours within the four days immediately prior to randomization and implant.
9. Pulmonary embolus within three weeks of randomization
10. Symptomatic cerebrovascular disease, stroke within 180 days of randomization or > 80% stenosis of carotid or cranial vessels.
11. Uncorrected moderate to severe aortic insufficiency. Correction may include repair or bioprosthesis at the time of implant.
12. Severe right ventricular failure as defined by the anticipated need for right ventricular assist device (RVAD) support or extracorporeal membrane oxygenation (ECMO) or right atrial pressure > 20 mmHg on multiple inotropes, right ventricular ejection fraction (RVEF) <15% or clinical signs
13. Active, uncontrolled infection diagnosed by a combination of clinical symptoms and laboratory testing.
14. Uncorrected thrombocytopenia or generalized coagulopathy (e.g., platelet count < 75,000, INR > 2.0 or PTT > 2.5 times control in the absence of anticoagulation therapy).
15. Intolerance to anticoagulant or antiplatelet therapies or any other peri- or postoperative therapy that the investigator may administer based upon the patient's health status.
16. Serum creatinine > 3.0 mg/dL within 72 hours of randomization or requiring dialysis (does not include use of ultra-filtration for fluid removal).
17. Specific liver enzymes [AST (SGOT) and ALT (SGPT)] > 3 times upper limit of normal within 72 hours of randomization.
18. A total bilirubin > 3 mg/dl within 72 hours of randomization, or biopsy proven liver cirrhosis or portal hypertension.
19. Pulmonary vascular resistance (PVR) is demonstrated to be unresponsive to pharmacological manipulation and the PVR > 6 Wood units.
20. Patients with a mechanical heart valve .
21. Etiology of heart failure is due to, or associated with, uncorrected thyroid disease, obstructive cardiomyopathy, pericardial disease, amyloidosis, active myocarditis or restrictive cardiomyopathy
22. History of severe Chronic Obstructive Pulmonary Disease (COPD) or severe restrictive lung disease
23. Participation in any other study involving investigational drugs or devices
24. Severe illness, other than heart disease, which would limit survival to < 3 years
25. Peripheral vascular disease with rest pain or ischemic ulcers of the extremities
26. Pregnancy
27. Patient unwilling or unable to comply with study requirements
28. Technical obstacles, which pose an inordinately high surgical risk, in the judgment of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HeartWare® VAS; Implant of HeartWare® Ventricular Assist System	Device: HeartWare® VAS; The HeartWare® VAS is an implantable centrifugal pump that was designed to provide flows up to 10 L/min in a small device that is both lightweight and simple to use.
Active Comparator: Control LVAD; Implant of FDA-approved LVADs approved for destination therapy	Device: Control LVAD; Any FDA-approved LVAD for destination therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stroke-Free Survival Probability for 2 Years Post Implant	The primary endpoint of the trial is stroke-free survival at two years, defined as alive on the originally implanted device, electively transplanted or explanted due to patient recovery and free from disabling stroke (Modified Rankin Scale >=4). The Modified Rankin Scale is scored from 0 to 6, where 0 indicates an absence of symptoms and 6 indicates death. A score of 4 or higher indicates moderately severe or greater disability. Weibull model estimates of survival probability (shown as a percent of 100) are used.	Implant to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Bleeding	Number of participants with bleeding, per Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definition. The event of bleeding is defined as: An episode of suspected internal or external bleeding that results in one or more of the following: Death,; Re-operation,; Hospitalization,; Transfusion of red blood cells as follows: During first 7 days post implant; Adults (≥ 50 kg): ≥ 4U packed red blood cells (PRBC) within any 24 hour period during first 7 days post implant. After 7 days post implant; Any transfusion of packed red blood cells (PRBC) after 7 days following implant.	Implant to two years
Number of Participants With Major Infections	Number of participants with major infections, per INTERMACS definition. A major infection is defined as: A clinical infection accompanied by pain, fever, drainage and/or leukocytosis that is treated by anti-microbial agents (non-prophylactic). A positive culture from the infected site or organ should be present unless strong clinical evidence indicates the need for treatment despite negative cultures. The general categories of infection include Localized non-device infection Percutaneous site and/or pocket infection Internal pump component, inflow or outflow tract infection Sepsis	Implant to two years
Overall Survival at 2 Years	Overall survival is the probability (expressed as a percent of 100) did not died within 2 years post implant via the Kaplan-Meier method. Participants that did not died were censored at the time of last follow-up or 2 years post implant, whichever occurred first.	Implant to two years
Number of Participants With Device Malfunctions	Number of Participants with device malfunctions per INTERMACS definition. Device malfunction denotes a failure of one or more of the components of the Mechanical Circulatory Support Device (MCSD) system which either directly causes or could potentially induce a state of inadequate circulatory support (low cardiac output state) or death. The manufacturer must confirm device failure. A failure that was iatrogenic or recipient-induced will be classified as an Iatrogenic/Recipient-Induced Failure. Device failure should be classified according to which components fails as follows: Pump failure (blood contacting components of pump and any motor or other pump actuating mechanism that is housed with the blood contacting components).; Non-pump failure (e.g., external pneumatic drive unit, electric power supply unit, batteries, controller, interconnect cable, compliance chamber)	Implant to two years
Health Status Change Measured by Kansas City Cardiomyopathy Questionnaire (KCCQ)	Health Status change as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score. The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (e.g., better functioning, fewer symptoms, better quality of life). The Overall Summary Score is calculated as the mean of the Physical Limitation, Total Symptom, Quality of Life and Social Limitation scores. A positive change in score from baseline indicates an improvement.	Change from baseline to 2 years
Health Status Change Measured by EuroQol EQ-5D (Version 3L)	The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). An adjustment was done on the response where the scores were normalized based on this paper: Johnson JA, Coons SJ. Comparison of the EQ-5D and SF-12 in an adult US sample. Qual Life Res. 1998 Feb;7(2):155-66.	Change from baseline to 2 years
Change in Functional Status Measured by New York Heart Association (NYHA) Class	Change in Functional status, as measured by New York Heart Association (NYHA) class. There are 4 levels of NYHA: I (Mild): No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea. II (Mild): Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea. III (Moderate): Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. IV (Severe): Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased. Improvement is defined as moving from a higher numerical NYHA level to a lower numerical NYHA level (e.g., IV to III).	Change from baseline to 2 years
Change in Functional Status as Measured by 6-minute Walk	Change in functional status, as measured by 6-minute walk test.	Change from baseline to 2 years
Length of Initial Hospitalization	Length of Initial Hospitalization post implant	Implant to the end of the initial hospitalization
Number of Participants Who Had a Re-hospitalization	Number of participants who had a re-hospitalization while on the device	Implant to two years
Duration of Re-hospitalization	Duration of Re-hospitalization while on device	Implant to two years
Cause of Re-hospitalization	Cause of Re-hospitalization while on device. The reason a participant may have been re-hospitalized was due to an adverse event, the need for an explant, or for various "Other" reasons.	Implant to two years

