Drug-Drug Interactions With DOACs: The Current Landscape of an Ongoing Concern

Michael E. Field, MD, FHRS; Barbara S. Wiggins, PharmD, FACC


December 28, 2022

This transcript has been edited for clarity.

Michael E. Field, MD, FHRS: Hi. I'm Michael Field. I'm a clinical cardiac electrophysiologist in Charleston, South Carolina.

Barbara S. Wiggins, PharmD, FACC: Hi. I'm Dr Barbara Wiggins. I'm a clinical pharmacy specialist in cardiology.

Field: Barb, thank you so much for being here. We're going to talk today about drug-drug interactions as they pertain to the direct-acting oral anticoagulants, or DOACs. You've had extensive experience as a clinical pharmacist in cardiology and have also published a number of manuscripts about drug-drug interactions with cardiovascular medicines. We're really excited to have you today and hope to learn more about this important topic.

Wiggins: Thank you, Dr Field. Yes, this is coming up almost on my 25th clinical year in cardiology. Drug-drug interactions are something I've become very passionate about over the years, as a result of patients being admitted to the hospital for what are seemingly adverse effects of a medication but actually were precipitated by drugs being combined.

Special Considerations Surrounding the Use of DOACs

Wiggins: I started on this journey a few years ago with a couple of publications, and the DOACs have really come to the forefront of this, in part because of their popularity in prescribing but also because of the risks involved. The concentration of these medications, actually, could potentially rise as a result of a drug interaction and potentially increase bleeding risk for patients. It's great to be here and I'm looking forward to our discussion.

Field: I think this is a really important and interesting topic for clinicians to learn more about. Many of us worked through the days of anticoagulation using vitamin K antagonists like warfarin, and we're certainly well aware of all the different drug interactions. It was part of a daily routine. For any new medication, we had to be aware of the potential for the international normalized ratio (INR) levels to change.

Now that the DOACs have made it to market, it's really changed our practice in so many positive ways, but I also understand that there are a number of important drug interactions that people need to be aware of. For clinicians now, because it is so much easier to use these drugs, we often lose sight of some of the important drug interactions that can be out there. We look forward to hearing more from you about what these are. Just to kick us off, what is the importance of the drug interactions? Why is this a topic worth discussing?

Wiggins: I think drug interactions are probably one of the biggest challenges for healthcare providers. We have many medical alerts that pop up in our electronic medical records (EMRs) today. I think the challenge is how to quantify the drug interactions.

The FDA requires certain drug interactions to be conducted before a drug is approved, but the challenge is that it's a limited number of medications. When a drug first comes out on the market, we don't know much about it other than how that particular agent is metabolized.

When you're trying to evaluate everything, it becomes very challenging because those few drugs that are evaluated for an interaction are not necessarily able to be extrapolated to the mass of medications, even within the same class in which those medications fall.

Recognizing those limitations really puts a big onus on the healthcare provider to be able to interpret what they're supposed to do in a given situation when a drug interaction alert occurs. It's very complicated because you have multiple mechanisms in play.

You have what most everyone's familiar with, cytochrome P450 3A4, but you have other mechanisms. If they are affected by multiple mechanisms and multiple medications, it creates an even bigger problem. After medications have been out for a while, we'll see pharmacokinetic studies that have been done or some that were done in development. That's helpful, but there are many limitations from those studies as well.

The studies usually involve relatively small numbers of patients. When I say small, I mean single digits to maybe 10 or 12 patients. Those are also healthy volunteers — not patients with comorbidities and not patients on multiple medications. Those two medications are being evaluated in a silo, and so what we see from that interaction is really the best-case scenario.

We have to recognize that we would have to make it more pronounced in someone who may have other issues, such as end-organ dysfunction, that would make it potentially even worse. That's the complexity of it, and it just continues to be problematic throughout clinical practice.

Drug-Drug Interactions With DOACs: What Mechanisms Are in Play?

Field: What are the most common mechanisms of drug-drug interactions with the DOACs?

Wiggins: Probably the most common is the 3A4 and you also have P-glycoprotein in play. For dabigatran, for example, you have P-glycoprotein. For 3A4, you have rivaroxaban and apixaban. It isn't just as simple as saying "This is 3A4 and this is P-glycoprotein," because even between the DOACs, one relies on 3A4 more for metabolism than another.

The significance of one drug interaction may be more severe with one of those agents vs another one. That's where it gets even more intricate with regard to drug interactions. For example, we have some pharmacokinetic data with rivaroxaban and amiodarone.

We know that when the creatinine clearance is slightly low — so, moderate: less than 80 but greater than 50 — there's about a 1.86-fold increase in rivaroxaban concentrations when combined with amiodarone. Any time you increase the level of an anticoagulant, your biggest concern is going to be bleed risk.

