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
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)