The Impact of Strong Inducers on Direct Oral Anticoagulant Levels

Sennesael, Anne-Laure; Larock, Anne-Sophie; Hainaut, Philippe; Lessire, Sarah; Hardy, Michaël; Douxfils, Jonathan; Spinewine, Anne; Mullier, François

doi:10.1016/j.amjmed.2021.06.003

Cited by 19 publications

(16 citation statements)

References 11 publications

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“…We compared the plasma DOAC levels with the expected range, as published in the recent practical guide update by European Heart Rhythm Association 9 but, because of the small sample size, we were not able to perform any inference between DOAC plasma levels and clinical outcomes or carbamazepine/phenytoin dose. Sennesael et al found in a retrospective study that, among seven patients cotreated with carbamazepine/phenytoin and DOACs, two had DOAC plasma levels below the expected range, whereas five showed normal levels 18 …”

Section: Discussionmentioning

confidence: 99%

“…but, because of the small sample size, we were not able to perform any inference between DOAC plasma levels and clinical outcomes or carbamazepine/phenytoin dose.Sennesael et al found in a retrospective study that, among seven patients cotreated with carbamazepine/phenytoin and DOACs, two had DOAC plasma levels below the expected range, whereas five showed normal levels 18. These data highlight that the measurement of plasma DOAC levels in patients treated with carbamazepine/phenytoin show a great variability.…”

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confidence: 95%

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Carbamazepine, phenytoin, and oral anticoagulants: Drug‐drug interaction and clinical events in a retrospective cohort

Candeloro

Eikelboom

Chan

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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Background Carbamazepine and phenytoin are potent inducers of enzymes that metabolize oral anticoagulants. Objectives To determine the clinical impact of drug‐drug interactions between these anticonvulsants and oral anticoagulants, and whether they affect the treatment with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs). Material and methods Data on patients cotreated with carbamazepine or phenytoin and an oral anticoagulant were retrospectively retrieved from medical records from 2011 to 2020. Outcomes were time in therapeutic range (TTR), DOAC levels, thromboembolic events, major bleeding, and all‐cause mortality. Results Among 85 patients (37% female, median age 68 years) treated with carbamazepine (n = 43 [51%]) or phenytoin (n = 42 [49%]), 53 (62%) were initially treated with VKAs and 32 (38%) with DOACs. TTR in VKA patients was 63%, which improved in year 2. Four of seven trough and five of 12 peak DOAC plasma levels were lower than expected. The incidence rate (95% confidence interval) per 100 person‐years for thromboembolism was 3.6 (3.1‐4.2) for VKA patients and 4.4 (3.5‐5.6) for DOAC patients; for major bleeding 1.8 (1.5‐2.1) and 1.5 (1.2‐1.9), and for all‐cause mortality 3.6 (3.1‐4.2) and 1.5 (1.2‐1.9), respectively. Incidence rates between VKAs and DOACs and between carbamazepine and phenytoin were similar. Conclusion There was a high incidence of thromboembolism in patients cotreated with anticoagulants and carbamazepine or phenytoin. The incidence rates of thrombotic and bleeding events were similar between VKA and DOAC patients. DOAC levels were lower than expected in 47% of cases tested, without correlation with clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

Carbamazepine, phenytoin, and oral anticoagulants: Drug‐drug interaction and clinical events in a retrospective cohort

Candeloro

Eikelboom

Chan

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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“…A case series examining coadministration of DOACs (apixaban n = 1, edoxaban n = 3, rivaroxaban n = 1) with rifampin was identified 45 …”

Section: Resultsmentioning

confidence: 99%

“…44 A case series examining coadministration of DOACs (apixaban n = 1, edoxaban n = 3, rivaroxaban n = 1) with rifampin was identified. 45 Patients at a single center who received a DOAC and a strong enzyme inducer and who had DOAC levels measured were retrospectively identified. The DOAC levels were reported in quartiles in reference to expected ranges of DOACs observed in clinical trials.…”

Section: Summary Of Studies Of Interactions Between Rifamycins and Doacsmentioning

confidence: 99%

Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

et al. 2022

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Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta‐analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English‐language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin‐warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.

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“…This inconsistency between DOAC drug levels and clinical outcomes has been reported in the literature previously. Sennesael et al 7 studied 17 patients on DOACs and a strong inducer drug and found below on‐therapy levels in only one‐third of the patients (clinical outcomes were not assessed). A systematic review of reported drug interactions resulting in clinical adverse events found above on‐therapy DOAC levels in all reported bleeding cases with available levels and only one below on‐therapy level in cases of thrombosis 2 .…”

mentioning

confidence: 99%

Anticoagulant drug‐drug interactions: Highlighting the need for antithrombotic stewardship and shared decision making

Vazquez

Barnes

2022

Research and Practice in Thrombosis and Haemostasis

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The Impact of Strong Inducers on Direct Oral Anticoagulant Levels

Cited by 19 publications

References 11 publications

Carbamazepine, phenytoin, and oral anticoagulants: Drug‐drug interaction and clinical events in a retrospective cohort

Carbamazepine, phenytoin, and oral anticoagulants: Drug‐drug interaction and clinical events in a retrospective cohort

Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Anticoagulant drug‐drug interactions: Highlighting the need for antithrombotic stewardship and shared decision making

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