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Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: A systematic review.

ABSTRACT: BACKGROUND:Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous thrombosis. Due to their novelty, pharmacokinetic DOAC drug-drug interactions (DDIs) that result in clinical adverse events have not been well-documented. OBJECTIVE:This study aims to systematically review reported pharmacokinetic DDIs resulting in clinical adverse events through documented observational evidence to better inform clinicians in clinical practice. METHODS:A comprehensive literature review of EMBASE, MEDLINE, and Ovid HealthStar was conducted through March 10th, 2020. Two independent reviewers screened and extracted data from eligible articles according to pre-established inclusion and exclusion criteria. Articles reporting bleeding or thrombotic outcomes in non-controlled (observational) settings resulting from suggested pharmacokinetic DOAC DDIs were included. RESULTS:A total of 5567 citations were reviewed, of which 24 were included following data extraction. The majority were case reports (n = 21) documenting a single adverse event resulting from a suspected DOAC DDI, while the remaining papers were a case series (n = 1) and cohort studies (n = 2). The most commonly reported interacting drugs were amiodarone and ritonavir (bleeding), and phenobarbital, phenytoin, and carbamazepine (thrombosis). Bleeding events more often resulted from a combined mechanism (P-glycoprotein AND CYP3A4 inhibition), whereas thrombotic events resulted from either combined OR single P-glycoprotein/CYP3A4 induction. CONCLUSION:Current literature evaluating the real-world risk of DOAC DDIs is limited to few case reports and retrospective observational analyses. Clinicians are encouraged to continue to report suspected drug interactions resulting in adverse events.

SUBMITTER: Li A

PROVIDER: S-EPMC7417902 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: A systematic review.

Li Allen A Li Ming K MK Crowther Mark M Vazquez Sara R SR

Thrombosis research 20200811

<h4>Background</h4>Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous thrombosis. Due to their novelty, pharmacokinetic DOAC drug-drug interactions (DDIs) that result in clinical adverse events have not been well-documented.<h4>Objective</h4>This study aims to systematically review reported pharmacokinetic DDIs resulting in clinical adverse events through documented observational evidence ...[more]

PMID: 33213849

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Project description:IntroductionPostmarketing pharmacovigilance reports have raised concerns about non-bleeding adverse events associated with direct oral anticoagulants (DOACs), but only limited results are available from large claims databases.ObjectiveThe aim of this study was to assess the potential association between DOAC initiation and the onset of four types of non-bleeding adverse events by sequence symmetry analysis (SSA).MethodsSSA was performed using nationwide data from the French National Healthcare databases (Régime Général, 50 million beneficiaries) to assess a cohort of 386,081 DOAC new users for the first occurrence of four types of non-bleeding outcomes: renal, hepatic, skin outcomes identified by using hospitalization discharge diagnoses, and gastrointestinal outcomes by using medication reimbursement. Asymmetry in the distribution of each investigated outcome occurring before and after initiation of DOAC therapy was used to test the association between DOAC therapy and these outcomes. SSA inherently controls for time-constant confounders, and adjusted sequence ratios were computed after correcting for temporal trends. Negative (glaucoma) and positive (bleeding, depressive disorders) control outcomes were used and analyses were replicated on a cohort of 310,195 patients initiating a vitamin K antagonist (VKA).ResultsThis study demonstrated the expected positive association between either DOAC or VKA therapy and hospitalised bleeding and initiation of antidepressant therapy, while no association was observed between either DOAC or VKA therapy and initiation of antiglaucoma medications. For DOAC therapy, signals were the associations with hepatic outcomes, including acute liver injury [for the 3-month time window, aSR3?=?2.71, 95% confidence interval (CI) 1.79-4.52]; gastrointestinal outcomes, including initiation of drugs for constipation and antiemetic drugs (aSR3?=?1.31, 95% CI 1.27-1.36; and 1.17, 95% CI 1.12-1.22, respectively); and kidney diseases (aSR3?=?1.33, 95% CI 1.29-1.37).ConclusionResults of this nationwide study suggest that DOACs are associated with rare but severe liver injury and more frequent gastrointestinal disorders. A low risk of kidney injury with DOAC therapy can also not be excluded.

Project description:ObjectiveTo investigate the associations between direct oral anticoagulants (DOACs) and risks of bleeding, ischaemic stroke, venous thromboembolism, and all cause mortality compared with warfarin.DesignProspective open cohort study.SettingUK general practices contributing to QResearch or Clinical Practice Research Datalink.Participants132 231 warfarin, 7744 dabigatran, 37 863 rivaroxaban, and 18 223 apixaban users without anticoagulant prescriptions for 12 months before study entry, subgrouped into 103 270 patients with atrial fibrillation and 92 791 without atrial fibrillation between 2011 and 2016.Main outcome measuresMajor bleeding leading to hospital admission or death. Specific sites of bleeding and all cause mortality were also studied.ResultsIn patients with atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (adjusted hazard ratio 0.66, 95% confidence interval 0.54 to 0.79) and intracranial bleeding (0.40, 0.25 to 0.64); dabigatran was associated with a decreased risk of intracranial bleeding (0.45, 0.26 to 0.77). An increased risk of all cause mortality was observed in patients taking rivaroxaban (1.19, 1.09 to 1.29) or on lower doses of apixaban (1.27, 1.12 to 1.45). In patients without atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (0.60, 0.46 to 0.79), any gastrointestinal bleeding (0.55, 0.37 to 0.83), and upper gastrointestinal bleeding (0.55, 0.36 to 0.83); rivaroxaban was associated with a decreased risk of intracranial bleeding (0.54, 0.35 to 0.82). Increased risk of all cause mortality was observed in patients taking rivaroxaban (1.51, 1.38 to 1.66) and those on lower doses of apixaban (1.34, 1.13 to 1.58).ConclusionsOverall, apixaban was found to be the safest drug, with reduced risks of major, intracranial, and gastrointestinal bleeding compared with warfarin. Rivaroxaban and low dose apixaban were, however, associated with increased risks of all cause mortality compared with warfarin.

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Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: A systematic review.

Publications

Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: A systematic review.

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