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Expert Perspectives on Reversal of Oral Anticoagulant Therapy in Patients With GI Bleeding

  • Authors: Truman Milling, Jr, MD, FACEP; Brooks D. Cash, MD, FACG, AGAF, FASGE
  • CME / ABIM MOC Released: 9/23/2022
  • Valid for credit through: 9/23/2023
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  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.25 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for emergency medicine physicians and gastroenterologists.

The goal of this activity is that learners will be better able to understand of the role of direct-acting oral anticoagulant (DOAC)-specific reversal agents in the management of major DOAC-related bleeding.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Role of reversal agents in managing urgent bleeding for patients on DOAC therapy


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  • Truman Milling, Jr, MD, FACEP

    Associate Professor, Department of Neurology
    Associate Professor, Department of Surgery and Perioperative Care
    Research Scholar, Emergency Medicine Residency
    Seton Dell Medical School Stroke Institute
    Austin, Texas


    Truman Milling, Jr, MD, FACEP, has the following relevant financial relationships:
    Consultant or advisor for: Cellphire; CSL Behring; Octapharma; Portola/Alexion/AstraZeneca Research funding from: CSL Behring; Octapharma; Portola/Alexion/AstraZeneca
    Research funding from: CSL Behring; Octapharma; Portola/Alexion/AstraZeneca

  • Brooks D. Cash, MD, FACG, AGAF, FASGE

    Dan and Lillie Sterling Professor of Medicine
    Chief, Gastroenterology, Hepatology, and Nutrition
    UT Health Science Center at Houston
    McGovern Medical School
    Houston, Texas


    Brooks D. Cash, MD, FACG, AGAF, FASGE, has the following relevant financial relationships:
    Consultant or advisor for: Phathom Pharmaceuticals; RedHill Biopharma 
    Speaker or member of speakers bureau for: RedHill Biopharma


  • Asha P. Gupta, PharmD, RPh

    Associate Medical Education Director, Medscape, LLC


    Asha P. Gupta, PharmD, RPh, has no relevant financial relationships.

  • Frederick Stange, DO

    Scientific Content Manager, Medscape, LLC


    Frederick Stange, DO, has no relevant financial relationships.

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  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Susan L. Smith, MN, PhD, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Expert Perspectives on Reversal of Oral Anticoagulant Therapy in Patients With GI Bleeding

Authors: Truman Milling, Jr, MD, FACEP; Brooks D. Cash, MD, FACG, AGAF, FASGEFaculty and Disclosures

CME / ABIM MOC Released: 9/23/2022

Valid for credit through: 9/23/2023


Activity Transcript

Truman Milling, Jr, MD, FACEP: Hi, I'm TJ Milling, an emergency physician from Austin, Texas, the Seton Dell Medical School Stroke Institute. 

I'm delighted to be joined by my colleague, Brooks Cash, who is the Dan and Lillie Sterling professor of medicine, chief of gastroenterology, hepatology, and nutrition at UT Health Science Center, just down the road in Houston at the McGovern Medical School. Welcome, Brooks!

Brooks D. Cash, MD, FACG, AGAF, FASGE: Thanks very much, Truman. I appreciate being able to join you today and I'm looking forward to our discussion.

Dr Milling: So, going over the GI bleeding burden, I know from studying all major hemorrhage that well over two-thirds of major hemorrhage patients, as defined by the clinical trials, are GI bleeds. They're an everyday occurrence in emergency departments and the major bleeding scenarios are very common, weekly for an individual physician. Dr Cash, would you like to go over the etiology and clinical presentation of bleeding, upper GI versus lower versus variceal, the types?

Dr Cash: You bet and thank you for segueing to this. And as Truman mentioned, this is a very common scenario, and also lower GI bleeds can often be upper GI bleeds. So upper GI bleeds can present with lower GI bleeds in extreme circumstances with a lot of blood loss. So, this is what we're thinking about when we get called by the emergency department or emergency room, or other providers, and we've got a history of GI bleeding. First and foremost, of course, peptic ulcer disease and we also are very careful to identify those patients who are at risk for esophageal variceal bleeding, so those patients with chronic liver disease and portal hypertension. 

But things that can cause significant bleeds, like Dieulafoy lesions, which is a caliber persistent artery. So, it's an artery that rises to the mucosa and then explodes, and then sinks back down. It can be very difficult to find, usually with a herald bleed type of situation, aortoenteric fistulas, that's why it's so important thinking about herald bleeds to get a history of abdominal aortic aneurysm (AAA) repairs. So, lots of different ideologies, lots of causes of peptic ulcer disease, which is by far the most common cause of upper GI bleeding, typically NSAIDs, but also H. pylori, malignancies can do this and some rare cancer syndromes and neurohormonal syndromes.

In general, patients are going to present with symptoms like hematemesis or melena. They may present with hematochezia. Remember, we always have to think about upper GI bleeds, even in patients who present with hematochezia. In those patients, it's critically important to assess their hemodynamics, take a risk factor history to think about those upper GI sources, and we may end up doing an endoscopy in those patients. Lightheadedness and syncope are also, actually, relatively worrisome symptoms, and we make decisions on when to scope based on risk scores, and those are symptoms that are included in our risk scores. 

In terms of the overall risk of bleeding in patients receiving anticoagulation therapy, that's another risk factor, and that is somewhere between 1.5% and 5%. Now, anticoagulants don't necessarily cause the lesion that causes the bleeding, but they accentuate the lesion that causes the bleeding and can lead to clinically significant bleeding and even death. 

And here's the outcomes that we see in patients with upper GI bleeding, and these have changed a bit over the last several decades. We used to say that GI bleeding carried as much of a risk factor as an MI in terms of death. Those numbers have come down. We've gotten better with regards to our medical therapies. We give proton pump inhibitors upfront. We continue those after intervention. We are better at supporting patients with blood products, and we've gotten a better idea of exactly how to do that and when to do that. So we have seen a gradual decrease in the significant mortality and even morbidity rates that are seen with GI bleeding, upper GI bleeding in particular.

But I think it still is important to recognize that patients can die from this condition. They can have MIs. They can have strokes, seizures. They may have to go to surgery. They can rebleed, that increases the cost of care, as well as complication rates. So, GI bleeding is a significant factor and carries a lot of morbidity, and even some mortality associated with it. 

Dr Milling: Thanks, Dr Cash. Yeah, it's a very good point that we forget. We get all excited about the STEMI when it comes in and the STEMI's mortality is about 8%.

Dr Cash: Yeah.

Dr Milling: And you look at an anticoagulated GI bleed, it's about 8%.

Dr Cash: Yeah.

Dr Milling: So, it should get our attention just as much when it hits the door. And of course, anticoagulants used to be simple, right? It was just warfarin and then maybe heparin, but probably not in a patient coming to the ER. They didn't have many people on heparin outpatient, enoxaparin maybe. But now, we have a whole monopoly of anticoagulants. Fortunately, just at the moment, 3 mechanisms, though there are others in the pathway in phase 2 and phase 3 trials. But right now, we have warfarin, the vitamin K antagonist, the classic. We have the factor Xa inhibitors, which directly interact with factor X, blocking its action, and that's rivaroxaban, apixaban. And dabigatran, the direct thrombin inhibitor. 

Each of these has a mechanistic reversal agent. They're not equally available and they're not equally costly either, but they have been developed and they're FDA-approved. So, for warfarin, the first anticoagulant got its reversal agent back in 2013, the 4-factor PCC. Now, warfarin blocks vitamin K epoxide reductase, so you lose all your vitamin K-dependent factors. They're more on the activated one, and that's step-- that's factors II, VII, IX, and X, protein C and S. 4-factor PCC preparations that are approved by the FDA in the U.S. contain those factors, including the anticoagulants proteins C and S. Then, of course, you can also give vitamin K. The problem with vitamin K is it just doesn't work quickly enough because the liver has to ramp up those factors, and that can take 4 or 5, 6 hours just to get started and up to a day to normalize. It doesn't mean you shouldn't give it because some, like factor VII, for instance, has a 2- or 3-hour half-life. You can see a factor fall-off and raise of the INR in 24 hours if you don't accompany that dose (of 4-factor PCC) with some vitamin K as well.

Plasma is our historical therapy used for decades. It's what I was trained in residency. It has a problem with volume. It has a problem with possible transmission, now that's very low in our current blood bank scenario, transmission of viral illness, and speed of getting it into the patient, also due to the volume necessary to get it. For the factor Xa inhibitors, there's the recombinant factor Xa, modified factor Xa molecule, which is what andexanet alfa is, which binds up the inhibitor, allowing your native factor Xa to function. And for idarucizumab, it's the monoclonal antibody, so that literally goes in and plucks the anticoagulant out of the picture with an antibody.

