Direct oral anticoagulant (DOAC) agents have become commonly used over the last 9 years for treatment and prophylaxis for thromboembolic conditions, following approvals by the United States Food and Drug Administration. These anticoagulant agents, which include a direct thrombin inhibitor and factor Xa inhibitors, offer potential advantages for patients over warfarin; however, bleeding emergencies with DOACs can present diagnostic and therapeutic challenges because, unlike traditional anticoagulants, their therapeutic effect cannot be easily monitored directly with common clotting assays. This review examines the growing body of evidence on the uses and risks of DOACs in the emergency department, including initiation of therapy and reversal strategies.
As you begin your shift, the first patient is a 70-year-old man brought in for a ground-level fall with isolated head injury. A review of the patient’s history reveals atrial fibrillation, and he is currently on anticoagulation with apixaban. A rapidly obtained CT scan of the head shows a subdural hematoma. As you resuscitate the patient, you wonder how best to assess his anticoagulation status and how best to address reversal.
Later in the shift, a 50-year-old woman is brought in by EMS for intentional overdose of medications, in a suicide attempt. Her list of home medications includes sedatives as well as dabigatran, prescribed for a recently diagnosed DVT. The patient is somnolent, so specific ingestants cannot be ascertained. You wonder if there are monitoring tests, beyond PT/PTT, that might determine whether a dabigatran overdose is present, and if so, how should it be managed to prevent further injury?
As your shift is coming to a close, a 45-year-old man presents with leg swelling and erythema after a recent airplane trip. Your bedside ultrasound is consistent with DVT. The patient hates the thought of frequent blood tests, and he asks whether there are any options for treatment besides warfarin. You know that DOACs may be an option for him, but you wonder what the best way is to engage in shared decision-making with him.
Since the approval by the United States Food and Drug Administration (FDA) of dabigatran in 2010, the prescription market for this new class of medications with direct anticoagulation effect has increased markedly. In the United States, DOACs now account for a similar proportion of office visits for anticoagulant use as warfarin. This trend has also been seen in other countries, as DOAC use has grown rapidly.1-3 Assuming that this trend continues, emergency clinicians will continue to see more patients taking DOACs, as these drugs replace alternative anticoagulant therapies.
Compared with warfarin and other oral anticoagulants, DOACs offer potential benefits, including reduced need for monitoring and a potential for reduced bleeding complications. However, the advisability of using the DOACs was initially challenged, due to the lack of an effective reversal agent to use in the event of an emergency and for the risk of unintentional overdose in patients with altered drug metabolism. As with traditional anticoagulants, patients using DOACs are often medically complex, and they may frequently present for emergency department (ED) care.
This issue of Emergency Medicine Practice focuses on updates to the body of literature on DOACs since the last review in 2013. Since that time, many studies, including longer-term follow-up from large trials and registry data for patients taking DOACs, have become available. Given the likelihood that these medications will continue to increase in popularity, emergency clinicians need to have expertise in dosing, monitoring, reversal, and risks in clinical practice. This review will focus on use of DOACs for the indications of stroke prevention in atrial fibrillation and treatment and prevention of recurrence in venous thromboembolism (VTE).
Terminology for this class of anticoagulants has included, most commonly, DOAC (for direct oral anticoagulant) or NOAC (for “novel” oral anticoagulant or “non–vitamin K” oral anticoagulant).4 Given their direct mechanism of action, and the time since approval for these agents, DOAC may be the preferred term in the future.
A literature search was performed in PubMed using the following terms: DOAC, NOAC, dabigatran, apixaban, edoxaban, rivaroxaban, betrixaban, pulmonary embolism, deep venous thrombosis, and prothrombin complex concentrate. Over 200 articles from 2000 to the present were reviewed. The Cochrane Database of Systematic Reviews was searched for systematic reviews using the key term DOAC, which identified 5 reviews. Guideline statements specifically regarding DOAC treatment and reversal were released by the American Heart Association (AHA) in 2017, the European Society of Cardiology in 2015, and the American College of Cardiology in 2017. These guidelines include data based on large randomized controlled trials for multiple conditions.
An appraisal of literature was performed, which favored large randomized trials over smaller cohort studies and case reports. Good-quality evidence regarding safety and efficacy of these medications in comparison to warfarin and heparin-based anticoagulants has been published based on long-term cohort studies. Unfortunately, direct comparisons between DOACs are limited to small numbers of studies with predominantly poor-quality evidence. Differences in inclusion and exclusion criteria, primary endpoints, and assessment of safety outcomes between studies also limits comparability between trials. When available, recommendations in this article are evidence-based. Recommendations based on accepted practice or expert consensus are explicitly noted as such.
1. “The patient denied taking warfarin or enoxaparin for his DVT, but we didn’t ask about other anticoagulants.“
DOACs are now being prescribed frequently, and patients should be questioned specifically about these medications if they have a condition that indicates they might be using them.
5. “The INR was below 2.0, so I didn’t think the anticoagulation effect was present.”
Standard coagulation testing is insensitive for evaluating DOAC anticoagulant effect, and even normal results can be present, despite therapeutic levels of medication.
9. “I didn’t think the patient would be at risk of clotting after DOAC reversal.”
Reversing DOACs can put patients at higher risk of new thrombosis, and discussion of the risks and benefits of reversal should be documented, if possible.
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available. In addition, the most informative references cited in this paper, as determined by the author, are highlighted.
Jeff: Welcome back to EMplify the podcast corollary to EB Medicine’s Emergency medicine Practice. I’m Jeff Nusbaum and I’m back with Nachi Gupta. This month, we are tackling a topic for which the literature continues to rapidly change - we’re talking about the ED management of patients taking direct oral anticoagulants or DOACs, previously called novel oral anticoagulants or NOACs.
Nachi: Specifically, we’ll be focusing on the use of DOACs for the indications of stroke prevention in atrial fibrillation and the treatment and prevention of recurrent venous thromboembolisms.
Jeff: This month’s article was authored by Dr. Patrick Maher and Dr. Emily Taub of the Icahn School of Medicine at Mount Sinai, and it was peer reviewed by Dr. Dowin Boatright from Yale, Dr. Natalie Kreitzer from the University of Cincinnati, and Dr. Isaac Tawil from the University of New Mexico.
Nachi: In their quest to update the last Emergency Medicine Practice issue on this topic which was published in 2013, they reviewed over 200 articles from 2000 to present in addition to 5 systematic reviews in the cochrane database, as well as guidelines from the American Heart Association, European society of cardiology, and the american college of cardiology.
Jeff: Thanks to a strong literature base, Dr’s Maher and Taub found good quality evidence regarding safety and efficacy of the DOACs in relation to warfarin and the heparin-based anticoagulants.
Nachi: But do note that the literature directly comparing the DOACs is far more limited and mostly of poor quality.
Show More vJeff: Fair enough, we’ll take what we can get.
Nachi: Well, I’m sure more of those studies are still coming.
Jeff: Agree. Let’s get started with some basics. Not surprisingly, DOACs now account for a similar proportion of office visits for anticoagulant use as warfarin.
Nachi: With huge benefits including reduced need for monitoring and a potential for reduced bleeding complications, this certainly isn’t surprising.
Jeff: Though those benefits are not without challenges - most notably the lack of an effective reversal agent and the risk of unintentional overdose in patients with altered drug metabolism.
Nachi: Like all things in medicine, it’s about balancing and finding an acceptable risk/benefit profile.
Jeff: True. Let’s talk pathophysiology for a minute - the control of coagulation in the human body is a balance between hemorrhage and thrombosis, mediated by an extensive number of procoagulant and anticoagulant proteins.
Nachi: Before the development of the DOACs, vitamin K antagonists controlled the brunt of the market. As their name suggests, they work by inhibiting the action of vitamin K, and thus reducing the production of clotting factors 2, 7, 9, and 10, and the anticoagulant proteins C and S.
Jeff: Unfortunately, these agents have a narrow therapeutic window and many drug-drug interactions, and they require frequent monitoring - making them less desirable to many.
Nachi: However, in 2010, the FDA approved the first DOAC, a real game-changer. The DOACs currently on the market work by one of two mechanisms - direct thrombin inhibition or factor Xa inhibition.
Jeff: DOACs are currently approved for stroke prevention in nonvalvular afib, treatment of VTE, VTE prophylaxis, and reduction of major cardiovascular events in stable cardiovascular disease. Studies are underway to test their safety and efficacy in arterial and venous thromboembolism, prevention of embolic stroke in afib, ACS, cancer-associated thrombosis, upper extremity DVT, and mesenteric thrombosis.
Nachi: Direct thrombin inhibitors like Dabigatran, tradename Pradaxa, was the first FDA approved DOAC. It works by directly inhibiting thrombin, or factor IIa, which is a serine protease that converts soluble fibrinogen into fibrin for clot formation.
Jeff: Dabigatran comes in doses of 75 and 150 mg. The dose depends on your renal function, and, with a half-life of 12-15 hours, is taken twice daily. Note the drastically reduced half-life as compared to warfarin, which has a half-life of up to 60 hours.
Nachi: The RE-LY trial for afib found that taking 150 mg of Dabigatran BID had a lower rate of stroke and systemic embolism than warfarin with a similar rate of major hemorrhage. Dabigatran also had lower rates of fatal and traumatic intracerebral hemorrhage than warfarin.
Jeff: A separate RCT found similar efficacy in treating acute VTE and preventing recurrence compared with warfarin, with reduced rates of hemorrhage!
Nachi: Less monitoring, less hemorrhage, similar efficacy, I’m sold!!!
Jeff: Slow down, there’s lots of other great agents out there, let’s get through them all first...
Nachi: Ok, so next up we have the Factor Xa inhibitors, Rivaroxaban, apixaban, edoxaban, and betrixaban.As the name suggests, these medications work by directly inhibiting the clotting of factor Xa, which works in the clotting cascade to convert prothrombin to thrombin.
Jeff: Rivaroxaban, trade name Xarelto, the second FDA approved DOAC, is used for stroke prevention in those with nonvalvular afib and VTE treatment. After taking 15 mg BID for the first 21 days, rivaroxaban is typically dosed at 20 mg daily with adjustments for reduced renal function.
Nachi: The Rocket AF trial found that rivaroxaban is noninferior to warfarin for stroke and systemic embolism prevention without a significant difference in risk of major bleeding. Interestingly, GI bleeding may be higher in the rivaroxaban group, though the overall incidence was very low in both groups at about 0.4% of patients per year.
Jeff: In the Einstein trial, patients with VTE were randomized to rivaroxaban or standard therapy. In the end, they reported similar rates of recurrence and bleeding outcomes for acute treatment. Continuing therapy beyond the acute period resulted in similar rates of VTE recurrence and bleeding episodes to treatment with aspirin alone.
Nachi: Next we have apixaban, tradename Eliquis. Apixaban is approved for afib and the treatment of venous thromboembolism. It’s typically dosed as 10 mg BID for 7 days followed by 5 mg BID with dose reductions for the elderly and those with renal failure.
Jeff: In the Aristotle trial, when compared to warfarin, apixaban was superior in preventing stroke and systemic embolism with lower mortality and bleeding. Rates of major hemorrhage-related mortality were also nearly cut in half at 30 days when compared to warfarin.
Nachi: For the treatment of venous thromboembolism, the literature shows that apixaban has a similar efficacy to warfarin in preventing recurrence with less bleeding complications.
Jeff: Unfortunately, with polypharmacy, there is increased risk of thromboembolic and hemorrhage risks, but this risk is similar to what is seen with warfarin.
Nachi: And as compared to low molecular weight heparin, apixaban had higher bleeding rates without reducing venous thromboembolism events when used for thromboprophylaxis. It’s also been studied in acute ACS, with increased bleeding and no decrease in ischemic events.
Jeff: Edoxaban is up next, approved by the FDA in 2015 for similar indications as the other Factor Xa inhibitors. It’s recommended that edoxaban be given parenterally for 5-10 days prior to starting oral treatment for VTE, which is actually similar to dabigatran. It has similar levels of VTE recurrence with fewer major bleeding episodes compared to warfarin. It has also been used with similar effects and less major bleeding for stroke prevention in afib. In the setting of cancer related DVTs specifically, as compared to low molecular weight heparin, one RCT showed lower rates of VTE but higher rates of major bleeding when compared to dalteparin.
Nachi: Next we have Betrixaban, the latest Factor Xa inhibitor to be approved, back in 2017. Because it’s utility is limited to venous thromboembolism prophylaxis in mostly medically ill inpatients, it’s unlikely to be encountered by emergency physicians very frequently.
Jeff: As a one sentence FYI though - note that in recent trials, betrixaban reduced the rate of VTE with equivalent rates of bleeding and reduced the rate of stroke with an increased rate of major and clinically relevant non-major bleeding as compared to enoxaparin.
Nachi: Well that was a ton of information and background on the DOACs. Let’s move on to your favorite section - prehospital medicine.
Jeff: Not a ton to add here this month. Perhaps, most importantly, prehospital providers should specifically ask about DOAC usage, especially in trauma, given increased rates of complications and potential need for surgery. This can help with destination selection when relevant. Interestingly, one retrospective study found limited agreement between EMS records and hospital documentation on current DOAC usage.
Nachi: Extremely important to identify DOAC use early. Once the patient arrives in the ED, you can begin your focused history and physical. Make sure to get the name, dose, and time of last administration of any DOAC. Pay particular attention to the med list and the presence of CKD which could point to altered DOAC metabolism.
Jeff: In terms of the physical and initial work up - let the sites of bleeding or potential sites of bleeding guide your work up. And don’t forget about the rectal exam, which potentially has some added value here - since DOACs increase the risk of GI bleeding.
Nachi: Pretty straight forward history and physical, let’s talk diagnostic studies.
Jeff: First up is CT. There are no clear cut guidelines here, so Drs. Maher and Taub had to rely on observational studies and expert opinion. Remember, most standard guidelines and tools, like the canadian and nexus criteria, are less accurate in anticoagulated patients, so they shouldn’t be applied. Instead, most studies recommend a low threshold for head imaging, even with minor trauma, in the setting of DOAC use.
Nachi: That is so important that it’s worth repeating. Definitely have a low threshold to CT the head for even minor head trauma patients on DOACs. Basically, if you’re on anticoagulation, and you made it to the ED for anything remotely related to your head, you probably win a spin.
Jeff: I suspect you are not alone with that stance... There is, however, much more debate about the utility of follow up imaging and admission after a NEGATIVE scan.
Nachi: Wait, is that a thing I should routinely be doing?
Jeff: Well there’s not great data here, but in one observational study of 1180 patients on either antiplatelet or anticoagulant therapy, a half a percent of them had positive findings 12 hours later, and importantly none required surgical intervention.
Nachi: Certainly reassuring. And for those with positive initial imaging, the authors recommend repeat imaging within 4-6 hours in consultation with neurosurgical services or even earlier in cases of unexpected clinical decline.
Jeff: Interestingly, though only a small retrospective study of 156 patients, one study found markedly reduced mortality, 4.9% vs 20.8% in those on DOACs vs warfarin with traumatic intracranial hemorrhage.
Nachi: Hmm that actually surprises me a bit with the ease of reversibility of warfarin.
Jeff: And we’ll get to that in a few minutes. But next we should talk about ultrasound. As always with trauma, guidelines recommend a FAST exam in the setting of blunt abdominal trauma. The only thing to be aware of here is that you should have an increased index of suspicion for bleeding, especially in hidden sites like the retroperitoneum.
Nachi: And just as with traumatic head bleeds, a small observational study of those with blunt abdominal trauma found 8% vs 30% mortality for those on DOACs vs warfarin, respectively.
Jeff: That is simply shocking! Let’s also talk lab studies. Hemoglobin and platelet counts should be obtained as part of the standard trauma work up. Assessing renal function via creatinine is also important, especially for those on agents which are renally excreted.
Nachi: Though you can, in theory, test for plasma DOAC concentrations, such tests are not routinely indicated as levels don’t correspond to bleeding outcomes. DOAC levels may be indicated in certain specific situations, such as while treating life-threatening bleeding, development of venous thromboembolism despite compliance with DOAC therapy, and treating patients at risk for bleeding because of an overdose.
Jeff: In terms of those who require surgery while on a DOAC - if urgent or emergent, the DOAC will need to be empirically reversed. For all others, the recommendation is to wait a half life or even multiple half-lives, if possible, in lieu of level testing.
Nachi: Coagulation tests are up next. Routine PT and PTT levels do not help assess DOACs, as abnormalities on either test can suggest the presence of a DOAC, but the values should not be interpreted as reliable measures of either therapeutic or supratherapeutic clinical anticoagulant effect.
Jeff: Dabigatran may cause prolongation of both the PT and the PTT, but the overall correlation is poor. In addition, FXa inhibitors may elevate PT in a weakly concentration dependent manner, but this may only be helpful if anti-fXa levels are unavailable.
Nachi: Which is a perfect segway into our next test - anti-factor Xa level activity. Direct measurements of the anti-Fxa effect demonstrates a strong linear correlation with plasma concentrations of these agents, but the anticoagulant effect does not necessarily follow the same linear fashion.
Jeff: Some labs may even have an anti-FXa effect measurement calibrated specifically to the factor 10a inhibitors.
Nachi: While measuring thrombin time is not routinely recommended, the result of thrombin time or dilute thrombin time does correlate well with dabigatran concentrations across normal ranges.
Jeff: And lastly, we have the Ecarin clotting time. Ecarin is an enzyme that cleaves prothrombin to an active intermediate that can be inhibited by dabigatran in the same way as thrombin. The ECT is useful for measuring dabigatran concentration - it’s not useful for testing for FXa inhibitors. A normal ECT value could be used to exclude the presence of dabigatran.
Nachi: So I think that rounds out testing. Let’s move into the treatment section.
Jeff: For all agents, regardless of the DOAC, the initial resuscitation follows the standard principles of hemorrhage control and trauma resuscitation. Tourniquet application, direct pressure, endoscopy for GI bleeds, etc... should all be used as needed. And most importantly, for airway bleeding, pericardial bleeding, CNS bleeding, and those with hemodynamic instability or overt bleeding, those with a 2 point drop in their hemoglobin, and those requiring 2 or more units of pRBC - they all should be considered to have serious, life threatening bleeds. This patient population definitely requires reversal agents, which we’re getting to in a minute.
Nachi: A type and screen should also be sent with the plan to follow standard transfusion guidelines, with the goal of a hemoglobin level of 7, understanding that in the setting of an active bleed, the hemoglobin level will not truly be representative.
Jeff: Interestingly, in the overdose literature that’s out there, bleeding episodes appear to be rare - occurring in just 5% of DOAC overdose cases.
Nachi: Finally, onto the section we’ve all been waiting for. Let’s talk specific reversal agents. Praxbind is up first.
Jeff: Idarucizumab or Praxbind, is the reversal agent of choice for dabigatran (which is also called pradaxa). According to data from the RE-LY trial, it reverses dabigatran up to the 99th percentile of levels measured in the trial.
Nachi: And praxbind should be given in two 2.5 g IV boluses 15 minutes apart to completely reverse the effects of dabigatran.
Jeff: As you would expect given this data, guidelines for DOAC reversal recommend it in major life-threatening bleeding events for patients on dabigatran.
Nachi: Next up is recombinant coagulation factor Xa (brand name Andexxa), which was approved in 2018 for the FXa inhibitors. This recombinant factor has a decoy receptor for the FXa agents, thus eliminating their anticoagulant effects.
Jeff: Recombinant factor Xa is given in either high or low dose infusions. High dose infusions for those on rivaroxaban doses of >10 mg or apixaban doses >5 mg within the last 8 hours and for unknown doses and unknown time of administration. Low dose infusions should be used for those with smaller doses within the last 8 hours or for last doses taken beyond 8 hours.
Nachi: In one trial of 352 patients, recombinant factor Xa given as an IV bolus and 2 hour infusion was highly effective at normalizing anti-FXa levels. 82% of the assessed patients at 12 hours achieved hemostasis, but there were also thrombotic events in 10% of the patients at 30 days.
Jeff: And reported thrombotic events aren’t the only downside. Though the literature isn’t clear, there may be limited use of recombinant factor Xa outside of the time of the continuous infusion, and even worse, there may be rebound of anti-Fxa levels and anticoagulant effect. And lastly, the cost is SUBSTANTIAL.
Nachi: Is there really a cost threshold for stopping life threatening bleeding…?
Jeff: Touche, but that means we need to save it for specific times and consider other options out there. Since this has only been around for a year or so, let’s let the literature play out on this too...
Nachi: And that perfectly takes us into our next topic, which is nonspecific reversal agents, starting with prothrombin complex concentrate, also called PCC.
Jeff: PCC is FDA approved for rapid reversal of vitamin K antagonist-related hemorrhagic events and is now being used off label for DOAC reversal.
Nachi: PCC comes in 3 and 4 factor varieties. 3-factor PCC contains factors 2, 9, 10 and trace amounts of factor 7. 4 factor PCC contains factors 2, 9 10, as well as purified factor 7 and proteins C and S.
Jeff: Both also contain trace amounts of heparin so can’t be given to someone with a history of HIT.
Nachi: PCC works by overwhelming the inhibitor agent by increasing the concentration of upstream clotting factors. It has been shown, in healthy volunteers, to normalize PT abnormalities and bleeding times, and to achieve effective bleeding control in patients on rivaroxaban, apixaban, and edoxaban with major bleeding events.
Jeff: In small studies looking at various end points, 4 factor PCC has been shown to be superior to 3 factor PCC.
Nachi: Currently it’s given via weight-based dosing, but there is interest in studying a fixed-dose to decrease both time to medication administration and cost of reversal.
Jeff: Guidelines currently recommend 4F PCC over 3F PCC, if available, for the management of factor Xa inhibitor induced bleeding, with studies showing an effectiveness of nearly 70%. As a result, 4F PCC has become an agent of choice for rapid reversal of FXa inhibitors during major bleeding events.
Nachi: Next we have activated PCC (trade name FEIBA). This is essentially 4Factor PCC with a modified factor 7. Though traditionally saved for bleeding reversal in hemophiliacs, aPCC is now being studied in DOAC induced bleeding. Though early studies are promising, aPCC should not be used over 4factor PCC routinely as of now but may be used if 4Factor PCC is not available.
Jeff: Next we have recombinant factor 7a (trade name novoseven). This works by activating factors 9 and 10 resulting in rapid increase in thrombin. Studies have shown that it may reverse the effect of dabigatran, at the expense of increased risk of thrombosis. As such, it should not be used as long as other agents are available.
Nachi: Fresh Frozen Plasma is the last agent to discuss in this section. Not a lot to say here - FFP is not recommended for reversal of any of the DOACs. It may be given as a part of of a balanced massive transfusion resuscitation, but otherwise, at this time, there doesn’t seem to be a clear role.
Jeff: Let’s move on to adjunct therapies, of which we have 3 to discuss.
Nachi: First is activated charcoal. Only weak evidence exists here - but, according to expert recommendations, there may be a role for DOAC ingestions within 2 hours of presentations.
Jeff: Perhaps more useful than charcoal is our next adjunct - tranexamic acid or TXA. TXA is a synthetic lysine analogue with antifibrinolytic activity through reversible binding of plasmin. CRASH-2 is the main trial to know here. CRASH-2 demonstrated reduced mortality if given within 3 hours in trauma patients. There is very limited data with respect to TXA and DOACs specifically, so continue to administer TXA as part of your standard trauma protocol without modification if the patient is on a DOAC, as it’s likely helpful based on what data we have.
Nachi: Next is vitamin K - there is no data to support routine use of vitamin K in those taking DOACs - save that for those on vitamin K antagonists.
Jeff: Also, worth mentioning here is the importance of hematology input in developing hospital-wide protocols for reversal agents, especially if availability of certain agents is limited.
Nachi: Let’s talk about some special circumstances and populations as they relate to DOACs. Patients with mechanical heart valves were excluded from the major DOAC trials. And of note, a trial of dabigatran in mechanical valve patients was stopped early because of bleeding and thromboembolic events. As such, the American College of Cardiology state that DOACs are reasonable for afib with native valve disease.
Jeff: DOACs should be used with caution for pregnant, breastfeeding, and pediatric patients. A case series of 233 pregnancies that occurred among patients on a DOAC reported high rates of miscarriage.
Nachi: Patients with renal impairment are particularly concerning as all DOACs are dependent to some degree on renal elimination. Current guidelines from the Anticoagulation Forum recommend avoiding dabigatran and rivaroxaban for patients with CrCL < 30 and avoiding edoxaban and betrixaban for patients with CrCl < 15.
Jeff: A 2017 Cochrane review noted similar efficacy without increased risk of major bleeding when using DOACs in those with egfr > 30 (that’s ckd3b or better) when compared to patients with normal renal function and limited evidence for safety below this estimated GFR.
Nachi: Of course, dosing with renal impairment will be different. We won’t go into the details of that here as you will probably discuss this directly with your pharmacist.
Jeff: We should mention, however, that reversal of the anticoagulant in the setting of renal impairment for your major bleeding patient is exactly the same as we already outlined.
Nachi: Let’s move on to some controversies and cutting-edge topics. The first one is a pretty big topic and that is treatment for ischemic stroke patients taking DOACs.
Jeff: Safety and efficacy of tPA or endovascular therapy for patients on DOACs continues to be debated. Current guidelines do not recommend tPA if the last DOAC dose was within the past 48 hours, unless lab testing specific to these agents shows normal results.
Nachi: Specifically, the American Heart Association suggests that INR and PTT be normal in all cases. ECT and TT should be tested for dabigatran. And calibrated anti-FXa level testing be normal for FXa inhibitors.
Jeff: The AHA registry actually included 251 patients who received tpa while on DOACs, which along with cohort analysis of 26 ROCKET-AF trial patients, suggest the risk of intracranial hemorrhage is similar to patients on warfarin with INR < 1.7 and to patients not on any anticoagulation who received tpa. However, given the retrospective nature of this data, we cannot exclude the possibility of increased risk of adverse events with tpa given to patients on DOACs.
Nachi: Endovascular thrombectomy also has not been studied in large numbers for patients on DOACs. Current recommendations are to discuss with your stroke team. IV lysis or endovascular thrombectomy may be considered for select patients on DOACs. Always include the patient and family in shared decision making here.
Jeff: There are also some scoring systems for bleeding risk to discuss briefly. The HAS-BLED has been used to determine bleeding risk in afib patients taking warfarin. The ORBIT score was validated in a cohort that included patients on DOACs and is similarly easy to use, and notably does not require INR values.
Nachi: There is also the ABC score which has demonstrated slightly better prediction characteristics for bleeding risk, but it requires high-sensitivity troponin, limiting its practical use.
Jeff: We won’t say more about the scoring tools here, but would recommend that you head over to MD Calc, where you can find them and use them in your practice.
Nachi: Let’s also comment on the practicality of hemodialysis for removal of the DOACs. Multiple small case series have shown successful removal of dabigatran, given its small size and low protein binding. On the other hand, the FXa inhibitors are less amenable to removal in this way because of their higher protein binding.
Jeff: Worth mentioning here also - dialysis catheters if placed should be in compressible areas in case bleeding occurs. The role of hemodialysis for overdose may be limited now that the specific reversal agent, praxbind, exists.
Nachi: In terms of cutting-edge tests, we have viscoelastic testing like thromboelastography and rotational thromboelastometry. Several studies have examined the utility of viscoelastic testing to detect presence of DOACs with varying results. Prolongation of clotting times here does appear to correlate with concentration, but these tests haven’t emerged as a gold standard yet.
Jeff: Also, for cutting edge, we should mention ciraparantag. And if you’ve been listening patiently and just thinking to yourself why can’t there be one reversal agent to reverse everything, this may be the solution. Ciraparantag (or aripazine) is a universal anticoagulant reversal agent that may have a role in all DOACs and heparins. It binds and inactivates all of these agents and it doesn’t appear to have a procoagulant effect.
Nachi: Clinical trials for ciraparantag have shown rapid and durable reversal of edoxaban, but further trials and FDA approval are still needed.
Jeff: We’ve covered a ton of material so far. As we near the end of this episode, let’s talk disposition.
Nachi: First, we have those already on DOACs - I think it goes without saying that any patient who receives pharmacological reversal of coagulopathy for major bleeding needs to be admitted, likely to the ICU.
Jeff: Next we have those that we are considering starting a DOAC, for example in someone with newly diagnosed VTE, or patients with an appropriate CHADS-VASC with newly diagnosed non-valvular afib.
Nachi: With respect to venous thromboembolism, both dabigatran and edoxaban require a 5 day bridge with heparin, whereas apixaban and rivaroxaban do not. The latter is not only easier on the patient but also offers potential cost savings with low risk of hemorrhagic complications.
Jeff: For patients with newly diagnosed DVT / PE, both the American and British Thoracic Society, as well as ACEP, recommend using either the pulmonary embolism severity index, aka PESI, or the simplified PESI or the Hestia criteria to risk stratify patients with PE. The low risk group is potentially appropriate for discharge home on anticoagulation. This strategy reduces hospital days and costs with otherwise similar outcomes - total win all around.
Nachi: Definitely a great opportunity for some shared decision making since data here is fairly sparse. This is also a great place to have institutional policies, which could support this practice and also ensure rapid outpatient follow up.
Jeff: If you are going to consider ED discharge after starting a DOAC - there isn’t great data supporting one over another. You’ll have to consider patient insurance, cost, dosing schedules, and patient / caregiver preferences. Vitamin K antagonists should also be discussed as there is lots of data to support their safety outcomes, not to mention that they are often far cheaper…. As an interesting aside - I recently diagnosed a DVT/PE in an Amish gentleman who came to the ED by horse - that was some complicated decision making with respect to balancing the potentially prohibitive cost of DOACs with the massive inconvenience of frequently checking INRs after a 5 mile horseback ride into town...
Nachi: Nice opportunity for shared decision making…
Jeff: Lastly, we have those patients who are higher risk for bleeding. Though I’d personally be quite uneasy in this population, if you are to start a DOAC, consider apixaban or edoxaban, which likely have lower risk of major bleeding.
Nachi: So that’s it for the new material for this month’s issue. Certainly, an important topic as the frequency of DOAC use continues to rise given their clear advantages for both patients and providers. However, despite their outpatient ease of use, it definitely complicates our lives in the ED with no easy way to evaluate their anticoagulant effect and costly reversal options. Hopefully all our hospitals have developed or will soon develop guidelines for both managing ongoing bleeding with reversal agents and for collaborative discharges with appropriate follow up resources for those we send home on a DOAC.
Jeff: Absolutely. Let’s wrap up with some the highest yield points and clinical pearls
Nachi: Dabigatran works by direct thrombin inhibition, whereas rivaroxaban, apixaban, edoxaban, and betrixaban all work by Factor Xa inhibition.
Jeff: The DOACs have a much shorter half-life than warfarin.
Nachi: Prehospital care providers should ask all patients about their use of anticoagulants.
Jeff: Have a low threshold to order a head CT in patients with mild head trauma if they are on DOACs.
Nachi: For positive head CT findings or high suspicion of significant injury, order a repeat head CT in 4 to 6 hours and discuss with neurosurgery.
Jeff: Have a lower threshold to conduct a FAST exam for blunt abdominal trauma patients on DOACs.
Nachi: Assessment of renal function is important with regards to all DOACs.
Jeff: While actual plasma concentrations of DOACs can be measured, these do not correspond to bleeding outcomes and should not be ordered routinely.
Nachi: The DOACs may cause mild prolongation of PT and PTT.
Jeff: Idarucizumab (Praxbind®) is an antibody to dabigatran. For dabigatran reversal, administer two 2.5g IV boluses 15 minutes apart. Reversal is rapid and does not cause prothrombotic effects.
Nachi: Recombinant FXa can be used to reverse the FXa inhibitors. This works as a decoy receptor for the FXa agents.
Jeff: Vitamin K and FFP are not recommended for reversal of DOACs.
Nachi: Consider activated charcoal to remove DOACs ingested within the last two hours in the setting of life-threatening hemorrhages in patient’s on DOACs.
Jeff: Hemodialysis can effectively remove dabigatran, but this is not true for the FXa inhibitors.
Nachi: 4F-PCC has been shown to be effective in reversing the effects of the FXa inhibitors. This is thought to be due to overwhelming the inhibitor agent by increased concentrations of upstream clotting factors.
Jeff: tPA is contraindicated in acute ischemic stroke if a DOAC dose was administered within the last 48 hours, unless certain laboratory testing criteria are met.
Nachi: Emergency clinicians should consider initiating DOACs in the ED for patients with new onset nonvalvular atrial fibrillation, DVT, or PE that is in a low-risk group.
Jeff: So that wraps up Episode 31!
Nachi: As always, additional materials are available on our website for Emergency Medicine Practice subscribers. If you’re not a subscriber, consider joining today. You can find out more at ebmedicine.net/subscribe. Subscribers get in-depth articles on hundreds of emergency medicine topics, concise summaries of the articles, calculators and risk scores, and CME credit. You’ll also get enhanced access to the podcast, including any images and tables mentioned. PA’s and NP’s - make sure to use the code APP4 at checkout to save 50%.
Jeff: And the address for this month’s cme credit is www.ebmedicine.net/E0819, so head over there to get your CME credit. As always, the [DING SOUND] you heard throughout the episode corresponds to the answers to the CME questions. Lastly, be sure to find us on iTunes and rate us or leave comments there. You can also email us directly at EMplify@ebmedicine.net with any comments or suggestions. Talk to you next month!
Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. (Randomized controlled trial; 2539 patients)
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. (Randomized controlled trial; 14,264 patients)
Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. (Randomized controlled trial; 18,201 patients)
Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104. (Randomized controlled trial; 21,105 patients)
Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016;375(6):534-544. (Randomized controlled trial; 7513 patients)
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. (Guidelines statement)
Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017;70(24):3042-3067. (Guidelines statement)
Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511-520. (Prospective cohort; 90 patients)
Drs. Nachi Gupta and Jeff Nusbaum are practicing emergency physicians in two busy EDs in the US. Join Jeff, a former firefighter, and Nachi, a former mathematician, as they take you through the August 2019 issue of Emergency Medicine Practice: Emergency Department Management of Patients Taking Direct Oral Anticoagulant Agents (Pharmacology CME).
Get quick-hit summaries of hot topics in emergency medicine. EMplify summarizes evidence-based reviews in a monthly podcast. Highlights of the latest research published in EB Medicine's peer-reviewed journals educate and arm you for life in the ED.
Why to Use
The ORBIT score is not superior to the HAS-BLED score (see the “Evidence Appraisal” section), but it was derived more recently and has been validated in the era of direct oral anticoagulants, so it may be more useful. The ORBIT score can be used in conjunction with the CHA2DS2-VASc score to risk stratify patients for clinically significant bleeding and help guide decisions about anticoagulation for stroke prevention.
When to Use
The ORBIT score is used for patients with atrial fibrillation for whom treatment with oral anticoagulants is being considered.
Next Steps
The presence of risk factors that are not included in the ORBIT score may influence the clinician’s decisions regarding anticoagulation in patients with atrial fibrillation. Patient preferences and values should also inform these decisions, in the context of the risks and benefits of taking oral anticoagulants for stroke prevention.
Hyunjoo Lee, MD
Jeffrey Marbach, MBBS, MS, FRCPC
Stroke prevention is part of the management plan for patients with atrial fibrillation. The CHADS2 or CHA2DS2-VASc scores are often used to calculate stroke risk in patients with atrial fibrillation. Drug therapies for stroke prevention can include antiplatelet therapy (eg, aspirin) or anticoagulation, depending on the risk for stroke; however, antico-agulation also creates bleeding risk. Other bleeding risk scores include HAS-BLED, ATRIA, and others; among these scores, HAS-BLED is best validated and likely the most used.
O’Brien et al (2015) derived and validated the ORBIT score as a way to assess bleeding risk in patients with atrial fibrillation. Derivation was based on data from ORBIT-AF, a prospective registry of patients with atrial fibrillation from 176 sites in the United States. Of the 10,132 patients in the registry, 7411 were analyzed (2721 patients were excluded because they were not on oral anticoagulants or because there were no follow-up data available). Major bleeding was defined as fatal bleeding, symptomatic bleeding in a critical organ, or bleeding with a hemoglobin drop requiring transfusion of ≥ 2 units of blood. The simplified 5-item ORBIT score was based on the 5 predictors with the strongest association with major bleeding.
The authors also validated the ORBIT score with data from the ROCKET-AF trial, a cohort of patients receiving either once-daily rivaroxaban or a vitamin K antagonist. The validation study showed that the ORBIT score had better discrimination than ATRIA or HAS-BLED (C statistic = 0.67, 0.66, and 0.64, respectively).
Subsequent studies in different patient populations did not show the ORBIT score to be superior to the other scores. Senoo et al (2016) studied 2293 patients in the AMADEUS trial and found that the HAS-BLED score performed better than the ORBIT score for predicting major bleeding (C statistic = 0.65 and 0.61, respectively; P = .001). Esteve-Pastor et al (2016) found that the ORBIT score was not superior to the HAS-BLED score in predicting major bleeding in 406 patients who underwent electrocardioversion (C statistic = 0.82 and 0.77, respectively; P = .08), or in 1276 patients with persistent atrial fibrillation who were in the FANTASIIA registry (C statistic = 0.70 and 0.63, respectively; P = .12). Wang et al (2017) conducted a meta-analysis that showed the HAS-BLED score to be superior to the ORBIT score in predicting major bleeding in 8079 patients with anticoagulated, nonvalvular atrial fibrillation patients from the United States, Britain, Spain, and the Netherlands.
The same studies also showed that the ORBIT score places more patients in the low-risk category than the HAS-BLED score, potentially underpredicting the major bleeding risk for these patients (Senoo 2016, Esteve-Pastor 2016, Wang 2017). This raises the concern that some at-risk patients may not be identified by the ORBIT score. Lip et al (2018) suggest that the HAS-BLED score has higher sensitivity but lower specificity for major bleeding risk as com-pared to the ORBIT score. As a result, care must be taken when clinically applying the results of either score.
Emily C. O’Brien, PhD
Original/Primary Reference
Other References
Why to Use
The HAS-BLED score can be used to help guide the decision on whether to start anticoagulation in patients with atrial fibrillation.
Next Steps
The patient-specific risks and benefits of anticoagulation must be weighed carefully for all patients who are potential candidates for long-term anticoagulation therapy.
Calvin Hwang, MD
Risk assessment is multifactorial for both stroke risk and bleeding risk.
The HAS-BLED score was developed by Pisters et al (2010) as a practical risk score to estimate the 1-year risk for major bleeding in patients with atrial fibrillation. The study included 5333 ambulatory and hospitalized patients with atrial fibrillation from both academic and nonacademic hospitals in 35 member countries of the European Society for Cardiology. Patients were followed up at 1 year for survival and major adverse cardiovascular events, such as major bleeding. (Major bleeding was defined as any bleeding that required hospitalization, caused a decrease in hemoglobin level of > 2 g/dL, or required blood transfusion, excluding hemorrhagic stroke.)
Researchers performed a retrospective univariate analysis to find potential bleeding risk factors when comparing the groups with and without major bleeding at the 1-year follow-up, and developed the score based on the results of their analysis as well as known significant risk factors for major bleeding. Results showed that the annual bleeding rate increased with increasing risk factors, with an overall major bleeding rate of 1.5%.
These findings were validated in a study by Lip et al (2011), who studied the score in 7329 patients with atrial fibrillation who participated in the SPORTIF clinical trial. They found a stepwise increase in rates of major bleeding with an increasing HAS-BLED score (P for the trend < .0001, C statistic = 0.50-0.67).
Apostolakis et al (2012) compared the HAS-BLED score with 2 alternative bleeding risk scores, HEMORRH2HAGES and ATRIA, using data from the AMADEUS trial cohort. AMADEUS was a multicenter randomized open-label noninferiority study comparing fixed-dose idraparinux (a novel oral anticoagulant) with warfarin or acenocoumarol (vitamin K antagonists) in nonvalvular atrial fibrillation. They found that the HAS-BLED score performed best for the primary endpoint of any clinically relevant bleeding. Patients in the cohort were already at low risk for stroke and major bleeding, which differs from many real-life scenarios.
Roldán et al (2013) conducted a study comparing the HAS-BLED score with the ATRIA score as both quantitative and dichotomized variables (ie, low-medium vs high risk) in 937 outpatients with atrial fibrillation on anticoagulation who had stable INR, and found that the HAS-BLED score more accurately predicted major bleeding. There were some criticisms of the study related to potential selection bias, as it excluded patients who were warfarin-naive and patients with unstable INR, and the study had limited applicability outside the clinic setting.
Ron Pisters, MD, PhD
Original/Primary Reference
Validation References
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