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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Heart Transplantation Clinical and Scientific Updates: Improving Long-term Outcomes


GOAL
To provide transplant surgeons, cardiologists, and nurses with up-to-date information on the treatment and management of heart transplantation.

TARGET AUDIENCE
This activity is designed for transplant surgeons, cardiologists, and nurses. No prerequisites required.

LEARNING OBJECTIVES
At the conclusion of this activity, the participant should be able to:

  • Assess new protocols using current immunosuppressive drugs to improve long-term graft survival in heart transplantation.
  • Discuss uses of new immunosuppressive agents and regimens to reduce toxicity in the prevention and treatment of acute allograft rejection.
  • Describe methods and the scientific rationale to minimize immunosuppressive complications leading to increased morbidity and mortality.  
  • Integrate newer prophylactic strategies to improve outcomes of at-risk patients with heart transplantations.

The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing take responsibility for the content, quality, and scientific integrity of this CE activity.

ACCREDITATION STATEMENT
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing. 

The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

This 1.4 contact hour Educational Activity (Provider Directed) is provided by The Institute for Johns Hopkins Nursing. Claim only those contact hours actually spent in the activity.

The estimated time to complete this educational activity: 2 hours.

After reading this monograph, participants may receive credit by completing the CE test, evaluation, and receiving a score of 70% or higher.

Release date: May 15, 2008. Expiration date: May 15, 2010.

This program is supported by an educational grant from Novartis Pharmaceuticals Corporation.

Full Disclosure Policy Affecting CE Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a provider has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Course Directors and Participating Faculty reported the following:

COURSE DIRECTORS

John Conte, MD
Associate Director, Division of Cardiac Surgery
Director of Heart and Lung Transplantation
Associate Professor of Surgery
The Johns Hopkins Hospital
Baltimore, Maryland
Dr Conte reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Stuart D. Russell, MD
Associate Professor of Medicine
Chief, Heart Failure and Transplantation
The Johns Hopkins Hospital
Baltimore, Maryland
Dr Russell reports having no significant financial or advisory relationships with corporate organizations related to this activity.

PARTICIPATING FACULTY

Debra J. Carter, MS, CRNP, CCTC
Lead Transplant Nurse Practitioner
Heart Transplant Program
The Johns Hopkins Hospital
Baltimore, Maryland
Ms Carter reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Howard J. Eisen, MD
Thomas J. Vischer Professor of Medicine
Drexel University College of Medicine
Chief, Division of Cardiology
Hahnemann University Hospital
Philadelphia, Pennsylvania
Dr Eisen reports receiving grants/research support from Medtronic, Novartis Pharmaceuticals Corporation, St. Jude, Thoratec, and Wyeth; serving as a consultant for Medtronic, Novartis  Pharmaceuticals Corporation, Roche Pharmaceuticals, Thoratec, Wyeth, and XDx, Inc; receiving honoraria from Medtronic, Novartis Pharmaceuticals Corporation, and XDx, Inc; and serving on the speakers' bureau for Medtronic, Novartis Pharmaceuticals Corporation, Thoratec, and XDx, Inc. His spouse is an employee of Merck & Co, Inc.

Jon A. Kobashigawa, MD
Clinical Professor of Medicine and Chief
Division of Clinical Faculty Medicine
The David Geffen School of Medicine
University of California at Los Angeles
Medical Director
Heart Transplant Program
Los Angeles, California
Dr Kobashigawa reports receiving grants/ research support from, serving as a consultant for, and receiving honoraria from Astellas Pharma, Novartis Pharmaceuticals Corporation, Roche Pharmaceuticals, and XDx, Inc.

