Abstract
Apixaban, a direct oral anticoagulant, has emerged over the past few years because it is considered to have a low risk of drug‐drug interactions compared to vitamin K antagonists. To better characterize these interactions, we systematically reviewed studies evaluating the drug‐drug interactions involving apixaban and analyzed the drug‐drug interactions resulting in an adverse drug reaction reported in case reports and VigiBase. We systematically searched Medline, Embase, and Google Scholar up to 20 August 2018 for articles that investigated the occurrence of an adverse drug reaction due to a potential drug interacting with apixaban. Data from VigiBase came from case reports retrieved up to the 2 January 2018, where identification of potential interactions is performed in terms of two drugs, one adverse drug reaction triplet and potential signal detection using Omega, a three‐way measure of disproportionality. We identified 15 studies and 10 case reports. Studies showed significant variations in the area under the curve for apixaban and case reports highlighted an increased risk of hemorrhage or thromboembolic events due to a drug‐drug interaction. From VigiBase, a total of 1617 two drugs and one adverse drug reaction triplet were analyzed. The most reported triplet were apixaban—aspirin—gastrointestinal hemorrhage. Sixty‐seven percent of the drug‐drug interactions reported in VigiBase were not described or understood. In the remaining 34%, the majority were pharmacodynamic drug‐drug interactions. These data suggest that apixaban has significant potential for drug‐drug interactions, either with CYP3A/P‐gp modulators or with drugs that may impair hemostasis. The most described adverse drug reactions were adverse drug reactions related to hemorrhage or thrombosis, mostly through pharmacodynamic interactions. Pharmacokinetic drug‐drug interactions seem to be poorly detected.
Highlights
Direct oral anticoagulants (DOACs) act by direct inhibition of coagulation factor II or factor Xa,1,2 in contrast with heparin or vitamin K antagonists (VKAs)
There is evidence suggesting a lower mortality risk after suffering a major hemorrhage in patients under DOACs than in patients taking VKAs or LMWHVKAs,5,6 but DOACs are associated with a higher risk of gastrointestinal hemorrhage
We found that the proportion of PD drug-drug interactions (DDIs) was higher than the proportion of PK DDIs, suggesting that apixaban might be at higher-risk of interacting with drugs with the same pharmacological profile than with CYP3A4/P-gp inhibitors or inducers
Summary
Direct oral anticoagulants (DOACs) act by direct inhibition of coagulation factor II (thrombin) or factor Xa, in contrast with heparin or vitamin K antagonists (VKAs). DOACs have emerged over the past few years from the need for a new generation of oral anticoagulants with a more predictable and safer pharmacological profile and more suitable for long-term use They have become an alternative to VKAs, the only drugs available for long-term anticoagulation for decades. DOACs have several advantages over other types of anticoagulants: rapid onset and offset of action, a wide therapeutic window and a predictable anticoagulant response that allows fixed doses and eliminates the need for routine monitoring. They are considered to be at low risk of drug-drug interactions (DDIs) and fooddrug interactions compared to VKAs.. Concerning safety, DOACs have been associated with a lower risk of intracranial hemorrhage compared to VKAs and to sequential treatment with low-molecular-weight heparin (LMWH) and VKAs, regardless of their therapeutic indication. There is evidence suggesting a lower mortality risk after suffering a major hemorrhage in patients under DOACs than in patients taking VKAs or LMWHVKAs, but DOACs are associated with a higher risk of gastrointestinal hemorrhage.
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