Induction immunosuppression in adults undergoing liver transplantation: a network meta-analysis

Cochrane Database Syst Rev. 2020 Jan 16;1(1):CD013203 doi: 10.1002/14651858.CD013203.pub2.
Abstract
BACKGROUND:

Liver transplantation is considered the definitive treatment for people with liver failure. As part of post-liver transplantation management, immunosuppression (suppressing the host immunity) is given to prevent graft rejections. Immunosuppressive drugs can be classified into those that are used for a short period during the beginning phase of immunosuppression (induction immunosuppression) and those that are used over the entire lifetime of the individual (maintenance immunosuppression), because it is widely believed that graft rejections are more common during the first few months after liver transplantation. Some drugs such as glucocorticosteroids may be used for both induction and maintenance immunosuppression because of their multiple modalities of action. There is considerable uncertainty as to whether induction immunosuppression is necessary and if so, the relative efficacy of different immunosuppressive agents.

OBJECTIVES:

To assess the comparative benefits and harms of different induction immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different induction immunosuppressive regimens according to their safety and efficacy.

SEARCH METHODS:

We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until July 2019 to identify randomised clinical trials in adults undergoing liver transplantation.

SELECTION CRITERIA:

We included only randomised clinical trials (irrespective of language, blinding, or status) in adults undergoing liver transplantation. We excluded randomised clinical trials in which participants had multivisceral transplantation and those who already had graft rejections.

DATA COLLECTION AND ANALYSIS:

We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, and hazard ratio (HR) with 95% credible intervals (CrIs) based on an available case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.

MAIN RESULTS:

We included a total of 25 trials (3271 participants; 8 treatments) in the review. Twenty-three trials (3017 participants) were included in one or more outcomes in the review. The trials that provided the information included people undergoing primary liver transplantation for various indications and excluded those with HIV and those with renal impairment. The follow-up in the trials ranged from three to 76 months, with a median follow-up of 12 months among trials. All except one trial were at high risk of bias, and the overall certainty of evidence was very low. Overall, approximately 7.4% of people who received the standard regimen of glucocorticosteroid induction died and 12.2% developed graft failure. All-cause mortality and graft failure was lower with basiliximab compared with glucocorticosteroid induction: all-cause mortality (HR 0.53, 95% CrI 0.31 to 0.93; network estimate, based on 2 direct comparison trials (131 participants; low-certainty evidence)); and graft failure (HR 0.44, 95% CrI 0.28 to 0.70; direct estimate, based on 1 trial (47 participants; low-certainty evidence)). There was no evidence of differences in all-cause mortality and graft failure between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). There was also no evidence of differences in serious adverse events (proportion), serious adverse events (number), renal failure, any adverse events (proportion), any adverse events (number), liver retransplantation, graft rejections (any), or graft rejections (requiring treatment) between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the studies reported health-related quality of life.

FUNDING:

the source of funding for 14 trials was drug companies who would benefit from the results of the study; two trials were funded by neutral organisations who have no vested interests in the results of the study; and the source of funding for the remaining nine trials was unclear.

AUTHORS' CONCLUSIONS:

Based on low-certainty evidence, basiliximab induction may decrease mortality and graft failure compared to glucocorticosteroids induction in people undergoing liver transplantation. However, there is considerable uncertainty about this finding because this information is based on small trials at high risk of bias. The evidence is uncertain about the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections. Future randomised clinical trials should be adequately powered, employ blinding, avoid post-randomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, graft failure, and health-related quality of life.

CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is a well conducted Cochrane systematic review of RCTs. Multiple databases were searched and references were screened in duplicate. 25 RCTs were included, with a median 12 months follow up (total 3271 patients). Data extraction was then conducted in duplicate to a pre-designed format. The standard Cochrane risk of bias assessment was used to appraise the included studies. Heterogeneity was assessed both statistically and by examination. As not all included trials made the same comparisons, a network meta-analysis was used to compare immune suppression induction regimens. Despite this approach the key conclusions only draw upon the results of 2 included studies: Basiliximab was associated with reduced all-cause mortality compared to glucocorticoids (131 patients). Only 1 study made the comparison between Basiliximab and glucocorticoids and presented the outcome of graft failure, which was less with Basiliximab (47 patients). This means that there is a low level of certainty with regards to the key outcomes of this systematic review. There is an even lower level of certainty when comparing other induction regimens and glucocorticoids.
Study Details
Aims: The aim of study was to compare the benefits and harms of using different immunosuppressive induction regimens among adult liver transplant recipients through a network meta-analysis and to rank the induction immunosuppressive regimens on the basis of their efficacy and safety.
Interventions: Electronic databases including Cochrane Central Register of Controlled Trials (CENTRAL), Science Citation Index Expanded (Web of Science), Embase Ovid and MEDLINE Ovid were searched for randomised controlled trials comparing two or more pre-specified induction immunosuppressive regimens of interest from inception to July 2019. The World Health Organization International Clinical Trials Registry Platform, the US National Institutes of Health Ongoing Trials Register, existing Cochrane Reviews and the references of the identified trials were also searched to identify additional trials. The study selection and data extraction were carried out by two independent authors. The risk of bias was assessed using the Cochrane Handbook for Systematic Reviews of Interventions.
Participants: 25 studies (3271 participants) were included in the review.
Outcomes: The primary outcomes were mortality from all causes at maximal follow-up, time to graft failure (retransplantation or death) at maximal follow up, health-related quality of life and incidence of serious adverse events. The secondary outcomes were incidence of any adverse event, time to liver retransplantation at maximal follow-up and acute rejection at maximal follow-up. The exploratory outcomes included costs at maximal follow-up.
Follow Up: N/A
Metadata
Funding: Non-industry funding
Publication type: Meta-Analysis, Systematic Review
Organ: Liver
Language: English
Author email: k.gurusamy@ucl.ac.uk
MeSH terms: Bayes Theorem; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Network Meta-Analysis; Quality of Life; Randomized Controlled Trials as Topic; Transplantation Immunology; 0 (Immunosuppressive Agents)