Use Of Steroids After Liver Transplantation Is Associated With Lower Risk Of Early Graft Failure

Transcription

1 Use Of Steroids After Liver Transplantation Is Associated With Lower Risk Of Early Graft Failure Insights From The Liver Match Prospective Study M. Angelico, T. Marianelli, U. Cillo, A. Nardi, R. Romagnoli, A. Ricci, P. Toniutto, M. Strazzabosco, on behalf of Liver Match investigators* Rome, Italy Study coordinators: AISF & CNT governing boards Study investigators: Directors of Italian Liver Transplant Centers and AISF fellowship recipients

2 Steroids and Liver transplantation A highly controversial area Steroids are commonly used perioperatively and after liver transplantation, yet there is a growing controversy on whether they t are useful, really needed, or even detrimental Traditionally, steroids are given at high doses at time of transplant, and then maintained at lower doses and slowly tapered within weeks ks- to-months Several retrospective studies have contributed to the current controversy, and only limited prospective data are available. Most of these are small sized RCTs from single centers, which have investigated the short-term term safety of early steroid withdrawal or, in few cases, complete steroid-free protocols

3 Steroids and Liver Transplantation A highly controversial area Steroid use after transplantation has been associated with diabetes, hypertension, hyperlipidemia, obesity, and rapidity of HCV recurrence. rence. Most steroid-free studies have suggested that steroid avoidance is associated with improvement of all these features Two recent meta-analyses analyses have explored this issue Segev DL et al.. Steroid avoidance in liver transplantation: meta-analysis analysis and meta-regression of randomized trials. Liver Transplantation 2008; 14: Gourakis G et al.. Corticosteroid-free immunosuppression in liver transplantation: a meta-analysis analysis and meta-regression of outcomes. Transplant International 2009;22:

4 Segev et al Liver Transplantation 2008;14: articles reporting RCT on steroid avoidance included No differences in terms of death and graft loss (RR 0.95 for steroid free groups) A trend toward reduced hypertension in steroid-free arms Significantly reduced CMV infection, HCV-recurrence and serum cholesterol in steroid-free groups

5 Meta-analysis analysis conclusion Segev et al, Liver Transplantation 2008;14: No short term detrimental effects of steroid avoidance However, available studies are very heterogeneous, the follow up is too short, and studies are small sized sized A large multicenter study is needed to clarify this matter Study Aims: To investigate this issue within the Liver Match Study, a large size multicenter study currently underway in Italy

6 Methodology & Structure of the study (1) Liver Match is a joint project sponsored by the Italian Association for the Study of the Liver (AISF) and the National Transplant Center (CNT) Designed in late 2006 primarily to investigate the impact of donor-recipient recipient matching on short- and long-term liver transplant outcomes, providing prospectively generated and evidence based data with the intent to optimize organ allocation in the Country Liver Match is a multicenter, nationwide, observational cohort study including all consecutive transplant perfomed at 20 Italian Liver Transplant Centers

7 Liver Match Coordinating Group: M. Angelico (coordinator) AISF:: U.Cillo, S.Fagiuoli, A.Gasbarrini, D.Prati, M.Strazzabosco CNT:: A. Nanni Costa, P. Burra Partecipating Centers & investigators: Torino (M. Salizzoni, R. Romagnoli, G. Bertolotti, D.Patrono) Milano Niguarda (L. De Carolis, J.M.E. Mangoni) Milano Policlinico (L. Caccamo, B. Antonelli) Milano Milano Tumori (V. Mazzaferro, E. Regalia, C. Sposito) Bergamo (M. Colledan, V. Corno, F. Tagliabue, S. Marin) Padova (U. Cillo, E. Gringeri) Verona (Donataccio, D. Donataccio) Udine Udine (F. Bresadola, D. Lorenzin) Genova (U. Valente, M. Gelli) Modena (G.E. Gerunda, G. Rompianesi) Bologna (A. Pinna, G.L. Grazi, A. Cucchetti) Ancona (A. Risaliti, M. G. Faraci), Roma Tor Vergata (G. Tisone, D. Sforza) Roma Gemelli (S. Agnes, M. Di Mugno) Roma POIT (G.M. Ettorre, L. Migloresi) Roma Roma Sapienza (M. Rossi, S. Ginanni Corradini, A. Molinaro) Napoli (F. Calise, V. Scuderi, O. Cuomo, G. Arenga) Bari (L. Lupo, G. Notarnicola) Palermo (B. Gridelli, S. Li Petri) Cagliari (F. Zamboni, G. Carbotta, S. Dedola) CNT Data Collection and Verification & Biostatistics T. Marianelli, A. Nardi, C. Gavrila, A. Ricci, F. Vespasiano

8 *Dati preliminari al 30 novembre 2009 Liver Transplants in Italy 1992/2009* Incluse Incluse tutte tutte le le combinazioni combinazioni Liver Match recruitment FONTE DATI: Dati Reports CIR

9 Methodology & Structure of the study (2) Study strengths Nationwide involvement Prospective methodology Observational nature Includes heterogenous approaches and management in surgical and post-operative care The data set of the current Interim Report includes 1094 consecutive non urgent adult transplants performed from June 1, 2007 to December 31, 2008, all with a follow-up >90 days (median f.u. 357 days): 849 (77.6%) patients who received steroids 245 (22.4%) patients who did not receive steroids

10 How were steroids used? The schedules of steroid use differed from Center to Center When steroids were used, a single intraoperative bolus of 1 g of prednisone was generally given (eventually mg in patients with HCV/HBV infection) Prednisone was then continued, usually at a dose of 20 mg/day,, and tapered in most cases within 90 to 180 days When initial steroid maintainance therapy was used, this was always associated with an intraoperative (induction) bolus of prednisone

11 Percent use of steroids in relation to indication for liver transplantation 100 % of patients Chi-Square: p= HCV cirrhosis HBV cirrhosis Alcoholic cirrhosis Other cirrhoses NonHCC MELD exceptions

12 Characteristics of 1094 Donors vs use of Steroids Characteristics YES Steroids (n= 849) NO Steroids (n= 245) Mean (SD) or n Median or % Mean (SD) or n Median or % p-value Wilcoxon or Chi sq. Age (years( years) 53.7 (18.8) (18.4) Male sex Death for trauma BMI 25.2 (3.6) BSA (m( 2 ) 1.84 (0.2) Sodium (9.5) Split Cold ischemia 447 (128) Cold ischemia time 600 mins % % Macrosteatosis 6.9 (10.5) Macrosteatosis % % n.s. DRI 1.61 (0.38) DRI > % %

13 Characteristics of 1094 Recipients vs use of Steroids Characteristics YES Steroids (n=849) Mean (SD) or n Median (or %) NO Steroids (n=245) Mean (SD) or n Median or % p-value Wilcoxon or Chi sq Age (years( years) 52.8 (9.5) (9.6) Male sex % % Diabetes (insulin-treated) % % Weight (kg( kg) 72.8 (13.6) (13.4) Height (cm( cm) 170 (9) (10) BMI 25.1 (3.8) (3.4) BSA (m( 2 ) 1.85 (0.2) (0.18) MELD 16.7 (7.8) (7.7) Sodium 137 (5) (5) Creatinine 1.2 (1) (0.6) Bilirubin 6.1 (9) (8.7) INR 1.56 (0.58) (0.42)

14 Methods (3) Early Graft Loss (EGL) Early Graft Loss was defined as death or retransplantation within 90 days from the first transplant A total of 109 (9.5%) Early Graft Losses occurred 29 (26.6%) within day 7 41 (37.6%) from day 8 to day (35.8%) from day 31 to day 90 Predictors of EGL were investigated by univariate and by logistic regression analyses Kaplan Meier method was also used to estimate graft survival curves

15 Percent Early Graft Loss in relation to indication for liver transplantation 20 % of patients Chi-Square: p= HCV cirrhosis HBV cirrhosis Alcoholic cirrhosis Other cirrhoses NonHCC MELD exceptions

