In collaboration with FDA’s Center for Devices and Radiologic Health, the NHLBI convened a workshop on the Current State of Thrombosis in Ventricular Assist Devices (VADs) on May 14, 2015, in Baltimore, Maryland. The workshop included cardiac surgeons, cardiologists, biostatisticians, bioengineers, and representatives from FDA, CMS, and the NHLBI to review available data on pump thrombosis, a major and potentially fatal complication of durable continuous-flow VADs, which are mechanical pumps that are used to support heart function and blood flow in people who have weakened hearts. Workshop members discussed possible approaches to mitigate pump thrombosis and other device-related serious adverse outcomes.
The workshop had the following specific goals:
- Review the available data on instances of pump thrombosis in currently marketed VADs by examining available evidence from clinical trials and relevant data from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), which includes a repository of clinical, demographic, and device-related information on patients who have VADs.
- Discuss device-associated risks and how best to mitigate them in clinical practice and research settings.
- Identify research needs and trial opportunities.
- Provide guidance on the conduct of interventional trials in advanced heart failure patients receiving VADs.
Since their initial development, VADs have extended and improved survival for thousands of advanced heart failure patients. However, recent findings have highlighted the risks involved in using these devices. For example, in November 2013, writing in the NEJM, investigators at the Cleveland Clinic reported an increase in the apparent rate of pump thrombosis. The INTERMACS investigators also published similar findings based on registry data in the Journal of Heart and Lung Transplantation (JHLT).
Since these reports were released, clinicians, researchers, regulatory agencies, and industry have closely monitored the incidence of pump thrombosis and had extensive discussions as to the cause and appropriate response to the apparent increase in pump thrombosis. In the spring of 2015, the NHLBI and FDA asked INTERMACS investigators to conduct an updated analysis of the pump thrombosis data. In response to this request, the University of Alabama at Birmingham, Cleveland Clinic, and the NHLBI, three organizations involved in INTERMACS, collaborated to conduct three independent analyses of INTERMACS data.
At the workshop, these three organizations presented the results of their analyses. In addition, others presented information on the following topics:
- clinical insights concerning pump thrombosis and stroke in German clinical practice;
- the FDA perspective on adverse event profiles of VADs; and
- findings from three clinical trials involving VADs—Endurance, Roadmap, and REVIVE-IT.
After these presentations, workshop participants discussed the following potential areas to mitigate pump thrombosis and associated events:
- pump speed (rate of flow) and pulsatility (the manner with which the device pumps the blood);
- anticoagulation therapies and general patient management;
- criteria for patient selection for VADs and pump selection; and
- surgical techniques and pump placement.
Based on the presentation and discussion, workshop participants identified a set of research and policy priorities that may improve the safe use and study of current and future devices. These priorities include the following:
- Evaluation of potential differences between clinical sites, both those in the U.S. and Europe, in the incidence of pump thrombosis and related events.
- Further investigation, possibly through a nested cohort study, of practice-specific and care management approaches to mitigate adverse outcomes, including the following approaches: anticoagulation, INR monitoring (which enables a determination of the effectiveness of anticoagulation therapy), assessment of platelet factors, and control of blood pressure, among other approaches. Such a study might also consider trans-continental differences.
- Development of a white paper facilitated by the NHLBI, FDA, CMS, and the medical societies to define the critical data elements that researchers should collect in future trials and registries pertaining to VADs.
In addition, workshop participants made suggestions concerning planned trials:
- Potential benefit of VADs in patients who are less sick than the patients for whom the device is approved — the workshop participants suggested that such a trial should not be launched until new VADs with improved safety profiles become available, which could occur in the next 5–10 years.
- Interventional trials involving heart failure patients receiving VADs — the workshop participants suggested that such trials utilize risk mitigation approaches and that the investigators rigorously monitor patients.
The INTERMACS analyses are slated for publication in the JHLT. A proceedings from this workshop is in development for publication in a peer-reviewed journal.
Jim Young, M.D., Cleveland Clinic
Presenters and Moderators:
James Kirklin, M.D., University of Alabama at Birmingham
Eugene Blackstone, M.D., Cleveland Clinic
Neal Jeffries, Ph.D., NHLBI
Martin Strueber, M.D., Spectrum Health
John Saperstein, M.D., FDA
Francis Pagani, M.D., Ph.D., University of Michigan
Randall Starling, M.D., M.P.H., Cleveland Clinic
Keigh Aaronson, M.D., M.S., University of Michigan
Patrick O’Gara, M.D., Brigham and Women’s Hospital
Todd Massey, M.D., University of Rochester
Jerry Estep, M.D., Methodist Hospital
Terry Yau, M.D., Toronto General Hospital
Robert Kormos, University of Pittsburgh Medical Center
Joseph Rogers, M.D., Duke University
Edwardo Rame, M.D., University of Pennsylvania
Michael Acker, M.D., University of Pennsylvania
Marissa Miller, D.V.M., M.P.H
J. Timothy Baldwin, Ph.D.
Wendy Taddei-Peters, Ph.D.
Neal Jeffries, Ph.D.
Catherine Burke, M.A.
Fernando Aguel, M.S.E., FDA
Deborah Ascheim, M.D., Mt. Sinai Medical Center
Lori Ashby, M.A., CMS
Daniel Caños, Ph.D., M.P.H., FDA
Ryan Cantor, M.S., M.P.H., University of Alabama, Birmingham
Mary Lynne Clark, B.S., University of Alabama, Birmingham
Craig Collum, M.P.H., University of Alabama, Birmingham
Arielle Drummond, Ph.D., FDA
Annetine Gelijns, Ph.D., Mt. Sinai Medical Center
Lydia Glaw, Ph.D., FDA
Claire Hambright, B.S., FDA
Matthew Hillebrenner, M.S.E., FDA
Douglas Horstmanshof, M.D., INTEGRIS Health
James Long, M.D., Ph.D., INTEGRIS Health
Julie Marders, R.N., M.S., FDA
Janella Miller, R.N., B.S.N., University of Alabama, Birmingham
Nicole Milligan, FDA
Susan Myers, B.B.A., Q.M.I.S., University of Alabama, Birmingham
David Naftel, Ph.D., University of Alabama, Birmingham
Ileana Piña, M.D., M.P.H., FDA
Jean Rinaldi, Ph.D., FDA
Stuart Russell, M.D., Johns Hopkins University
Jyme Schafer, M.D., M.P.H., CMS
Craig Selzman, M.D., University of Utah
Mark Slaughter, M.D., University of Louisville
Nick Smedira, M.D., Cleveland Clinic Foundation
Josef Stehlik, M.D., M.P.H., University of Utah
Garrick Stewart, M.D., Harvard/Brigham & Women's Hospital
Joseph Su, Ph.D., M.P.H., FDA
Leon Sun, Ph.D., FDA
Marissa Miller, D.V.M., M.P.H.
Marissa.Miller@nih.gov Tel: 301 594 1542