The question is, if you have all of those available, then you have to decide who to use them in. And the question for GI bleeding, and it's a difficult one to answer, even with the Rockall Score or Blatchford, ‘How life-threatening is the bleeding scenario in front of me?’ You can measure the INR for warfarin, but it's not so easy for the DOACs. And there are some assays, but they're not broadly available. So you can tell by an INR, "This patient's anticoagulant, warfarin." To a lesser degree, you can get a qualitative sense for rivaroxaban with the INR, but not with apixaban.

Time is not a great surrogate, but it's all we have. When did they last take the anticoagulant? If it was within a couple of half-lives, which the half-lives of apixaban or rivaroxaban are 8 to 11 hours, we probably are dealing with the anticoagulant in addition to the bleeding scenario. If it's beyond that, if it's been a day or 2 and assuming normal kidneys, because these are all excreted renally to some degree, then you probably aren't and you're just dealing with the bleeding, not the anticoagulant. So, time can be helpful and, frankly, it's all most of us have right now when it comes to DOACs to determine how much of the drug may be onboard.


Dr Cash: I absolutely agree with everything you said, and this is a tough management scenario. These patients are sick. We do generally use a pre-endoscopy score to help us triage the patient, but also decide on our management side of it. From a GI standpoint, we've got a number of different options with regards to these patients. Because they are high-risk for significant complications, we do recommend that they'd be in an intensive care setting. Sometimes, that's the ED. More often than not these days it's in the ED because our hospitals are full, but it can also be in an ICU, even a SICU or a trauma ICU even. But they need to be in an intensive care setting with appropriate hemodynamic support, that's really key.

We have realized over the last decade or so that we were coming in too quickly to scope patients, and that's part of the... Our consultants are yelling at us saying, "You've got to scope. You've got to scope. You've got to scope!" and we often react to that. We actually need to resuscitate these patients first, and we've found that we're harming patients by coming in and scoping too soon before they were resuscitated. The same thing with regards to blood transfusions. About 10, 15 years ago, we realized that we were transfusing too aggressively. And now, our new goal is 7 for hemoglobin. In most patients, cardiac patients, about 9. When I trained, it was 10 for hemoglobin, 10 and 30 was what we wanted, and that's gone by the wayside.

So, when we're specifically thinking about anticoagulated GI bleeders, we can watch them, which we do most of the time. As Truman noted, we have timing guesses that we make with the DOACs. We don't want to reverse patients necessarily with vitamin K. It can take a long time to get them back. There's a thrombotic risk. You also can remove therapy with things like activated charcoal and hemodialysis. But, of course, if you're going to use activated charcoal, that messes up your plans for GI bleed endoscopy, so that's not really practical and hemodialysis isn't either, and these patients are already hemodynamically stable. So, we’re really left with -- really I think the binary choice is that we watch and we resuscitate and then scope, or we decide to take an active intervention and reverse them somehow, either with those factors that Dr Milling discussed or perhaps some other approach, but that's generally how we manage these patients.

The other conditions or other questions that we need to ask is, ‘Where do we think that bleeding is located -- is it upper GI bleed versus lower GI bleed?’ We tend to think of upper GI bleeds as being a bit more morbid or having greater risks than lower GI bleeds. Most lower GI bleeding is diverticular, and it usually stops on its own. What agent is the patient taking? When did they receive it? What was their dose? Are they on any other therapies? So, are they on an NSAID or an antiplatelet agent that could affect hemostasis? And what are their comorbidities? And I think that's really the key question is, what are their comorbidities? When do we reverse them? What are the risks? I think we need to do this in a very collegial and constructive fashion, talking to the co-managers of these patients' comorbidities. They're the people who are writing for their anticoagulation, who understand it better than we, the gastroenterologists, do.

And finally, I think we have to decide and make a case that if we are going to reverse, that this needs to be a life-threatening scenario because there are risks, so to say, with reversing people's anticoagulation. Thrombosis, of course, is the big one. We don't have good randomized controlled trials to dictate who we reverse, who we don't reverse, and there are so many different situations that it's tough to come up with exact decision rules. So, a lot of this is a judgment call, just like the decision on when to do endoscopy, and we have to balance those decisions about reversal and risk of thrombosis in these patients and their subsequent risk of complications from bleeding. So it is a difficult decision without a real clear answer.

