causality assessment in drug induced liver injury - AASLD

Note - presentation notes may be read by double clicking on the icon to the leftGlobalProduct PatientSafetyLiver Transplantation forDrug Induced Acute Liver Failure in the USAn UpdateArie Regev, M.D.Global Patient SafetyEli Lilly and Company

DILI and Acute Liver Failure (ALF)• DILI is the leading cause of ALF in the US 1 and EU 2• Exceeds all other ALF causes combined• Liver transplant is the ultimate treatment for DIALF• The United Network for Organ Sharing (UNOS) databasecontains data on LT performed in the US since 19871. Lee WM, et al. Hepatology 2008;47:1401-14152. Larrey D, Pageaux GP. Eur J Gastroenterol Hepatol 2005;17:141-143.3.

Outcome of Liver Transplantation for Drug Induced Acute LiverFailure in the United States. Analysis of the United Network forOrgan Sharing Database.Ayse L. Mindikoglu, M.D., M.P.H. 1 , Laurence S. Magder, Ph.D., M.P.H. 2and Arie Regev, M.D. 3From the 1 Department of Medicine, Division of Gastroenterology and Hepatology,University of Maryland School of Medicine, Baltimore, MD;2Department of Epidemiology and Preventive Medicine, Division of Biostatistics andBioinformatics, University of Maryland School of Medicine, Baltimore, MDand 3 Global Patient Safety, Eli-Lilly & Company, Indianapolis, IN

Company ConfidentialCopyright© 2007 Eli Lilly and Company

Objectives Identify patterns and demographics of DIALF requiring LT‣ Predisposed groups‣ Risk factors‣ Typical presentation Identify drug groups associated with DIALF and LT Identify leading drugs associated with DIALF and LT Determine survival rates after LT for DIALF

Methods Retrospective cohort study UNOS database from Oct 1987 through Dec 2006 Patients with diagnosis other than DIALF were excluded Collected for each patient:‣ 21 recipient variables‣ 6 donor variable Age, gender, ethnicity, life support, dialysis, serum total bilirubin,serum creatinine, serum albumin, serum ALT, PT-INR, cold ischemiatime, warm ischemia time, multiorgan transplant, days on the liver waitinglist, transplant region, ABO blood type, hepatitis B surface antigen(HBsAg), hepatitis C virus antibody (HCVAb), number of transplants, etc.

Results A total of 73,977 liver transplantations performed in the USbetween October 01, 1987 and Dec 31, 2006 (19 years)(Russo et al:51,741) 661 patients diagnosed as DIALF (Russo et al: 357)‣ 567 adults‣ 94 pediatric (

Drug groups among DIALF patientsundergoing liver transplant

Drug Group (Total) Drug PatientsTotal 661Acetaminophen 265Anti-TB 50INH alone 48INH & another anti-TB 2Antiepileptic 46Phenytoin 20Valproic acid 20Carbamazepine 3Other antiepileptics 3Antibiotics 39Nitrofurantoin 12Ketoconazole 8Amoxicillin and clavulanate 5Trimethoprim-sulfamethoxazole 5Other antibiotics 9

Drug Group (Peds.) Drug PatientsTotal 94Acetaminophen 27Antiepileptic 22Valproic acid 16Phenytoin 3Other antiepileptics 3Anti-TB INH 8Propylthiouracil 6

ALF Due to Non-APAP Drugs Total number of ALF cases due to non-APAP drugs- 396 4 drugs were implicated in 28% of the non-APAP‣ Isoniazid (13%)‣ Phenytoin (5%)‣ Valproic acid (5%)‣ Propylthiouracil (5%) Statins were implicated in 12 cases (3%) Herbals were implicated in 6 cases

Patient DemographicsAPAP Anti-TB Antiepliptics Antibiotics P valuePatients (%) 265 (40) 50 (8) 46 (7) 39 (6)Age (SD) 31 (12) 38 (18) 21 (18) 43 (14)

Pre-transplant liver testsAPAP Anti-TB Antiepliptics Antibiotics P valueALT (IU/L)TBIL (mg/dL)PT-INRCreatinine(mg/dL)Albumin(mg/dL)3,777 341 1,027 1,235

Proportion of patients requiring dialysispre-transplantAnti TBAntibiotics

Patients requiring life supportpre-transplant

Post liver transplant mortalityRecipient VariablesHazardRatioPValueDrugGroupsAntituberculosis vsAcetaminophen0.8610.585Antiepileptics vsAcetaminophenAntiepilepticsAmong those age > 181.0280.938Among those age < 184.127

Post-transplant survival10080ACETAMINOPHENANTITUBERCULOSIS DRUGSANTIEPILEPTIC DRUGSOTHER DRUGSSURVIVAL (%)604020001 2 3 4 5 6 7YEARS AFTER LIVER TRANSPLANTATION8

Independent predictors ofpost-transplant survivalPretransplantPrognostic FactorLife Support atTransplantAntiepileptic at age

Conclusions (I) A total of 661 people underwent liver transplantation in the USdue to DIALF between 1987 and 2006. 75 drugs were associated with DIALF leading to LT. The leading drug groups associated with DIALF and LT wereAPAP, anti-TB, antiepileptics and antibiotics. The leading non-APAP drugs were INH, phenytoin, valproate,and propylthiouracil DIALF leading to LT occurred at a higher frequency in womenregardless of drug group.

Conclusions (II) African Americans had a significantly higher proportion ofALF due to non-APAP drugs compared to Caucasians. Patients transplanted for APAP-related ALF presented withsignificantly higher ALT levels and required dialysis at asignificantly higher rate compared to all other drugs Patients who had ALF due to antiepileptics had a significantlyhigher risk of death after LT compared to other drugs ALF due to antiepileptics was an independent predictors ofpoor survival after LT for DIALF.