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. 2017 Mar 31;3(3):CD011639.
doi: 10.1002/14651858.CD011639.pub2.

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

Manuel Rodríguez-Perálvarez  1 , Marta Guerrero-Misas  2 , Douglas Thorburn  3 , Brian R Davidson  4 , Emmanuel Tsochatzis  3 , Kurinchi Selvan Gurusamy  4
Affiliations

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

Manuel Rodríguez-Perálvarez et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

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Conflict of interest statement

This report is independent research funded by the National Institute for Health Research (NIHR Cochrane Programme Grants, 13/89/03 ‐ Evidence‐based diagnosis and management of upper digestive, hepato‐biliary, and pancreatic disorders). The views expressed in this publication are those of the review authors and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health.

Kurinchi Gurusamy, Manuel Rodríguez‐Perálvarez, Marta Guerrero‐Misas, Emmanuel Tsochatzis, and Brian Davidson have no financial disclosures. Astellas funded Douglas Thorburn for his attendance at the International Liver Transplantation Society meeting in 2014. Douglas Thorburn also received GBP 25,000 from Boston Scientific to fund a clinical research fellow in 2013. We have no other financial disclosures to report.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
The network plots showing the comparisons in which there were at least two trials. The size of the node (circle) provides a measure of the number of trials in which the particular Intervention was included as one of the intervention groups. The thickness of the line provides a measure of the number of direct comparisons between two nodes (Interventions). Only two outcomes (mortality at maximal follow‐up and graft rejections requiring treatment) have treatment comparisons in which direct and indirect estimates were available. Although 'closed loops' are present in some other outcomes (e.g. graft loss at maximal follow‐up, adverse events (proportion), renal impairment, and graft rejections (any)), this was due to a trial with three intervention groups. Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Sir = sirolimus; Ever = everolimus; Std = glucocorticosteroids; _ = plus
5
5
IF (Inconsistency Factor) plots of outcomes in which there were comparisons for which direct and indirect estimates were available (i.e. mortality at maximal follow‐up and graft rejection requiring treatment). There was no evidence of inconsistency in these outcomes, as the confidence intervals of the inconsistency factor overlapped one.
6
6
Forest plot of mortality at maximal follow‐up (network meta‐analysis estimates and direct comparisons when available). Both fixed‐effect model and random‐effects model for other Interventions compared to tacrolimus are provided. The direct estimates and network meta‐analysis estimates are similar except for tacrolimus plus sirolimus versus tacrolimus. Tacrolimus plus sirolimus causes more mortality at maximal follow‐up in the direct comparison involving one trial and fixed‐effect model of network meta‐analysis but not in the random‐effects model of network meta‐analysis. We used the more conservative random‐effects model to arrive at conclusions. Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Sir = sirolimus; Ever = everolimus; Std = glucocorticosteroids; _ = plus
7
7
The table provides the effect estimate (hazard ratio) of each pairwise comparison for mortality at maximal follow‐up. The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison. Treatment effects with evidence of difference are shown in italics. As presented, there is no evidence of difference in any of the pairwise comparisons in the network meta‐analysis, although direct comparison showed that tacrolimus plus sirolimus had higher mortality than tacrolimus, and tacrolimus plus glucocorticosteroids had lower mortality than cyclosporine A plus azathioprine plus glucocorticosteroids in single trials. * = single trial Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Sir = sirolimus; Ever = everolimus; Std = glucocorticosteroids; _ = plus
8
8
Mortality (maximal follow‐up) A. The figure shows the surface area under the curve constructed on the basis of the ranking probabilities.
 B. The figure shows the probability of each Intervention being best, second best, third best, and so on. There was no evidence that one Intervention is clearly better than any of the other Interventions.
 
 Legend: 1: tacrolimus; 2: cyclosporine A; 3: cyclosporine A plus azathioprine; 4: cyclosporine A plus azathioprine plus glucocorticosteroids; 5: cyclosporine A plus mycophenolate plus glucocorticosteroids; 6: cyclosporine A plus glucocorticosteroids; 7: everolimus; 8: tacrolimus plus azathioprine; 9: tacrolimus plus everolimus; 10: tacrolimus plus mycophenolate plus glucocorticosteroids; 11: tacrolimus plus sirolimus; 12: tacrolimus plus glucocorticosteroids.
9
9
Forest plot of graft loss at maximal follow‐up (network meta‐analysis estimates and direct comparisons when available). Both fixed‐effect model and random‐effects model for other Interventions compared to tacrolimus are provided. The direct estimates and network meta‐analysis estimates are similar except for tacrolimus plus sirolimus versus tacrolimus. Tacrolimus plus sirolimus causes more graft loss at maximal follow‐up in the direct comparison involving one trial and fixed‐effect model of network meta‐analysis but not in the random‐effects model of network meta‐analysis. We used the more conservative random‐effects model to arrive at conclusions. Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Sir = sirolimus; Ever = everolimus; Std = glucocorticosteroids; _ = plus
10
10
The table provides the effect estimate (hazard ratio) of each pairwise comparison for graft loss at maximal follow‐up. The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison. Treatment effects with evidence of difference are shown in italics. As presented, there was no evidence of difference in any of the pairwise comparisons in the network meta‐analysis, although tacrolimus plus sirolimus appears to increase graft loss at maximal follow‐up compared to tacrolimus. * single trial Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Sir = sirolimus; Ever = everolimus; Std = glucocorticosteroids; _ = plus
11
11
Graft loss (maximal follow‐up) A. The figure shows the surface area under the curve constructed on the basis of the ranking probabilities.
 B. The figure shows the probability of each Intervention being best, second best, third best, and so on. There was no evidence that one intervention is clearly better than any of the other interventions.
 
 Legend: 1: tacrolimus; 2: cyclosporine A; 3: cyclosporine A plus azathioprine; 4: everolimus; 5: tacrolimus plus azathioprine; 6: tacrolimus plus everolimus; 7: tacrolimus plus mycophenolate plus glucocorticosteroids; 8: tacrolimus plus sirolimus; 9: tacrolimus plus glucocorticosteroids.
12
12
Forest plot of adverse events (proportion) (network meta‐analysis estimates and direct comparisons when available). Both fixed‐effect model and random‐effects model for other interventions compared with tacrolimus are provided. The direct estimates and network meta‐analysis estimates are similar. As there was only trial for each comparison, the random‐effects model for the direct comparisons is not provided. There was no evidence of difference between any of the comparisons. Abbreviations: Tac = tacrolimus; Ever = everolimus; Sir = sirolimus
13
13
The table provides the effect estimate (odds ratio) of each pairwise comparison for adverse events (proportion) corresponding to intervention B. The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison.
 
 Treatment effects with evidence of difference are shown in italics. As presented, there was no evidence of difference in any of the pairwise comparisons. * single trial Abbreviations: Tac = tacrolimus; Ever = everolimus; Sir = sirolimus
14
14
Adverse events (proportion) A. The figure shows the surface area under the curve constructed on the basis of the ranking probabilities.
 B. The figure shows the probability of each Intervention being best, second best, third best, and so on. Although the figure shows that tacrolimus plus sirolimus was the worst intervention in terms of adverse events (proportion), there was no evidence of differences in the odds ratios between the different interventions.
 
 Legend: 1: tacrolimus; 2: everolimus; 3: tacrolimus plus everolimus; 4: tacrolimus plus sirolimus.
15
15
Forest plot of adverse events (number) (network meta‐analysis estimates and direct comparisons when available). Both fixed‐effect model and random‐effects model for other interventions compared to tacrolimus are provided. The direct estimates and network meta‐analysis estimates are similar. The number of adverse events appears to be higher for cyclosporine A than for tacrolimus. There was no evidence of difference in the remaining comparisons with tacrolimus. Abbreviations: Cy = cyclosporine A; Tac = tacrolimus; Ever = everolimus; Myc = mycophenolate; Sir = sirolimus; Std = glucocorticosteroids
16
16
The table provides the effect estimate (rate ratio) of each pairwise comparison for adverse events (number) corresponding to intervention B. The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison.
 
 Treatment effects with evidence of difference are shown in italics. As presented, cyclosporine A appears to be associated with fewer adverse events than tacrolimus and cyclosporine A plus glucocorticosteroids (based on both network meta‐analysis and direct comparisons), and fewer adverse events than tacrolimus plus mycophenolate and tacrolimus plus mycophenolate plus glucocorticosteroids based on network meta‐analysis. Tacrolimus plus mycophenolate also appears to be associated with more adverse events than everolimus based on network meta‐analysis. * single trial Abbreviations: Cy = cyclosporine A; Tac = tacrolimus; Ever = everolimus; Myc = mycophenolate; Sir = sirolimus; Std = glucocorticosteroids
17
17
Adverse events (number) A. The figure shows the surface area under the curve constructed on the basis of the ranking probabilities.
 B. The figure shows the probability of each Intervention being best, second best, third best, and so on. Although the figure shows that tacrolimus plus mycophenolate appears to be the worst intervention in terms of number of adverse events, the pairwise comparisons show that there was no evidence of difference between tacrolimus plus mycophenolate and other comparisons except everolimus. Cylosporine A, which has a high probability of being in the top two ranks, was associated with fewer adverse events than other interventions with the exception of everolimus in the pairwise comparisons.
 
 Legend: 1: tacrolimus; 2: cyclosporine A; 3: cyclosporine A plus glucocorticosteroids; 4: everolimus; 5: tacrolimus plus mycophenolate; 5: tacrolimus plus mycophenolate plus glucocorticosteroids.
18
18
Forest plot of renal impairment (network meta‐analysis estimates and direct comparisons when available). Both fixed‐effect model and random‐effects model for other interventions compared to tacrolimus are provided. The direct estimates and network meta‐analysis estimates are similar except for tacrolimus plus mycophenolate plus glucocorticosteroids versus tacrolimus. Tacrolimus plus mycophenolate plus glucocorticosteroids causes less renal impairment in the direct comparison involving one trial and fixed‐effect model of network meta‐analysis but not in the random‐effects model of network meta‐analysis. We used the more conservative random‐effects model to arrive at conclusions. Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Ever = everolimus; Std = glucocorticosteroids; _ = plus
19
19
The table provides the effect estimate (hazard ratio) of each pairwise comparison for renal impairment. The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison. Treatment effects with evidence of difference are shown in italics. As presented, there was no evidence of difference in any of the pairwise comparisons in the network meta‐analysis, although tacrolimus plus mycophenolate plus glucocorticosteroids was associated with less renal impairment than tacrolimus in a single trial. * single trial Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Ever = everolimus; Std = glucocorticosteroids; _ = plus
20
20
Renal impairment A. The figure shows the surface area under the curve constructed on the basis of the ranking probabilities.
 B. The figure shows the probability of each Intervention being best, second best, third best, and so on. There was no evidence that one intervention is clearly better than any of the other interventions.
 
 Legend: 1: tacrolimus; 2: cyclosporine A; 3: cyclosporine A plus azathioprine plus glucocorticosteroids; 4: everolimus; 5: tacrolimus plus everolimus; 6: tacrolimus plus mycophenolate; 7: tacrolimus plus mycophenolate plus glucocorticosteroids; 8: tacrolimus plus glucocorticosteroids.
21
21
Forest plot of retransplantation (network meta‐analysis estimates and direct comparisons when available). Both fixed‐effect model and random‐effects model for other interventions compared to tacrolimus are provided. The direct estimates and network meta‐analysis estimates are similar, although the random‐effects model was more conservative. Cyclosporine A resulted in higher incidence of retransplantation than tacrolimus. Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Std = glucocorticosteroids; _ = plus
22
22
The table provides the effect estimate (hazard ratio) of each pairwise comparison for retransplantation. The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison. Treatment effects with evidence of difference are shown in italics. As presented, cyclosporine A is associated with a higher incidence of retransplantation than tacrolimus, and tacrolimus plus mycophenolate plus glucocorticosteroids showed a lower incidence of retransplantation than tacrolimus plus mycophenolate. * single trial Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Std = glucocorticosteroids; _ = plus
23
23
Retransplantation A. The figure shows the surface area under the curve constructed on the basis of the ranking probabilities.
 B. The figure shows the probability of each Intervention being best, second best, third best, and so on. There was no evidence that one intervention is clearly better than any of the other interventions.
 
 Legend: 1: tacrolimus; 2: cyclosporine A; 3: cyclosporine A plus azathioprine; 4: cyclosporine A plus azathioprine plus glucocorticosteroids; 5: tacrolimus plus azathioprine; 6: tacrolimus plus mycophenolate; 7: tacrolimus plus mycophenolate plus glucocorticosteroids; 8: tacrolimus plus glucocorticosteroids
24
24
Forest plot of graft rejections (any) (network meta‐analysis estimates and direct comparisons when available). Both fixed‐effect model and random‐effects model for other interventions compared to tacrolimus are provided. The direct estimates and fixed‐effect network meta‐analysis estimates are similar and demonstrate fewer graft rejections (any) for tacrolimus plus everolimus and tacrolimus plus mycophenolate plus glucocorticosteroids than for tacrolimus, while cyclosporine A and everolimus were associated with more graft rejections (any) than tacrolimus. However, the random‐effects model did not demonstrate any evidence of difference in graft rejections (any) for any comparison. We used the more conservative random‐effects model to arrive at conclusions. Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Ever = everolimus; Std = glucocorticosteroids; _ = plus
25
25
The table provides the effect estimate (hazard ratio) of each pairwise comparison for graft rejections (any). The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison. Treatment effects with evidence of difference are shown in italics. As presented, there was no evidence of difference in any of the pairwise comparisons in the network meta‐analysis, although direct comparison showed fewer graft rejections (any) for tacrolimus plus everolimus and tacrolimus plus mycophenolate plus glucocorticosteroids than for tacrolimus, while cyclosporine A and everolimus were associated with more graft rejections (any) than tacrolimus in single trials. Tacrolimus plus everolimus also showed fewer graft rejections (any) than everolimus based on evidence from a single trial. * = single trial Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Ever = everolimus; Std = glucocorticosteroids; _ = plus
26
26
Graft rejections (any) A. The figure shows the surface area under the curve constructed on the basis of the ranking probabilities.
 B. The figure shows the probability of each Intervention being best, second best, third best, and so on. There was no evidence that one intervention is clearly better than any of the other interventions.
 
 Legend: 1: tacrolimus; 2: cyclosporine A; 3: cyclosporine A plus azathioprine; 4: cyclosporine A plus azathioprine plus corticosteroids; 5: cyclosporine A plus mycophenolate; 6: cyclosporine A plus glucocorticosteroids; 7: everolimus; 8: tacrolimus plus azathioprine; 9: tacrolimus plus everolimus; 10: tacrolimus plus mycophenolate; 11: tacrolimus plus mycophenolate plus glucocorticosteroids; 12: tacrolimus plus glucocorticosteroids.
27
27
Forest plot of graft rejections requiring treatment (network meta‐analysis estimates and direct comparisons when available). Both fixed‐effect model and random‐effects model for other interventions compared to tacrolimus are provided. The direct estimates and network meta‐analysis estimates are similar except for everolimus versus tacrolimus. Everolimus causes more graft rejections than tacrolimus in the direct comparison involving one trial and fixed‐effect model of network meta‐analysis but not in the random‐effects model of network meta‐analysis. We used the more conservative random‐effects model to arrive at conclusions. Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Sir = sirolimus; Ever = everolimus; Std = glucocorticosteroids; _ = plus
28
28
The table provides the effect estimate (hazard ratio) of each pairwise comparison for graft rejection requiring treatment. The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison. Treatment effects with evidence of difference are shown in italics. As presented, there was no evidence of difference in any of the pairwise comparisons in the network meta‐analysis, although direct comparison showed that everolimus caused more graft rejections requiring treatment than tacrolimus and tacrolimus plus everolimus in a single trial. * = single trial Abbreviations: Tac = tacrolimus; Cy = cyclosporine A; Myc = mycophenolate; Aza = azathioprine; Sir = sirolimus; Ever = everolimus; Std = glucocorticosteroids; _ = plus
29
29
Graft rejections requiring treatment A. The figure shows the surface area under the curve constructed on the basis of the ranking probabilities.
 B. The figure shows the probability of each Intervention being best, second best, third best, and so on. There was no evidence that one intervention is clearly better than any of the other interventions.
 
 Legend: 1: tacrolimus; 2: cyclosporine A; 3: cyclosporine A plus glucocorticosteroids; 4: everolimus; 5: tacrolimus plus everolimus.
30
30
Trial Sequential Analysis of mortality at maximal follow‐up for cyclosporine A versus tacrolimus. We used an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20% (upper figure) and that observed in trials (12%) (lower figure), control group proportion (Pc) observed in the trials (15.4% mortality), and I2 of 0% (upper figure) and that observed in the trials (I2 = 39%) (lower figure). The accrued sample size (1176) is only a fraction of the information size (IS) (6528 trial participants) or heterogeneity‐adjusted information size (HIS) (31,317 trial participants). As shown in all of the comparisons, the cumulative Z‐curves (blue line) do not cross any of the trial sequential monitoring boundaries (red lines), and neither do they cross the conventional alpha boundary of 2.5% (green line).
31
31
Trial Sequential Analysis of mortality at maximal follow‐up for cyclosporine A plus azathioprine versus tacrolimu. We used an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20% (upper figure) and that observed in trials (12%) (lower figure), control group proportion (Pc) observed in the trials (15.4% mortality), and I2 of 0% (heterogeneity observed in the trials). The accrued sample size (202) is only a fraction of the information size (IS) (6528 trial participants) or heterogeneity‐adjusted information size (HIS) (2242 trial participants). As shown in all of the comparisons, the cumulative Z‐curves (blue line) do not cross any of the trial sequential monitoring boundaries (red lines), and neither do they cross the conventional alpha boundary of 2.5% (green line).
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Update of

References

References to studies included in this review

Asrani 2014 {published data only}
    1. Asrani SK, Wiesner RH, Trotter JF, Klintmalm G, Katz E, Maller E, et al. De novo sirolimus and reduced‐dose tacrolimus versus standard‐dose tacrolimus after liver transplantation: the 2000‐2003 phase II prospective randomized trial. American Journal of Transplantation 2014;14(2):356‐66. - PubMed
Baiocchi 2006 {published data only}
    1. Baiocchi L, Angelico M, Luca L, Ombres D, Anselmo A, Telesca C, et al. Cyclosporine a versus tacrolimus monotherapy. Comparison on bile lipids in the first 3 months after liver transplant in humans. Transplant International 2006;19(5):389‐95. - PubMed
Belli 1998 {published data only}
    1. Belli LS, Carlis L, Rondinara GF, Romani F, Alberti A, Pirotta V, et al. Prospective randomized trial of steroid withdrawal in liver transplant patients: Preliminary report. Transplant International 1994;7 Suppl 1:S88‐90. - PubMed
    1. Belli LS, Carlis L, Rondinara G, Alberti AB, Bellati G, Gasperi A, et al. Early cyclosporine monotherapy in liver transplantation: A 5‐year follow‐up of a prospective, randomized trial. Hepatology 1998;27(6):1524‐9. - PubMed
    1. Carlis L, Belli LS, Colella G, Rondinara GF, Slim AO, Alberti A, et al. Serum lipid changes in liver transplantation: Effect of steroids withdrawn in a prospective randomized trial under cyclosporine a therapy. Transplantation Proceedings 1999;31(1‐2):391‐3. - PubMed
    1. DeCarlis L, Belli LS, Rondinara GF, Alberti A, Sansalone CV, Colella G, et al. Early steroid withdrawal in liver transplant patients: Final report of a prospective randomized trial. Transplantation Proceedings 1997;29(1‐2):539‐42. - PubMed
Boudjema 2011 {published data only}
    1. Boudjema K, Camus C, Saliba F, Calmus Y, Salame E, Pageaux G, et al. Reduced‐dose tacrolimus with mycophenolate mofetil vs. standard‐dose tacrolimus in liver transplantation: a randomized study. American Journal of Transplantation 2011;11(5):965‐76. - PubMed
Chen 2002 {published data only}
    1. Chen JW, Pehlivan M, Gunson BK, Buckels JA, McMaster P, Mayer D. Ten‐year results of a randomised prospective study of FK506 versus cyclosporine in management of primary orthotopic liver transplantation. Transplantation Proceedings 2002;34(5):1507‐10. - PubMed
    1. Dmitrewski J, Ayres S, Gunson BK, Buist LJ, Buckels JA, McMaster P, et al. Steroid withdrawal 3 months after liver transplantation ‐ does FK 506 confer any advantage over cyclosporin?. Transplant International 1994;7 Suppl 1:S85‐7. - PubMed
    1. Krentz AJ, Cramb R, Dousset B, Mayer D, McMaster P, Buckels J, et al. Serum lipids and apolipoproteins in liver transplant recipients: a comparative study of cyclosporin A and FK 506. Journal of Laboratory & Clinical Medicine 1994;124(3):381‐5. - PubMed
    1. Krentz AJ, Dmitrewski J, Mayer D, McMaster P, Buckels J, Dousset B, et al. Postoperative glucose metabolism in liver transplant recipients. A two‐year prospective randomized study of cyclosporine versus FK506. Transplantation 1994;57(11):1666‐9. - PubMed
    1. Krentz AJ, Dousset B, Mayer D, McMaster P, Buckels J, Cramb R, et al. Metabolic effects of cyclosporin a and FK 506 in liver transplant recipients. Diabetes 1993;42(12):1753‐9. - PubMed
Cholongitas 2011 {published data only}
    1. Chau TN, Quaglia A, Rolles K, Burroughs AK, Dhillon AP. Histological patterns of rejection using oral microemulsified cyclosporine and tacrolimus (FK506) as monotherapy induction after orthotopic liver transplantation. Liver 2001;21(5):329‐34. - PubMed
    1. Cholongitas E, Shusang V, Germani G, Tsochatzis E, Raimondo ML, Marelli L, et al. Long‐term follow‐up of immunosuppressive monotherapy in liver transplantation: Tacrolimus and microemulsified cyclosporin. Clinical Transplantation 2011;25(4):614‐24. - PubMed
    1. Rolles K, Davidson BR, Burroughs AK. A pilot study of immunosuppressive monotherapy in liver transplantation: tacrolimus versus microemulsified cyclosporin. Transplantation 1999;68(8):1195‐8. - PubMed
De Simone 2012 {published data only}
    1. Bernhardt P, Dong G, Lopez P, Hustache G, Bader G. Evaluation of the major adverse cardiac events risk with everolimus‐based calcineurin inhibitor reduction or withdrawal regimen in liver transplant recipients: 3‐year post‐hoc analysis of the randomized H2304 extension study. American Journal of Transplantation 2016;16:234.
    1. Charlton MR, Rinella ME, Heimbach J. Everolimus is associated with lower weight gain two years following liver transplantation ‐ results of a randomized multicenter study. Hepatology 2015;62:816A. - PMC - PubMed
    1. Simone P, Nevens F, Carlis L, Metselaar HJ, Beckebaum S, Saliba F, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. American Journal of Transplantation 2012;12(11):3008‐20. - PMC - PubMed
    1. Simone P, Nevens F, Carlis L, Metselaar HJ, Beckebaum S, Saliba F, et al. Evolution of renal function with early everolimus‐facilitated reduction or elimination of tacrolimus in 719 de novo liver transplant recipients: 12 month data of the H2304 study. American Journal of Transplantation 2012;12:238.
    1. Simone P, Saliba F, Dong G, Escrig C, Fischer L. Do patient characteristics influence efficacy and renal outcomes in liver transplant patients receiving everolimus?. Clinical Transplantation 2016;30(3):279‐88. - PubMed
Fernandez‐Miranda 1998 {published data only}
    1. Fernández‐Miranda C, Guijarro C, Calle A, Loinaz C, Gonzalez‐Pinto I, Gómez‐Izquierdo T, et al. Lipid abnormalities in stable liver transplant recipients ‐ effects of cyclosporin, tacrolimus, and steroids. Transplant International 1998;11(2):137‐42. - PubMed
Fisher 1998 {published data only}
    1. Fisher RA, Ham JM, Marcos A, Shiffman ML, Luketic VA, Kimball PM, et al. A prospective randomized trial of mycophenolate mofetil with neoral or tacrolimus after orthotopic liver transplantation. Transplantation 1998;66(12):1616‐21. - PubMed
    1. Fisher RA, Shiffman ML, Naar JD, Ham JM, Seaman D, Luketic VA. A prospective randomized trial of mycophenolate mofetil (mmf) with neoral or tacrolimus induction following orthotopic liver transplantation (OLT). Hepatology 1996;24(4 (Pt 2)):511a.
    1. Fisher RA, Stone JJ, Wolfe LG, Rodgers CM, Anderson ML, Sterling RK, et al. Four‐year follow‐up of a prospective randomized trial of mycophenolate mofetil with cyclosporine microemulsion or tacrolimus following liver transplantation. Clinical Transplantation 2004;18(4):463‐72. - PubMed
Fung 1991 {published data only}
    1. DiMartini AF, Trzepacz PT, Pajer KA, Faett D, Fung J. Neuropsychiatric side effects of FK506 vs. cyclosporine a. First‐week postoperative findings. Psychosomatics 1997;38(6):565‐9. - PubMed
    1. Fung J, Abu‐Elmagd K, Jain A, Gordon R, Tzakis A, Todo S, et al. A randomized trial of primary liver transplantation under immunosuppression with FK 506 vs cyclosporine. Transplantation Proceedings 1991;23(6):2977‐83. - PMC - PubMed
    1. Fung J, Todo S, Abu‐Elmagd K, Jain A, Tzakis A, Martin M, et al. Randomized trial in primary liver transplantation under immunosuppression with FK 506 or cyclosporine. Transplantation Proceedings 1993;25(1 Pt 2):1130. - PMC - PubMed
    1. Kusne S, Fung J, Alessiani M, Martin M, Torre‐Cisneros J, Irish W, et al. Infections during a randomized trial comparing cyclosporine to FK 506 immunosuppression in liver transplantation. Transplantation Proceedings 1992;24(1):429‐30. - PMC - PubMed
Greig 2003 {published data only}
    1. Greig P, Lilly L, Scudamore C, Erb S, Yoshida E, Kneteman N, et al. Early steroid withdrawal after liver transplantation: the Canadian tacrolimus versus microemulsion cyclosporin a trial: 1‐year follow‐up. Liver Transplantation 2003;9(6):587‐95. - PubMed
Jain 2001 {published data only}
    1. Jain A. Prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil: Complete report on 350 primary adult liver transplantations. Transplantation Proceedings 2001;33(1‐2):1342‐4. - PMC - PubMed
    1. Jain A, Kashyap R, Demetris AJ, Eghstesad B, Pokharna R, Fung JJ. A prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis C. Liver Transplantation 2002;8(1):40‐6. - PubMed
    1. Jain A, Kashyap R, Dodson F, Kramer D, Hamad I, Khan A, et al. A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: a single center report. Transplantation 2001;72(6):1091‐7. - PMC - PubMed
    1. Jain AB, Hamad I, Rakela J, Dodson F, Kramer D, Demetris J, et al. A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil in primary adult liver transplant recipients: an interim report. Transplantation 1998;66(10):1395‐8. - PMC - PubMed
Jonas 2005 {published data only}
