Risks of Oral Anticoagulants: Interactions with Drugs and Medicinal Plants

Abstract

Oral anticoagulants, including warfarin, a vitamin K antagonist, have been used for anticoagulation therapy, but their limitations, such as drug interactions and complex dosing, have prompted the development of direct oral anticoagulants (DOACs) like rivaroxaban, apixaban, dabigatran, and edoxaban. This study reviews the interactions of both warfarin and DOACs, particularly those influenced by cytochrome P450 enzymes and P-glycoprotein. Warfarin is metabolized by various cytochrome P450 isoforms, making it vulnerable to interactions with medications and herbs that modulate these enzymes. In contrast, DOACs, while having fewer interactions, are still affected by strong inducers or inhibitors of cytochrome 3A4 and P-glycoprotein, depending on the specific drug. Some herbs may also interfere with these pathways. Continuous monitoring of these interactions is crucial to ensure the safe use of oral anticoagulants. The findings underscore the importance of identifying and understanding these interactions to improve patient safety and guide appropriate anticoagulant therapy.

1. Introduction

Although medications provide health benefits, their combined use can lead to interactions, increasing the risk of adverse reactions. This is common in clinical practice, especially among polypharmacy patients, such as the elderly, who are more vulnerable to these effects [1].

The risk of interactions between these products and drugs is not widely recognized by the public, and healthcare professionals are often uninformed about their use. Consequently, pharmacists should play a pivotal role in informing and educating the public about these potential risks [2,3,4]. The integration of pharmacists into multidisciplinary care teams, coupled with continuous patient education and the strategic use of electronic health records for prescription monitoring, contributes significantly to improving medication safety and optimizing therapeutic outcomes [5]. Pharmacists play a pivotal role in safeguarding pharmacotherapy, bearing the critical responsibility of proactively identifying potential drug interactions and promptly informing both physicians and patients to prevent adverse outcomes [6]. Pharmacists are indispensable in the promotion of safe and effective pharmacotherapy by educating patients, fostering adherence, and continuously monitoring drug regimens, interventions that have been consistently associated with improved clinical outcomes [7]. Polypharmacy is common, with individuals often adding over-the-counter drugs, like vitamins, which may interact with prescribed drugs. Scientific validation of these interactions is crucial for clinical practice [3]. Analyzing potential interactions and implementing measures to reduce risk is crucial [4].

Anticoagulants, particularly warfarin, are commonly used in the elderly, who often have multiple comorbidities and are on several medications, increasing their susceptibility to drug interactions [8]. Elderly patients are more vulnerable to harmful drug interactions due to changes in pharmacokinetics, such as decreased renal function and altered liver metabolism [9]. A small reduction in drug metabolism may not affect younger individuals, but in the elderly, impaired metabolic functions can make even minor interactions cause significant adverse effects. Additionally, polypharmacy, multiple chronic conditions, and care from several providers further increase the risk. Vigilant medication monitoring and reducing polypharmacy are crucial to prevent adverse drug-related events [9].

Reintroducing anticoagulants in elderly patients after ischemic stroke is complex due to comorbidities and polypharmacy. Early use may prevent thromboembolism but raises bleeding risk. Thus, decisions should be individualized, balancing thrombosis and hemorrhage risks with the patient’s overall condition [10].

Currently, the use of oral anticoagulants, particularly warfarin, is significant for the prevention of cerebrovascular events [11,12]. However, in recent years, new oral anticoagulants known as direct oral anticoagulants (DOACs), including rivaroxaban, apixaban, and dabigatran, have been introduced in the market, followed by edoxaban [13,14].

Warfarin has a higher rate of interactions compared to DOACs, primarily due to its complex metabolism mediated by CYP450 isoforms [15,16,17]. These interactions frequently result in adverse drug reactions, including serious and potentially fatal hemorrhages [18].

While NOACs have clear benefits over warfarin, including superior stroke prevention in terms of atrial fibrillation (AF) and non-valvular atrial fibrillation (NVAF), lower bleeding risk, ease of use, fewer interactions, and no need for regular monitoring, they are not without limitations. Their higher cost and limited clinical experience remain concerns. NOAC are also not recommended during pregnancy, in children, or for patients with mechanical mitral valves, or antiphospholipid syndrome. Ongoing research will help define their role in treating thromboembolic diseases [19].

This narrative review aims to address interactions between oral anticoagulants, including warfarin and DOACs, with other drugs and medicinal plants, without temporal restrictions, providing significant value by examining interactions with both medicinal plants and drugs, unlike studies that focus solely on warfarin [20,21]. Additionally, some studies have focused exclusively on comparisons among DOACs, without mentioning warfarin [22,23]. It is also important to highlight that some studies provide information solely regarding interactions with either medicinal plants or drugs, rather than addressing both [20,21,22,23,24,25,26]. The review provides added value by incorporating the latest findings and advancements in the field since previous publications. This allows for a more comprehensive and innovative review and highlights significant gaps not addressed in earlier narrative reviews. These factors justify the need for an updated study in 2025, reflecting recent developments and changes in the topic.

