Four‐year follow‐up of a prospective randomized trial of mycophenolate mofetil with cyclosporine microemulsion or tacrolimus following liver transplantation

Fisher, Robert A.; Stone, Juliana; Wolfe, Luke; Rodgers, C.; Anderson, Melodie; Sterling, Richard K.; Shiffman, Mitchell L.; Luketic, Velimer A; Contos, Melissa J.; Mills, A. Scott; Ferreira‐Gonzalez, Andrea; Posner, Marc P.

doi:10.1111/j.1399-0012.2004.00192.x

Cited by 50 publications

(42 citation statements)

References 35 publications

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“…A 4-year follow-up prospective randomized trial from Fisher et al (35) found for primary immunosuppression with ciclosporin microemulsion or Tac in combination with MMF no statistical differences in patient (96% vs. 90%; P ϭ NS) or graft survival (90% vs. 88%; P ϭ NS) and for the incidence of rejection episodes (34% vs. 24%; Pϭ0.28) in a total of 99 patients. Furthermore, infection rates were similar in both goups (CsA 76.1% vs. Tac 72.7%;).…”

Section: De Novo Therapy With Mmfmentioning

confidence: 84%

Indications of Mycophenolate Mofetil in Liver Transplantation

et al. 2005

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Mycophenolate mofetil (MMF) is approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation as well as for pediatric patients after kidney transplantation. MMF, a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), blocks de novo purine synthesis which leads to an effective inhibition of proliferation selectively in T and B lymphocytes, smooth muscle cells, and fibroblasts. MMF shows additional effects with inhibition of the expression of activating and adhesion molecules on the surface of lymphocytes. The beneficial safety profile with distinct side effects compared to calcineurin inhibitors (CNI) enable efficacious combination with ciclosporin or tacrolimus as de novo therapy after liver transplantation. Furthermore, recent studies show the possibility to reduce CNI induced toxicities by adding MMF to primary immunosuppression. MMF is also used to enable early steroid withdrawal after liver transplantation. MMF can increase efficacy of immunosuppressive therapy and thereby support the treatment of steroid resistant acute rejections, chronic rejections and chronic graft dysfunction.

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Section: De Novo Therapy With Mmfmentioning

confidence: 84%

Indications of Mycophenolate Mofetil in Liver Transplantation

et al. 2005

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“…Graft loss was reported in 5 of the 11 included studies, with a total of 80 events over 12 months of follow-up in 1,168 patients (Fig 3) [25–28,32]. Of the 594 patients on ciclosporin-based immunosuppression, 41 patients experienced graft loss, compared with 39 of 574 patients on tacrolimus, yielding a graft loss RR of 1.20 (95% CI 0.57, 2.53; P = 0.63) with ciclosporin relative to tacrolimus.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, NODAT rate at 12 months after transplantation was reported in five of the studies, with 101 of 748 patients on ciclosporin compared with 168 of 733 on tacrolimus experiencing NODAT after transplantation (Fig 6), resulting in a significant NODAT risk ratio of 0.60 (95% CI 0.47–0.77; P<0.0001) for ciclosporin relative to tacrolimus [24,25,28,32,33]. NODAT definitions included “patients who were not diabetic at baseline [who] were treated for diabetes at 12 months”, “changes from pretransplant diabetic treatment”, and “sustained (>1 month) requirement for oral hypoglycemic agents or an insulin requirement in a patient not already known to be diabetic”.…”

Section: Resultsmentioning

confidence: 99%

“…NODAT definitions included “patients who were not diabetic at baseline [who] were treated for diabetes at 12 months”, “changes from pretransplant diabetic treatment”, and “sustained (>1 month) requirement for oral hypoglycemic agents or an insulin requirement in a patient not already known to be diabetic”. NODAT was reported but not defined in two studies [24,25,28,32,33]. …”

Section: Resultsmentioning

confidence: 99%

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Systematic Review and Meta-Analysis of Tacrolimus versus Ciclosporin as Primary Immunosuppression After Liver Transplant

Muduma

Saunders²,

Odeyemi

et al. 2016

PLoS ONE

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Background and AimsSeveral meta-analyses comparing ciclosporin with tacrolimus have been conducted since the 1994 publication of the tacrolimus registration trials, but most captured data from randomized controlled trials (RCTs) predating recent improvements in waiting list prioritization, induction protocols and concomitant medications. The present study comprised a systematic review and meta-analysis of ciclosporin and tacrolimus in liver transplant recipients using studies published since January 2000.MethodsSearches of PubMed, the Cochrane Library and EMBASE identified RCTs of tacrolimus and ciclosporin as the immunosuppressant in adult primary liver transplant recipients, published between January 2000 and August 6, 2014. A random effects meta-analysis was conducted to evaluate the relative risk of death, graft loss, acute rejection (AR), new-onset diabetes after transplantation (NODAT) and hypertension with tacrolimus relative to ciclosporin at 12 months.ResultsThe literature search identified 11 RCTs comparing ciclosporin with tacrolimus. Relative to ciclosporin, tacrolimus was associated with significantly improved outcomes in terms of patient mortality (risk ratio [RR] with ciclosporin of 1.26; 95% confidence interval [95%CI] 1.01–1.58). Tacrolimus was superior to ciclosporin in terms of hypertension (RR with ciclosporin 1.26; 95%CI 1.07–1.47), but inferior in terms of NODAT (RR with ciclosporin 0.60; 95%CI 0.47–0.77). There were no significant differences between ciclosporin and tacrolimus in terms of graft loss or AR.ConclusionsMeta-analysis of RCTs published since 2000 showed tacrolimus to be superior to ciclosporin in terms of patient mortality and hypertension, while ciclosporin was superior in terms of NODAT. No significant differences were identified in terms of graft loss or AR. These findings provide further evidence supporting the use of tacrolimus as the cornerstone of immunosuppressive therapy in liver transplant recipients.

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“…The majority of trials have noted no significant difference between the two compounds on these outcomes. [47][48][49][50][51] Wiesner et al 52 reported that in their HCVpositive patients the 5-year graft survival was greater with FK-506 than CyA, 79% vs. 61% (P ¼ 0.04).…”

Section: Cn Inhibition and Hcv: Evidence After Bone Marrow Transplantmentioning

confidence: 97%

Review article: hepatitis C virus and calcineurin inhibition after renal transplantation

Fabrizi

Bromberg

Elli

et al. 2005

Aliment Pharmacol Ther

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SUMMARYThe impact of hepatitis C virus on patient and graft survival after renal transplantation remains controversial. However, recent studies have given emphasis on the detrimental role of hepatitis C on long-term patient and graft survival after renal transplantation. Various mechanisms can promote the lower survival in hepatitis C virus-positive recipients, i.e. post-transplant diabetes mellitus, liver disease and infections.Novel evidence has been accumulated showing the inhibitory activity of ciclosporin on the hepatitis C virus replication rate in human hepatocytes; ciclosporin has been shown in vitro to suppress hepatitis C virus replication as effectively as interferon alpha. This effect has not been seen with tacrolimus and is separate from its immunosuppressive activity. Data from patients with normal kidney function or after bone marrow transplantation show that ciclosporin inhibits hepatitis C virus replication. It appears that the progression of liver fibrosis is slower in hepatitis C virus-positive liver transplant recipients treated with ciclosporin than tacrolimus. In contrast, the clinical outcome of hepatitis C in hepatitis C virus-positive patients after liver transplantation treated with ciclosporin vs. tacrolimus has given mixed results. No information after renal transplantation is available.Various parameters can promote the worsening of hepatitis C after renal transplantation but choice of calcineurin inhibition is one of the few risk factors that can potentially be modified by the physician. Prospective, comparative trials of ciclosporin and tacrolimus with large size and adequate follow-up after renal transplantation are in progress.

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Four‐year follow‐up of a prospective randomized trial of mycophenolate mofetil with cyclosporine microemulsion or tacrolimus following liver transplantation

Abstract: Use of MMF induction and maintenance following OLT in conjunction with either N or FK and an identical steroid taper, resulted in an acceptable long-term incidence of rejection and infection, without an increase in long-term graft or patient morbidity.

Cited by 50 publications

References 35 publications

Indications of Mycophenolate Mofetil in Liver Transplantation

Indications of Mycophenolate Mofetil in Liver Transplantation

Systematic Review and Meta-Analysis of Tacrolimus versus Ciclosporin as Primary Immunosuppression After Liver Transplant

Review article: hepatitis C virus and calcineurin inhibition after renal transplantation

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