Tacrolimus Monotherapy Without Steroids After Liver Transplantation – A Prospective Randomized Double-Blinded Placebo-Controlled Trial

Abstract

Early steroid withdrawal after liver transplantation (LT) is desirable in order to reduce steroid side effects. Between February 2000 and August 2004, 110 patients after LT were included in this prospective, randomized, double-blind, placebo-controlled trial. Randomization was performed before LT. In all patients, tacrolimus was used without induction therapy. All patients received methylprednisolon for 14 days, thereafter a double-blinded medication containing either placebo (n = 56) or methylprednisolon (n = 54) for 6 months, which was completely stopped thereafter. End points were patient and graft survival, acute and chronic rejection, and incidence of steroid side effects during the first year after LT. One-year patient survival was 85.7% (placebo) and 88.8% (steroid) (p = 0.572). Twentyseven (48.2%) and 19 (35.2%) patients experienced acute rejection (placebo versus steroid, respectively; p = 0.116). Two patients in the placebo group but none in the steroid group experienced chronic rejection (p = 0.257). The rates of side effects were (placebo versus steroid, respectively): CMV infection 25% versus 33% (p = 0.336), post-transplant diabetes 30% versus 53% (p = 0.024), hypertension 39% versus 52% (p = 0.248), hypercholesterolemia 10% versus 41% (p = 0.002) and hypertriglyceridemia 32% versus 54% (p = 0.046). In conclusion, early steroid withdrawal after LT is feasible under tacrolimus monotherapy without increased rejection rates and with a lower rate of side effects.

A systematic review of the adverse effects of tacrolimus in organ transplant patients

“…Mean age (± SD) Diagnosis Tacrolimus dosage Tacrolimus level (<3 months) Tacrolimus level (>3 months) Margarit et al (2005) 57 ± 7 End-stage liver cirrhosis 0.05 mg/kg twice daily 10-15 ng/ml 8-12 ng/ml Margreiter et al (2002) 42.4 ± 10.4 End-stage renal disease 0.15 mg/kg twice daily 10-20 ng/ml 5-15 ng/ml Mayer et al (1997) 46.6 ± 25 End-stage renal disease 0.15 mg/kg twice daily 10-20 ng/ml 5-15 ng/ml Moench et al (2007) 53.5 ± 8.3 End-stage liver disease 0.20 mg/kg twice daily 10-15 ng/ml 5-10 ng/ml Murphy et al (2003) 45 ± 12 End-stage renal disease 0.10 mg/kg twice daily 8-15 ng/ml 5-10 ng/ml O'grady et al (2002) 52 ± 10 End-stage liver cirrhosis 0.10 mg/kg twice daily 5-15 ng/ml 5-15 ng/ml US Multicenter (1994) 44 ± 18 End-stage liver cirrhosis 0.15 mg/kg twice daily <0.2 or >5 ng/ml if toxicity occurred <0.2 or >5 ng/ml if toxicity occurred trials", "tacrolimus and controlled trials" and "tacrolimus and organ transplantation". Sixteen articles were further evaluated and assessed for suitability to be included in this review.…”

“…In terms of appropriate randomization, five out of seven studies did not clearly describe their steps of randomization (Mayer et al, 1997;Margreiter et al, 2002;Murphy et al, 2003; The US Multicenter FK 506 Liver Study Group, 1994;Margaritet al, 2005). Only one study (Moench et al, 2007) fulfilled all the criteria of evaluation.…”

“…Tacrolimus was compared to cyclosporine in one trial (Mayer et al, 1997), microemulsified cyclosporine in four trials (Margreiter et al, 2002;Murphy et al, 2003;O'grady et al, 2002;The US Multicenter FK 506 Liver Study Group, 1994) and two trials compared tacrolimus to steroids (Margarit et al, 2005;Moench et al, 2007). The compared drug would be referred as "control" in this analysis.…”

“…Five trials were conducted for twelve months (Mayer et al, 1997;Murphy et al, 2003;O'grady et al, 2002; The US Multicenter FK 506 Liver Study Group, 1994;Moench et al, 2007), one trial was conducted for five years (Margarit et al, 2005) and another one trial was conducted for six months (Margreiter et al, 2002). All trials involved adults from 42 years old to 57 years old.…”

“…Four out of seven studies were conducted in patients who underwent liver transplantation, mostly due to end-stage liver cirrhosis (O'grady et al, 2002;The US Multicenter FK 506 Liver Study Group, 1994;Margaritet al, 2005;Moench et al, 2007) while three studies involved renal transplant recipients due to end-stage renal disease (Mayer et al, 1997;Margreiter et al, 2002;Murphy et al, 2003). Five trials were conducted for twelve months (Mayer et al, 1997;Murphy et al, 2003;O'grady et al, 2002; The US Multicenter FK 506 Liver Study Group, 1994;Moench et al, 2007), one trial was conducted for five years (Margarit et al, 2005) and another one trial was conducted for six months (Margreiter et al, 2002).…”