Rivaroxaban postmarketing risk of liver injury

Abstract

BACKGROUND: Rivaroxaban 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. METHODS: Report of 14 cases of liver injury associated with rivaroxaban, including two with liver biopsy, and search queries in three large international pharmacovigilance databases for comparable cases. RESULTS: Formal causality assessment classified rivaroxaban as the "highly probable", "probable" and "possible" cause in 4, 7 and 3 patients, respectively. Search results from three large international pharmacovigilance databases revealed a considerable number of additional hepatic adverse events where rivaroxaban was reported as a suspected cause. CONCLUSIONS: We interpret the presented information as a relevant safety signal that should be followed by pharmacoepidemiological studies in order to reliably estimate absolute and relative risks of liver injury associated with rivaroxaban in support of rational risk-benefit assessment. Meanwhile, incident symptoms and signs of liver disease in patients treated with rivaroxaban should be considered as a potential adverse drug reaction, and if no other likely cause can be identified rivaroxaban should be stopped as soon as possible. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Hepatotoxicity of New Oral Anticoagulants (NOACs)

“…The findings in the report of Russmann et al [35] with a dominant portal lymphocytic and eosinophil infiltrate were compatible with an allergic reaction. This is supported by the findings of Barrett et al [29], who diagnosed a DRESS syndrome in their patient, which is considered as an HLAassociated cellular hypersensitivity reaction [36,37].…”

“…Four liver biopsies from four patients with liver injury associated with rivaroxaban have so far been reported. In two biopsies, centroacinar cholestasis in combination with bile duct injury and lymphocytic and eosinophilic portal infiltrates were the main findings [35]. In a third biopsy, focal non-zonal areas of hepatocyte necrosis and mild portal infiltrates with sporadic eosinophil granulocytes were the main findings [29].…”

“…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 first publication, 14 patients with rivaroxaban-associated liver injury that had been reported to a regional Pharmacovigilance Center in Switzerland were described [35]. The patients had a median age of 71 years (range 41-91 years), nine were female and five male.…”

Reply

“…Recently, several cases of probable rivaroxaban-induced liver injury have been reported with elevation of serum transaminases and bilirubin concentration; the majority recovered after rivaroxaban discontinuation. 5 Theoretically, there is an increased risk of bleeding in patients with impaired hepatic synthetic function. Finally, selftesting of international normalized ratio is feasible, well accepted, and cost-effective.…”