Dr Milling: Yeah, I think that there's a tipping point. You have the obvious, right? The variceal bleeder, person who is just actively hemorrhaging and then shock. And then it's not just a question of reversal. It's a question of, as you said, resuscitation, probably massive transfusion protocols, tranexamic acid (TXA), all these other interventions to stabilize the patient, and reversal would be part of that. Then there's the patient who's not quite there yet, and that's the harder decision. Do I reverse them? Are they going to become unstable? Because the instability, once it happens, it's Pandora's box and you have to do a lot of things all at once.

Let's talk about the guidelines which give us some guidance on once we have decided to reverse, what to use, right? And that's an important question, and what to use ideally may not be what's available in your center either, so there's some second-tier recommendations as well. 

Dr Cash: If you're thinking about using specific reversal agents, you need to have a very good discussion with your pharmacy folks because they're the ones who are going to have to make it up very quickly and administer it very quickly, and they need to know what they're doing when they do that. So, it's a close coordination between the emergency department and the pharmacy and the end user, or person who's saying, "I think we need to reverse this," which is generally the endoscopist. 

Dr Milling: So, there's some consensus across guidelines, but there's also some wrinkles between them. What are your thoughts on that?

Dr Cash: You're right, there's guidelines from cardiology groups and intensive care groups. Of course, as a gastroenterologist, I'm going to be mostly aligned with the GI guidelines. The ACG and the Canadian Association of Gastroenterology came up with some guidelines, published these in The American Journal of Gastroenterology in 2022, and basically said, "If you're going to reverse warfarin, then use 4-factor PCC." Don't use fresh frozen plasma, don't use vitamin K. If you're going to use platelets, the only real situation to do that is in somebody who's actively bleeding with thrombocytopenia. Otherwise, don't bother, don't stop aspirin. There's nothing you can do really to reverse that.

And then, specifically for the DOACs, in the case of life-threatening bleeds, they were a bit soft in terms of their statements, but they said, "We suggest that you consider using one of the specific reversal agents." And quite frankly, that's exactly what we do. We take each case individually, we talk to the prescriber if we can find them or get ahold of them, make sure that we understand the implications for reversal, the risks for reversal, and then make sure that we actually have it in-house and that the pharmacy is able to do it. Sometimes, that's not the case and we shift over to 4-factor PCC. So, I think we tie in with the guidelines very nicely, and these recent guidelines don't really deviate that much from the other guidelines as well, which recommend either PCC or direct-acting reversal agents. So, I think they're relatively in line, but it's hard to anticipate every single scenario, so you really have to individualize the approach.

Dr Milling: All right. Well, I think that brings us to take-home points from the talk. The common clinical presentation we're dealing with, with a high morbidity and high mortality, I think resuscitation is an important part of the care here. It's not just about the anticoagulant reversal; it's about treating the whole patient. Upper GI bleeds need a proton pump inhibitor for acid suppression, antibiotics, and if they have a variceal source, they need octreotide. And when the anticoagulant is present and pretty sure it's part of the bleeding scenario, we need to consider reversal with some of the methods we discussed about. And endoscopy, of course, is the mainstay of the definitive treatment for an upper GI bleed. Dr Cash, is there anything you'd like to add?

Dr Cash: Yeah, I think that you really hit the high points. I think the last bullet is something that we do need to keep in mind, and that is that our guidelines are exactly that -- they're expert opinion based on existing evidence. We don't have a lot of evidence to support some of the things that we do in the management of these patients, and anticoagulation reversal is one of those areas. So, while there are recommendations, a lot of the recommendations are a bit soft in terms of how demonstrative they are with regards to reversing which patients and when. Every patient is different, and it's hard to anticipate all of those scenarios.

So, I think it's incumbent on us to use those risk assessment scores and make sure that we are consulting with the patient's provider who's writing for the anticoagulation, assessing that risk of reversal, talking to the patient about that as well, if we're able to, and those things, I think, can't be underscored in that decision to reverse. And I would also underscore that if we do decide to reverse, then we need to be committed to going to the next step relatively quickly, and that usually is going to be endoscopy.

Dr Milling: Right, and then the step beyond that, of course, which is resumption at some point, when we're all going to be thinking about thrombotic risk down the road. 

Dr Cash: Yep.

Dr Milling: Dr Cash, thank you so much for this great discussion and thank you to the audience for participating. Please continue on and answer the questions that follow to get your CME to complete the evaluation. Thank you.

This transcript has not been copyedited.

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