Joseph G. Rogers, MD
Associate Professor of Medicine
Medical Director
Cardiac Transplant and Mechanical Circulatory Support Programs
Duke University Medical Center
Duke University Medical School
Durham, North Carolina
Dr Rogers reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Notice: No faculty member has indicated that his or her presentation will include information on off-label products.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Heart Transplantation Clinical and Scientific Updates: Improving Long-term Outcomes
John Conte, MD,* and Stuart D. Russell, MD

Despite continuing declines in overall mortality due to coronary artery disease–a result of improved use of medications, technology, and guidelines in addition to risk factor reduction1–heart disease remains the number 1 killer in the United States.2 In fact, several cardiovascular risk factors are still on the rise, and 1 of every 3 American adults already has some type or degree of cardiovascular disease.2 As the population ages, the demand for solutions to advanced heart disease will grow and the direct economic cost of cardiovascular disease (already estimated at $296 billion per year for 2008 vs $89 billion for cancers2) will increase in kind.

For a select group of patients with end-stage heart disease, cardiac transplantation remains an established therapeutic option. Although transplantation has been perpetually limited by availability of donor hearts, the number of procedures performed in the United States remains over 2000 per year, and the worldwide total is estimated at over 5000 per year.3,4 Outcomes have improved steadily over the last decade (Figure),3 with the 1- and 5-year adjusted patient survival rates now at 88% and 76% respectively.3

figure 1

Since the introduction of cyclosporine in the early 1980s, the main factor driving improved survival rates has been development of combination immunosuppressive regimens.5 In particular, the widespread use of combination regimens containing a calcineurin inhibitor (CNI), a corticosteroid, and an adjunct immunosuppressant (eg, azathioprine or mycophenolate mofetil [MMF]) has very effectively reduced the risk of early graft loss due to acute rejection.6 Improved induction regimens and better detection and prompt treatment of rejection have also boosted survival. One clear legacy of the CNI-based triple therapy era is the growing number of long-term survivors (17 327 in 2004 vs 12 827 in 1996).3 However, another consequence of success is the growing concern over long-term complications of immunosuppression itself. These complications include nephrotoxicity, bacterial infections, cardiac allograft vasculopathy (CAV), malignancy, hypertension, and hyperlipidemia. Late graft loss due to CAV has become especially problematic for transplant teams and now stands as the leading cause of death in the second and third years after transplantation.4,7

In an attempt to avoid or diminish therapy-related risks and toxicities, creative approaches have been developed to reduce immunosuppression as early as possible posttransplantation. Minimizing CNI exposure is one possible strategy for circumventing nephrotoxicity,8 for example, and steroid minimization is another often-stated goal for limiting hypertension and bone density problems in the transplanted patient.9 Alternative immunosuppressive agents, such as proliferation signal inhibitors (eg, sirolimus and everolimus) and MMF, now offer additional or complementary strategies for improving long-term outcomes.

Balancing the pros and cons of the various alternative combinations and then individualizing an immunosuppression regimen for a particular patient can be challenging. Evidence from clinical trials provides some guidance. For example, studies show that sirolimus and everolimus can indeed prevent rejection and allow reduced doses of nephrotoxic CNIs while also reducing the severity and incidence of CAV.8,10,11 However, these agents may also lead to myelosuppression, bacterial infections, dyslipidemia, and wound complications.10,12,13 Similarly, although MMF has proved vastly superior to azathioprine as an antiproliferative agent for reducing rejection rates and also for minimizing CAV,14 this agent has been associated with opportunistic viral infections and gastrointestinal intolerance.5,14

How to weigh the emerging evidence about each new immunosuppressive agent and how to begin constructing rational protocols for everyday use in transplant centers was the subject of the roundtable summarized in this issue of Johns Hopkins Advanced Studies in Medicine. After completing this monograph, transplant surgeons, cardiologists, and nurses should have a better understanding of current immunosuppressive drug options, including how to reduce toxicity, minimize key complications, such as CAV and nephrotoxicity, and integrate new prophylactic strategies into everyday practice to improve long-term graft survival and patient outcomes.
Howard J. Eisen, MD, begins by reviewing the basics of graft rejection in heart transplantation. His overview includes a recap of the main pathways of the alloimmune response and the specific mechanisms of immunosuppressive agents. An update on new molecular methods for early diagnosis of rejection is also provided.

Stuart D. Russell, MD, then provides an overview of specific immunosuppressive therapies and their rationales. This article covers induction and longer-term immunosuppressive therapies, highlighting major randomized clinical trials with each agent in the setting of heart transplantation.
Jon A. Kobashigawa, MD, then discusses ways to improve long-term graft survival in terms of CAV. After describing the immune and nonimmune contributors to CAV pathogenesis, the article reviews methods for detecting CAV and studies that have evaluated medical therapies for reducing CAV development. Surgical approaches to limit the impact of existing CAV are also covered.
Finally, Joseph G. Rogers, MD, discusses other aspects related to long-term graft survival, including major complications of immunosuppression, such as nephrotoxicity, infections, and malignancies. As in all the articles, Dr Rogers' review is guided by evidence from major clinical trials and the ensuing roundtable discussion explores the practical consequences left by gaps or contradictions in that existing evidence base.

These articles, the discussions, and the case study provided by John Conte, MD, are all intended to highlight current treatment protocols and clinical strategies for improving long-term clinical outcomes in patients who receive a heart transplant. In presenting the pros and cons of the many immunosuppressive regimens, the focus for clinicians in heart centers must remain on how to individualize care for patients and how to prevent rather than treat complications. Until new ventricular assistive devices, stem cell-based strategies, or other novel treatments mature, transplantation will remain a life-extending and life-enhancing necessity for thousands of patients every year. Careful attention to evolving immunosuppressive regimens will ensure that the miracle of transplantation not only exists but also endures in more patients.

REFERENCES

1. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356:2388-2398.
2. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25-146.
3. Department of Health and Human Services. US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients 2006 Annual Report; VI. Heart and Lung Transplantations. 2006. Available at: http://www.optn.org/ar2006/default.htm. Accessed February 16, 2008.
4. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult heart transplant report–2007. J Heart Lung Transplant. 2007;26:769-781.
5. Kobashigawa JA, Patel JK. Immunosuppression for heart transplantation: where are we now? Nat Clin Pract Cardiovasc Med. 2006;3:203-212.
6. Eisen H, Ross H. Optimizing the immunosuppressive regimen in heart transplantation. J Heart Lung Transplant. 2004;23:S207-S213.
7. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation. 2003;108:48-53.
8. Fiocchi R, Iacovoni A, Sebastiani R, et al. Possible role of everolimus in improving renal function in long-term heart transplantation. Transplant Proc. 2007;39:1967-1969.
9. Oaks TE, Wannenberg T, Close SA, et al. Steroid-free maintenance immunosuppression after heart transplantation. Ann Thorac Surg. 2001;72:102-106.
10. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349:847-858.
11. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation. 2004;110:2694-2700.
12. Tenderich G, Fuchs U, Zittermann A, et al. Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart transplant recipients. Clin Transplant. 2007;21:536-543.
13. Kuppahally S, Al-Khaldi A, Weisshaar D, et al. Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients. Am J Transplant. 2006;6:986-992.
14. Kobashigawa J, Miller L, Renlund D, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators. Transplantation. 1998;66:507-515.

*Associate Director, Division of Cardiac Surgery, Director of Heart and Lung Transplantation, Associate Professor of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland.
 Associate Professor of Medicine, Chief, Heart Failure and Transplantation, The Johns Hopkins Hospital, Baltimore, Maryland.
Address correspondence to: John Conte, MD, Associate Director, Division of Cardiac Surgery, Director of Heart and Lung Transplantation, Associate Professor of Surgery, The Johns Hopkins Hospital, 600 North Wolfe Street, Blalock 618, Baltimore, MD 21287. E-mail: jconte@jhmi.edu.

The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his/her article and all its contents.





Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.