Episode 89 – DOACs Part 2: Bleeding and Reversal Agents

This is EM Cases Episode 89 – DOACs Part 2: Bleeding and Reversal Agents.

In Part 1 of this two part series on DOACs we talked about how DOACs work, their efficacy and safety compared to Warfarin, how to dose them, and when to avoid them. We also covered management of isolated calf DVTs, superficial vein thrombosis and anticoagulation in atrial fibrillation. In this Part 2, with Dr. Walter Himmel, Dr. Jim Douketis and Dr. Ben Bell, DOACs Bleeding and Reversal Agents we discuss the management of bleeding in patients taking DOACs with minor risk bleeds, like epistaxis where local control is easy to access, moderate risk bleeds, like stable GI bleeds and high risk bleeds, like intracranial hemorrhage.

In DOACs Bleeding and Reversal we will answer questions such as: How do we weigh the risks and benefits of stopping the DOAC in minor, moderate and high risk bleeds? When is reversal of the DOAC is advised? How best do we accomplish the reversal of DOACs? Is there any good evidence for the newest reversal agent? When should we stop DOACs for different procedures, and when should we delay the procedure?

Written Summary and blog post written by  Anton Helman December, 2016

Three categories of illnesses for bleeding risk in patients taking DOACs

It is helpful to divide patients into low, moderate and high risk for poor outcomes from bleeding when considering whether to hold or stop DOACs.

Low Risk: Bleeding where there is easy access to local bleeding control measures such as epistaxis and hemorrhoidal bleeding

Moderate Risk: Stable GI bleed

High Risk: Intracranial bleed, unstable GI bleed, bleeding into a closed space (eye, spinal cord, pericardium)

 

Case 1: Low Risk Bleed

“Treat local problems with local solutions”

An 89 year-old man with a history of atrial fibrillation and TIA on a DOAC for stroke prevention comes in with a few hours of brisk epistaxis that isn’t controlled with local pressure. You try some of the usual local maneuvers but the bleeding continues. His hemoglobin is normal.

Would you stop the DOAC? Would you reverse the DOAC?

Holding 1-2 doses of DOAC is akin to giving vitamin K to a warfarin-treated patient as vitamin K takes approximately 6-12 hours to take effect, similar to the approximate half life of the DOACs.

Our experts recommend not stopping the DOAC in this case, as the patient likely has a high CHADS2 score and the increased risk of cardioembolic stroke would likely outweigh the risk of complications of the anticoagulation effect of the DOAC. Efforts to stop the bleeding should be centered on employing localemergency management of pediatric seizures methods such as wrapping a tampon in gelfoam or surgicel, a nasal balloon, applying ice to the palate (popsicles, ice in the mouth) which has been shown to reduce nasal blood flow up to 25%.

For epistaxis, tonsillar or oral bleeding consider local application of 5% oral tranexamic acid solution (25mg of IV tranexamic acid solution) in addition to your local measures (soak gauze or surgicel or gelfoam in this solution and directly apply or swish and spit).

Go to Episode 38: ENT Emergencies Pearls Pitfalls and Tricks for step by step management of epistaxis

 

Case 2: Moderate Risk Bleed

A 42 year-old woman who was told by her internist that she would be on a DOAC for life after being diagnosed with a pulmonary embolism six months prior comes into your ED with a one day history of hematochezia and no other symptoms. Her vitals are normal, there is a small amount of bright red blood on rectal exam and her hemoglobin comes back a bit low.

Would you stop the DOAC? Would you reverse the DOAC?

Our experts recommend not stopping the DOAC in this case, monitoring the patient carefully, admitting them to hospital, repeating the hemoglobin and emergency management of pediatric seizuresarranging endoscopy. The risk of life-threatening or life-altering pulmonary embolism for this patient not being anticoagulated outweighs the risk of serious complications from the GI bleed.

 

Indications for consideration of reversing the anticoagulant effects of DOACs

  1. Intracranial hemorrhage
  2. Hemodynamically unstable GI bleed not controlled by endoscopy or interventional radiology
  3. Bleeding into an enclosed, fixed space (intraocular, pericardium, spinal cord)
  4. Failure of local measures and ongoing bleeding
  5. Emergency surgery necessary for aortic dissection or aneurysm repair

 

Management of non-traumatic hemorrhagic shock in patients taking DOACs

The most important principle to remember in the management of hemodynamically unstable patients who are bleeding and taking DOACs is that reversing or withholding a DOAC does not stop bleeding, but rather, returns the patient to an un-anticoagulated state. It is therefore imperative that resuscitative measures to stop the bleeding are taken as a priority over reversing the DOAC.

