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The Cochrane Database of Systematic... Jun 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 antibody induction for preventing rejection after liver transplantation.
OBJECTIVES
To assess the benefits and harms of immunosuppressive T-cell specific antibody induction compared with placebo, no induction, or another type of T-cell specific antibody 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) until September 2013.
SELECTION CRITERIA
Randomised clinical trials assessing immunosuppression with T-cell specific antibody induction compared with placebo, no induction, or another type of antibody induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should have received the same maintenance immunosuppressive therapy. We planned to include trials with all of the different types of T-cell specific antibodies that are or have been used for induction (ie., polyclonal antibodies (rabbit of horse antithymocyte globulin (ATG), or antilymphocyte globulin (ALG)), monoclonal antibodies (muromonab-CD3, anti-CD2, or alemtuzumab), and interleukin-2 receptor antagonists (daclizumab, basiliximab, BT563, or Lo-Tact-1)).
DATA COLLECTION AND ANALYSIS
We used RevMan analysis 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 the risk of systematic errors (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance). We presented outcome results in a summary of findings table.
MAIN RESULTS
We included 19 randomised clinical trials with a total of 2067 liver transplant recipients. All 19 trials were with high risk of bias. Of the 19 trials, 16 trials were two-arm trials, and three trials were three-arm trials. Hence, we found 25 trial comparisons with antibody induction agents: interleukin-2 receptor antagonist (IL-2 RA) versus no induction (10 trials with 1454 participants); monoclonal antibody versus no induction (five trials with 398 participants); polyclonal antibody versus no induction (three trials with 145 participants); IL-2 RA versus monoclonal antibody (one trial with 87 participants); and IL-2 RA versus polyclonal antibody (two trials with 112 participants). Thus, we were able to compare T-cell specific antibody induction versus no induction (17 trials with a total of 1955 participants). Overall, no difference in mortality (RR 0.91; 95% CI 0.64 to 1.28; low-quality of evidence), graft loss including death (RR 0.92; 95% CI 0.71 to 1.19; low-quality of evidence), and adverse events ((RR 0.97; 95% CI 0.93 to 1.02; low-quality evidence) outcomes was observed between any kind of T-cell specific antibody induction compared with no induction when the T-cell specific antibody induction agents were analysed together or separately. Acute rejection seemed to be reduced when any kind of T-cell specific antibody induction was compared with no induction (RR 0.85, 95% CI 0.75 to 0.96; moderate-quality evidence), and when trial sequential analysis was applied, the trial sequential monitoring boundary for benefit was crossed before the required information size was obtained. Furthermore, serum creatinine was statistically significantly higher when T-cell specific antibody induction was compared with no induction (MD 3.77 μmol/L, 95% CI 0.33 to 7.21; low-quality evidence), as well as when polyclonal T-cell specific antibody induction was compared with no induction, but this small difference was not clinically significant. We found no statistically significant differences for any of the remaining predefined outcomes - infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension - when the T-cell specific antibody induction agents were analysed together or separately. Limited data were available for meta-analysis on drug-specific adverse events such as haematological adverse events for antithymocyte globulin. No data were found on quality of life.When T-cell specific antibody induction agents were compared with another type of antibody induction, no statistically significant differences were found for mortality, graft loss, and acute rejection for the separate analyses. When interleukin-2 receptor antagonists were compared with polyclonal T-cell specific antibody induction, drug-related adverse events were less common among participants treated with interleukin-2 receptor antagonists (RR 0.23, 95% CI 0.09 to 0.63; low-quality evidence), but this was caused by the results from one trial, and trial sequential analysis could not exclude random errors. We found no statistically significant differences for any of the remaining predefined outcomes: infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension. No data were found on quality of life.
AUTHORS' CONCLUSIONS
The effects of T-cell antibody induction remain uncertain because of the high risk of bias of the randomised clinical trials, the small number of randomised clinical trials reported, and the limited numbers of participants and outcomes in the trials. T-cell specific antibody induction seems to reduce acute rejection when compared with no induction. No other clear benefits or harms were associated with the use of any kind of T-cell specific antibody induction compared with no induction, or when compared with another type of T-cell specific antibody. Hence, more randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with placebo, and compared with another type of antibody, for prevention of rejection in liver transplant recipients. Such trials ought to be conducted with low risks of systematic error (bias) and low risk of random error (play of chance).
