Tacrolimus + mycophenolate mofetil & steroids: Safe, effective in preventing acute cardiac rejection

04/23/04

Six month clinical study results assessing anti-rejection combination therapies for cardiac transplant recipients announced at ISHLT

Initial findings of an immunosuppressant combination study in de novo cardiac transplant recipients presented today at the 24th annual meeting of the International Society for Heart and Lung Transplantation show a regimen of tacrolimus (TAC) + mycophenolate mofetil (MMF) and steroids to be the safest and most effective in preventing acute cardiac rejection the most common cause of mortality in the first year after cardiac transplantation.

The randomized, prospective, multi-center, three-arm comparison study was designed to establish which combination of immunosuppressive agents is most advantageous to cardiac transplant patients in preventing acute rejection. The study evaluated tacrolimus + mycophenolate mofetil and steroids, vs. cyclosporine microemulsion (CYA) + MMF and steroids, vs. tacrolimus + sirolimus (SRL) and steroids.

"Though significant improvements in survival have been made over the past two decades as a result of advances in immunosuppression, no one combination of anti-rejection therapy has been proven as the safest and most effective," said Dr. Jon Kobashigawa, M.D., lead investigator of the study, and professor of medicine at the University of California, Los Angeles, Medical Center. "These initial data are quite strong and we believe the final results of this study will help to establish the best practice of combination immunosuppressants for heart transplant recipients."

The primary objective of the 28-site study enrolling 343 patients was to compare any incidence of rejection requiring treatment in the three triple-therapy regimens. Secondary objectives were to compare in each treatment regimen: patient and graft (transplanted organ) survival, incidence of normal lipid profile (indicating cardiovascular function), safety (infectious complications, malignancies, adverse drug effects) and cumulative total dose of steroids and doses at six and 12 months.

After six months, initial study results show a few trends emerging, while other measurable objectives are undifferentiated between the three therapy regimens.

  • There appeared to be no difference between the treatment groups in patient survival.
  • A significant difference was reported in the incidence of any treated rejection with lowest incidence in both of the tacrolimus-based groups.
  • Median serum creatinine(SCr) was significantly lower in the tacrolimus/mycophenolate mofetil participants compared to the two other treatment regimens, a key indicator that renal function was significantly better in the tacrolimus/mycophenolate mofetil group
  • Cholesterol levels were significantly better in the tacrolimus/mycophenolate mofetil group compared to the cyclosporine/mycophenolate mofetil group despite treatment with lipid lowering medications in all groups
  • No difference between treatment groups in development of diabetes according to criteria established by the American Diabetes Association

Additional findings from the 6-month results reported that most patients: discontinued cyclosporine for refractory rejection, discontinued tacrolimus and/or sirolimus for renal dysfunction, and discontinued mycophenolate mofetil for leucopenia. There were also significantly more cytomegalovirus (CMV) infections in the cyclosporine/mycophenolate mofetil study group and significantly more Candida infections in the tacrolimus and/or sirolimus group. There was however, no difference in hypertension or in incidence of malignancy between the three therapy regimens.

"The tacrolimus, MMF, steroid combination seems to be a strong combination therapy in preventing acute cardiac rejection," said Dr. Kobashigawa. "It has been encouraging to see efficacy and safety trends begin to emerge after only six months, and we are hopeful that in only six more months, we'll be able to determine the safest and most effective triple therapy regimen for cardiac transplant recipients."

The efficacy and safety endpoints will be assessed again upon conclusion of the 12-month study.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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