title: Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis.
abstract: BACKGROUND
  As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body against transplanted organ or tissues from a different person whose tissue antigens are not compatible with those of the recipient. The optimal maintenance immunosuppressive regimen after liver transplantation remains uncertain.
  
  
  OBJECTIVE
  To assess the comparative benefits and harms of different maintenance immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy.
  
  
  METHODS
  We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until October 2016 to identify randomised clinical trials on immunosuppression for liver transplantation.
  
  
  METHODS
  We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adult participants undergoing liver transplantation (or liver retransplantation) for any reason. We excluded trials in which participants had undergone multivisceral transplantation or participants with established graft rejections. We considered any of the various maintenance immunosuppressive regimens compared with each other.
  
  
  METHODS
  We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.
  
  
  RESULTS
  We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta-analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow-up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta-analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health-related quality of life, or costs.
  
  
  BACKGROUND
  14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding.
  
  
  CONCLUSIONS
  Based on low-quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow-up compared with tacrolimus. Based on very low-quality evidence from network meta-analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low-quality evidence from network meta-analysis and low-quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross-overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors.
authors.affiliation: Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Avenida Menéndez Pidal s/n, Córdoba, Spain, 14004.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Perálvarez
authors.affiliation: Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Guerrero-Misas
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, Pond Street, London, UK, NW3 2QG.
authors.forename: Douglas
authors.initials: D
authors.lastname: Thorburn
authors.affiliation: Department of Surgery, Royal Free Campus, UCL Medical School, Pond Street, London, UK, NW3 2QG.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Davidson
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, Pond Street, London, UK, NW3 2QG.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tsochatzis
authors.affiliation: Department of Surgery, Royal Free Campus, UCL Medical School, Pond Street, London, UK, NW3 2QG.
authors.forename: Kurinchi Selvan
authors.initials: KS
authors.lastname: Gurusamy
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use; D001499:Bayes Theorem; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000401:mortality; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016031:Liver Transplantation / Q000401:mortality; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000627:therapeutic use; D016017:Odds Ratio; D019233:Retreatment / Q000706:statistics & numerical data; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use; D014181:Transplantation Immunology
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid; D001379:Azathioprine; D020123:Sirolimus; D016559:Tacrolimus