Topics: Acute Disease; Antibodies, Monoclonal; Antibody Formation; Graft Rejection; Humans; Immunity, Cellular; Immunosuppression Therapy; Liver Transplantation; Randomized Controlled Trials as Topic; T-Lymphocytes
PubMed: 24901467
DOI: 10.1002/14651858.CD010253.pub2 -
Annals of Hematology Feb 2021Graft-versus-host disease (GVHD) prophylaxis based on post-transplant cyclophosphamide (PTCy) or antithymocyte globulin (ATG) is widely used in allogeneic hematopoietic... (Comparative Study)
Comparative Study Meta-Analysis
Graft-versus-host disease (GVHD) prophylaxis based on post-transplant cyclophosphamide (PTCy) or antithymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantations (allo-HCT). The differential impacts of PTCy and ATG on transplantation outcomes are not well characterized. Here we report a meta-analysis of PTCy versus ATG in allo-HCT. Ten studies were eligible, and a total of 1871 patients were included. The incidence of II-IV aGVHD, III-IV aGVHD, and NRM were significantly lower in PTCy arm (HR = 0.63, 95% CI 0.45-0.89; HR = 0.35, 95% CI 0.16-0.77; HR = 0.59, 95% CI 0.48-0.73). PTCy was associated with a better OS and PFS (HR = 0.62, 95% CI = 0.53-0.73; HR = 0.76, 95% CI 0.62-0.93). The relapse rate and cGVHD incidence were not significantly different between PTCy and ATG (HR = 0.85, 95% CI 0.68-1.07; HR = 0.65, 95% CI 0.38-1.12). Thus, compared with ATG, PTCy has a better aGVHD control and OS benefit, without increasing relapse risk, which needs further validation in prospective randomized trials.
Topics: Allografts; Antilymphocyte Serum; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Recurrence; Risk Factors
PubMed: 33420575
DOI: 10.1007/s00277-021-04399-x -
The Cochrane Database of Systematic... Sep 2012Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host disease (GVHD), a condition frequently occurring after HSCT, is the result of host tissues being attacked by donor immune cells. One strategy for the prevention of GVHD is the administration of anti-thymocyte globulins (ATG), a set of polyclonal antibodies directed against a variety of immune cell epitopes, leading to immunosuppression and immunomodulation.
OBJECTIVES
To assess the effect of ATG used for the prevention of graft-versus-host disease (GVHD) in patients undergoing allogeneic HSCT with regard to overall survival, incidence and severity of acute and chronic GVHD, incidence of relapse, incidence of infectious complications, non-relapse mortality, early mortality within 100 days of transplantation, progression-free survival, quality of life and adverse events.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (January 1950 to February 2012), trials registries and conference proceedings. The search was conducted in October 2010 and was updated in July 2011 and February 2012. We did not apply any language restrictions.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) investigating the impact of ATG on GVHD prophylaxis in adults suffering from haematological diseases and undergoing allogeneic HSCT. Treatment arms had to differ only in the addition of ATG to the standard GVHD prophylaxis regimen.
DATA COLLECTION AND ANALYSIS
Two review authors screened abstracts, extracted data and analysed the data independently. We contacted study authors for additional information.
MAIN RESULTS
We included in the meta-analysis six RCTs which met the pre-defined selection criteria, involving a total of 568 participants. Quality of data reporting was heterogeneous among these studies with a lack of detailed information in the early studies.The primary outcome of overall survival was not significantly changed by the addition of ATG for the prophylaxis of GVHD (harms ratio (HR) 0.88; 95% CI 0.67 to 1.15, P = 0.33).The incidence of treatment-requiring or severe acute GVHD (grade II to IV) was significantly lower in patients who received ATG (risk ratio (RR) 0.68; 95% CI 0.55 to 0.85, P = 0.009; number needed to treat (NNT) 8). Also, the incidence of severe acute GVHD (grade III to IV) was significantly reduced (HR 0.53; 95% CI 0.33 to 0.85, P = 0.0005; NNT 7) but comparable data were available for rabbit ATG only. However, pooled study results regarding the incidence of acute GVHD of all grades (I to IV) showed no significant benefit of ATG treatment (RR 0.89; 95% CI 0.74 to 1.06, P = 0.20).Meta-analysis of data regarding the incidence of overall chronic GVHD (both, limited and extensive) was not possible. Nevertheless, studies reporting on extensive chronic GVHD (only studies evaluating rabbit ATG) suggested a lower incidence of extensive chronic GVHD whereas others that only reported on overall chronic GVHD did not show an advantage for ATG.Pooled results regarding the incidence of relapse were not significantly different (RR 1.13; 95% CI 0.75 to 1.68, P = 0.56), as well as pooled results regarding non-relapse mortality (HR 0.82; 95% CI 0.55 to 1.24, P = 0.35).Due to the lack of comparable data, we could not perform meta-analysis of data regarding the incidence of chronic GVHD, relapse-related mortality, progression-free survival, quality of life, adverse events and engraftment.
