EPIDEMIOLOGY AND CLINICAL OUTCOMES

S. Goring¹, O. Eyawo², E.J. Mills³, A. Levy⁴, G.J. L'italien⁵, D. Trivedi⁶, B. Kasiske^7
1Epidemiology, Oxford Outcomes, Vancouver/CANADA, ², Oxford Outcomes, Vancouver/CANADA, ³, University of Ottawa, Ottawa/CANADA, ⁴Community Health And Epidemiology, Dalhousie University, Halifax, NS/CANADA, ⁵, Bristol Myers Squibb, Wallingford/CT/UNITED STATES OF AMERICA, ⁶Health Economics And Outcomes Research, Bristol-Myers Squibb, Plainsboro/NJ/UNITED STATES OF AMERICA, ⁷, University of Minnesota, Minneapolis/UNITED STATES OF AMERICA

Body: Purpose The pharmacopeia for post-renal transplant immunosuppression has recently expanded to include belatacept, a selectiveco-stimulation blocker. As the efficacy and safety of the current mainstays of immunosuppression - tacrolimus and cyclosporine - have been synthesized using meta-analysis of randomized trials, that information needs to be updated to include belatacept. The objective of this study was to estimate the efficacy and cardiometabolic safety of a low-doseregimen of belatacept relative to tacrolimus and cyclosporine among adults receiving a single kidney transplant. Methods We conducted a systematic review of randomized controlled trials published between January 1990 and April 2009 using EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials. We also included the results from two unpublished phase three trials of belatacept (Bristol-Myers Squibb, on file). We used Bayesian mixed treatment comparison methods to compare the efficacy rates by applying a star-shaped network of treatments. Efficacy outcomes included mortality, graft loss, and acute rejection and cardiometabolic safety outcomes included new-onset diabetes, and cardiovascular events. We compared estimates and identified sources of heterogeneity using a classical pair-wise meta-analysis framework. Results We identified 26 randomized controlled trials comparing cyclosporine with tacrolimus, three trials comparing cyclosporine with belatacept, and no trials comparing tacrolimus with belatacept. A majority of trials were 12 months duration (range three to 60 months). The odds of death for patients treated with belatacept were 69% lower than for those treated with tacrolimus (odds ratio [OR] = 0.31, 95% credible interval [CrI] 0.11 to 0.82) and 59% lower than for those treated with cyclosporine (OR=0.41, 95% CrI 0.15 to 1.00). The odds ratios of graft loss for belatacept were not statistically different relative to cyclosporine (OR=0.70, 95% CrI, 0.32 to 1.50) or tacrolimus (OR=0.82, 95% CrI 0.35 to 1.84). Belatacept had a significantly increased risk of acute rejection relative to tacrolimus. The risk of new-onset diabetes was significantly lower for belatacept versus cyclosporine (OR=0.42, 95% CrI 0.20 to 0.89) and versus tacrolimus (OR = 0.19, 95% CrI 0.08 to 0.42).Conclusions Based on state-of-the-art statistical methodology incorporating the results of randomized trials, this studyindicates that relative to tacrolimus, belatacept has an increased risk of acute rejection and reduced risk of new onset diabetes mellitus and death. These effects indicate that, with the exceptionof acute rejection, the benefits and cardiometabolic risks with belatacept are better than existing immunosuppressants.

Disclosure: All authors have declared no conflicts of interest.