Tacrolimus Monotherapy in Cardiac Transplantation

Heart failure is a nation-wide epidemic with 5 million Americans affected, and it is the leading cause of death in the world. Cardiac transplantation is the current gold-standard to treating end-stage heart failure. The one-year survival rate of cardiac transplantation is greater than 80% when patients are placed on an immunosuppressive regimen including medications such as corticosteroids, azathioprine, and cyclosporine A. Prior to the 1980s, success with cardiac transplantation was very limited. The introduction of cyclosporine A in 1980, when used in combination with azathioprine and corticosteroids, was the reason for the increase in one-year graft and patient survival. The use of a three-drug regimen was became a main-stay in cardiac transplant recipients in the prophylaxis of acute rejection. Shortly after 1980, tacrolimus was identified as a potential immunosuppressive agent that had comparable efficacy to cyclosporine A with significantly decreasing the incidence and severity of acute rejection following cardiac transplantion. In vivo and in vitro studies both suggest that cyclosporine A and tacrolimus operate through slightly different mechanisms. Tacrolimus is successful in providing ongoing prophylaxis of rejection due to the suppression of IL-10 and inhibition of IL-10-mediated cytotoxic cell infiltration into the transplant. There was no statistically significant difference in freedom from ISHLT Grade 3A rejection when using tacrolimus compared to cyclosporine. However tacrolimus demonstrated a better cardiovascular risk profile than cyclosporine A. A newer randomized controlled open-label trial investigated the use of tacrolimus monotherapy to the use of tacrolimus in combination with mofetil mycophenolate (MMF) as prophylaxis of acute rejection in cardiac transplantation. The goal of this trial was to determine if outcomes were similar between monotherapy and combination groups. The primary outcome was the 6-month mean International Society of Heart and Lung Transplant (ISHLT) biopsy score, and the secondary outcomes included all-cause mortality, incidence of ISHLT grade 2R/3R rejection over 6- and 12-month time points, one-year mean cumulated ISHLT biopsy score, and incidence of allograft vasculopathy. The researchers found the incidence of 6-month freedom from rejection in the monotherapy group was 85.9% and in the combination group was 94.4%, but the findings were not statistically significant (p = 0.14). There was no significant reduction in rejection, allograft vasculopathy, or 3-year survival. The purpose of this project is to further establish the efficacy and safety of the use of tacrolimus monotherapy for immunosuppression in cardiac transplant recipients at UNC medical center.Doctor of Pharmac