16 Characteristics of Donors vs Early Graft Loss Characteristics With Early Graft Loss (n= 109) Mean (SD) or n Median or % Without Early Graft Loss (n= 985) Mean (SD) or n Median or % p-value (Wilcoxon or Chi-sq) Age (years( years) 55.1 (19.2) (18.4) Male sex 56% 57% Death for trauma 25.6% 26.9% BMI 26.1 (4.1) (3.6) Sodium 150 (10.8) (9.7) Split 7 6.4% % Cold ischemia 459 (130) (123) Cold ischemia time 600 mins Macrosteatosis (n=795) 11% 11.4% 9.5% 6.7% Macrosteatosis % % n.s. DRI 1.69 (0.40) (0.37) DRI > % 41.8%

17 Characteristics of Recipients vs Early Graft Loss Characteristics With Early Graft Loss (n=109) Mean (SD) or n Median (or %) Without Early Graft Loss (n=985) Mean (SD) or n Median or % p-value (Wilcoxon or Chi-sq) Age (years( years) 53.7 (10.9) (9.3) Male sex 77.9% 81.2% Diabetes (insulin- treated) 18.4% 15.6% Weight (kg( kg) 73.1 (16.4) (13.2) Height (cm( cm) 168 (13) (8) BMI 24.9 (3.4) (3.8) MELD 19.3 (8.5) (7.5) Sodium 137 (5) (5) Creatinine 1.31 (1) (0.9) Bilirubin 8.2 (10.4) (9.4) INR 1.67 (0.73) (0.52) Use of steroids % % <

18 Early Graft Loss in relation to Time after Number of patients transplant and use of Steroids 17 NO Steroids, n=245 YES Steroids, n= :07 <8 days 7 30 days days 0 90 days 8

19 Early Graft Loss in relation to Time after transplant and use of Steroids Number of patients NO Steroids, n=245 YES Steroids, n=849 P<0.001 % of patients 16.8% 8% 0 <8 days 8 30 days days 0 90 days

20 Logistic Regression Analysis Odds Ratio Estimates for Early Graft Loss (including 1023 transplants with complete records) VARIABLE Odds ratio 95% c.l. P-value MELD (bioch( bioch) ) at transplant HCV-cirrhosis vs HBV- cirrhosis Non viral-cirrhosis vs HBV- cirrhosis Alcoholic-cirrhosis cirrhosis vs HBV- cirrhosis Non-HCC exceptions vs HBV Cirrhosis Donor Age Donor sodium Steroid use <0.0001

21 Logistic Regression Analysis Odds Ratio Estimates for Early Graft Loss (limited to 725 transplants with available histological data) VARIABLE Odds ratio 95% c.l. P-value MELD (bioch( bioch) ) at transplant HCV-cirrhosis vs HBV-cirrhosis Non viral-cirrhosis vs HBV- cirrhosis Alcoholic-cirrhosis cirrhosis vs HBV- cirrhosis Non-HCC exceptions vs HBV cirrhosis Macrovesicular steatosis Donor sodium Steroid use <0.0001

22 Graft Survival and Steroid Use Kaplan-Meier estimates vs recipient MELD MELD Log rank: n.s MELD Log rank: n.s

23 Graft Survival and Steroid Use Kaplan-Meier estimates vs recipient MELD MELD MELD >20 Log rank: p = MELD 16-20

24 Graft Survival and Steroid Use Kaplan-Meier estimates vs recipient etiology HBV cirrhosis Log rank: n.s HCV cirrhosis Log rank: n.s

25 Graft Survival and Steroid Use Kaplan-Meier estimates vs recipient etiology HBV cirrhosis Alcoholic cirrhosis Log rank: p = HCV cirrhosis

26 Conclusions Patients receiving steroids early after liver transplantation have a lower risk of developing Early Graft Loss compared to those who are not given steroids This advantage continues to be significant after adjusting for a variety of donor, recipient and perioperative related related confounders, as evidenced by logistic regression analysis The lower risk of Early Graft Loss associated with the use of steroids is greater in recipients with more severe liver disease and in those transplanted for alcoholic cirrhosis Whether this favourable effect of steroids reflects the correction of an adrenal insufficiency coexisting with these conditions remains to be established