AUTHORS' CONCLUSIONS
Our systematic review suggests that the addition of ATG during allogeneic HSCT significantly reduces the incidence of severe grades (II to IV) of acute GvHD, whereas the incidence of overall acute GVHD (grades I to IV) was not significantly lowered. This indicates a reduction of the severity but not the incidence of acute GVHD. However, this effect did not lead to a significant improvement of overall survival, which may be due to the severe potential side effects of the consecutively increased immunosuppression.Furthermore, future research is needed to clarify the effect of ATG on the incidence and severity of chronic GVHD and consequently on all aspects of quality of life.From the currently available data, no recommendation on the general use of ATG in allogeneic HSCT can be supported. Therefore, a careful consideration of the use of ATG based on the patient's condition and the risk factors of the transplantation setting should be made.
Topics: Acute Disease; Adult; Antilymphocyte Serum; Bone Marrow Transplantation; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Randomized Controlled Trials as Topic; Recurrence; Transplantation, Homologous
PubMed: 22972135
DOI: 10.1002/14651858.CD009159.pub2 -
The Cochrane Database of Systematic... Apr 2006Registry data shows that between 15-35% kidney recipients will undergo treatment for at least one episode of acute rejection within the first post transplant year.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Registry data shows that between 15-35% kidney recipients will undergo treatment for at least one episode of acute rejection within the first post transplant year. Treatment options include pulsed steroid therapy, the use of an antibody preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the US, 61.4% patients with an acute rejection episode received steroids, 20.4% received an antibody preparation and 18.2% received both.
OBJECTIVES
To determine the benefits and harms of mono- or polyclonal antibodies (Ab) used to treat acute rejection in kidney transplant recipients.
SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library, issue 2, 2005), MEDLINE (1966-June 2005), EMBASE (1980-June 2005), and the specialised register of the Cochrane Renal Group (June 2005).
SELECTION CRITERIA
Randomised controlled trials (RCTs) in all languages comparing all mono- and polyclonal antibody preparations, given in combination with any other immunosuppressive agents, for the treatment of acute graft rejection, when compared to any other treatment for acute rejection.
DATA COLLECTION AND ANALYSIS
Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as relative risk (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Twenty one trials (49 reports, 1387 patients) were identified. Trials were generally small, incompletely reported, especially for potential harms, and did not define outcome measures adequately. Fourteen trials (965 patients) compared therapies for first rejection episodes. Ab was better than steroid in reversing rejection (RR 0.57, 95% CI 0.38 to 0.87) and preventing graft loss (death censored RR 0.74, CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection or death at one year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection. There was no benefit of muromonab-CD3 over ATG or ALG in either reversing rejection, preventing subsequent rejection, preventing graft loss or death.
AUTHORS' CONCLUSIONS
In reversing first rejection, any antibody is better than steroid and also prevents graft loss, but subsequent rejection and patient survival are not significantly different. In reversing steroid-resistant rejection the effects of different antibodies are also not significantly different. Given the clinical problem caused by acute rejection, data are very sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed.
Topics: Acute Disease; Antibodies; Antibodies, Monoclonal; Antilymphocyte Serum; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Randomized Controlled Trials as Topic
PubMed: 16625610
DOI: 10.1002/14651858.CD004756.pub3 -
Clinical Transplantation Jul 2020The role of antithymocyte globulin (ATG) in patients with hematologic diseases undergoing umbilical cord blood transplantation (UCBT) remains controversial. This... (Meta-Analysis)
Meta-Analysis
The role of antithymocyte globulin (ATG) in patients with hematologic diseases undergoing umbilical cord blood transplantation (UCBT) remains controversial. This systematic review and meta-analysis was conducted to comprehensively evaluate this issue. PubMed, Embase, and the Cochrane Library were systematically searched. Clinical studies reporting the impact of ATG- vs non-ATG-containing conditioning regimens on transplantation outcomes were identified. Twenty-five studies were included. ATG significantly prevented grade II-IV and grade III-IV acute graft-vs-host disease (GVHD) (11 studies, 5020 patients, HR: 0.49, 95% CI: 0.42-0.56, P < .001; 5 studies, 5490 patients, HR: 0.60, 95% CI: 0.46-0.80, P < .001) but not chronic GVHD (8 studies, 5952 patients, HR: 0.78, 95% CI: 0.51-1.20, P = .266). However, use of ATG was associated with increased transplantation-related mortality and inferior overall survival (9 studies, 4244 patients, HR: 1.79, 95% CI: 1.38-2.33, P < .001; 8 studies, 5438 patients, HR: 1.96, 95% CI: 1.56-2.46, P < .001). Our study did not recommend routine use of ATG in UCBT. Individualizing the ATG timing and dose based on patient characteristics to retain the prophylactic effects of ATG on GVHD without compromising the survival of UCBT recipients may be reasonable.
Topics: Antilymphocyte Serum; Cord Blood Stem Cell Transplantation; Graft vs Host Disease; Hematologic Diseases; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Transplantation Conditioning
PubMed: 32277839
DOI: 10.1111/ctr.13876 -
Frontiers in Immunology 2020Thymoglobulin (THG) and antithymocyte globulin-Fresenius (ATG-F) have not been compared directly as induction therapies in kidney transplantation. We performed a... (Meta-Analysis)
Meta-Analysis
Thymoglobulin (THG) and antithymocyte globulin-Fresenius (ATG-F) have not been compared directly as induction therapies in kidney transplantation. We performed a Bayesian network meta-analysis to compare THG with ATG-F by pooling direct and indirect evidence. Surface under the cumulative ranking curve (SUCRA) values were used to compare the superiority of one method over the other. A total of 27 randomized controlled trials (RCT) were eligible for the network meta-analysis. Efficacy endpoints, as well as safety indicators, were statistically comparable. For efficacy endpoints, THG seemed inferior to ATG-F in preventing delayed graft function [odds ratio (OR): 1.27; SUCRA: 78% vs. 58%], patient deaths (OR: 2.78; SUCRA: 83% vs. 34%), and graft loss (OR: 1.40; SUCRA: 83% vs. 59%), but superior to ATG-F in biopsy-proven acute rejection (BPAR; OR: 0.59; SUCRA: 78% vs. 39%) and steroid-resistant BPAR prevention (OR: 0.61; SUCRA: 76% vs. 49%) within the first year. For safety endpoints, THG was associated with higher risk of infection (OR: 1.49, SUCRA: 79% vs. 54%), cytomegalovirus infection (OR: 1.04; SUCRA: 40% vs. 37%), diabetes (OR: 1.10; SUCRA: 90% vs. 30%), and malignancy (OR: 8.40; SUCRA: 89% vs. 6%) compared to ATG-F. A subgroup analysis of patients at high risk for immunologic complications revealed similar results, but THG performed better for graft loss (OR: 0.82; SUCRA: 68% vs. 54%). ATG-F seemed to be more effective than THG in improving the short-term kidney transplantation outcomes. Prospective head-to-head comparison of THG and ATG-F with larger sample sizes and longer follow-up is still required.
Topics: Antilymphocyte Serum; Bayes Theorem; Delayed Graft Function; Graft Rejection; Immunosuppressive Agents; Kidney Transplantation; Network Meta-Analysis; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome
PubMed: 32318057
DOI: 10.3389/fimmu.2020.00457 -
International Urology and Nephrology Apr 2020The aim of this meta-analysis is to explore the effect of IL-2RA vs rATG on the rate of acute rejection, post-transplant infections, and graft as well as patient's... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
The aim of this meta-analysis is to explore the effect of IL-2RA vs rATG on the rate of acute rejection, post-transplant infections, and graft as well as patient's survival in standard- and high-risk renal transplant patients receiving tacrolimus-based maintenance immunotherapy.
METHODS
Random effects model was the method used for identifying risk difference. Confidence interval including the value 1 was used as evidence for statistically significant risk difference. Heterogeneity was assessed using Der Simonian analysis. Heterogeneity was evident at the level of P value < 0.1 RESULTS: The random effects model showed no significant differences in both acute rejection rates between IL-2RA and rATG induction therapies with relative risk of 1.24 graft survival with relative risk 0.90. Patient survival also did not demonstrate any significant difference with a relative risk of 1.19. Random effects for CMV infection showed a lesser tendency for CMV infection in IL-2RA group compared to ATG group the with a relative risk of 0.73.In subgroup analysis, the random effects model for acute rejection rates in high-risk transplants showed a higher risk of acute rejection in the IL-2RA group compared to rATG (relative risk equals 1.55) In standard-risk transplants, there were no significant differences between both groups with relative risk equals 1.02 CONCLUSIONS: This meta-analysis revealed no significant difference in patient and graft survival when using IL-2RA vs rATG with the tacrolimus-based maintenance immunosuppression era. However, subgroup analysis showed less incidence of rejection in high-risk renal transplant recipient's population using rATG compared to IL-2RA.
Topics: Antilymphocyte Serum; Basiliximab; Cytomegalovirus Infections; Daclizumab; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Transplantation; Maintenance Chemotherapy; Models, Statistical; Receptors, Interleukin-2; Survival Rate; Tacrolimus
PubMed: 32170593
DOI: 10.1007/s11255-020-02418-w