  1. Maintain a good urine output because DOACs are excreted renally (especially dabigatran and rivaroxaban).
  2. Use all the usual local measures.
  3. Call for help early – interventiaonal radiology, ICU, hemotology, for GI bleed call GI for early endoscopy.
  4. This is not the time to get too obsessed with a restrictive policy for red cell transfusion (in the event of major bleeding); if massive bleeding > 5 units in 3 hrs and ongoing: begin your institutional massive transfusion protocol and don’t forget the cryoprecipitate after 10 units of blood if the fibrinogen is low.
  5. Activated charcoal 1g/kg if DOAC taken in within 1-2 hours or for massive intentional overdose and the patient is protecting their airway.

 

Reversing the anticoagulant effects of DOACs

An important consideration is the time of last ingestion of the DOAC. If it was more than 12-14hrs, then the anticoagulation effects have likely worn off and reversal is likely unnecessary.

The reversal of DOACs is different depending on the specific DOAC. The following recommendations are based on expert opinion taking into account the paucity of evidence on this topic.

 

For Xa inhibitors apixaban or rivaroxaban

First line: 4-factor PCC (Octaplex, Beriplex, Kcentra) at a dose of 50 IU/kg up to 2,000 units.

Note that if you highly suspect a Xa inhibitor intracranial bleed before obtaining a CT head, it is reasonable to give 1,500 units of 4 factor PCC on speculation.

Second Line: Tranexamic acid, 1 gm over 10 minutes and then 1 gm over the next 8 hrs if 4-factor PCC is ineffective.

 

For Dabigitran

First Line: Idarucizumab (Praxbind)

 

Idarucizumab (Praxbind): Antidote for Dabigitran

Idarucizumab is a monoclonal antibody that works immediately to reverse bleeding parameters.

Dose: 5 gm IV over 15 minutes

Cost: wholesale cost in U.S is $3500

The REVERSE-AD study from NEJM included 90 patients with either a major bleed or having to undergo emergency surgery. Almost all of the patients were taking dabigatran for atrial fibrillation. Reversal, as assessed by both the dilute thrombin time and ecarin clotting time within 4 hrs, was 100%. However, it took an average of 11.4 hrs to reach clinical hemostasis. For the subgroup that required emergency surgery, the majority of patients who were given idarucizumab had clinical hemostasis as assessed by the surgeon in the O.R.

Bottom Line: While Idarucizumab appears to reverse bleeding parameters effectively in patients taking Dabigitran, it’s effectiveness in clinical outcomes have yet to be determined and their safety requires further study.

Idarucizumab is the best we’ve got…..so far.

 

Andexanet Alfa*: Antidote for Rivaroxiban and Apixaban

*not available in Canada as of this publication date

Andexanet Alfa is a decoy antigen; it competitively binds rivaroxaban and apixaban and is given as an ongoing infusion.

The Siegal et al article from NEJM enrolled 65 patients on Apixaban and 80 patients on Rivaroxiban. All of these patients were healthy volunteers given DOAC for 4 days followed by either Adexanet Alfa or placebo. The primary outcome, a lab measure – anti factor Xa activity, was decreased by >90% in the DOAC groups compared to 45% in the placebo groups.

The Connolly et al article from NEJM was a prospective open label trial which included 67 patients with major bleeding on Apixiban or Rivaroxiban. All patients received Adexanet Alfa. There was no control group. 80% of patients had “good” or “excellent” hemostasis by 12 hours. Note, however that the half-life of these drugs is only about 6-12 hours. Thrombotic events occurred in 18% of patients. Mortality was 15%.

Bottom Line: We don’t know if Andexanet Alfa is clinically effective or safe. We need more robust clinical outcome data before we start to use Andexanet Alfa in the ED to reverse Xa inhibitors.

 

Periprocedural Management of DOACs

For patients taking DOACs whom you need to a procedure on, the approach stems from whether or not the procedure is low risk or high risk if bleeding complications occur.

Case 3: To LP or not to LP

A patient on Apixiban post surgery for a femur fracture comes in with rigors, headache and neck stiffness. He’s got jolt accentuation, a rigid neck and you think he might have the words bacterial meningitis written on his forehead. You order up 2g of Cefriaxone and 1g of Vancomycin, and as you’re getting set up for the LP you pause because your resident asks you if it’s okay to do the LP if the patient is on Abixiban.

Would you do an LP on this patient in the ED?

emergency management of pediatric seizuresThe simple answer is no. Bleeding into a closed space such as the spinal epidural space is a real risk and can be devastating.

High risk procedures for patients on DOACs include lumbar puncture and subclavian central line.

Low risk procedures for patients on DOACs include paracentesis, thoracentesis and non-subclavian central line.

The skill of the operator is the number one predictor of bleeding complications for these procedures, so be sure that the provider with the best skills does the procedure.

 

Perioperative Management of DOACs

For major surgery it is normally recommended to stop DOACs 2 days before surgery (i.e. skip 2 doses), which corresponds to approximately 4-5 half-lives elapsed between stopping the DOAC and surgery, assuming normal renal function. However, for patients needing to go for emergency surgery – reverse them, but only if it’s a true emergency surgery. Reversal should not be used for patients who require a non-emergent operation just to reduce the time to surgery.

 

Dose reduction for older patients taking DOACs for stroke prevention in atrial fibrillation

Apixiban

The dose of Apixiban should be reduced from 5 mg bid to 2.5 mg bid in patients with 2 of 3 of the following characteristics:

  1. serum creatinine ≥ 133 µmol/L
  2. age ≥ 80 years or
  3. body weight ≤60 kg

Dabigitran

The dose of Dabigitran should be reduced from 150 mg bid to 110 mg bid in patients aged 80 years and older, or over 75 years old with 1 risk factor for bleeding.

Rivaroxiban does not require dose adjustment in the elderly and should be given as 20 mg daily.

It is important to remember that DOAC dosing for venous thromboembolism is fixed and no dose reduction is required in older patients.

For calculating DOAC dosing on shift taking into account patient age, renal function and weight try the Thrombosis Canada app

 

Dr. Himmel has no conflicts of interest to declare.

Dr. Douketis and Dr. Bell have received financial compensation for educational endeavours from companies that make DOACs.

Dr. Helman received financial compensation for participating in an educational video by the makers of Octaplex.

 

References

Raja AS, Geyer B. Emergency department management of patients on novel oral anticoagulant agents. Emerg Med Pract. 2013;15(10):1-18.

Zahed R, Moharamzadeh P, Alizadeharasi S, Ghasemi A, Saeedi M. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. Am J Emerg Med. 2013;31(9):1389-92.

Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511-20.

Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015;386(9994):680-90.

Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373(25):2413-24.

Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016; 375:1131-1141.

Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e326S-50S.

Bell BR, Spyropoulos AC, Douketis JD. Perioperative Management of the Direct Oral Anticoagulants: A Case-Based Review. Hematol Oncol Clin North Am. 2016;30(5):1073-84.

 

Other FOAMed Resources on DOACs Bleeding and Reversal Agents

Salim Rezaie in Rebel EM calls it Norersaban

Ken Milne does deep EBM dive into idarucizumab for dabigitran reversal

 

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About the Author:

Dr. Anton Helman is an Emergency Physician at North York General in Toronto. He is an Assistant Professor at the University of Toronto, Division of Emergency Medicine, the Education Innovation Lead at the Schwartz-Reisman Emergency Medicine Instititute and is on the advisory board of The Teaching Institute. He is the founder and host of Emergency Medicine Cases.

3 Comments

  1. Scott December 9, 2016 at 9:45 am - Reply

    Hello Anton,

    Thanks again for all the hard work you do and for this episode. I understand as of now, for the Xa inhibitors and a massive GIB, the way to reverse is with 4 factor PCC. However, if you are resuscitating with your massive transition protocol and using FFP, do you really need the PCC as well? Will it aid in your reversal at all if you are already using FFP? Should we use both? My question is really only for patients with a massive GIB where the volume of FFP is helpful.

    Thank you so much again.

    – Scott

    • Anton Helman December 21, 2016 at 9:39 am - Reply

      Great question Scott. My understanding is simply that 4 factor PCCs would (theoretically) work faster than FFP to reverse the anticoagulation effects of Xa inhibitors. I don’t know if there efficacy differs significantly. There is usually a delay to starting the FFP as a few units of red cells are usually given before the massive transfusion protocol is activated. On the other hand if you activated the massive transfusion protocol early, I think it would be reasonable to skip the 4 factor PCCs which, by the way, are very expensive (about $1300 for 2000U). Agree that FFP has the advantage of volume in the unstable bleeder. If your patient is circling the drain and you think the typewriter should be thrown at them I think it’s reasonable to give both 4 factor PCC and FFP. Will ask Dr. Himmel to chime in….

  2. Martin Chénier March 9, 2017 at 11:40 am - Reply

    Did I heard that we should not do an LP for Aspirin users?

    Thanks for the quality of your work

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