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Jignesh K Patel
Assistant Clinical Professor
Jon A Kobashigawa
Clinical Professor of Medicine
Division of Cardiology
David Geffen School of Medicine at UCLA
Los Angeles, CA
Cardiac transplantation has become an established and acceptable therapeutic option for selected patients with endstage heart disease. Therapeutic success in cardiac transplantation can largely be attributed to the introduction of effective immunosuppressive agents. Ciclosporin A (CsA), a calcineurin inhibitor with a mechanism of immunosuppression specific to T-cells, was shown to improve patient survival over conventional therapy.(1) By 1998, actuarial survival rates had improved to 85% at one year and 75% at five years.(2)
The use of CsA, however, is associated with a number of adverse effects, including hypertension, nephrotoxicity, hepatotoxicity, gingival hyperplasia, hypertrichosis, involuntary tremor and increased risk of malignancy. As the drug has no significant effect on antibody production, response to bacterial and fungal infection is relatively preserved. Ciclosporin has little effect on reducing the incidence and severity of herpes infections and also likely predisposes to Pneumocystis carinii infection, necessitating the use of prophylaxis, especially within the first year following cardiac transplantation. However, compared with immunosuppressive therapy with azathioprine and prednisone, the use of CsA has generally decreased the incidence of infection (especially cytomegalovirus).(3)
A microemulsion formulation of CsA (mCsA) demonstrated greater bioavailability and more predictable pharmacokinetics than oil-based CsA.(4) Randomised studies demonstrated equivalent graft and patient survival compared with CsA at 24 months,(5) but lower rates of rejection requiring treatment.(6–8) Microemulsion CsA was also better tolerated, with fewer discontinuations of the study drug, and the average corticosteroid dose was lower in the mCsA group.
Another agent with a similar mode of action, tacrolimus, has been used as an alternative to CsA. Randomised trials(9,10) comparing tacrolimus to the oil-based CsA formulation (both combined with azathioprine and steroids) in heart transplant patients displayed similar patient survival rates and incidences of rejection, nephrotoxicity, diabetes and infections. Tacrolimus treatment, however, was associated with a lower incidence of arterial hypertension, gingival hyperplasia (and, in one study, dyslipidaemia). Tacrolimus has also been effective for rescue from steroid-resistant rejection.(11–13) Currently, tacrolimus is used as primary therapy, conversion for acute rejection or conversion for CsA toxicity.(14)
A recent five-year analysis comparing the use of tacrolimus with mCsA under a standardised immunosuppression protocol confirmed comparable long-term outcome in terms of survival, allograft rejection and cardiac allograft vasculopathy (CAV) as determined by intravascular ultrasound (IVUS).(15) In this study, tacrolimus was also associated with a significant decrease in renal impairment at five years.
Mycophenolate mofetil (MMF) is hydrolysed to mycophenolic acid (MPA) after oral administration, which inhibits de-novo purine synthesis. This results in inhibition of proliferation of both T- and B-cells. A multicentre, double-blind, randomised trial demonstrated a significant reduction in one-year mortality in the MMF-treated patients following cardiac transplantation compared with azathioprine on the background of CsA- and corticosteroid-based immunosuppression.(16) The study also demonstrated a significant reduction in the requirement of rejection treatment with MMF. This study has led to a widespread acceptance of the use of MMF over azathioprine, but gastrointestinal intolerance and leukopenia limit the use of this drug. A further analysis of patients who underwent IVUS in the study suggests a lower incidence of CAV with MMF, although clinical benefit in this regard has yet to be demonstrated.(17)
Proliferation signal inhibitors, or target of rapamycin (TOR) inhibitors (sirolimus and everolimus), block activation of T-cells following autocrine stimulation by interleukin-2. Their action is therefore complementary to that of the calcineurin inhibitors. Sirolimus has been shown to prevent acute graft rejection effectively and inhibit refractory acute graft rejection in heart transplant recipients.(18) In the Australian randomised study of an open-label trial comparing sirolimus and azathioprine, sirolimus was shown to reduce allograft rejection.(19) No differences in one-year mortality were noted, but sirolimus significantly worsened renal function, and its use was associated with a higher incidence of hypertension. Other adverse outcomes included hyperlipidaemia, skin malignancies, leukopenia, thrombocytopenia and anaemia. Importantly, sirolimus, which is also known to have antiproliferative effects on smooth muscle cells, was shown to decrease the development of CAV as assessed by IVUS at six months,(19) and the benefit was maintained at two years.(20) In another angiographic study of cardiac transplant patients with established CAV, sirolimus was also shown to slow down disease progression.(21)
Recently, a randomised, double-blind clinical trial comparing everolimus with azathioprine in recipients of a first heart transplant was performed.(22) Patients were randomly assigned to receive one of two doses of everolimus, or AZA, in combination with CsA, corticosteroids and statins. At six months, the percentage of patients who had reached the primary efficacy endpoint (a composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proven severe acute rejection or rejection with haemodynamic compromise) was significantly smaller in the groups receiving everolimus compared with the group receiving AZA. Intimal thickening by IVUS 12 months after transplantation was significantly less in the two everolimus groups compared with the AZA group. The rates of cytomegalovirus infection were significantly lower in the everolimus groups than in the AZA group. However, rates of bacterial infection were significantly higher in the high-dose everolimus group than in the AZA group. Serum creatinine levels were also significantly higher in the two everolimus groups than in the azathioprine group.
Given the multitude of immunosuppression regimens available, a multicentre study was recently carried out to compare the relative efficacy of tacrolimus, MMF and steroids versus tacrolimus, sirolimus and steroids versus CsA, MMF and steroids in de-novo cardiac transplant recipients.(23) The combination of tacrolimus and MMF yielded the best immunological outcome with the least adverse effects. A number of studies have now confirmed the benefit of HMGCoA-reductase inhibitors (statins) in cardiac transplantation.(24,25) These studies have shown not only a decrease in the development of CAV and improved survival, but also a surprising reduction in the number of allograft rejection episodes. Statins effectively repress the induction of major histocompatibility complex class II (MHC-II) expression by interferon-g, thereby inhibiting T-cell proliferation.(26) Given these beneficial effects, statin therapy has now become an integral part of the immunosuppressive regimen in cardiac transplantation.
A variety of immunosuppressive agents are now available. Their use has led to a significant decrease in allograft rejection, and newer agents also show some promise in reducing CAV, which limits long-term graft survival. However, all agents have a significant adverse reaction profile and potential for drug interactions. Thus, their use requires careful monitoring.
Cambridge and Oxford Heart Transplantation Organisation
International Society of Heart and Lung Transplantation