Tacrolimus as Intervention in the Treatment of Hyperlipidemia after Liver Transplant Andre ´ Roy, 1,8 Norman Kneteman, 2 Leslie Lilly, 3 Paul Marotta, 4 Kevork Peltekian, 5 Charles Scudamore, 6 and Jean Tchervenkov 7 Background. To measure the effect on serum lipids and other risk factors for cardiovascular disease, we converted the primary immunosuppression of dyslipidemic stable liver transplant recipients from cyclosporine A to tacrolimus. Methods. Patients underwent a four-month dietary stabilization period (American Heart Association Step II diet) and serum lipid samples were collected for analysis at a central laboratory. After conversion, dietary counseling and lipid analyses were performed over a six-month postconversion observation period. Results. Enrollment was terminated prematurely due to low patient recruitment rates. Thirteen patients were enrolled and provided postconversion data showing surprisingly strong results. At six months postconversion, total cholesterol (C) was reduced by a mean of 0.61 mmol/L (P=0.017), high density lipoprotein cholesterol (HDL-C) remained unchanged; the mean total C:HDL-C ratio was reduced by 0.87 (P=0.001). Low density lipoprotein cholesterol (LDL-C) reductions were not statistically significant, but we observed a significant and persistent decrease in apoli- poprotein B (-0.15 g/L six months postconversion, P=0.031). No changes in homocysteine or in vitamins B6 and B12 were discerned, but although red cell folate remained stable, serum folate increased after conversion. We observed no rejection episodes or any other clinically notable events following conversion. Conclusions. In this study, conversion from cyclosporine to tacrolimus provided a safe and well-tolerated alternative that reduced hyperlipidemia and other recognized cardiovascular risk factors. Keywords: Cardiovascular risk, Conversion, Cyclosporine. (Transplantation 2006;82: 494–500) I ncreasingly sophisticated surgical techniques and refine- ments in immunosuppressive treatment regimens have contributed in recent years to improved short-term graft and patient survival following orthotopic liver transplantation. The focus is now shifting to long-term graft and patient sur- vival, driven to no small degree by an extensive literature on renal transplant recipients. In this population, death with a functioning graft is well established as the current leading cause of renal allograft loss and accounts for nearly half of all graft failures in the first five years posttransplantation (1). Of these deaths, U.S. renal transplant registry data indicate that death from cardiovascular disease is the most common, ac- counting for 33 to 37% of all cases (2). The prevalence of both cardiovascular risk factors and associated clinical disease is higher in solid organ transplant recipients as compared to the general population (3). Al- though end-stage liver disease is associated with deranged lipid metabolism and hypocholestoralemia, up to 45% of liver transplant recipients demonstrate elevated lipid levels posttransplantation (3–5). Indeed, risk for cardiovascular morbidity and mortality after orthotopic liver transplanta- tion is significant, with an estimated risk for cardiovascular death of approximately 2.6 over age-matched controls (6). At the time of inception of this study, results of several previous studies indicated that tacrolimus-based immuno- suppression is correlated with superior serum lipid profiles as compared to cyclosporine-based regimens (7–14). Such stud- ies, however, failed to reach complete consensus on this point. We set out to improve upon the limitations of some of these studies, which included design features such as single- center and retrospective data collection, confounding factors such as a lack of standardization in steroid therapy among patient groups, and analytical limitations such as local rou- tine service laboratory determinations of lipid variables. In this prospective multicenter study, stable cyclosporine- maintainedliver allograft recipients with hyperlipidemia were converted to tacrolimus. Steroids were maintained in all pa- tients at 10 mg/day over the course of the study and lipid and lipoprotein profiles were determined at a central refer- ence laboratory. Dietary counseling, according to the Amer- ican Heart Association (AHA) Step II diet, was conducted over the entire course of the study. METHODS This prospective trial of conversion from cyclosporine to tacrolimus in hyperlipidemic liver transplant recipients was conducted at all seven Canadian adult liver transplant centers in accordance with the Declaration of Helsinki. The study was approved by each center’s institutional ethics com- This study was supported by Astellas Pharma Canada. 1 University of Montreal, CHUM-Hopital St-Luc, Montreal, Quebec, Canada. 2 University of Edmonton, Walter C. MacKenzie Centre, Edmonton, Al- berta, Canada. 3 University of Toronto, University Health Network–Toronto General Hos- pital, Toronto, Ontario, Canada. 4 University of Western Ontario, London Health Sciences Centre, London, Ontario, Canada. 5 Dalhousie University, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada. 6 University of British Columbia (British Columbia Transplant Society), Vancouver, British Columbia, Canada. 7 McGill University, MUHC—Royal Victoria Hospital, Montreal, Quebec, Canada. 8 Address correspondence to: Andre Roy, M.D., CHUM, Hopital St. Luc, 1058 St. Denis, 9e e ´tage 9403B, Montre ´al PQ H2X 3J4, Canada. E-mail: andre.roy.chum@ssss.gouv.qc.ca Received 1 December 2005. Revision requested 3 April 2006. Accepted 4 April 2006. Copyright © 2006 by Lippincott Williams & Wilkins ISSN 0041-1337/06/8204-494 DOI: 10.1097/01.tp.0000231711.82193.41 494 Transplantation • Volume 82, Number 4, August 27, 2006