title: Calcineurin inhibitor minimisation versus continuation of calcineurin inhibitor treatment for liver transplant recipients.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To assess the benefits and harms of calcineurin inhibitor minimisation for liver transplant recipients without substitution by another immunosuppressive agent.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital,Copenhagen, Denmark. LP@ctu.rh.dk. luitpenninga@hotmail.com.
authors.forename: Luit
authors.initials: L
authors.lastname: Penninga
authors.forename: Andre
authors.initials: A
authors.lastname: Wettergren
authors.forename: An-Wen
authors.initials: AW
authors.lastname: Chan
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Steinbrüchel
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
mesh_terms: D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016031:Liver Transplantation; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D016559:Tacrolimus / Q000008:administration & dosage
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus