Almost every liver transplant recipient is treated with either the drug tacrolimus or the drug cyclosporine to prevent rejection of the transplanted liver. These drugs are part of a group of drugs called calcineurin inhibitors. Both tacrolimus and cyclosporine have serious and common adverse effects and, therefore, dose reduction or discontinuation of these drugs is frequently applied in clinical practice. The aim of the review was to compare reduction or withdrawal of tacrolimus or cyclosporine without substitution with another immunosuppressive agent with continuation of tacrolimus or cyclosporine. Through systematic searches of medical databases we found one ongoing randomised clinical trial investigating total withdrawal of immunosuppressive drugs but, at the time of conducting this review, no trial results on the outcome measures of interest to this review were published. Thus, we cannot reach any conclusion on beneficial or harmful effects of calcineurin inhibitor minimisation for liver transplant recipient patients.
This review shows that strategies regarding calcineurin inhibitor minimisation, that is, reduction or withdrawal, without substitution versus continuation of calcineurin inhibitor treatment lack evidence from randomised trials.
More research with calcineurin inhibitor reduction and withdrawal regimens is needed to optimise dosing and timing of calcineurin inhibitor treatment in order to achieve optimal patient and graft survival with a minimum of adverse events.
Specifically regarding calcineurin inhibitor reduction versus no reduction, we recommend that randomised trials evaluating calcineurin inhibitor reduction versus continuation of calcineurin inhibitor treatment are conducted.
Regarding calcineurin inhibitor withdrawal, we recommend that mechanisms for tolerance and 'graft acceptance' are clarified, and patient groups likely to tolerate calcineurin inhibitor withdrawal are identified in order to select the right patients for total withdrawal of calcineurin inhibitors without substitution with another immunosuppressive drug. The randomised trials should only be performed in highly selected patients.
The therapeutic success of liver transplantation has been largely attributable to the development of effective immunosuppressive treatment regimens. In particular, calcineurin inhibitors were essential in reducing acute rejection and improving early survival. Currently, more than 90% of all liver transplant recipients are treated with the calcineurin inhibitor cyclosporine or tacrolimus. Unfortunately, calcineurin inhibitors cause adverse events, such as nephrotoxicity, and because of this, minimisation (reduction and withdrawal) regimens of calcineurin inhibitor have been developed and studied. However, the benefits and harms of these minimisation regimens are unclear.
To assess the benefits and harms of calcineurin inhibitor minimisation for liver transplant recipients without substitution by another immunosuppressive agent.
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2010), Cochrane Central Register of Controlled Clinical Trials (CENTRAL) in The Cochrane Library, MEDLINE (OvidSP), EMBASE (OvidSP), Science Citation Index Expanded (Royle 2003), and the World Health Organization (WHO) international clinical trials registry platform (www.who.int/ictrp) until August 2011. In addition, we searched bibliographies of relevant articles as well as US Food and Drug Administration (FDA) and European Medicines Agency (EMA) drug approval reviews for additional trials.
We planned to select all randomised clinical trials investigating calcineurin inhibitor reduction or withdrawal in liver transplant recipients, irrespective of blinding, publication status, or language. Quasi-randomised clinical studies and cohort studies that were obtained through the searches were considered only for the reporting of harms. Trials investigating substitution of one calcineurin inhibitor by another calcineurin inhibitor were excluded. Trials investigating calcineurin inhibitor withdrawal concurrently with switching over to a mammalian target of rapamycin (mTOR) inhibitor-based regimen (everolimus or sirolimus) or mycophenolate mofetil-based regimen are the subject of a separate review.
Search strategies were used to obtain titles and abstracts of studies that were relevant for the review. Two authors independently scanned the references and assessed trial eligibility.
A total of 1299 references were identified by the searches. After removal of duplicates, 794 references were left. Out of these, two abstract reports of one ongoing randomised trial fulfilled the inclusion criteria of the review. This ongoing trial studies total withdrawal of immunosuppression in patients who receive a calcineurin inhibitor (cyclosporine or tacrolimus) or mycophenolate mofetil as the only immunosuppressive agent. The trial compares withdrawal of calcineurin inhibitor or mycophenolate mofetil with continuation of calcineurin inhibitor or mycophenolate mofetil. However, no trial results on the outcomes of interest to this review were available.