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between January 1990 and December 2013 using EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, and unpublished study reports from two belatacept RCTs.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.

[1]  A. Matas,et al.  Long‐Term Exposure to Belatacept in Recipients of Extended Criteria Donor Kidneys , 2013, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[2]  L. Rostaing,et al.  Long‐Term Belatacept Exposure Maintains Efficacy and Safety at 5 Years: Results From the Long‐Term Extension of the BENEFIT Study , 2013, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  M. R. Silveira,et al.  Safety of Immunosuppressive Drugs Used as Maintenance Therapy in Kidney Transplantation: A Systematic Review and Meta-Analysis , 2013, Pharmaceuticals.

[4]  Alex J. Sutton,et al.  Evidence Synthesis for Decision Making 2 , 2013, Medical decision making : an international journal of the Society for Medical Decision Making.

[5]  Kristian Thorlund,et al.  Modelling heterogeneity variances in multiple treatment comparison meta-analysis – Are informative priors the better solution? , 2013, BMC Medical Research Methodology.

[6]  A. Loundou,et al.  A Randomized Trial With Steroids and Antithymocyte Globulins Comparing Cyclosporine/Azathioprine Versus Tacrolimus/Mycophenolate Mofetil (CATM2) in Renal Transplantation , 2012, Transplantation.

[7]  A. Sharif,et al.  Meta-analysis of calcineurin-inhibitor-sparing regimens in kidney transplantation. , 2011, Journal of the American Society of Nephrology : JASN.

[8]  Joseph C Cappelleri,et al.  Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 1. , 2011, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[9]  David C Hoaglin,et al.  Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2. , 2011, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[10]  Dolca Thomas,et al.  Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. , 2011, Clinical journal of the American Society of Nephrology : CJASN.

[11]  W. Marks,et al.  Immunosuppression with Belatacept‐Based, Corticosteroid‐Avoiding Regimens in De Novo Kidney Transplant Recipients , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[12]  Dolca Thomas,et al.  An Integrated Safety Profile Analysis of Belatacept in Kidney Transplant Recipients , 2010, Transplantation.

[13]  J. Campistol,et al.  A Phase III Study of Belatacept Versus Cyclosporine in Kidney Transplants from Extended Criteria Donors (BENEFIT‐EXT Study) , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  L. Rostaing,et al.  A Phase III Study of Belatacept‐based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients (BENEFIT Study) , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[15]  D. Brennan,et al.  BK‐Virus and the Impact of Pre‐Emptive Immunosuppression Reduction: 5‐Year Results , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  F. Schena,et al.  Conversion From Calcineurin Inhibitors to Sirolimus Maintenance Therapy in Renal Allograft Recipients: 24-Month Efficacy and Safety Results From the CONVERT Trial , 2009, Transplantation.

[17]  L. Hilbrands,et al.  Reduced exposure to calcineurin inhibitors in renal transplantation. , 2008, The New England journal of medicine.

[18]  W. Meyers,et al.  Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes. , 2008, Transplant immunology.

[19]  Kuo-Hsin Chen,et al.  Favorable results of concomitant tacrolimus and sirolimus therapy in Taiwanese renal transplant recipients at 12 months. , 2008, Journal of the Formosan Medical Association = Taiwan yi zhi.

[20]  Alan B Leichtman,et al.  Kidney transplantation as primary therapy for end-stage renal disease: a National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[21]  G. Russ,et al.  Trends in adult post‐kidney transplant immunosuppressive use in Australia, 1991–2005 , 2008, Nephrology.

[22]  E. Porrini,et al.  Randomized Controlled Study Comparing Reduced Calcineurin Inhibitors Exposure Versus Standard Cyclosporine-Based Immunosuppression , 2007, Transplantation.

[23]  S. Chadban,et al.  Results of an International, Randomized Trial Comparing Glucose Metabolism Disorders and Outcome with Cyclosporine Versus Tacrolimus , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[24]  S. Giannouli,et al.  A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia , 2006, European Journal of Epidemiology.

[25]  Kim-Ming Wong,et al.  Paired kidney analysis of tacrolimus and cyclosporine microemulsion‐based therapy in Chinese cadaveric renal transplant recipients , 2006, Transplant international : official journal of the European Society for Organ Transplantation.

[26]  J. D. de Fijter,et al.  No difference in degree of interstitial Sirius red-stained area in serial biopsies from area under concentration-over-time curves-guided cyclosporine versus tacrolimus-treated renal transplant recipients at one year. , 2005, Journal of the American Society of Nephrology : JASN.

[27]  V. Dharnidharka.  Costimulation blockade with belatacept in renal transplantation. , 2005, The New England journal of medicine.

