Randomized Controlled Study Comparing Reduced Calcineurin Inhibitors Exposure Versus Standard Cyclosporine-Based Immunosuppression

Hernández, Domingo; Miquel, Rosa; Porrini, Esteban; Fernandez, Armida; González-Posada, José Manuel; Hortal, L; Checa, María Dolores; Rodríguez, Aurelio; García, José Javier; Rufino, Margarita; Torres, Armando

doi:10.1097/01.tp.0000282872.17024.b7

Cited by 42 publications

(47 citation statements)

References 20 publications

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“…The method of concealment of allocation was clearly reported in 12 trials (two induction studies, 97,128 nine maintenance studies, 58,114,129,130,133,140,147,150,152 and one study 136 of both induction and maintenance treatment). Fifty-four trials 51,[72][73][74][76][77][78][79][81][82][83][84][85][87][88][89][91][92][93]95,96,[98][99][100][102][103][104][105][106][108][109][110][111][112][113][115][116][117][118][119][120]124,…”

Section: Concealment Of Allocationmentioning

confidence: 99%

“…The method of random allocation, 71,86,128 including the method of sequence generation, was clearly stated and adequate in only two induction studies 71,128 and 18 maintenance studies, 86,103,110,112,119,122,124,126,127,[129][130][131][132][133][134][135][136]150 whereas 65 studies (nine induction studies [72][73][74]87,95,98,137 and 54 maintenance studies 51,58,59,75-85,88,89,91-94,99-102, 104-109,111,113-118,120,121,125,138-147,152-155 ) and both of the studies of induction and maintenance treatment 123,148 did not clearly specify the method used. The remaining maintenance study 149 used a minimisation technique that included a random element.…”

Section: Random Allocationmentioning

confidence: 99%

“…Nine trials (eight maintenance studies 88,89,92,[110][111][112]122,148 and one study 148 of both induction and maintenance) reported significant baseline between-group differences for key factors, including PRA grade, number of previous transplants, patient age, pretransplant diabetes mellitus, HLA mismatches and ECD donor kidneys. A further six maintenance studies 91,101,130,133,140,155 were rated as 'partial' because they reported a baseline difference in patient sex.…”

Section: Baseline Characteristicsmentioning

confidence: 99%

“…The majority of trials (52 maintenance studies, 51,[75][76][77][79][80][81][82][83][84]86,89,[91][92][93][94][99][100][101][102][104][105][106]108,109,[111][112][113][114][116][117][118][119][120][121][122]130,131,133,138,140,141,[144][145][146][147][148][149][151][152][153]155 nine induction studies, [71][72][73]…”

Section: Treatment Allocation Masked From Outcome Assessorsmentioning

confidence: 99%

“…Five induction studies, 87,96,98,128,137 47 maintenance studies 51,59,76,[78][79][80][82][83][84]86,88,[92][93][94]103,[105][106][107][108]111,113,116,118,125,126,[129][130][131][132][133][134][135][138][139][140][141][142][144][145][146][147][148][149][151][152][153]155 and both of the studies of induction and maintenance treatment 123,148 did not blind participants to treatment allocation.…”

Section: Treatment Allocation Masked From Participantsmentioning

confidence: 99%

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Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

Jones-Hughes

Snowsill

Haasova

et al. 2016

Health Technol Assess

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BackgroundEnd-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.ObjectivesTo 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.MethodsClinical 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.ResultsEighty-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.LimitationsFor 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 workHigh-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.ConclusionOnly 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.Study registrationThis study is registered as PROSPERO CRD42014013189.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Section: Concealment Of Allocationmentioning

confidence: 99%

Section: Random Allocationmentioning

confidence: 99%

Section: Baseline Characteristicsmentioning

confidence: 99%

Section: Treatment Allocation Masked From Outcome Assessorsmentioning

confidence: 99%

Section: Treatment Allocation Masked From Participantsmentioning

confidence: 99%

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Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

Jones-Hughes

Snowsill

Haasova

et al. 2016

Health Technol Assess

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Interleukin 2 receptor antagonists for kidney transplant recipients

Webster

Ruster

McGee

et al. 2010

Cochrane Database of Systematic Reviews

144

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Given a 38% risk of rejection, per 100 recipients compared with no treatment, nine recipients would need treatment with IL2Ra to prevent one recipient having rejection, 42 to prevent one graft loss, and 38 to prevent one having CMV disease over the first year post-transplantation. Compared with ATG treatment, ATG may prevent some experiencing acute rejection, but 16 recipients would need IL2Ra to prevent one having CMV, but 58 would need IL2Ra to prevent one having malignancy. There are no apparent differences between basiliximab and daclizumab. IL2Ra are as effective as other antibody therapies and with significantly fewer side effects.

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Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients

Karpe

Talaulikar

Walters

2017

Cochrane Database of Systematic Reviews

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CNI avoidance increased acute rejection and CNI withdrawal increases acute rejection but reduced graft loss at least over the short-term. Low dose CNI with induction regimens reduced acute rejection and graft loss with no major adverse events, also in the short-term. The use of mTOR-I reduced CMV infections but increased the risk of acute rejection. These conclusions must be tempered by the lack of long-term data in most of the studies, particularly with regards to chronic antibody-mediated rejection, and the suboptimal methodological quality of the included studies.

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Randomized Controlled Study Comparing Reduced Calcineurin Inhibitors Exposure Versus Standard Cyclosporine-Based Immunosuppression

Abstract: Immunosuppressive regimens with reduced CNI exposure provide similar preservation of renal function compared with standard dose of CsA after KT and do not lead to underimmunosuppression.

Cited by 42 publications

References 20 publications

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

Interleukin 2 receptor antagonists for kidney transplant recipients

Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients

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