doi: 10.1161/CIRCULATIONAHA.107.737965
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(Circulation. 2007;116:2666-2668.)
© 2007 American Heart Association, Inc.
Editorial |
Sirolimus and Cardiac Transplantation
Is It the "Magic Bullet"?
From the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Gilbert H. Mudge, Jr, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail gmudge{at}partners.org
Key Words: Editorials • sirolimus • transplantation
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Introduction |
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The Holy Grail of transplantation has been the hope to achieve lifelong tolerance to a transplanted organ without the need for nonspecific immunosuppression and its attendant side effects; the "magic bullet" is the means to achieve graft tolerance while avoiding complications. The biological and clinical complexities that have now emerged with solid organ transplantation have raised questions as to the relevance of a magic bullet. However, the article in this issue of Circulation by Raichlin and colleagues1 suggests that we now need to revisit and perhaps redesign current long-term immunosuppressive strategies.
Article p 2726
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Have Long-Term Complications of Heart Transplantation Changed in the Past 20 Years? |
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 TopIntroduction Have Long-Term Complications of... What Are the Current...Has There Been a...Do Primary Immunosuppressants...Should We Develop a...What Are the Current...So, Is Sirolimus the...References |
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The Registry of the International Society for Heart and Lung Transplantation presents a unique opportunity to understand the evolution of heart transplantation. It characterizes the care and complexities of >100 000 worldwide heart transplantations during the past 24 years.2 Recent analysis suggests that the major improvements in survival have occurred within the first year of transplantation; this reflects the use of induction protocols with antithymocyte antibody or interleukin-2 antibody therapy and standardized initial immunosuppressant therapy. There has been a gradual improvement in the half-life of graft survival, but causes of long-term morbidity and mortality after cardiac transplantation have not changed in a decade.2 By 8 years after transplantation, virtually all patients have hypertension, 40% have diabetes, and 40% have angiographic cardiac allograft vasculopathy (CAV); renal insufficiency is common, with long-term dialysis required in 10% of patients. The 3 leading causes of mortality and morbidity remain the same. CAV and unexplained graft failure (that may represent undetected CAV) account for 30% of mortality; malignancy accounts for 22% of mortality; and renal failure is the third cause of long-term morbidity. Infectious complications, acute rejection, and cytomegalovirus infections are germane in the first year after transplantation but not relevant to long-term follow-up, and noncytomegalovirus infection accounts for only 10% of the late deaths.2
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What Are the Current Therapies to Address Long-Term Complications? |
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Current therapies to address the long-term morbidity and mortality are by and large reactive. A number of studies report a favorable impact on CAV with HMG Co-A reductase inhibitors, angiotensin-converting enzyme inhibitors, calcium antagonists, and antioxidants,3–7 but it is difficult to document that these strategies have changed the natural history of CAV. Calcineurin inhibitor (CNI) dose usually is adjusted to limit nephrotoxicity, but it is rarely discontinued. The presence of a malignancy prompts minimization of immunosuppression as appropriate oncology therapy is initiated. Because the causes of late morbidity and mortality have not changed, it is difficult to make a compelling case that any changes in secondary therapy have had a favorable prognostic impact.
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Has There Been a Change in Long-Term Immunosuppressant Therapy? |
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The same database provides interesting insights into the evolution of the immunosuppressive strategy.2 If nothing has changed in late causes of morbidity, nothing has really changed in immunosuppressant regimens. More than 80% of patients at 1 and 5 years after heart transplantation remain on 2 CNIs, cyclosporine or tacrolimus; a clear preference has not yet emerged. Major variations in immunosuppressant protocols reflect the variable use of azathioprine, mycophenolate mofetil, and prednisone. There may be a modest reduction in acute rejection episodes with the use of mycophenolate mofetil rather than azathioprine, but the current choice often is center specific. Enthusiasm for developing a prednisone-free regimen has waned, and maintenance prednisone remains secondary therapy for the vast majority of heart transplant patients. Hence, CNIs are still considered primary immunosuppressant therapy, the latter 3 considered secondary immunosuppressants. Moreover, no effort has been made to differentiate therapy as to early or late immunosuppressant requirements; the same regimens apply to the first and fifth years after transplantation.
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Do Primary Immunosuppressants Contribute to Long-Term Complications? |
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Although CNIs are clearly the gold standard of early immunosuppressant therapy and have facilitated excellent early results and availability of heart transplantation, CNI agents may well have contributed to the 3 major long-term morbidities and mortalities. Nephrotoxicity of the CNIs is well established.8,9 The renal histological changes seen with CNIs often are irreversible; hence, reducing the CNI dosage will not substantially improve renal function. In addition, concomitant diabetes and hypertension compound nephrotoxicity. Compelling laboratory data indicate that CNIs may promote malignancies in immunocompromised animals10,11; it is postulated that CNIs enhance the production of growth factors (transforming growth factor-β, interleukin-6, and vascular endothelial growth factor), which theoretically enhance tumor growth and metastasis by angiogenesis. CNI-treated tumor lines may acquire an invasive phenotype that is independent of the immune system; thus, the state of immunosuppression does not explain the malignancies induced by CNIs. As for CAV, there is little current evidence that choice or blood level of CNI will alter the degree of disease.
