Scolaris Content Display Scolaris Content Display

Cochrane Database of Systematic Reviews Protocol - Intervention

Mycophenolate mofetil for liver‐transplanted patients

Authors' declarations of interest

Version published: 08 October 2008 Version history

https://doi.org/10.1002/14651858.CD007446
Collapse all Expand all

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess benefits and harms of mycophenolate mofetil and enteric‐coated mycophenolate sodium as immunosuppressive agents for liver‐transplanted patients. To assess separately usefulness for achieving current (or improved) targets in anti‐rejection therapy and reducing calcineurin inhibitor side‐effects of mycophenolate mofetil and enteric‐coated mycophenolate sodium as immunosuppressive agents for liver‐transplanted patients.

Background

Over the last decades, liver transplantation has moved from an experimental treatment to standard management for end‐stage liver disease. Liver grafts can be obtained from living or post‐mortem donors. One possibility to manage the insufficient supply of liver grafts is the split liver method, where one organ is split between an adult and a paediatric recipient. There are on average 1277 liver transplantations (liver, split liver) per annum from post‐mortem donors in the Eurotransplant region (Eurotransplant 2006). In the United States, 6690 livers were transplanted in 2005 (Punch 2007).

Long‐term survival after orthotopic liver transplantation is mainly influenced by graft function and adverse events caused by immunosuppression. Therapy with calcineurin inhibitors, namely cyclosporine A and tacrolimus, is a key component of immunosuppressive regimens for patients undergoing transplantation (Haddad 2006). The use of calcineurin inhibitors has substantially decreased the risk of acute rejection and improved short‐term outcomes (Olyaei 2001). However, calcineurin inhibitors are also implicated as a principal cause of post‐transplantation renal dysfunction and end‐stage renal disease which may lead to severe tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and arterioles. This arteriolar vasoconstriction could cause decreased glomerular filtration rates (GFR), manifested clinically by raised serum creatinine (Bennett 1996; Olyaei 2001).

Chronic renal failure is a major cause of morbidity and mortality after orthotopic liver transplantation (Fisher 1998). Age, female sex, pre‐transplantation hepatitis C infection, systemic hypertension, diabetes mellitus, and postoperative acute renal failure are seen as further risk factors for an increased risk of chronic renal failure (Ojo 2003). Another analysis could only consider cyclosporine A as independent risk factor of chronic renal failure and could not find any correlations to age, gender, rejection/retransplantation, or diabetes mellitus (Schmitz 2008).

The nephrotoxicity of calcineurin inhibitors can be classified as an acute, functional, and dose‐dependent decrease in renal blood flow and glomerular filtration rates or chronic structural changes and dose independent interstitial fibrosis (Bennett 1998). Apart from intestinal transplants, liver transplant recipients have with 18.1% the highest five‐year incidence of chronic renal failure of any non‐renal solid organ transplant recipients. Approximately 29% of the patients who develop chronic renal failure require dialysis or renal transplantation and the risk of death after transplantation is at least fourfold higher in these patients (relative risk 4.55; 95% CI 4.38 to 4.74) (Ojo 2003). In patients who survived at least one year after orthotopic liver transplantation, 4% had severe chronic renal failure and of these patients, 48% developed end‐stage renal disease (Fisher 1998). Nearly three‐quarter of chronic renal dysfunction after liver transplantation were caused by calcineurin inhibitor toxicity (Gonwa 2001).

Description of the intervention

Strategies to reduce nephrotoxicity in liver transplant recipients consist of calcineurin inhibitor minimisation or calcineurin‐inhibitor‐free regimens by using sirolimus or mycophenolate mofetil (Flechner 2008). This review is focused on calcineurin‐inhibitor‐sparing regimens with mycophenolate mofetil.

