- Email: [email protected]
Everolimus in de novo liver transplant recipients: a systematic review
Everolimus in LT Meta-Analysis
Everolimus in de novo liver transplant recipients: a systematic review Cheng-Yong Tang, Ai Shen, Xu-Fu Wei, Qing-Dong Li, Rui Liu, He-Jun Deng, Yong-Zhong Wu and Zhong-Jun Wu Chongqing, China
BACKGROUND: Everolimus has no nephrotoxicity and is used to treat patients with post-liver transplant chronic renal insufficiency. The present systematic review was to evaluate the efficacy and safety of everolimus in de novo liver transplant patients.
creased tBPAR (RR: 1.71; 95% CI: 1.15-2.53; P<0.01). Everolimus decreased the risk of neoplasms/tumor recurrence after liver transplant (RR: 0.60; 95% CI: 0.34-1.03; P=0.06), but was associated with greater risk of adverse events which resulted in drug discontinuation (RR: 1.98; 95% CI: 1.49-2.64; P<0.01).
DATA SOURCES: Randomized controlled trials comparing everolimus for de novo liver transplant in PubMed, the Cochrane Library, and ScienceDirect published up to March 31, 2014 were searched by two independent reviewers. Mean differences and 95% confidence interval (95% CI) for renal function, relative risk (RR) and 95% CI for treated biopsy-proven acute rejection (tBPAR), graft loss, death, neoplasms/tumor recurrence, and adverse events were collected. Meta-analyses were performed with RevMan version 5.10.
CONCLUSIONS: Early introduction of everolimus combined with low-dose or no CNI in de novo liver transplant significantly improves renal function one year post treatment. Everolimus combined with low-dose CNI decreases the risk of tBPAR one year after liver transplant, but everolimus administered without CNIs increases tBPAR. (Hepatobiliary Pancreat Dis Int 2015;14:461-469)
KEY WORDS: everolimus; calcineurin inhibitors; RESULTS: A total of four randomized controlled trials coverliver transplantation; ing 1119 cases were included. The meta-analyses revealed that systematic review compared with standard exposure of calcineurin inhibitors (CNIs), everolimus combined with reduced CNIs improved creatinine clearance (calculated with the Cockcroft-Gault formula) by 5.13 mL/min at one year (95% CI: 0.42-9.84; P=0.03), Introduction and decreased tBPAR (RR: 0.56; 95% CI: 0.35-0.90; P=0.02). alcineurin inhibitors (CNIs) are the first line Everolimus initiation with CNIs elimination improved glotherapy for liver transplantation (LT) patients,[1, 2] merular filtration rate (GFR, measured with the modification but they have side effects such as chronic nephof diet in renal disease formula) of 10.42 mL/min/1.73 m2 (95% CI: 3.44-17.41; P<0.01) one year after treatment, but in- rotoxicity that progressively reduces renal function. Ap-
C
Author Affiliations: Department of Pharmacy (Tang CY) and Department of Hepatobiliary Surgery (Wei XF, Liu R and Wu ZJ), First Affiliated Hospital of Chongqing Medical University, Chongqing 404100, China; Department of Hepatobiliary Surgery (Shen A, Li QD and Deng HJ) and Department of Radiotherapy (Wu YZ), Chongqing Cancer Institute, Chongqing 400030, China Corresponding Author: Zhong-Jun Wu, MD, PhD, Department of Hepatobiliary Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing 404100, China (Fax: +86-23-68711487; Email: [email protected]) © 2015, Hepatobiliary Pancreat Dis Int. All rights reserved. doi: 10.1016/S1499-3872(15)60419-2 Published online September 17, 2015.
proximately 10% of the patients suffer from chronic renal failure within five years after liver transplantation because of CNI treatment.[3] Everolimus, an immunosuppressant of the mammalian target of rapamycin (mTOR),[4-6] has been approved for heart and renal transplantation[7, 8] and can be used with or without CNIs to reduce CNI-induced drug toxicity.[8, 9] Everolimus given with a low dose of CNI or without CNI significantly improves renal function after LT,[10-13] allowing FDA approval for use of this drug after LT as well.[14] Still, the outcomes of everolimus-based immunosuppression in LT recipients have not been systematically reviewed. The present study was to evaluate the efficacy and safety of everolimus in de novo LT patients at one year after LT.
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Methods Literature search PubMed, the Cochrane Library, and ScienceDirect were searched using the terms "everolimus" and "liver transplant" or "liver transplantation" or "hepatic transplantation" or "hepatic graft" or "LT" before March 31, 2014 without language limitations. Two reviewers (Tang CY and Shen A) independently searched articles based on titles, abstract and key words. Disagreements over articles were discussed until consensus was reached. Only published data were retrieved and included. Inclusion and exclusion criteria 1) Study subjects included only de novo LT patients. 2) Each trial was designed to evaluate both the efficacy and safety of everolimus. 3) Follow-up time must exceed 1 year. 4) Case reports, review articles, editorials, letters, and single-arm studies were excluded. 5) Only randomized controlled trials (RCTs) were included. Outcome of interest The primary outcome of interest was one-year efficacy of everolimus in de novo LT patients, using renal function, treated biopsy-proven acute rejection (tBPAR), graft loss, death, and neoplasm/tumor recurrence. The secondary outcome measure was to assess the safety of everolimus in de novo LT patients.
heterogeneity. Values between 0% and 25% indicated that heterogeneity might not be important. Values between 25% and 50% indicated moderate inconsistency. Values of 50% to 75% were indicated substantial heterogeneity. Values between 75% and 100% indicated considerable inconsistency. When inconsistency was detected, the reason for the heterogeneity was explored using sensitivity and subgroup analysis. A two-tailed P value of 0.05 was deemed statistically significant. All statistical calculations for this article were performed using Review Manager 5.1. These results were reported using the Cochrane Handbook for Systematic Reviews of Interventions.[15]
Results Trial selection Six RCTs that evaluated the efficacy and safety of everolimus in LT patients were included. Of these, four were enrolled in this review (Fig. 1).[11, 12, 17, 18] One RCT was excluded due to recruitment of maintenance LT patients;[19] another was due to the only observation of the efficacy of everolimus in LT patients at 3 months after treatment.[20] Of the 4 studies enrolled in the present analysis, one evaluated the efficacy, safety and tolerability of the different dosage of everolimus under controlled CNIs in LT patients[17] (reference 17 never mentioned "reduced CNIs". On the contrary, "steady-state administration of cyclosporine". As a matter of fact, the authors
Data extraction and quality analysis Two reviewers (Tang CY and Shen A) independently extracted the data as follows: article authors, time of publication, trial region, number of cases, age of participants, gender of participants, route of drug administration, renal function, efficacy events and safety events. Disagreements about extraction were resolved via discussion. The two reviewers independently evaluated the quality of each study according to the Cochrane Handbook for Systematic Reviews of Interventions (http://handbook.cochrane.org/).[15] Statistical analysis The pooled standard mean differences (SMD), mean differences (MD), and 95% confidence intervals (CI) were reported for continuous data. Pooled relative risk (RR) and 95% CI were reported for dichotomous data. The Chi-square test-based Q statistic of RR and trials with P<0.1 were considered heterogeneous. When P>0.1, the DerSimonian-Laird random effects model was used to control for heterogeneity in the meta-analysis.[16] Q-based I2 statistics were used to evaluate quantitative Fig. 1. Literature search process. 462 • Hepatobiliary Pancreat Dis Int，Vol 14，No 5 • October 15，2015 • www.hbpdint.com
Everolimus in LT
controlled the CNI dosage to test the safety and tolerability of everolimus at different doses); two assessed the efficacy and safety of CNI conversion to everolimus in LT patients[12, 18] and one compared the efficacy and renal function between everolimus initiation with reduced-exposure tacrolimus and standard-exposure tacrolimus.[11] The baseline characteristics of included patients are detailed in Table 1 and the immunosuppression regimen is detailed in Table 2.
