New oral anticoagulants (NOAC) and liver injury
Authors: Nicholas Moore, Patrick Blin, Sinem-Ezgi Gulmez
Journal: Journal of Hepatology (2014)

Rivaroxaban postmarketing risk of liver injuryJournal of HepatologyVol. 61Issue 2PreviewRivaroxaban is an oral direct factor Xa inhibitor that has been marketed worldwide since 2008 for the primary and secondary prevention and treatment of thromboembolic disorders. Although liver injury was observed in premarketing trials of rivaroxaban, there are no published postmarketing cases of liver injury associated with rivaroxaban. Full-Text PDF Russmann et al. describe spontaneous reports of drug-induced liver injury after rivaroxaban to the Swiss pharmacovigilance system [[1]Russmann S. Niedrig D.F. Budmiger M. Schmidt C. Stieger B. Hurlimann S. et al.Rivaroxaban postmarketing risk of liver injury.J Hepatol. 2014; 61: 293-300Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. They also found a similar signal in large spontaneous report databases (EMA, USFDA, WHO UMC monitoring centre). The causality of rivaroxaban in these cases is plausible, and rivaroxaban may indeed be associated with liver injury, as most drugs are. However caution may be warranted in the interpretation of these findings, and especially before any firm conclusions are drawn or actions suggested. Ten of the fourteen reported cases occurred after surgery, mostly total knee replacement, which involves anaesthetics and other drugs that may be hepatotoxic. Surgery itself may result in hepatic injury through transient low output syndrome in these often elderly patients. Most would also receive analgesics such as NSAIDs, even if this would be unlikely because of the use of anticoagulants, or paracetamol with or without opiates. Paracetamol may also be hepatotoxic even at "normal" doses [[2]Gulmez S.E. Larrey D. Pageaux G.P. Lignot S. Lassalle R. Jove J. et al.Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study.Drug Saf. 2013; 36: 135-144Crossref PubMed Scopus (81) Google Scholar]. This does not seem to have been mentioned in the case descriptions. In the cases that occurred in patients using the anticoagulant for atrial fibrillation (AF) there is no anaesthetic or analgesic risk but AF can cause episodes of low cardiac output that may also be injurious, and other hepatotoxic drugs such as amiodarone are often used. Therefore, considering the drug and the medical environment, one is not surprised at finding cases of hepatic injury in such patients. Causality may point to rivaroxaban as the more suspect drug, but causality assessment, even for hepatic-specific methods such as RUCAM [[3]Lewis J.H. Larrey D. Olsson R. Lee W.M. Frison L. Keisu M. Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran.Int J Clin Pharmacol Ther. 2008; 46: 327-339Crossref PubMed Scopus (21) Google Scholar], is only as trustworthy as the data used, and the lack of description of anaesthetic procedures, or analgesic or other drugs is a little worrisome [[4]Gulmez S.E. Moore N. Pageaux G.P. Lignot S. Horsmans Y. Stricker B. et al.Causality of drugs involved in acute liver failure leading to transplantation: results from the Study of Acute Liver Transplant (SALT).Drug Saf. 2014; 37Google Scholar]. Looking at other reporting databases is useful to support a signal. However, the WHO UMC database includes information from other databases, since it simply compiles data sent by individual countries. As such it is a secondary database, not a primary one. It would duplicate Eudravigilance data, and the FDA data. The FDA database itself includes cases occurring within the US, and industry-reported cases from outside the US: these may also be found in Eudravigilance, and in the WHO database. A very small number of cases may become an epidemic. These databases show that cases may exist, but the actual number of cases and their meaning are uncertain. Careful analysis of the individual cases might help identify duplicate reports in the different databases and give a clearer vision of real numbers of individual reports. However, it will certainly not provide actual event rates [[5]Moore N. Gulmez S.E. Larrey D. Pageaux G.P. Lignot S. Lassalle R. et al.Choice of the denominator in case population studies: event rates for registration for liver transplantation after exposure to NSAIDs in the SALT study in France.Pharmacoepidemiol Drug Saf. 2013; 22: 160-167Crossref PubMed Scopus (24) Google Scholar]. Even if the cases were to demonstrate the existence of hepatic injury associated with rivaroxaban, is this drug worse than the alternatives? There are reports of hepatic injury with warfarin and fluindione [[6]Ehrenforth S. Schenk J.F. Scharrer I. Liver damage induced by coumarin anticoagulants.Semin Thromb Hemost. 1999; 25: 79-83Crossref PubMed Scopus (35) Google Scholar]. Ximelagatran was stopped because of hepatic injury during clinical trials [[7]Keisu M. Andersson T.B. Drug-induced liver injury in humans: the case of ximelagatran.Handb Exp Pharmacol. 2010; : 407-418Crossref PubMed Scopus (123) Google Scholar]. There is as yet little or no post-marketing information on the other NOACs. A meta-analysis of clinical trials concerning NOACs and vitamin-K antagonists (VKA) found no difference between NOACs and VKA for hepatic problems [[8]Caldeira D. Barra M. Santos A.T. de Abreu D. Pinto F.J. Ferreira J.J. et al.Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis.Heart. 2014; 100: 550-556Crossref PubMed Scopus (85) Google Scholar]. Watkins et al. did not find an increased risk of liver injury compared to enoxaparin in another meta-analysis of clinical trials [[9]Watkins P.B. Desai M. Berkowitz S.D. Peters G. Horsmans Y. Larrey D. et al.Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery.Drug Saf. 2011; 34: 243-252Crossref PubMed Scopus (93) Google Scholar]. Several NOACs (rivaroxaban, apixaban, dabigatran, and others) have been recently or will be put on the market and are being carefully monitored for relative effectiveness and bleeding risk. Carefully designed pharmacoepidemiological studies may also be able to give a reasonable answer for a possible hepatotoxicity, differential or not. If confirmed, it will obviously also have to be put in balance with the other risks of these drugs, especially of intracranial bleeding. Unless the liver toxicity leads to transplantation [[2]Gulmez S.E. Larrey D. Pageaux G.P. Lignot S. Lassalle R. Jove J. et al.Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study.Drug Saf. 2013; 36: 135-144Crossref PubMed Scopus (81) Google Scholar], the liver usually recovers. The same can unfortunately not be said of the brain after stroke. Proactive safety monitoring is certainly warranted before any firm conclusion is drawn or regulatory action is taken. There may be a signal, and there may even be an alert. But is it really an alarm? The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.