    1. Jonas S, Guckelberger O, Bechstein WO, Berg T, Muller AR, Platz KP, et al. Five‐year follow‐up of tacrolimus as primary immunosuppressant after liver transplantation. Transplantation Proceedings 1998;30(5):2179‐81. - PubMed
    1. Jonas S, Guckelberger O, Tullius SG, Steinmuller T, Muller AR, Grauhan O, et al. Corticosteroid‐free therapy after tacrolimus‐based dual immunosuppression versus cyclosporine‐based quadruple‐induction therapy. Transplantation Proceedings 2001;33(3):2232‐3. - PubMed
    1. Jonas S, Kling N, Bechstein WO, Blumhardt G, Lohmann R, Lobeck H, et al. Rejection episodes after liver transplantation during primary immunosuppression with FK506 or a cyclosporine‐based regimen: a controlled, prospective, randomized trial. Clinical Transplantation 1995;9(5):406‐14. - PubMed
    1. Jonas S, Neuhaus R, Junge G, Klupp J, Theruvat T, Langrehr JM, et al. Primary immunosuppression with tacrolimus after liver transplantation: 12‐years follow‐up. International Immunopharmacology 2005;5(1):125‐8. - PubMed
    1. Mueller AR, Platz KP, Bechstein WO, Schattenfroh N, Stoltenburg‐Didinger G, Blumhardt G, et al. Neurotoxicity after orthotopic liver transplantation: a comparison between cyclosporine and FK506. Transplantation 1994;58(2):155‐69. - PubMed
Loinaz 2001 {published data only}
    1. Loinaz C, Marin LM, Gonzalez‐Pinto I, Gomez R, Jimenez C, Moreno E. A single‐centre experience with cyclosporine microemulsion versus tacrolimus in 100 randomized liver transplant recipients: Midterm efficacy and safety. Transplantation Proceedings 2001;33(7‐8):3439‐41. - PubMed
Manousou 2014 {published data only}
    1. Manousou P, Cholongitas E, Samonakis D, Tsochatzis E, Corbani A, Dhillon AP, et al. Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: Randomised trial long term outcomes. Gut 2014;63(6):1005‐13. - PMC - PubMed
    1. Manousou P, Samonakis D, Cholongitas E, Patch D, O'Beirne J, Dhillon AP, et al. Outcome of recurrent hepatitis C virus after liver transplantation in a randomized trial of tacrolimus monotherapy versus triple therapy. Liver Transplantation 2009;15(12):1783‐91. - PubMed
    1. Manousou P, Samonakis D, Tsochatzis E, Cholongitas E, Davidson J, Patch D, et al. Long term ‐ 8 year follow up of a randomized trial of tacrolimus monotherapy versus triple therapy after liver transplantation for HCV cirrhosis. Journal of Hepatology 2013;58:S11.
    1. Samonakis DN, Cholongitas E, Triantos CK, Quaglia A, Senzolo M, Dhillon AP, et al. Randomised trial of tacrolimus monotherapy vs. tacrolimus/azathioprine/prednisolone after liver transplantation for HCV cirrhosis: Preliminary results. Journal of Hepatology 2005;42(Suppl 2):47.
    1. Samonakis DN, Mela M, Quaglia A, Triantos CK, Thalheimer U, Leandro G, et al. Rejection rates in a randomised trial of tacrolimus monotherapy versus triple therapy in liver transplant recipients with hepatitis C virus cirrhosis. Transplant Infectious Disease 2006;8(1):3‐12. - PubMed
Martin 2004 {published data only}
    1. Martin P, Busuttil RW, Goldstein RM, Crippin JS, Klintmalm GB, Fitzsimmons WE, et al. Impact of tacrolimus versus cyclosporine in hepatitis C virus‐infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial. Liver Transplantation 2004;10(10):1258‐62. - PubMed
Masetti 2010 {published data only}
    1. Masetti M, Montalti R, Rompianesi G, Codeluppi M, Gerring R, Romano A, et al. Early withdrawal of calcineurin inhibitors and everolimus monotherapy in de novo liver transplant recipients preserves renal function. American Journal of Transplantation 2010;10(10):2252‐62. - PubMed
    1. Montalti R, Masetti M, Rompianesi G, Romano A, Ballarin R, Denedetto F. Calcineurin inhibitor‐free immunosuppressive protocol with everolimus monotherapy in de novo liver transplantation. Liver Transplantation 2008;14(7 (Suppl 1)):S226.
O'Grady 2002 {published data only}
    1. Burroughs A, Rolles K, Gimson A, Jamieson N, Hudson M, Thick M, et al. Tacrolimus versus microemulsified cyclosporine in liver transplantation ‐ the TMC randomised trial final results at one year (abstract). Journal of Hepatology 2002;36(Suppl 1):26.
    1. O'Grady JG. TMC trial: 3 year follow‐up on randomised controlled trial of tacrolimus versus microemulsified cyclosporine in liver transplantation. Hepatology 2004;40(4 Suppl 1):551a.
    1. O'Grady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A. Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial. Lancet 2002;360(9340):1119‐25. - PubMed
    1. O'Grady JG, Hardy P, Burroughs AK, Elbourne D. Randomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation: Poststudy surveillance to 3 years. American Journal of Transplantation 2007;7(1):137‐41. - PubMed
Pageaux 2004 {published data only}
    1. Pageaux GP, Calmus Y, Boillot O, Ducerf C, Vanlemmens C, Boudjema K, et al. Steroid withdrawal at day 14 after liver transplantation: a double‐blind, placebo‐controlled study. Liver Transplantation 2004;10(12):1454‐60. - PubMed
Pelletier 2013 {published data only}
    1. Pelletier SJ, Ammori JB, Englesbe MJ, Sung RS, Magee JC, Fontana RJ. A prospective, randomized trial of complete steroid avoidance in liver transplantation. Liver Transplantation 2008;14(7 (Suppl 1)):S224. - PubMed
    1. Pelletier SJ, Nadig SN, Lee DD, Ammori JB, Englesbe MJ, Sung RS, et al. A prospective, randomized trial of complete avoidance of steroids in liver transplantation with follow‐up of over 7 years. HPB 2013;15(4):286‐93. - PMC - PubMed
    1. Pelletier SJ, Vanderwall K, Debroy MA, Englesbe MJ, Sung RS, Magee JC, et al. Preliminary analysis of early outcomes of a prospective, randomized trial of complete steroid avoidance in liver transplantation. Transplantation Proceedings 2005;37(2):1214‐6. - PubMed
Pham 1998 {published data only}
    1. Pham H, Lemoine A, Salvucci M, Azoulay D, Frenoy N, Samuel D, et al. Occurrence of gammopathies and lymphoproliferative disorders in liver transplant recipients randomized to tacrolimus (FK506)‐ or cyclosporine‐based immunosuppression. Liver Transplantation & Surgery 1998;4(2):146‐51. - PubMed
Porayko 1994 {published data only}
    1. Porayko MK, Textor SC, Krom RA, Hay JE, Gores GJ, Richards TM, et al. Nephrotoxic effects of primary immunosuppression with FK‐506 and cyclosporine regimens after liver transplantation. Mayo Clinic Proceedings 1994;69(2):105‐11. - PubMed
    1. Porayko MK, Textor SC, Krom RA, Hay JE, Gores GJ, Wahlstrom HE, et al. Nephrotoxicity of FK 506 and cyclosporine when used as primary immunosuppression in liver transplant recipients. Transplantation Proceedings 1993;25(1 Pt 1):665‐8. - PubMed
Shenoy 2008 {published data only}
    1. Shenoy S, Hardinger K, Laflin MA, Kemp D, Desai N, Lowell J, et al. The economic impact of immunosuppression using cyclosporine (CsA) with 2 hour post dose monitoring vs tacrolimus (FK) following de novo liver transplantation ‐ results of a prospective, randomized trial (abstract no: 1377). American Journal of Transplantation 2005;5(Suppl 11):506.
    1. Shenoy S, Hardinger KL, Crippin J, Karenblat K, Lisker‐Melman M, Lowell JA, et al. A randomized, prospective, pharmacoeconomic trial of neoral 2‐hour postdose concentration monitoring versus tacrolimus trough concentration monitoring in de novo liver transplant recipients. Liver Transplantation 2008;14(2):173‐80. - PubMed
Stegall 1997 {published data only}
    1. Stegall MD, Everson GT, Wachs M, Schroter G, Karrer F, Bilir B, et al. Prednisone withdrawal 14 days after adult liver transplantation with mycophenolate mofetil (mm). Hepatology 1996;24(4 (Pt 2)):174a.
    1. Stegall MD, Wachs ME, Everson G, Steinberg T, Bilir B, Shrestha R, et al. Prednisone withdrawal 14 days after liver transplantation with mycophenolate ‐ a prospective trial of cyclosporine and tacrolimus. Transplantation 1997;64(12):1755‐60. - PubMed
Sterneck 2000 {published data only}
    1. Fischer L, Sterneck M, Gahlemann C, Gundlach M, Rogiers X, Broelsch CE. Safety and efficacy of mycophenolate mofetil versus azathioprine as primary immunosuppressive therapy in liver transplant recipients. Transplantationsmedizin 1999;11(4):274‐8.
    1. Sterneck M, Fischer L, Gahlemann C, Gundlach M, Rogiers X, Broelsch C. Mycophenolate mofetil for prevention of liver allograft rejection: Initial results of a controlled clinical trial. Annals of Transplantation 2000;5(1):43‐6. - PubMed
Zervos 1998 {published data only}
    1. Zervos XA, Weppler D, Fragulidis GP, Torres MB, Nery JR, Khan MF, et al. Comparison of tacrolimus with microemulsion cyclosporine as primary immunosuppression in hepatitis C patients after liver transplantation. Transplantation 1998;65(8):1044‐6. - PubMed