Quality of trials included in the systematic review The method of generating a random sequence was not reported in Levy's study.[17] Three trials did not report whether or not the allocation concealment was used. Only Levy et al used a placebo-controlled double-blinded method.[17] Three studies[11, 12, 18] did not mention the blindness of the result evaluations. Randomization of everolimus combined with elimination of tacrolimus was terminated prematurely because of a higher rate of tBPAR in De Simone's study.[11] Levy's study[17] included three different doses of everolimus, which may have introduced bias. All four studies were found to have a high risk of bias (Table 3).
observed (I2=52%; Fig. 2). However, sensitivity analysis confirmed stability in this set of results. Subgroup analysis demonstrated that everolimus initiation with reduced CNIs significantly improved the CrCl (MD: 5.13; 95% CI: 0.42-9.84; P=0.03; I2=0%) at one year[11, 17] compared with standard exposure of CNIs (Fig. 3). Everolimus initiation with CNIs elimination also significantly improved GFR by 10.42 mL/min/1.73 m2 (MD: 10.42; 95% CI: 3.44-17.41; P<0.01; I2=69%; Fig. 3).[11, 12, 18] Heterogeneity may be attributed mainly to Masetti's study, for which cyclosporine in the control group was elevated gradually.[18]
tBPAR, graft loss, death and neoplasms/tumor recurrence Everolimus combined reduced CNIs in de novo LT decreased the risk of tBPAR one year after treatment.[11, 17] However, everolimus initiation with elimination of CNIs increased the risk of tBPAR.[11, 12, 18] Neither everolimus combined with CNIs reduction nor everolimus initiation with CNIs elimination was associated with more risk of graft loss and death one year after treatment compared to the control group. All included studies reported relevant Efficacy data regarding neoplasms/tumor recurrence and our analysis confirmed that everolimus decreased the risk of Renal function Some studies used creatinine clearance (CrCl; Cock- neoplasms/tumor recurrence one year after transplantacroft-Gault) to evaluate renal function;[12, 17] others used tion although it has no statistical significance (Table 4). glomerular filtration rate (GFR; modification of diet in renal disease formula) or both.[11, 12, 18] The pooled SMD Safety Not all trials provided a complete report about everowas reported in this way. Meta-analyses demonstrated that everolimus-based treatment significantly improves limus side effects.[17, 18] Meta-analyses confirmed that renal function one year after treatment (SMD: 0.35; 95% everolimus significantly increased the risk of adverse CI: 0.13-0.57; P<0.01), but substantial heterogeneity was events and discontinuation of therapy (Tables 4 and 5). Table 1. Baseline characteristics of included studies Studies De Simone et al
[11]
Countries
Group
Cases (n)
Age (yr) (mean±SD)
Male (%)
HCV (%)
Baseline of RF Measurement of RF
Multicenter
EVR+TAC reduction EVR+TAC elimination Control EVR+CNI elimination Control EVR+CYC reduction* EVR+CYC reduction* EVR+CYC reduction* Control EVR+CYC elimination Control
245 231 243 101 102 28 30 31 30 52 26
53.6±9.2 53.2±10.8 54.5±8.7 52.3±9.9 52.9±10.1 46.3±11.2 48.2±12.0 48.8±10.2 51.6±9.0 53.7±9.8 55.6±7.4
73.5 71.0 73.7 56.3 69.4 64.3 43.3 71.0 50.0 76.9 76.9
31.8 31.2 31.3 7.3 8.2 32.1 23.3 25.8 20.0 38.5 30.8
81.1±32.6 82.6±37.2 78.1±27.5 78.0±27.4 74.9±24.6 87.5±25.3 96.7±30.4 96.0±35.8 95.9±35.0 81.7±29.5 74.7±24.6
Fischer et al[12]
Germany
Levy et al[17]
Canada
Masetti et al[18]
Italy
MDRD-GFR/CG-CrCl
MDRD-GFR/CG-CrCl CG-CrCl
MDRD-GFR
*: In the three everolimus groups, everolimus was administered at 0.5, 1.0, and 2.0 mg, BID. EVR: everolimus; CYC: cyclosporine; CNI: calcineurin inhibitor; TAC: tacrolimus; HCV: hepatitis C virus; RF: renal function; GFR: glomerular filtration rate; CG: Cockcroft-Gault; MDRD: modification of diet in renal disease; SD: standard deviation.
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Table 2. Immunosuppression regimens of included studies Studies Group De Simone et al[11] EVR+TAC reduction
EVR dose Initial: 1.0 mg BID within 24 hours of randomization (30 ±5 days), adjusted from day 5 to achieve a C0 level at 3-8 ng/mL until month 4 and kept the same thereafter. EVR+TAC Initial: 1.0 mg BID within elimination 24 hours of randomization (30±5 days), adjusted from day 5 to achieve a C0 level at 3-8 ng/mL until month 4, then 6-10 ng/mL. Control None
CNI dose Other immunosuppression TAC was tapered off to 3-5 ng/mL once the Corticosteroids were started at the time EVR C0 level was within 3-8 ng/mL, by of transplant and administered accordweek 3 and left unchanged thereafter. ing to local practice, with a continued minimum oral dose of 5 mg prednisolone/day after randomization until at least month 6 after LT. TAC: was tapered to a C0 level of 3-5 ng/mL Mycophenolicacids, if used, were adminby week 3 after randomization, and then istered according to local practice but decreased after EVR C0 achieved 6-10 ng/mL needed to be stopped by the time of at the start of month 4 posttransplant if randomization. liver function was adequate. TAC was completely eliminated by the end of month 4. TAC: 8-12 ng/mL until month 4, 6-10 ng/mL Same as the EVR group thereafter.
Fischer et al[12]
EVR+CNI When CNI was tapered off by CNIs were discontinued after 8 weeks of Basiliximab was administered intraveelimination 70% of the initial CNI dose, CNI reduction if rejection-free for at least nously (20 mg) on days 0 and 4 after LT. EVR was started at a dose 4 weeks. CNI was administered with or without of 1.5 mg BID and adjusted corticosteroids and with or without into a C0 level of 5-12 ng/mL fection prophylaxis after LT according (8-12 ng/mL in patients beto local practice. ing treated with CYC). Control None Not described in detail Same as the EVR group
Levy et al[17]
EVR+CYC reduction
0.5 mg BID orally
EVR+CYC reduction EVR+CYC reduction Control
1.0 mg BID orally
[18]
Masetti et al
CYC C0 level: 1-4 weeks, 150-450 ng/mL 2-6 months, 100-300 ng/mL 7-12 months, 75-300 ng/mL
Methylprednisolone was administered intravenous before, during, or immediately after LT. Oral prednisone or equivalent methylprednisolone was tapered off to ≥5.0 mg per day by month 3. Thereafter, it was maintained, tapered off, or discontinued.
Same as the EVR group
Same as the EVR group
2.0 mg BID orally Placebo
EVR+CYC The initial dose (day 10) CYC: The initial dose was 2 mg/kg per day, Basiliximab was administered intraveelimination of EVR was 2.0 mg/d to divided into two daily doses, kept at 100± nously (20 mg) on day 0 (within 6 h of achieve a C0 level of 6-10 25 ng/mL until day 30. reperfusion of the liver graft) and on ng/mL. On day 30, when day 5 after LT. CYC was abruptly disconMethylprednisolone was administered tinued, the EVR dose was intravenously (500 mg) on day 0 and increased to maintain a C0 tapered within 5 weeks. level of 8-12 ng/mL until Prednisone (or equivalent) was adminthe end of month 6. Thereistered 20 mg/day in a single morning after, 6-10 ng/mL. dose in week 1, 16 mg/d in week 2, 12 mg/d in week 3, 8 mg/d in week 4 and 4 mg/d in week 5. Thereafter, the drug was discontinued. The initial dose was 2 mg/kg per day, di- Same as the EVR group Control None vided into two daily doses, kept at 100±25 ng/mL in the first 10 days. Then it was adjusted to 225±25 ng/mL until day 30, 200 ± 25 ng/mL until the end of month 6 and 150±25 ng/mL thereafter. When patients experienced CNI related complications, the CYC dose was decreased to reduce the C0 level by about 50% and mycophenolate mofetil was introduced at an initial dose of 1 g BID and then kept at 500 mg TID.
EVR: everolimus; CYC: cyclosporine; CNI: calcineurin inhibitor; TAC: tacrolimus; LT: liver transplantation.
