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Review
. 2020 Aug;59(8):967-980.
doi: 10.1007/s40262-020-00879-x.

Drug-Drug Interactions with Direct Oral Anticoagulants

Kathrin I Foerster  1 , Simon Hermann  1 , Gerd Mikus  2 , Walter E Haefeli  1
Affiliations
Review

Drug-Drug Interactions with Direct Oral Anticoagulants

Kathrin I Foerster et al. Clin Pharmacokinet. 2020 Aug.

Erratum in

Abstract

A large body of evidence suggests that not only direct anticoagulant effects but also major bleeding events and stroke prevention depend on plasma concentrations of direct oral anticoagulants (DOACs). Concomitant drugs that cause drug-drug interactions (DDIs) alter DOAC exposure by increasing or decreasing DOAC bioavailability and/or clearance; hence, they might affect the efficacy and safety of DOAC therapy. Patients with renal impairment already receive smaller DOAC maintenance doses because avoidance of elevated DOAC exposure might prevent serious bleeding events. For other causes of increased exposure such as DDIs, management is often less well-defined. Considering that DOAC patients are often older and have multiple co-morbidities, polypharmacy is highly prevalent. However, the effect of multiple drugs on DOAC exposure, and especially the impact of DDIs when concurring with drug-disease interactions as observed in renal impairment, has not been thoroughly elucidated. In order to provide effective and safe anticoagulation with DOACs, understanding the mechanisms and magnitude of DDIs appears relevant. Instead of avoiding drug combinations with DOACs, more DDI trials should be conducted and new strategies such as dose adjustments based on therapeutic drug monitoring should be investigated. However, dose adjustments based on concentration measurements cannot currently be recommended because evidence-based data are missing.

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Conflict of interest statement

KIF and SH declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. GM received consulting honoraria and data and safety monitoring board honoraria from Boehringer Ingelheim and Bayer outside the submitted work. WEH received consulting honoraria, speaker’s honoraria, and travel support from BMS, Boehringer Ingelheim, and Daiichi Sankyo and research support from Bayer and Daichii-Sankyo outside the submitted work.

Figures

Fig. 1
Fig. 1
Primary direct oral anticoagulant (DOAC) clearance/elimination pathways. Data were extracted from per oral (po; apixaban, edoxaban, and rivaroxaban) and intravenous (iv; betrixaban and dabigatran) mass balance studies [2, 38, 48, 57]. The rivaroxaban pie chart is a modification from Mueck and co-workers [63]. BCRP breast cancer resistance protein, CES carboxylesterase, CYP cytochrome P450, P-gp P-glycoprotein
Fig. 2
Fig. 2
Area under the concentration–time curve ratios (AUCR) and maximum (peak) concentration ratios (CmaxR) of apixaban with and without concomitantly taken drugs. Results of drug–drug interaction trials that have been conducted and published up to January 2020 are depicted [, , , , , , –101]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. 1Ketoconazole 400 mg investigated. 2DOAC microdoses administered. 3Rifampicin was given repeatedly
Fig. 3
Fig. 3
Area under the concentration–time curve ratios (AUCR) and maximum (peak) concentration ratios (CmaxR) of betrixaban with and without concomitantly taken drugs. Results of drug–drug interaction trials that have been conducted and published up to January 2020 are depicted [2]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. 1Verapamil provided in an extended-release formulation. 2Ketoconazole 200 mg investigated. 3The antacid mixture was composed of aluminium hydroxide and magnesium hydroxide
Fig. 4
Fig. 4
Area under the concentration–time curve (AUC) ratios (AUCR) and maximum (peak) concentration (Cmax) ratios (CmaxR) of dabigatran with and without concomitantly taken drugs. Results of drug–drug interaction (DDI) trials that have been conducted and published up to January 2020 are depicted [, , , , –113]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. Red bars: AUCR and CmaxR ≥ 5. 1DOAC microdoses administered. 2Ketoconazole 200 mg investigated. 3A single dose of rifampicin was provided. 4The figure depicts the greatest effect of clarithromycin on dabigatran pharmacokinetics that has been reported. Results from DDI trials are ambiguous. Although the same dose of clarithromycin was administered, one trial did not observe any change in dabigatran exposure and the other reported a smaller AUCR than depicted (AUCR 1.49) [103, 105]. 5Verapamil was provided in an extended-release formulation. Immediate-release verapamil given 1 h before dabigatran etexilate had greater impact on dabigatran exposure. Immediate-release verapamil given 2 h after dabigatran etexilate did not alter dabigatran exposure to a relevant extent. 6Only loading doses of clopidogrel (300–600 mg) affected dabigatran exposure. 7Loading doses of ticagrelor (180 mg) administered 2 h after dabigatran etexilate 110 mg or maintenance doses of ticagrelor (90 mg) administered concomitantly increased dabigatran exposure as depicted. Lower doses of dabigatran etexilate (75 mg) were affected to a greater extent by ticagrelor (AUC 1.73-fold, Cmax 1.95-fold). 8Rifampicin was given repeatedly
Fig. 5
Fig. 5
Area under the concentration–time curve ratios (AUCR) and maximum (peak) concentration ratios (CmaxR) of edoxaban with and without concomitantly taken drugs. Results of drug–drug interaction trials that have been conducted and published up to January 2020 are depicted [, , , , –117]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. Red bars: AUCR and CmaxR ≥ 5. 1DOAC microdoses administered. 2Ketoconazole 400 mg investigated. 3Verapamil provided in an extended-release formulation. 4Acetylsalicylic acid (ASA) 325 mg/day administered. 5ASA 100 mg/day administered. 6Rifampicin was given repeatedly
Fig. 6
Fig. 6
Area under the concentration–time curve ratios (AUCR) and maximum (peak) concentration ratios (CmaxR) of rivaroxaban with and without concomitantly taken drugs. Results of drug–drug interaction trials that have been conducted and published up to January 2020 are depicted [, , , , –, , , –122]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. 1Ketoconazole 400 mg investigated. 2DOAC microdoses administered. 3Trial was performed in patients with moderate renal impairment. 4Rivaroxaban 40 mg administered. 5Ketoconazole 200 mg investigated. 6Trial was performed in patients with mild renal impairment. 7Rivaroxaban 10 mg administered. 8The antacid mixture was composed of aluminium hydroxide and magnesium hydroxide. 9Rifampicin was given repeatedly
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