-
Health Technology Assessment... Aug 2016End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival.
OBJECTIVES
To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [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), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation.
DATA SOURCES
Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost).
REVIEW METHODS
Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.
RESULTS
Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC.
LIMITATIONS
The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence.
CONCLUSIONS
TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42014013544.
FUNDING
The National Institute for Health Research HTA programme.
Topics: Abatacept; Antibodies, Monoclonal; Antilymphocyte Serum; Azathioprine; Basiliximab; Child; Clinical Trials as Topic; Cost-Benefit Analysis; Drug Therapy, Combination; Everolimus; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Economic; Mycophenolic Acid; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Technology Assessment, Biomedical
PubMed: 27557331
DOI: 10.3310/hta20610 -
Health Technology Assessment... Dec 2006To review the clinical and cost-effectiveness of basiliximab, daclizumab, tacrolimus, mycophenolate mofetil (MMF), mycophenolate sodium (MPS) and sirolimus as possible... (Review)
Review
OBJECTIVES
To review the clinical and cost-effectiveness of basiliximab, daclizumab, tacrolimus, mycophenolate mofetil (MMF), mycophenolate sodium (MPS) and sirolimus as possible immunosuppressive therapies for renal transplantation in children.
DATA SOURCES
Electronic databases were searched up to November 2004.
REVIEW METHODS
Data from selected studies were extracted and quality assessed. An economic model [Birmingham Sensitivity Analysis paediatrics (BSAp)] was produced based on an adaptation of a model previously developed for the assessment of the cost-effectiveness of immunosuppressants in adults following renal transplant.
RESULTS
For the addition of basiliximab, one unpublished paediatric randomised control trial (RCT), reported that the addition of basiliximab to tacrolimus-based triple therapy (BTAS) failed to significantly improve 6-month biopsy-proven acute rejection (BPAR), graft function, graft loss and all-cause mortality. No significant difference between groups was seen in 6-month or 1-year or longer graft loss, all-cause mortality and side-effects. In a meta-analysis of adult RCTs, the addition of basiliximab to a ciclosporin, azathioprine and steroid regimen (CAS) significantly reduced short-term BPAR. There was no significant difference in short- or long-term graft loss, all-cause mortality or side-effects. One adult RCT was included for the addition of daclizumab to CAS, which reported reduced 1-year BPAR, although no difference between groups was seen in either 1- or 3-year graft loss, all-cause mortality and side-effects. For tacrolimus versus ciclosporin, one unpublished paediatric RCT found that a regimen of tacrolimus, azathioprine and a steroid (TAS) reduced 6-month BPAR and improved graft function [glomerular filtration rate (GFR)] compared with CAS. This improvement in BPAR with tacrolimus was as shown in the meta-analysis of adult RCTs. There was evidence, particularly in children, that in comparison with ciclosporin, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. The total level of withdrawal in children was reduced in children receiving tacrolimus. Adult RCTs showed an increase in post-transplant diabetes mellitus with tacrolimus. For MMF versus azathioprine, a meta-analysis of adult RCTs showed MMF [regimen of ciclosporin, MMF and a steroid (CMS)] to reduce 1-year BPAR compared with azathioprine (CAS). There was evidence, particularly in children, that in comparison with azathioprine, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. There was an increase in the level of cytomegalovirus infection with MMF, although the overall level of withdrawal due to adverse events was not different to that of azathioprine-treated adults. No study comparing MPS with azathioprine (CAS) was identified. In an adult RCT comparing MMF with MPS, there was no significant difference between groups in 1-year efficacy or side-effects. One unpublished paediatric RCT assessed the addition of sirolimus to CAS. BPAR, graft loss and all-cause mortality were not reported. In two adult RCTs, compared with azathioprine, sirolimus reduced 1-year BPAR, reduced graft function (as assessed by an increased serum creatinine) and increased the level of hyperlipidaemia. No significant differences were seen in other efficacy and side-effect outcomes. On an adult RCT comparing sirolimus with ciclosporin, there were no significant differences between groups in 1-year efficacy or side-effects with the exception of an increased level of hyperlipidaemia with sirolimus substitution. Both the assessment group and drug companies assessed the cost-effectiveness of the newer renal immunosuppressants currently licensed in children using an adaptation (BSAp) of the Birmingham Sensitivity Analysis (BSA) model. This model is based on a 10-year extrapolation of 1-year BPAR results sourced from paediatric RCTs or adult RCTs (where paediatric RCTs were not available). The addition of basiliximab and that of daclizumab to CAS was found to increase quality-adjusted life-years (QALYs) and decreased overall costs, a finding that was robust to sensitivity analyses. The incremental cost-effectiveness ratio (ICER) of replacing ciclosporin with tacrolimus was highly sensitive to the selection of the hazard ratio for graft loss from acute rejection, dialysis costs and the incorporation (or not) of side-effects. The ICERs for tacrolimus versus ciclosporin ranged from about 46,000 pounds/QALY to about 146,000 pounds/QALY. Although sensitive to varying the hazard ratio for graft loss with acute rejection, the ICER for replacing azathioprine with MMF remained in excess of 55,000 pounds/QALY.
