Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis

Abstract

As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body against transplanted organ or tissues from a different person whose tissue antigens are not compatible with those of the recipient. The optimal maintenance immunosuppressive regimen after liver transplantation remains uncertain. To assess the comparative benefits and harms of different maintenance immunosuppressive regimens in adults undergoing liver transplantation through a network meta‐analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy. We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until October 2016 to identify randomised clinical trials on immunosuppression for liver transplantation. We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adult participants undergoing liver transplantation (or liver retransplantation) for any reason. We excluded trials in which participants had undergone multivisceral transplantation or participants with established graft rejections. We considered any of the various maintenance immunosuppressive regimens compared with each other. We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available‐case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta‐analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow‐up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow‐up between the different maintenance immunosuppressive regimens based on the network meta‐analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow‐up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta‐analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health‐related quality of life, or costs. Funding: 14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding. Based on low‐quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow‐up compared with tacrolimus. Based on very low‐quality evidence from network meta‐analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low‐quality evidence from network meta‐analysis and low‐quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross‐overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors. Background 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 mounts a response against it in a way similar to the natural body defence mechanism against infections (immune response). This can lead to graft rejection and graft loss resulting in death of the organ recipient. Various medical interventions are used either alone or in combination (immunosuppressive regimen) to prevent graft rejections. The combination of interventions used in the first few months after liver transplantation (induction immunosuppressive regimen) often differs from the combination used for the rest of the patient's life (maintenance immunosuppression). It is unclear which immunosuppressive regimen after liver transplantation is the best. We sought to identify the best maintenance immunosuppressive regimen by searching for existing studies on the topic. We included all randomised clinical trials reported until October 2016. We included only trials of participants who had previously undergone liver transplantation. We excluded trials of participants who had undergone multi‐organ transplantation (e.g. liver and kidney transplantations) or participants with established graft rejections. Apart from using standard Cochrane methods, which allow comparison of only two interventions at a time (direct comparison), we also employed advanced methods that allow comparison of the many different interventions individually compared in the trials (network meta‐analysis). Study characteristics We identified 26 randomised clinical trials with a total of 3842 participants. Of these, 23 randomised clinical trials (3693 participants) provided information for one or more outcomes. The trials mainly included participants undergoing liver transplantation for the first time, for various reasons. Funding: 14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding. Quality of evidence The overall quality of the evidence was low or very low, and all of the trials were at high risk of bias, which means it is possible that the conclusions made could overestimate the benefits or underestimate the harms of a given intervention because of the way the trials were conducted. In addition, because of insufficient information, the results of network meta‐analysis are not entirely reliable. Key results Several medical drugs were compared in the trials. We found no evidence of difference in the risk of death or graft loss between the different immunosuppressive regimens based on the network meta‐analysis. In the direct comparison, based on a single trial including 222 participants, the risk of death and graft loss was higher with tacrolimus plus sirolimus than with tacrolimus alone. There was no evidence of differences between the various immunosuppressive regimens in percentage of people who developed serious adverse events, percentage of people who developed any adverse events, risk of poor kidney function requiring dialysis or kidney transplantation (kidney dysfunction), prolonged kidney disease, graft rejections requiring treatment, and any graft rejections. The number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens. The risk of retransplantation was higher with cyclosporine A than with tacrolimus. None of the trials reported number of serious adverse events, health‐related quality of life, or costs. There is significant uncertainty as to the optimal maintenance immunosuppressive regimen after liver transplantation; further well‐designed randomised clinical trials are required. Future trials should be performed in people who are generally seen in the clinic rather than in highly selected participants and report clinically important outcomes such as death, graft loss, kidney dysfunction, long‐term kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors.