In recent years direct oral anticoagulants (DOACs) have become the anticoagulant treatment of choice. DOACs were initially considered drugs with no significant food interactions; however, clinical observations from daily practice have proved otherwise as interactions with food ingredients have been reported. Food, dietary supplements or herbs may contain substances that, when administered concomitantly with DOACs, can potentially affect the plasma concentration of the drugs.
For almost 60 years, vitamin K antagonists (VKAs) were the mainstay of anticoagulation therapy [3]. In 2008, a new class of drugs was introduced in the markets of the European Union and the United States, which was a promising alternative to VKAs in the prevention of embolic complications in non-valvular AF, as well as in the treatment of patients with deep vein thrombosis and pulmonary embolism [4]. These were new-generation oral anticoagulants, originally referred to as new/novel oral anticoagulants (NOACs) and now as direct oral anticoagulants (DOACs) [5]. They act as direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban and betrixaban) or direct thrombin inhibitors (dabigatran) [2,6]. Their anticoagulant effect is more predictable and stable (i.e., less dependent on interactions with food, herbal supplements and other drugs) compared to warfarin and acenocoumarol [7]. The use of DOACs does not require individual dose adjustment or routine monitoring of blood coagulation parameters, such as the international normalized ratio (INR), activated partial thromboplastin time (APTT) and thrombin time [2]. Using VKA therapy, the therapeutic INR range of 2.0 ̶ 3.0 is recommended in the prevention of embolic complications in non-valvular AF, in the treatment of deep vein thrombosis and pulmonary embolism. It is recommended that time in therapeutic range (TTR) be >70% during VKA therapy, which in the context of significant dietary interactions and individual pharmacokinetic profiles mandates frequent INR control. Therefore, thecost-effectiveness and safety of long-term VKA treatment are considerably lower [2]. However, contrary to common belief, some pharmacokinetic variations secondary to interactions with food, herbal supplements and other drugs should still be considered in patients treated with DOACs [8,9].
In a 2018 study on DOACs, the authors emphasize that long-term therapy may require more effective stomach protection through the use of proton pump inhibitors (PPIs) [46]. PPIs have also been shown to be useful in alleviating indigestion associated with dabigatran [47].
In the event of DOAC overdose, the use of activated charcoal may be considered. In vitro data indicate that dabigatran can be effectively absorbed by activated carbon. Importantly, the administration of activated charcoal is recommended in the event of bleeding if no more than 2 h have passed since the last dose [49].
Some authors suggest that intermittent fasting can be a method of prevention of cardiovascular diseases [55]. This suggestion is based on a slight decrease in LDLcholesterol concentration observed after fasting, but so far it has not been confirmed in direct clinical trials. Moreover, from the point of view of pharmacokinetics, prolonged fasting in patients on active pharmacological treatment may be dangerous due to the possible changes in drug absorption leading to ineffective therapy and therefore potentially to myocardial infarction, stroke and other thrombotic events.
Studies on interactions between apixaban, edoxaban, dabigatran and individual macronutrients showed that the presence of proteins, fats and carbohydrates did not significantly affect the bioavailability of these drugs [21,28,35]. However, the results of an in vitro study by Raiola et al. showed that the presence of insoluble and soluble fiber as well as cellulose may cause a decrease in the bioavailability of dabigatran, rivaroxaban and apixaban. The presence of a high amount of insoluble and soluble dietary fiber significantly decreased DOAC bioavailability. However, a low or moderate amount of fiber did not have a significant effect on the bioavailability of DOACs, i.e., when they were a component of a balanced meal containing all the macronutrients. The study results suggest that it may be necessary to maintain a time interval between taking DOACs and a meal containing a high amount of cellulose and inulin. The authors of the study emphasize that further in vivo research is needed to evaluate the effect of dietary fiber on the bioavailability of anticoagulants [59].
When choosing these products, patients often follow the opinion of pharmacists, who do not always have sufficient knowledge about their indications [69]. Dietary supplements are used in the treatment of cardiovascular diseases such as hypertension, hyperlipidemia, coronary artery disease, stroke and peripheral arterial disease. In addition, they delay the aging process and reduce the risk of dementia [70,71,72]. However, their use alongside DOAC therapy carries the risk of bleeding or a reduction in the therapeutic effect (Table 1). Some of these agents have antiplatelet effects, which in conjunction with DOACs can potentially significantly increase the risk of bleeding, as is obviously the case when combining anti-platelet drugs with DOACs [73].
