American Society of Consultant Pharmacists
View all recommendations from this societyReleased June 8, 2022
Don’t use strong CYP3A4 and P-glycoprotein inhibitors or inducers with Direct Oral Anticoagulants (DOACs) and periodically assess the medication regimen for such drug-drug interactions.
Direct Oral Anticoagulants (DOACs) such as dabigatran, rivaroxaban, and apixaban have significantly fewer drug-drug interactions (DDIs) as compared to warfarin. However, there are notable DDIs with strong CYP3A4 and P-glycoprotein (p-gp) inhibitors with DOACs, which clinicians need to consider necessitating dosage adjustments and monitoring for their older patients.
As a general principle, drugs that are inhibitors block the metabolic activity of one or more CYP450 enzymes and their effects usually occur immediately.Inducers, on the other hand increase CYP450 enzyme activity by increasing enzyme synthesis thereby causing a delay before this increased enzymatic activity has an impact on metabolism.
Each of the DOACs is a substrate for p-glycoprotein (p-gp), an efflux transporter located in the gut mucosa, and therefore, all DOACs are susceptible to drugs that induce or inhibit p-gp. Dabigatran requires efflux transportation by the p-gp, however it is independent of the CYP450 enzyme system. Apixaban and rivaroxaban, on the other hand undergo minor hepatic metabolism by CYP enzymes. Moreover, alterations in varying rates of renal elimination of DOACs should be equally considered as possibly additive to the metabolic effects affecting outcome from DDIs.
Since drug product labeling does provide specific guidance for management of inhibitor interactions, it is highly recommended to consult this information before prescribing decisions are made. It is prudent for clinicians to exercise caution when co-prescribing a DOAC and a strong CYP3A4 and/or p-gp inhibitor to minimize bleeding or conversely in the case of a strong inducer (rifampin) to prevent the risk of thrombotic events. Pharmacokinetic DOAC drug-drug interactions are clinically important because patient harm may go unnoticed due to no INR-equivalent testing and monitoring for DOACs as compared to warfarin.
In a recent review, the most significant interacting drugs to cause bleeding events with DOACs were amiodarone and ritonavir via inhibition of p-gp and CYP3A4. Conversely, a reduction in DOAC levels has been observed in some case reports and pharmacokinetic studies when used concomitantly with enzyme inducers (rifampin, carbamazepine) potentially resulting in therapeutic failure.
It is advisable for all clinicians to periodically assess the patient’s medication regimen for DDIs when DOACs are prescribed. Advanced age, low body weight, renal impairment, or concomitant antiplatelet medications are additional factors that may impact the severity and outcome of DOAC drug-drug interactions.
These items are provided solely for informational purposes and are not intended as a substitute for consultation with a medical professional. Patients with any specific questions about the items on this list or their individual situation should consult their physician.
How The List Was Created
(1–5)
A deprescribing task force led by chair (Manju T. Beier, Pharm D, BCGP, FASCP) was created by ASCP in November 2018. Members comprised of pharmacists practicing in academia, community and long-term care settings. The chair also invited pharmacists from international countries (Canada and Australia) where deprescribing initiatives have a strong focus and literature base. The collective experience and knowledge represent a focus on medication management, medication selection and reconciliation, and monitoring for drug-drug interactions (DDIs). The emphasis is on older adults no matter where they reside in step with ASCP’s mission.
Definition wise, deprescribing is a stepwise reduction of unnecessary or potentially inappropriate medications in concert with patient and family goals and wishes. We recognize that even with the best of intentions, many older adults are left on unnecessary and potentially dangerous or duplicative medications that might precipitate adverse events and other negative outcomes.
The task force prioritized formulation of the Choosing Wisely (CW) List, since the goals of CW intersect and overlap with deprescribing initiatives. The list was created to address general medication regimen review statements, and more importantly to address the paucity of statements that address DDIs with several incriminating medication therapeutic classes prescribed for older adults. After a review of published CW statements on www.choosingwisely.org and also a review of CW statements published by international countries, it was decided by consensus to have a strong emphasis on DDIs.
After several virtual meetings, the CW workgroup was divided into subgroups to formulate DDIs that have a strong evidence base in the literature and those that focus on CNS therapeutic classes, anticholinergic burden, heightened bleeding risk, and other pivotal pharmacokinetic and pharmacodynamic DDIs. For each statement the group formulated a rationale that was evidence-based accompanied with several recent, pertinent references. The compiled list (after several virtual meetings and email discussion) was further reduced to top ten statements with the strongest evidence base and practice trends on medication management in older adults.
The top five list was selected by consensus for initial submission.
Attached is a recently published guest editorial in ASCP’s journal that highlights the emphasis on DDIs.
Beier MT. Vigilance of Drug-Drug Interactions to Mitigate ADRs: Front and Center for Pharmacists (Guest Editorial). Sr Care Pharm 2020; 35:336-7.
(6–10)
A deprescribing task force led by chair (Manju T. Beier, Pharm D, BCGP, FASCP) was created by ASCP in November 2018. Members comprised of pharmacists practicing in academia, community and long-term care settings. The chair also invited pharmacists from international countries (Canada and Australia) where deprescribing initiatives have a strong focus and literature base. The collective experience and knowledge represent a focus on medication management, medication selection and reconciliation, and monitoring for drug-drug interactions (DDIs). The emphasis for all our statements is on older adults no matter where they reside in step with ASCP’s mission. Our first 5 CW statements were published in May 2021.
As previously addressed, the rationale for the new 2022 list (statements 6–10) includes one medication review statement in older adults with limited life expectancy, and three statements emphasizing the adverse combination of CNS medications that have a strong evidence base in the literature including tramadol’s potential for greater harm than benefit for pain relief, especially in older adults. We had previously highlighted pharmacodynamic DDIs for heightened bleeding risk, and this time our statement addresses the complexity of pharmacokinetic DDIs with Direct Oral Anticoagulants (DOACs).
Sources
Vazquez SR. Drug-drug interactions in an era of multiple anticoagulants: a focus on clinically relevant drug interactions. Hematology Am Soc Hematol Educ Program 2018(1):339-347.
Harskamp RE, Teichert M, Lucassen WAM, van Weert HCPM, Lopes RD. Impact of Polypharmacy and P-Glycoprotein- and CYP3A4-Modulating Drugs on Safety and Efficacy of Oral Anticoagulation Therapy in Patients with Atrial Fibrillation. Cardiovasc Drugs Ther 2019;33(5):615–23.
Wiggins BS, Dixon DL, Neyens RR, Page RL, Gluckman TJ. Select Drug-Drug Interactions with Direct Oral Anticoagulants. J Am Coll Cardiol 2020;75(11):1341–50.
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.
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):1052–1060.
Li A, Li MK, Crowther M, Vazquez SR. Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: A systematic review. Thromb Res. 2020;194:240-245.
Lee JY, Oh IY, Lee JH, et al. Drug-drug interactions in atrial fibrillation patients receiving direct oral anticoagulants. Sci Rep. 2021;11(1):22403.
