Reversal of DOACs: Making critical advancements

(contemplative electronic music) - This is Lab Medicine Rounds, a curated podcast for physicians, laboratory professionals, and students. I'm your host, Justin Kreuter, the Bow Tie Bandit of Blood, a Transfusion Medicine pathologist at Mayo Clinic. Today, we're rounding with Dr. Meera Sridharan, Assistant Professor of Medicine and Oncology and senior associate consultant in the Department of Hematology for today's topic on DOAC reversal, so direct oral anticoagulant reversal.

So thank you for joining us today, Dr. Sridharan. - Yeah, great. Thank you so much for having me. Excited to be here. - So let's kick us off with, you know,

why is it important for physicians to understand about the reversal of these direct oral anticoagulants? - Yeah, so, you know, it's been about 10 years since the first approval of the first direct oral anticoagulant. And the first FDA approved direct oral anticoagulant was the direct thrombin inhibitor dabigatran in 2010. About a year later, rivaroxaban was the first direct factor 10a inhibitor, and that was approved and followed by apixaban in about 2012.

And then there was another one, edoxaban, that was approved in 2014. All of these direct oral anticoagulants are at least as effective as vitamin K antagonists or warfarin for the prevention of stroke in patients with atrial fibrillation or for the treatment of venous thromboembolism. In addition, these agents are associated with less life-threatening bleeding, particularly less intracranial hemorrhage.

So given all of these good things about direct oral anticoagulants, since their introduction to the market, they are increasingly prescribed. And along with warfarin, DOACs are among the top 10 drugs contributing to ER visits in the United States.

So when the DOACs first came out in the market, one of the fears or barriers for some providers talking about these medications with their patients was the fear of what would we do if we needed to reverse the medication, whether that be for reversal of a serious bleed or for needing to reverse the medication because someone needed an urgent surgery. With its counterpart warfarin, we have a long track record.

Now, because of that long track record, we have kind of well set guidelines for what to do if a patient comes in with supratherapeutic INR and needs to be reversed for bleeding, or if they come in because they need a more urgent surgery. For the direct oral anticoagulants, it's important that we come up with a very similar framework for what to do if someone comes in for bleeding or needs a more urgent procedure.

- I'm glad you kind of brought this up because it really kind of gives us a good understanding of the landscape, this idea that, so as I'm hearing you, we have a long background and experience with Coumadin, warfarin, and that you're saying that starting in 2010, this anticoagulation field got a lot more complex, it sounds like. You listed off dabigatran, rivaroxaban, apixaban, edoxaban. So a lot more complex. And I think I heard you to say

that the complications or the bleed rate was a lot less with these direct oral anticoagulants. - That is correct. So compared to warfarin, the risk of severe bleeding, so particularly when I think of severe bleeding, I'm thinking of bleeds like into the head, they are less with direct oral anticoagulants than when compared to its counterpart warfarin.

But that brings up other kind of bigger questions as to because you have less severe bleeding, who is that best person that you would consider for a reversal of anticoagulation? - I see, 'cause that's how you're targeting which direction or which pathway to follow. Kind of the traditional warfarin anti-coagulant or one of these direct oral anticoagulants. - Correct. - Oh, fantastic. And then you were kind of getting at the idea

that although there's less severe bleeding, there was a concern by patients and physicians about if it is severe, what's the plan? - No, exactly. So, you know, when these medications first came out in the market, we were still learning about how they actually perform in clinical practice. So now with 10 years of experience, I think we're more comfortable saying that yes, the bleeding rates with direct oral anticoagulants seem to be less than with its counterpart warfarin.

But back then, whether we would counsel that for all patients at that time would not have been as strong of a statement. So through that experience, now, when I counsel patients, I can tell them that yes, compared to warfarin, we do see decreased bleeding rates. However, if there is a bleeding episode where we need to consider reversal, there are options. And then that's what we're gonna be talking about today. - That's awesome.

So then what have we learned new? I mean, you were talking about what we now have a decade plus of experience here. I imagine, are we learning more about what patient population to use them in and as well as the plans to reverse them? - Yeah. So in terms of the direct oral anticoagulants itself, we now have a general idea of which patient is a good candidate for a direct oral anticoagulant versus warfarin.