2. The Literature Search

This study aims to evaluate the risks linked to these medications by identifying, analyzing, and synthesizing their key interactions with both pharmaceutical drugs and medicinal plants, based on the latest scientific evidence, regardless of whether such interactions are documented in the Summary of Product Characteristics (SmPCs).

The literature search was designed to identify relevant studies and information on interactions between oral anticoagulants, drugs, and medicinal plants until 2024. The search strategy included the following steps: databases searched included PubMed and Google Scholar. Initially, keywords used in the search included “warfarin,” “NOAC,” “DOAC,” “direct oral anticoagulants,” “drug-drug interactions,” “dabigatran,” “rivaroxaban,” “apixaban,” “edoxaban,” “anticoagulants,” “herb-drug interactions,” “herbal interactions,” and “medicinal plants interactions”. Relevant Portuguese articles were emphasized due to the authors’ familiarity with the local context and the need to include region-specific data, particularly regarding the use of medicinal plants in Portugal. This was considered important for providing a more comprehensive understanding of interactions in a specific population. For interactions with medicinal plants, the Observatory of Herb-Drug Interactions (OIPM) and the Drug Interaction Checker website were also utilized to assess potential interactions [24,25]. The Observatory of Herb-Drug Interactions (OIPM) was used to assess potential interactions between medicinal plants and oral anticoagulants. The OIPM provides a comprehensive database of herb–drug interactions, which was particularly useful for identifying interactions involving medicinal plants commonly used in Portugal.

3. Interactions Involving Oral Anticoagulants

3.1. Summary

This section summarizes interactions related to oral anticoagulants, divided into two categories: drug interactions and drug/medicinal herb interactions. Understanding these interactions and their mechanisms is essential for predicting their effects.

Table 1. Comparison of drug interactions with oral anticoagulants and their consequences on plasma levels. Adapted from Vranckx, P et al. (2018) [27], Steffel, J et al. (2021) [28], Vilares, Clara et al. (2017) [29], EMA e INFARMED (2022) [30,31] and Drug Interaction Checker (2024) [32], Mendell et al. (2013) [33], Philip L. Mar et al. (2022) [34], Kvasnicka T et al. (2017) [35], Mueck W et al. (2014) [36], Fernandez S. (2020) [36], Corsini A. (2020) [37], Ferri N. (2022) [38], Undas A (2013) [39], Stangier J. (2008) [39], and Byon W (2019) [40].

Mechanism		Warfarin	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Antiarrhythmics
Amiodarone	Moderate inhibitor of P-glycoprotein and CYP3A4 inhibitor	+12% to 60% AUC ~10–40%) Cmax (SmPC)	+12% to 60% (SmPc)	Minimal effect (SmPC)	(SmPC)	+40%
Diltiazem	CYP3A4 inhibitor and weak P-glycoprotein inhibitor	~10% to 20% AUC	No effect (SmPc)	No effect		39.8% AUC
Propafenone	CYP3A4 inhibitor	~10% to 20% AUC (SmPC)
Dronedarone	CYP3A4 and P-glycoprotein inhibitor		+70% to 100%	Moderate effects. Combination to be avoided	With caution	+85% (dose reduction to 30 mg once a daily by label) (SmPC)
Propranolol	CYP1A2 inhibitor		No relevant interaction	No relevant interaction	No relevant interaction	No relevant interaction
Quinidine	P-glycoprotein inhibitor and CYP2D6 inhibitor	~30% to 53% AUC Cmax ~15% a 25%	+53% (SmPc)	Unknown increase extension		+77% (No dose reduction required by label)
Verapamil	Weak CYP3A4 inhibitor and P-glycoprotein inhibitor	+12% to +180% AUC	+12% to 180% (if taken simultaneously) (SmPC)	+40% (probably not relevant)	(SmPC)	+53 (no dose reduction required by label) (SmPC)
Other Cardiovascular Drugs
Atorvastatin	P-glycoprotein inhibitor and CYP3A4 competition	3–5% AUC (SmPC)	No relevant interaction	No relevant interaction	With caution	Decreased the 24-h concentration for edoxaban by 25.7%
Ticagrelor	P-glycoprotein inhibitor and CYP3A4 inhibitor	No significant change	+24% to 65% (give loading dose 2 h after dabigatran) (SmPC)	With caution	With caution	With caution
Antibiotics
Clarithromycin	Strong CYP3A4 inhibitor and P-glycoprotein inhibitor	+19% a to 40% AUC +15% a 30% Cmax	+19% AUC +15% Cmax (SmPC)	+50% AUC +40% Cmax	+60% AUC + 30% Cmax (SmPC)	+53% AUCa +27% Cmax (SmPC)
Erythromycin	Strong CYP3A4 inhibitor and P-glycoprotein inhibitor	30% AUC +30% Cmax 15% (SmPC)	+19% AUC + 15% Cmax (SmPC)	+30% AUC +30% Cmax (SmPC)	(SmPC)	+85% AUC + 68% Cmax (dose reduction to 30 mg once daily by label) (SmPC)
Rifampicin	CYP3A4, P-glycoprotein/BCRP and CYP2C9 inducer	−67% AUC −22% to 35% Cmax (SmPC)	−66% AUC −67% Cmax (SmPC)	−50% AUC −22% Cmax (SmPC)	−54% AUC −42% Cmax (SmPC)	−35% AUC (but with compensatory increase of active metabolite) (SmPC)
Isoniazid	CYP2C9 inhibitor		No relevant interaction	No relevant interaction	No relevant interaction	No relevant interaction
Metronidazole	CYP1A2 and CYP2C9 inhibitor	+40% AUC +20% to 50% Cmax (SmPC)	No relevant interaction	No relevant interaction	No relevant interaction	No relevant interaction
Quinolones	Strong CYP1A2 inhibitor (Ciprofloxacin)		No relevant interaction	No relevant interaction	No relevant interaction	No relevant interaction
Sulfamethoxazole + Trimethoprim	Inhibitor CYP3A4 and CYP2C9		No relevant interaction	No relevant interaction	No relevant interaction	No relevant interaction
Antivirals
Protease inhibitors (e.g., ritonavir)	CYP3A4 inhibitor and P-glycoprotein/BCRP inhibition or induction	+53% AUC + 55% Cmax (SmPC)	Variable decrease or increase (SmPC)	+153% AUC + 55% Cmax (SmPC)		Elevated risk of bleeding.
Antifungals
Fluconazole	Moderate CYP3A4 and CYP2C9 inhibitor	+42% AUC + 30% Cmax (SmPC)	No relevant interaction	+42% AUC + 30% Cmax (SmPC)	~+40% AUC	No relevant interaction
Voriconazole	Strong CYP3A4 inhibitor	+80% to 100% AUC + 60% to 80% Cmax (SmPC)	No data	Combination to be avoided (SmPC)	Combination to be avoided (SmPC)	No data
Ketoconazole	Strong CYP3A4 inhibitor and P-glycoprotein/BCRP competition	+140% to 150% AUC + 100% to 160% Cmax (SmPC)	+140% to 150% AUC		+100% AUC + 64% Cmax	+160% AUC + 72% Cmax (SmPC)
Itraconazole	Strong CYP3A4 inhibitor and P-glycoprotein/BCRP competition	+70% to 100% AUC + 50% to 70% Cmax (SmPC)
Posaconazole	Strong CYP3A4 inhibitor and P-glycoprotein	(SmPC)	With caution	Combination to be avoided	Combination to be avoided	With caution
Others
Carbamazepine	Strong CYP3A4 and P-glycoprotein inducer	+66% to 75% AUC + 50% to 60% Cmax (SmPC)	(SmPC)	(SmPC)	(SmPC)	(SmPC)
Phenytoin	Strong CYP3A4 inducer and P-glycoprotein competition	+20% to 40% AUC + 20% to 30% Cmax (SmPC)	(SmPC)	(SmPC)	(SmPC)	(SmPC)
Naproxen	P-glycoprotein competition. Pharmacodynamic interaction (increased bleeding time)	(SmPC)	Increase the risk of bleeding.	No significant difference in AUC (SmPC)	+55% AUC + 61% Cmax (SmPC)	No significant effect on AUC (SmPC)
H2 Receptor Antagonists, PPIs, Antacids (Aluminum Hydroxide + Magnesium Hydroxide)	Gastrointestinal absorption		Minimal effect	No relevant interaction	No relevant interaction	No relevant interaction
SSRIs, SNRIs	Pharmacodynamic effect on platelets		With caution (SmPC)	With caution (SmPC)	With caution (SmPC)	With caution(SmPC)

Note: BCRP (breast cancer resistance protein); CYP (cytochrome P450); ↑ (increase in plasma levels); ↓ (decrease in plasma levels); PPIs (proton pump inhibitors); SSRIs (selective serotonin reuptake inhibitors); SNRIs (serotonin and norepinephrine reuptake inhibitors); AUC (area under the curve); C_max (maximum concentration).

highlights key drug interactions with oral anticoagulants, with a detailed description of these interactions provided in the following section.

