|Utility of monitoring mycophenolic acid in solid organ transplant patients
|Oremus M, Zeidler J, Ensom M H, Matsuda-Abedini M, Balion C, Booker L, Archer C, Raina P
This review assessed the impact of mycophenolic acid (MPA) monitoring on health outcomes including rejection and adverse events in solid organ transplant patients. The authors concluded that there is almost no evidence to suggest that MPA monitoring affects these outcomes. This was a well-conducted review and the conclusion is likely to be reliable.
To assess whether monitoring mycophenolic acid (MPA) in patients with a solid organ transplant results in lower incidence of transplant rejections and adverse events compared with non-monitored patients, and to investigate factors affecting the impact of monitoring.
MEDLINE, EMBASE, BIOSIS Previews, the Cochrane Database of Systematic Reviews and the Cochrane CENTRAL Register were searched to October 2007. In addition, the reference lists of recently published systematic reviews were checked and a panel of experts was consulted. Only studies published in English were eligible for inclusion.
Randomised controlled trials (RCTs), observational studies with comparison groups, or case series were eligible for inclusion. RCTs, cohort studies, case-control studies and case series were included in the review.
Eligible studies included adults or children with allograft solid organ transplants whether from a live or cadaveric donor. The majority of the included studies assessed patients with kidney transplants, but heart, liver and small bowel transplant recipients were also included. Studies were performed in both paediatric and adult populations. The patients were taking a range of medications, including steroids to prevent transplant rejection.
Studies in which MPA was measured in either serum or plasma at least once using any method of measurement were eligible for inclusion. Eligible health outcomes included transplant rejection, graft survival, mortality, adverse events, and biomarkers such as serum creatinine and glomerular filtration rate. Studies which did not link the MPA outcome measure to a health outcome were excluded from the review. The length of follow-up in the included studies ranged from 28 days to over 6 years.
Two reviewers independently assessed both abstracts and then full publications of studies for inclusion in the review. Any disagreements were resolved by consensus or by a third reviewer.
Assessment of study quality
Two reviewers independently assessed the studies for validity using the core criteria of the Evidence-based Practice Centre Methods Manual. The criteria used included allocation concealment, randomisation, blinding, intention-to-treat analysis and loss to follow-up for controlled trials, and sample size, participant selection, baseline comparability, confounding, loss to follow-up and blinding for observational studies. Any discrepancies were resolved by consensus.
At least two reviewers extracted the data using a pre-specified form. At least one other reviewer checked the extraction.
Methods of synthesis
The studies were combined in a narrative. Studies were grouped according to the review sub-question addressed.
Results of the review
Eighty-nine studies were included in the review: 12 RCTs and 77 observational studies. The numbers of patients were not reported.
The quality of the RCTs was fair or good, although reporting of randomisation methods and blinding was lacking. Almost all observational studies failed to report blinding, the great majority did not report losses to follow-up, and only 29 of the 77 studies attempted to control for confounding factors. However, most studies described methods of measurement and had clearly defined outcomes.
Three studies including one RCT compared the incidence of adverse events and transplant rejection in an MPA-monitored group with that in a non-monitored group. The RCT (n=130) compared kidney transplant patients given a fixed dose of mycophenolate mofetil (MMF), adjusted on the basis of physician experience, with patients whose MMF dose was calculated to achieve an MPA target dose of 40 mg h/L using data from an MPA limited area under the curve monitoring strategy. There were significantly more treatment failures in the fixed-dose group than in the concentration-controlled group (47.7% versus 29.2%, p=0.03). The only statistically significant difference in adverse events was a higher incidence of herpes in the concentration-controlled group (p<0.05). In the remaining 2 studies one reported fewer rejections in the controlled group but did not report the statistical results, while the other found a non significant effect of more rejections in this group (p>0.05).
The impact of the following factors on transplant rejections and adverse events was also assessed: MPA dose and dose frequency, type of MPA, total versus free MPA, albumin levels, genetic differences, MPA metabolites, assay method, analytical method of MPA monitoring, and patients' age, gender, ethnicity, co-morbidity and their use of concomitant medication. No conclusive evidence for the impact of these factors was reported.
The authors searched for evidence of the cost-effectiveness of MPA monitoring, but found no studies which reported such data.
There is almost no direct evidence to suggest that MPA monitoring would reduce the incidence of rejection or adverse events in solid organ transplant patients.
The review questions and the inclusion criteria were clear. The authors searched a number of relevant databases and made additional efforts to identify studies. However, the decision to limit the review to published studies reported in English might have increased the possibility that some relevant studies were not included in the review. The authors reported using methods designed to minimise bias and error in the study selection, validity assessment and data extraction processes. The validity assessment used appropriate criteria and was utilised in the synthesis. Given the clinical and methodological heterogeneity of the included studies, the decision to employ a narrative synthesis appears appropriate. This was a well-conducted review and the authors' conclusions accurately reflect the paucity of available evidence.
Implications of the review for practice and research
Practice: The authors stated that patients, clinicians and funders should decide on a case-by-case basis whether the possible but uncertain evidence of benefit from MPA monitoring justifies the time and expense involved.
Research: The authors appear to suggest that RCTs are required to address the utility of routine MPA monitoring and factors which may impact on its efficacy.
Agency for Healthcare Research and Quality, contract number 290-02-0020.
Oremus M, Zeidler J, Ensom M H, Matsuda-Abedini M, Balion C, Booker L, Archer C, Raina P. Utility of monitoring mycophenolic acid in solid organ transplant patients. Rockville, MD, USA: Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment; 164. 2008
Other publications of related interest
Balion CM, McKelvie RS, Reichert S, et al. Monitoring the response to pharmacologic therapy in patients with stable chronic heart failure: Is BNP or NT-proBNP a useful assessment tool? Clinical Biochemistry 2008;41:266-276.
Subject indexing assigned by CRD
Mycophenolic Acid /administration & dosage; Organ Transplantation /adverse effects
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.