Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model
BACKGROUND: 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. OBJECTIVES: To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect((R)), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin((R)), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport((R)), Sandoz; Capexion((R)), Mylan; Modigraf((R)), Astellas Pharma; Perixis((R)), Accord Healthcare; Prograf((R)), Astellas Pharma; Tacni((R)), Teva; Vivadex((R)), Dexcel Pharma), prolonged-release tacrolimus (Advagraf((R)) Astellas Pharma), belatacept (BEL) (Nulojix((R)), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip((R)), Zentiva; CellCept((R)), Roche Products; Myfenax((R)), Teva), mycophenolate sodium (MPS) (Myfortic((R)), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune((R)), Pfizer) and everolimus (EVL) (Certican((R)), Novartis) as maintenance therapy in adult renal transplantation. METHODS: 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. RESULTS: 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 pound20,000 and pound30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at pound20,000 and pound30,000 per QALY. LIMITATIONS: 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. FUTURE WORK: 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. CONCLUSION: Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at pound20,000-30,000 per QALY. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013189. FUNDING: The National Institute for Health Research Health Technology Assessment programme.
Citation
@article{t.2016,
author = {Jones-Hughes, T. and Snowsill, T. and Haasova, M. and
Coelho, H. and Crathorne, L. and Cooper, C. and Mujica-Mota, R. and
Peters, J. and Varley-Campbell, J. and Huxley, N. and Moore, J. and
Allwood, M. and Lowe, J. and Hyde, C. and Hoyle, M. and Bond, M. and
Anderson, R.},
title = {Immunosuppressive Therapy for Kidney Transplantation in
Adults: A Systematic Review and Economic Model},
journal = {Health Technology Assessment},
volume = {20},
number = {62},
date = {2016-09-01},
url = {https://tristansnowsill.co.uk/immunosuppressive-therapy-for-kidney-transplantation-in-adults.html},
doi = {10.3310/hta20620},
langid = {en},
abstract = {BACKGROUND: 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.
OBJECTIVES: To review and update the evidence for the clinical
effectiveness and cost-effectiveness of basiliximab (BAS)
(Simulect((R)), Novartis Pharmaceuticals UK Ltd) and rabbit
anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin((R)),
Sanofi) as induction therapy, and immediate-release tacrolimus (TAC)
(Adoport((R)), Sandoz; Capexion((R)), Mylan; Modigraf((R)), Astellas
Pharma; Perixis((R)), Accord Healthcare; Prograf((R)), Astellas
Pharma; Tacni((R)), Teva; Vivadex((R)), Dexcel Pharma),
prolonged-release tacrolimus (Advagraf((R)) Astellas Pharma),
belatacept (BEL) (Nulojix((R)), Bristol-Myers Squibb), mycophenolate
mofetil (MMF) (Arzip((R)), Zentiva; CellCept((R)), Roche Products;
Myfenax((R)), Teva), mycophenolate sodium (MPS) (Myfortic((R)),
Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune((R)),
Pfizer) and everolimus (EVL) (Certican((R)), Novartis) as
maintenance therapy in adult renal transplantation. METHODS:
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. RESULTS: 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 pound20,000 and pound30,000 per
quality-adjusted life-year (QALY). When comparing all regimens, only
BAS + TAC + MMF was cost-effective at pound20,000 and pound30,000
per QALY. LIMITATIONS: 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. FUTURE
WORK: 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.
CONCLUSION: Only a regimen of BAS induction followed by maintenance
with TAC and MMF is likely to be cost-effective at
pound20,000-30,000 per QALY. STUDY REGISTRATION: This study is
registered as PROSPERO CRD42014013189. FUNDING: The National
Institute for Health Research Health Technology Assessment
programme.}
}