Mycophenolate mofetil (MMF, CellCept®) is a non‐nephrotoxic immunosuppressant specific for T‐ and B‐lymphocytes, smooth muscle cells, and fibroblasts. Mycophenolate mofetil is a morpholinoethyl ester and prodrug of mycophenolic acid. After absorption, mycophenolate mofetil is rapidly hydrolyzed to mycophenolic acid, a noncompetitive reversible inhibitor of inositol‐monophosphate‐dehydrogenase, a key enzyme in the de novo purine synthesis (Klupp 2005). Mycophenolate mofetil has been associated with gastrointestinal adverse effects such as nausea, vomiting, gastritis, and abdominal cramps (Ettenger 2005). To reduce these significant gastrointestinal symptoms, enteric‐coated mycophenolate sodium (EC‐MPS, Myfortic®), an enteric‐coated tablet containing mycophenolic acid as the sodium salt, was developed. After administration of both formulations, mycophenolate mofetil and enteric‐coated mycophenolate sodium, mycophenolic acid (MPA) is the active drug (Perry 2007).

How the intervention might work

Several studies have shown efficacy of immunosuppressive regimens containing mycophenolate mofetil in adult (Wiesner 2001; Fisher 2004; Wiesner 2005) and also paediatric hepatic allograft recipients (Renz 1999; Chardot 2001; Toyoki 2002; Evans 2005). It is reported that the use of mycophenolate mofetil by reducing the dose of calcineurin inhibitors or using protocols with mycophenolate mofetil‐monotherapy may prevent and/or improve renal dysfunction in liver transplantation (Olyaei 2001; Klupp 2005; Manzia 2005; Schmeding 2006). On the other hand, the partial or complete replacement of calcineurin inhibitors with mycophenolate mofetil is associated with an increased risk of acute cellular and severe ductopaenic rejection (Herrero 1999; Stewart 2001). One single‐centre retrospective analyses of 1173 liver transplant recipients could not find differences in renal function between patients on calcineurin inhibitor monotherapy (tacrolimus or cyclosporine A) compared to those who had mycophenolate mofetil added (Schmitz 2008). In summary, the overall effect still remains unclear.

We were not been able to identify meta‐analyses or systematic reviews analysing consequences of introducing mycophenolate mofetil and replacing calcineurin inhibitors in liver‐transplanted patients to prevent or reduce chronic renal dysfunction.

Objectives

To assess benefits and harms of mycophenolate mofetil and enteric‐coated mycophenolate sodium as immunosuppressive agents for liver‐transplanted patients. To assess separately usefulness for achieving current (or improved) targets in anti‐rejection therapy and reducing calcineurin inhibitor side‐effects of mycophenolate mofetil and enteric‐coated mycophenolate sodium as immunosuppressive agents for liver‐transplanted patients.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised clinical trials of parallel or cross‐over design evaluating the effect of mycophenolate mofetil and/or enteric‐coated mycophenolate sodium for patients after liver transplantation.

For cross‐over trials we will use data from the first period only.

We will apply no restrictions on date of publication, language of publication, or publication status (published or unpublished work).

Types of participants

People of any age, sex, and ethnic group after liver transplantation, in any care setting, irrespective of diagnosis and disease stage, postmortem or living donor, or prescribed medication will be eligible for this review.

Types of interventions

We will include trials that compare different protocols of immunosuppression with mycophenolate mofetil after orthotopic liver transplantation as follows:

  • Mycophenolate mofetil‐monotherapy or enteric‐coated mycophenolate sodium monotherapy versus no treatment or placebo.

  • Mycophenolate mofetil‐monotherapy or enteric‐coated mycophenolate sodium monotherapy versus immunosuppression with calcineurin inhibitors.

  • Mycophenolate mofetil‐monotherapy or enteric‐coated mycophenolate sodium monotherapy versus immunosuppression with calcineurin inhibitors and mycophenolate mofetil.

  • Any combination therapy of mycophenolate mofetil or enteric‐coated mycophenolate sodium (e.g., studies which combine mycophenolic acid with sirolimus or calcineurin inhibitors or monoclonal antibodies) versus similar immunosuppression without mycophenolate mofetil or enteric‐coated mycophenolate sodium.

  • Early initiation of mycophenolic acid soon after transplantation versus late initiation of mycophenolic acid after transplantation once renal function is poor.

  • Mycophenolic acid with drug level monitoring was used to regulate dosage versus no mycophenolic acid drug level monitoring.

Additional immunosuppression with corticosteroids and/or azathioprine should be administered equally in the trial arms.

Comparisons between different types or dosages of mycophenolate mofetil are eligible, too.

Types of outcome measures

Primary outcomes

  • Mortality.

  • Patient and graft survival.

  • Serological markers for renal function (eg, serum creatinine, creatinine clearance, glomerular filtration rate, cystatin C).

  • Number of biopsy‐proven rejection episodes (acute and chronic rejection episodes).

Secondary outcomes

  • Disease recurrence (hepatitis C, hepatitis B).

  • Changes in markers over intervals up to and beyond one year after starting mycophenolic acid.

  • Changes in calcineurin inhibitors‐related adverse health effects (eg, renal dysfunction, systolic and diastolic blood pressure, serum uric acid, diabetes mellitus, hypertension).

  • Drug‐related adverse effects (eg, infections (bacterial/fungal/viral), leucopenia, cytamegalovirus (CMV) infection and disease, post‐transplant lymphoproliferative disease (PTLD), nausea, vertigo, vomiting, diarrhoea).

  • Cost effectiveness.

  • Health‐related quality of life

All additionally frequently reported outcomes will also be considered.

Search methods for identification of studies

Electronic searches

We will search The Cochrane Hepato‐Biliary Group Specialised Trials Register (Gluud 2008), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and Social Sciences Citation Index (Royle 2003). We have given the preliminary search strategies in Appendix 1 with the time span for the searches. As the review progresses, we will develop the search strategies if necessary.

The authors, KG and GL, will independently search for eligible trials for the earliest entrance date possible until the latest search date.

Searching other resources

We will contact experts in the field, such as scientific societies for liver transplantation and ask whether they have been involved in any further trials or are aware of recent or ongoing trials on the effects of mycophenolate mofetil for immunosuppression after liver transplantation. We will try to identify unpublished studies by contacting the manufacturer of CellCept® (Hoffmann‐La Roche AG, Basel, Switzerland) and Myfortic® (Novartis Pharma AG, Basel, Switzerland).

We will search the following sources additionally by hand from 1997 to present:

  • Conference Proceedings of the Pan‐Arab Liver Transplantation Society;

  • Conference Proceedings of the International Liver Transplantation Society;

  • Conference Proceedings of the American Transplant Colleagues;

  • Journal of Liver Transplantation;

  • American Journal of Transplantation;

  • Transplantation;

  • Abstracts from the annual meetings of the American Association for the Study of Liver Diseases (AASLD);

  • Abstracts from the annual meetings of the European Association for the Study of the Liver (EASL).

We will search the reference lists of identified trials for additional publications of interest.

All references will be managed with EndNote® (Thomson Reuters).

Data collection and analysis

Trial selection and data extraction

Two authors (KG and GL) will independently assess the retrieved references for eligibility and will resolve disagreement by discussion with another author (SS). The excluded studies and the reasons for their exclusion will be listed in the Table of excluded studies.

We will extract data on source, inclusion and exclusion criteria, description of participants and setting, interventions and co‐interventions, outcomes, and sample size calculation using a data extraction sheet.

Assessment of methodological quality

The authors will follow the instructions given in The Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2008) and The Cochrane Hepato‐Biliary Group Module (Gluud 2008). The authors, KG and GL, will independently assess the methodological quality of the trials, without masking the trial names. Disagreements between KG and GL will be resolved by discussion and arbitrated with SS. KG will assess the risk of bias associated with incomplete outcome data. Due to the risk of biased overestimation of intervention effects in randomised trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008), the methodological quality of the trials will be assessed based on generation of allocation sequence, allocation concealment, blinding of (participants, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, and other sources of bias. If information is not available in the published trial, we will contact authors of the publications in order to assess the trials correctly. Quality components will be classified as follows:

Generation of allocation sequence

  • Adequate, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing dice will be considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.

  • Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described.

  • Inadequate, if a system involving dates, names, or admittance numbers were used for the allocation of patients. These studies are known as quasi‐randomised and will be excluded from the review.

Allocation concealment

  • Adequate, if the allocation of patients involved a central independent unit, on‐site locked computer, or sealed envelopes.

  • Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.

  • Inadequate, if the allocation sequence was known to the investigators who assigned participants. Such studies will be excluded.

Blinding of participants, personnel, and outcome assessors

  • Low risk of bias (blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding).

  • Uncertain risk of bias (there is insufficient information to assess whether the type of blinding used is likely to induce bias on the estimate of effect).

  • High risk of bias (no blinding or incomplete blinding, and the outcome or the outcome measurement is likely to be influenced by lack of blinding).

Incomplete outcome data

  • Low risk of bias (the underlying reasons for missingness are unlikely to make treatment effects departure from plausible values, or proper methods have been employed to handle missing data).

  • Uncertain risk of bias (there is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data is likely to induce bias on the estimate of effect).

  • High risk of bias (the crude estimate of effects (eg, complete case estimate) will clearly be biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory).

Selective outcome reporting

  • Low risk of bias (the trial protocol is available and all of the trial's pre‐specified outcomes that are of interest in the review have been reported or similar).

  • Uncertain risk of bias (there is insufficient information to assess whether the magnitude and direction of the observed effect is related to selective outcome reporting).

  • High risk of bias (not all of the trial's pre‐specified primary outcomes have been reported or similar).

Other sources of bias

  • Low risk of bias (the trial appears to be free of other sources of bias).

  • Uncertain risk of bias (there is insufficient information to assess whether other sources of bias are present).

  • High risk of bias (it is likely that potential sources of bias related to specific design used, early termination due to some data‐dependent process, lack of sample size or power calculation, or other bias risks are present).

Statistical methods

We plan primary analyses in a series of categories:

1. Mycophenolate mofetil monotherapy.
2. Therapy with mycophenolate mofetil and reduced dose of calcineurin inhibitors.

We will perform meta‐analyses of these categories according to the recommendations of The Handbook (Higgins 2008) and The Cochrane Hepato‐Biliary Group Module (Gluud 2008). We will use the software package Review Manager 5 (RevMan 2008). For dichotomous variables, we will calculate the relative risk (RR) with 95% confidence interval. For continuous variables, we will calculate the weighted mean difference (WMD) with 95% confidence interval. We will use a random‐effects model (DerSimonian 1986) and a fixed‐effect model (DeMets 1987). In case of discrepancy between the two models we will report both results; otherwise we will report only the results from the random‐effects model. Heterogeneity will be explored by chi‐squared test with significance set at P value 0.10, and the quantity of heterogeneity will be measured by I2 (Higgins 2002). If the results in the fixed‐effect and random‐effects model do not differ, we will report the fixed‐effect model. Otherwise, we will report both model results.

Subgroup analysis

We will perform the following subgroup analyses:

  • Paediatric compared to adult liver transplantation;

  • Different types of mycophenolate mofetil;

  • Different dosages of mycophenolate mofetil;

  • Different types of calcineurin inhibitors;

  • Low bias risk trials compared to high bias risk trials.

Bias

We will use a funnel plot to explore bias (Egger 1997; Macaskill 2001). We will use linear regression approach described by Egger et al to determine funnel plot asymmetry (Egger 1997).

Additionally we will use arcsine tests for bias for dichotomous outcomes (Rücker 2007).