Special Considerations in the Cardiac Transplant Patient: CyA is the core immunosuppressant of choice for the majority of transplant patients. The introduction of Neoral, a new microemulsion formulation of CyA, and more recently a range of adjunctive immunosuppressants have further enhanced the efficacy and tolerability of CyA-based immunosuppression. In the first year following transplantation the major causes of morbidity and death are graft failure, acute rejection, and systemic infection. Patients with deteriorated pulmonary circulation before transplantation are at increased risk of early postoperative death. Risk factors for early acute rejection include female donor sex, young donor age, and multiple HLA-DR mismatches. The principal cause of death in the long term is graft vasculopathy which accounted for 40% of all deaths. Risk factors that have been hypothesized to play a role in the pathogenesis of graft vasculopathy 4 include hyperlipidemia, recipient age and gender, donor age, the number of HLA AB and DR mismatches, and CMV infection. Strategies proposed to reduce the risk of graft vasculopathy include aggressive use of lipid-lowering agents, avoidance of low CyA doses, and the use of adjunctive rapamycin or RAD therapy. Rejection surveillance therefore relies on routine serial endomyocardial biopsy. Recent research suggests that a more accurate assessment of the state of the graft can be obtained by considering the results across a number of biopsy samples obtained from different parts of the heart, rather than basing clinical judgment on the worst single result obtained. New molecular markers such as granzyme A mRNA are likely to improve the power of histology to diagnose and predict rejection. Neoral Immunosuppression in De Novo Patients: Neoral pharmacokinetics give greater bioavailability and less intrapatient variability than Sandimmune. In the keynote OLN 351 study comparing Neoral with Sandimmune in de novo heart transplant recipients, fewer Neoral patients needed antilymphocyte therapy to treat rejection, fewer female patients had rejection episodes in the Neoral group, the tolerability of the two formulations was equivalent, and there was a lower incidence of infections in the Neoral group. The clinical impact of Neoral in comparison with Sandimmune in de novo heart transplant patients has been investigated in a number of additional trials, including long-term studies, which have confirmed that Neoral is associated with: Lower CyA doses than Sandimmune. Equal or greater antirejection efficacy than Sandimmune. Comparable tolerability to Sandimmune. During the administration of intravenous CyA as an induction therapy in the days immediately following transplantation, there is evidence to suggest that a 6-hour infusion given twice daily, which mimics the pharmacokinetic profile of oral dosing, may be clinically more effective than a continuous 24-hour infusion. Neoral Immunosuppression in the Maintenance Patient: Milligram-for-milligram dose conversion from Sandimmune to Neoral is feasible. Following conversion, a reduction in the CyA dose may be required in the majority of patients to maintain target levels. In pediatric patients, the rate of elimination of CyA is greater and bioavailability increases with increasing age. Younger patients (less than 8 years of age) may be managed more effectively with a 3-times-daily, rather than a twice-daily dosing schedule. A number of studies have compared the clinical effects of Sandimmune and Neoral in maintenance therapy for cardiac transplant patients. As with de novo patients, these studies have found the new formulation of CyA to be associated with lower rates of acute rejection, lower therapeutic doses, and comparable tolerability. Milligram-to-milligram conversion from the old to the new CyA formulation is generally well tolerated, although in a minority of patients there is a significant increase in CyA levels. These may be associated with a transient increase in side effects which resolve on dose reduction. There is a dose-sparing effect with Neoral. Routine monitoring of both CyA and serum creatinine levels are advisable to optimize the tolerability and safety of therapy. Recent research indicates that drug monitoring 2 hours after CyA dosing provides a more accurate indication of AUC than trough level measurements. Patients with persistently low CyA levels are likely to be at increased risk of graft loss due to both acute rejection and chronic graft vasculopathy. New evidence suggests the use of C-2 CyA level monitoring to determine whether adequate drug is being absorbed. This TDM approach is not only recommended as a diagnostic tool but as a method for optimising Neoral immunosuppression. Long-term Side Effects of CyA Therapy: The major long-term safety problems directly associated with CyA-based immunosuppression include nephrotoxicity, hypertension, diabetes mellitus, and PTLD. CyA nephrotoxicity No clear risk factors for CyA nephrotoxicity have been identified and no correlation has been observed between CyA levels and serum creatinine levels. Overactivation of the renin-angiotensin system may play a role in the development of CyA nephrotoxicity, in which case early introduction of an ACE inhibitor would be expected to be of benefit. This possibility has yet to be investigated in a clinical trial. Reducing the CyA dose to treat renal dysfunction should be carried out with care, because this increases the risk of acute rejection. The introduction of additional, non- nephrotoxic adjunctive therapies such as MMF should be considered when substantially reducing the CyA dose. Hypertension: Management of hypertension requires careful attention to dietary sodium intake. Reducing the dose of CyA - as well as steroids, which also contribute to the problem - is important although care must be taken to avoid increasing the risk of rejection. The use of nonsteroidal anti-inflammatory agents should be avoided in hypertensive patients receiving CyA, because this may lead to further impairment of renal function. Because hypertension is often at its greatest in the early morning in cardiac transplant patients and the normal diurnal variation in blood pressure is absent, optimal management is often achieved by giving larger doses of antihypertensive agents at bedtime. PTLD: The optimal treatment for PTLD has not yet been determined, but strategies involving a reduction of immunosuppression in combination with aggressive chemotherapy have reported significant success. Prophylactic use of antiviral therapy is also recommended. Diabetes and Steroid Withdrawal: Steroid-sparing protocols are an important strategy for reducing posttransplant diabetes and should especially be considered in patients judged on the basis of preoperative metabolic parameters to be at a high risk of developing diabetes. Although steroid-sparing protocols are undoubtedly beneficial to many patients receiving immunosuppression with CyA or other agents, there is continuing debate over the clinical benefits of complete steroid withdrawal. Adjunct Immunosuppression Agents: Although CyA remains the cornerstone of maintenance immunosuppression therapy, the use of new adjunctive agents can reduce the risk of rejection; enable lower, better-tolerated doses of CyA and steroids to be administered; and enable therapy to be better tailored to clinical needs. Simulect (basiliximab) and daclizumab induction therapy within a CyA-based protocol has been shown to be highly effective in reducing the incidence of early acute rejection episodes in two major trials in renal transplantation, and similar results are anticipated in heart transplantation. Substitution of MMF for azathioprine reduces the frequency and severity of acute rejection episodes, may delay the development of chronic graft vasculopathy, and may improve patient survival in CyA-treated heart transplant patients. Sirolimus (rapamycin) and RAD have complementary mode of action to CyA. Early indications are that they offer significant clinical benefits in heart transplantation, including reduced rejection rates, lower CyA toxicity through reduced doses, and possibly a reduced incidence of chronic graft vasculopathy. Tacrolimus has a similar mode of action to CyA and the two agents should not be used in combination. In terms of clinical outcomes, no clear advantage has been demonstrated for either agent in comparison with the other. However, in some circumstances it may be appropriate to switch patients from CyA to tacrolimus-based therapy or vice versa, either to treat refractory rejection in CyA patients, or to treat severe tacrolimus toxicity. A range of options is available for the treatment of acute rejection; these options vary according to rejection severity and persistence. Many of these use adjunctive immunosuppressants including MMF, rapamycin, or RAD.