References to studies excluded from this review

Abdelmalek 2012 {published data only}
    1. Abdelmalek MF, Humar A, Stickel F, Andreone P, Pascher A, Barroso E, et al. Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial. American Journal of Transplantation 2012;12(3):694‐705. - PubMed
Barnes 1997 {published data only}
    1. Barnes D, Talenti D, Cammell G, Goormastic M, Farquhar L, Henderson M, et al. A randomized clinical trial of ursodeoxycholic acid as adjuvant treatment to prevent liver transplant rejection. Hepatology 1997;26(4):853‐7. - PubMed
Beckebaum 2004 {published data only}
    1. Beckebaum S, Cicinnati VR, Klein CG, Brokalaki E, Yu Z, Malago M, et al. Impact of combined mycophenolate mofetil and low‐dose calcineurin inhibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: Preliminary results of an open prospective study. Transplantation Proceedings 2004;36(9):2671‐4. - PubMed
    1. Beckebaum S, Klein CG, Sotiropoulos GC, Saner FH, Gerken G, Paul A, et al. Combined mycophenolate mofetil and minimal dose calcineurin inhibitor therapy in liver transplant patients: Clinical results of a prospective randomized study. Transplantation Proceedings 2009;41(6):2567‐9. - PubMed
Becker 2008 {published data only}
    1. Becker T, Foltys D, Bilbao I, D'Amico D, Colledan M, Bernardos A, et al. Patient outcomes in two steroid‐free regimens using tacrolimus monotherapy after daclizumab induction and tacrolimus with mycophenolate mofetil in liver transplantation. Transplantation 2008;86(12):1689‐94. - PubMed
Benitez 2010 {published data only}
    1. Benitez CE, Puig‐Pey I, Lopez M, Martinez‐Llordella M, Lozano JJ, Bohne F, et al. ATG‐fresenius treatment and low‐dose tacrolimus: Results of a randomized controlled trial in liver transplantation. American Journal of Transplantation 2010;10(10):2296‐304. - PubMed
Berenguer 2006 {published data only}
    1. Aguilera V, Prieto M, Rubin A, Risalde B, Ortiz C, San Juan F. Calcineurin inhibitors and outcome of liver transplantation in HCV‐positive recipients: Final results of a prospective randomized study. Hepatology 2009;50(4 (Suppl)):549a.
    1. Aguilera V, Prieto M, Rubín A, Risalde B, Ortiz Cantó C, San Juan F. Calcineurin inhibitors and outcome of liver transplantation in HCV‐positive recipients: Final results of a prospective randomized study. Journal of Hepatology 2010;52(Suppl 1):S43.
    1. Berenguer M, Aguilera V, Prieto M, San Juan F, Rayon JM, Benlloch S, et al. Effect of calcineurin inhibitors on survival and histologic disease severity in HCV‐infected liver transplant recipients. Liver Transplantation 2006;12(5):762‐7. - PubMed
Biancofiore 2004 {published data only}
    1. Biancofiore G, Della Rocca G, Bindi L, Romanelli A, Esposito M, Meacci L, et al. Use of fenoldopam to control renal dysfunction early after liver transplantation. Liver Transplantation 2004;10(8):986‐92. - PubMed
Bilbao 2009 {published data only}
    1. Bilbao I, Otto G, Becker T, D'Amico D, Colledan M, Bernardos A. Safety and efficacy of steroid‐free immunosuppression post‐liver transplantation: a randomised phase iii trial comparing tacrolimus monotherapy after daclizumab induction versus tacrolimus+mmf dual therapy. Journal of Hepatology 2009;50(Suppl 1):S58.
Bogetti 2005 {published data only}
    1. Bogetti D, Sankary HN, Jarzembowski TM, Manzelli A, Knight PS, Thielke J, et al. Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury. Clinical Transplantation 2005;19(4):507‐11. - PubMed
Boillot 2000 {published data only}
    1. Boillot O, Poncet G, Mechet I, Dumortier J, Delafosse B, Sagnard P, et al. Randomized trial of triple based immunosuppression using tacrolimus, mycophenolate mofetil and steroids versus quadruple regimen induction with thymoglobulin in liver transplantation. Hepatology 2000;32(4):599A.
Boillot 2001 {published data only}
    1. Boillot O, Baulieux J, Wolf P, Messner M, Cherqui D, Gugenheim J, et al. Low rejection rates with tacrolimus‐based dual and triple regimens following liver transplantation. Clinical Transplantation 2001;15(3):159‐66. - PubMed
Boillot 2005 {published data only}
    1. Boillot O, Mayer DA, Boudjema K, Salizzoni M, Gridelli B, Filipponi F, et al. Corticosteroid‐free immunosuppression with tacrolimus following induction with daclizumab: a large randomized clinical study. Liver Transplantation 2005;11(1):61‐7. - PubMed
Boillot 2009 {published data only}
    1. Boillot O, Seket B, Dumortier J, Pittau G, Boucaud C, Bouffard Y, et al. Thymoglobulin induction in liver transplant recipients with a tacrolimus, mycophenolate mofetil, and steroid immunosuppressive regimen: a five‐year randomized prospective study. Liver Transplantation 2009;15(11):1426‐34. - PubMed
Boleslawski 2004 {published data only}
    1. Boleslawski E, BenOthman S, Grabar S, Correia L, Podevin P, Chouzenoux S, et al. Cd25, cd28 and cd38 expression in peripheral blood lymphocytes as a tool to predict acute rejection after liver transplantation. Clinical Transplantation 2008;22(4):494‐501. - PubMed
    1. Boleslawski E, Conti F, Sanquer S, Podevin P, Chouzenoux S, Batteux F, et al. Defective inhibition of peripheral cd8+ t cell il‐2 production by anti‐calcineurin drugs during acute liver allograft rejection. Transplantation 2004;77(12):1815‐20. - PubMed
Calmus 2010 {published data only}
    1. Calmus Y, Kamar N, Gugenheim J, Duvoux C, Ducerf C, Wolf P, et al. Assessing renal function with daclizumab induction and delayed tacrolimus introduction in liver transplant recipients. Transplantation 2010;89(12):1504‐10. - PubMed
    1. Calmus Y, Rostaing L, Gugenheim J, Duvoux C, Ducerf C, Wolf P. Evaluation of the benefit on renal function of a delayed introduction of tacrolimus in liver transplant recipients at 13 French centers. Hepatology 2007;46(4 (Suppl 1)):482a‐3a.
Chen 2005 {published data only}
    1. Chen G, He Y, Wang HZ, Lu Q, Yang SZ, Yang ZY, et al. Cyclosporine microemulsion C2 monitoring in Chinese adult liver transplant recipients: a preliminary randomized control trial. Chung‐Hua Wai Ko Tsa Chih 2005;43(19):1243‐7. - PubMed
Cicinnati 2007 {published data only}
    1. Cicinnati VR, Yu Z, Klein CG, Sotiropoulos GC, Saner F, Malago M, et al. Clinical trial: Switch to combined mycophenolate mofetil and minimal dose calcineurin inhibitor in stable liver transplant patients ‐ assessment of renal and allograft function, cardiovascular risk factors and immune monitoring. Alimentary Pharmacology & Therapeutics 2007;26(9):1195‐208. - PubMed
Cillo 2014 {published data only}
    1. Cillo U, Vitale A, Salizzoni M, Coledan M, Rossi G, Baccarani U, et al. Early introduction of everolimus in de novo liver transplantation: 3‐months final results (primary endpoint) of a multicenter randomized clinical trial (EPOCAL). Liver Transplantation 2014;20:S105‐6.
    1. Cillo U, Vitale A, Salizzoni M, Colledan M, Rossi G, Baccarani U, et al. Early introduction of everolimus in de novo liver transplantation: Final results of a multicenter randomized clinical trial (EPOCAL). Transplant International 2015;28:74.
Cosimi 1987 {published data only}
    1. Cosimi AB, Cho SI, Delmonico FL. A randomized clinical trial comparing OKT3 and steroids for treatment of hepatic allograft rejection. Transplantation 1987;43(1):91‐5. - PubMed
Cosimi 1990 {published data only}
    1. Cosimi AB, Jenkins RL, Rohrer RJ, Delmonico FL, Hoffman M, Monaco AP. A randomized clinical trial of prophylactic OKT3 monoclonal antibody in liver allograft recipients. Archives of Surgery 1990;125(6):781‐4. - PubMed
Cuervas‐Mons 2015 {published data only}
    1. Cuervas‐Mons V, Herrero JI, Gomez MA, Gonzalez‐Pinto I, Serrano T, Mata M, et al. Impact of tacrolimus and mycophenolate mofetil regimen vs. a conventional therapy with steroids on cardiovascular risk in liver transplant patients. Clinical Transplantation 2015;29(8):667‐77. - PubMed
Day 2004 {published data only}
    1. Day CP, O'Grady J, Simpson K, Millson CE, Solomons N, Duncan J, et al. A randomised controlled trial of calcineurin inhibitor (CNI) replacement with mycophenolate mofetil and steroids in liver transplant patients with renal dysfunction. Hepatology 2004;40(4 Suppl 1):547a.
De Simone 2009 {published data only}
    1. Simone P, Metselaar HJ, Fischer L, Dumortier J, Boudjema K, Hardwigsen J, et al. Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: a prospective, randomized, multicenter trial. Liver Transplantation 2009;15(10):1262‐9. - PubMed
De Simone 2015 {published data only}
    1. Simone P, Carrai P, Coletti L, Precisi A, Campani D, Filipponi F. Efficacy and safety of once‐daily everolimus with minimized once‐daily tacrolimus after liver transplantation. American Journal of Transplantation 2015;15(S3):Abstract number: 1281.
    1. Simone P, Carrai P, Precisi A, Coletti L, Campani D, Filipponi F. Efficacy and safety of once‐daily everolimus with minimized once‐daily tacrolimus after liver transplantation. Transplantation 2015;99(7 Suppl 1):274‐5.
    1. Simone P, Carrai P, Precisi A, Coletti L, Ducci J, Campani D, et al. Efficacy and safety of a combination schedule with once‐daily everolimus and once‐daily tacrolimus in maintenance liver transplantation. Transplant International 2015;28:74.
Duvoux 2015 {published data only}
    1. Duvoux C, Villamil F, Renner EL, Grazi GL, Firpi RJ, Pageaux G, et al. Sustained virological response to antiviral therapy in a randomized trial of cyclosporine versus tacrolimus in liver transplant patients with recurrent hepatitis C infection. Annals of Transplantation 2015;20:25‐35. - PubMed
Eason 2003 {published data only}
    1. Eason JD, Blazek J, Mason A, Loss GE. Steroid‐free immunosuppression trough thymoglobulin induction in liver transplantation: Results of a prospective randomized trial (abstract). Hepatology 2000;32(4):208a.
    1. Eason JD, Loss GE, Blazek J, Nair S, Mason AL. Steroid‐free liver transplantation using rabbit antithymocyte globulin induction: Results of a prospective randomized trial. Liver Transplantation 2001;7(8):693‐7. - PubMed