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Table 3. Quality of the RCTs included in this systematic review Studies
Random
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Other bias
De Simone et al[11] Fischer et al[12] Levy et al[17] Masetti et al[18]
Yes Yes Unclear Yes
Unclear Unclear Yes Unclear
No No Yes No
Unclear Unclear Yes Unclear
No Yes Yes Yes
Yes Yes No Yes
No Yes No No
Table 4. Meta-analyses of primary outcomes at one year after treatment Outcome measurements Biopsy-proven acute rejection EVR+ reduced CNIs vs control EVR+ eliminated CNIs vs control Graft loss EVR+ reduced CNIs vs control EVR+ eliminated CNIs vs control Death EVR+ reduced CNIs vs control EVR+ eliminated CNIs vs control Neoplasm/tumor recurrence EVR vs control Serious adverse events EVR vs control Drug discontinuation EVR vs control
No. of trials
No. of cases (EVR/control)
RR (M-H, fixed)
95% CI
P value
I2 (%)
2 3
334/273 379/367
0.56 1.71
0.35, 0.90 1.15, 2.53
0.02 <0.01
15 45
2 2
334/273 327/341
1.42 1.46
0.51, 3.92 0.47, 4.54
0.50 0.52
0 0
2 3
334/273 379/367
1.04 1.32
0.51, 2.09 0.67, 2.61
0.92 0.42
17 0
4
463/391
0.60
0.34, 1.03
0.06
0
3
665/373
1.25
1.10, 1.42
<0.01
0
3
660/369
1.98
1.49, 2.64
<0.01
0
EVR: everolimus; CNI: calcineurin inhibitor.
Fig. 2. Meta-analysis of RCTs comparing the overall mean change in renal function of everolimus to that of the control group at one year.
Fig. 3. Meta-analysis of RCTs comparing the mean change in renal function of the everolimus+reduced CNIs group or everolimus+ eliminated CNIs group to that of the control group at one year. Hepatobiliary Pancreat Dis Int，Vol 14，No 5 • October 15，2015 • www.hbpdint.com • 465
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Table 5. Meta-analyses of adverse events in the included trials Adverse events Infection Cytomegalovirus infection Pneumonia Urinary tract infection Nasopharyngitis Anemia Leukopenia Thrombocytopenia Incisional hernia Wound healing Biliary complication Hyperlipidemia Hypercholesterolemia Type 2 diabetes mellitus Renal failure Proteinuria Peripheral edema Nervous system disorders Headaches Tremors Pyrexia Hypertension Nausea Diarrhea Hepatic arterial thrombosis HCV recurrence Oral ulcer
No. of trials 3 4 2 1 1 2 3 3 3 2 2 3 2 2 4 2 2 2 1 2 1 2 1 1 3 2 1
No. of patients 979 886 919 203 203 919 1038 1038 997 919 794 767 322 493 1116 919 794 281 716 794 716 919 716 716 1107 744 78
Discussion One study including 36 849 LT patients suggested that the cumulative incidence of chronic renal failure was -20% three years after transplantation and this was associated with a 4-fold increase in the risk of death.[21] One major contributor to renal dysfunction in LT recipients was CNIs.[22] Because CNIs are the backbone of immunosuppressive treatment of LT, better regimens must be formulated to reduce this risk.[1] The present systematic review demonstrated that everolimus-based immunosuppression can significantly improve renal function one year after treatment and it does not increase the risk of graft loss or death. Also, everolimus combined with reduced CNIs improves renal function at one year without an increased risk of graft loss or death and these benefits were long-lasting. Saliba's group remarked that combination treatment improves GFR of LT patients three years post transplantation.[10, 13] This systemic review showed that everolimus plus reduced-dose CNIs decrease the risk of tBPAR by 44%. This may be a synergistic effect of everolimus and CNIs.[23, 24] Experimental studies demonstrated that
RR 1.16 0.81 1.40 1.24 1.01 1.30 1.97 1.64 1.47 1.17 0.84 1.84 2.18 0.92 0.66 4.86 1.73 0.68 0.95 0.67 1.56 1.09 1.03 1.02 0.45 1.07 2.55
95% CI 1.02, 1.31 0.51, 1.28 0.63, 3.11 0.63, 2.45 0.52, 1.96 0.87, 1.95 1.24, 3.12 0.80, 3.34 0.90, 2.39 0.86, 1.58 0.44, 1.61 0.75, 4.51 1.16, 4.12 0.47, 1.81 0.16, 2.73 1.44, 16.35 1.15, 2.60 0.20, 2.33 0.69, 1.31 0.43, 1.05 1.02, 2.39 0.80, 1.48 0.68, 1.58 0.76, 1.39 0.14, 1.46 0.67, 1.69 0.13, 51.20
P value 0.03 0.37 0.40 0.53 0.98 0.21 <0.01 0.18 0.12 0.32 0.60 0.18 0.02 0.81 0.57 0.01 <0.01 0.54 0.75 0.08 0.04 0.60 0.88 0.87 0.18 0.78 0.54
I2 (%) 0 9 0
5 0 0 0 0 0 51 0 40 69 0 0 70 0 6
27 39
everolimus and cyclosporine have synergistic effect on corneal and kidney transplantations in immunosuppression in rats.[23, 24] A study of 240 LT patients confirmed that transition from CNIs to everolimus increases GFR by 4.2 mL/min with a low risk of tBPAR.[25] However, our systematic review suggested that everolimus combined with early withdrawal of CNIs increased the risk of tBPAR by 77% compared with controls, even though everolimus treatment improved renal function. Similar results were observed in renal transplantation patients.[26] This may be attributed to the fact that the mean time of the introduction of everolimus in Saliba's study (mean: 4.9±5.2 years post transplantation) was later than that in the trials included in the present review.[25] In the reviewed studies everolimus treatment began within 30 days after the transplant procedure and CNI treatment was terminated earlier. However, re-starting CNI treatment immediately after tBPAR detection did not increase the overall risk of graft loss or death.[11, 12, 18] Saliba's group also reported that the mean change of GFR was significantly different depending on whether everolimus treatment began dur-
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ing or after the first year after transplantation (12.5 vs 5.5 mL/min).[25] Therefore, after a certain time, everolimus treatments do not improve renal function because this improvement has already occurred due to the reduction of CNI dose.[19] Renal function in the everolimus group is better than that in the controls, this may be explained mainly by minimization of exposure to CNIs.[7, 18, 19, 25] One RCT suggested that low doses of cyclosporine are associated with significantly better renal function in kidney transplantation patients than in those who received full doses of cyclosporine at one year.[27] Everolimus may also have contributed to improve renal function. Experimental studies suggested that everolimus can significantly improve glomerular hypertrophy in diabetic mice and therefore, everolimus improves renal function.[28] Most importantly, everolimus allows dose reduction or elimination of CNIs not only in LT, but also after transplantation of other solid organs. Everolimus combined with reduced CNIs also improves post-transplantation renal function while preserving graft function in kidney,[29-31] thoracic,[32] and heart transplantations.[33] The present systematic review confirmed that everolimus inhibits tumor recurrence. Everolimus decreased the risk of tumor recurrence by 40%, similar to that of sirolimus (odds ratio: 0.42; 95% CI: 0.21-0.83).[34] Both drugs inhibit the mTOR serine/threonine kinase by binding to 12-kDa immunophilin FK506-binding protein (FKBP12) to prevent tumors,[35] and each can inhibit angiogenesis by blocking the PI3K-Akt-mTOR signaling pathway and preventing fibrosis by inhibiting the mTOR/p70S6k/procollagen 1 pathway.[24] The present systematic review revealed serious side effects in everolimus-treated patients compared to controls (RR: 1.25; 95% CI: 1.10-1.42; P=0.0007). The risk of drug discontinuation was 2-fold greater in everolimus-treated patients than that in controls but lower than that in sirolimus group (RR: 1.98 vs 3.61).[36] This may be attributed to everolimus's short half-life (28 hours vs sirolimus's 60 hours), greater solubility, greater bioavailability, and weaker binding affinity to FKBP12.[14] Everolimus increases the risk of leukopenia likely due to the inhibition of cell proliferation by blocking the cell from the G1 to S phase.[4] Everolimus also increases the risk of bacterial infection,[17, 18, 37] perhaps due to the deterioration of immune function associated with leukopenia. However, even serious infections did not affect the overall patient survival.[11, 12, 17-19] Everolimus increases low-density lipoprotein cholesterol. Although the importance of dyslipidemia caused by everolimus is unknown,[38] this dyslipidemia should be managed. Another side effect of everolimus is proteinuria, the possible
