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Clinical Use of Ventricular Assist Devices

Executive Summary

The National Heart, Lung, and Blood Institute (NHLBI) convened a working group of experts on heart failure cardiology, cardiac surgery, clinical trial design, medical ethics, and regulatory affairs on March 27-28, 2008 in Crystal City, Virginia to advise the NHLBI on research directions for the treatment of advanced heart failure through clinical trials using ventricular assist devices (VADs).

The working group addressed three challenges of the 2007 NHLBI Strategic Plan: (1) to enhance the evidence available to guide the practice of medicine, and improve public health (Challenge 2.4); (2) to accelerate the translation of basic research findings into clinical studies and trials and to promote the translation of clinical research findings back to the laboratory (Challenge 2.1); and (3) to discover biomarkers that differentiate clinically relevant disease subtypes and that identify new molecular targets for application to prevention and diagnosis—including imaging, and therapy (Challenge 1.2).

Discussion:

VADs are currently used to bridge patients to heart transplantation, to allow their own hearts to recover or as permanent (“destination”) therapy. Using VADs to bridge to heart transplantation is inherently limited by the number of available donor organs and VAD-assisted cardiac recovery occurs in only a very limited number of cases.  Due to associated device risks, destination therapy is currently limited in the US to those advanced heart failure patients who are not transplant eligible, have less than two years of life expectancy, and are on maximal heart failure medication. Recognizing the clinical advances offered by the current generation of smaller, more reliable, rotary VADs and in patient care and selection, the working group considered the highest priority to be a clinical trial to assess the use of VAD therapy in patients who are less ill than those currently eligible for destination therapy.  Discussions focused on critical issues related to the potential trial such as: equipoise, patient characteristics, expected treatment effects, anticipated survival rates, trial results in similar patient populations, device characteristics and costs, the use of multiple devices, results of recent VAD trials, risk factors, competing therapies, and regulatory issues.

The working group reached consensus on the following points:

  • An unmet clinical need currently exists for heart failure patients who remain symptomatic with a depressed ejection fraction despite conventional medical therapy.

  • Equipoise exists for designing a scientifically rigorous clinical trial evaluating the current generation of circulatory assist devices in less ill patients.

Recommendations:

The Working Group proposed that a randomized clinical trial be designed to test the hypothesis whether VAD therapy may improve both survival and quality of life in those advanced heart failure patients who are neither inotrope-dependent nor exercise-intolerant and have not yet developed serious consequences such as malnourishment, end-organ damage, and immobility. The importance of testing a strategy of therapy rather than a specific device was emphasized, noting that the field of mechanical circulatory support would best be served by including multiple devices, if feasible. The Working Group considered NHLBI’s leadership role as necessary for the scientific objectivity in the trial design and administration, as well as to enhance access to shared data.  NHLBI could also best facilitate the potential for including more than one device in the trial. Additionally, a large majority of the funding for the trial should be provided by industry and NHLBI could help to facilitate the industrial partnerships for the trial.

The following patient criteria and trial design characteristics were recommended.

Patient Population

  • Patients should be ill enough to potentially experience both functional and survival benefits from the therapy without undue risk.
  • The estimated mortality rate for this group should be no less than 30% at one year.
  • Inclusion criteria include:
    • hospitalization in past 6 months,
    • New York Heart Association (NYHA) Class IV or Advanced Class III *
    • maximal evidence-based therapies for 3 months,
    • duration of heart failure of at least a year, and
    • no inotropic support for 30 days prior to enrollment.

Trial Design

  • Randomized control trial design with VAD and optimal medical management (OMM) arms
  • 1:1 randomization ratio between OMM and VAD therapy
  • Initial pilot phase followed by a larger definitive phase.
    • Initial phase to assess feasibility of enrollment and refine the target population, endpoints, and definitions.
    • Pilot phase patients could be rolled over into the definitive phase of the trial.
    • Criteria for moving to the definitive phase might include good enrollment, low complication rates, and estimation of an event rate sufficient to complete the trial.
    • Initial estimates of the number of patients needed to adequately power such a trial is 250-300.
  • A composite primary endpoint of survival and functional status was recommended where the improvement in functional status would need to be substantial and assessed through objective metrics.
  • Survival would need to be at least as good as that in the control group.
  • Secondary endpoints would be hospitalizations, complications, and quality-of-life metrics.
  • VADs would need to be qualified for the trial based on well-defined requirements.
  • If two devices or more are qualified and included in the trial, randomization of patients to the devices available at each site rather than randomization of every patient might be considered in order to capitalize on surgical experience with specific devices.
  • Investigators could pre-specify which device or devices are to be used at their center and sites would be chosen to ensure equal use of qualified devices.
  • Conduct the trial at leading centers by surgeons who have performed a least 12 implants of the VAD(s) to be used at the specific center for the trial.

Publication Plans:

A manuscript is planned for publication in a peer-reviewed journal.    

NHLBI Contact:

J. Timothy Baldwin, Ph.D., NHLBI, NIH
baldwint@nhlbi.nih.gov

Working Group Members:

Chair:

  • Douglas L. Mann, MD, Baylor College of Medicine

Members:

  • Michael A. Acker, MD, University of Pennsylvania Medical Center
  • Maria R. Costanzo, MD, Edward Hospital Center for Advanced Heart Failure
  • Walter P. Dembitsky, MD, Sharp Memorial Hospital
  • Timothy J. Gardner, MD, Christiana Care Medical Center
  • Annetine C. Gelijns, PhD, Columbia University Medical Center
  • Bartley P. Griffith, MD, University of Maryland School of Medicine
  • Judith S. Hochman, MD, New York University School of Medicine
  • Allan S. Jaffe, MD, Mayo Clinic
  • Robert L. Kormos, MD, University of Pittsburgh Medical Center
  • James W. Long, MD, PhD, Integris Baptist Medical Center
  • Donna M. Mancini, MD, New York Presbyterian Hospital at Columbia
  • Kenneth B. Margulies, MD, University of Pennsylvania
  • Barry M. Massie, MD, San Francisco VA Hospital
  • Leslie W. Miller, MD, Washington Hospital Center & Georgetown University Hospital
  • James D. Neaton, Ph.D., University of Minnesota
  • Francis D. Pagani, MD, PhD, University of Michigan Health System
  • Eric A. Rose, MD, Columbia University Medical Center
  • Randall C. Starling, MD, MPH, Cleveland Clinic Foundation
  • Jeremy Sugarman, MD, MPH, MA, John Hopkins University

NHLBI Program Staff

  • Patrice Desvigne-Nickens, MD
  • Neal O. Jeffries, PhD
  • Marvin A. Konstam, MD
  • Alice M. Mascette, MD
  • Marissa A. Miller, DVM, MPH
  • George Sopko, MD
  • Karen L. Ulisney, MSN, CCNP
  • Helen K. Wegman, MPIA

FDA Staff

  • Eric Chen, MS
  • Sonna M. Patel, PhD
  • Kathryn O'Callaghan
  • Ileana Piña, MD, Case Western Reserve University
  • Wolf Sapirstein, MD, MPH
  • Bram D. Zuckerman, MD

Last updated: May 22, 2008

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