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Should We Develop a New Approach to Long-Term Immunosuppression? |
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Because long-term therapy and complications have not changed in the past 2 decades, perhaps we should be developing a more thoughtful approach to heart transplant management; an initial approach that addresses early immunosuppressant needs and infectious complications until baseline therapy and acceptable graft tolerance is achieved; and a different, evolving strategy to address the long-term consequences of CAV, renal insufficiency, and malignancy. Could this be a magic bullet?
The report by Raichlin and coworkers1 on using sirolimus for primary immunosuppression is unique and noteworthy in this regard. By substituting sirolimus for CNI 
3 years after transplantation, the burden of CAV as judged by intravascular ultrasound was substantially reduced. Treatment with azathioprine or mycophenolate mofetil did not independently affect the results; there was no difference in late rejection episodes. Moreover, renal function improved in the sirolimus group. Although the authors correctly point out the obvious limitations of the study in terms of sample size and lack of randomization, this single-center study represents the first evidence that complete and slow CNI withdrawal can be achieved safely and that replacement with sirolimus may have long-term beneficial effects. This finding is supported by other investigations. A derivative of sirolimus, everolimus, was substituted as a secondary immunosuppressive and slowed the progression of CAV and clinically significant events12; a similar protocol with sirolimus showed similar promising results.13 In these studies, however, CNIs were not discontinued, and hence long-term nephrotoxicity and predisposition to malignancy may not have been addressed.
The rationale for using sirolimus as a long-term primary immunosuppressant in this patient population for CAV and cellular rejection is well established. Its antiproliferative and antimigratory actions above and beyond modulation of B-cell and T-cell function make it a particularly unique immunosuppressant. Sirolimus also may alter the long-term consequences of renal dysfunction and malignancy by obviating the need for CNI therapy. The renal-sparing effect seems unequivocal. The long-term impact on posttransplantation malignancy also can be postulated. By inhibiting tumor growth by alternating tumor cell proliferation, inducing tumor cell apoptosis, and suppressing tumor angiogenesis, these agents have been shown to have a potential impact on abolishing the tumor-promoting effects of CNI.11 The renal transplantation literature has explored this issue. In a large multicenter study involving 450 patients, those who were withdrawn from CNIs and treated with sirolimus had a reduced incidence of cutaneous and noncutaneous neoplasm 5 years after randomization.14 Another retrospective analysis of >36 000 individuals 2 years after kidney transplantation showed a 50% reduction in the relative risk of cancer when patients were given sirolimus rather than CNIs.11
There is an understandable reluctance to extrapolate the results of renal to heart transplantation. Cardiac transplantation is not based on HLA matching, has biopsy criteria for rejection, has dire potential consequences of rejection, and is complicated by CAV. The immunosuppressant load of heart transplant patients is usually much greater. Nevertheless, once long-term tolerance is achieved, the secondary toxicities of CNIs may be quite similar between the 2 forms of solid organ transplantation.
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What Are the Current Limitations to This Magic Bullet? |
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There are substantial side effects that are consistent with drugs of similar potency. Diarrhea, the most intolerant of these,15 has been the cause for discontinuation in many patients. Other side effects include hypercholesterolemia, hypertriglyceridemias, thrombocytopenia, rash, hypertension, anemia, and hypokalemia. Photosensitivity may be an ongoing problem. Sirolimus delays wound healing16 and hence cannot be initiated early in the posttransplantation course. Other and more profound toxicities may be revealed with wider clinical application.
The most disturbing potential limitation to using sirolimus as a primary immunosuppressant is reflected in the 2007 data from the Heart Save the Nephron (STN) clinical trial that prompted premature termination of the study.17 This was an effort to assess the potential nephron-sparing impact of sirolimus in heart transplantation 12 weeks after transplantation. Patients were initially treated with CNIs but then at 12 weeks were randomized to either CNIs or sirolimus; mycophenolate mofetil and prednisone were the secondary immunosuppressants. The study was terminated prematurely because 4 of 7 patients randomized to sirolimus experienced a grade IIIA rejection episode. Three of 4 episodes occurred at 1 transplant center, and 1 patient experienced hemodynamic compromise. It is noted that low blood levels of sirolimus were recorded in 2 patients. Unfortunately, limited data are available from this initial randomization of a very small number of patients to provide additional insights into the susceptibility to and precipitating factors for rejection. Moreover, it must be emphasized that this study represents an assessment of sirolimus in the acute phases of heart transplantation, before long-term histological stability, baseline immunosuppressive therapy, and graft tolerance were achieved. It was an assessment of sirolimus during the acute phases of cardiac transplantation, that initial period of immunosuppression when CNIs have been of proven efficacy. The long-term consequences of such therapy deserve our attention.
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So, Is Sirolimus the Magic Bullet? |
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"Magic" carries the connotation of mystery, the unexpected, and the unexplained. As evidenced by the Raichlin et al1 article, a rational basis exists for its use in heart transplant patients. The potential impact of sirolimus on the long-term and unremitting complications mandates a large multicenter study. This must be undertaken once clinical and histological stability has been achieved. Although a magic bullet oversimplifies biological and clinical complexities, sirolimus remains uniquely poised as a primary immunosuppressant to address the 3 causes of morbidity and mortality seen in the long-term care of heart transplant patients.
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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