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Tacrolimus Monotherapy Without Steroids After Liver Transplantation – A Prospective Randomized Double-Blinded Placebo-Controlled Trial

2007; Elsevier BV; Volume: 7; Issue: 6 Linguagem: Inglês

10.1111/j.1600-6143.2007.01804.x

1600-6143

Christian Moench, A.P. Barreiros, M. Schuchmann, F. Bittinger, Judith Thiesen, Gerhard Hommel, I. KRAEMER, G. Otto,

Renal Transplantation Outcomes and Treatments

American Journal of TransplantationVolume 7, Issue 6 p. 1616-1623 Free Access Tacrolimus Monotherapy Without Steroids After Liver Transplantation – A Prospective Randomized Double-Blinded Placebo-Controlled Trial C. Moench, C. Moench Department of Transplantation and Hepatobiliarypancreatic SurgerySearch for more papers by this authorA.P. Barreiros, A.P. Barreiros Medical Department ISearch for more papers by this authorM. Schuchmann, M. Schuchmann Medical Department ISearch for more papers by this authorF. Bittinger, F. Bittinger Department of PathologySearch for more papers by this authorJ. Thiesen, J. Thiesen Department of Pharmacy, Johannes Gutenberg University Mainz Hospital, Langenbeckstrasse 1, 55131 Mainz, GermanySearch for more papers by this authorG. Hommel, G. Hommel Department of Biomathematics and StatisticsSearch for more papers by this authorI. Kraemer, I. Kraemer Department of Pharmacy, Johannes Gutenberg University Mainz Hospital, Langenbeckstrasse 1, 55131 Mainz, GermanySearch for more papers by this authorG. Otto, G. Otto Department of Transplantation and Hepatobiliarypancreatic SurgerySearch for more papers by this author C. Moench, C. Moench Department of Transplantation and Hepatobiliarypancreatic SurgerySearch for more papers by this authorA.P. Barreiros, A.P. Barreiros Medical Department ISearch for more papers by this authorM. Schuchmann, M. Schuchmann Medical Department ISearch for more papers by this authorF. Bittinger, F. Bittinger Department of PathologySearch for more papers by this authorJ. Thiesen, J. Thiesen Department of Pharmacy, Johannes Gutenberg University Mainz Hospital, Langenbeckstrasse 1, 55131 Mainz, GermanySearch for more papers by this authorG. Hommel, G. Hommel Department of Biomathematics and StatisticsSearch for more papers by this authorI. Kraemer, I. Kraemer Department of Pharmacy, Johannes Gutenberg University Mainz Hospital, Langenbeckstrasse 1, 55131 Mainz, GermanySearch for more papers by this authorG. Otto, G. Otto Department of Transplantation and Hepatobiliarypancreatic SurgerySearch for more papers by this author First published: 15 May 2007 https://doi.org/10.1111/j.1600-6143.2007.01804.xCitations: 51 * Corresponding author: Christian Moench, christian.moench@kgu.de christian.moench@kgu.de AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Early steroid withdrawal after liver transplantation (LT) is desirable in order to reduce steroid side effects. Between February 2000 and August 2004, 110 patients after LT were included in this prospective, randomized, double-blind, placebo-controlled trial. Randomization was performed before LT. In all patients, tacrolimus was used without induction therapy. All patients received methylprednisolon for 14 days, thereafter a double-blinded medication containing either placebo (n = 56) or methylprednisolon (n = 54) for 6 months, which was completely stopped thereafter. End points were patient and graft survival, acute and chronic rejection, and incidence of steroid side effects during the first year after LT. One-year patient survival was 85.7% (placebo) and 88.8% (steroid) (p = 0.572). Twenty-seven (48.2%) and 19 (35.2%) patients experienced acute rejection (placebo versus steroid, respectively; p = 0.116). Two patients in the placebo group but none in the steroid group experienced chronic rejection (p = 0.257). The rates of side effects were (placebo versus steroid, respectively): CMV infection 25% versus 33% (p = 0.336), post-transplant diabetes 30% versus 53% (p = 0.024), hypertension 39% versus 52% (p = 0.248), hypercholesterolemia 10% versus 41% (p = 0.002) and hypertriglyceridemia 32% versus 54% (p = 0.046). In conclusion, early steroid withdrawal after LT is feasible under tacrolimus monotherapy without increased rejection rates and with a lower rate of side effects. Introduction Tacrolimus (FK506) is a potent and effective immunosuppressant agent and currently the standard basic treatment for liver transplant recipients. It guarantees long-term patient and graft survival with a low incidence of graft rejection and side effects (1). FK506 is well known for a steroid sparing effect due to its potent immunosuppression. However, many centers combine FK506 with corticosteroids as a long-term maintenance therapy (2). Since corticosteroids are associated with numerous post-transplant complications (3), there is a worldwide trend of reducing steroid usage after solid organ transplantation (4, 5). The main side effects of corticosteroids contributing to patient mortality and morbidity after transplantation are post-transplant diabetes mellitus (PTDM) (6), hypertension, hyperlipidemia, infectious disease, osteoporosis (7) and others (8). Numerous publications about steroid reduction in liver transplant recipients have been published (9-12). However, there is almost no data generated in a prospective randomized and double-blinded trial. Cyclosporine A failed in effectivity in early steroid reduction (13) with significant increase of rejection rates under steroid withdrawal. Although steroids were eliminated in some immunosuppressive protocols, they have often been replaced either by induction therapy (14, 15) or by long-term use of additional drugs like mycophenolate mofetil or azathioprin (16, 17). Thereby, no true minimization of immunosuppression was performed. In order to create evidence-based data on early steroid withdrawal after orthotopic liver transplantation (OLT) under tacrolimus, we performed this prospective, randomized, placebo-controlled double-blinded trial: patients following OLT received either tacrolimus and placebo or tacrolimus and steroids with a follow-up of 1 year. Patients and Methods Study design This was a 12-month, prospective, randomized, double-blinded, placebo-controlled investigator driven, monocenter trial comparing early FK506 monotherapy with FK506 plus steroids. The study was performed in accordance to the declaration of Helsinki. The local ethic committee approved the protocol before the trial was implemented. Patient care and study conduct complied with good clinical practice. 1:1 randomization was performed by a blinded randomization list generated by the Biomathematical Institute prior to transplantation in eligible patients (Figure 1). Patients transplanted at the Johannes Gutenberg University were included into the protocol between February 2000 and July 2004. Figure 1Open in figure viewerPowerPoint Randomization in the trial and time-schedule. Tacrolimus was used as the basic immunosuppressive therapy and was given to the patients during the whole follow-up. The first dose was administered within 12 h after transplantation. The initial dose of tacrolimus was 0.2 mg/kg per day and was given in two divided doses. Target whole-blood trough levels were 10–15 ng/mL between day 0 and 42 and 5–10 ng/mL thereafter. Methylprednisolon was used in both groups between day 0 and day 14. It was started with a bolus of 1000 mg intravenously before reperfusion of the graft. Postoperatively, we used 100 mg at day 1, 75 mg at day 2, 48 mg at day 3 and 4, 36 mg at day 5 and 6, 24 mg at day 7 and 8, 16 mg from day 9 to 13 and 12 mg at day 14. After day 14, patients received study medication, either placebo or methylprednisolon capsules in a double-blinded way. Study medication was manufactured, packed and blinded by the Pharmacy Department of Johannes Gutenberg University Hospital. While the placebo contained no steroids, the steroid group received 12 mg methylprednisolon from day 15 to day 60 and 8 mg from day 61 until day 180. Since the groups were blinded until the end of the study period after 1 year, at day 181 the medication in both groups was tapered to 0 mg during 2 weeks and then stopped. All episodes of acute or chronic rejection had to be verified by histological examination after liver biopsy. Biopsy confirmed acute rejection episodes were treated by i.v. administration of methylprednisolon (500 mg per day for 3 days). After an episode of acute rejection, FK506 was adjusted to a higher trough level when the trough levels prior to rejection were insufficient. There was no other intensification of immunosuppression after an episode of acute rejection. Patients who experienced three or more episodes of acute rejection during the follow-up were excluded from the trial, unblinded and received individualized immunosuppressive therapy. Patients who had to stop tacrolimus usage for more than 3 days were also excluded from the trial. Patients Eligible patients were 18 years or older and undergoing OLT for any indication. Recipients of whole or partial liver grafts from brain dead donors as well as living-related donors were included. All patients gave their written and oral informed consent before randomization and beginning of any study-related procedures. Exclusion criteria were previous organ transplants including liver retransplantation, initial, sequential or parallel therapy with other immunosuppressive drugs besides the study protocol, corticosteroid therapy within 6 months before transplantation, patients with human immunodeficiency virus infection, pregnancy and breast feading, allergy to or intolerance of study medication, participation in another clinical trial. Efficacy and safety assessments The primary end points were the incidence of PTDM, hyperlipidemia (cholesterol and triglycerides), hypertension and cytomegalovirus (CMV) infection. Secondary end points were the incidence and time to first rejection episode, the overall frequency of acute and chronic rejection and the severity of acute rejection as well as patient and graft survival. Patients were assessed at baseline, day 1, 7, 14, 30, 90, 180 and 360. Post-transplant diabetes was defined according to the international consensus paper from 2003 concerning the guidelines for new-onset diabetes mellitus after transplantation (18). Post-transplant diabetes was either treated with insulin or by diet. Hyperlipidemia and hypertension were defined according to the definition of the World Health Organization (WHO) and were treated with statins if indicated. CMV infection was defined as any detection of pp65 positive cells in patients whole blood. The safety evaluation was based on the incidence of severe adverse events, patient and graft survival, changes in laboratory parameters and vital signs. Graft loss was defined as retransplantation or death. An adverse event was defined serious if it resulted in death, was life-threatening, resulted in persistent disability or incapacity, resulted in hospitalization or prolonged hospitalization or required intervention. Statistics The statistic analysis was performed in cooperation with the Institute of Biomathematics and Statistics of Johannes Gutenberg University. The planned sample size of a minimum of 100 patients (50 per treatment group) was based on an estimated difference in incidence of 15% between the primary study end points, a power of 80%, a 5% level of significance and a dropout rate of 10%. We included a total of 110 patients. Efficacy and safety were analyzed using an intention-to-treat analysis that included all patients that received at least one dose of study medication. Continuous variables were evaluated using the Student´s t-test or the Wilcoxon rank-sum test as indicated. Categorical variables were analyzed with Pearson´s chi-square test or Fisher´s exact test as indicated. Time-to-event data were estimated using the Kaplan-Meier method and were compared with the log-rank test. P values < 0.05 were considered statistically significant. Microsoft windows, Microsoft office and SPSS were used for calculation on personal computer. Results Patients A total of 110 patients were recruited. Fifty-four (49.1%) were randomized to steroid group and 56 (50.9%) were randomized to placebo group. All patients received study medication and therefore were included in the intention-to-treat analysis. Patients demographics and baseline characteristics were comparable in both groups and are demonstrated in Table 1. Table 1. Patient demographics and baseline characteristics Steroid group n = 54 Placebo group n = 56 p value Mean age (years) ± SD 53.5 ± 8.3 53.6 ± 10.4 0.946 Male:female ratio 36:18 38:18 0.894 Caucasian, n (%) 53 (98.1) 53 (94.6) 0.323 Indication for OLT HCC, n (%) 19 (35,2) 21 (37,5) 0.801 Hepatitis B, n (%) 7 (13) 12 (21.4) n.s. Hepatitis C, n (%) 15 (27.8) 16 (28.6) n.s. Alcohol, n (%) 21 (38.9) 16 (26.8) n.s. PSC/PBC, n (%) 5 (9.3) 3 (5.4) n.s. Partial graft, n (%) 3 (5.6) 3 (5.4) 0.643 Deceased donor, n (%) 50 (92.6) 50 (89.3) 0.394 Diabetes mellitus pre-OLT, n (%) 12 (22.2) 9 (16.1) 0.412 Hypercholesterolemia pre-OLT, n (%) 10 (18.5) 8 (14.3) 0.549 Hypertriglyceridemia pre-OLT, n (%) 7 (13.0) 12 (21.4) 0.240 Hypertension pre-OLT, n (%) 17 (31.5) 9 (17.0) 0.080 The number of patients completing the follow-up were 35 (66.7%) in the steroid group and 36 (62.5%) in the placebo group (p = 0.801, chi-square). Reasons for withdrawal from the trial were death (n = 14, 12.7%), recurrent rejection (n = 11, 10.0%), severe adverse events (n = 10, 9.1%) and secondary refusal to informed consent (n = 1, 0.9%). Fourteen (12.7%) patients died during follow-up, 6 (11.1%) in the steroid group and 8 (14.3%) in the placebo group (p = 0.617, chi-square). At month 6, 46 patients were still in the steroid and the placebo group. Eight patients were withdrawn from the steroid group and 10 patients were withdrawn from the placebo group during the first 6 months. At month 12, 35 patients were still in the steroid group and 36 patients were still in the placebo group. Eleven patients were withdrawn from the steroid group and 10 patients were withdrawn from the placebo group during month 6 until month 12. Tables 1–4 include all patients that were randomized to the trial. Tables 5–8 include only those patients that were still in the trial as mentioned above. Only one patient had to undergo retransplantation for primary nonfunction in the placebo group but died later on. Figure 2 shows the Kaplan-Meier estimation of patient survival in both groups. All initially randomized patients were included in the Kaplan-Meier analysis. The causes of death are summarized in Table 2. Table 2. Causes of death in steroid and placebo group include the whole follow-up during 1 year Steroid group (n = 54) Placebo group (n = 56) P value Total 6 8 0.617 Infection 4 3 n.s. Tumor 1 1 n.s. Rejection 1 0 n.s. Primary nonfunction 0 1 n.s. Respiratory failure 0 2 n.s. PTLD 0 1 n.s. Table 3. Severe adverse events during the whole follow-up during 1 year Steroid group (n = 54) Placebo group (n = 56) p value Total 5 5 0.952 Neurological side effects of FK 506 3 3 n.s. Kidney function abnormal 2 1 n.s. Liver function abnormal 0 1 n.s. Table 4. Summary of acute and chronic rejection for the 1-year study period, all patients Steroid group (n = 54) Placebo group (n = 56) p value Biopsy proven acute rejection Overall 19 (35.2%) 27 (48.2%) 0.166 Recurrent 5 (9.3%) 7 (12.5%) 0.586 Steroidresistant 0 1 (0.9%) 0.509 Histological grade Mild (RAI I) 5 (10.9%) 9 (19.6%) n.s. Moderate (RAI II) 13 (28.3%) 16 (34.8%) n.s. Severe (RAI III) 1 (0.9%) 2 (1.8%) n.s. Biopsy proven chronic rejection Overall 0 2 (1.8%) 0.257 Table 5. Tacrolimus dosage and trough levels during the trial, steroid and placebo group at different time points Steroid group Placebo group p value FK506 whole blood trough levels, (ng/mL), mean ± SD Day 14 8.6 ± 3.3 8.8 ± 3.1 0.794 Month 6 9.6 ± 2.3 8.5 ± 3.7 0.171 Month 12 7.7 ± 3.2 7.5 ± 3.5 0.885 Daily FK506 dose, (mg), mean ± SD Day 14 8.8 ± 4.1 8.4 ± 4.4 0.376 Month 6 7.2 ± 3.7 5.6 ± 2.5 0.107 Month 12 5.4 ± 2.7 4.7 ± 1.7 0.333 Creatinin (mg/dL), mean ± SD Day 14 1.26 ± 0.79 1.41 ± 1.09 0.405 Table 6. Glucose metabolism and post-transplant diabetes mellitus (PTDM) in steroid and placebo group Fasting blood glucose levels Steroid group Mg/dL Means ± SD Placebo group mg/dL Means ± SD p value Pre-OLT 125 ± 53 125 ± 52 0.985 Month 6 130 ± 69 112 ± 45 0.225 Month 12 100 ± 21 101 ± 28 0.919 p month 6 vs. month 12 > ASTS Members >> FiguresReferencesRelatedInformation