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

Abstract

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.

Author(s)

Lawrence MJ Best, Jeffrey Leung, Suzanne C Freeman, Alex J Sutton, Nicola J Cooper, Elisabeth Jane Milne, Maxine Cowlin, Anna Payne, Dana Walshaw, Douglas Thorburn, Chavdar S Pavlov, Brian R Davidson, Emmanuel Tsochatzis, Norman R Williams, Kurinchi Selvan Gurusamy

Abstract

Plain language summary

Medical interventions to prevent early graft rejection after liver transplantation

What is the aim of this Cochrane Review?

Liver transplantation is the main treatment option for people with severe advanced liver disease. When organs or tissues are transplanted from one person (organ donor) to another (organ recipient), the body of the organ recipient identifies the donor organ (or graft) as a foreign body and initiates a response against it in a way similar to the natural body defence mechanism against infections (immune response). This can sometimes lead to rejection or failure of the donor liver, which can result in the death of the organ recipient. Various medical interventions (immunosuppressive regimen) are used either alone or in combination to prevent rejection. The combination of interventions used in the first few months after liver transplantation (induction immunosuppressive regimen) is often different from the combination used for the rest of the patient's life (maintenance immunosuppression). It is unclear which induction immunosuppressive regimen after liver transplantation is the most effective.

The review authors collected and analysed all relevant research studies to answer this question and found 25 randomised clinical trials (studies in which participants are randomly assigned to one of two groups). During analysis of data, authors used standard Cochrane methods, which allow comparison of only two treatments at a time. Authors also used advanced techniques that allow comparison of multiple treatments simultaneously (usually referred to as 'network (or indirect) meta‐analysis').

Date of literature search
 July 2019

Key messages
 Only one of the 25 studies was conducted without flaws and most of the studies were small in terms of the number of participants included. Because of this, there is high or very high uncertainty in the obtained analysis results in this review. Overall, a drug called basiliximab may halve the number of deaths and graft failures in people who have had a liver transplant compared to the standard induction immunosuppressive regimen of glucocorticoids.

The funding source was unclear in nine studies. Commercial organisations funded 14 of the studies. There were no concerns regarding the source of funding for the remaining two trials.

What was studied in the review?

This review studied adults of any sex, age, and ethnic origin, who underwent liver transplantation for various reasons. Participants were given different induction immunosuppressive agents or no induction immunosuppressive agents. The review authors excluded studies in people who underwent other organ transplants (such as kidney transplant) in addition to the liver, and studies in which people had already developed graft rejection. The average age of participants, when reported, ranged from 48 years to 62 years. The administered induction immunosuppressive groups included glucocorticosteroids, anti‐thymocyte globulin, basiliximab, or dacluzimab either alone or in combination with glucocorticosteroids. The review authors wanted to gather and analyse data on death, graft failure, quality of life, serious and non‐serious adverse events, kidney failure, time to liver retransplantation, and graft rejections.

What were the main results of the review?

The 25 studies included a small number of participants in total (3271 participants). Study data were sparse. Twenty‐three studies with 3017 participants altogether provided data for analyses. The follow‐up of participants in the trials ranged from three to 76 months: the average follow‐up in the trials was 12 months. The review shows that:
 ‐ seven out of every 100 people died and 12 out of every 100 people developed graft failure;
 ‐ compared with the standard induction immunosuppression of glucocorticosteroids, basiliximab may halve the number of deaths and graft failure; however this information is based on small studies with flaws. Therefore, there is a lot of uncertainty about the effect of basiliximab;
 ‐ the evidence is uncertain about the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections;
 ‐ none of the trials reported health‐related quality of life;
 ‐ future well‐designed trials are needed.

Author(s)

Lawrence MJ Best, Jeffrey Leung, Suzanne C Freeman, Alex J Sutton, Nicola J Cooper, Elisabeth Jane Milne, Maxine Cowlin, Anna Payne, Dana Walshaw, Douglas Thorburn, Chavdar S Pavlov, Brian R Davidson, Emmanuel Tsochatzis, Norman R Williams, Kurinchi Selvan Gurusamy

Reviewer's Conclusions

Authors' conclusions

Implications for practice

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 regarding the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections.

Implications for research

Further well‐designed randomised clinical trials are necessary. Some aspects of the design of the randomised clinical trials should be as follows.

  • Study design: double‐blind, placebo‐controlled, parallel, randomised clinical trial.
  • Participants: people undergoing liver transplantation.
  • Intervention: basiliximab induction.
  • Control: glucocorticosteroid induction or no active intervention (if it is feasible to include this as one of the control groups).
  • Outcomes
    • Primary outcome: graft failure (1 year)
    • Secondary outcomes: all‐cause mortality (1 year), health‐related quality of life, adverse events, graft rejections requiring treatment
    • Minimum length of follow‐up: one year
  • Sample size: for a simple two‐arm, parallel, randomised clinical trial, the sample size required to detect a relative risk reduction of 30% in the experimental group from the control group proportion of 12.2% graft failure (median proportion in glucocorticosteroid induction), type I error of 5%, and type II error of 20%, 2176 participants are required.
  • Other aspects: trials need to be conducted and reported according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement (Chan 2013) and CONSORT statement (Schulz 2010).

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