3.2. Interactions with Drugs and Oral Anticoagulants

In Table 1, the interactions are marked with the abbreviation SmPC, referring to the Summary of Product Characteristics.

Dabigatran interacts due to its role as a substrate of P-glycoprotein. It exhibits interactions with potent inhibitors or inducers of P-glycoprotein [16]. As seen in Table 1, dabigatran interacts with medications like amiodarone, clarithromycin, certain antifungals (itraconazole, ketoconazole), quinidine, and protease inhibitors. Its use with dronedarone, protease inhibitors, itraconazole, and ketoconazole is discouraged due to elevated dabigatran plasma levels [28]. Similarly, its use with cyclosporine and tacrolimus is contraindicated/disrecommended [28]. Caution is necessary when co-administering with verapamil, amiodarone, quinidine, clarithromycin, ticagrelor, and posaconazole [41].

Short-term use of nonsteroidal anti-inflammatory medications (NSAIDs) with dabigatran does not increase bleeding risk, but prolonged use with dabigatran or warfarin does [41]. Caution is advised when combining dabigatran with clopidogrel or aspirin due to their synergistic effect [42]. The use of dabigatran with serotonin and norepinephrine reuptake inhibitors (SNRIs) increases bleeding risk [41].

Rivaroxaban and apixaban interact with P-glycoprotein and CYP450 inducers and inhibitors [16]. They are also substrates for breast cancer resistance protein (BCRP) [27]. These anticoagulants interact with medications like ketoconazole, itraconazole, clarithromycin, rifampicin, carbamazepine, and phenytoin. Their use with protease inhibitors, ketoconazole, itraconazole, voriconazole, and posaconazole is contraindicated/disrecommended due to increased rivaroxaban and apixaban plasma levels [28]. Erythromycin, when co-administered with rivaroxaban, elevates its plasma levels, which is clinically insignificant for most patients given erythromycin’s additive effect in renal impairment scenarios. Fluconazole also heightens rivaroxaban plasma levels, particularly impactful in patients with renal impairment. Co-administration of rivaroxaban with SSRIs and SNRIs poses bleeding risks owing to their platelet effects [43]. Because of the increased risk of bleeding, caution should be exercised when using rivaroxaban with clopidogrel, aspirin, or naproxen [43].

Apixaban with diltiazem increases plasma levels, as with naproxen [44]. Because of their enhanced antithrombotic actions, aspirin or clopidogrel should be continuously monitored. Bleeding risk is increased while using SSRIs, SNRIs, or NSAIDs cautiously. Because of the increased risk of bleeding, do not combine with other thrombolytic or platelet aggregation inhibitors [44].

Edoxaban is minimally metabolized by CYP450 but is a substrate of P-glycoprotein [16]. It interacts with drugs like amiodarone, dronedarone, quinidine, erythromycin, ketoconazole, or verapamil, increasing its plasma levels. Similarly, cyclosporine also raises edoxaban levels [31]. Caution is needed when combining edoxaban with other P-glycoprotein inducers such as phenytoin, carbamazepine, and phenobarbital, as they may decrease its plasma concentrations [31]. Combining with aspirin or platelet aggregation inhibitors like clopidogrel increases bleeding risk, though less than with warfarin [31]. Edoxaban does not significantly affect AUC with naproxen but should not be combined with NSAIDs due to extended bleeding time. Combining with SSRIs and SNRIs also increases bleeding risk due to platelet effects [31].

3.3. Interactions with Drugs and Wafarin, and Their Effects on INR

Table 2. Drug interactions with warfarin and their effects on INR. Adapted from Lima, N. (2008) [11] and Di Minno, A. et al. (2017) [18].

Increase in INR

Decrease in INR

Citalopram, Disulfiram, Entacapone, Phenytoin, Fluoxetine, Fluvoxamine, Paracetamol, Allopurinol, Celecoxib, Indomethacin, Methylprednisolone, Piroxicam, Tramadol, Cimetidine, Omeprazole, Orlistat, CMF, Ifosfamide, Levonorgestrel, Tamoxifen, Acetylsalicylic acid, Amiodarone, Dronedarone, Atorvastatin, Quinidine, Clofibrate, Diltiazem, Fenofibrate, Glucagon, Lovastatin, Propafenone, Propranolol, Simvastatin, Fluconazole, Miconazole, Lysine acetylsalicylate, Acetylsalicylic acid, NSAIDs, Clopidogrel, Dipyridamole, SSRIs, Ticlopidine, Thyroxine, Erythromycin, Isoniazid, Levofloxacin, Metronidazole, Sulfamethoxazole

Barbiturates (phenobarbital, thiopental), Carbamazepine, Chlordiazepoxide, Propofol, Azathioprine, Mesalazine, Sulfasalazine, Cyclosporine, Mercaptopurine, Metamizole, Raloxifene, Cholestyramine, Telmisartan, Rifampicin, Phenobarbital, Ritonavir, Saquinavir, Estrogens, Dicloxacillin, Griseofulvin

Note: International normalized ratio (INR), cyclophosphamide, methotrexate, fluorouracil (CMF), nonsteroidal anti-inflammatory medications (NSAIDs), selective serotonin reuptake inhibitors (SSRIs).

presents the main drug interactions involving warfarin, highlighting how these drugs can alter the International Normalized Ratio (INR). These interactions may increase or decrease warfarin’s anticoagulant effect, impacting the risk of bleeding or thrombosis. Understanding these drug interactions is essential for the safe and effective management of patients undergoing warfarin therapy.

The (INR) is the preferred test for patients using vitamin K antagonists (VKAs) and is required to monitor their anticoagulant therapy. It aids in determining bleeding risk and coagulation state, allowing for dose modifications [45]. Certain drugs boost the anticoagulant action of the drug, raising INR levels. SSRIs, quinidine, fenofibrate, and paracetamol are a few examples. Since CYP3A4 metabolizes statins (atorvastatin, lovastatin, and simvastatin), it also raises INR. Antibiotics like ciprofloxacin and azithromycin, along with antifungal medications like miconazole and fluconazole, raise INR and hence increase the risk of bleeding [11,18].

Thyroxine increases INR by augmenting warfarin’s anticoagulant effect, heightening the risk of hemorrhage and enhancing clotting factor catabolism [18], as shown in Table 2. On the other hand, medications like rifampicin and phenobarbital accelerate warfarin elimination, reducing its anticoagulant effect. Warfarin use with protease inhibitors (e.g., ritonavir, saquinavir) decreases INR, necessitating careful monitoring [18], as shown in Table 2.

Drugs that inhibit platelet aggregation, including acetylsalicylic acid, clopidogrel, and NSAIDs, interact pharmacodynamically with warfarin, increasing INR and bleeding risk due to additive effects [11,18]. Because oral contraceptives increase coagulation factors caused by estrogen, they reverse the anticoagulant effect of warfarin and increase the risk of thrombosis when compared to placebo [11,18]. Cholestyramine can reduce the absorption of warfarin [18], as shown in Table 2.

The interactions between medicinal plants and warfarin are similar to drug interactions, primarily through pharmacokinetic mechanisms involving CYP450 enzymes and efflux proteins like P-glycoprotein, influenced by compounds in certain medicinal plants [46]. Numerous studies indicate clinically significant interactions between medicinal plants and medications, including warfarin [47]. The documented interactions between medicinal plants and warfarin are listed in

Table 3. Possible interactions between medicinal plants and warfarin. Adapted from Di Minno, A. et al. (2017) [18]; Tan, CSS; Lee, SWH (2021) [21]; Leite, PM et al. (2021) [20]; Ge, B et al. (2014) [24]; OIPM (2024) [48]; Izzo, AA et al. (2016) [49], Gamboa, A et al. (2020) [50] and Abdul, M. I. et al. (2010) [51].

