Long-Term Renal Allograft Function on a Tacrolimus-Based, Pred-Free Maintenance Immunosuppression Comparing Sirolimus vs. MMF

Gallon, Lorenzo; Perico, Norberto; Dimitrov, Borislav D.; Winoto, Johan; Remuzzi, Giuseppe; Leventhal, Joseph R.; Gaspari, Flavio; Kaufman, Dixon B.

doi:10.1111/j.1600-6143.2006.01340.x

Cited by 68 publications

(65 citation statements)

References 30 publications

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“…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]124,127,131,134,135,139,141,[143][144][145][153][154][155] did not report any information on allocation concealment, whereas 20 trials 71,…”

Section: Concealment Of Allocationmentioning

confidence: 99%

“…Fifty-seven trials (48 maintenance studies, 51,58,77,[80][81][82]84,86,94,99,100,102,[104][105][106][107][108][109][113][114][115][116][117][119][120][121][124][125][126][127]131,132,134,138,139,[141][142][143][144][145][146][147]149,150,152,154,156,157 eight induction studies 71,72,74,87,97,128,137 and one study …”

Section: Baseline Characteristicsmentioning

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: Baseline Characteristicsmentioning

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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“…9,[14][15][16][17][18][19][20][21][22] In several studies, reduced renal function was observed when SRL was combined with standard doses of CNI, including the two Phase 3 randomized, controlled trials comparing SRL with placebo and azathioprine (AZA), respectively, in combination with full-dose CsA and steroids. 14,15 Despite lower acute rejection rates, SRL-treated patients were found to have lower glomerular fi ltration rates (GFRs) through the fi rst year post transplant.…”

Section: Mtor-is In De Novo Renal Transplantationmentioning

confidence: 99%

“…14,15 Despite lower acute rejection rates, SRL-treated patients were found to have lower glomerular fi ltration rates (GFRs) through the fi rst year post transplant. Similarly, when SRL was combined with full-dose TAC, renal function was worse in SRL-treated patients compared with either mycophenolate mofetil (MMF) 16 or reduced TAC, 19 which resulted in termination of the standard TAC arm in the latter study. These fi ndings were confi rmed in two pivotal trials with EVR, further supporting the rationale to lower CNI dosages when combined with mTOR-Is.…”

Section: Mtor-is In De Novo Renal Transplantationmentioning

confidence: 99%

The role of mTOR inhibition in renal transplant immune suppression

Patel

Dawson

Knight

et al. 2011

Dialysis & Transplantation

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The mammalian target of rapamycin inhibitors (mTOR‐Is) sirolimus and everolimus represent a class of proliferation signal inhibitors with a wide spectrum of activities, including suppression of T‐cell proliferation and reduction of tumor growth. In solid‐organ transplantation, mTOR inhibitors are an option for maintenance immune suppression due to their relative lack of nephrotoxicity compared with the current backbone of most regimens, the calcineurin inhibitors (CNIs). This property, in conjunction with their unique pharmacology, allows mTOR‐Is to be used as an adjunct or alternative to CNIs. Earlier studies of their use in de novo renal transplantation have delineated potential strategies for use of this class of drugs in groups of patients in whom mTOR inhibition may be useful. From recent kidney studies it appears that the time for introduction of mTOR‐I therapy may be prior to the development of proteinuria or signiﬁcant graft deterioration. Consideration should also be given to the use of mTOR‐Is in patients with or at high risk of post‐transplant malignancy. Due to potential toxicities, knowledge of the adverse effects and pharmacokinetic proﬁles of mTOR‐Is is necessary for proper management of patients receiving these agents.

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Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

Webster

Lee

Chapman

et al. 2006

Cochrane Database of Systematic Reviews

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TOR-I have been evaluated in four different primary immunosuppressive algorithms; as replacement for CNI and for antimetabolites, in combination with CNI at low and high dose and with variable dose of CNI. Generally, surrogate endpoints for graft survival favour TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust RCTs are still needed.

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Long-Term Renal Allograft Function on a Tacrolimus-Based, Pred-Free Maintenance Immunosuppression Comparing Sirolimus vs. MMF

Abstract: It is not known how different steroid-free immuno-

Cited by 68 publications

References 30 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

The role of mTOR inhibition in renal transplant immune suppression

Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

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