Collaborators and Investigators

• Sponsor: Medtronic Cardiac Rhythm and Heart Failure

Publications and helpful links

General Publications

• Rogers JG, Pagani FD, Tatooles AJ, Bhat G, Slaughter MS, Birks EJ, Boyce SW, Najjar SS, Jeevanandam V, Anderson AS, Gregoric ID, Mallidi H, Leadley K, Aaronson KD, Frazier OH, Milano CA. Intrapericardial Left Ventricular Assist Device for Advanced Heart Failure. N Engl J Med. 2017 Feb 2;376(5):451-460. doi: 10.1056/NEJMoa1602954.
• Mahr C, McGee E Jr, Cheung A, Mokadam NA, Strueber M, Slaughter MS, Danter MR, Levy WC, Cheng RK, Beckman JA, May DM, Ismyrloglou E, Tsintzos SI, Silvestry SC. Cost-Effectiveness of Thoracotomy Approach for the Implantation of a Centrifugal Left Ventricular Assist Device. ASAIO J. 2020 Aug;66(8):855-861. doi: 10.1097/MAT.0000000000001209. Erratum In: ASAIO J. 2021 Aug 1;67(8):e148.
• Silvestry SC, Mahr C, Slaughter MS, Levy WC, Cheng RK, May DM, Ismyrloglou E, Tsintzos SI, Tuttle E, Cook K, Birk E, Gomes A, Graham S, Cotts WG. Cost-Effectiveness of a Small Intrapericardial Centrifugal Left Ventricular Assist Device. ASAIO J. 2020 Aug;66(8):862-870. doi: 10.1097/MAT.0000000000001211. Erratum In: ASAIO J. 2021 Aug 1;67(8):e149.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2017

Study Registration Dates

• First Submitted: July 16, 2010
• First Submitted That Met QC Criteria: July 19, 2010
• First Posted (Estimate): July 21, 2010

Study Record Updates

• Last Update Posted (Actual): September 6, 2018
• Last Update Submitted That Met QC Criteria: September 4, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: HW004 ENDURANCE