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DOACs Update Part II

This is Part II in a series.

Part I

BLEEDING COMPLICATIONS

Studies have shown that there is a similar or increased rate of occurrence of gastrointestinal bleeding in patients taking DOACs when compared to warfarin9. Decreased rates of intracranial hemorrhage (ICH), smaller hematoma size, and decreased hematoma expansion have been noted in patients taking DOACs versus those taking warfarin 10,11, 12. Studies show no difference in morbidity or mortality in patients taking DOACs versus warfarin for patients with ICH or GI bleeds9,10,11.

  1. Singer, et al., 2016 9: studied ED management of bleeding in patients on NOACs

  2. 3-year study period: 95 patients on NOACs and 342 patients on warfarin with bleeding complications

  3. Reversal strategies rarely used

  4. Low case fatality rates and similar for patients taking NOACs versus warfarin (GI bleed: 7% for both groups; ICH: 18% for warfarin, 4% with NOACs with no statistically significant difference)

  5. Takahashi H, et al., 2016 10: studied difference in intracerebral hemorrhage occurrence and expansion in patients on NOACs versus warfarin

  6. ICH in patients taking NOACs tend to present within 22 hours, similar to patients taking vitamin K antagonists

  7. Decreased size and expansion of ICH in patients on NOACs

  8. Mayer, SA., 2016 11: review of management of ICH in patients on NOACs (RASUNOA trial- Registry of Acute Stroke Under New Oral Anticoagulants)

  9. Patients typically received prothrombin complex concentrate (PCC) for treatment of ICH if more severe clinical deficits, deep hemorrhage, or more recent NOAC ingestion were present

  10. No difference in frequency of hematoma expansion or clinical outcome between patients who received PCC or not (but conclusions about effectiveness of PCC use for NOAC reversal were unclear in this study)

BLEEDING MANAGEMENT

Targeted therapeutic options are limited for emergent reversal of DOACs. Vitamin K and FFP are useful to reverse anticoagulation in patients taking warfarin, but are not useful for reversing the effects of direct thrombin inhibitors or Xa inhibitors.13 Prothrombin complex concentrates (PCCs) are thought to be more effective as reversal agents.13 PCC was shown to be effective for the immediate and complete reversal of anticoagulation from rivaroxaban in one study, but there was no influence on the action of dabigatran.14 Dabigatran has low plasma binding, so hemodialysis may be used for systemic removal, and it is also the only newer oral anticoagulant to date with an FDA-approved specific antidote, idarucizumab.7,15

Early trials of specific antidotes for DOACs are promising for efficacy and safety in patients requiring emergent or urgent reversal of a life-threatening bleed or for a life-saving procedure; however, they are still ongoing and clinical data remains limited.

DrugMechanismEvidenceIdarucizumab (Praxbind)– Humanized monoclonal antibody fragment

– Binds free and thrombin-bound dabigatran, renal excretion of bound complex

– Binds dabigatran with affinity 350x higher than affinity of dabigatran for thrombin16– Phase I trials: no adverse event for drug, no clinically significant difference in adverse events between treatment groups

– Dose-dependent reversal; return of ECT, aPTT and TT levels to baseline

– Phase III trials: reversal of TT and ECT lab values to baseline within 4 hours of treatment for severe bleeding or urgent procedures on dabigatran16

NEJM interim analysis showed free dabigatran clearance was rapid, but hemostasis times remained high (>11 hours) in treatment group (study did not include control group for comparison)15

– FDA-approved in 2015 for dabigatran reversal for emergency surgery, urgent procedures, or life-threatening or uncontrolled bleedingAndexanet alfa– Reversal of Xa inhibitors

– Recombinant modified human factor Xa decoy protein

– Binds to factor Xa inhibitors at site of action with high affinity to remove factor Xa inhibitor and increase endogenous factor Xa activity16– >80% decreased bleeding in animal models on rivaroxaban16

– Phase II trials: rapid dose-dependent reversal in healthy volunteers given factor Xa inhibitors, no complications16,17

– Two phase III trials: ANNEXA-A (reversal of apixaban) and ANNEXA-R (reversal of rivaroxaban)16

– >90% decreased anti-FXa activity for apixaban and rivaroxaban, thrombin generation restored in 96-100% of subjects within 2-5 minutes.17 Transient increase in D-dimer and prothrombin fragments, normalized within 24 to 72 hours. No serious complications, adverse events, or thromboembolic events17

– ANNEXA-4 study ongoing for use in cases of major bleeding17Ciraparantag (formerly aripazine)– Small, synthetic, water-soluble molecule that binds to unfractionated heparin, low molecular weight heparin, and direct-acting oral anticoagulants

– Blocks binding of anticoagulants to target sites of factor IIa and factor Xa via hydrogen bonds– Animal studies: no significant adverse effects, anticoagulant reversal, and decreased bleeding of > 90% with dabigatran, rivaroxaban, and apixaban in rat tail injury models16,17

– In vitro human studies: dose-dependent reversal of anti-FXa levels

–  In vivo human studies: increased whole blood clotting time reversal within 5 minutes without procoagulation in healthy patients on enoxaparin and edoxaban17

– Ongoing phase II studies: being developed as a “universal” anticoagulant reversal agent17

– Clinical endpoints of mortality and morbidity are limited and expected to be included as primary outcomes of future studies

GUIDELINE

Data is limited and there is no clear consensus for management of bleeding complications in patients on DOACs. Some institutions have developed guidelines or protocols to address this issue and include recommendations, such as discontinuation of the oral anticoagulant, supportive care for moderate bleeding episodes, and the use of PCC or aPCC for severe or life-threatening hemorrhage.18, 19

A needs assessment performed of emergency medicine residents and faculty at Temple University Hospital indicated that more than 97% of emergency medicine physicians agree that a departmental guideline for treatment of patients taking novel oral anticoagulants would be helpful. Based on the available data, we developed an educational resource in the form of a guideline for the emergency department management of bleeding complications in patients taking direct oral anticoagulants (DOACs).

