Overview

Direct oral anticoagulants (DOACs) are often used if oral anticoagulation is required, such as to prevent thromboembolism for patients with nonvalvular atrial fibrillation or for treatment and prevention of venous thromboembolism. One advantage of DOACs is their predictable response and limited need for routine laboratory monitoring. However, drug-drug interactions with these agents are common and may increase the risk of bleeding or thrombosis. Important DOAC interactions are often due to medications that affect increase bleeding propensity or cytochrome P450 (CYP450) enzymes or transport proteins. Clinicians require practical considerations for managing common drug interactions involving DOACs.

Education Category: Pharmacology
Release Date: 11/01/2023
Expiration Date: 10/31/2026

Table of Contents

  1. INTRODUCTION
  2. REVIEW OF CYP450 AND TRANSPORTER INTERACTIONS
  3. MANAGING DOAC INTERACTIONS
  4. CONCLUSION
  5. RESOURCES
  6. Works Cited
  7. Evidence-Based Practice Recommendations Citations

Audience

This course is designed for physicians, physician assistants, and nurses involved in the care of patients who require anticoagulation therapy.

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This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide prescribers and other healthcare professionals with the knowledge and skills necessary to identify and act to avoid or address drug-drug interactions that occur in patients taking direct oral anticoagulants.

Learning Objectives

Upon completion of this course, you should be able to:

  1. Summarize common mechanisms of drug interactions with direct oral anticoagulants.
  2. Identify commonly used medications that may increase or decrease the effects of direct oral anticoagulants.
  3. Implement appropriate management of drug interactions with direct oral anticoagulants.

Faculty

Jeff Langford, PharmD, BCPS-AQ Cardiology, BCCP, is a board-certified cardiology pharmacist with strong clinical, teaching, and interpersonal skills developed through experience in both inpatient and outpatient pharmacy. Dr. Langford is an Assistant Editor at TRC Healthcare and adjunct assistant professor at University of South Carolina College of Pharmacy. His inpatient practice includes focus in cardiovascular pharmacotherapy, and his outpatient practice includes extensive patient interaction and departmental management experience.

Faculty Disclosure

Contributing faculty, Jeff Langford, PharmD, BCPS-AQ Cardiology, BCCP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

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#95010: Managing Drug Interactions with Direct Oral Anticoagulants

INTRODUCTION

Direct oral anticoagulants (DOACs) are often used if oral anticoagulation is required, such as to prevent thromboembolism for patients with nonvalvular atrial fibrillation or for treatment and prevention of venous thromboembolism. One advantage of DOACs is their predictable response and limited need for routine laboratory monitoring. However, drug-drug interactions with these agents are common and may increase the risk of bleeding or thrombosis. Important DOAC interactions are often due to medications that increase bleeding propensity or affect cytochrome P450 (CYP450) enzymes or transport proteins. Clinicians require practical considerations for managing common drug interactions involving DOACs [1,2].

REVIEW OF CYP450 AND TRANSPORTER INTERACTIONS

The characterization of drug interactions by metabolic pathways is complex. Simply because a medication interacts with one substrate of a particular cytochrome P450 pathway does not mean it affects all substrates of that isozyme. Genetics, age, nutrition, stress, liver function, hormones, and other endogenous chemicals also influence drug metabolism. Additional influences on drug interactions include dosing (e.g., dose, timing, sequence, route of administration, duration of therapy), concomitant medications, potential for a concurrent pharmacodynamic interaction (e.g., a DOAC plus aspirin), and specific drug features (e.g., narrow therapeutic index, high extraction ratio, side effect profile, multiple metabolic pathways) [3].

Pharmacokinetics can also be affected by drug transporters (e.g., P-glycoprotein, breast cancer resistance protein [BCRP], multidrug and toxin excluders [MATEs], organic anion transporting polypeptides [OATPs]). All of these proteins help move medications into or out of cells, which can impact drug absorption, distribution, or elimination [4; 5].

We are still learning about the significance of these transporters on pharmacokinetics. Most of the available data are related to P-glycoprotein (P-gp, multidrug resistance protein 1 [MDR1]). P-gp is a drug efflux pump found in the gut, liver, kidney, blood-brain barrier, and cancer cells. It pumps drugs out of cells and into the gut, bile, and/or urine for excretion [6]. Other examples include BCRP, which pumps drugs out of cells in the gut, liver, and kidney, and OATPs (e.g., OATP1B1, OATP1B3), which move drugs into the liver [5].

Generally, CYP450 interactions and drug transporter interactions involve substrates, inhibitors, and inducers. Inhibitors may increase levels of CYP450 or P-gp substrates, and inducers may decrease levels of CYP450 or P-gp substrates. For many interactions, CYP450 enzyme inhibition or induction is also involved, and P-glycoprotein substrates are often also CYP3A4 substrates, so the contribution of P-gp inhibition/induction versus CYP450 inhibition/induction can be difficult to discern [7,8,9]. For example, apixaban and rivaroxaban are metabolized by CYP3A4 (Table 1), and absorption of all DOACs is affected by P-glycoprotein (Table 2) [2,10].

SELECT CYP450-3A4 PATHWAY DRUG INTERACTIONS

DOAC SubstratescSelect InhibitorsSelect Inducers
Apixaban
Rivaroxaban
Amiodarone
Amlodipine
Atazanavira
Cimetidine
Ciprofloxacina
Clarithromycinb
Cobicistatb
Conivaptana
Cyclosporinea
Diltiazema
Dronedaronea
Erythromycina
Ethinyl estradiol
Fluconazolea
Fluoxetine
Fluvoxaminea
Fosamprenavira
Grapefruitb
Indinavirb
Isoniazid
Itraconazoleb
Ketoconazoleb
Lansoprazole
Lopinavir/ritonavirb
Mifepristone
Nefazodoneb
Nelfinavirb
Nicardipine
Posaconazoleb
Ritonavirb
Saquinavir/ritonavirb
Ticagrelor
Tipranavir/ritonavirb
Verapamila
Voriconazoleb
Voxelotor
Carbamazepine
Modafinil
Nafcillin
Nevirapine
Oxcarbazepine
Phenobarbital
Phenytoin
Rifabutin
Rifampin
Rifapentine
St. John's wort
Topiramate
aModerate inhibitors (≥2 to <5-fold increase in exposure, or 50% to 80% decrease in clearance of substrate). For many medications, strength of inhibition in vivo is undetermined.
bStrong inhibitors (≥5-fold increase in exposure or >80% decrease in clearance of substrate)
cDabigafran is not a substrate, inducer, or inhibitor of CYP450 enzymes. Edoxaban is only minimally metabolized by CYP450.
Table 1
Source: [1,2,3]

SELECT P-GLYCOPROTEIN DRUG INTERACTIONS

DOAC SubstratesSelect InhibitorsSelect Inducersa
Apixaban
Dabigatran
Edoxaban
Rivaroxaban
Amiodarone (moderate or strong inhibitor)
Atorvastatin
Azithromycin
Canagliflozin (weak inhibitor)
Captopril
Carvedilol
Clarithromycinc (strong inhibitor)
Cobicistat
Conivaptanb
Cyclosporineb (strong inhibitor)
Diclofenac
Diltiazemb
Dronedaroneb (strong inhibitor)
Erythromycinb (strong inhibitor)
Esomeprazole
Ibuprofen
Indomethacin
Itraconazolec
Ketoconazolec (strong inhibitor)
Lansoprazole
Lopinavir/ritonavirc
Lovastatin
Mirabegron
Naproxen
Nefazodonec
Nelfinavirc
Nifedipine
Omeprazole
Posaconazolec
Propafenone
Quinidine (strong inhibitor)
Quinine
Rabeprazole
Ranolazine
Ritonavirc
Saquinavir/ritonavirc
Simvastatin
Spironolactone
Telmisartan
Tetracycline
Ticagrelor
Trimethoprim
Tipranavir/ritonavirc
Verapamilb (strong inhibitor)
Vilazodone
Voriconazole (strong inhibitor)
Carbamazepine
Phenobarbital
Phenytoin
Rifabutin
Rifampin
St. John's wort
Venlafaxine
aAll are strong inducers, except venlafaxine.
bModerate CYP3A inhibitors
cStrong CYP3A inhibitors
Table 2
Source: [4]

MANAGING DOAC INTERACTIONS

The American Academy of Family Physicians recommend that apixaban should be avoided or reduced in dose when combined with P-glycoprotein and strong CYP3A4 inhibitors.

(https://www.aafp.org/pubs/afp/issues/2019/1001/p426.html Last Accessed: October 12, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

Drug experts from Pharmacist's Letter and Prescriber Insights provide the following practical approach to managing DOAC interactions [11]:

  • Pinpoint critical DOAC interactions, and act if necessary.

  • Generally avoid combining DOACs with strong CYP3A4 and P-glycoprotein inducers (e.g., phenytoin, rifampin, St. John's wort). These may lower DOAC levels and increase thrombosis risk.

  • If these interacting medications cannot be avoided, switch to warfarin, because it is easier to monitor than a DOAC.

  • Watch for strong CYP3A4 and P-glycoprotein inhibitors (e.g., ritonavir, itraconazole), as these may raise DOAC levels and increase bleeding risk.

To manage these drug interactions, consider the specific DOAC, dose, and indication (Table 3). One example that blends consideration of these factors is use of nirmatrelvir/ritonavir for treatment of COVID-19 in patients receiving a DOAC. This combination introduces potential risk for drug interactions, because ritonavir is a strong CYP3A4 and P-glycoprotein inhibitor. For instance, when a patient is receiving nirmatrelvir/ritonavir for COVID-19, apixaban being given for atrial fibrillation should be reduced to 2.5 mg twice per day during treatment and for three days after. However, coadministration of nirmatrelvir/ritonavir and rivaroxaban should be avoided [12].

COMPARISON OF DOACs

DrugApproved Indications and Dosing (Adults)Select Interactions
Apixaban (Eliquis)

Thromboembolism (e.g., stroke) prevention in nonvalvular atrial fibrillation: 5 mg BID or 2.5 mg BID for patients with ≥2 of the following:

  • Age ≥80 years

  • Weight ≤60 kg

  • Serum creatinine ≥1.5 mg/dL

VTE prevention post-hip or knee replacement: 2.5 mg BID for 35 days (hip) or 12 days (knee) starting 12 to 24 hours post-operative
DVT/PE treatment: 10 mg BID for seven days, then 5 mg BID
DVT/PE prevention of recurrence: 2.5 mg BID after at least six months of treatment
Atrial fibrillation: A reasonable anticoagulant choice for patients with CrCl <15 mL/min or on dialysis
Reduce dose by 50% with strong inhibitors of both CYP3A4 and P-gp (e.g., itraconazole, ketoconazole, ritonavir). Avoid in patients already taking 2.5 mg BID. Resume usual dose three days after the last dose of nirmatrelvir/ritonavir (Paxlovid).
Avoid strong inducers of both CYP3A4 and P-gp (e.g., phenobarbital, carbamazepine, phenytoin, St. John's wort, rifampin).
Caution with antiplatelets and anticoagulants.
Dual antiplatelet therapy about doubles bleeding risk.
Dabigatran (Pradaxa)
Thromboembolism (e.g., stroke) prevention in nonvalvular atrial fibrillation: 150 mg BID
DVT/PE treatment (following 5 to 10 days' treatment with a parenteral anticoagulant) or prevention of recurrence: 150 mg BID. Start 0 to 2 hours before the next dose of parenteral anticoagulant would have been due, or at the time of discontinuation of heparin drip.
VTE prevention post-hip replacement: 220 mg once daily for 28 to 35 days. If started on day of surgery (1 to 4 hours post-surgery, assuming hemostasis achieved), initial dose is 110 mg.
Atrial fibrillation: Use 75 mg BID if CrCl 15 to 30 mL/min. No dosing information for CrCl <15 mL/min or dialysis.
DVT/PE treatment/prevention (adults) and VTE prevention post-hip replacement: No dosing information for CrCl ≤30 mL/min or dialysis
P-gp inhibitors may increase dabigatran levels.
For atrial fibrillation indication: Avoid P-gp inhibitors (e.g., amiodarone) if CrCl <30 mL/min. Reduce dose to 75 mg BID with ketoconazole or dronedarone if CrCl 30–50 mL/min.
For VTE/PE treatment/prevention (including post-hip replacement): Avoid use of P-gp inhibitors if CrCl <50 mL/min. Consider separating by several hours if CrCl ≥50 mL/min (hip replacement indication).
P-gp inducers could decrease dabigatran efficacy. Avoid P-gp inducers per labeling.
Use caution with antiplatelets. Co-administration with aspirin or clopidogrel about doubles bleeding risk.
Drugs that increase gastric pH could reduce efficacy. Take dabigatran at least two hours before antacids.
Edoxaban (Savaysa)
Thromboembolism (e.g., stroke) prevention in nonvalvular atrial fibrillation: 60 mg once daily in patients with CrCl 50 to ≤95 mL/min
DVT/PE treatment (following 5 to 10 days' treatment with a parenteral anticoagulant): 60 mg once daily, or 30 mg once daily if body weight ≤60 kg
Atrial fibrillation: 60 mg once daily for CrCl 50 to ≤95 mL/min, or 30 mg once daily for CrCl 15–50 mL/min. Not for use in patients with CrCl 95 mL/min.
DVT/PE treatment: 30 mg once daily for CrCl 15–50 mL/min (after 5 to 10 days of parenteral anticoagulant)
Not recommended if CrCl <15 mL/min
Use with other anticoagulants is not recommended, except when switching.
Caution with antiplatelets. Can use with aspirin ≤100 mg/day, with caution.
Avoid rifampin (a P-gp inducer).
Reduce dose to 30 mg once daily for DVT/PE indication in patients taking certain P-gp inhibitors (e.g., azithromycin, clarithromycin, erythromycin, itraconazole [oral], ketoconazole [oral], quinidine, verapamil).
Rivaroxaban (Xarelto)
VTE prevention post-hip or knee replacement: 10 mg once daily for 35 days [hip] or 12 days [knee] starting 6 to 10 hours post-surgery, assuming hemostasis achieved. Avoid if CrCl <15 mL/min.
Thromboembolism (e.g., stroke) prevention in nonvalvular atrial fibrillation: 20 mg once daily with evening meal to improve absorption. Dose is 15 mg with evening meal for CrCl ≤50 mL/min. Consider rivaroxaban 10 mg or 15 mg once daily in patients undergoing hemodialysis based on pharmacokinetic and limited clinical outcome data.
DVT/PE treatment or prevention of recurrence: 15 mg BID (with food to improve absorption) for three weeks, then 20 mg once daily with food for at least six months, then 10 mg once daily. Avoid if CrCl <15 mL/min.
VTE prevention in acutely ill medical patients at risk for VTE but without high risk of bleeding: 10 mg once daily for 31 to 39 days. Avoid if CrCl <15 mL/min.
Cardiovascular risk reduction in patients with CAD or PAD: 2.5 mg BID, with aspirin 75–100 mg once daily. (Patients with eGFR <15 mL/min were excluded from clinical trial, and <1% of included patients had eGFR <30 mL/min.)
Avoid use with drugs that are both P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, posaconazole, ritonavir, cobicistat).
In patients with CrCl 15 to <80 mL/min, the decision to use a combined P-gp/moderate CYP3A4 inhibitor (e.g., erythromycin) is a risk/benefit determination. Avoid with amiodarone or verapamil if CrCl is <80 mL/min.
Drugs that are P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) may decrease efficacy and should be avoided.
Avoid use with other anticoagulants. Caution with antiplatelets, including clopidogrel.
BID = twice per day, CAD = coronary artery disease, CrCl = creatinine clearance, DVT = deep vein thrombosis, eGFR = estimated glomerular filtration rate, PAD = peripheral arterial disease, PE = pulmonary embolism, VTE = venous thromboembolism.
Table 3
Source: [16]

It is also important to be aware that management of some DOAC interactions may vary based on kidney function. For example, verapamil increases DOAC levels. Rivaroxaban with verapamil should typically be avoided in patients with creatinine clearance less than 80 mL/min. In these cases, use of apixaban is acceptable [1].

Caution should be exercised when prescribing DOAC and medications that increase the risk of bleeding (e.g., antiplatelets, non-steroidal anti-inflammatory drugs [NSAIDs]). Ensuring the need for both agents is the first step. For example, aspirin used for cardiovascular primary prevention can usually be discontinued; aspirin for cardiovascular primary prevention is no longer routinely recommended, regardless of DOAC use [13; 14]. Duration of combination therapy is another concern. For instance, clopidogrel can be discontinued one-year post-stent placement for most patients with atrial fibrillation on a long-term DOAC. Limited evidence suggests that DOAC monotherapy is often sufficient at this point [15].

CONCLUSION

Managing drug-drug interactions with DOACs is of high importance to minimize preventable adverse effects. Clinicians should assess the importance of specific DOAC interactions and act to minimize their impact, if necessary. Therapeutic modification or additional monitoring may be necessary with some interactions [1,2].

RESOURCES

Indiana University School of Medicine
Drug Interactions Flockhart Table
http://medicine.iupui.edu/clinpharm/ddis/table.aspx
National Institutes of Health
Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications
https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/ritonavir-boosted-nirmatrelvir--paxlovid-/paxlovid-drug-drug-interactions
University of Liverpool COVID-19 Drug Interaction Checker
https://www.covid19-druginteractions.org

Works Cited

1. Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select drug-drug interactions with direct oral anticoagulants: JACC Review Topic of the Week. J Am Coll Cardiol. 2020;75(11):1341-1350.

2. Herink MC, Zhuo YF, Williams CD, DeLoughery TG. Clinical management of pharmacokinetic drug interactions with direct oral anticoagulants (DOACs). Drugs. 2019;79(15):1625-1634.

3. TRC Healthcare. Clinical Resource: Cytochrome P450 (CYP) Drug Interactions. Pharmacist's Letter/Prescriber's Letter. June 2020.

4. TRC Healthcare. Clinical Resource: P-glycoprotein Drug Interactions.Pharmacist's Letter/Prescriber's Letter. June 2020.

5. Tirona RG, Kim RB. Introduction to clinical pharmacology. In: Robertson D, Williams GH (eds). Clinical and Translational Science: Principles of Human Research. 2nd ed. London: Elsevier; 2017.

6. Bailey DG. Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol. 2010;70(5):645-655.

7. U.S. Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Last accessed October 6, 2023.

8. Lin JH. Drug-drug interaction mediated by inhibition and induction of P-glycoprotein. Adv Drug Deliv Rev. 2003;55(1):53-81.

9. Akamine Y, Yasui-Furukori N, Uno T. Drug-drug interactions of P-gp substrates unrelated to CYP metabolism. Curr Drug Metab. 2019;20(2):124-129.

10. Anticoagulation Centers of Excellence. Direct Oral Anticoagulant (DOAC) Drug-Drug Interaction Guidance. Available at https://acforum-excellence.org/Resource-Center/resource_files/-2023-02-08-064454.pdf. Last accessed October 6, 2023.

11. TRC Healthcare. Know Which DOAC Interactions Require a Med Change. Pharmacist's Letter/Prescriber's Letter. May 2023.

12. Abraham S, Nohria A, Neilan TG, et al. Cardiovascular drug interactions with nirmatrelvir/ritonavir in patients with COVID-19: JACC Review Topic of the Week. J Am Coll Cardiol. 2022;80(20):1912-1924.

13. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596-e646.

14. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227-3337.

15. Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet therapy in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with atherosclerotic cardiovascular disease: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021;77(5):629-658.

16. TRC Healthcare. Clinical Resource: Comparison of Oral Anticoagulants. Pharmacist's Letter/Pharmacy Technician's Letter/Prescriber's Letter. March 2023.

Evidence-Based Practice Recommendations Citations

1. Wigle P, Bernheisel CR. Anticoagulation: updated guidelines for outpatient management. Am Fam Phys. 2019;100(7):426-434. Available at https://www.aafp.org/pubs/afp/issues/2019/1001/p426.html. Last accessed October 12, 2023.

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