A network meta-analysis of the efficacy of belatacept, cyclosporine and tacrolimus for immunosuppression therapy in adult renal transplant recipients

Abstract

Belatacept is a first in-class co-stimulation blocker developed for primary maintenance immunosuppression following renal transplantation. The objective of this study was to estimate the efficacy of belatacept relative to tacrolimus and cyclosporine among adults receiving a single kidney transplant.

A systematic review was conducted of randomized clinical trials (RCTs) published between January 1990 and December 2013 using EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, and unpublished study reports from two belatacept RCTs. Bayesian network meta-analysis (NMA) methods were used to compare the efficacy measures, mortality, graft loss, acute rejection and glomerular filtration rate (GFR). Heterogeneity was quantified using statistical metrics and potential sources were evaluated using meta-regression and subgroup analysis.

A total of 28 RCTs comparing tacrolimus with cyclosporine, and three comparing belatacept with cyclosporine, were identified.

All three agents provided comparable graft and patient survival, despite a higher risk of acute rejection associated with belatacept and cyclosporine. Belatacept was associated with significant improvement in GFR versus cyclosporine. Compared with tacrolimus, this difference was clinically meaningful yet statistically non-significant. The probability of being the best treatment was highest for belatacept for graft survival (68%), patient survival (97%) and renal function (89%), and highest for tacrolimus for acute rejection (99%).Variability in donor, recipient, and trial characteristics was present in the included RCTs; however, minimal statistical heterogeneity was detected in the analysis of acute rejection, graft or patient survival, and none of the characteristics were found to be significantly associated with relative effect. Although the direction of effect of immunosuppressants on GFR was consistent across RCTs, precise estimation of its magnitude was limited by a small number of RCTs and heterogeneity in relative effect sizes.

Clinicians often seek an alternative to CNIs due to their nephrotoxic effects. The results of this indirect comparison indicate that belatacept is an effective immunosuppressive agent in renal transplantation among adults.

Keywords::

• Belatacept
• Cyclosporine
• Immunosuppression
• Kidney transplantation
• Meta-analysis
• Tacrolimus

Transparency

Declaration of funding

This study was funded by Bristol-Myers Squibb.

All coauthors participated in research design. S.M.G. was responsible for the primary draft and all coauthors provided critical revision. S.M.G. and O.E. collected the data and performed the research. S.M.G. and I.G. performed the data analysis. All coauthors provided critical review and interpretation of the study findings.

Declaration of financial/other relationships

S.M.G. has disclosed that she is an employee of Oxford Outcomes (now ICONplc), a company that received funding from Bristol-Myers Squibb for the development of this study. O.E. has disclosed that he was an employee of Oxford Outcomes at the time this study was developed. I.G. and A.R.L. have disclosed that they were consultants to Oxford Outcomes. B.K. has no relevant financial relationships to declare. G.J.L. and A.K. have disclosed that they are employees and shareholders of Bristol-Myers Squibb.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships no disclose.