    1. Eason JD, Nair S, Cohen AJ, Blazek JL, Loss GE Jr. Steroid‐free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy. Transplantation 2003;75(8):1396‐9. - PubMed
Ericzon 1997 {published data only}
    1. Ericzon BG, Eusufzai S, Soderdahl G, Duraj F, Einarsson K, Angelin B. Secretion and composition of bile after human liver transplantation: Studies on the effects of cyclosporine and tacrolimus. Transplantation 1997;63(1):74‐80. - PubMed
Farges 1994 {published data only}
    1. Farges O, Ericzon BG, Bressonhadni S, Lynch SV, Hockerstedt K, Houssin D, et al. A randomized trial of OKT3‐based versus cyclosporine‐based immunoprophylaxis after liver‐transplantation ‐ long‐term results of a European and Australian multicenter study. Transplantation 1994;58(8):891‐8. - PubMed
Filipponi 2004 {published data only}
    1. Filipponi F, Callea F, Salizzoni M, Grazi GL, Fassati LR, Rossi M, et al. Double‐blind comparison of hepatitis C histological recurrence rate in HCV+ liver transplant recipients given basiliximab + steroids or basiliximab + placebo, in addition to cyclosporine and azathioprine. Transplantation 2004;78(10):1488‐95. - PubMed
Firpi 2006 {published data only}
    1. Firpi RJ, Zhu H, Morelli G, Abdelmalek MF, Soldevila‐Pico C, Machicao VI, et al. Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation. Liver Transplantation 2006;12(1):51‐7. - PubMed
Firpi 2010 {published data only}
    1. Firpi RJ, Soldevila‐Pico C, Morelli GG, Cabrera R, Levy C, Clark VC, et al. The use of cyclosporine for recurrent hepatitis C after liver transplant: a randomized pilot study. Digestive Diseases and Sciences 2010;55(1):196‐203. - PubMed
    1. Firpi RJ, Soldevila‐Pico C, Morelli GJ, Machicao VI, Levy C, Cabrera R. A randomized controlled trial of cyclosporine vs tacrolimus immunosuppression in patients receiving pegylated interferon and ribavirin for recurrence hepatitis C virus infection after liver transplantation. Hepatology 2006;44(4 (Suppl 1)):421a.
Fischer 2012 {published data only}
    1. Fischer L, Klempnauer J, Beckebaum S, Metselaar HJ, Neuhaus P, Schemmer P, et al. A randomized, controlled study to assess the conversion from calcineurin‐inhibitors to everolimus after liver transplantation ‐ PROTECT. American Journal of Transplantation 2012;12(7):1855‐65. - PubMed
    1. Fischer L, Simone P, Nevens F, Metselaar HJ, Dumortier J, Duvoux C. Calcineurin inhibitor withdrawal in the presence of everolimus is feasible in maintenance liver transplant recipients. Hepatology 2008;48(4 (Suppl)):566a.
    1. Sterneck M, Kaiser G, Heyne N, Richter N, Rauchfuss F, Pascher A, et al. 5‐year follow‐up of the protect randomised liver transplantation study showed superior renal function with everolimus and early calcineurin inhibitor withdrawal. Transplant International 2015;28:90.
    1. Sterneck M, Kaiser G, Heyne N, Richter N, Rauchfuss F, Pascher A, et al. Everolimus and early calcineurin inhibitor withdrawal is associated with superior renal function: 5‐year follow‐up of the randomized PROTECT liver transplantation study. American Journal of Transplantation 2015;15(Suppl 3):Abstract: 732.
    1. Sterneck M, Kaiser GM, Heyne N, Richter N, Rauchfuss F, Pascher A, et al. 5‐year follow‐up results of the everolimus and calcineurin inhibitor withdrawal combination from the randomized PROTECT liver transplantation study. Transplantation 2015;99(7 Suppl 1):89‐90.
Fleckenstein 1996 {published data only}
    1. Fleckenstein J, Parades M, Thuluvath PJ. A prospective randomized double‐blind trial evaluating the efficacy of ursodeoxycholic acid (UDCA) in preventing acute rejection. Hepatology 1996;24(4 (Pt 2)):177a. - PubMed
Garcia Gonzalez 2005 {published data only}
    1. Garcia Gonzalez M, Pera Madrazo C, Bernardos Rodriguez A, Gomez Gutierrez M, Ignacio Herrero J, Mir Pallardo J, et al. An open, randomized, multicenter clinical trial of oral tacrolimus in liver allograft transplantation: a comparison of dual vs. triple drug therapy. Liver Transplantation 2005;11(5):515‐24. - PubMed
    1. Gonzalez MG, Bernardos A, Gomez M, Ortiz de Urbina J. Both dual and triple regimens of tacrolimus are effective and safe in liver transplantation (abstract). Journal of Hepatology 2001;34(1):8.
Garcia‐Saenz‐de‐Sicilia 2014 {published data only}
    1. Garcia‐Saenz‐de‐Sicilia M, Olivera‐Martinez MA, Grant WJ, Mercer DF, Baojjang C, Langnas A, et al. Impact of anti‐thymocyte globulin during immunosuppression induction in patients with hepatitis C after liver transplantation. Digestive Diseases and Sciences 2014;59(11):2804‐12. - PubMed
Geissler 2016 {published data only}
    1. Geissler EK, Schnitzbauer AA, Zolke C, Lamby PE, Proneth A, Duvoux C, et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open‐label phase 3 trial. Transplantation 2016;100(1):116‐25. - PMC - PubMed
    1. Schnitzbauer AA, Zuelke C, Graeb C, Rochon J, Bilbao I, Burra P, et al. A prospective randomised, open‐labeled trial comparing sirolimus‐containing versus mTOR‐inhibitor‐free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 2010;10:190. - PMC - PubMed
Gerhardt 2009 {published data only}
    1. Gerhardt T, Terjung B, Knipper P, Palmedo H, Woitas RP, Kalff J, et al. Renal impairment after liver transplantation ‐ a pilot trial of calcineurin inhibitor‐free vs. calcineurin inhibitor sparing immunosuppression in patients with mildly impaired renal function after liver transplantation. European Journal of Medical Research 2009;14(5):210‐5. - PMC - PubMed
Gonzalez‐Pinto 2005 {published data only}
    1. Gonzalez‐Pinto IM, Rimola A, Margarit C, Cuervas‐Mons V, Abradelo M, Alvarez‐Laso C, et al. Five‐year follow‐up of a trial comparing tacrolimus and cyclosporine microemulsion in liver transplantation. Transplantation Proceedings 2005;37(4):1713‐5. - PubMed
Grant 2012 {published data only}
    1. Grant W, Botha J, Mercer D, Olivera‐Martinez M, McCashland T, Langnas A. A randomized, single‐center trial comparing thymoglobulin (TG) induction therapy and delayed initiation of tacrolimus to no induction with immediate initiation of tacrolimus in liver transplant (LT) recipients to assess the impact on renal function. American Journal of Transplantation 2012;12:539.
Hardinger 2004 {published data only}
    1. Hardinger KL, Chapman WC, Lowell J, Desai N, Crippin J, Lisker‐Melman M. Interim analysis of a single‐center, prospective, randomized trial compaing tacrolimus versus cyclosporine immunosuppression using 2 hour post dose (c2) monitoring in de novo liver transplant recipients. Transplantation 2004;78(2):377‐8.
Herlenius 2010 {published data only}
    1. Herlenius G, Felldin M, Norden G, Olausson M, Backman L, Gustafsson B, et al. Conversion from calcineurin inhibitor to either mycophenolate mofetil or sirolimus improves renal function in liver transplant recipients with chronic kidney disease: Results of a prospective randomized trial. Transplantation Proceedings 2010;42(10):4441‐8. - PubMed
Hodge 2002 {published data only}
    1. Hodge EE, Reich DJ, Clavien PA, Kim‐Schluger L. Use of mycophenolate mofetil in liver transplant recipients experiencing renal dysfunction on cyclosporine or tacrolimus ‐ randomized, prospective, multicenter study results. Transplantation Proceedings 2002;34(5):1546‐7. - PubMed
Hytiroglou 1993 {published data only}
    1. Hytiroglou P, Lee R, Sharma K, Theise ND, Schwartz M, Miller C, et al. Fk506 versus cyclosporine as primary immunosuppressive agent for orthotopic liver allograft recipients. Histologic and immunopathologic observations. Transplantation 1993;56(6):1389‐94. - PubMed
Junge 2005 {published data only}
    1. Junge G, Neuhaus R, Schewior L, Klupp J, Guckelberger O, Langrehr JM, et al. Withdrawal of steroids: A randomized prospective study of prednisone and tacrolimus versus mycophenolate mofetil and tacrolimus in liver transplant recipients with autoimmune hepatitis. Transplantation Proceedings 2005;37(4):1695‐6. - PubMed
Kato 2007 {published data only}
    1. Kato T, Gaynor JJ, Yoshida H, Montalvano M, Takahashi H, Pyrsopoulos N, et al. Randomized trial of steroid‐free induction versus corticosteroid maintenance among orthotopic liver transplant recipients with hepatitis C virus: impact on hepatic fibrosis progression at one year. Transplantation 2007;84(7):829‐35. - PubMed
    1. Kato T, Yoshida H, Sadfar K, Martinez E, Nishida S, Moon J, et al. Steroid‐free induction and preemptive antiviral therapy for liver transplant recipients with hepatitis C: a preliminary report from a prospective randomized study. Transplantation Proceedings 2005;37(2):1217‐9. - PubMed
Keiding 1997 {published data only}
    1. Keiding S, Hockerstedt K, Bjoro K, Bondesen S, Hjortrup A, Isoniemi H, et al. The Nordic multicenter double‐blind randomized controlled trial of prophylactic ursodeoxycholic acid in liver transplant patients. Transplantation 1997;63(11):1591‐4. - PubMed
Klintmalm 1994 {published data only}
    1. Klintmalm GB. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. New England Journal of Medicine 1994;331(17):1110‐5. - PubMed
    1. Lake JR, Gorman KJ, Esquivel CO, Wiesner RH, Klintmalm GB, Miller CM, et al. The impact of immunosuppressive regimens on the cost of liver transplantation ‐ results from the U.S. Fk506 multicenter trial. Transplantation 1995;60(10):1089‐95. - PubMed
    1. Porayko MK, Wiesner RH. United States multicenter prospective randomized trial comparing primary immunosuppression with FK506 vs cyclosporine (CyA) following liver‐transplantation. Gastroenterology 1993;104(4):A974.
    1. Wiesner RH. A long‐term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation ‐ a report of the United States FK506 study group. Transplantation 1998;66(4):493‐9. - PubMed
Klintmalm 2007 {published data only}