CONCLUSIONS
In general, compared with a regimen of ciclosporin, azathioprine and steroid, the newer immunosuppressive agents consistently reduced the incidence of short-term biopsy-proven acute rejection. However, evidence of the impact on side-effects, long-term graft loss, compliance and overall health-related quality of life is limited. Cost-effectiveness was estimated based on the relationship between short-term acute rejection levels from RCTs and long-term graft loss. Both the addition of daclizumab and that of basiliximab were found to be dominant strategies, that is, regarding cost savings and increased QALYs. The incremental cost-effectiveness of tacrolimus relative to ciclosporin was highly sensitive to key model parameter values and therefore may well be a cost-effective strategy. The incremental cost-effectiveness of MMF compared with azathioprine, although also sensitive to model parameter, was unattractive. There is a particular need for RCTs to assess the use of MMF, MPS and daclizumab for renal transplantation in children where no such evidence currently exists. Future comparative studies need to report not only on the impact of the newer immunosuppressants on short- and long-term clinical outcomes but also on side-effects, compliance, healthcare resource, costs and health-related quality of life.
Topics: Child; Cost-Benefit Analysis; Humans; Immunosuppression Therapy; Kidney Transplantation; Models, Economic; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; United Kingdom
PubMed: 17134597
DOI: 10.3310/hta10490 -
Frontiers in Immunology 2021Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Corticosteroid is the first-line... (Meta-Analysis)
Meta-Analysis
Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Corticosteroid is the first-line treatment for aGVHD, but its response rate is only approximately 50%. At present, no uniformly accepted treatment for steroid-refractory aGVHD (SR-aGVHD) is available. Blocking interleukin-2 receptors (IL-2Rs) on donor T cells using pharmaceutical antagonists alleviates SR-aGVHD. This meta-analysis aimed to compare the efficacy and safety of four commercially available IL-2R antagonists (IL-2RAs) in SR-aGVHD treatment. A total of 31 studies met the following inclusion criteria (1): patients of any race, any sex, and all ages (2); those diagnosed with SR-aGVHD after HSCT; and (3) those using IL-2RA-based therapy as the treatment for SR-aGVHD. The overall response rate (ORR) at any time after treatment with basiliximab and daclizumab was 0.81 [95% confidence interval (CI): 0.74-0.87)] and 0.71 (95% CI: 0.56-0.82), respectively, which was better than that of inolimomab 0.54 (95% CI: 0.39-0.68) and denileukin diftitox 0.56 (95% CI: 0.35-0.76). The complete response rate (CRR) at any time after treatment with basiliximab and daclizumab was 0.55 (95% CI: 0.42-0.68) and 0.42 (95%CI: 0.29-0.56), respectively, which was better than that of inolimomab 0.30 (95% CI: 0.16-0.51) and denileukin diftitox 0.37 (95% CI: 0.24-0.52). The ORR and CRR were better after 1-month treatment with basiliximab and daclizumab than after treatment with inolimomab and denileukin diftitox. The incidence of the infection was higher after inolimomab treatment than after treatment with the other IL-2RAs. In conclusion, the efficacy and safety of different IL-2RAs varied. The response rate of basiliximab was the highest, followed by that of daclizumab. Prospective, randomized controlled trials are needed to compare the efficacy and safety of different IL-2RAs.
Topics: Antibodies, Monoclonal; Basiliximab; Daclizumab; Diphtheria Toxin; Drug Resistance; Graft vs Host Disease; Humans; Immunosuppressive Agents; Interleukin-2; Receptors, Interleukin-2; Recombinant Fusion Proteins; Steroids
PubMed: 34621279
DOI: 10.3389/fimmu.2021.749266 -
The Cochrane Database of Systematic... Nov 2014Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage.
OBJECTIVES
1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased).
SEARCH METHODS
We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
SELECTION CRITERIA
Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI). Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity.
MAIN RESULTS
We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73).The belatacept dose used (high versus low), type of donor kidney the recipient received (extended versus standard criteria) and whether the kidney transplant recipient received tacrolimus or cyclosporin made no difference to kidney transplant survival, incidence of acute rejection or estimated GFR. Selective outcome reporting meant that data for some key subgroup comparisons were sparse and that estimates of the effect of treatment in these groups of recipients remain imprecise.
AUTHORS' CONCLUSIONS
There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.
Topics: Abatacept; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Prednisone; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus
PubMed: 25416857
DOI: 10.1002/14651858.CD010699.pub2 -
The Cochrane Database of Systematic... Nov 2013Lung transplantation has become a valuable and well-accepted treatment option for most end-stage lung diseases. Lung transplant recipients are at risk of transplanted... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Lung transplantation has become a valuable and well-accepted treatment option for most end-stage lung diseases. Lung transplant recipients are at risk of transplanted organ rejection, and life-long immunosuppression is necessary. Clear evidence is essential to identify an optimal, safe and effective immunosuppressive treatment strategy for lung transplant recipients. Consensus has not yet been achieved concerning use of immunosuppressive antibodies against T-cells for induction following lung transplantation.
OBJECTIVES
We aimed to assess the benefits and harms of immunosuppressive T-cell antibody induction with ATG, ALG, IL-2RA, alemtuzumab, or muromonab-CD3 for lung transplant recipients.
SEARCH METHODS
We searched the Cochrane Renal Group's Specialised Register to 4 March 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE.
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) that compared immunosuppressive monoclonal and polyclonal T-cell antibody induction for lung transplant recipients. An inclusion criterion was that all participants must have received the same maintenance immunosuppressive therapy within each study.
DATA COLLECTION AND ANALYSIS
Three authors extracted data. We derived risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Methodological risk of bias was assessed using the Cochrane risk of bias tool and trial sequential analyses were undertaken to assess the risk of random errors (play of chance).
MAIN RESULTS
Our review included six RCTs (representing a total of 278 adult lung transplant recipients) that assessed the use of T-cell antibody induction. Evaluation of the included studies found all to be at high risk of bias.We conducted comparisons of polyclonal or monoclonal T-cell antibody induction versus no induction (3 studies, 140 participants); polyclonal T-cell antibody versus no induction (3 studies, 125 participants); interleukin-2 receptor antagonists (IL-2RA) versus no induction (1 study, 25 participants); polyclonal T-cell antibody versus muromonab-CD3 (1 study, 64 participants); and polyclonal T-cell antibody versus IL-2RA (3 studies, 100 participants). Overall we found no significant differences among interventions in terms of mortality, acute rejection, adverse effects, infection, pneumonia, cytomegalovirus infection, bronchiolitis obliterans syndrome, post-transplantation lymphoproliferative disease, or cancer.We found a significant outcome difference in one study that compared antithymocyte globulin versus muromonab-CD3 relating to adverse events (25/34 (74%) versus 12/30 (40%); RR 1.84, 95% CI 1.13 to 2.98). This suggested that antithymocyte globulin increased occurrence of adverse events. However, trial sequential analysis found that the required information size had not been reached, and the cumulative Z-curve did not cross the trial sequential alpha-spending monitoring boundaries.None of the studies reported quality of life or kidney injury. Trial sequential analyses indicated that none of the meta-analyses achieved required information sizes and the cumulative Z-curves did not cross the trial sequential alpha-spending monitoring boundaries, nor reached the area of futility.
AUTHORS' CONCLUSIONS
No clear benefits or harms associated with the use of T-cell antibody induction compared with no induction, or when different types of T-cell antibodies were compared were identified in this review. Few studies were identified that investigated use of antibodies against T-cells for induction after lung transplantation, and numbers of participants and outcomes were also limited. Assessment of the included studies found that all were at high risk of methodological bias.Further RCTs are needed to perform robust assessment of the benefits and harms of T-cell antibody induction for lung transplant recipients. Future studies should be designed and conducted according to methodologies to reduce risks of systematic error (bias) and random error (play of chance).
Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Daclizumab; Graft Rejection; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Muromonab-CD3; Randomized Controlled Trials as Topic; Receptors, Interleukin-2; Recombinant Fusion Proteins; T-Lymphocytes
PubMed: 24282128
DOI: 10.1002/14651858.CD008927.pub2 -
Experimental and Clinical... May 2021Induction immunosuppression for simultaneous pancreas-kidney transplant has helped reduce graft loss due to early rejection. Both thymoglobulin and interleukin 2... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Induction immunosuppression for simultaneous pancreas-kidney transplant has helped reduce graft loss due to early rejection. Both thymoglobulin and interleukin 2 receptor antagonists are the most commonly used induction agents; however, some high-volume centers prefer alemtuzumab.Thisnetwork meta-analysis aimedto compare differentinductionregimens for simultaneouspancreaskidney transplantin terms ofbothpancreas and patient graft survival, as well to assess acute rejection.
MATERIALS AND METHODS
A systematic review was conducted to identify randomized clinical trials up to October 31, 2019, that examined induction regimens for simultaneous pancreas-kidney transplant. Study characteristics, postoperative data (patient, pancreas, and kidney graft survival), complications (eg, bleeding), infection rates, and malignancy rates were extracted. We compared all regimens using randomeffects network meta-analyses to maintain randomization within trials.
RESULTS
This study identified 7 randomized clinical trials that involved 536 patients, which reported 5 induction regimens. These regimens included antithymocyte globulin (97 patients), alemtuzumab (42 patients), 2 doses (113 patients) or 5 doses (164 patients) of daclizumab, and no induction therapy (120 patients). In the network meta-analysis, a regimen with 2 doses of daclizumab was consistently ranked first for patient survival and kidney and pancreas graft survival. In contrast, alemtuzumab was ranked best for acute rejection (both pancreas and kidney). Rates of majorinfection (ie, cytomegalovirus) and malignancy were reported in 3 studies, precluding a reliable analysis.
CONCLUSIONS
Daclizumab with 2 doses, given before simultaneous pancreas-kidney transplant, was associated with the best rates of patient and graft survival. Despite the recent withdrawal of daclizumab, an alternative anti-interleukin 2 induction regimen (basiliximab) has demonstrated promising results in nonrandomized series, warranting that further highquality large-scale randomized clinical trials are still needed.
Topics: Alemtuzumab; Daclizumab; Humans; Immunosuppression Therapy; Kidney Transplantation; Neoplasms; Network Meta-Analysis; Pancreas Transplantation; Randomized Controlled Trials as Topic
PubMed: 34053419
DOI: 10.6002/ect.2020.0231 -
Health Technology Assessment... May 2005To examine the clinical effectiveness and cost-effectiveness of the newer immunosuppressive drugs for renal transplantation: basiliximab, daclizumab, tacrolimus,... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To examine the clinical effectiveness and cost-effectiveness of the newer immunosuppressive drugs for renal transplantation: basiliximab, daclizumab, tacrolimus, mycophenolate (mofetil and sodium) and sirolimus.
DATA SOURCES
Electronic databases. Industry submissions. Current Clinical Trials register. Cochrane Collaboration Renal Disease Group.
REVIEW METHODS
The review followed the InterTASC standards. Each of the five company submissions to the National Institute for Clinical Excellence (NICE) contained cost-effectiveness models, which were evaluated by using a critique covering (1) model checking, (2) a detailed model description and (3) model rerunning.
RESULTS
For induction therapy, three randomised controlled trials (RCTs) found that daclizumab significantly reduced the incidence of biopsy-confirmed acute rejection and patient survival at 6 months/1 year compared with placebo, but not compared with the monoclonal antibody OKT3. There was no significant gain in patient survival or graft loss at 3 years. The incidence of side-effects with daclizumab reduced compared to OKT3. Eight RCTs found that basiliximab significantly improved 6-month/1-year biopsy-confirmed acute rejection compared to placebo, but not compared to either ATG or OKT3. There was no significant gain in either 1-year patient survival or graft loss. The incidence of side-effects with basiliximab was not significantly different compared to OKT3/ATG. For initial/maintenance therapy, 13 RCTs found that tacrolimus reduced the 6-month/1-year incidence of biopsy-proven acute rejection compared to ciclosporin. There was no significant improvement in either 1-year or long-term (up to 5 years) graft loss or patient survival. The acute rejection benefit of tacrolimus over ciclosporin appeared to be equivalent for Sandimmun and Neoral. There were important differences in the side-effect profile of tacrolimus and ciclosporin. Seven RCTs found that mycophenolate mofetil (MMF) reduced the incidence of acute rejection. There was no significant difference in patient survival or graft loss at 1-year or 3-year follow-up. There appeared to be differences in the side-effect profiles of MMF and azathioprine (AZA). No RCTs comparing MMF with AZA were identified. One RCT compared mycophenolate sodium (MPS) to MMF and reported no difference between the two drugs in 1-year acute rejection rate, graft survival, patient survival or side-effect profile. Two RCTs suggest that addition of sirolimus to a ciclosporin-based initial/maintenance therapy reduces 1-year acute rejections in comparison to a ciclosporin (Neoral) dual therapy alone and substituting azathioprine with sirolimus in initial/maintenance therapy reduces the incidence of acute rejection. Graft and patient survival were not significantly different with either sirolimus regimen. Adding sirolimus increases the incidence of side-effects. The side-effect profiles of azathioprine and sirolimus appear to be different. For the treatment of acute rejection, three RCTs suggested that both tacrolimus and MMF reduce the incidence of subsequent acute rejection and the need for additional drug therapy. Only one RCT and one subgroup analysis in children (<18 years) were identified comparing ciclosporin to tacrolimus and sirolimus, respectively.
CONCLUSIONS
The newer immunosuppressant drugs (basiliximab, daclizumab, tacrolimus and MMF) consistently reduced the incidence of short-term (1-year) acute rejection compared with conventional immunosuppressive therapy. The independent use of basiliximab, daclizumab, tacrolimus and MMF was associated with a similar absolute reduction in 1-year acute rejection rate (approximately 15%). However, the effects of these drugs did not appear to be additive (e.g. benefit of tacrolimus with adjuvant MMF was 5% reduction in acute rejection rate compared with 15% reduction with adjuvant AZA). Thus, the addition of one of these drugs to a baseline immunosuppressant regimen was likely to affect adversely the incremental cost-effectiveness of the addition of another. The trials did not assess how the improvement in short-term outcomes (e.g. acute rejection rate or measures of graft function), together with the side-effect profile associated with each drug, translated into changes in patient-related quality of life. Moreover, given the relatively short duration of trials, the impact of the newer immunosuppressants on long-term graft loss and patient survival remains uncertain. The absence of both long-term outcome and quality of life from trial data makes assessment of the clinical and cost-effectiveness on the newer immunosuppressants contingent on modelling based on extrapolations from short-term trial outcomes. The choice of the most appropriate short-term outcome (e.g. acute rejection rate or measures of graft function) for such modelling remains a matter of clinical and scientific debate. The decision to use acute rejection in the meta-model in this report was based on the findings of a systematic review of the literature of predictors of long-term graft outcome. Only a very small proportion of the RCTs identified in this review assessed patient-focused outcomes such as quality of life. Since immunosuppressive drugs have both clinical benefits and specific side-effects, the balance of these harms and benefits could best be quantified through future trials using quality of life measures. The design of future trials should be considered with a view to the impact of drugs on particular renal transplant groups, particularly higher risk individuals and children. Finally, there is a need for improved reporting of methodological details of future trials, such as the method of randomisation and allocation concealment. A number of issues exist around registry data, for example the use of multiple drug regimens and the need to assess the long-term outcomes. An option is the use of observational registry data including, if possible, prospective data on all consecutive UK renal transplant patients. Data capture for each patient should include immunosuppressant regimens, clinical and patient-related outcomes and patient demographics.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Cost-Benefit Analysis; Daclizumab; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Models, Econometric; Mycophenolic Acid; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Survival Analysis; Tacrolimus
PubMed: 15899149
DOI: 10.3310/hta9210 -
The Cochrane Database of Systematic... May 2014Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell specific antibody induction compared with corticosteroid induction of immunosuppression after liver transplantation.