mechanism is that everolimus inhibits the secretion of vascular endothelial growth factor (VEGF) and blocks its signaling pathway.[40] Patients with proteinuria can be treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.[41] The peripheral edema caused by everolimus may be explained by decreased plasma osmolality because of proteinuria that causes interstitial fluid reflux disorder and edema. It is noteworthy that cyclosporine and tacrolimus were coadministered with everolimus in different trials, but no study focused on the difference between the two combination strategies. Early study[42] demonstrated that cyclosporine can increase everolimus blood levels by 2.7-fold, so that cyclosporine reduction may decrease the levels of everolimus in the blood. However, everolimus exposure is not affected when tacrolimus blood levels are down-titrated within range of 1.5-7 ng/mL.[43] This may indicate that tacrolimus may be more suitable for immunosuppressive treatment than cyclosporine when coadministerd with everolimus. Further studies are warranted. Although the present study demonstrated that everolimus had an efficacy and safety profile in adult liver transplantation, it has several drawbacks that should be acknowledged. First, renal function measurement was not uniform; however, sensitivity analysis confirmed stable results. Moreover, subgroup analyses confirmed stable conclusions. Second, one trial arm in De Simone's et al's study[11] ended early because of profound adverse events. This may cause random bias, but the baseline characteristics of the included patients were similar to the controls.[11] Third, many studies are not placebo-controlled trials which may cause performance bias. However, regular monitoring of the drug blood levels may have made the placebo-controlled method difficult to conduct. Fourth, the small number of included trials may have introduced publication bias.[44, 45] Several ongoing studies (NCT01888432, NCT01551212, NCT01625377, etc.) may diminish this bias in future meta-analyses.[24] Fifth, only published data were extracted, and some data were extracted indirectly using a formula. This may have decreased the accuracy of the results, but these methods are permitted by the Cochrane Collaborative Group when raw data are not available.[15] Sixth, many of the studies included here only evaluated the efficacy and safety of everolimus one year after treatment rather than at other time points. Long-term effects need further study. Finally, this article only addressed the efficacy and safety of everolimus in adult LT recipients. There is still a lack of robust data about everolimus efficacy and safety in pediatric LT recipients, although Nielsen's study has produced promising results.[46] Ongoing trials (NCT01598987, CRAD001H2305, etc.) may eventually
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V, Segovia J, et al. Everolimus immunosuppression in de novo be informative in this regard. heart transplant recipients: what does the evidence tell us now? In conclusion, early introduction of everolimus in de Transplant Rev (Orlando) 2013;27:76-84. novo LT patients (within 30 days after transplantation) 9 Castroagudín JF, Molina E, Romero R, Otero E, Tomé S, Varo can significantly improve renal function one year after E. Improvement of renal function after the switch from a caltreatment. Everolimus combined with reduced doses cineurin inhibitor to everolimus in liver transplant recipients of CNIs may decrease tBPAR at one year. However, the with chronic renal dysfunction. Liver Transpl 2009;15:17921797. everolimus initiation with eliminated CNIs increased the rate of acute rejection. Everolimus also decreases the risk 10 Saliba F, De Simone P, Nevens F, De Carlis L, Metselaar HJ, Beckebaum S, et al. Renal function at two years in liver transof neoplasms and tumor recurrence after LT at one year. plant patients receiving everolimus: results of a randomized, Everolimus is associated with a higher risk of infections, multicenter study. Am J Transplant 2013;13:1734-1745. leukopenia, hypercholesterolemia, proteinuria, and pe- 11 De Simone P, Nevens F, De Carlis L, Metselaar HJ, Beckebaum S, Saliba F, et al. Everolimus with reduced tacrolimus improves ripheral edema. Contributors: TCY and SA put forward this idea, extracted the data, carried out statistical analysis of this study, and wrote the manuscript. WXF and LR searched the literature, extracted the data, carried out the critical appraisal of included studies. LQD and DHJ performed the statistical analysis and edited figures of this paper. WYZ and WZJ revised this article. TCY and SA contributed equally to this paper. WZJ is the guarantor. Funding: This study was supported by grants from the National Nature Science Foundation of China (81171562), the Chongqing Medical Research Project (2011-2-081), the Frontier and Applied Basic Research Project of Chongqing (cstc2013yykfA0093) and the Science and Technology Talent Cultivation Project of Chongqing (Young Talents of New Product Innovation) (cstc2013kjrcqnrc10006). Ethical approval: Not needed. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
References 1 Shapiro R, Young JB, Milford EL, Trotter JF, Bustami RT, Leichtman AB. Immunosuppression: evolution in practice and trends, 1993-2003. Am J Transplant 2005;5:874-886. 2 Yu SF, Wu LH, Zheng SS. Genetic factors for individual administration of immunosuppressants in organ transplantation. Hepatobiliary Pancreat Dis Int 2006;5:337-344. 3 Garces G, Contreras G, Carvalho D, Jaraba IM, Carvalho C, Tzakis A, et al. Chronic kidney disease after orthotopic liver transplantation in recipients receiving tacrolimus. Clin Nephrol 2011;75:150-157. 4 Nashan B. Review of the proliferation inhibitor everolimus. Expert Opin Investig Drugs 2002;11:1845-1857. 5 Treiber G. mTOR inhibitors for hepatocellular cancer: a forwardmoving target. Expert Rev Anticancer Ther 2009;9:247-261. 6 Yang YJ, Li LX, He Q, Fan H, Jin ZK, Lang R, et al. Sirolimus as primary immunosuppressant for calcineurin inhibitor-related renal insufficiency after liver transplantation. Hepatobiliary Pancreat Dis Int 2007;6:376-378. 7 Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U, et al. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an openlabel, randomised, controlled trial. Lancet 2011;377:837-847. 8 Zuckermann A, Wang SS, Epailly E, Barten MJ, Sigurdardottir
renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant 2012;12:3008-3020. 12 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. Am J Transplant 2012;12:1855-1865. 13 Fischer L, Saliba F, Kaiser GM, De Carlis L, Metselaar HJ, De Simone P, et al. Three-year Outcomes in De Novo Liver Transplant Patients Receiving Everolimus With Reduced Tacrolimus: Follow-Up Results From a Randomized, Multicenter Study. Transplantation 2015;99:1455-1462. 14 Bhat M, Charlton M. Preserving flow in liver transplant recipients: mTOR inhibitors everolimus and sirolimus are not peas from a pod. Am J Transplant 2013;13:1633-1635. 15 Higgins J, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). [serial online]. Available from: www.cochrane-handbook.org 16 DerSimonian R, Kacker R. Random-effects model for metaanalysis of clinical trials: an update. Contemp Clin Trials 2007;28:105-114. 17 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 Transpl 2006;12:1640-1648. 18 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. Am J Transplant 2010;10:2252-2262. 19 De 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 Transpl 2009;15:1262-1269. 20 Cillo U, Vitale A, Salizzoni M, Coledan M, Rossi G, Baccarani U, et al. F-47 Early introduction of everolimus in de novo liver transplantation: a multicenter randomized clinical trial (EPOCAL). Dig Liver Dis 2013;45:S45. 21 Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931-940. 22 Morard I, Mentha G, Spahr L, Majno P, Hadengue A, Huber O, et al. Long-term renal function after liver transplantation is related to calcineurin inhibitors blood levels. Clin Transplant 2006;20:96-101. 23 Schuurman HJ, Cottens S, Fuchs S, Joergensen J, Meerloo T,