Substance | Source of Substance | Mechanism of Action | Effect on DOACs |
---|---|---|---|
Alpha-lipoic acid | Exhibits antiplatelet activity | Potentially increases the risk of bleeding when used concomitantly with DOACs | |
Apigenin * | M. chamomilla (Camomile) M. officinalis (Lemon balm) P. emblica (Emblic myrobalan) S. costus (Costus) |
Inhibition of cytochrome P450 (1A2, 2C9, 2C19, 3A4), P-gp and BCRP Exhibits antiplatelet activity |
Potentially increases plasma concentration of all DOACs Potentially increases the risk of bleeding when used concomitantly with DOACs |
α-Asarone | A. calamus (Sweet flag) A. gramineus (Japanese sweet flag) |
Inhibition of cytochrome P450 (1A1, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1) and P-gp | Potentially increases plasma concentration of all DOACs |
β-Asarone | A. calamus (Sweet flag) A. gramineus (Japanese sweet flag) R. acori |
Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
Avenanthramide (A, B, C) * | A. sativa (Oat) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Bacoside (A, B) * | B. monnieri(Water hyssop) | Inhibition of cytochrome P450 (1A2, 3A4, 2C9, 2C19) | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Berberine * | C. chinensis (Chinese goldthread) C. japonica (Camellia) |
Inhibition of cytochrome P450 (1A2, 3A4, 2C9, 2D6), P-gp and BCRP | Potentially increases plasma concentration of all DOACs |
Bilobalide * | G. biloba (Ginko) | Inhibition of cytochrome P450 (1A1, 1A2, 3A4, 2B6, 2C9, 2E1) and P-gp | Potentially increases plasma concentration of all DOACs |
Biochanin A * | T. pratense (Red clover) | Inhibition of CYP3A4, P-gp and BCRP Exhibits antiplatelet activity. May enhance effects of anticoagulant |
Potentially increases plasma concentration of all DOACs Potentially increases the risk of bleeding when used concomitantly with DOACs |
Caffein * | C. arabica (Arabian coffee) I. paraguariensis (Yerba mate) P. cupana (Guaraná) T. cacao (Cacao tree) C. sinensis (Chinese liver fluke) |
Inhibition of cytochrome P450 (1A2, 3A4) and BCRP | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Capsaicin * | Capsicum (Chili peppers) |
Induction of CYP3A4 and inhibition of P-gp | Potentially increases plasma concentration of dabigatran and betrixaban |
Carbolines (Harmine) * | L. meyenii (Maca) M. pruriens (Velvet bean) P. harmala (Wild rue) |
Inhibition of cytochrome P450 (1A1,1A2, 2C9, 2C19, 2D6, 2E1) and BCRP | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Casticin * | V. agnus-castus (Chaste tree) | Inhibition of cytochrome P450 (3A4, 2C9) | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Catechin * | C. rotundus (Coco-grass) L. bicolor (Shrub lespedeza) M. chamomilla (Camomile) T. cacao (Cacao tree) |
Inhibition of cytochrome P450 (1A2, 3A4, 2C9) and P-gp | Potentially increases plasma concentration of all DOACs |
Chebulagic acid * | T. chebula (Chebulic myrobalan) P. emblica (Emblic myrobalan) |
Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Chicoric acid, Alkylamides * |
G. Echinacea (nine known species) |
Inhibition of CYP3A4 | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Cinnamaldehyde * | C. wilsonii | Inhibition of cytochrome P450 (1A2, 2E1) and P-gp | Potentially increases plasma concentration of all DOACs |
Coniferyl ferulate * | A. sinensis(Dong quai) | Inhibition of cytochrome P450 (3A4, 2D6) and P-gp | Potentially increases plasma concentration of all DOACs |
Coraria lactone | Alismaorientalis (Alismataceae) | Induction of P-gp | Potentially decreases plasma concentration of all DOACs |
Coumarin * | A. hippocastanum (Horse chestnut) Cassia cinnamon (Cinnamon) |
Exhibits antiplatelet activity | Potentially increases the risk of bleeding when used concomitantly with DOACs |
Crocin * | C. sativus (Saffron) | Inhibition of cytochrome P450 (3A4, 3A5, 3A7,2B6) and P-gp | Potentially increases plasma concentration of all DOACs |
Curcumin * | C. longa (Turmeric) | Inhibition of cytochrome P450 (1A2, 3A4, 2B6, 2C9, 2D6) and P-gp, induction/inhibition of BCRP Exhibits antiplatelet activity. May enhance effects of anticoagulant. |
