Drug-Drug Interactions with DOACs: Proceed with Caution!

In modern day medicine, where most patients with atrial fibrillation (AF) are on a pharmacopeia of prescription medications, the concern about drug-drug interactions becomes a priority for a physician considering adding an oral anticoagulant to the mix, especially when many of the medications already on board utilize similar metabolic pathways. Unfortunately, in many large-scale clinical trials, the heterogeneity of patient prescriptions and multitude of medications used can sometimes make it challenging to accurately identify all the potential associations between drugs.

That's why observational studies and meta-analyses can be of particular use in post-marketing surveillance. In a previous report presented on Patient Care Online in December 2016, we highlighted a study published in the Canadian Medical Association Journal¹ that reported a possible interaction between the direct-acting oral anticoagulant (DOAC) dabigatran (Pradaxa) and statin drugs, where an increased risk of bleeding with dabigatran was noted with the use of lovastatin and simvastatin.

A recent study from a large Taiwanese cohort, published in JAMA in October 2017,² has analyzed many more drugs with which DOACs share metabolic pathways, highlighting interactions that could result in alterations of risk for major bleeding. Medications selected to study were ones commonly used in AF patients also taking DOACs, ie, diltiazem (22.7%), amiodarone (21.1%), digoxin (22.5%), atorvastatin (27.6%), or medications that affect either P-glycoprotein (digoxin, verapamil, diltiazem, amiodarone, cyclosporine) or CYP3A4 (-azole antifungals) or both metabolic pathways (atorvastatin, dronedarone, phenytoin, rifampin, erythromycin).

There were a large number of patients (n=91,330, mean age ~75 years, ~56% men) retrospectively analyzed from the Taiwan National Health Insurance Database with exposure to DOACs as follows: ~50% dabigatran, ~59% rivaroxaban, 14% apixaban (some patients were exposed to more than one DOAC). The study reported that there was an increased bleeding risk with DOACS when used concurrently with amiodarone (adjusted increase incidence difference of ~14 events/1000 person-years), fluconazole, rifampin, and phenytoin and a decreased risk of major bleeding when used with atorvastatin, digoxin, erythromycin and clarithromycin. Other cardiovascular medications, such as diltiazem, verapamil and dronedarone, were not associated with an increased bleeding risk. The different DOACs performed similarly.

3 key points to note:

1. Amiodarone, despite its side effect profile, is being prescribed to one-fifth of patients with AF on DOACs in Taiwan. Given the increased risk of bleeding with amiodarone and DOACs, this combination of medications should be used with extreme caution.

2. Atorvastatin, despite sharing metabolic pathways with DOACs, does not appear to increase risk of bleeding when used with DOACs and the two medications can probably safely be used together. It is unclear whether this conclusion about atorvastatin extends to other statins as other smaller studies have shown some data to the contrary.¹

3. Fluconazole taken concurrenlty with a DOAC was associated wtih the highest bleeding risk (138.5 events per 1000 person-years). When –azole antifungals or antibiotics are being prescribed in someone on DOACs, it is always beneficial to consult with the pharmacist and proceed with caution.

Points of caution:

 â–º This is a geographically and racially homogenous population (Taiwan-only study) so widespread conclusions to other areas and types of populations are limited.

 â–º This is a retrospective study (as opposed to a randomized controlled trial) and therefore, any conclusions are subject to residual confounding despite adjustment (ie, patients who received atorvastatin could have been “healthier” and with lower bleeding risk; conversely, those who received amiodarone could have a lower bleeding risk due to being sicker patients)

References:

1. Kohli P. Statins and dabigatran: Possible interaction? Patient Care Online. Dec 1, 2016.

2. 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;318:1250–1259. doi:10.1001/jama.2017.13883