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Sedrani R, et al. SDZ RAD, a new rapamycin derivative: synergism with cyclosporine. Transplantation 1997;64:32-35. 24 Ganschow R, Pollok JM, Jankofsky M, Junge G. The role of everolimus in liver transplantation. Clin Exp Gastroenterol 2014;7:329-343. 25 Saliba F, Dharancy S, Lorho R, Conti F, Radenne S, NeauCransac M, et al. Conversion to everolimus in maintenance liver transplant patients: a multicenter, retrospective analysis. Liver Transpl 2011;17:905-913. 26 Mjörnstedt L, Sørensen SS, von Zur Mühlen B, Jespersen B, Hansen JM, Bistrup C, et al. Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. Am J Transplant 2012;12:2744-2753. 27 Nashan B, Curtis J, Ponticelli C, Mourad G, Jaffe J, Haas T, et al. Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label study. Transplantation 2004;78:1332-1340. 28 Cheng L, Chen J, Mao X. Everolimus vs. rapamycin for treating diabetic nephropathy in diabetic mouse model. J Huazhong Univ Sci Technolog Med Sci 2011;31:457-462. 29 Oh CK, Huh KH, Ha J, Kim YH, Kim YL, Kim YS. Safety and efficacy of the early introduction of everolimus with reducedexposure cyclosporine a in de novo kidney recipients. Transplantation 2015;99:180-186. 30 Ferraresso M, Belingheri M, Ginevri F, Murer L, Dello Strologo L, Cardillo M, et al. Three-yr safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients. Pediatr Transplant 2014;18:350-356. 31 Cibrik D, Silva HT Jr, Vathsala A, Lackova E, Cornu-Artis C, Walker RG, et al. Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation. Transplantation 2013;95:933-942. 32 Gullestad L, Mortensen SA, Eiskjær H, Riise GC, Mared L, Bjørtuft O, et al. Two-year outcomes in thoracic transplant recipients after conversion to everolimus with reduced calcineurin inhibitor within a multicenter, open-label, randomized trial. Transplantation 2010;90:1581-1589. 33 Gonzalez-Vilchez F, Vazquez de Prada JA, Paniagua MJ, Gomez-Bueno M, Arizon JM, Almenar L, et al. Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: calcineurin-inhibitors conversion or minimization? Int J Cardiol 2014;171:15-23. 34 Liang W, Wang D, Ling X, Kao AA, Kong Y, Shang Y, et al. Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl
2012;18:62-69. 35 Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004;4:335-348. 36 Asrani SK, Leise MD, West CP, Murad MH, Pedersen RA, Erwin PJ, et al. Use of sirolimus in liver transplant recipients with renal insufficiency: a systematic review and meta-analysis. Hepatology 2010;52:1360-1370. 37 Klintmalm GB, Nashan B. The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence. J Transplant 2014;2014:845438. 38 Kasiske BL, de Mattos A, Flechner SM, Gallon L, MeierKriesche HU, Weir MR, et al. Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. Am J Transplant 2008;8:1384-1392. 39 Alegre C, Jiménez C, Manrique A, Abradelo M, Calvo J, Loinaz C, et al. Everolimus monotherapy or combined therapy in liver transplantation: indications and results. Transplant Proc 2013;45:1971-1974. 40 Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002;8:128-135. 41 Oroszlán M, Bieri M, Ligeti N, Farkas A, Meier B, Marti HP, et al. Sirolimus and everolimus reduce albumin endocytosis in proximal tubule cells via an angiotensin II-dependent pathway. Transpl Immunol 2010;23:125-132. 42 Kovarik JM, Curtis JJ, Hricik DE, Pescovitz MD, Scantlebury V, Vasquez A. Differential pharmacokinetic interaction of tacrolimus and cyclosporine on everolimus. Transplant Proc 2006;38:3456-3458. 43 Rostaing L, Christiaans MH, Kovarik JM, Pascual J. The pharmacokinetics of everolimus in de novo kidney transplant patients receiving tacrolimus: an analysis from the randomized ASSET study. Ann Transplant 2014;19:337-345. 44 Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-1101. 45 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629-634. 46 Nielsen D, Briem-Richter A, Sornsakrin M, Fischer L, Nashan B, Ganschow R. The use of everolimus in pediatric liver transplant recipients: first experience in a single center. Pediatr Transplant 2011;15:510-514. Received November 20, 2014 Accepted after revision June 29, 2015
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Everolimus in de novo liver transplant recipients: a systematic review Cheng-Yong Tang, Ai Shen, Xu-Fu Wei, Qing-Dong Li, Rui Liu, He-Jun Deng, Yong-Zhong Wu and Zhong-Jun Wu Chongqing, China
BACKGROUND: Everolimus has no nephrotoxicity and is used to treat patients with post-liver transplant chronic renal insufficiency. The present systematic review was to evaluate the efficacy and safety of everolimus in de novo liver transplant patients.
creased tBPAR (RR: 1.71; 95% CI: 1.15-2.53; P<0.01). Everolimus decreased the risk of neoplasms/tumor recurrence after liver transplant (RR: 0.60; 95% CI: 0.34-1.03; P=0.06), but was associated with greater risk of adverse events which resulted in drug discontinuation (RR: 1.98; 95% CI: 1.49-2.64; P<0.01).
DATA SOURCES: Randomized controlled trials comparing everolimus for de novo liver transplant in PubMed, the Cochrane Library, and ScienceDirect published up to March 31, 2014 were searched by two independent reviewers. Mean differences and 95% confidence interval (95% CI) for renal function, relative risk (RR) and 95% CI for treated biopsy-proven acute rejection (tBPAR), graft loss, death, neoplasms/tumor recurrence, and adverse events were collected. Meta-analyses were performed with RevMan version 5.10.
CONCLUSIONS: Early introduction of everolimus combined with low-dose or no CNI in de novo liver transplant significantly improves renal function one year post treatment. Everolimus combined with low-dose CNI decreases the risk of tBPAR one year after liver transplant, but everolimus administered without CNIs increases tBPAR. (Hepatobiliary Pancreat Dis Int 2015;14:461-469)
KEY WORDS: everolimus; calcineurin inhibitors; RESULTS: A total of four randomized controlled trials coverliver transplantation; ing 1119 cases were included. The meta-analyses revealed that systematic review compared with standard exposure of calcineurin inhibitors (CNIs), everolimus combined with reduced CNIs improved creatinine clearance (calculated with the Cockcroft-Gault formula) by 5.13 mL/min at one year (95% CI: 0.42-9.84; P=0.03), Introduction and decreased tBPAR (RR: 0.56; 95% CI: 0.35-0.90; P=0.02). alcineurin inhibitors (CNIs) are the first line Everolimus initiation with CNIs elimination improved glotherapy for liver transplantation (LT) patients,[1, 2] merular filtration rate (GFR, measured with the modification but they have side effects such as chronic nephof diet in renal disease formula) of 10.42 mL/min/1.73 m2 (95% CI: 3.44-17.41; P<0.01) one year after treatment, but in- rotoxicity that progressively reduces renal function. Ap-
C
Author Affiliations: Department of Pharmacy (Tang CY) and Department of Hepatobiliary Surgery (Wei XF, Liu R and Wu ZJ), First Affiliated Hospital of Chongqing Medical University, Chongqing 404100, China; Department of Hepatobiliary Surgery (Shen A, Li QD and Deng HJ) and Department of Radiotherapy (Wu YZ), Chongqing Cancer Institute, Chongqing 400030, China Corresponding Author: Zhong-Jun Wu, MD, PhD, Department of Hepatobiliary Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing 404100, China (Fax: +86-23-68711487; Email: [email protected]) © 2015, Hepatobiliary Pancreat Dis Int. All rights reserved. doi: 10.1016/S1499-3872(15)60419-2 Published online September 17, 2015.
proximately 10% of the patients suffer from chronic renal failure within five years after liver transplantation because of CNI treatment.[3] Everolimus, an immunosuppressant of the mammalian target of rapamycin (mTOR),[4-6] has been approved for heart and renal transplantation[7, 8] and can be used with or without CNIs to reduce CNI-induced drug toxicity.[8, 9] Everolimus given with a low dose of CNI or without CNI significantly improves renal function after LT,[10-13] allowing FDA approval for use of this drug after LT as well.[14] Still, the outcomes of everolimus-based immunosuppression in LT recipients have not been systematically reviewed. The present study was to evaluate the efficacy and safety of everolimus in de novo LT patients at one year after LT.