Potentially increases plasma concentration of all DOACs Potentially increases the risk of bleeding when used concomitantly with DOACs |
Decursin * | A. gigas (Korean angelica) | Inhibition of cytochrome P450 (1A1, 1A2) and P-gp | Potentially increases plasma concentration of all DOACs |
Dehydroepiandrosterone * | Soybean (Glycine max) | Inhibition of CYP3A4 | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Delphinidin * | V. uliginosum L. (Bog bilberry) | Inhibition of cytochrome P450 (3A4, 2B6, 2C9), and BCRP | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Ellagic acid * | T. chebula (Chebulic myrobalan) P. emblica (Emblic myrobalan) |
Inhibition of BCRP | Potentially increases plasma concentration of rivaroxaban and apixaban |
Ent-kaurane * | C. tonkinensis | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Ephedrine * | Angelica sinensis(Apiaceae) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Epicatechin gallate (ECG) * Epigallocatechin-3-gallate (EGCG) * |
C. sinensis (Chinese liver fluke) | Inhibition of cytochrome P450 (1A1, 1A2, 3A4) and P-gp | Potentially increases plasma concentration of all DOACs |
Eucalyptus oil | E. globulus (Eucalyptus) | Inhibition of cytochrome P450 (1A2, 2C9, 2C19, 3A4) | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Feverfew oil | T. parthenium *(Feverfew) | Inhibition of cytochrome P450 (1A2, 2C9, 2C19, 3A4) Exhibits antiplatelet activity |
Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban Potentially increases the risk of bleeding when used concomitantly with DOACs |
Galantamine * | G. nivalis (Snowdrop) G. woronowii (Green snowdrop) L. radiata (Red spider lily) N. confusus (Lily of Mary) P. illyricum |
Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Gallic acid * | M. pruriens (Velvet bean) P. emblica (Emblic myrobalan) T. chebula (Chebulic myrobalan) |
Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
Gingerol * | A. melegueta (Melegueta pepper) Z. officinaleRosc (Ginger) |
Inhibition of cytochrome P450 (3A4, 2C9, 2C19) and P-gp Exhibits antiplatelet activity |
Potentially increases plasma concentration of all DOACs Potentially increases the risk of bleeding when used concomitantly with DOACs |
Ginkgolide A, B * | G. biloba (Ginkgo) |
Inhibition of cytochrome P450 (3A4, 2C9) and induction of P-gp Exhibits antiplatelet activity |
Potentially decreases plasma concentration of dabigatran and betrixaban Potentially increases the risk of bleeding when used concomitantly with DOACs |
Ginsenoside Rb, Rd * | P. ginseng (Ginseng) |
Inhibition of cytochrome P450 (3A4, 2C9), BCRP Exhibits antiplatelet activity |
Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban Potentially increases the risk of bleeding when used concomitantly with DOACs |
Glabridin * | G. glabra (Licorice) | Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
Grapefruit juice | C. paradisi (Grapefruit) | Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
Guggulsterone * | Guggul (Commiphoramukul) | Induction CYP3A4 and inhibition of P-gp | Potentially increases plasma concentration of dabigatran and betrixaban |
Honokiol * | P. kaempferi (Pinaceae) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Hydrastine * | Hydrastis canadensis (Goldenseal) | Inhibition of CYP3A4 | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Hyperforin, hypericin * | H. perforatum (St. John’s wort) |
Induction of cytochrome P450 (1A2, 2C9, 3A4) and P-gp | Decreases plasma concentration of all DOACs Concomitant use with dabigatran and rivaroxaban should be avoided. Concomitant administration with edoxaban and apixaban should be used with caution (according to EHRA) |
1,2,3,4,6-Penta-O-galloyl- -d-glucose * |
T. chebula (Chebulic myrobalan) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
E-Harpagoside * | S. buergeriana (Buerger’s Figwort) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Kavalactones * | Piper methysticum (Kava) |
Inhibition of cytochrome P450 (1A2, 2C9, 3A4) and induction of P-gp | Potentially decreases plasma concentration of dabigatran and betrixaban |
Lime extract | C.aurantifolia (Lime) | Inhibition of CYP3A4 | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Luteolin * | L. bicolor (Shrub raspedeza) M. chamomilla (Camomile) M. officinalis (Lemon balm) P. emblica (Emblic myrobalan) R. officinalis (Rosemary) |
Inhibition of cytochrome P450 (1A2, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1) and P-gp Exhibits antiplatelet activity |
Potentially increases plasma concentration of all DOACs Potentially increases the risk of bleeding when used concomitantly with DOACs |
Malvidin 3-galactoside * | V. angustifolium (Wild lowbush blueberry) | Inhibition of cytochrome P450 (3A4, 2C9), BCRP, P-gp | Potentially increases plasma concentration of all DOACs |
Malvidin 3-glucoside * | V. angustifolium (Wild lowbush blueberry) V. uliginosum L. (Bog bilberry) |
Inhibition of cytochrome P450 (3A4, 2C9), BCRP, P-gp | Potentially increases plasma concentration of all DOACs |
Mangiferin * | M. indica (Mango) | Inhibition of cytochrome P450 (1A1,1A2, 3A4, 2B6, 2C8, 2D6) and P-gp | Potentially increases plasma concentration of all DOACs |
Myricetin * | M. peregrina (Ben tree) R. nigrum (Blackcurrant) |
Inhibition of cytochrome P450 (1A2, 3A4, 2D6), BCRP and P-gp | Potentially increases plasma concentration of all DOACs |
Naringenin | L. bicolor (Shrub lespedeza) M. lucida (Brimstone tree) |
Inhibition of cytochrome P450 (3A4, 2C9, 2C19, 2E1), P-gp and BCRP | Potentially increases plasma concentration of all DOACs |
Nobiletin * | C. reticulata (Mandarin) | Inhibition of CYP3A4, BCRP and P-gp | Potentially increases plasma concentration of all DOACs |
Oleanolic acid * | M. lucida (Brimstone tree) R. officinalis (Rosemary) |
Inhibition of cytochrome P450 (1A2, 3A4), BCRP and P-gp | Potentially increases plasma concentration of all DOACs |
Omega-3 polyunsaturated fatty AIDS (n-3 PUFA) | Fish oil | Exhibits antiplatelet activity | Potentially increases the risk of bleeding when used concomitantly with DOACs |
Paeoniflorin * | Paeonia alba (Paeoniaceae) | Induction of P-gp | Potentially decreases plasma concentration of all DOACs |
p-Synephrine * | C. aurantium (Bitter orange) | Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
Paeonol * | P. lactiflora (Chinese peony) | Inhibition of BCRP | Potentially increases plasma concentration of rivaroxaban and apixaban |
Palmatine | C. chinensis (Chinese goldthread) C. speciosa |
Induction of CYP3A4 and P-gp | Potentially decreases plasma concentration of all DOACs |
Phellamurin | Phellodendronwilsonii(Rutaceae) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Phyllanthin * | P. emblica (emblic myrobalan) | Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
Piperine * | P. nigrum (Black pepper) P. longum (Long pepper) |
Inhibition of cytochrome P450 (3A4, 2C9, 2E1), P-gp and BCRP | Potentially increases plasma concentration of all DOACs |
Polyphenols * | Theaceae (Green tea leaf) |
Short-term inhibition and long-term induction of CYP3A4, induction of P-gp Exhibits antiplatelet activity |
Potentially decreases plasma concentration of all DOACs Potentially increases the risk of bleeding when used concomitantly with DOACs |
Prunus avium extract | P. avium (Wild cherry) | Inhibition of CYP3A4 | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Pyranocoumarins | P. praeruptorum (Ningqianhu) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Quercetin * | A. melegueta (Melegueta pepper) C. sativus (Saffron) C. rotundus (Coco-grass) H. perforatum (St. John’s wort) I. paraguariensis (Yerba mate) L. meyenii (Maca) M. lucida (Brimstone tree) P. emblica (Emblic myrobalan) R. nigrum (Blackcurrant) S. costus (Costus) V. uliginosum L. (Bog bilberry) |
Inhibition of cytochrome P450 (1A1, 1A2, 3A4, 2C8, 2C9, 2C19, 2D6) and P-gp, induction of BCRP Exhibits antiplatelet activity |
Potentially increases plasma concentration of dabigatran, edoxaban and betrixaban Potentially increases the risk of bleeding when used concomitantly with DOACs |
Quercetin-3-O--Dglucuronide | P. pterocarpum (Copperpod) | Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
Resveratrol * | V. vinifera (Grape) | Inhibition of cytochrome P450 (1A1, 1A2, 3A4, 2C8, 2C9, 2C19, 2D6) and P-gp, induction of BCRP | Potentially increases plasma concentration of dabigatran, edoxaban and betrixaban |
Rosmarinic acid * | M. officinalis (Lemon balm) M. spicata (Spearmint) R. officinalis (Rosemary) |
Inhibition of cytochrome P450 (3A4, 2C9, 2C19, 2D6, 2E1), P-gp and BCRP | Potentially increases plasma concentration of all DOACs |
Rutin * | H. perforatum (St. John’s wort) L. bicolor (Shrub laspedeza) M. chamomilla (Camomile) M. flexuosa (Moriche palm) M. lucida (Brimstone tree) M. peregrina (Ben tree) V. uliginosum L. (Bog bilberry) |
Inhibition of CYP3A4, P-gp and BCRP Exhibits antiplatelet activity |
Potentially increases plasma concentration of all DOACs Potentially increases the risk of bleeding when used concomitantly with DOACs |
Safranal * | C. sativus (Saffron) | Inhibition of P-gp and BCRP | Potentially increases plasma concentration of all DOACs |
Salidroside * | R. rosea (Golden root) | Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
S-allyl-l-cysteine sulphoxides (alliin) * | A. sativum (Garlic) |
Induction of P-gp and BCRP Exhibits antiplatelet activity |
Potentially decreases plasma concentration of all DOACs Potentially increases the risk of bleeding when used concomitantly with DOACs |
Salvianolic acid * | M. spicata (Spearmint) S. miltiorrhiza (Danshen) |
Inhibition of cytochrome P450 (1A2, 3A4) and P-gp, induction of BCRP | Potentially increases plasma concentration of dabigatran, edoxaban and betrixaban |
Schisandrin B * | S. chinensis (Magnolia vine) | Inhibition of cytochrome P450 (3A4, 3A5) and P-gp | Potentially increases plasma concentration of all DOACs |
Silymarin * | Silybum marianum (Asteraceae) | Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
β-Sitosterol * | A. lancea C. pluricaulis (Shankhpushpi) M. peregrina (Ben tree) M. pruriens (Velvet bean) |
Inhibition of BCRP | Potentially increases plasma concentration of apixaban and rivaroxaban |
Stigmasterol * | A. lancea | Inhibition of cytochrome P450 (3A4, 3A5) and P-gp | Potentially increases plasma concentration of all DOACs |
Tannic acid * | T. chebula (Chebulic myrobalan) | Inhibition of cytochrome P450 (1A2, 3A4, 2B6) and P-gp | Potentially increases plasma concentration of all DOACs |
Tanshinone I * | S. miltiorrhiza (Danshen) | Inhibition of P-gp and BCRP | Potentially increases plasma concentration of all DOACs |
Tanshinone IIA * | S. miltiorrhiza (Danshen) | Inhibition of P-gp and BCRP | Potentially increases plasma concentration of all DOACs |
Tenacissimoside A | Marsdeniatenacissima (Asclepiadaceae) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Tetrandrine * | Stephania tetrandra (Menispermaceae) | Inhibition of CYP3A4 and P-gp | Potentially increases plasma concentration of all DOACs |
Thymol, γ-terpinene | C. copticum (CarumAjowan) | Inhibition of CYP3A4 | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Timosaponin AIII * | A. asphodeloides (RhizomaAnemarrhenae) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Trigonelline * | T. foenum-graecum (Fenugreek) | Induction of BCRP | Potentially decreases plasma concentration of apixaban and rivaroxaban |
Ursolic acid * | R. officinalis (Rosemary) | Inhibition of cytochrome P450 (1A2, 3A4, 2C8, 2C9, 2C19, 2D6) and BCRP | Potentially increases plasma concentration of apixaban, rivaroxaban and edoxaban |
Valerenic acid * | V. officinalis (Valerian) |
Inhibition of CYP3A4 | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
Vauqueline | A. sinensis (Dong quai) | Inhibition of P-gp | Potentially increases plasma concentration of all DOACs |
Vitamin E | Exhibits antiplatelet activity | Potentially increases the risk of bleeding when used concomitantly with DOACs | |
F. multiflora (Fo-ti-root) | Inhibition of cytochrome P450 (1A2, 2C9, 2C19, 3A4) | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban | |
Lamiaceae (Scutellaria) | Inhibition of CYP3A4 and induction of P-gp | Potentially decreases plasma concentration of dabigatran and betrixaban | |
Sucralose | Induction of CYP3A4 and P-gp | Potentially decreases plasma concentration of all DOACs | |
U. tomentosa (Cat’s claw) | Inhibition of CYP3A4 | Potentially increases plasma concentration of rivaroxaban, apixaban and edoxaban |
This entry is adapted from the peer-reviewed paper 10.3390/ijms22168531