    1. Fasola CG, Heffron TG, Sher L, Douglas DD, Brown R, Ham J, et al. Multicenter randomized hepatitis C (HCV) three trial post liver transplantation (OLT): a 90‐day report. Hepatology 2004;40(4 Suppl 1):163a.
    1. Klintmalm G, Fasola CG, Jennings LW. Hepatitis C (HCV)‐3 study: Day‐90 protocol biopsy (PB) grade is a surrogate marker for severe HCV recurrence (R), on PB, at years 1 and 2 post liver transplantation (OLT). Hepatology 2009;50(4 (Suppl)):1028a.
    1. Klintmalm GB, Davis GL, Teperman L, Netto GJ, Washburn K, Rudich SM, et al. A randomized, multicenter study comparing steroid‐free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C. Liver Transplantation 2011;17(12):1394‐403. - PubMed
    1. Klintmalm GB, Fasola CG, Jennings L, Heffron TG, Sher L, Mulligan D. Hepatitis C (HCV)‐3 study: Benefits of a steroid‐free immunosuppression (IS) regimen in HCV‐infected liver transplant recipients (OLT) may become evident only after long‐term follow up. Liver Transplantation 2008;14(7 (Suppl 1)):S105.
    1. Klintmalm GBG, Washburn WK, Rudich SM, Heffron TG, Teperman LW, Fasola C, et al. Corticosteroid‐free immunosuppression with daclizumab in HCV+ liver transplant recipients: 1‐year interim results of the HCV‐3 study. Liver Transplantation 2007;13(11):1521‐31. - PubMed
Klintmalm 2014 {published data only}
    1. Klintmalm GB, Feng S, Lake JR, Vargas HE, Wekerle T, Agnes S, et al. Belatacept‐based immunosuppression in de novo liver transplant recipients: 1‐year experience from a phase ii randomized study. American Journal of Transplantation 2014;14(8):1817‐27. - PMC - PubMed
Klupp 1998 {published data only}
    1. Klupp J, Bechstein WO, Pratschke J, Tullius SG, Gebhard A, Lobeck H, et al. Risk and benefit of antibody induction therapy in combination with tacrolimus immunosuppression after liver transplantation. Transplantation Proceedings 1998;30(4):1443‐4. - PubMed
Langrehr 1997 {published data only}
    1. Langrehr JM, Nussler NC, Neumann U, Guckelberger O, Lohmann R, Radtke A, et al. A prospective randomized trial comparing interleukin‐2 receptor antibody versus antithymocyte globulin as part of a quadruple immunosuppressive induction therapy following orthotopic liver transplantation. Transplantation 1997;63(12):1772‐81. - PubMed
    1. Lemmens HP, Langrehr JM, Bechstein WO, Blumhardt G, Keck H, Lüsebrink R, et al. Interleukin‐2 receptor antibody vs ATG for induction immunosuppression after liver transplantation: Initial results of a prospective randomized trial. Transplantation Proceedings 1995;27(1):1140‐1. - PubMed
Langrehr 1998a {published data only}
    1. Langrehr JM, Glanemann M, Guckelberger O, Klupp J, Neumann U, Machens C, et al. A randomized, placebo‐controlled trial with anti‐interleukin‐2 receptor antibody for immunosuppressive induction therapy after liver transplantation. Clinical Transplantation 1998;12(4):303‐12. - PubMed
Langrehr 1998b {published data only}
    1. Langrehr JM, Glanemann M, Schneller A, Neumann U, Guckelberger O, Lohmann R, et al. A randomized trial comparing anti‐interleukin‐2 receptor antibody and placebo for immunosuppressive therapy after OLT. Transplantation Proceedings 1998;30(4):1445‐6. - PubMed
Langrehr 2001 {published data only}
    1. Langrehr JM, Klupp J, Junge G, Jonas S, Neuhaus R, Bechstein WO, et al. Quadruple versus dual tacrolimus‐based induction after liver transplantation: a prospective, randomized trial. Transplantation Proceedings 2001;33(3):2330‐1. - PubMed
    1. Langrehr JM, Klupp J, Pfitzmann R, Neumann U, Lohmann R, Jonas S, et al. A prospective, randomized trial with quadruple versus dual tacrolimus‐based induction after liver transplantation. Transplantation Proceedings 2001;33(1‐2):1520. - PubMed
Langrehr 2002 {published data only}
    1. Langrehr JM, Neumann UP, Lang M, Muller AR, Jonas S, Settmacher U, et al. First results from a prospective randomized trial comparing steroid‐free induction therapy with tacrolimus and mmf versus tacrolimus and steroids in patients after liver transplantation for HCV. Transplantation Proceedings 2002;34(5):1565‐6. - PubMed
Lerut 2005 {published data only}
    1. Lerut J, Thuyne V, Mathijs J, Lemaire J, Talpe S, Roggen F, et al. Anti‐cd2 monoclonal antibody and tacrolimus in adult liver transplantation. Transplantation 2005;80(9):1186‐93. - PubMed
Lerut 2008 {published data only}
    1. Bonaccorsi‐Riani E, Sempoux C, Piette N, Julliard O, Kabamba B, Ciccarelli O, et al. Impact of steroid‐avoidance immunosuppression on long‐term outcome after liver transplantation for HCV cirrhosis: the need for well documented long‐term follow‐up. Acta Gastroenterologica Belgica 2012;75(4):411‐8. - PubMed
    1. Lerut J, Mathys J, Verbaandert C, Talpe S, Ciccarelli O, Lemaire J, et al. Tacrolimus monotherapy in liver transplantation: One‐year results of a prospective, randomized, double‐blind, placebo‐controlled study. Annals of Surgery 2008;248(6):956‐67. - PubMed
    1. Lerut JP, Pinheiro RS, Lai Q, Stouffs V, Orlando G, Juri JM, et al. Is minimal, (almost) steroid‐free immunosuppression a safe approach in adult liver transplantation? Long‐term outcome of a prospective, double blind, placebo‐controlled, randomized, investigator‐driven study. Annals of Surgery 2014;260(5):886‐91; discussion 91‐2. - PubMed
Levy 2004 {published data only}
    1. Levy G, Grazi GL, Muhlbacher F, Samuel D, Friman S, Jones R, et al. 12‐month follow‐up analysis of a multicenter, randomized, prospective trial in de novo liver transplantation recipients (LIS2T) comparing cyclosporine microemulsion (c2 monitoring) and tacrolimus. Liver Transplantation 2006;12(10):1464‐72. - PubMed
    1. Levy G, Villamil F, Samuel D, Sanjuan F, Grazi GL, Wu Y, et al. Results of LIS2T, a multicenter, randomized study comparing cyclosporine microemulsion with c2 monitoring and tacrolimus with c0 monitoring in de novo liver transplantation. Transplantation 2004;77(11):1632‐8. - PubMed
    1. Tanaka K, Lake J, Villamil F, Levy G, Marotta P, Mies S, et al. Comparison of cyclosporine microemulsion and tacrolimus in 39 recipients of living donor liver transplantation. Liver Transplantation 2005;11(11):1395‐402. - PubMed
Levy 2006 {published data only}
    1. Levy G, Schmidli H, Punch J, Tuttle‐Newhall E, Mayer D, Neuhaus P, et al. Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12‐ and 36‐month results. Liver Transplantation 2006;12(11):1640‐8. - PubMed
Levy 2014 {published data only}
    1. Levy G. REFINE: A multicenter, randomized open‐label study to compare liver fibrosis at 12 months after transplantation for hepatitis C cirrhosis using cyclosporine microemulsion (csa‐me) or tacrolimus (tac). Liver Transplantation 2013;1:S88.
    1. Levy G, Villamil FG, Nevens F, Metselaar HJ, Clavien PA, Klintmalm G, et al. REFINE: A randomized trial comparing cyclosporine a and tacrolimus on fibrosis after liver transplantation for hepatitis C. American Journal of Transplantation 2014;14(3):635‐46. - PubMed
    1. Lilly L, Tzakis A, Klintmalm G, Villamil FG, Jones RM. Comparison between steroid‐treated and steroid‐free cohorts in CNI‐treated patients: 6‐month interim analysis of the REFINE trial, a randomized study to compare the development of liver fibrosis at 12 months after transplantation for hepatitis C cirrhosis. Hepatology 2008;48(4 (Suppl)):548a‐9a.
Llado 2006 {published data only}
    1. Llado L, Xiol X, Figueras J, Ramos E, Memba R, Serrano T, et al. Immunosuppression without steroids in liver transplantation is safe and reduces infection and metabolic complications: Results from a prospective multicenter randomized study. Journal of Hepatology 2006;44(4):710‐6. - PubMed
    1. Lladó L, Fabregat J, Castellote J, Ramos E, Xiol X, Torras J, et al. Impact of immunosuppression without steroids on rejection and hepatitis C virus evolution after liver transplantation: Results of a prospective randomized study. Liver Transplantation 2008;14(12):1752‐60. - PubMed
Llado 2014 {published data only}
    1. Llado L, Fabregat J, Baliellas C, Ramos E, Torras J, Secanella L, et al. Influence of the type of calcineurin inhibitor on HCV recurrence after liver transplantation. Results of a prospective randomized study. Liver Transplantation 2014;20:S332.
Lu 2006a {published data only}
    1. Lu AW, Zheng SS, Wu J, Liang TB, Wang WL, Shen Y, et al. Dual, triple, and quadruple oral tacrolimus‐based immunosuppression regimens after orthotopic liver transplantation: a randomised comparative study of regimens. Chung‐Hua i Hsueh Tsa Chih 2006;86(48):3389‐92. - PubMed
Lupo 2008 {published data only}
    1. Lupo L, Panzera P, Tandoi F, Carbotta G, Giannelli G, Santantonio T, et al. Basiliximab versus steroids in double therapy immunosuppression in liver transplantation: a prospective randomized clinical trial. Transplantation 2008;86(7):925‐31. - PubMed
    1. Lupo L, Ricci P, Caputi L, Tandoi F, Aquilino F, Palma G, et al. Basiliximab vs steroids in liver transplantation immunosuppression. A prospective randomized clinical trial. Liver Transplantation 2005;11(7):C75.
Margarit 2005 {published data only}
    1. Margarit C, Bilbao I, Castells L, Lopez I, Pou L, Allende E, et al. A prospective randomized trial comparing tacrolimus and steroids with tacrolimus monotherapy in liver transplantation: the impact on recurrence of hepatitis C. Transplant International 2005;18(12):1336‐45. - PubMed
McDiarmid 1991 {published data only}
    1. McDiarmid SV, Busuttil RW, Levy P, Millis MJ, Terasaki PI, Ament ME. The long‐term outcome of OKT3 compared with cyclosporine prophylaxis after liver transplantation. Transplantation 1991;52(1):91‐7. - PubMed
McDiarmid 1991a {published data only}
    1. McDiarmid SV, Millis MJ, Terasaki PI, Ament ME, Busuttil RW. OKT3 prophylaxis in liver transplantation. Digestive Diseases and Sciences 1991;36(10):1418‐26. - PubMed
    1. Millis JM, McDiarmid SV, Hiatt JR, Brems JJ, Colonna JO, Klein AS, et al. Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation. Transplantation 1989;47(1):82‐8. - PubMed
McDiarmid 1993 {published data only}
    1. McDiarmid SV, Colonna JO 2nd, Shaked A, Ament ME, Busuttil RW. A comparison of renal function in cyclosporine‐ and FK‐506‐treated patients after primary orthotopic liver transplantation. Transplantation 1993;56(4):847‐53. - PubMed
Moench 2007 {published data only}
    1. Moench C, Barreiros AP, Schuchmann M, Bittinger F, Thiesen J, Hommel G, et al. Tacrolimus monotherapy without steroids after liver transplantation ‐ a prospective randomized double‐blinded placebo‐controlled trial. American Journal of Transplantation 2007;7(6):1616‐23. - PubMed
    1. Weiler N, Thrun I, Hoppe‐Lotichius M, Zimmermann T, Kraemer I, Otto G. Early steroid‐free immunosuppression with FK506 after liver transplantation: Long‐term results of a prospectively randomized double‐blinded trial. Transplantation 2010;90(12):1562‐6. - PubMed
Mor 1994 {published data only}
    1. Mor E, Patel T, Glabman S, Sheiner P, Emre S, Guy S, et al. Comparison of short and long‐term renal function in liver transplant patients receiving cyclosporin or FK 506. Transplant International 1994;7 Suppl 1:S77‐80. - PubMed
Nashan 1996 {published data only}
    1. Nashan B, Schlitt HJ, Schwinzer R, Ringe B, Kuse E, Tusch G, et al. Immunoprophylaxis with a monoclonal anti‐il‐2 receptor antibody in liver transplant patients. Transplantation 1996;61(4):546‐54. - PubMed
Neuberger 2009 {published data only}
    1. Neuberger JM, Mamelok RD, Neuhaus P, Pirenne J, Samuel D, Isoniemi H, et al. Delayed introduction of reduced‐dose tacrolimus, and renal function in liver transplantation: the 'ReSpECT' study. American Journal of Transplantation 2009;9(2):327‐36. - PubMed
Neuhaus 1993 {published data only}
    1. Neuhaus P, Bechstein WO, Blumhardt G, Wiens M, Lemmens P, Langrehr JM, et al. Comparison of quadruple immunosuppression after liver transplantation with ATG or IL‐2 receptor antibody. Transplantation 1993;55(6):1320‐7. - PubMed
Neuhaus 1994 {published data only}
    1. Devlin J, Williams R, Neuhaus P, McMaster P, Calne R, Pichlmayr R, et al. Renal complications and development of hypertension in the European study of FK 506 and cyclosporin in primary liver transplant recipients. Transplant International 1994;7 Suppl 1:S22‐6. - PubMed
    1. Ericzon B, Groth C, Bismuth H, Calne R, McMaster P, Neuhaus P, et al. Glucose metabolism in liver transplant recipients treated with FK 506 or cyclosporin in the European multicentre study. Transplant International 1994;7 Suppl 1:S11‐4. - PubMed
    1. McMaster P. Patient and graft survival in the European multicentre liver study ‐ FK 506 vs cyclosporin a. Transplant International 1994;7 Suppl 1:S32‐6. - PubMed
    1. Muhlbacher F. Tacrolimus versus cyclosporin microemulsion in liver transplantation: Results of a 3‐month study. Transplantation Proceedings 2001;33(1‐2):1339‐40. - PubMed
    1. Neuhaus P, McMaster P, Calne R, Pichlmayr R, Otto G, Williams R, et al. Neurological complications in the European multicentre study of FK 506 and cyclosporin in primary liver transplantation. Transplant International 1994;7 Suppl 1:S27‐31. - PubMed
Neuhaus 1997 {published data only}
    1. Neuhaus P, Langrehr JM, Williams R, Calne RY, Pichlmayr R, McMaster P. Tacrolimus‐based immunosuppression after liver transplantation: a randomised study comparing dual versus triple low‐dose oral regimens. Transplant International 1997;10(4):253‐61. - PubMed
Neuhaus 2000 {published data only}
    1. Neuhaus P, Klupp J, Langrehr JM, Neumann U, Gebhardt A, Pratschke J, et al. Quadruple tacrolimus‐based induction therapy including azathioprine and ALG does not significantly improve outcome after liver transplantation when compared with standard induction with tacrolimus and steroids: Results of a prospective, randomized trial. Transplantation 2000;69(11):2343‐53. - PubMed
Neuhaus 2002 {published data only}
    1. Neuhaus P, Clavien PA, Kittur D, Salizzoni M, Rimola A, Abeywickrama K, et al. Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: Results from a double‐blind randomized placebo‐controlled trial. Liver Transplantation 2002;8(2):132‐42. - PubMed
Neumann 2012 {published data only}
    1. Neumann U, Samuel D, Trunecka P, Gugenheim J, Gerunda GE, Friman S. A randomized multicenter study comparing a tacrolimus‐based protocol with and without steroids in HCV‐positive liver allograft recipients. Journal of Transplantation 2012;2012:894215. - PMC - PubMed
Nevens 2007 {published data only}
    1. Nevens F, Sterneck M, Metselaar H, Dumortier J, Giostra E, Boudjema K. Multicenter, randomized trial of conversion to everolimus with calcineurin inhibitor minimization or discontinuation in liver transplant patients with renal impairment. Hepatology 2007;46(4 (Suppl 1)):486a‐7a.
Northup 2006 {published data only}
    1. Northup PG, Chong TW, Iezzoni JC, Kerr SE, Burns AS, Pruett TL. Tacrolimus versus cyclosporine based immunosuppression in hepatitis C patients after liver transplantation: Long‐term follow‐up of a randomized controlled trial. Hepatology 2006;44(4 (Suppl 1)):412a‐3a.
Otero 2009 {published data only}
    1. Otero A, Varo E, Urbina JO, Martin‐Vivaldi R, Cuervas‐Mons V, Gonzalez‐Pinto I, et al. A prospective randomized open study in liver transplant recipients: Daclizumab, mycophenolate mofetil, and tacrolimus versus tacrolimus and steroids. Liver Transplantation 2009;15(11):1542‐52. - PubMed
Pageaux 1995 {published data only}
    1. Pageaux GP, Blanc P, Perrigault PF, Navarro F, Fabre JM, Souche B, et al. Failure of ursodeoxycholic acid to prevent acute cellular rejection after liver transplantation. Journal of Hepatology 1995;23(2):119‐22. - PubMed
Pageaux 2006 {published data only}
    1. Pageaux GP, Rostaing L, Calmus Y, Duvoux C, Vanlemmens C, Hardgwissen J, et al. Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Liver Transplantation 2006;12(12):1755‐60. - PubMed
Pascher 2015 {published data only}
    1. Pascher A, De PS, Pratschke J, Salame E, Pirenne J, Isoneimi H, et al. Protein kinase C inhibitor sotrastaurin in de novo liver transplant recipients: a randomized phase II trial. American Journal of Transplantation 2015;15(5):1283‐92. - PubMed
Ramirez 2013 {published data only}
    1. Ramirez CB, Doria C, Frank AM, Armenti ST, Marino IR. Completely steroid‐free immunosuppression in liver transplantation: a randomized study. Clinical Transplantation 2013;27(3):463‐71. - PubMed
    1. Ramirez CB, Doria C, Frank AM, Navarro V, Herrine S, Rossi S. Enteric coated mycophenolate sodium with basiliximab induction, tacrolimus with or without steroids is safe and effective in adult liver transplantation. Liver Transplantation 2008;14(7 (Suppl 1)):S109.
    1. Ramirez CB, Doria C, Frank AM, Navarro V, Herrine S, Rossi S. Safety and efficacy of steroid‐free immunosuppression using basiliximab induction, tacrolimus and enteric coated mycophenolate sodium in adult liver transplantation. Liver Transplantation 2008;14(7 (Suppl 1)):S109.
Reding 1993 {published data only}
    1. Reding R, Feyaerts A, Vraux H, Latinne D, Parra B, Cornet A, et al. Prophylactic immunosuppression with anti‐interleukin‐2 receptor monoclonal antibody lo‐tact‐1 versus OKT3 in liver allografting. A two‐year follow‐up study. Transplantation 1996;61(9):1406‐9. - PubMed
    1. Reding R, Vraux H, Ville de Goyet J, Sokal E, Hemptinne B, Latinne D, et al. Monoclonal antibodies in prophylactic immunosuppression after liver transplantation. A randomized controlled trial comparing OKT3 and anti‐il‐2 receptor monoclonal antibody LO‐tact‐1. Transplantation 1993;55(3):534‐41. - PubMed
Reggiani 2005 {published data only}
    1. Reggiani P, Arru M, Regazzi M, Gatti S, Molinaro MD, Caccamo L, et al. A "steroid‐free" tacrolimus and low‐dose mycophenolate mofetil primary immunosuppression does not prevent early acute rejection after liver transplantation. Transplantation Proceedings 2005;37(4):1697‐9. - PubMed
Reich 2005 {published data only}
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Saliba 2016 {published data only}
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Saliba 2016a {published data only}
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Schmeding 2007 {published data only}
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Shenoy 2007 {published data only}
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Simone 2008 {published data only}
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Studenik 2005 {published data only}
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Therapondos 2002 {published data only}
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Villamil 2014 {published data only}
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Washburn 2001 {published data only}
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Watson 2007 {published data only}
    1. Watson CJ, Gimson AE, Alexander GJ, Allison ME, Gibbs P, Smith JC, et al. A randomized controlled trial of late conversion from calcineurin inhibitor (cni)‐based to sirolimus‐based immunosuppression in liver transplant recipients with impaired renal function. Liver Transplantation 2007;13(12):1694‐702. - PubMed
Wiesner 2001 {published data only}
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Yoshida 2005 {published data only}
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References to ongoing studies

Nashan 2015 {published data only}
    1. Nashan B, Schemmer P, Braun F, Dworak M, Wimmer P, Schlitt H. Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus‐facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial. Trials 2015;16:118. - PMC - PubMed
Simone 2014 {published data only}
    1. Simone P, Cescon M, Cillo U, Tisone G, Guarisco R, Fagiuoli S. Exploring the impact of everolimus‐based immunosuppression on renal function: the REFLECT study. Liver Transplantation 2014;20:S319.

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