Medicinal Plant	Interaction Mechanism	Interaction Outcome
Danshen (Salvia milthiorriza)	Anticoagulant and vasodilator properties that potentiate warfarin’s anticoagulant effect.	Increased anticoagulant effect.
Don quai (Angelica sinensis)	Contains natural coumarin derivatives as well as antithrombotic and antiarrhythmic properties that potentiate warfarin’s effect.	Increased anticoagulant effect.
Ginseng (Panax quinquefolius)	Exact mechanism unknown but thought to induce warfarin metabolism due to ginsenoside’s steroid effects.	Decreased anticoagulant effect.
Goji berries (Lycium barbarum)	CYP2C9 inhibition.	Increased anticoagulant effect.
St. John’s Wort (Hypericum perforatum)	Induction of CYP1A2, CYP2C9, and CYP3A4.	Decreased anticoagulant effect.
Green Tea (Camellia sinensis)	Antagonizes warfarin’s effect due to vitamin K content.	Decreased anticoagulant effect. High doses of green tea reduce INR.
Ginkgo (Ginkgo biloba)	Platelet aggregation inhibition.	Increased anticoagulant effect.
Chamomile (Matricaria recutita)	In vitro inhibition of CYP3A4 and CYP1A2 activity.	Increased anticoagulant effect.
Ginger (Zingiber officinale)	Anticoagulant properties that potentiate warfarin’s effect.	Increased anticoagulant effect.
Cannabis (Cannabis sativa)	CYP2C9 inhibition.	Increased anticoagulant effect.
Gotu Kola (Centella asiatica)	In vitro inhibition of CYP2C9.	Increased anticoagulant effect.
Licorice (Glycyrrhiza glabra)	Inhibition of CYP3A4.	Increased anticoagulant effect.
Milk Thistle (Silybum marianum)	Inhibition of CYP2C9.	Increased anticoagulant effect.
Myrrh (Commiphora myrrha)	Liver enzyme inducer.	Decreased anticoagulant effect.
Soy (Glycine max)	May increase warfarin’s effect due to in vitro inhibition of CYP3A4 and CYP2C9. May also reduce its effect due to vitamin K content.	Decreased or increased anticoagulant effect.
Sweet Clover (Melilotus officinalis)	Contains coumarin that is converted to dicoumarol which causes a reduction in levels of coagulation factors II, VII, IX, and X.	Increased anticoagulant effect.
Turmeric (Curcuma longa)	Curcumin potentiates the effects of warfarin.	Increased anticoagulant effect.
Aloe Vera (Aloe barbadensis)	Decreased intestinal absorption of warfarin and/or increased renal elimination.	Decreased anticoagulant effect.
Garlic (Allium sativum)	Inhibition of platelet aggregation.	Increased anticoagulant effect.
Cranberry (Vaccinium macrocarpon)	Contains anthocyanins that are metabolized by CYP2C9 and CYP3A4.	Increased anticoagulant effect.
Devil’s Claw (Harpagophytum procumbens)	Inhibits in vitro activity of CYP2C8, CYP2C9, CYP2C19, and CYP3A4.	Increased anticoagulant effect.
Bilberry (Vaccinium myrtillus)	Antiplatelet properties that can increase warfarin’s anticoagulant effect.	Increased anticoagulant effect.
Horse Chestnut (Aesculus hippocastanum)	Synergistic effect with warfarin.	Increased anticoagulant effect.
Echinacea (Echinacea purpurea)	Accelerates the breakdown of warfarin, reducing its effectiveness.	Decreased anticoagulant effect.
Saw Palmetto (Serenoa repens)	Inhibits some cytochrome P450 isoenzymes, including CYP2D6,CYP2C9, and CYP3A4.	Increased anticoagulant effect.
Red Clover (Trifolium pratense)	Inhibits CYP2C9 and contained coumarins.	Increased anticoagulant effect.

and are further explained in the section that follows.

3.4. Possible Interactions Between Medicinal Plants and Warfarin

Danshen (Salvia miltiorrhiza) enhances warfarin’s effects due to its anticoagulant properties. Dong quai (Angelica sinensis) interacts with warfarin through coumarin derivatives, while goji berries (Lycium barbarum) inhibit CYP2C9, potentially raising INR levels with high intake [21].

St. John’s Wort (Hypericum perforatum) induces CYP1A2, CYP2C9, and CYP3A4, speeding up warfarin metabolism and reducing its anticoagulant effect [18]. Ginkgo (Ginkgo biloba) may heighten bleeding risk with warfarin, necessitating INR monitoring despite limited data [18].

Chamomile (Matricaria recutita) and Ginger (Zingiber officinale) increase bleeding risk. Cannabis (Cannabis sativa) containing cannabidiol (CBD) inhibits CYP2C9, potentially increasing warfarin levels [21]. Gotu kola (Centella asiatica) enhances warfarin’s anticoagulant effect by inhibiting CYP2C9 [21].

Licorice (Glycyrrhiza glabra) and milk thistle (Silybum marianum) affect warfarin levels through CYP3A4 and CYP2C9, respectively [18,21]. Ginseng (Panax quinquefolius) and myrrh (Commiphora myrrha) reduce warfarin’s effect. Green tea (Camellia sinensis), rich in vitamin K, lowers INR at high doses [18,21].

Soy (Glycine max) affects warfarin via CYP3A4 and CYP2C9, while aloe vera (Aloe barbadensis) and garlic (Allium sativum) pose bleeding risks [20]. Cranberry (Vaccinium macrocarpon) affects warfarin metabolism through CYP2C9 and CYP3A4 [21].

Devil’s claw (Harpagophytum procumbens) enhances warfarin’s effect by inhibiting multiple CYP enzymes [24]. Bilberry (Vaccinium myrtillus) and horse chestnut (Aesculus hippocastanum) increase bleeding risk with warfarin [20,48].

3.5. Possible Interactions Between Medicinal Plants and DOACs

While medicinal plants can influence P-glycoprotein or CYP3A4, potentially impacting DOACs, clinical trials do not directly link these interactions. Caution is especially needed with St. John’s Wort, a potent inducer of both P-glycoprotein and CYP3A4, which may reduce DOAC effectiveness [23]. Additionally, caution is advised when using echinacea, valerian, garlic (CYP3A4 inhibitors), green tea, ginkgo (P-glycoprotein inhibitors), and other anticoagulant plants such as ginger, ginseng, and horse chestnut with DOACs [28].

