Advances in medicine and the possibility of keeping multiple diseases under control via medication have increased the number of prescriptions per patient in the last few years (1). As a result, drug exposure for each patient needs to be carefully evaluated, considering the possible drug−drug interactions (DDIs). In some cases, the pharmacological effect of one drug can be altered by the effect of another medication, either increasing or decreasing its bioavailability and causing unpredictable adverse effects (2).
The evaluation of DDI is pivotal in oncology and hematology, where the administration of multiple drugs (polypharmacy), acting either on the tumor or on hemostasis, needs to be critically considered, to avoid toxic and adverse events. In the context of cancer-associated thrombosis, the use of two categories of drugs has been rapidly increased in the last decade: tyrosine kinase inhibitors (TKIs) and direct oral anticoagulants (DOACs).
TKIs are commonly used in the therapy of several cancer types (3), and despite practical advantages, such as oral and easy daily administration, they may induce a variety of adverse effects (4). TKIs are mainly metabolized by cytochrome P450 3A4 (CYP3A4) and permeability glycoprotein (P-gp) in the gastrointestinal tract and the liver (5). CYP3A4, in particular, is responsible for the metabolism of a number of different compounds, and its state of induction or inhibition may alter the metabolism of several drugs (6). Pharmacodynamic interactions have been reported for TKIs including the use of antibiotics which alter the gut flora interfering with the enterohepatic circulation of TKIs decreasing their absorption (5), and the proton-pump inhibitors which may modify the bioavailability of TKIs (5). Therapeutic drug monitoring is suggested in clinical practice for patients taking cyclosporin or tacrolimus and concomitant TKIs (5). In order to avoid adverse events due to DDI, a series of considerations should be followed:
- listing all prescribed drugs, but also food, drinks, and supplements consumed by the patient;
- physical examination and evaluation of cardiac risk factors;
- close cooperation of all the healthcare professionals involved in the care of the patient in order to provide a comprehensive overview of the patient’s characteristics.
The risk and consequences of DDIs for patients treated with DOACs are still poorly investigated, especially in a real-world setting. Indeed, this is a central issue, considering the increase in the use of DOACs as a replacement of traditional anticoagulants for stroke prevention in atrial fibrillation (7) and for the prevention and treatment of venous thromboembolism associated with cancer (8). A modification of the mode of action of DOACs may cause either an increase in bleeding episodes or thrombotic events, situations that would require immediate intervention and could require hospitalization. The risk of major bleeding has been shown to be greater in older subjects (9), representing a vulnerable group of patients who often suffer already from comorbidities. Therefore, there is a clear urgent need to better understand the possible adverse effects due to DDIs with the use of DOACs.
Dabigatran, rivaroxaban, and apixaban are substrates of P-gp efflux transporter and of CYP3A4, which is responsible for drug metabolism in the liver. Some pharmacokinetic studies have evaluated the change in drug exposure with concomitant administration of P-gp and CYP3A4 inhibitors and inducers (10,11), such as the macrolide antibiotic clarithromycin, whose potent inhibitory effect on both P-gp and CYP3A4 has been reported to significantly increase DOAC serum levels (12). Nevertheless, product labeling for the correct use or dose adjustment of DOACs is not exhaustive and there is a lack of practical clinical guidance on the risk, outcomes, and appropriate management.
Two recent publications based on retrospective studies aimed to provide knowledge on the potential bleeding risk due to DDIs including:
- the administration of rivaroxaban and apixaban for atrial fibrillation together with P-gp and moderate CYP3A4 inhibitor (e.g. amiodarone, dronedarone, diltiazem, verapamil or erythromycin) (13);
- use of dabigatran, apixaban, or rivaroxaban with concomitant clarithromycin (which inhibits CYP3A4 and P-gp) or azithromycin (which has a weaker inhibitory effect on CYP3A4 and P-gp) as a comparison (14).
The primary outcomes for the study of Hanigan et al included major, clinically relevant non-major, and minor bleeding as defined by the International Society on Thrombosis and Haemostasis for the study of Hanigan et al. (13) with the primary outcomes for the study by Hill et al was hospital admission or emergency department visit with major hemorrhage. (14).
There are limitations in both studies consisting mainly in the retrospective design, the difference in baseline within examined groups, age of the population (which included patients with an average age of 68 years in the work of Hanigan et al.  and only patients older than 66 years in the study of Hill et al. ) and the lack of control of dose adjustment for DOACs, P-gp and CYP3A4 inhibitors and antibiotics. Nevertheless, the results of the two studies point toward an effect of DDIs on bleeding outcomes summarized as follows:
- the use of moderate P-gp and CYP3A4 inhibitors together with rivaroxaban or apixaban is associated with increased bleeding events compared to the use of DOACs alone. A composite of major, clinically relevant non-major and minor bleeding was experienced in 26.4% vs 18.4%, (hazard ratio 1.8; 95% CI: 1.19−2.73; p=0.006) of patients in the DDI and control group, respectively;
- the study failed to demonstrate any bleeding risk when analyzing inhibitor drugs alone;
- the use of clarithromycin together with DOACs (apixaban, dabigatran, or rivaroxaban) was associated with a small but statistically significant increased risk of hospitalization due to major hemorrhagic events compared to the use of azithromycin (95.9 [95% CI: 89.3−102.9] per 1000 person-years for clarithromycin group vs 53.1 [95% CI: 50.2−56.2] per 1000 person-years for azithromycin group).
The two studies differ with regard to the population tested. In the study of Hanigan et al. (13), the smaller population size did not allow for evaluation of the contribution of renal dysfunction. On the other hand, data from Hill et al. (14) showed a DDI between DOACs and clarithromycin after adjustment for kidney dysfunction. Both studies suggest a clinically significant risk based on real-world study populations, showing the possible outcome of the use of DOACs with specific P-gp and CYP3A4 inhibitors. These studies provide clinicians with further evidence supporting the necessity for checking potential DDI when managing anticoagulation treatment in CAT patients.
This article has been sponsored by an unrestricted educational grant from LEO Pharma A/S.
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- January CT, Wann LS, Calkins H et al. AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol 2019;74:132.
- Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
- Canadian Institute for Health Information. Adverse drug reaction-related hospitalizations among seniors, 2006 to 2011. Canadian Institute for Health Information; 2013. https://secure.cihi.ca/free_products/Hospitalizations%20for%20ADR-ENweb.pdf
- Vakkalagadda B, Frost C, Byon W, Boyd RA, Wang J, Zhang D, Yu Z, Dias C, Shenker A, LaCreta F. Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa. Am J Cardiovasc Drugs 2016;16(2):119–127.
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- Hanigan S, Das J, Pogue K, Barnes GD, Dorsch MP. The real-world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding. J Thromb Thrombolysis. 2020;49(4):636-643. doi:10.1007/s11239-020-02037-3.
- Hill K, Sucha E, Rhodes E, et al. Risk of hospitalization with hemorrhage among older adults taking clarithromycin vs azithromycin and direct oral anticoagulants. JAMA Intern Med. 2020;180(8):1-10.