Hepatotoxicity of New Oral Anticoagulants (NOACs)

Abstract

Case reports and analyses of clinical studies and of pharmacovigilance data suggest that new oral anticoagulants (NOACs) are associated with a small risk for hepatotoxicity. The objective of this publication is to summarize the current data about this subject, with a special emphasis on pharmacovigilance data in the World Health Organization (WHO) Global Individual Case Safety Reports (ICSR) database and on potential mechanisms of hepatotoxicity. For that, all available case reports as well as published analyses of clinical studies were obtained with a detailed search in PubMed. In addition, pharmacovigilance data from VigiBase(®), the WHO Global ICRS database, were extracted and analyzed. The data show that liver injury associated with NOACs was reported in clinical studies and in pharmacovigilance databases. Several case reports described potentially life-threatening hepatotoxicity in patients treated with rivaroxaban or dabigatran. For rivaroxaban, most affected patients were symptomatic and liver injury was most often hepatocellular or mixed. The frequency was between 0.1 and 1 % in clinical studies and was by trend lower than for comparators (mostly enoxaparin or warfarin). Comparing the pharmacovigilance reports for the individual NOACs, more hepatic adverse events were reported for rivaroxaban than for dabigatran or apixaban. With the exception of edoxaban, for which only few reports are available, patients with acute liver failure have been reported for every NOAC, but most patients had concomitant drugs or diseases. So far, there are no clear mechanisms explaining the hepatotoxicity of these drugs. We conclude that hepatotoxicity appears to be associated with all NOACs currently on the market. Hepatotoxicity associated with NOACs is idiosyncratic; it appears at therapeutic doses, is rare and the mechanism is not related to the pharmacological action of these drugs. Prescribers should inform patients about possible symptoms of hepatotoxicity and stop these drugs in patients presenting with severe liver injury.

Risk–Benefit Profile of Direct-Acting Oral Anticoagulants in Established Therapeutic Indications: An Overview of Systematic Reviews and Observational Studies

“…within the first month) may be considered, at least in patients under complex treatment regimens with comorbidities; subsequently, liver function can be monitored on a yearly basis [80]. Therefore, vigilance should be maintained by both clinicians, pharmacovigilance experts and patients, who should timely communicate early clinical signs/symptoms, consider on a case-by-case basis the role of DOACs as well as concomitant therapies, and report suspect cases to the national pharmacovigilance services [99]. …”

“…The use of DOACs in patients with renal impairment is also debated (they are all excreted via the kidney, at least partially) and insufficiently investigated. The 2015 EHRA practical guide suggested a 3-month interval monitoring of renal function, using the Cockcroft–Gault method, in elderly patients [82]Other safety issues beyond bleeding complicationsWhile, for coronary risk, recent data, including observational studies, are partially reassuring [104], evidence on the risk of liver injury is accruing (case series and disproportionality analysis) [98, 99]. With regard to renal injury, fewer data exist; a meta-analysis of ten RCTs found no differences in the risk of renal failure (compared with VKAs), although rivaroxaban showed a trend for increased risk and an increased risk of creatinine elevation (RR 1.25, 95 % CI 1.08–1.45; I 2  = 0 %) [25]The impact of polypharmacy and drug–drug interactionsPost-analyses of ROCKET-AF (rivaroxaban) and ARISTOTLE (apixaban) revealed that two-thirds and three-quarters of patients had polypharmacy, respectively.…”

Apixaban-induced liver injury

“…However, case reports, pharmacovigilance data and patient series reveal hepatotoxicity associated with DOACs in patients with normal and impaired liver function 2 8 10 11. Of all available DOACs, apixaban is less frequently associated with hepatotoxicity 12 13. However, other DOACs such as rivaroxaban and dabigatran have been available on the market longer than apixaban, making this statement vulnerable to bias 12.…”

“…Of all available DOACs, apixaban is less frequently associated with hepatotoxicity 12 13. However, other DOACs such as rivaroxaban and dabigatran have been available on the market longer than apixaban, making this statement vulnerable to bias 12. Apixaban-induced hepatotoxicity resulting in permanent severe liver injury is rare, but it has been reported 8.…”

Adverse events associated with the use of direct-acting oral anticoagulants in clinical practice: beyond bleeding complications

“…However, data from large international SRSs highlighted that rivaroxaban is reported to cause liver damage in 3.7% to 3.9% of total reports, whereas 1.7% to 1.8% of cases submitted for dabigatran mentioned potential liver injury. 48,49 Rivaroxaban is identified as the suspect drug in all but one DILI reports published so far: most patients are characterized by hyperbilirubinemia with hepatocellular or mixed liver injury pattern, usually recovered…”