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Methods Literature search PubMed, the Cochrane Library, and ScienceDirect were searched using the terms "everolimus" and "liver transplant" or "liver transplantation" or "hepatic transplantation" or "hepatic graft" or "LT" before March 31, 2014 without language limitations. Two reviewers (Tang CY and Shen A) independently searched articles based on titles, abstract and key words. Disagreements over articles were discussed until consensus was reached. Only published data were retrieved and included. Inclusion and exclusion criteria 1) Study subjects included only de novo LT patients. 2) Each trial was designed to evaluate both the efficacy and safety of everolimus. 3) Follow-up time must exceed 1 year. 4) Case reports, review articles, editorials, letters, and single-arm studies were excluded. 5) Only randomized controlled trials (RCTs) were included. Outcome of interest The primary outcome of interest was one-year efficacy of everolimus in de novo LT patients, using renal function, treated biopsy-proven acute rejection (tBPAR), graft loss, death, and neoplasm/tumor recurrence. The secondary outcome measure was to assess the safety of everolimus in de novo LT patients.
heterogeneity. Values between 0% and 25% indicated that heterogeneity might not be important. Values between 25% and 50% indicated moderate inconsistency. Values of 50% to 75% were indicated substantial heterogeneity. Values between 75% and 100% indicated considerable inconsistency. When inconsistency was detected, the reason for the heterogeneity was explored using sensitivity and subgroup analysis. A two-tailed P value of 0.05 was deemed statistically significant. All statistical calculations for this article were performed using Review Manager 5.1. These results were reported using the Cochrane Handbook for Systematic Reviews of Interventions.[15]
Results Trial selection Six RCTs that evaluated the efficacy and safety of everolimus in LT patients were included. Of these, four were enrolled in this review (Fig. 1).[11, 12, 17, 18] One RCT was excluded due to recruitment of maintenance LT patients;[19] another was due to the only observation of the efficacy of everolimus in LT patients at 3 months after treatment.[20] Of the 4 studies enrolled in the present analysis, one evaluated the efficacy, safety and tolerability of the different dosage of everolimus under controlled CNIs in LT patients[17] (reference 17 never mentioned "reduced CNIs". On the contrary, "steady-state administration of cyclosporine". As a matter of fact, the authors
Data extraction and quality analysis Two reviewers (Tang CY and Shen A) independently extracted the data as follows: article authors, time of publication, trial region, number of cases, age of participants, gender of participants, route of drug administration, renal function, efficacy events and safety events. Disagreements about extraction were resolved via discussion. The two reviewers independently evaluated the quality of each study according to the Cochrane Handbook for Systematic Reviews of Interventions (http://handbook.cochrane.org/).[15] Statistical analysis The pooled standard mean differences (SMD), mean differences (MD), and 95% confidence intervals (CI) were reported for continuous data. Pooled relative risk (RR) and 95% CI were reported for dichotomous data. The Chi-square test-based Q statistic of RR and trials with P<0.1 were considered heterogeneous. When P>0.1, the DerSimonian-Laird random effects model was used to control for heterogeneity in the meta-analysis.[16] Q-based I2 statistics were used to evaluate quantitative Fig. 1. Literature search process. 462 • Hepatobiliary Pancreat Dis Int，Vol 14，No 5 • October 15，2015 • www.hbpdint.com
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controlled the CNI dosage to test the safety and tolerability of everolimus at different doses); two assessed the efficacy and safety of CNI conversion to everolimus in LT patients[12, 18] and one compared the efficacy and renal function between everolimus initiation with reduced-exposure tacrolimus and standard-exposure tacrolimus.[11] The baseline characteristics of included patients are detailed in Table 1 and the immunosuppression regimen is detailed in Table 2.
Quality of trials included in the systematic review The method of generating a random sequence was not reported in Levy's study.[17] Three trials did not report whether or not the allocation concealment was used. Only Levy et al used a placebo-controlled double-blinded method.[17] Three studies[11, 12, 18] did not mention the blindness of the result evaluations. Randomization of everolimus combined with elimination of tacrolimus was terminated prematurely because of a higher rate of tBPAR in De Simone's study.[11] Levy's study[17] included three different doses of everolimus, which may have introduced bias. All four studies were found to have a high risk of bias (Table 3).
observed (I2=52%; Fig. 2). However, sensitivity analysis confirmed stability in this set of results. Subgroup analysis demonstrated that everolimus initiation with reduced CNIs significantly improved the CrCl (MD: 5.13; 95% CI: 0.42-9.84; P=0.03; I2=0%) at one year[11, 17] compared with standard exposure of CNIs (Fig. 3). Everolimus initiation with CNIs elimination also significantly improved GFR by 10.42 mL/min/1.73 m2 (MD: 10.42; 95% CI: 3.44-17.41; P<0.01; I2=69%; Fig. 3).[11, 12, 18] Heterogeneity may be attributed mainly to Masetti's study, for which cyclosporine in the control group was elevated gradually.[18]
tBPAR, graft loss, death and neoplasms/tumor recurrence Everolimus combined reduced CNIs in de novo LT decreased the risk of tBPAR one year after treatment.[11, 17] However, everolimus initiation with elimination of CNIs increased the risk of tBPAR.[11, 12, 18] Neither everolimus combined with CNIs reduction nor everolimus initiation with CNIs elimination was associated with more risk of graft loss and death one year after treatment compared to the control group. All included studies reported relevant Efficacy data regarding neoplasms/tumor recurrence and our analysis confirmed that everolimus decreased the risk of Renal function Some studies used creatinine clearance (CrCl; Cock- neoplasms/tumor recurrence one year after transplantacroft-Gault) to evaluate renal function;[12, 17] others used tion although it has no statistical significance (Table 4). glomerular filtration rate (GFR; modification of diet in renal disease formula) or both.[11, 12, 18] The pooled SMD Safety Not all trials provided a complete report about everowas reported in this way. Meta-analyses demonstrated that everolimus-based treatment significantly improves limus side effects.[17, 18] Meta-analyses confirmed that renal function one year after treatment (SMD: 0.35; 95% everolimus significantly increased the risk of adverse CI: 0.13-0.57; P<0.01), but substantial heterogeneity was events and discontinuation of therapy (Tables 4 and 5). Table 1. Baseline characteristics of included studies Studies De Simone et al
[11]
Countries
Group
Cases (n)
Age (yr) (mean±SD)
Male (%)
HCV (%)
Baseline of RF Measurement of RF
Multicenter
EVR+TAC reduction EVR+TAC elimination Control EVR+CNI elimination Control EVR+CYC reduction* EVR+CYC reduction* EVR+CYC reduction* Control EVR+CYC elimination Control
245 231 243 101 102 28 30 31 30 52 26
53.6±9.2 53.2±10.8 54.5±8.7 52.3±9.9 52.9±10.1 46.3±11.2 48.2±12.0 48.8±10.2 51.6±9.0 53.7±9.8 55.6±7.4
73.5 71.0 73.7 56.3 69.4 64.3 43.3 71.0 50.0 76.9 76.9
31.8 31.2 31.3 7.3 8.2 32.1 23.3 25.8 20.0 38.5 30.8
81.1±32.6 82.6±37.2 78.1±27.5 78.0±27.4 74.9±24.6 87.5±25.3 96.7±30.4 96.0±35.8 95.9±35.0 81.7±29.5 74.7±24.6
Fischer et al[12]
Germany
Levy et al[17]
Canada
Masetti et al[18]
Italy
MDRD-GFR/CG-CrCl
MDRD-GFR/CG-CrCl CG-CrCl
MDRD-GFR
*: In the three everolimus groups, everolimus was administered at 0.5, 1.0, and 2.0 mg, BID. EVR: everolimus; CYC: cyclosporine; CNI: calcineurin inhibitor; TAC: tacrolimus; HCV: hepatitis C virus; RF: renal function; GFR: glomerular filtration rate; CG: Cockcroft-Gault; MDRD: modification of diet in renal disease; SD: standard deviation.