4. Discussion

Warfarin, unlike DOACs, exhibits a higher rate of interactions mediated by CYP450 isoforms, affecting INR values and often resulting in ADRs that can lead to severe and potentially fatal bleeding events [18]. These data are consistent with those obtained in this narrative review.

All DOACs are P-glycoprotein substrates with fewer interactions than warfarin, but strong CYP3A4 and P-glycoprotein inducers and inhibitors should be avoided [25,52]. Enzymatic inducers can lower DOAC concentrations, increasing the risk of thromboembolic events, while inhibitors can raise DOAC concentrations, leading to a risk of bleeding [25,52].

When combined with DOACs, the most common drugs that cause bleeding are amiodarone and ritonavir, which inhibit P-glycoprotein and CYP3A4, as well as medications that cause thrombotic events, such as phenytoin and carbamazepine, which strongly induce P-glycoprotein and CYP3A4 [52]. Furthermore, drugs that decrease platelet aggregation, such as NSAIDs and SSRIs, can increase the risk of bleeding when used with anticoagulants, therefore their usage should be carefully considered [17]. DOACs have fewer clinically significant drug interactions than warfarin, making them generally preferable, though thorough evaluation is still needed before prescribing [38]. These results are consistent with those found during the narrative review.

Warfarin’s narrow therapeutic window and numerous interactions complicate its safe management, necessitating ongoing monitoring to prevent serious complications from inadequate or excessive anticoagulation [53].

The results obtained in this narrative review reveal that warfarin affects the metabolism of medicinal plants through CYP450 enzymes. These findings are in accordance with those reported in another study [21]. While interactions are rarely reported, most products may not need strict avoidance. Warfarin affects medicinal plant metabolism via CYP450 enzymes, and while interactions are rare, caution is advised for older adults and those with a history of gastrointestinal bleeding, liver or kidney disease, or bleeding disorders [21]. Analyzing the interactions between warfarin and medicinal plants reveals that cranberry flavonoids may alter CYP isoenzyme production, particularly CYP2C9, impacting S-warfarin metabolism. Additionally, cranberry juice may interact with warfarin through a VKORC1 genotype-dependent mechanism [54]. Green tea (Camellia sinensis), known for its health benefits, may contain significant levels of vitamin K, which can be problematic for individuals taking warfarin [54].

As shown in the results, ginkgo (Ginkgo biloba) can inhibit platelet aggregation, as it contains, among other compounds, ginkgolide B [21]. Ginsenosides, the active compounds in ginseng (Panax quinquefolius), may inhibit platelet aggregation and thromboxane synthesis. While a potential interaction with warfarin exists, caution is advised due to unclear effects on warfarin’s efficacy [24].

Excessive use of ginger (Zingiber officinale) can impair platelet aggregation and increase bleeding risk when taken with warfarin [53]. Danshen (Salvia miltiorrhiza) enhances warfarin’s effects by promoting vasodilation and inhibiting platelet aggregation, increasing bleeding risk, and should be avoided in warfarin users. [55] Dong quai (Angelica sinensis), containing vitamin K antagonists and ferulic acid, also enhances warfarin’s anticoagulant effect, increasing bleeding risk [53].

The exact mechanisms of the warfarin–myrrh (Commiphora myrrha) interaction are likely due to aqueous extracts of myrrh inducing liver enzymes, leading to faster breakdown of warfarin. This interaction was observed in only a single case report [54]. Coumarin in sweet clover is converted to dicumarol, which inhibits vitamin K epoxide reductase in the liver, reducing clotting factors II, VII, IX, and X [21].

Garlic (Allium sativum) has antithrombotic properties that reduce platelet aggregation and bleeding risk without increasing INR levels, but limited case reports suggest a plausible interaction with warfarin [24]. The coumarin in horse chestnut (Aesculus hippocastanum) may interact with warfarin and other plants like garlic, ginger, ginkgo biloba, and turmeric, potentially affecting platelet aggregation. However, the literature does not document any significant bleeding cases linked to these interactions [56]. Bilberry has minimal influence on drug metabolism, but it may affect platelet aggregation, potentially increasing the risk of severe bleeding in patients on anticoagulants such as warfarin [57]. Echinacea (Echinacea purpurea) reduced plasma concentrations of S-warfarin and increased its clearance, but did not affect warfarin’s pharmacodynamic response [51].

Saw palmetto (Serenoa repens) may inhibit CYP2C9, potentially interacting with warfarin, but limited evidence makes this interaction unclear [24]. Red clover may increase bleeding risk or enhance warfarin’s effectiveness due to its natural coumarins and CYP2C9 suppression [24]. Natural coumarins in red clover may raise INR levels and increase bleeding risk [58].

