Elsevier

The Lancet

Volume 359, Issue 9308, 2 March 2002, Pages 741-746
The Lancet

Articles
Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study*

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Summary

Background

In previous comparative studies tacrolimus was superior to the standard formulation of ciclosporin in preventing acute rejection after renal transplantation. We have compared the microemulsion formulation of ciclosporin with tacrolimus in a multicentre randomised trial.

Methods

The 6-month open study involved 560 patients in 50 European centres. 287 patients were randomly assigned tacrolimus and 273 ciclosporin microemulsion plus azathioprine and corticosteroids. The initial oral daily doses were 0·30 mg/kg for tacrolimus and 8–10 mg/kg for ciclosporin. The primary endpoint was the proportion of patients with biopsy-proven acute rejection and the time to this event.

Findings

The two study groups were similar in terms of baseline characteristics. Three patients did not receive study treatment or did not undergo transplantation (one tacrolimus, two ciclosporin). The rate of biopsy-confirmed acute rejection was significantly lower with tacrolimus than with ciclosporin microemulsion (56 patients [19·6%] vs 101 [37·3%]; 17·7% difference [95% CI 10·3-25·1]; p<0·0001). Biopsy-confirmed corticosteroid-resistant rejection was also significantly lower with tacrolimus (27 [9·4%] vs 57 [21·0%]; 11·6% difference [5·7-17·5]; p<0·0001). Cross-over between therapies because of biopsy-proven rejection was judged necessary in one of 286 (0·3%) tacrolimus-group patients and 27 of 271 (10·0%) ciclosporin-group patients (p<0·0001). There were no significant differences in survival of patients or grafts or in renal function. The overall frequency of adverse events was similar in the two groups, though hypertension and hypercholesterolaemia were more common in the ciclosporin group and tremor and hypomagnesaemia were more frequent in the tacrolimus group.

Interpretation

Tacrolimus was significantly more effective than ciclosporin microemulsion in preventing acute rejection after renal transplantation and had a superior cardiovascular-risk profile.

Introduction

Tacrolimus and ciclosporin are important immuno-suppressive agents for the prevention of acute rejection in renal-allograft recipients. Two 12-month, large-scale, randomised, multicentre trials undertaken in the mid-1990s compared the clinical efficacy and safety of tacrolimus and the standard formulation of ciclosporin when used together with azathioprine and corticosteroids.1, 2 These studies showed that the rate of acute allograft rejection was significantly lower with tacrolimus-based therapy than with ciclosporin.1, 2 In a European study,2 there was a difference of 19·8% in the frequency of biopsy-confirmed acute rejection between the two treatment groups (p<0·001). A recent meta-analysis of all randomised trials comparing tacrolimus and ciclosporin (standard formulation) in kidney transplantation confirmed a lower risk of rejection with tacrolimus therapy, but this drug was also associated with a higher rate of diabetes mellitus.3

Since those studies were undertaken, a microemulsified formulation of ciclosporin has become available and is now more widely prescribed than the standard formulation. The new formulation has better bioavailability and less variability between patients in ciclosporin absorption.4, 5 We have investigated whether the previously observed difference in efficacy between tacrolimus and ciclosporin is also found with ciclosporin microemulsion, in a multicentre randomised trial in renal-allograft recipients.

Section snippets

Patients

Patients with end-stage renal disease were eligible for the study if they were suitable candidates for renal transplantation and were aged between 18 and 60 years. Premenopausal women had to be using adequate contraception. All patients had to have received a renal graft from a donor of compatible ABO blood type, aged 5–60 years. Reasons for exclusion were: previous organ transplantation (other than renal) or immune-mediated renal graft failure within the previous year; high risk of allograft

Results

A total of 560 patients were randomly assigned to receive tacrolimus (n=287) or ciclosporin (273) therapy (figure 1). Three patients were excluded from the intention-to-treat analysis because they did not receive study drug or did not undergo transplantation. Thus, there were 557 patients in the intention-to-treat population. Six patients died (two in the tacrolimus group and four in the ciclosporin group). 42 (14·7%) patients were withdrawn from the tacrolimus group compared with 80 (29·5%)

Discussion

We showed that the 6-month rate of acute rejection in renal-allograft recipients was significantly lower in those treated with a combination of tacrolimus, azathioprine, and corticosteroids than in those who received a ciclosporin-microemulsion-based regimen. The finding of lower rates of acute rejection, corticosteroid-resistant acute rejection, and recurrent acute rejection with tacrolimus therapy may have important clinical implications. Previous studies have shown that acute rejection is a

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