The increased risk of bleeding due to drug-drug interactions in patients administered direct oral anticoagulants

Lee, Ji Yun; Oh, Il Young; Lee, Ju Hyeon; Kim, Sang Young; Kwon, Seong Soon; Yang, Hyeon Jong; Kim, Yang Ki; Bang, Soo Mee

doi:10.1016/j.thromres.2020.07.054

Cited by 31 publications

(23 citation statements)

References 43 publications

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“…In reviewing the literature, we found only 3 cohort studies that evaluated the drug interactions with NOACs in AF. [31][32][33] Nevertheless, these studies did not test mortality and examined only specific drug interactions by generic drugs that result in bleeding. The most frequently interacting drugs in these 3 large studies were phenytoin, nonsteroidal antiinflammatory drugs (NSAIDs), diltiazem, amiodarone, rifampicin, and verapamil.…”

Section: Discussionmentioning

confidence: 99%

Novel Drug Interaction index and Risk of Mortality in Older Patients With Atrial Fibrillation Receiving Non Vitamin K Oral Anticoagulants (NOEL Drug)

Ersoy

2021

Clin Appl Thromb Hemost

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Drug interactions with novel oral anticoagulants (NOACs) may decrease their advantages. We aimed to explore the drug interaction rates with NOACs and impacts of drug interaction index (DII) on mortality among older patients with atrial fibrillation (AF). In this retrospective cohort study, we enrolled 704 eligible patients aged 65≤ with AF between January 1, 2018 and December 30, 2019 in a tertiary outpatient cardiology clinic. We recorded demographic, clinical characteristics, and medications for the last 3 months. At the end of the evaluation visit (March 1, 2020), death events and dates were recorded. All medications were checked for drug interactions using Lexicomp® software. Each drug interaction was annotated according to risk grade. Moreover, we determined a new index ratio of C/D/X classes to total interactions called DII. The mean age was 75.19 ± 7.13 and 398 (56%) were male. Death events were observed in 106 (15%) patients. A total of 9883 drugs were analyzed for drug interactions. The majority of drug interactions were in class A (80.7%). Clinically relevant interactions were 14.6% (Class C/D/X). The area under receiver operating characteristic curve was 0.704 (95% confidence interval: 0.653-0.754) and 0.167 cutoff value (68.9% sensitivity and 80.2% specificity [3.11 positive likelihood ratio]) for DII to predict mortality. This study showed an overview of the NOACs interactions in older patients with AF. Additionally, the inappropriate NOAC dose and DII showed an association with mortality. NOAC treatment should be guided by drug interaction applications to reduce mortality.

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Section: Discussionmentioning

confidence: 99%

Novel Drug Interaction index and Risk of Mortality in Older Patients With Atrial Fibrillation Receiving Non Vitamin K Oral Anticoagulants (NOEL Drug)

Ersoy

2021

Clin Appl Thromb Hemost

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“…A growing number of case reports have also highlighted a direct role of drug-drug interactions in bleeding or thrombotic events involving DOACs 8,9 . Several large registry-based retrospective studies have also suggested an increased risk of bleeding when DOACs are coadministered with P-glycoprotein (Pgp) or cytochrome P450 (CYP) 3A4/5 inhibitors [10][11][12] . A multidisciplinary team (composed of clinical pharmacologists and pharmacists, internal medicine physicians and hemostasis physicians) proposes here practical recommendations for pharmacokinetic drug-drug interactions, based on the best available clinical and pharmacological evidence that can be implemented easily at the patient's bedside (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Drug-Drug Interactions with Direct Oral Anticoagulants: Practical Recommendations for Clinicians

