EUROPEAN MULTICENTER STUDY COMPARING A DUAL VS. TRIPLE LOW-DOSE TACROLIMUS REGIMEN IN RENAL TRANSPLANTATION

Abstract

603 Background: The similar efficacy and safety of dual versus triple tacrolimus-based therapy in renal transplantation was reported earlier from a single-center study at the University of Pittsburgh. Here we report the first European, multicenter, randomized, parallel-group study to compare dual therapy (tacrolimus and corticosteroids) with triple therapy (tacrolimus, corticosteroids and azathio-prine). Methods: In this 3-month study, 7 centers in the United Kingdom and 1 center in Hungary recruited 249 adult patients (125 dual therapy, 124 triple therapy). Patients in both treatment groups received oral tacrolimus (initial daily dose of 0.2 mg/kg) and oral prednisone (20 mg tapered to 5 mg). Patients in the triple therapy group also received oral azathioprine (1-2 mg/kg/day). Results: The baseline characteristics were similar for the treatment groups. Mean daily tacrolimus doses were 0.18 mg/kg (dual) and 0.19 mg/kg (triple) at Day 1, and 0.16 mg/kg for both regimens at Day 91. Mean blood levels were 16.2 ng/ml (dual) and 16.4 ng/ml (triple) at Day 1, and decreased to 10.8 ng/ml (dual) and 11.0 ng/ml (triple) at Day 91. At the end of the 3-month follow-up, Kaplan Meier patient survival rates were 97.6% (dual) and 96.7% (triple). Graft survival rates were also similar: 92.7% (dual) and 91.7% (triple). During the study, 1 patient died in each therapy group of heart failure. After withdrawal from study, two patients died (CMV pneumonitis, myocardial infarction) in the dual therapy group, and 3 patients died (peritonitis, sepsis, sudden death) in the triple therapy group. Biopsies were performed for more than 95% of rejection episodes with clinical signs and symptoms. Biopsy-proven rejection rates were 28.2% (dual) and 26.4% (triple). Banff grading by maximum intensity revealed a mild episode for 10.5% (dual) and 12.4% (triple) of patients, moderate for 10.5% and 8.3% of patients, and severe for 7.3% and 5.8% of patients. The incidences of corticosteroid-resistant rejection were 10.5% (dual) and 11.6% (triple). Adverse events most frequently reported were hypertension (32.3% vs. 26.4%), increased creatinine (30.6% vs. 27.3%), and hyperkalemia (25.8% vs. 24.8%). A difference between treatment groups was found in the incidence of constipation (21.8% vs. 9.9%), leukopenia (1.6% vs. 11.6%) and infection (22.6% vs. 14.0%). The overall incidence of insulin use during the study was 18.1% (dual) and 17.3% (triple). At study end, the frequency of insulin-dependent diabetes mellitus was 5.7% and 5.1%, respectively. Mean serum creatinine at month 3 was 1.94 mg/dl in the dual therapy group and 1.97 mg/dl in the triple therapy group. Conclusion: Tacrolimus proved to be efficacious and safe under both dual and triple low-dose regimens. The addition of azathioprine to a tacrolimus/corticosteroid-based immunosuppressive therapy did not convey an increased efficacy.