OBJECTIVES
To assess the benefits and harms of T-cell specific antibody induction versus corticosteroid induction for prevention of acute rejection in liver transplant recipients.
SEARCH METHODS
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 30 September 2013 together with reference checking, citation searching, contact with trial authors and pharmaceutical companies to identify additional trials.
SELECTION CRITERIA
We included all randomised clinical trials assessing immunosuppression with T-cell specific antibody induction versus corticosteroid induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should have received the same maintenance immunosuppressive therapy.
DATA COLLECTION AND ANALYSIS
We used RevMan for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CIs). We assessed risk of systematic errors (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance).
MAIN RESULTS
We included 10 randomised trials with a total of 1589 liver transplant recipients, which studied the use of T-cell specific antibody induction versus corticosteroid induction. All trials were with high risk of bias. We compared any kind of T-cell specific antibody induction versus corticosteroid induction in 10 trials with 1589 participants, including interleukin-2 receptor antagonist induction versus corticosteroid induction in nine trials with 1470 participants, and polyclonal T-cell specific antibody induction versus corticosteroid induction in one trial with 119 participants.Our analyses showed no significant differences regarding mortality (RR 1.01, 95% CI 0.72 to 1.43), graft loss (RR 1.12, 95% CI 0.82 to 1.53) and acute rejection (RR 0.84, 95% CI 0.70 to 1.00), infection (RR 0.96, 95% CI 0.85 to 1.09), hepatitis C virus recurrence (RR 0.89, 95% CI 0.79 to 1.00), malignancy (RR 0.59, 95% CI 0.13 to 2.73), and post-transplantation lymphoproliferative disorder (RR 1.00, 95% CI 0.07 to 15.38) when any kind of T-cell specific antibody induction was compared with corticosteroid induction (all low-quality evidence). Cytomegalovirus infection was less frequent in patients receiving any kind of T-cell specific antibody induction compared with corticosteroid induction (RR 0.50, 95% CI 0.33 to 0.75; low-quality evidence). This was also observed when interleukin-2 receptor antagonist induction was compared with corticosteroid induction (RR 0.55, 95% CI 0.37 to 0.83; low-quality evidence), and when polyclonal T-cell specific antibody induction was compared with corticosteroid induction (RR 0.21, 95% CI 0.06 to 0.70; low-quality evidence). However, when trial sequential analysis regarding cytomegalovirus infection was applied, the required information size was not reached. Furthermore, diabetes mellitus occurred less frequently when T-cell specific antibody induction was compared with corticosteroid induction (RR 0.45, 95% CI 0.34 to 0.60; low-quality evidence), when interleukin-2 receptor antagonist induction was compared with corticosteroid induction (RR 0.45, 95% CI 0.35 to 0.61; low-quality evidence), and when polyclonal T-cell specific antibody induction was compared with corticosteroid induction (RR 0.12, 95% CI 0.02 to 0.95; low-quality evidence). When trial sequential analysis was applied, the trial sequential monitoring boundary for benefit was crossed. We found no subgroup differences for type of interleukin-2 receptor antagonist (basiliximab versus daclizumab). Four trials reported on adverse events. However, no differences between trial groups were noted. Limited data were available for meta-analysis on drug-specific adverse events such as haematological adverse events for antithymocyte globulin. No data were available on quality of life.
AUTHORS' CONCLUSIONS
Because of the low quality of the evidence, the effects of T-cell antibody induction remain uncertain. T-cell specific antibody induction seems to reduce diabetes mellitus and may reduce cytomegalovirus infection when compared with corticosteroid induction. No other clear benefits or harms were associated with the use of T-cell specific antibody induction compared with corticosteroid induction. For some analyses, the number of trials investigating the use of T-cell specific antibody induction after liver transplantation is small, and the numbers of participants and outcomes in these randomised trials are limited. Furthermore, the included trials are heterogeneous in nature and have applied different types of T-cell specific antibody induction therapy. All trials were at high risk of bias. Hence, additional randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with corticosteroid induction for liver transplant recipients. Such trials ought to be conducted with low risks of systematic error and of random error.
