Abstract: 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.

Plain-language summary: 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. 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. 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.