Evidence-based medicine and clinical trials in renal transplantation
- Rita R Alloway, PharmD, BCPS
Rita R Alloway, PharmD, BCPS
- Research Professor of Medicine
- Director, Transplant Clinical Research
- Director, Transplant Specialty Residency and Fellowship
- University of Cincinnati
- Nicole A Pilch, PharmD, MSCR, BCPS
Nicole A Pilch, PharmD, MSCR, BCPS
- Clinical Specialist
- Medical University of South Carolina
Since the introduction of cyclosporine [1,2], there has been a dramatic increase in the number of successful renal transplants and use of non-cyclosporine immunosuppressive agents [3-20]. As the donor and recipient selection criteria for transplantation expand, in combination with the continued introduction of new immunosuppressive agents, the ability to identify the optimal immunosuppressive regimen for a given individual has grown increasingly complex [3-21]. In addition, with improved graft and patient survival secondary to improved immunosuppression, trial outcome measures have also evolved, making individual trial results difficult to compare. To combat this difficulty, a critical, systematic, and scientific method for evaluating ongoing results from clinical trials is needed.
Evidence-based medicine is the explicit and judicious use of current and best evidence to guide clinical decisions [21,22]. Evidence-based medicine must be considered in the context of clinical expertise and with the understanding that its use is based on published literature, which is subject to reporting bias [21,23,24]. Several guidelines for the publication and design of clinical trials in solid organ transplant recipients have been developed [25-27].
This topic provides an overview of the principles of evidence-based medicine in the evaluation of immunosuppressive regimens in renal transplantation. More general issues related to evidence-based medicine and decision analysis are discussed separately. (See "Evidence-based medicine" and "Decision analysis".)
Randomized, double-blind, controlled clinical trials are the most appropriate design to prove the effectiveness of a new treatment. However, this design may not always be feasible or ethical in renal transplantation [23,28,29].
Previously, the gold standard used to assess the efficacy of a new immunosuppressant agent alone or in combination was graft survival and the incidence of acute rejection, with the latter being a predictor for long-term graft survival. However, improvements in short- and long-term allograft survival and the significant decrease in acute rejection rates have led researchers to alternative study designs and endpoints .
- Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet 1983; 2:986.
- Canadian Multicentre Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 1983; 309:809.
- Mayer AD, Dmitrewski J, Squifflet JP, 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. Transplantation 1997; 64:436.
- Johnson C, Ahsan N, Gonwa T, et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 2000; 69:834.
- Miller J, Mendez R, Pirsch JD, Jensik SC. Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant Study Group. Transplantation 2000; 69:875.
- Shapiro R, Jordan ML, Scantlebury VP, et al. A prospective, randomized trial of tacrolimus/prednisone versus tacrolimus/prednisone/mycophenolate mofetil in renal transplant recipients. Transplantation 1999; 67:411.
- Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group. Lancet 1995; 345:1321.
- Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60:225.
- A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1996; 61:1029.
- Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 1997; 63:977.
- Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation 1999; 67:1011.
- Nashan B, Moore R, Amlot P, et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet 1997; 350:1193.
- Kahan BD, Rajagopalan PR, Hall M. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Study Group. Transplantation 1999; 67:276.
- Nashan B, Light S, Hardie IR, et al. Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group. Transplantation 1999; 67:110.
- Vincenti F, Kirkman R, Light S, et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med 1998; 338:161.
- Groth CG, Bäckman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67:1036.
- Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet 2000; 356:194.
- MacDonald AS, RAPAMUNE Global Study Group. A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71:271.
- Kreis H, Cisterne JM, Land W, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69:1252.
- Cecka JM. The UNOS Scientific Renal Transplant Registry. In: Clinical Transplant 1998, Cecka JM, Terasaki PI (Eds), UCLA Tissue Typing Laboratory, Los Angeles 1998. p.1.
- Evidence-Based Medicine Working Group. Evidence-based medicine. A new approach to teaching the practice of medicine. JAMA 1992; 268:2420.
- Fritsche L, Einecke G, Fleiner F, et al. Reports of large immunosuppression trials in kidney transplantation: room for improvement. Am J Transplant 2004; 4:738.
- Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000; 342:1878.
- García López FJ, Amenábar Iríbar JJ. The intricate relationship between evidence and clinical practice in kidney transplantation. J Nephrol 2000; 13:405.
- Humar A, Michaels M, AST ID Working Group on Infectious Disease Monitoring. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant 2006; 6:262.
- Budde K, Fritsche L. Proposal for guidelines for publication of randomized trials in the American Journal of Transplantation. Am J Transplant 2005; 5:644.
- Fleiner F, Budde K, Dragun D, et al. Differences in reporting of acute rejections between American and European publications of large immunosuppressive trials impair comparability of study results. Transplant Proc 2005; 37:2048.
- Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000; 342:1887.
- Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996; 276:637.
- Hariharan S, McBride MA, Cohen EP. Evolution of endpoints for renal transplant outcome. Am J Transplant 2003; 3:933.
- Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ 1999; 318:1104.
- Halloran P, Mathew T, Tomlanovich S, et al. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation 1997; 63:39.
- Szczech LA, Berlin JA, Feldman HI. The effect of antilymphocyte induction therapy on renal allograft survival. A meta-analysis of individual patient-level data. Anti-Lymphocyte Antibody Induction Therapy Study Group. Ann Intern Med 1998; 128:817.
- Sacks HS, Berrier J, Reitman D, et al. Meta-analyses of randomized controlled trials. N Engl J Med 1987; 316:450.
- Villar J, Carroli G, Belizán JM. Predictive ability of meta-analyses of randomised controlled trials. Lancet 1995; 345:772.
- Cappelleri JC, Ioannidis JP, Schmid CH, et al. Large trials vs meta-analysis of smaller trials: how do their results compare? JAMA 1996; 276:1332.
- Meier-Kriesche HU, Steffen BJ, Hochberg AM, et al. Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration. Transplantation 2003; 75:1341.
- Ojo AO, Meier-Kriesche HU, Hanson JA, et al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 2000; 69:2405.
- Kaplan B, Schold J, Meier-Kriesche HU. Overview of large database analysis in renal transplantation. Am J Transplant 2003; 3:1052.
- Hanto DW. Reliability of voluntary and compulsory databases and registries in the United States. Transplantation 2003; 75:2162.
- van der Meulen JH, Jacob M, Copley L. Assessing the quality of the data in a transplant registry: the European Liver Transplant Registry. Transplantation 2003; 75:2164.
- Dans AL, Dans LF, Guyatt GH, Richardson S. Users' guides to the medical literature: XIV. How to decide on the applicability of clinical trial results to your patient. Evidence-Based Medicine Working Group. JAMA 1998; 279:545.
- McAlister FA, Straus SE, Guyatt GH, Haynes RB. Users' guides to the medical literature: XX. Integrating research evidence with the care of the individual patient. Evidence-Based Medicine Working Group. JAMA 2000; 283:2829.
- Wallemacq P, Armstrong VW, Brunet M, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit 2009; 31:139.
- Lo A, Alloway RR. Strategies to reduce toxicities and improve outcomes in renal transplant recipients. Pharmacotherapy 2002; 22:316.
- Le Bricon T, Thervet E, Froissart M, et al. Plasma cystatin C is superior to 24-h creatinine clearance and plasma creatinine for estimation of glomerular filtration rate 3 months after kidney transplantation. Clin Chem 2000; 46:1206.
- Salvadori M, Rosati A, Bock A, et al. Estimated one-year glomerular filtration rate is the best predictor of long-term graft function following renal transplant. Transplantation 2006; 81:202.
- Schold JD, Kaplan B. Design and analysis of clinical trials in transplantation: principles and pitfalls. Am J Transplant 2008; 8:1779.
- Tedesco-Silva H, Mourad G, Kahan BD, et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation 2005; 79:1553.
- Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353:770.
- Teschner S, Geyer M, Wilpert J, et al. Remission of polyomavirus-induced graft nephropathy treated with low-dose leflunomide. Nephrol Dial Transplant 2006; 21:2039.
- Moher D, Schulz KF, Altman D, CONSORT Group. The CONSORT Statement: revised recommendations for improving the quality of reports of parallel-group randomized trials 2001. Explore (NY) 2005; 1:40.
- www.consort-statement.org (Accessed on February 07, 2011).
- Kalil AC, Mattei J, Florescu DF, et al. Recommendations for the assessment and reporting of multivariable logistic regression in transplantation literature. Am J Transplant 2010; 10:1686.
- Couser WG, Drueke TB, Halloran PF, et al. A uniform clinical trial registration policy for journals of kidney diseases, dialysis and transplantation. Am J Transplant 2005; 5:643.