Couple that with a patient who may have had a fresh stent, is on aspirin, a P2Y12 inhibitor, both, or all three, and then it just manifests even more. You may argue that if you see nearly a twofold increase, then you could just reduce the dose. Well, maybe. Maybe you could.

I think the better clinical judgment might be to try to find a DOAC that isn't going to interact as significantly to try to reduce that risk as much as you can. Again, the biggest challenge is a limitation of data to help us quantify these. Quantifying it helps you be able to make a more well-informed decision. 

Cardiovascular Drug Classes and Their Connection to DOACs

Field: Let's talk specifically. You mentioned amiodarone and rivaroxaban. For the practicing clinician, what are some of the big drug-drug interactions that they need to be aware of with regard to, for example, the antiarrhythmic drugs, the calcium channel blockers, and other classes? What are the ones that you want people, after hearing this session, to take home and remember?

Wiggins: I think some of the bigger ones are those select cardiovascular agents that are metabolized by or rely on 3A4. You're going to be dealing with drugs like verapamil, diltiazem, amiodarone, and dronedarone. Those are your bigger ones to be aware of.

Amiodarone is well known to have many drug interactions, and when you combine it with a DOAC, there's always that risk as well. Obviously, the severity is going to vary depending on other drugs that they're on, and renal insufficiency or impaired renal function also compounds that.

It's best to really become very familiar with certain agents, such as whatever DOAC you feel is best for your patients or whichever one you're most comfortable with, and really know the drug interactions that affect that particular DOAC.

When you know you've hit a roadblock or a potential concern, look at another one and see if it also has the same issues. We have to do that for a multitude of classes of medications. We do it for the P2Y12 inhibitors. We tease out which one we're going to choose for most of our patients.

I think you go down that same path with the DOACs as well. Which one appears to have the least amount of drug interaction concern for the patients that I'm seeing? I think that's where you start, but recognize that you may have to switch gears to a different agent if need be.

Field: Many clinicians are aware of drug interactions that are affected through inhibition of the 3A4 pathway, which results in, for example, higher levels potentially of the DOAC in the patient, and similarly, with the P-glycoprotein drug interactions. Tell us a little more about inducers and how that might be important. I think many clinicians aren't as aware of the relevance of certain drug interactions that have to do with drugs that are inducers.

Wiggins: The inducers, actually, are problematic, even for warfarin. They include the DOACs and warfarin. The main difference is that with warfarin you can monitor INR, so you can modify and adjust your dosing based on that induction.

Essentially, an induction is going to accelerate metabolism, resulting in reduced levels of the anticoagulation and potential increase in thromboembolic risk. I think probably, some of the highlights with medications that fall into that category include phenytoin, primidone, and phenobarbital. Although phenobarbital is not "used that much," primidone is actually metabolized to phenobarbital.

There's a significant concern that you're going to have reduced efficacy from a DOAC when combined with primidone, so you have to be very careful. St John's wort is an over-the-counter option. Many patients take St John's wort. It's also known to be an inducer, so that's something that clinicians should also be aware of. We don't have a large amount of data, but we do know it is an inducer, and in terms of trying to be optimally safe for patients, it's likely best that they do not continue taking it.

DOACs, COVID-19, and the Use of Paxlovid: A Complicated Landscape

Field: That's helpful, Barb. Let's shift gears a little bit to COVID-19 and the drug Paxlovid. I know many people have now, as they practice, gotten messages from patients or notifications that the patient has COVID-19 and they want to start Paxlovid as oral treatment. There are just so many different drug-drug interactions with this new agent. If you wouldn't mind, give an overview as to why Paxlovid is associated with so many drug-drug interactions.

Wiggins: Paxlovid is a combination product of nirmatrelvir and ritonavir. Ritonavir is very well known to be an inhibitor of 3A4, and it's added as a boosting agent in order to minimize its metabolism to increase efficacy.

Because it is such a strong inhibitor of 3A4, it is going to have a high propensity to cause many drug interactions. That's probably one of the biggest issues that we're facing. With regard to data, it's sparse. Many of the drugs or medications that we use, from a cardiovascular perspective, are not studied in combination with Paxlovid, so it really is unknown territory.

Many of the recommendations that you see out there are really drawn from the interaction of the 3A4 and how Paxlovid is metabolized, and how the medication that you're using is metabolized and how that interplay will unfold potentially in a clinical setting. That's how that pans out with regard to Paxlovid, and there are many significant drug interactions from a cardiovascular perspective with this combination product.

Field: What is a practical way for a clinician taking care of a patient, who's being asked to contemplate whether or not it's safe to start Paxlovid, looking through all their drugs that they're on? What's an overview or a general approach that works or that people can take home to try to understand how they might approach that subject?

Wiggins: There are many things to take into consideration. First of all, has the patient had prior COVID-19 infection? Have they been vaccinated? What is their overall risk? What is their age? What's their renal function? All of those are patient-specific parameters to be taken into consideration. Also, you have to think about the medication that is interacting with the Paxlovid.

