title: Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model.
abstract: End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival.
  
  
  
  To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation.
  
  
  
  Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.
  
  
  
  Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY.
  
  
  
  For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled.
  
  
  
  High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome.
  
  
  
  Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY.
  
  
  
  This study is registered as PROSPERO CRD42014013189.
  
  
  
  The National Institute for Health Research Health Technology Assessment programme.
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Tracey
authors: T
authors: Jones-Hughes
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Tristan
authors: T
authors: Snowsill
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Marcela
authors: M
authors: Haasova
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Helen
authors: H
authors: Coelho
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Louise
authors: L
authors: Crathorne
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Chris
authors: C
authors: Cooper
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Ruben
authors: R
authors: Mujica-Mota
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Jaime
authors: J
authors: Peters
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Jo
authors: J
authors: Varley-Campbell
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Nicola
authors: N
authors: Huxley
authors: Exeter Kidney Unit, Royal Devon and Exeter Foundation Trust Hospital, Exeter, UK.
authors: Jason
authors: J
authors: Moore
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Matt
authors: M
authors: Allwood
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Jenny
authors: J
authors: Lowe
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Chris
authors: C
authors: Hyde
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Martin
authors: M
authors: Hoyle
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Mary
authors: M
authors: Bond
authors: Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.
authors: Rob
authors: R
authors: Anderson
mesh_terms: D000069594:Abatacept / Q000191:economics / Q000627:therapeutic use; D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D000077552:Basiliximab; D001499:Bayes Theorem; D003362:Cost-Benefit Analysis; D000068338:Everolimus / Q000191:economics / Q000627:therapeutic use; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics* / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000601:surgery*; D016030:Kidney Transplantation / Q000379:methods*; D018803:Models, Economic; D009173:Mycophenolic Acid / Q000191:economics / Q000627:therapeutic use; D011788:Quality of Life; D019057:Quality-Adjusted Life Years; D016032:Randomized Controlled Trials as Topic; D011993:Recombinant Fusion Proteins; D020123:Sirolimus / Q000191:economics / Q000627:therapeutic use; D016559:Tacrolimus / Q000191:economics / Q000627:therapeutic use; D013673:Technology Assessment, Biomedical
chemical_list: D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D000077552:Basiliximab; D000068338:Everolimus; C512542:thymoglobulin; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus