HDCN Article Review/Hyperlink

Ponticelli C, Tarantino A, Segoloni GP, et al for the Italian Multicenter Study Group for Renal Tx

A randomized study comparing three cyclosporine-based regimens in cadaveric renal transplantation

J Am Soc Nephrol (Apr) 8:638-646 1997

Although cyclosporine is in widespread use for immunosuppression in renal transplantation, a randomized controlled trial comparing monotherapy (cyclosporine alone), double therapy (cyclosporine plus steroids), and triple therapy (cyclosporine, steroids, and azathioprine) has not been previously conducted. This study sought to compare mono, double, and triple cyclosporine therapy in cadaveric renal transplant recipients using a randomized multicenter approach.

Patients were excluded if they were less than 16 years or older than 70 years, if they had acute rejection, or required dialysis in the first five days post-transplant. Patients were treated for the first 5 days post-transplant with cyclosporine and methylprednisolone then randomized to monotherapy, double therapy or triple therapy per protocol. The study was not blinded. Patients who were assigned to monotherapy who had two or more rejections were switched to double or triple therapy. Acute rejection was diagnosed clinically. An intention to treat analysis was used. Survival data was analyzed using the Kaplan-Meier product limit estimate. Endpoints included graft failure and death.

193 persons were excluded from the study. 354 patients were randomized. 53% of the patients assigned to monotherapy and 20% of the patients assigned to double or triple therapy were crossed over to another regime. Four year actuarial graft survival was similar on monotherapy, double therapy and triple therapy (84%, 77%, 88% respectively) as was patient survival (97%, 91%, and 96% respectively). A subgroup analysis revealed that patients with PKD and low creatinine at the time of randomization were at lower risk of crossing over while those with SLE and high creatinine were are higher risk. Patients who remained on monotherapy were found to have a lower graft survival than those who crossed over. Patients assigned to monotherapy had lower CrCl at three years than those on double or triple therapy.

Comment: There was an enormous amount of crossover between regimes making the results difficult to interpret. Although an intention to treat analysis is appropriate, the high rate of crossover will make the therapies will look more alike, making it more difficult to identify differences in outcomes. The results tell the clinician what the difference in graft survival is between the assigned regimes knowing that they may not (and in the case of monotherapy, probably not) continue on the assigned regime for the duration of follow-up.

Secondly, the patients with the poorest prognosis (those with early rejection and early dialysis) were excluded from the study. This approach likely introduced selection and allows generalization only to patients who have not had early rejection or post-transplant dialysis requirements. Finally, rejections were diagnosed clinically and criteria varied by study center introducing potential misclassificatione of the major endpoints. (Catherine Stehman MD MS, University of Washington, Seattle)