Topics: Acute Disease; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibody Specificity; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Induction Chemotherapy; Liver Transplantation; Randomized Controlled Trials as Topic; Receptors, Interleukin-2; T-Lymphocytes
PubMed: 24880007
DOI: 10.1002/14651858.CD010252.pub2 -
Health Technology Assessment... Aug 2016End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal... (Review)
Review
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(®), 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.
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 £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.
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 £20,000-30,000 per QALY.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42014013189.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Abatacept; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Bayes Theorem; Cost-Benefit Analysis; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Economic; Mycophenolic Acid; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Technology Assessment, Biomedical
PubMed: 27578428
DOI: 10.3310/hta20620 -
The Cochrane Database of Systematic... Jan 2010Interleukin 2 receptor antagonists (IL2Ra) are used as induction therapy for prophylaxis against acute rejection in kidney transplant recipients. Use of IL2Ra has... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Interleukin 2 receptor antagonists (IL2Ra) are used as induction therapy for prophylaxis against acute rejection in kidney transplant recipients. Use of IL2Ra has increased steadily since their introduction, but the proportion of new transplant recipients receiving IL2Ra differs around the globe, with 27% of new kidney transplant recipients in the United States, and 70% in Australasia receiving IL2Ra in 2007.
OBJECTIVES
To systematically identify and summarise the effects of using an IL2Ra, as an addition to standard therapy, or as an alternative to another immunosuppressive induction strategy.
SEARCH STRATEGY
We searched the Cochrane Renal Group's specialised register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to identify new records, and authors of included reports were contacted for clarification where necessary.
SELECTION CRITERIA
Randomised controlled trials (RCTs) in all languages comparing IL2Ra to placebo, no treatment, other IL2Ra or other antibody therapy.
DATA COLLECTION AND ANALYSIS
Data was extracted and assessed independently by two authors, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI).
MAIN RESULTS
We included 71 studies (306 reports, 10,537 participants). Where IL2Ra were compared with placebo (32 studies; 5,784 patients) graft loss including death with a functioning graft was reduced by 25% at six months (16 studies: RR 0.75, 95% CI 0.58 to 0.98) and one year (24 studies: RR 0.75, 95% CI 0.62 to 0.90), but not beyond this. At one year biopsy-proven acute rejection was reduced by 28% (14 studies: RR 0.72, 95% CI 0.64 to 0.81), and there was a 19% reduction in CMV disease (13 studies: RR 0.81, 95% CI 0.68 to 0.97). There was a 64% reduction in early malignancy within six months (8 studies: RR 0.36, 95% CI 0.15 to 0.86), and creatinine was lower (7 studies: MD -8.18 micromol/L 95% CI -14.28 to -2.09) but these differences were not sustained.When IL2Ra were compared to ATG (16 studies, 2211 participants), there was no difference in graft loss at any time point, or for acute rejection diagnosed clinically, but the was benefit of ATG therapy over IL2Ra for biopsy-proven acute rejection at one year (8 studies:, RR 1.30 95% CI 1.01 to 1.67), but at the cost of a 75% increase in malignancy (7 studies: RR 0.25 95% CI 0.07 to 0.87) and a 32% increase in CMV disease (13 studies: RR 0.68 95% CI 0.50 to 0.93). Serum creatinine was significantly lower for IL2Ra treated patients at six months (4 studies: MD -11.20 micromol/L 95% CI -19.94 to -2.09). ATG patients experienced significantly more fever, cytokine release syndrome and other adverse reactions to drug administration and more leucopenia but not thrombocytopenia. There were no significant differences in outcomes according to cyclosporine or tacrolimus use, azathioprine or mycophenolate, or to the study populations baseline risk for acute rejection. There was no evidence that effects were different according to whether equine or rabbit ATG was used.
AUTHORS' CONCLUSIONS
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.
Topics: Creatinine; Cytomegalovirus Infections; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Randomized Controlled Trials as Topic; Receptors, Interleukin-2
PubMed: 20091551
DOI: 10.1002/14651858.CD003897.pub3