1 All oral anticoagulants are renally cleared. All half-lives may be prolonged in elderly patients or those with renal insufficiency. Assessment of renal function should be considered in patients presenting with hemorrhage on oral anticoagulants.

2 There is no clinical data to support use of oral activated charcoal. Manufacturer package inserts state consider activated charcoal if last dose was ingested within 2hrs for dabigatran, 3hrs for apixaban, and 8hrs for rivaroxaban. The package insert for edoxaban does not mention charcoal.

3 Thrombin Time has 1 day turnaround time and requires Hematology consult prior to ordering.

4 Major bleeding defined as any of the following: requires blood transfusion of two or more units within 24 hours; bleeding in body cavity; intracranial or retroperitoneal bleeding; or bleeding that leads to a hemoglobin level decrease of >2 g/dl

5 Idarucizumab and Hemodialysis have each been shown to rapidly clear free dabigatran levels in serum, though neither has definitively shown a decrease in time to hemostasis. No other reversal therapies (e.g. PCC, aPCC) have shown an impact on coagulation parameters in patients on dabigatran.

6 Chromogenic Anti-Factor Xa assay has 2-5 day turnaround time and should only be ordered in consultation with Hematologist.

_____________________________________

References:

Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis. 2015; 39(3): 395–402.

Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost. 2014; 111: 189–198.

Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. A randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011; 124(14): 1573–1579.

Hatfield L and Chen S. Emergent anticoagulation reversal in the ED. UNC Healthcare ED Anticoagulation Reversal Guidelines. 2013.

Pollack CV, Reilly PA, Eikelboom J. Idarucizumab for dabigatran reversal. The New England Journal of Medicine. 2015; 373(6): 511-520.

Ansell, JE. Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. Journal of Thrombosis and Thrombolysis. 2016; 41(2): 248-252.

Van Ryn J, Stangier J, Haertter S, Liessenfeld KH, Wienan W, Feuring M, Clemens A. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010; 103(6): 1116-1127.

Contacts (for comment on this draft):

Daniel del Portal, MD (Daniel.delPortal@tuhs.temple.edu)

Alyssa Karl, MD PGY3 (Alyssa.Karl@tuhs.temple.edu)

____________________________________________________________________________________

REFERENCES

  1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine. 2009; 361: 1139-1151.

  2. Gonzalves WI, Pruthi RK, Patnaik MM. The new oral anticoagulants in clinical practice. Mayo Clin Proc. 2013; 88(5): 495-511.

  3. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England Journal of Medicine. 2011; 365: 883-891.

  4. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine. 2011; 365: 981-992.

  5. Giugliano RP, Ruff CT, Braunwalkd E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine. 2013; 369: 2093-2104.

  6. Miesbach W and Seifried E. New direct oral anticoagulants – current therapeutic options and treatment recommendations for bleeding complications. Thrombosis and Haemostasis. 2012; 108: 625-632.

  7. Miller MP, Trujillo TC, Nordenholz KE. Practical considerations in emergency management of bleeding in the setting of target-specific oral anticoagulants. American Journal of Emergency Medicine. 2014; 32: 375-382.

  8. Fawole A, Daw HA, Crowther MA. Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. Cleveland Clinic Journal of Medicine. 2013; 80(7): 443-451.

  9. Singer AJ, Quinn A, Dasgupta N, Thode HC. Management and outcomes of bleeding events in patients in the emergency department taking warfarin or a non-vitamin K antagonist oral anticoagulant. Journal of Emergency Medicine. 2017; 52(1): 1-7.

  10. Takahashi H, et al. Intracerebral hematoma occurring during warfarin versus non-vitamin K antagonist oral anticoagulant therapy. The American Journal of Cardiology. 2016; 118(2): 222-225.

  11. Mayer, SA. Emergency Reversal of Novel Oral Anticoagulants. JAMA Neurol. 2016;73(2): 155-156.

  12. Piccini J, et al. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. European Heart Journal. 2014; 35: 1873-1880.

  13. Thigpen JL and Limdi NA. Reversal of oral anticoagulation. Pharmacotherapy. 2013; 33(11): 1199-1213.

  14. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011; 124(14): 1573-1579.

  15. Pollack CV, Reilly PA, Eikelboom J. Idarucizumab for dabigatran reversal. The New England Journal of Medicine. 2015; 373(6): 511-520.

  16. Tummala R, Kavtaradze A, Gupta A, Ghosh RK. Specific antidotes against direct oral anticoagulants: a comprehensive review of clinical trials data. Int J Cardiol.2016; 214:292-298.

  17. Milling TJ, Kaatz S. Preclinical and clinical data for factor Xa and “universal” reversal agents. The American Journal of Emergency Medicine. 2016; 34(11): 39-45.

  18. Hatfield L and Chen S. Emergent anticoagulation reversal in the ED. UNC Healthcare ED Anticoagulation Reversal Guidelines. 2013.

  19. Dhakal P, et al. Reversal of anticoagulation and management of bleeding in patients on anticoagulation. Clinical and Applied Thrombosis/Hemostasis. 2017; 23(5): 410-415.

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DOACs Update

WHAT ARE THE DOACs? The term direct oral anticoagulants (DOACs, previously NOAC for novel oral anticoagulants) describes two classes of medications: direct thrombin inhibitor and factor Xa inhibitors.

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