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Table 2. Immunosuppression regimens of included studies Studies Group De Simone et al[11] EVR+TAC reduction
EVR dose Initial: 1.0 mg BID within 24 hours of randomization (30 ±5 days), adjusted from day 5 to achieve a C0 level at 3-8 ng/mL until month 4 and kept the same thereafter. EVR+TAC Initial: 1.0 mg BID within elimination 24 hours of randomization (30±5 days), adjusted from day 5 to achieve a C0 level at 3-8 ng/mL until month 4, then 6-10 ng/mL. Control None
CNI dose Other immunosuppression TAC was tapered off to 3-5 ng/mL once the Corticosteroids were started at the time EVR C0 level was within 3-8 ng/mL, by of transplant and administered accordweek 3 and left unchanged thereafter. ing to local practice, with a continued minimum oral dose of 5 mg prednisolone/day after randomization until at least month 6 after LT. TAC: was tapered to a C0 level of 3-5 ng/mL Mycophenolicacids, if used, were adminby week 3 after randomization, and then istered according to local practice but decreased after EVR C0 achieved 6-10 ng/mL needed to be stopped by the time of at the start of month 4 posttransplant if randomization. liver function was adequate. TAC was completely eliminated by the end of month 4. TAC: 8-12 ng/mL until month 4, 6-10 ng/mL Same as the EVR group thereafter.
Fischer et al[12]
EVR+CNI When CNI was tapered off by CNIs were discontinued after 8 weeks of Basiliximab was administered intraveelimination 70% of the initial CNI dose, CNI reduction if rejection-free for at least nously (20 mg) on days 0 and 4 after LT. EVR was started at a dose 4 weeks. CNI was administered with or without of 1.5 mg BID and adjusted corticosteroids and with or without into a C0 level of 5-12 ng/mL fection prophylaxis after LT according (8-12 ng/mL in patients beto local practice. ing treated with CYC). Control None Not described in detail Same as the EVR group
Levy et al[17]
EVR+CYC reduction
0.5 mg BID orally
EVR+CYC reduction EVR+CYC reduction Control
1.0 mg BID orally
[18]
Masetti et al
CYC C0 level: 1-4 weeks, 150-450 ng/mL 2-6 months, 100-300 ng/mL 7-12 months, 75-300 ng/mL
Methylprednisolone was administered intravenous before, during, or immediately after LT. Oral prednisone or equivalent methylprednisolone was tapered off to ≥5.0 mg per day by month 3. Thereafter, it was maintained, tapered off, or discontinued.
Same as the EVR group
Same as the EVR group
2.0 mg BID orally Placebo
EVR+CYC The initial dose (day 10) CYC: The initial dose was 2 mg/kg per day, Basiliximab was administered intraveelimination of EVR was 2.0 mg/d to divided into two daily doses, kept at 100± nously (20 mg) on day 0 (within 6 h of achieve a C0 level of 6-10 25 ng/mL until day 30. reperfusion of the liver graft) and on ng/mL. On day 30, when day 5 after LT. CYC was abruptly disconMethylprednisolone was administered tinued, the EVR dose was intravenously (500 mg) on day 0 and increased to maintain a C0 tapered within 5 weeks. level of 8-12 ng/mL until Prednisone (or equivalent) was adminthe end of month 6. Thereistered 20 mg/day in a single morning after, 6-10 ng/mL. dose in week 1, 16 mg/d in week 2, 12 mg/d in week 3, 8 mg/d in week 4 and 4 mg/d in week 5. Thereafter, the drug was discontinued. The initial dose was 2 mg/kg per day, di- Same as the EVR group Control None vided into two daily doses, kept at 100±25 ng/mL in the first 10 days. Then it was adjusted to 225±25 ng/mL until day 30, 200 ± 25 ng/mL until the end of month 6 and 150±25 ng/mL thereafter. When patients experienced CNI related complications, the CYC dose was decreased to reduce the C0 level by about 50% and mycophenolate mofetil was introduced at an initial dose of 1 g BID and then kept at 500 mg TID.
EVR: everolimus; CYC: cyclosporine; CNI: calcineurin inhibitor; TAC: tacrolimus; LT: liver transplantation.
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Table 3. Quality of the RCTs included in this systematic review Studies
Random
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Other bias
De Simone et al[11] Fischer et al[12] Levy et al[17] Masetti et al[18]
Yes Yes Unclear Yes
Unclear Unclear Yes Unclear
No No Yes No
Unclear Unclear Yes Unclear
No Yes Yes Yes
Yes Yes No Yes
No Yes No No
Table 4. Meta-analyses of primary outcomes at one year after treatment Outcome measurements Biopsy-proven acute rejection EVR+ reduced CNIs vs control EVR+ eliminated CNIs vs control Graft loss EVR+ reduced CNIs vs control EVR+ eliminated CNIs vs control Death EVR+ reduced CNIs vs control EVR+ eliminated CNIs vs control Neoplasm/tumor recurrence EVR vs control Serious adverse events EVR vs control Drug discontinuation EVR vs control
No. of trials
No. of cases (EVR/control)
RR (M-H, fixed)
95% CI
P value
I2 (%)
2 3
334/273 379/367
0.56 1.71
0.35, 0.90 1.15, 2.53
0.02 <0.01
15 45
2 2
334/273 327/341
1.42 1.46
0.51, 3.92 0.47, 4.54
0.50 0.52
0 0
2 3
334/273 379/367
1.04 1.32
0.51, 2.09 0.67, 2.61
0.92 0.42
17 0
4
463/391
0.60
0.34, 1.03
0.06
0
3
665/373
1.25
1.10, 1.42
<0.01
0
3
660/369
1.98
1.49, 2.64
<0.01
0
EVR: everolimus; CNI: calcineurin inhibitor.
Fig. 2. Meta-analysis of RCTs comparing the overall mean change in renal function of everolimus to that of the control group at one year.
Fig. 3. Meta-analysis of RCTs comparing the mean change in renal function of the everolimus+reduced CNIs group or everolimus+ eliminated CNIs group to that of the control group at one year. Hepatobiliary Pancreat Dis Int，Vol 14，No 5 • October 15，2015 • www.hbpdint.com • 465
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Table 5. Meta-analyses of adverse events in the included trials Adverse events Infection Cytomegalovirus infection Pneumonia Urinary tract infection Nasopharyngitis Anemia Leukopenia Thrombocytopenia Incisional hernia Wound healing Biliary complication Hyperlipidemia Hypercholesterolemia Type 2 diabetes mellitus Renal failure Proteinuria Peripheral edema Nervous system disorders Headaches Tremors Pyrexia Hypertension Nausea Diarrhea Hepatic arterial thrombosis HCV recurrence Oral ulcer
No. of trials 3 4 2 1 1 2 3 3 3 2 2 3 2 2 4 2 2 2 1 2 1 2 1 1 3 2 1
No. of patients 979 886 919 203 203 919 1038 1038 997 919 794 767 322 493 1116 919 794 281 716 794 716 919 716 716 1107 744 78
Discussion One study including 36 849 LT patients suggested that the cumulative incidence of chronic renal failure was -20% three years after transplantation and this was associated with a 4-fold increase in the risk of death.[21] One major contributor to renal dysfunction in LT recipients was CNIs.[22] Because CNIs are the backbone of immunosuppressive treatment of LT, better regimens must be formulated to reduce this risk.[1] The present systematic review demonstrated that everolimus-based immunosuppression can significantly improve renal function one year after treatment and it does not increase the risk of graft loss or death. Also, everolimus combined with reduced CNIs improves renal function at one year without an increased risk of graft loss or death and these benefits were long-lasting. Saliba's group remarked that combination treatment improves GFR of LT patients three years post transplantation.[10, 13] This systemic review showed that everolimus plus reduced-dose CNIs decrease the risk of tBPAR by 44%. This may be a synergistic effect of everolimus and CNIs.[23, 24] Experimental studies demonstrated that
RR 1.16 0.81 1.40 1.24 1.01 1.30 1.97 1.64 1.47 1.17 0.84 1.84 2.18 0.92 0.66 4.86 1.73 0.68 0.95 0.67 1.56 1.09 1.03 1.02 0.45 1.07 2.55
95% CI 1.02, 1.31 0.51, 1.28 0.63, 3.11 0.63, 2.45 0.52, 1.96 0.87, 1.95 1.24, 3.12 0.80, 3.34 0.90, 2.39 0.86, 1.58 0.44, 1.61 0.75, 4.51 1.16, 4.12 0.47, 1.81 0.16, 2.73 1.44, 16.35 1.15, 2.60 0.20, 2.33 0.69, 1.31 0.43, 1.05 1.02, 2.39 0.80, 1.48 0.68, 1.58 0.76, 1.39 0.14, 1.46 0.67, 1.69 0.13, 51.20
P value 0.03 0.37 0.40 0.53 0.98 0.21 <0.01 0.18 0.12 0.32 0.60 0.18 0.02 0.81 0.57 0.01 <0.01 0.54 0.75 0.08 0.04 0.60 0.88 0.87 0.18 0.78 0.54
I2 (%) 0 9 0
5 0 0 0 0 0 51 0 40 69 0 0 70 0 6
27 39
everolimus and cyclosporine have synergistic effect on corneal and kidney transplantations in immunosuppression in rats.[23, 24] A study of 240 LT patients confirmed that transition from CNIs to everolimus increases GFR by 4.2 mL/min with a low risk of tBPAR.[25] However, our systematic review suggested that everolimus combined with early withdrawal of CNIs increased the risk of tBPAR by 77% compared with controls, even though everolimus treatment improved renal function. Similar results were observed in renal transplantation patients.[26] This may be attributed to the fact that the mean time of the introduction of everolimus in Saliba's study (mean: 4.9±5.2 years post transplantation) was later than that in the trials included in the present review.[25] In the reviewed studies everolimus treatment began within 30 days after the transplant procedure and CNI treatment was terminated earlier. However, re-starting CNI treatment immediately after tBPAR detection did not increase the overall risk of graft loss or death.[11, 12, 18] Saliba's group also reported that the mean change of GFR was significantly different depending on whether everolimus treatment began dur-
