Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data

Abstract

Objective: To compare the positive and negative effects of tacrolimus and ciclosporin as initial treatment for renal transplant recipients.

Design: Systematic review.

Data sources and study selection: Reports of comparative randomised trials of tacrolimus and ciclosporin identified by searches of Medline, Embase, the Cochrane Register of Controlled Trials, the Cochrane Renal Group Specialist Register, and conference proceedings.

Data extraction and synthesis: Two reviewers assessed trials for eligibility and quality and extracted data independently. Data were synthesised (random effects model) and results expressed as relative risk (RR), with values < 1 favouring tacrolimus. Subgroup analysis and meta-regression were used to examine potential effect modification by differences in trial design and immunosuppressive co-interventions.

Results: 123 reports from 30 trials (4102 patients) were included. At six months, graft loss was significantly reduced in tacrolimus treated recipients (RR = 0.56, 95% confidence interval 0.36 to 0.86), and this effect persisted up to three years. The relative reduction in graft loss with tacrolimus diminished with higher concentrations of tacrolimus (P = 0.04) but did not vary with ciclosporin formulation (P = 0.97) or ciclosporin concentration (P = 0.38). At one year, tacrolimus treated patients had less acute rejection (RR = 0.69, 0.60 to 0.79) and less steroid resistant rejection (RR = 0.49, 0.37 to 0.64) but more diabetes mellitus requiring insulin (RR = 1.86, 1.11 to 3.09), tremor, headache, diarrhoea, dyspepsia, and vomiting. The relative excess of diabetes increased with higher concentrations of tacrolimus (P = 0.003). Ciclosporin treated recipients had significantly more constipation and cosmetic side effects. No differences were seen in infection or malignancy.

Conclusions: Treating 100 recipients with tacrolimus instead of ciclosporin for the first year after transplantation avoids 12 patients having acute rejection and two losing their graft but causes an extra five patients to develop insulin dependent diabetes. Optimal drug choice may vary between patients.

Fig 1

Flowchart showing process of identification of randomised controlled trials for inclusion in systematic review. RCT=randomised controlled trial. ^*Not all trials reported outcomes with sufficient detail to allow data to contribute to meta-analysis

Fig 2

Graft loss, censored for death

Fig 3

Steroid resistant acute rejection

Fig 4

New requirement for insulin for ≥30 days in previously non-diabetic participants. ^*Trial Miller 2002 is largely responsible for the heterogeneity among trials at one year. Sensitivity analysis showed a relative risk of 2.19 (1.42 to 3.38), and much reduced heterogeneity (P=0.18, I²=27.5%) when this trial was removed from the analysis

Fig 5

Relative risk of graft loss (censored for death) versus weighted average of tacrolimus concentrations (calculated by using the midpoint of each trial's declared intention to treat target range at the 12 hour post-dose nadir) over the first year after transplantation. Each circle represents a trial, with area proportional to inverse of variance of estimated treatment effect (larger circles show trials given more weight in meta-analysis). Colour of circles represents formulation of ciclosporin used in each trial: red circles are ciclosporin solution; white circles are ciclosporin microemulsion

Fig 6

Relative risk of diabetes mellitus requiring insulin treatment for >30 days in previously non-diabetic patients versus weighted average of tacrolimus concentrations (calculated by using the midpoint of each trial's declared intention to treat target range at the 12 hour post-dose nadir) over the first year after transplantation. Each circle represents a trial, with area proportional to inverse of variance of estimated treatment effect (larger circles show trials given more weight in meta-analysis). Colour of circles represents formulation of ciclosporin used in each trial: red circles are ciclosporin solution; white circles are ciclosporin microemulsion