As Effective, But Safer
Ciclosporin v. tacrolimus in immunosuppression in liver transplantation
Although considered the most effective immunosuppressive agents, calcineu-rin inhibitors, especially if combined with steroids, could be nephrotoxic and diabetogenic. The need to balance the benefits with the risks is especially important in dealing with transplant patients, to whom the development of diabetes could compromise their overall health and survival.
Said Dr. Federico Villamil, professor of medicine at the Favaloro University in Buenos Aires, Argentina and president of the International Liver Transplant Society (ILTS): "Diabetes increases the patient's risk of organ failure, the long-term risk of cardiovascular disease, and finally the risk of death. Minimizing the risk of diabetes in transplant patients is a key challenge facing physicians today."
And so recently, the risks and benefits in the use of two calcineurin inhibitors-ciclosporin microemulsion (Neoral) and tacrolimus-in liver transplant patients were investigated. This randomized, multicenter study is the first ever head-to-head comparison between ciclosporin and tacrolimus, where ciclosporin was monitored by C2 blood levels.
Previous studies based the comparison of ciclosporin and tacrolimus on trough monitoring (C0). Beginning with a study by Levy et al. (Transplantation 2002), however, the use of ciclosporin in liver transplant patients showed improved clinical outcomes if the monitoring is based on two-hour post-dose levels.
Randomized for the study were 499 patients from 17 countries. The patients were stratified according to HCV status, and were set to receive either ciclosporin with C2 monitoring or tacrolimus with C0 monitoring 24 hours after transplantation. Starting dose for ciclosporin was 10 to 15mg/kg/daily, while for tacrolimus it was 0.1 to 0.15 mg/kg/day. Aside from these, both groups received steroids with or without azathioprine. Their progress was monitored for six months.
For the first three months, the recommended C2 levels for ciclosporin were between 800 and 1,200 ng/ml, while the C0 levels for tacrolimus were between five and 15 ng/ml. Between months four and six, meanwhile, the target C2 levels for ciclosporin were 700 to 900 ng/ml while the target C0 levels for tacrolimus were five to 12 ng/ml.
The study set the primary end point as the incidence of biopsy-proven acute rejection at three months. The secondary efficacy end points, meanwhile, were the incidence of biopsy-proven acute rejection at six months, graft loss, graft loss and retransplant at three and six months, and patient death. As for issues of safety, the occurrence of adverse events, infections, and malignancies were identified as the end points.
The study population was also divided into subgroups during the data analysis: HCV-positive v. HCV-negative; those who received from living donors v. those from cadaveric donors; patients in dual therapy v. those in triple therapy.
The results of the study, presented last year at the ILTS meeting held in Barcelona, Spain, showed equal effectiveness for ciclosporin and tacrolimus in preventing acute allograft rejection (graft rejection rate for the ciclosporin group was 29 percent, while for the tacrolimus group it was 25 percent). The incidences of graft loss and death were also comparable between the two (11 percent in ciclosporin and 12 percent in tacrolimus).
Across the different population subgroups, no statistically significant differences were noted, except in the issue of graft loss or death in the HCV-positive subgroup. By the sixth month, six percent of HCV-positive patients in the cyclosporin arm suffered graft loss or death, while the tacrolimus group registered a graft loss/death rate of 15 percent (p<0.05).
The patients on the tacrolimus arm achieved the target C0 levels two days after the start of drug therapy, while those on ciclosporin reached the ideal C2 levels within five to seven days.
Patients with diabetes, hypertension, and renal impairment were proportionally similar in both groups.
However, the similarities ended there-the study proved that significantly more patients in the tacrolimus group suffered from new-onset diabetes and diarrhea within the six-month study period. Fourteen percent of the patients in the tacrolimus group had new-onset diabetes, as opposed to seven percent in the ciclosporin group (p<0.05). As for diarrhea, the rates were 28 percent for tacrolimus and 14 percent for ciclosporin (p<0.001).
Concluded Dr. Villamil, who presented the results at the ILTS meeting: "The important result to note is that Neoral and tacrolimus have comparable efficacy and that there is a difference in tolerability."
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