Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis

Caldeira, Daniel; Barra, Márcio; Santos, A.; Abreu, Daisy; Pinto, Fausto J.; Ferreira, Joaquim J.; Costa, João

doi:10.1136/heartjnl-2013-305288

Cited by 96 publications

(73 citation statements)

References 48 publications

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“…As expected, the meta-analytic approach by Caldeira et al, 52 did not highlight an increased risk, although a trend towards statistical significance emerged for rivaroxaban. 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.…”

Section: -53supporting

confidence: 54%

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

Raschi¹,

Bianchin²,

Ageno³

et al. 2016

Polish Archives of Internal Medicine

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Non-vitamin K oral anticoagulants, also known as direct-acting oral anticoagulants (DOACs), have entered the market in 2008 with the expected breakthrough potential of circumventing limitations related to treatment with vitamin K antagonists (eg, warfarin) by virtue of their pharmacological properties. Although data derived from premarketing randomized clinical trials have largely demonstrated the clinical benefit of DOACs, especially in terms of reduced risk of intracranial bleeding, it is important to monitor the safety in the postmarketing phase, which better reflects real-world patients with comorbidities and polypharmacotherapy, in order to assess the actual risk-benefit profile. In this critical review, we aimed to evaluate the evidence on the latest debated safety issues. In the first section, we will discuss: 1) the need for pharmacovigilance (ie, the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems in the real-world setting), and 2) the importance of properly interpreting postmarketing data to avoid unnecessary alarm. In the second section, emerging and debated safety issues potentially associated with the use of DOACs in the postmarketing setting will be assessed: 1) the potential coronary risk (which emerged during the preapproval period); 2) the occurrence of liver injury (a risk undetected in clinical trials and highlighted by case reports or series); and 3) the potential for renal damage (a still unclear safety issue). It is anticipated that hepatic and renal issues still require dedicated postauthorization safety studies to ultimately assess causality.

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Section: -53supporting

confidence: 54%

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

Raschi¹,

Bianchin²,

Ageno³

et al. 2016

Polish Archives of Internal Medicine

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“…There were a large number of cases with ALT elevations >3x ULN including many with concomitant total bilirubin >2x ULN subsequent to the use of those drugs. At the same time there were no evident risk differences between the individual studied new oral anticoagulants, and a lower risk of such events when compared to low molecular weight heparins [9]. However, safety analyses of clinical trials' data have intrinsic limitations.…”

Section: Discussionmentioning

confidence: 99%

Rivaroxaban postmarketing risk of liver injury

Russmann

Niedrig

Budmiger

et al. 2014

Journal of Hepatology

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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.

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“…In contrast to VKAs, NOACs have a lower risk of major bleeding events such as intracranial hemorrhage [4], a faster onset of action, a predictable dose-response relationship, and does not require frequent anticoagulation intensity evaluation, similar to INR testing in patients treated with VKA [5]. Different from ximelagatran (an oral anti-IIa inhibitor withdrawn due to the high risk of liver injury), recent NOACs did not show increased risk of drug-induced liver injury [6].…”

Section: Introductionmentioning

confidence: 99%

Non-vitamin K antagonist oral anticoagulants in the cardioversion of patients with atrial fibrillation: systematic review and meta-analysis

et al. 2015

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Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis

Abstract: NOACs are not associated with an increased risk of DILI. The unexpected 'protective' effect of NOAC is probably due to LMWH-associated hepatotoxicity.

Cited by 96 publications

References 48 publications

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

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

Rivaroxaban postmarketing risk of liver injury

Non-vitamin K antagonist oral anticoagulants in the cardioversion of patients with atrial fibrillation: systematic review and meta-analysis

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