So for example, a lot of my patients that come in with acute venous thrombotic events, I am discussing a direct oral anticoagulant for them. Oftentimes, they opt to do a direct oral anticoagulant because there's no need to do the routine INR monitoring, which is huge for patients. Some reasons why a patient may consider warfarin over a direct oral anticoagulant are the underlying disorder that they have, warfarin may be better.

And there are still some disorders where we would want to use warfarin over a direct oral anticoagulant. Other considerations are mainly related to cost. - I see. We have really kind of a triad of the audience of this podcast. We've got physicians, we've got laboratory professionals, and we have students. And I think in the context of maybe for our laboratory professionals

and for our students, could you maybe elaborate a little bit about you brought up the idea that weekly monitoring for INR is really a huge thing. That's a big deal. And I think for some people, it's just maybe not that obvious on why is that a big deal? I mean, it's just a simple INR test, right? - Right. So it's a simple test, but it's a test. So for some patients, particularly when you're first starting warfarin, that could mean multiple visits to a provider a week.

Our hope is that eventually, we can get patients on a stable dose of warfarin where they don't need to be coming in that frequently. And I have some patients that often don't need an INR check for a month or so. But still, that's an additional laboratory test that they have to leave their house for, unless they are hooked up with some home INR monitoring, which all patients are not candidates for.

And so just having that taken off of their to do list for the day for a lot of patients makes a huge deal, especially if they're busy and don't have time to go to appointments, or for some of our elderly population where maybe they don't have people that can help them take them on a ride or something to go to a doctor's appointment, that could be an additional barrier as well. - Maybe just one follow up question on that.

I was curious, you mentioned that not everyone's really eligible for a home INR test. And I see your point on if people have difficulty getting rides why it might be a brilliant option for some folks,

but could you give us an example, maybe one example where it really wouldn't be ideal to do home INR monitoring for given patient? - So I guess the best candidate for someone who you could do home INR monitoring with is first of all, you need to make sure that you're dealing with a patient that reliably can monitor their INR at home and relay those results to the clinics. So that would be the first barrier if you're dealing with a patients that couldn't do that.

The second one is if you have a patient that is having kind of more fluctuant INRs, home INR monitoring may be more difficult because you may be needing to get more frequent checks. And sometimes, we prefer to use a typical lab assay rather than using a point of care lab essay type thing when we have INR values that are very fluctuant.

And so the ideal patient that I think of for home INR monitoring is someone that has been on a stable dose of warfarin, who has kind of very reliable INRs, is a reliable patient in that they can take their medication and also report out those results to the nurse team. - That makes perfect sense. And thank you for really kind of sharing with us a little bit on what that clinically looks like.

You know, why that INR testing is a big deal, why somebody may do home versus coming into a hospital and getting INR checked.

I had interrupted you. You were gonna talk about, I think the kind of updates to the, you know, what the reversal plans are for direct oral anticoagulants. How have they changed recently? - Yeah. So I guess it depends on what we define as recently, but at least since the introduction of direct oral anticoagulants into our treatment algorithm, we do have two specific reversal agents available. Each agent is specific to the class of medications.

So in 2018, idarucizumab was approved as a reversal agent for the direct thrombin inhibitor dabigatran. So idarucizumab is a humanized monoclonal antibody fragment that binds free and thrombin bound dabigatran and neutralizes its activity. And then later that year in May 2018, andexanet alfa was approved for the reversal of the direct factor 10a inhibitors apixaban and rivaroxaban.

So andexanet alfa is a recombinantly produced, catalytically inactive form of factor 10a that acts as a decoy to bind and sequester the anticoagulant medication. So these are the two FDA approved drugs that are specific for reversal of direct thrombin inhibitors and direct factor 10a inhibitors. For idarucizumab, which is the direct thrombin inhibitor reversal, the FDA approval is for patients who have severe bleeding or patients that need a more urgent surgery.

Whereas the FDA approval for Andexxa, which is the direct factor 10a reversal agent is only for patients with severe bleeding, although it's been used on kind of off label uses for urgent reversal for surgery as well. In addition to those two specific agents, prior to the FDA approval of idarucizumab and andexanet alfa, we had been using kind of non-specific reversal agents for the reversal of direct oral anticoagulants.

And so these nonspecific agents, and what I'm talking about are prothrombin complex concentrates, and so there's activated and nonactivated forms of that. And in reviewing kind of retrospective cohort data, looking at efficacy of these compounds, it appears that there may be some clinical efficacy for use of these agents. And so in many hospitals where andexanet alfa or idarucizumab may not be available, these prothrombin complex concentrates often work as an alternative medication.

