CBD and Direct Oral Anticoagulants

Rationale

Direct oral anticoagulants (DOACs) have been recommended as the preferred stroke reduction prophylactic treatment for patients with atrial fibrillation (AF) by the American Heart Association since their 2014 guideline update. The currently available DOACs consist of apixaban, edoxaban, rivaroxaban, and dabigatran.1 The most prominent adverse effect with DOACs is increased risk of bleeding. This bleeding risk can be of concern when considering the potential metabolic inhibition of DOACs through drug-drug interactions. Metabolic inhibition of DOACs can cause an increase in drug levels which further leads to an increase in medication adverse events, such as bleeding, as suggested by previous studies. Apixaban and rivaroxaban are inhibited by cytochrome P450 (CYP450) metabolism and P-glycoprotein(P-gp) inhibition, whereas edoxaban and dabigatran are mainly inhibited through P-gp inhibition.2 Research supports, albeit not extensively, the ability of cannabinoids to inhibit both P-gp and CYP enzymes which may lead to metabolic inhibition of DOACS and potentially bleeding events.

As of 2016, about 22.2 million people used cannabis for recreational or medical use. The percentage of users for recreational use, medicinal reasons, and both were 53%, 11%, and 36% respectively.3,4,5 With many states in the US legalizing marijuana for medicinal use and a few states beginning to allow recreational use, the number of cannabis users will only continue to grow as more states follow suit and begin to legalize cannabis use for medicinal and recreational purposes at the state level.2 Due to the increasing use of cannabinoids for both medicinal and recreational purposes, it is important to understand the risks associated with the use of cannabinoids with DOACs.

Algorithm

Explanation

The currently available DOACs are substrates of P-glycoprotein (P-gp). Product labels for these agents warn against the use of P-gp inhibitors due to decreased metabolism that leads to increased concentration and exposure, and ultimately, an increased risk of bleeding.6,7,8,9 In a group of 91,330 nonvalvular atrial fibrillation patients receiving DOACs (apixaban, edoxaban, rivaroxaban, and dabigatran), the major bleeding incidence rate differences per 1000 person-years of for a DOAC combined with amiodarone (P-gp inhibitor) vs DOAC alone was 13.94 (99% CI, 9.76-18.13). An additional analysis was done using the 12 concurrent medications categorized into two groups: a P-gp competitors’ group (digoxin, verapamil, diltiazem, amiodarone, and cyclosporine) and P-gp competitors and CYP3A4 inhibitors group (atorvastatin; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; erythromycin or clarithromycin; and dronedarone). In this analysis, the concurrent use of a DOAC with either group was associated with an increased risk of bleeding.10

In a separate case-control study, 89,284 patients with AF and venous thromboembolism were evaluated for increased risk of bleeding due to effects of P-gp/CYP3A inhibition or induction effect. For the P-gp inhibitors verapamil and amiodarone, verapamil was associated with a significant bleeding risk in univariate and multivariate analysis 1.61 (95% CI 1.06–2.50), 1.56 (1.02–2.39), respectively. Amiodarone bleeding risk in univariate and in multivariate analysis was 1.31 (1.04–1.64) and, 1.22 (0.98–1.54), respectively. The highest bleeding risks were associated with dabigatran‐verapamil, rivaroxaban‐verapamil, and rivaroxaban‐amiodarone with odds ratios of 2.29 (1.13–4.60), 2.18 (1.07–4.40), and 1.68 (1.14–2.49), respectively.11

Dabigatran (brand name: Pradaxa) additionally has warnings with potential severe renal impairment. According to the product labeling for dabigatran, concomitant use of P-gp inhibitors could possibly cause increased exposure of dabigatran compared to either factor alone.8 Few studies have been conducted evaluating P-gp inhibition effects of CBD containing substances; however, evidence supports CBD being a potent P-gp inhibitor. Zhu et. al. showed that CBD had similar P-gp inhibition effect as compared to verapamil on the accumulation of doxorubicin and rhodamine 123(Rh123), both known P-gp substrates. The intracellular accumulation of Rh123 was increased 1.4 to 2.2-fold in the presence of 10 and 30 uM CBD, respectively. The intracellular accumulation of doxorubicin was increased by 3.7 and 7.4-fold in the presence of 10 and 30 uM CBD, respectively.12 Due to the possibility of potent P-gp inhibition, concomitant use of CBD and DOACs should be used with caution as detailed by the above algorithm.

Artifacts for implementers

References

  1. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society [published correction appears in J Am Coll Cardiol. 2019 Jul 30;74(4):599]. J Am Coll Cardiol. 2019;74(1):104-132. doi:10.1016/j.jacc.2019.01.011
  2. Bose J, Hedden SL, Lipari RN, and Park-LeeKey E (2016) Substance Use and Mental Health Indicators in the United States: Results from the 2015 National Survey on Drug Use and Health. https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2015/NSDUH-FFR1-2015/ NSDUH-FFR1-2015.pdf
  3. Cox EJ, Maharao N, Patilea-Vrana G, Unadkat JD, Rettie AE, McCune JS, and Paine MF (2019) A marijuana-drug interaction primer: precipitants, pharmacology, and pharmacokinetics. Pharmacol Ther. 201:25–38.
  4. Schauer Gillian L., King Brian A., Bunnell Rebecca E., Promoff Gabbi, and McAfee Timothy A. (2016) Toking, Vaping, and Eating for Health or Fun. American Journal of Preventive Medicine. 50 (1):1–8.
  5. Paduch M, Thomason AR. Potential Drug Interactions Between Cannabinoids and Its Derivatives and Oral Anticoagulants. Hosp Pharm. 2022;57(1):188-192. doi:10.1177/0018578720985438
  6. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc.; March 2017.
  7. Eliquis (apixaban) [prescribing information]. New York, NY : Pfizer Inc; July 2016.
  8. Pradaxa (dabigatran etexilate). [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; November 2019.
  9. Sayvaysa (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo Inc; September 2017.
  10. Chang S, Chou I, Yeh Y, et al. Association Between Use of Non–Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation. JAMA. 2017;318(13):1250–1259. doi:10.1001/jama.2017.13883
  11. Gronich N, Stein N, Muszkat M. Association between use of pharmacokinetic interacting drugs and effectiveness and safety of direct acting oral anticoagulants: nested case-control study. Clin Pharmacol Ther. 2021;110(6):1526-1536.
  12. Zhu HJ, Wang JS, Markowitz JS, et al. Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. J Pharmacol Exp Ther. 2006;317(2):850-857. doi:10.1124/jpet.105.098541

Authorship

Author: Dr. Kojo Abanyie with input from Dr. Daniel Malone, Dr. Lorenzo Villa-Zapata, Dr. Xiaotong Li

Email: koa27@pitt.edu

Date: September 17, 2023