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ing or after the first year after transplantation (12.5 vs 5.5 mL/min).[25] Therefore, after a certain time, everolimus treatments do not improve renal function because this improvement has already occurred due to the reduction of CNI dose.[19] Renal function in the everolimus group is better than that in the controls, this may be explained mainly by minimization of exposure to CNIs.[7, 18, 19, 25] One RCT suggested that low doses of cyclosporine are associated with significantly better renal function in kidney transplantation patients than in those who received full doses of cyclosporine at one year.[27] Everolimus may also have contributed to improve renal function. Experimental studies suggested that everolimus can significantly improve glomerular hypertrophy in diabetic mice and therefore, everolimus improves renal function.[28] Most importantly, everolimus allows dose reduction or elimination of CNIs not only in LT, but also after transplantation of other solid organs. Everolimus combined with reduced CNIs also improves post-transplantation renal function while preserving graft function in kidney,[29-31] thoracic,[32] and heart transplantations.[33] The present systematic review confirmed that everolimus inhibits tumor recurrence. Everolimus decreased the risk of tumor recurrence by 40%, similar to that of sirolimus (odds ratio: 0.42; 95% CI: 0.21-0.83).[34] Both drugs inhibit the mTOR serine/threonine kinase by binding to 12-kDa immunophilin FK506-binding protein (FKBP12) to prevent tumors,[35] and each can inhibit angiogenesis by blocking the PI3K-Akt-mTOR signaling pathway and preventing fibrosis by inhibiting the mTOR/p70S6k/procollagen 1 pathway.[24] The present systematic review revealed serious side effects in everolimus-treated patients compared to controls (RR: 1.25; 95% CI: 1.10-1.42; P=0.0007). The risk of drug discontinuation was 2-fold greater in everolimus-treated patients than that in controls but lower than that in sirolimus group (RR: 1.98 vs 3.61).[36] This may be attributed to everolimus's short half-life (28 hours vs sirolimus's 60 hours), greater solubility, greater bioavailability, and weaker binding affinity to FKBP12.[14] Everolimus increases the risk of leukopenia likely due to the inhibition of cell proliferation by blocking the cell from the G1 to S phase.[4] Everolimus also increases the risk of bacterial infection,[17, 18, 37] perhaps due to the deterioration of immune function associated with leukopenia. However, even serious infections did not affect the overall patient survival.[11, 12, 17-19] Everolimus increases low-density lipoprotein cholesterol. Although the importance of dyslipidemia caused by everolimus is unknown,[38] this dyslipidemia should be managed. Another side effect of everolimus is proteinuria, the possible
mechanism is that everolimus inhibits the secretion of vascular endothelial growth factor (VEGF) and blocks its signaling pathway.[40] Patients with proteinuria can be treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.[41] The peripheral edema caused by everolimus may be explained by decreased plasma osmolality because of proteinuria that causes interstitial fluid reflux disorder and edema. It is noteworthy that cyclosporine and tacrolimus were coadministered with everolimus in different trials, but no study focused on the difference between the two combination strategies. Early study[42] demonstrated that cyclosporine can increase everolimus blood levels by 2.7-fold, so that cyclosporine reduction may decrease the levels of everolimus in the blood. However, everolimus exposure is not affected when tacrolimus blood levels are down-titrated within range of 1.5-7 ng/mL.[43] This may indicate that tacrolimus may be more suitable for immunosuppressive treatment than cyclosporine when coadministerd with everolimus. Further studies are warranted. Although the present study demonstrated that everolimus had an efficacy and safety profile in adult liver transplantation, it has several drawbacks that should be acknowledged. First, renal function measurement was not uniform; however, sensitivity analysis confirmed stable results. Moreover, subgroup analyses confirmed stable conclusions. Second, one trial arm in De Simone's et al's study[11] ended early because of profound adverse events. This may cause random bias, but the baseline characteristics of the included patients were similar to the controls.[11] Third, many studies are not placebo-controlled trials which may cause performance bias. However, regular monitoring of the drug blood levels may have made the placebo-controlled method difficult to conduct. Fourth, the small number of included trials may have introduced publication bias.[44, 45] Several ongoing studies (NCT01888432, NCT01551212, NCT01625377, etc.) may diminish this bias in future meta-analyses.[24] Fifth, only published data were extracted, and some data were extracted indirectly using a formula. This may have decreased the accuracy of the results, but these methods are permitted by the Cochrane Collaborative Group when raw data are not available.[15] Sixth, many of the studies included here only evaluated the efficacy and safety of everolimus one year after treatment rather than at other time points. Long-term effects need further study. Finally, this article only addressed the efficacy and safety of everolimus in adult LT recipients. There is still a lack of robust data about everolimus efficacy and safety in pediatric LT recipients, although Nielsen's study has produced promising results.[46] Ongoing trials (NCT01598987, CRAD001H2305, etc.) may eventually
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V, Segovia J, et al. Everolimus immunosuppression in de novo be informative in this regard. heart transplant recipients: what does the evidence tell us now? In conclusion, early introduction of everolimus in de Transplant Rev (Orlando) 2013;27:76-84. novo LT patients (within 30 days after transplantation) 9 Castroagudín JF, Molina E, Romero R, Otero E, Tomé S, Varo can significantly improve renal function one year after E. Improvement of renal function after the switch from a caltreatment. Everolimus combined with reduced doses cineurin inhibitor to everolimus in liver transplant recipients of CNIs may decrease tBPAR at one year. However, the with chronic renal dysfunction. Liver Transpl 2009;15:17921797. everolimus initiation with eliminated CNIs increased the rate of acute rejection. Everolimus also decreases the risk 10 Saliba F, De Simone P, Nevens F, De Carlis L, Metselaar HJ, Beckebaum S, et al. Renal function at two years in liver transof neoplasms and tumor recurrence after LT at one year. plant patients receiving everolimus: results of a randomized, Everolimus is associated with a higher risk of infections, multicenter study. Am J Transplant 2013;13:1734-1745. leukopenia, hypercholesterolemia, proteinuria, and pe- 11 De Simone P, Nevens F, De Carlis L, Metselaar HJ, Beckebaum S, Saliba F, et al. Everolimus with reduced tacrolimus improves ripheral edema. Contributors: TCY and SA put forward this idea, extracted the data, carried out statistical analysis of this study, and wrote the manuscript. WXF and LR searched the literature, extracted the data, carried out the critical appraisal of included studies. LQD and DHJ performed the statistical analysis and edited figures of this paper. WYZ and WZJ revised this article. TCY and SA contributed equally to this paper. WZJ is the guarantor. Funding: This study was supported by grants from the National Nature Science Foundation of China (81171562), the Chongqing Medical Research Project (2011-2-081), the Frontier and Applied Basic Research Project of Chongqing (cstc2013yykfA0093) and the Science and Technology Talent Cultivation Project of Chongqing (Young Talents of New Product Innovation) (cstc2013kjrcqnrc10006). Ethical approval: Not needed. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
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