Calcineurin inhibitors in heart transplantation

The use of calcineurin inhibitors (CNIs; cyclosporine and tacrolimus) has dramatically increased medium-term life expectancy after heart transplantation but has had only limited impact on long-term outcomes for heart transplant recipients. The original oil-based formulation of cyclosporine has been superceded by a microemulsion formulation (Neoral), which has more predictable pharmacokinetics and allows more precise dose-tailoring. Cyclosporine microemulsion and tacrolimus (Prograf) have a similar efficacy in the prevention of acute rejection of heart transplants, but their use is accompanied by nephrotoxicity and by cardiovascular side effects. The efficacy of immunosuppression can be improved by adjunctive therapy, such as azathioprine, mycophenolate mofetil (MMF; Cellcept), corticosteroids, and induction therapy. One of the most important predictors of patient mortality at >5 years after heart transplantation is cardiac allograft vasculopathy (CAV)/late graft failure, which accounts for 31% of deaths. Neither cyclosporine nor tacrolimus have been shown to prevent the development of CAV. In terms of efficacy, MMF provides a modest advantage over azathioprine in preventing CAV, and the combination of cyclosporine plus MMF results in significantly lower mortality than cyclosporine plus azathioprine. Overall, CNIs have multiple cardiovascular side effects, such as hypertension, hyperlipidemia and new-onset diabetes after transplantation, although cyclosporine and tacrolimus have somewhat different cardiovascular side-effect profiles. The challenge in choosing the best immunosuppressive regimen is to balance efficacy and safety to optimize graft and patient survival over the course of many decades. Because cyclosporine and tacrolimus have similar efficacy against acute rejection the choice of CNI for heart transplant recipients should be based on the relative risk of cardiovascular and renal side effects.