Terrier

Gaspar

Fontana

et al. 2021

The American Journal of Medicine

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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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“…The potentially inappropriate concomitant medications were mostly antithrombotic agents in both VKA and DOAC groups. Concomitant use of DOACs and antiplatelet agents may increase the risk of bleeding, especially major bleeding, via a pharmacodynamic interaction that leads to an additive effect 76‐79 . Furthermore, a higher risk of major bleeding has been reported in patients treated with VKAs and antiplatelet therapy 80 .…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, an Austrian cohort study indicated that the co‐medication of SSRIs and OACs has no substantial impact on bleeding events, compared with the concomitant administration of OACs with other antidepressants 90 . Other concomitant bleeding‐risk medicines include nonsteroidal anti‐inflammatory drugs (NSAIDs) such as ketoprofen and ibuprofen, having an additive effect on haemostasis 76,91,92 . Dabigatran and rivaroxaban were also reported in combination with omega‐3‐acid ethyl esters.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, the concomitant use of dabigatran and simvastatin was reported to significantly increase the risk of major bleeding by 46% compared with other statins 96 . Findings on bleeding with DOACs and amiodarone remain inconclusive 76 : a recent meta‐analysis showed that the coadministration of DOACs and amiodarone does not appear to influence efficacy or safety outcomes in subjects with atrial fibrillation, 97 while another study revealed that the coadministration of amiodarone and edoxaban was associated with an increase in clinically relevant non‐major bleeding 98 . Another potential interaction was reported for rivaroxaban and sofosbuvir/ledipasvir, as ledipasvir is a P‐gp inhibitor and may therefore increase the plasma concentrations of rivaroxaban to a clinically relevant extent, which may lead to an increased risk of bleeding 99,100 …”

Section: Resultsmentioning

confidence: 99%

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Adverse drug reactions with oral anticoagulants: data from sicilian spontaneous reporting system database

Cutroneo¹,

Baratelli

Cicala

et al. 2021

J Clin Pharm Ther

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Objective Direct oral anticoagulants (DOACs) were developed to avoid the limitations of vitamin K antagonists (VKAs). DOACs are associated with a greater incidence of gastrointestinal bleeding and a smaller number of intracranial haemorrhages than VKAs. Therefore, it is important to deepen our knowledge of their safety profiles. The aim of this study was thus to analyse adverse drug reaction (ADR) reports on DOACs and VKAs using the Sicilian Spontaneous Reporting System (SRS) database. Methods All ADR reports with DOACs and VKAs as suspected drugs that were entered into the Sicilian SRS database during the period 2001–2019 were selected. In detail, all reports with the following single active substances were included: dabigatran etexilate, rivaroxaban, apixaban and edoxaban; acenocoumarol and warfarin were included as a comparator group. Descriptive statistical methodology was used to evaluate characteristics of the reported cases with a case‐by‐case assessment. Results and Discussion Out of 521 reports related to anticoagulants, 444 (85.2%) and 77 (14.8%) involved DOACs and VKAs, respectively. DOAC‐related reports were mainly of gastrointestinal disorders. In contrast, VKAs were mostly associated with blood and lymphatic system disorders, injury, investigations and vascular disorders. Many more cases of ADRs in the form of gastrointestinal disorders concerned dabigatran etexilate (n = 179, 73.7%) than the other DOACs, while ADRs in the form of blood disorders were mainly associated with acenocoumarol (n = 27, 57.4%). The most commonly reported Preferred Terms for DOACs were dyspepsia (n = 89, 17.1%), upper abdominal pain (n = 41, 9.2%) and pruritus (n = 26, 5.8%), whereas for VKAs, they were anaemia (n = 21, 27.3%) and hypocoagulable state (n = 18, 3.5%). Potentially interacting concomitant medications particularly included antithrombotic agents (n = 19, 4.3%) for DOACs and proton‐pump inhibitors (PPIs) (n = 37, 48.1%) and antithrombotic agents (n = 13, 16.9%) for VKAs. Conclusion The ADRs most commonly associated with DOACs, especially dabigatran, were gastrointestinal disorders, particularly gastrointestinal bleeding. Our study also highlights the potential role of drug‐drug interactions in the ADRs. The cases of gastrointestinal bleeding highlight the need for careful prescribing of DOACs and use of potentially interacting concomitant drugs.

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The increased risk of bleeding due to drug-drug interactions in patients administered direct oral anticoagulants

Cited by 31 publications

References 43 publications

Novel Drug Interaction index and Risk of Mortality in Older Patients With Atrial Fibrillation Receiving Non Vitamin K Oral Anticoagulants (NOEL Drug)

Novel Drug Interaction index and Risk of Mortality in Older Patients With Atrial Fibrillation Receiving Non Vitamin K Oral Anticoagulants (NOEL Drug)

Drug-Drug Interactions with Direct Oral Anticoagulants: Practical Recommendations for Clinicians

Adverse drug reactions with oral anticoagulants: data from sicilian spontaneous reporting system database

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