IMR Press / RCM / Volume 23 / Issue 3 / DOI: 10.31083/j.rcm2303098
Open Access Original Research
Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) do not Increase the Risk of Hepatic Impairment in Patients with Non-Valvular Atrial Fibrillation: Insights from Multi-Source Medical Data
Zhi-Chun Gu1,2,†Jia Wang1,†Chi Zhang1,2Bin Zhao3,*Zhi-Ling Li4,*
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1 Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 200127 Shanghai, China
2 Shanghai Anticoagulation Pharmacist Alliance, Shanghai Pharmaceutical Association, 200040 Shanghai, China
3 Department of Pharmacy, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 100730 Beijing, China
4 Department of Pharmacy, Shanghai Children’s Hospital, Shanghai Jiao Tong University, 200062 Shanghai, China
*Correspondence: (Bin Zhao); (Zhi-Ling Li)
These authors contributed equally.
Academic Editors: Ichiro Wakabayashi and Klaus Groschner
Rev. Cardiovasc. Med. 2022, 23(3), 98;
Submitted: 26 January 2022 | Revised: 24 February 2022 | Accepted: 1 March 2022 | Published: 12 March 2022
(This article belongs to the Special Issue Risk Factors for Cardiovascular Diseases)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: There is controversy over whether non-vitamin K antagonist oral anticoagulants (NOACs) use increase the risk of hepatic impairment in patients with non-valvular atrial fibrillation (NVAF). We conducted a comprehensive assessment using multi-source medical data. Methods: We first performed a systematic search of the PubMed, Embase, and Cochrane Library databases (through 11 August 2021) for randomised controlled trials (RCTs) and real-world studies (RWSs) that reported hepatic impairment events in patients with NVAF administered NOACs or vitamin K antagonists (VKAs) therapy. The primary outcomes were hepatic impairment identified by diagnostic liver injury (DLI) or abnormal liver enzyme (ALE). The secondary outcome was hepatic failure. Relative risks (RRs) for RCTs and adjusted hazard ratios (aHRs) for RWSs were calculated separately using random-effects models. We also conducted a disproportionality analysis by extracting reports of hepatic impairment associated with NOACs from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Reporting odds ratios (RORs) were calculated to identify the statistical associations between NOACs and hepatic impairment. Scenario analyses were further performed to eliminate event- and drug-related competition bias. Results: A total of 559,873 patients from five RCTs and four RWSs were included in the pooled analysis. For RCTs, NOACs use was not associated with an increased risk of DLI (RR: 0.96, 95% confidence intervals (CI): 0.73–1.28) or ALE (RR: 0.91, 95% CI: 0.69–1.19) compared with VKAs. The merged results of RWSs also showed a similar risk of DLI (aHR: 0.88, 95% CI: 0.72–1.09) or ALE (aHR: 0.91, 95% CI: 0.82–1.00) between NOACs and VKAs. The results of hepatic failure were in accordance with the primacy outcomes. Analyses of individual NOACs did not significantly affect the results. Insights from the FAERS database failed to detect hepatic impairment signals for overall NOACs agents (ROR: 0.34, 95% CI: 0.32–0.37). Scenario analyses confirmed the primary results. Conclusions: Insights from multi-source medical data confirmed that NOACs use was not associated with an increased risk of hepatic impairment in patients with NVAF.

vitamin K antagonists
liver injury
drug adverse event
real-world data
Fig. 1.
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