[28]  A. Webster,et al.  Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. , 2005, The Cochrane database of systematic reviews.

[29]  W. Almawi,et al.  Tacrolimus (FK506) versus cyclosporine microemulsion (neoral) as maintenance immunosuppression therapy in kidney transplant recipients. , 2005, Transplantation proceedings.

[30]  Daniel C. Brennan,et al.  A Randomized, Prospective, Pharmacoeconomic Trial of Tacrolimus versus Cyclosporine in Combination with Thymoglobulin in Renal Transplant Recipients , 2005, Transplantation.

[31]  G. Lu,et al.  Combination of direct and indirect evidence in mixed treatment comparisons , 2004, Statistics in medicine.

[32]  M. Nicholson,et al.  Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis , 2003, The British journal of surgery.

[33]  J. Squifflet,et al.  A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients1 , 2003, Transplantation.

[34]  C. Ming,et al.  Randomized trial of tacrolimus in combination with mycophenolate mofetil versus cyclosporine with mycophenolate mofetil in cadaveric renal transplant recipients with delayed graft function. , 2003, Transplantation proceedings.

[35]  M. Abbud Filho,et al.  One-year follow-up of a Brazilian randomized multicenter study comparing tacrolimus versus cyclosporine in kidney transplantation. , 2002, Transplantation proceedings.

[36]  N. Barthe,et al.  One year evolution of bone mineral density in kidney transplant recipients receiving tacrolimus versus cyclosporine. , 2002, Transplantation proceedings.

[37]  Christopher P. Johnson,et al.  Post-transplant renal function in the first year predicts long-term kidney transplant survival. , 2002, Kidney international.

[38]  S. Thompson,et al.  How should meta‐regression analyses be undertaken and interpreted? , 2002, Statistics in medicine.

[39]  R. Margreiter.  Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study , 2002, The Lancet.

[40]  S. Busque,et al.  Canadian multicentre trial of tacrolimus/azathioprine/steroids versus tacrolimus/mycophenolate mofetil/steroids versus neoral/mycophenolate mofetil/steroids in renal transplantation. , 2001, Transplantation proceedings.

[41]  X. Wang,et al.  Tacrolimus vs CyA Neoral in combination with MMF and steroids after cadaveric renal transplantation. , 2000, Transplantation proceedings.

[42]  Y. Wang,et al.  Clinical experience with Prograf (tacrolimus, FK 506) in Chinese patients after renal transplantation. , 2000, Transplantation proceedings.

[43]  A. Levey,et al.  A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation , 1999, Annals of Internal Medicine.

[44]  K. Ivens,et al.  Distal tubular acidosis induced by FK506. , 1998, Clinical transplantation.

[45]  E. Langhoff,et al.  Tacrolimus/"low-dose" mycophenolate mofetil versus microemulsion cyclosporine/"low-dose" mycophenolate mofetil after kidney transplantation--1-year follow-up of a prospective, randomized clinical trial. , 1998, Transplantation proceedings.

[46]  H. Schlitt,et al.  Pronounced renal vasoconstriction and systemic hypertension in renal transplant patients treated with cyclosporin A versus FK 506 , 1998, Transplant international : official journal of the European Society for Organ Transplantation.

[47]  G. Smith,et al.  Bias in meta-analysis detected by a simple, graphical test , 1997, BMJ.

[48]  J. Squifflet,et al.  Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection - A report of the European Tacrolimus Multicenter Renal Study Group , 1997 .

[49]  A. Matas,et al.  One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group. , 1996, Transplantation.

[50]  Mahesh S. Patel.  An introduction to meta-analysis. , 1989, Health policy.

[51]  M. H. Gault,et al.  Prediction of creatinine clearance from serum creatinine. , 1975, Nephron.

[52]  Keith Abrams,et al.  Use of Indirect and Mixed Treatment Comparisons for Technology Assessment , 2012, PharmacoEconomics.

[53]  E. Ok,et al.  Comparison of tacrolimus and cyclosporin in renal transplantation by the protocol biopsies. , 2004, Transplantation proceedings.

[54]  B. Wolffenbuttel,et al.  Glucose metabolism in the first 3 years after renal transplantation in patients receiving tacrolimus versus cyclosporine-based immunosuppression. , 2002, Journal of the American Society of Nephrology : JASN.

[55]  Eld,et al.  COMPARISON OF MORTALITY IN ALL PATIENTS ON DIALYSIS , PATIENTS ON DIALYSIS AWAITING TRANSPLANTATION , AND RECIPIENTS OF A FIRST CADAVERIC TRANSPLANT , 2000 .

[56]  Cockcroft Dw,et al.  Prediction of Creatinine Clearance from Serum Creatinine , 1976 .