- It's interesting to kind of hear about. And I think right now, we're talking about off-label use, and you're talking about some of the clinical experience that we've navigated. Certainly, been an interesting road since the introduction of these direct oral anticoagulants. It sounds like now with idarucizumab and andexanet alfa, we're really having specific reversal agents, as you mentioned.

And so I think that's kind of what the ideal was as we had four factor PCC as reversal for warfarin, and now we've got specific reversal agents for the other direct oral anticoagulants. Is it kind of problem solved, check, and and move on to solve other challenges?

Or are there still some challenges that remain for reversing these direct oral anticoagulants? - Yeah, so good question. So I think there are still challenges and I think they're mainly challenges to nuances of care. So I think one of the biggest challenges is who is the best candidate for DOAC reversal.

So as we spoke about before, some of the notable differences of the direct oral anticoagulants compared to warfarin is that direct oral anticoagulants often will have decreased life-threatening bleeding risk. And then the other kind of nuance is that direct oral anticoagulants have a shorter half-life than warfarin. And because of that shorter half-life, a reversal agent may not be absolutely necessary for all patients.

And often, managing the patient with supportive care alone with fluid resuscitation, transfusion support, while holding the anticoagulant and waiting for that anticoagulant to leave the patient's body may be enough treatment for that specific clinical scenario. However, there are certain clinical scenarios where you don't have that time to wait.

And so that's the scenario where we would say, okay, we really want to use this reversal agent because I don't think I have that time to wait for that anticoagulant to leave the patient's system.

The other challenge that I think we face, more so in hospitals that maybe don't have kind of an algorithmic approach for how we deal with reversal of anticoagulants is that now that we have these approved medications for reversal of anticoagulation, we also have our experience with the prothrombin complex concentrates. So the question comes, which one do we choose?

Do we go with the FDA approved indicated medications or do we go with the PCCs that we may have a little bit more experience with, and may also be cheaper for some hospitals? And so I think coming up with good protocols on guidelines of which patient is the best candidate for which product is very necessary. With the prothrombin complex concentrates, so I'm spending a lot of time talking about that because it is an option for facilities that cannot afford andexanet alfa and idarucizumab.

One of the things that needs to happen is we need to have data that shows that PCCs are at least equally effective as these other reversal agents. And right now, we don't have that. There are some trials that are trying to answer these questions. And so hopefully in the upcoming years, we'll be able to get a better handle on is andexanet alfa or idarucizumab definitely better than PCCs, or can we not actually say that?

Meta analyses and retrospective cohorts make me question whether the specific reversal agents are truly better than PCCs, but more data is to come on that. In terms of other questions that still remain. So the big kind of underlying question when you're giving a patient one of these reversal agents is you want to provide benefit without causing too much harm. And so when we're giving these reversal agents, we have to be cautious for potential side effects.

And one of the main side effects I think about are thrombotic risks. And when we're looking at the data for thrombotic risks from these studies, we have to look at that data in the lens of you're looking at a population where they're already at a really high thrombotic risk. You're taking away a medication, the anticoagulant that was supposed to prevent that thrombotic risk.

And then you're adding a medication that's supposed to help stop bleeding for an appropriate situation, but in that, you can also be causing more thrombosis. And so when you see the data regarding thrombosis rates and things like that, it's very important to look at when was that patient started back on the anticoagulation? Was the patient started back on anticoagulation? And that all sometimes is hard to capture in retrospective cohorts.

So prospective cohorts need to be done to explore that more, particularly when we're looking at comparative data of andexanet alfa, idarucizumab, and PCCs. And then the last challenge I think of is more of a challenge regarding acquisition of these medications for certain hospitals who may not have access to specific reversal agents. There's also problems that hospitals have to deal with with cost and acquiring these medications.

And then lastly, there's the kind of barrier that some facilities don't have standardized protocols to allow for appropriate utilization of these medications, meaning protocols to ensure that that right patient is getting the right medication rather than patients getting over-treated or under-treated. - Dr. Sridharan, I asked you for what you were thinking about for challenges and you gave us four brilliant ones right off the bat there, which is fantastic.

I think just to summarize for the audience, you brought the idea of sort of that nuance and I think your first and your third one, I kind of linked together with the idea of who should we be reversing, thinking about, as I hear you say, really that big clinical picture on where are we in the half-life of their dose. Is it even of value to reverse? And then the flip side of that, the third challenge you brought up was this kind of challenge versus harm.

The idea that if somebody is pro-thrombotic, that's why they're on the anticoagulant, and if you reverse them, we're back to that pro-thrombotic state. And so I really loved this idea. And I think particularly probably for the students listening, this idea of in clinical medicine, it's really important to kind of get that, take that larger viewpoint.

Each one of these are a topic where there's guidance and stuff out there, but really, it takes a clinician in combination with a lab to answer what's the best thing to do in this situation. As you said yourself, the nuance of the situation. I'm really also interested this idea you bring up about experience versus what's approved. And that's really a challenging space.

And I think highlights probably to our audience that this is an interesting topic, and it's going to remain an interesting topic as I hear you talk. And the fourth one about acquisition, I think that probably highlights probably for physicians as well as laboratorian listeners the idea you brought up that hospitals can develop their protocols for how are they going to use these medications or what are they going to do in situations.

And so I think you're highlighting for our audience the fact of if this is an interesting topic for you to get engaged, find out if your hospital has one of these protocols. If you are a pathologist or hematologist, look to see if you can participate on these committees that are making local policies. I really liked those points that you summarized for us because they are really wicked challenges. Next question I got for you, which really kind of wraps this up.

I'm kind of curious what do you think

that the future looks like for anticoagulant reversal? - So I think kind of piggybacking kind of off the last couple of points I mentioned, I think I've hopefully highlighted that essential to appropriate and safe use of anticoagulant reversal agents is having guidelines from national societies regarding how to address reversal of DOACs. So we're already off to a great start.

In 2019, the Anticoagulant Forum, which is a North American organization of anticoagulation providers published a manuscript providing guidance regarding use of DOAC reversal agents. And this manuscript kind of nicely outlines how you would approach a patient coming in with bleeding on a DOAC, puts patients in categories considering yes, you would want to reverse, no, you don't want to reverse, yes, it's okay to wait, no, it's not okay to wait.

And I really like guideline statements like that because it allows for people who maybe don't have as much time to go through all the literature to look at one document and have something to summarize the highlights. In the near future, I anticipate other groups will offer similar insights based off of new data emerging from other trials.

And as someone that works in the coagulation lab currently, I hope that as more facilities start having easier access to laboratory assessment, for example, direct factor 10a inhibitors, I hope to see utilization of these assays incorporated into our decision-making for DOAC reversal. I mean, to be quite honest, the only way to allow for that though is for our assays to be resulted in a very quick manner, which I think one of the barriers right now.

But I think we've already made a lot of progress in regards to that in the last several years. So that's something I hope to see improvements on in the upcoming years. As I kind of already mentioned, I would like to see some data comparing prospectively the specific reversal agents with the more general prothrombin complex concentrates because if it's a cost benefit ratio, and they both work exactly the same, and they have the same thrombotic risk, then it's an easy decision, right?

So I would like to see that data. And hopefully, that'll be coming. I guess thinking more broadly into the future, we're always hearing about new medications on the pipeline. One of the more exciting ones that I've heard about is a medication called ciraparantag. Hopefully I didn't butcher that too much. But it's a small synthetic molecule that's designed to bind to all DOACs. So that would be direct thrombin inhibitors, 10a inhibitors.

And then also, it's supposed to have activity in blocking some heparin medications like low molecular weight heparin. So if you think about it, that's basically a medication that's like the magic bullet of reversal agents, right? - It's the skeleton key, come on. - Yeah. So I mean, it sounds great. We need to still see some more data in clinical practice obviously. And when you have a medication that has such broad targeting, you then also have to worry about the thrombosis risks.

So there's probably pros and cons to this, but I think it'll be exciting to see how a medication like this performs in clinical trials. - Wow. Thank you so much, Dr. Sridharan. I think that it really highlights for our audience the importance of this topic, the idea that it's a moving, evolving field. There have been critical advances, really a lot of opportunities to participate and to get engaged for our audience listeners.

And really appreciate your expertise where you really have a strong background both in clinical medicine and laboratory medicine, which makes you a brilliant person for a given this podcast to our listeners. Thank you. - Thank you.

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