title: Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system.
abstract: OBJECTIVE
  We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS).
  
  
  METHODS
  We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications.
  
  
  RESULTS
  DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively).
  
  
  CONCLUSIONS
  The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Raschi
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Poluzzi
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Ariola
authors.initials: A
authors.lastname: Koci
authors.affiliation: University of Bordeaux, U657, F33000, Bordeaux, France.|INSERM U657, F33000, Bordeaux, France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvo
authors.affiliation: University of Bordeaux, U657, F33000, Bordeaux, France.|INSERM U657, F33000, Bordeaux, France.|CIC Bordeaux CIC1401, F33000, Bordeaux, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Pariente
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Biselli
authors.affiliation: Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Moretti
authors.affiliation: University of Bordeaux, U657, F33000, Bordeaux, France.|INSERM U657, F33000, Bordeaux, France.|CIC Bordeaux CIC1401, F33000, Bordeaux, France.
authors.forename: Nicholas
authors.identifier: http://orcid.org/0000-0003-1212-2817
authors.initials: N
authors.lastname: Moore
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Ponti
mesh_terms: D000284:Administration, Oral; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology* / Q000209:etiology*; D016208:Databases, Factual; D006801:Humans; D011358:Product Surveillance, Postmarketing / Q000706:statistics & numerical data*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000925:Anticoagulants
keywords: FAERS; disproportionality; hepatotoxicity; liver injury; novel oral anticoagulants; spontaneous reporting system