Symptomatic Hepatocellular Liver Injury With Hyperbilirubinemia in Two Patients Treated With Rivaroxaban

Abstract

IMPORTANCE Treatment with the new oral anticoagulant rivaroxaban can be associated with severe liver injury. OBSERVATIONS We report 2 patients with predominantly hepatocellular liver injury that had onset during treatment with rivaroxaban. Both were symptomatic, had massively elevated transaminase activity levels and hyperbilirubinemia, and fulfilled the criteria of Hy's law. Liver biopsy in 1 patient revealed centroacinar hepatocyte necrosis as the predominant finding. Both patients showed a rapid biochemical and clinical recovery after discontinuing rivaroxaban therapy. Between 2008 and 2013, 42 cases of liver injury possibly associated with rivaroxaban treatment have been reported to the Swiss Agency of Therapeutic Products (Swissmedic). Thirteen of these patients fulfilled the criteria of Hy's law. CONCLUSIONS AND RELEVANCE Treatment with rivaroxaban can be associated with severe, symptomatic liver injury. Physicians should be aware of this adverse drug reaction. We propose rapid discontinuation of treatment with rivaroxaban in case of symptomatic liver injury and, taking into account its severity, avoiding reexposure.

Hepatotoxicity of New Oral Anticoagulants (NOACs)

“…On the other hand, exposure-dependent hepatotoxicity was a clearly identified preclinical finding in several animal species, suggesting non-allergic toxicity. Non-allergic idiosyncratic toxicity is compatible with the fourth liver biopsy finding, showing centroacinar necrosis [32]. Centrocainar necrosis is compatible with the formation of toxic metabolites, since CYPs are located in this area [38].…”

“…In comparison, N-dealkylated metabolites of amiodarone show a more accentuated hepatotoxicity than the parent substance [41,42]. Although the patient described by Liakoni et al [32] had no concomitant drugs inducing CYP3A4, the variability of CYP3A4 activity is so large in the population that also non-induced patients may show this type of hepatotoxicity.…”

“…This patient had eosinophilia, skin eruptions and impaired renal function, compatible with a DRESS syndrome. The fourth biopsy showed centroacinar confluent necrosis with only a mild lymphocytic portal infiltration [32].…”

“…The search was performed on May 23, 2015, and yielded 45 references, which were checked manually for relevance. Seven references [29][30][31][32][33][34][35] were considered to be relevant concerning postmarketing liver injury data.…”

“…In a second case report, again from Switzerland, two patients with liver injury associated with rivaroxaban were described [32]. Both patients, a 52-year-old man and a 73-year-old woman, were treated with 10 mg of rivaroxaban after leg surgery and knee joint replacement, respectively.…”