Many of these recommendations are to hold the select cardiovascular agent, such as a DOAC or an antiarrhythmic, but that may, obviously, not always be feasible. For a drug like dofetilide, which requires hospitalization for initiation and continuation, that's not something that you necessarily want to discontinue.

When discontinuation is prohibitive, I think the obvious thing to do is to either look for an alternative agent to Paxlovid, or you just, unfortunately, have to forego treatment, from that perspective. Now, there are some varying recommendations with some of the DOACs out there that you may see — anywhere from holding it (again, depending on risk) to perhaps a dose reduction, specifically with apixaban.

The Importance of an Individualized Approach

Wiggins: Again, I think we have to be careful in that it was evaluated in a small number of HIV patients. If you have the ability to monitor apixaban levels, that may be a feasible option. In the absence of that, we just don't know the extent of the interaction. In the absence of monitoring, there is no general guidance in terms of how to dose these agents that is generalizable to all cases. I really think, in general, that all of these have to be individualized.

Field: Thank you. We'll include with this session some references at the bottom. You've published a guidance document that I think will be helpful for clinicians as a review of the various cardiovascular medicines, how they might interact with Paxlovid, and then a framework of how to approach that. I think that's going to be a helpful reference.

Wiggins: Dr Field, one of the reasons why my colleagues and I put many of these resources together was to inform and to highlight the importance of being aware of drug interactions. Hopefully, this will provide some level of guidance on how to manage them, realizing that, as I said before, it's going to have to be very individualized, based on the patient-specific parameters and overall risks involved, and, obviously, the medications that you're trying to combine and adjust for a given patient.

It is difficult because of the lack of data, and EMRs don't always quantify because we may not be able to. From a provider perspective, I would like to get your insight. Give me a sense of how you go about evaluating this when you see it in your practice every single day. What is your walk-through of how you evaluate this? What do you think would be helpful going forward?

Field: That's an excellent question. First and foremost is having the awareness that there are important drug-drug interactions with the DOACs. It's become all too easy to just prescribe the DOACs and figure out what you think the dosing should be based on certain patient-specific parameters but really not pay attention to all the other drugs the patient is on.

Just having that awareness of the possibility of important drug-drug interactions with the DOAC, first and foremost, I think goes a long way. Like you brought up, there's a large amount of alert fatigue when it comes to the EMR. Even some of the applications that we can use on our smartphone or portable devices that allow us to search for drug-drug interaction don't really help us understand if it is something that's minor or something that's more significant that we really have to be concerned about.

I think that's where having a collaborative relationship with a pharmacist is really important. I've seen many health systems incorporate their clinical pharmacists that previously primarily were involved in vitamin K antagonist monitoring (warfarin), INR monitoring, being utilized to educate patients on and monitor follow-up testing with DOACs. Those have been extremely helpful in our health system.

Practical Recommendations for Clinicians: An Essential Tool in Decision-Making

Field: On the inpatient side, interdisciplinary rounding to help catch drug interactions, avoid errors, and really help with the dosing has been really important. We alluded to some of the guidance documents out there. You've done a great job of collaborating and publishing very practical, hands-on documents that can be referenced. We'll include some of those in this session for clinicians to reference.

[Editor's note: Please refer to the following documents: Drug-Drug Interactions with Direct Oral Anticoagulants: Practical Recommendations for Clinicians; 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee; Select Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic of the Week]

Those documents provide the level of granularity and detail that we need to look a little deeper into the subject. Even just having the tables in these references that list the various DOAC drug interactions can be helpful. I think they also are worth a read because it really highlights, as you alluded to earlier, the fact that many of these recommendations are based on limited or incomplete data. We really have to take into account all the complexities of individual patients and their comorbidities and make a best guess.

Last, we need good clinical judgment, trying to really understand whether this is the right drug, are there other options, what are the individual patient bleeding risks vs stroke risk, and go from there. 

The Way Forward

Wiggins: I appreciate that. I have one other thought on this. I know it seems intuitive. You touched on when we have pharmacists in an anticoagulation clinic setting, and that is reviewing the patient's medication profile, looking at all the medications they're on, and stressing to patients the importance of utilizing one pharmacy and getting all their medications from a single source, so that they can minimize the risks of a significant drug-drug interaction.

Because medications are being prescribed by different providers, it's not always as easy as, "Oh, let me look at this and see if I can find it." It's not that simple because they may have received a prescription that you are completely unaware of. That pharmacy can certainly catch it on the very back end and potentially avoid something very serious.

Again, shared information with the patients and helping them recognize that having a sole source of medications are so vitally important; it helps everyone be able to optimize patient care and minimize the risk as well.

Field: That's great. I really appreciate your time. It's been really informative for me. Again, thank you so much for the information on what you do.

Wiggins: Thank you, Dr Field.

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