As obtained from the narrative review data, caution is advised when DOACs are used with echinacea, valerian, green tea, ginkgo, garlic, ginger, ginseng, and horse chestnut. The use of DOACs with St. John’s wort should be avoided [22].

The interactions reported by the authors should influence physicians’ clinical practice by emphasizing the need for careful monitoring of patients on warfarin who are also using medicinal plants. Since plants like St. John’s wort, aloe vera, and ed clover can alter warfarin’s effectiveness by modulating CYP2C9 and CYP3A4 or affecting absorption, regular INR monitoring is crucial to adjust warfarin doses and prevent bleeding or thromboembolic events. Physicians should also educate patients about the risks of medicinal supplements and encourage professional guidance to avoid adverse interactions. A personalized, vigilant approach to managing both prescribed medications and medicinal plants is essential for ensuring patient safety and optimal therapeutic outcomes.

The likelihood of drug–drug and drug–food interactions is affected by the duration of anticoagulant therapy, which differs according to the clinical indication. This review offers a comprehensive and clinically relevant synthesis of interactions between oral anticoagulants and both conventional medications and herbal products. Its originality lies in bridging two often separated therapeutic domains, evidence-based pharmacology and complementary medicine, within a single framework that reflects the complexity of real-world patient care. In doing so, it highlights not only pharmacokinetic and pharmacodynamic interactions but also a critical communication gap between healthcare providers and patients. This review demonstrates a comprehensive coverage of interactions, with a particular focus on the novel oral anticoagulants and their interactions with herbal products, an area that remains relatively underexplored in the literature.

Despite increasing awareness of the potential effects of herbal products such as ginkgo biloba, St. John’s wort, and garlic on anticoagulant therapy, these interactions remain underreported and poorly managed in clinical settings. Physicians frequently neglect to inquire about herbal use, and patients are not systematically educated to disclose it, particularly when under the care of multiple providers. This omission represents a significant and avoidable risk. Considering these issues, we argue that improving communication strategies, enhancing clinical training, and integrating herbal screening into standard medication reviews are essential steps toward safer anticoagulation management. As the popularity of herbal medicine continues to grow, these considerations are not only relevant but urgent. Moreover, choosing the right oral anticoagulant for patients with AF who are on multiple medications is a complex challenge for clinicians, given the potential impact of comorbidities, adverse drug reactions, and especially drug–drug interactions, which can result in under-prescription, inadequate dosing, or premature discontinuation of anticoagulant therapy [59].

The interactions between DOACs and antiarrhythmic or antiviral agents are of critical importance, particularly in the context of managing chronic atrial fibrillation and COVID-19-related pulmonary embolism, where such interactions may significantly impact therapeutic efficacy and patient safety [60].

5. Limitations

This study is limited by the prevalence of case reports. While case reports provide valuable insights, they typically lack control groups, standardized methodologies, and larger sample sizes, making it difficult to draw definitive conclusions or generalize findings to broader populations. The section on “Possible interactions between medicinal plants and warfarin” presents potential mechanisms, such as CYP3A4 and P-gp modulation. However, due to the limited available information, the sources of evidence for the data in Table 3, whether from animal studies, clinical studies, or case reports, could not be fully specified. This limitation weakens the ability to assess the strength and relevance of the findings, as the lack of clear study categorization complicates the interpretation of the data’s applicability to clinical practice.

Although the Drug Interaction Probability Scale (DIPS) tool can be used to estimate the likelihood of drug interactions based on structured criteria, its application in this review was not feasible due to insufficient information and the absence of studies applying this tool to the interactions investigated. This lack of DIPS application prevents a standardized and objective evaluation of interaction probability, limiting the ability to quantitatively assess the interactions and their clinical significance. Nonetheless, its mention underscores the need for a more consistent, evidence-based approach to evaluating drug interactions in future studies.

Furthermore, there is insufficient data on interactions between medicinal plants and oral anticoagulants, particularly with direct oral anticoagulants (DOACs). The lack of robust evidence on these interactions limits our ability to make informed clinical recommendations regarding the safe co-use of medicinal plants and DOACs. More research is urgently needed to establish their safety profiles and guide clinicians in managing these potential interactions.

6. Conclusions

This study demonstrated that both warfarin and DOACs have clinically significant interaction with medical plants and drug profiles, albeit to different extents. Given that oral anticoagulants are commonly prescribed to elderly patients, who are more vulnerable to adverse reactions, and considering the frequent nondisclosure of medical plant use, healthcare professionals must maintain vigilance to identify potential interactions.

Although this study provides valuable insights, further real-world research and ongoing safety monitoring are necessary to better understand and manage DOAC-associated risks, ultimately improving patient safety and outcomes.