Managing Blooding Patients on Warfarin Vs the New Anticoagulants

Allen Tran, MD, FRCPC Blood Matters 2018 • Speaker honorarium from Pfizer Disclosures • Subinvestigator for NASH trials involving Genfit, Novo Nordisk, and Shire Objectives Have an organized approach to a patient on oral anticoagulants who is bleeding

Know indications for the use of reversal agents for oral anticoagulants

Acknowledge the role of the time from last dose of anticoagulant and laboratory levels

List which pharmacologic reversal agents can be considered for each oral anticoagulant Cases Agnelli G, et al. N Engl J Med. 2013. Granger CB, et al. N Engl J Med. 2011. Connolly SJ, et al. N Engl J Med. 2009. Schulman S, et al. N Engl J Med. 2009. Giugliano RP, et al. N Engl J Med. 2013. EINSTEIN Investigators. N Engl J Med. 2010. Patel MR, et al. N Engl J Med. 2011. HOKSUAI Investigators. N Engl J Med. 2013. Bleeding rates Swinkels BM, et al. Netherlands Hear J. 2015;23:111–5. SerebruanyVL, et al.Am J Hematol. 2004;75:40–7. N Engl J Med. 1994;330:507–9. Mauri L, et al. N Engl J Med. 2014. ICH GI Major CRNMB

AF 0.33 - 0.8% 0.76 - 3.15% 2.13 – 3.6% 4.07 - 11.8%

VTE 0 - 0.3% 0.3 - 4.2% 0.8 - 1.9% 3.8 - 8.9%

Mechanical valve 0.6 - 0.7% 3 - 4.7%

SAPT 0.1% 0.3 - 0.7% 1.7 - 2.7%

DAPT 0.1 - 0.2% 0.7 - 1.3% 2.6 - 3.7% Agnelli G, et al. N Engl J Med. 2013. Granger CB, et al. N Engl J Med. 2011. Connolly SJ, et al. N Engl J Med. 2009. Schulman S, et al. N Engl J Med. 2009. Giugliano RP, et al. N Engl J Med. 2013. EINSTEIN Investigators. N Engl J Med. 2010. Patel MR, et al. N Engl J Med. 2011. HOKSUAI Investigators. N Engl J Med. 2013. Bleeding rates Swinkels BM, et al. Netherlands Hear J. 2015;23:111–5. SerebruanyVL, et al.Am J Hematol. 2004;75:40–7. N Engl J Med. 1994;330:507–9. Mauri L, et al. N Engl J Med. 2014. ICH GI Major CRNMB

AF 0.33 - 0.8% 0.76 - 3.15% 2.13 – 3.6% 4.07 - 11.8%

VTE 0 - 0.3% 0.3 - 4.2% 0.8 - 1.9% 3.8 - 8.9%

Mechanical valve 0.6 - 0.7% 3 - 4.7%

SAPT 0.1% 0.3 - 0.7% 1.7 - 2.7%

AF 0.33 - 0.8% 0.76 - 3.15% 2.13 – 3.6% 4.07 - 11.8%

VTE 0 - 0.3% 0.3 - 4.2% 0.8 - 1.9% 3.8 - 8.9%

Mechanical valve 0.6 - 0.7% 3 - 4.7%

SAPT 0.1% 0.3 - 0.7% 1.7 - 2.7%

AF 0.33 - 0.8% 0.76 - 3.15% 2.13 – 3.6% 4.07 - 11.8%

VTE 0 - 0.3% 0.3 - 4.2% 0.8 - 1.9% 3.8 - 8.9%

Mechanical valve 0.6 - 0.7% 3 - 4.7%

SAPT 0.1% 0.3 - 0.7% 1.7 - 2.7%

DAPT 0.1 - 0.2% 0.7 - 1.3% 2.6 - 3.7% Shih AW, Crowther MA. ASH Educ Progr B. 2016;2016:612–9.

HASHTI

Hold the drug

•-Timing of last dose and creatinine Antidote consideration •-Activated charcoal?

Supportive treatment for hemodynamics

Local +/- pharmacologic (antifibrinolytics Hemostasis or DDAVP)

Transfusion (PRBCs and/or platelets)

Investigate for cause LAB TESTS • Therapeutic range? Lab tests • Warfarin – INR • Dabigatran – Normal APTT ≠ non-therapeutic levels – Elevated APTT = dabigatran probably present – Normal thrombin time (TT) = no dabigatran – Dilute TT with dabigatran calibrator strongly correlates with dabigatran levels • Xa inhibitors – Anti-Xa activity calibrated to specific agent correlates with plasma concentration – Negative anti-Xa level (uncalibrated) = no Xa inhibitor – Normal PT ≠ non-therapeutic levels

Douxfils J, et al. J Thromb Haemost. 2017;:209–19. Samuelson BT, et al. Chest. 2017;151:127–38. PHARMACOKINETICS

Shih AW, Crowther MA. ASH Educ Progr B. 2016;2016:612–9. REVERSING Indications and Risks Emergent/urgent surgery Indications: Life-threatening or major bleed

Thrombosis Allergic reactions Risks: Antibody formation WARFARIN Warfarin reversal: 4F PCC vs FFP PCC

Hemostasis PCC FFP FFP

Goldsten JN, et al. Lancet. 2015;385:2077–87. Sarode R, et al. Circulation. 2013;128:1234–43. Warfarin reversal: PCC – 4F PCC vs FFP 3.6 h Infusion to procedure FFP – 8.5 h

Goldsten JN, et al. Lancet. 2015;385:2077–87. Sarode R, et al. Circulation. 2013;128:1234–43. Warfarin reversal: 4F PCC vs FFP PCC

INR reduction by 30 min FFP

Goldsten JN, et al. Lancet. 2015;385:2077–87. Sarode R, et al. Circulation. 2013;128:1234–43. Warfarin reversal: 4F PCC vs FFP

Adverse events PCC FFP

Goldsten JN, et al. Lancet. 2015;385:2077–87. Sarode R, et al. Circulation. 2013;128:1234–43. Warfarin • Immediate reversal – PCC + vitamin K reversal: – FFP only if PCC not available or history of Agents HIT • + vitamin K • Reversal within 12 – 24 hours – Vitamin K • Study dosing: PCC – INR 2 - 4  PCC 25 units/kg – INR 4 - 6  PCC 35 units/kg – INR > 6  PCC 50 units/kg – Cap at 100 kg • NAC suggested dosing: – INR < 3  1000 units – INR 3 – 5  2000 units – INR > 5  3000 units • INR 2 - 4  FFP 10 mL/kg FFP • INR 4 - 6  FFP 12 mL/kg • INR > 6  FFP 15 mL/kg • Cap at 100 kg DOAC • Cohort design Reversal • Laboratory endpoints

Trials • “Effective hemostasis” DABIGATRAN • 503 patients RE-VERSE • Group A = Major bleeding requiring reversal AD: • Group B = Invasive surgery/procedure needed within 8 hours Design • 2.5 g IV idarucizumab x 2 (no more than 15 min apart) – Could get another 5 g if needed • Primary endpoint – maximum amount of reversal from end of 1st dose to 4 hours after 2nd dose • Secondary endpoint of hemostasis judged by treating clinician

Pollack C V, et al. N Engl J Med. 2017 RE-VERSE AD: Population

301 in 202 in 78 years 75 kg 82% white AF in 95% 91.7% with Group A Group B old high ECT 45.5% GI bleed Median time Analysis only 32.6% ICH from drug to included these procedure was patients 25.9% trauma 1.6 hours RE-VERSE AD: Efficacy RE-VERSE AD: Efficacy RE-VERSE AD: Efficacy RE-VERSE AD: Safety Dabigatran • Immediate – Idarucizumab 2.5 g IV x 2 within 15 minutes • Non-immediate – Based on CrCl and drug interactions – 1 - 5 days of holding XA INHIBITORS • Decoy protein ANNEXA: • Ongoing cohort study Design • Apixaban, rivaroxaban, edoxaban, or enoxaparin (therapeutic dose) taken within the last 18 hours • Included patients with severe bleeding • Andexanet bolus for 15 - 30 min, then 2 hour infusion • Co-primary endpoints – Percent change in anti-factor Xa activity – Rate of excellent or good hemostasis at 12 hours after infusion

Connolly SJ, et al. N Engl J Med. 2016;375:1131–41. ANNEXA: Population

67 patients 77 years 81% white BMI 28 4.8 hours AF in 70% Enoxa = 4 at interim old to bolus patients analysis 47 had elevated Xa levels ANNEXA: Efficacy Anti Xa levels ANNEXA: 300 Efficacy 250 200

150

100

0 Baseline End of bolus End of 4 hr 8 hr 12 hr infusion Rivaroxaban Apixaban ANNEXA: Efficacy ANNEXA: Efficacy ANNEXA: Safety All Xa • Immediate – Andexanet alfa in the US for apixaban and rivaroxaban – FDA approved – Health Canada has not approved any agent • Non-immediate – Waiting 24 - 48 hours Cost EXPERIMENTAL TREATMENTS FOR DOAC REVERSAL PCC and bleeding aPCC PCC and Riva/Apix time

14 patients on Improved with 84 patient cohort dabigatran and edoxaban study bleeding Not with rivaroxaban 69.1% effective • Moderate to good hemostasis rate hemostasis with no poor hemostasis • ICH – 38% effective • No TE and 1 death hemostasis • 2 strokes (day 5 and 10) No studies with Xa and 1 possible PE (day 15) inhibitors in bleeding • 18% died within 1 week patients • Partially corrects anti-Xa in healthy patients

Majeed A, et al. Blood. 2017. Schulman S, et al. Thromb Res. 2017. Experimental Shaw JR and Siegal DM. Res PrThromb Haemost. 2018;2 January:251–65.

Tornkvist M, et al. Thromb Res. 2018;162 December 2017:22–31. Burnett A, et al. BMJ. 2017;357:1–8. Almegren M. Vasc Health Risk Manag. 2017;13:287–92. • DDAVP and TXA Adjuncts – Have not been studied in DOAC-related bleeding • Ciraparantag/PER977 Universal – Binds to all anticoagulants by charge interaction – Used in healthy volunteers and lab endpoints – Improved whole blood clotting time within 10 minutes on edoxaban and LMWH – Up to 24 hours after a single dose – No thrombotic events – Phase III clinical trial with edoxaban is ongoing

Hu TY, et al. Vasc Health Risk Manag. 2016. Ansell JE, et al. N Engl J Med. 2014;371:2141–2. Ansell JE, et al. Thromb Haemost. 2017. Ansell JE, et al. Thromb Res. 2016. SOURCE CONTROL Case resolution Summary

Timing of last PCC and dose, indication Idarucizumab HASHTI vitamin K for for reversal, and for dabigatran warfarin urgency

Andexanet alfa soon for Xa inhibitors but costly References • 1. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013. • 26. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban. N Engl J Med. 2014;371:2141–2. doi:10.1056/NEJMc1411800. • 2. Al-Majzoub O, Rybak E, Reardon DP, Krause P, Connors JM. Evaluation of Warfarin Reversal with 4-Factor Prothrombin Complex Concentrate Compared to 3-Factor Prothrombin Complex Concentrate at a Tertiary Academic Medical Center. J Emerg Med. 2016. • 27. Shaw JR and Siegal DM. Pharmacological reversal of the direct oral anticoagulants—A comprehensive review of the literature. Res Pr Thromb Haemost. 2018;2 January:251– 65. • 3. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso MA, Brown K, et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost. 2017. • 28. DeAngelo J, Jarrell D, Cosgrove R, Camamo J, Edwards C, Patanwala AE. Comparison of 3-Factor Versus 4-Factor Prothrombin Complex Concentrate With Regard to Warfarin Reversal, Blood Product Use, and Costs. Am J Ther. 2018;25:e326–32. • 4. Ansell JE, Laulicht BE, Bakhru SH, Hoffman M, Steiner SS, Costin JC. Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin. Thromb Res. 2016. • 29. Holt T, Taylor S, Abraham P, Mcmillian W, Harris S, Curtis J, et al. Three- versus four-factor prothrombin complex concentrate for the reversal of warfarin-induced bleeding. Int J Crit Illn Inj Sci. 2018;8:36–40. doi:10.4103/IJCIIS.IJCIIS_40_17. • 5. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. N Engl J Med. 2015. • 30. Kuroski JE, Young S. Comparison of the safety and efficacy between 3-factor and 4-factor prothrombin complex concentrates for the reversal of warfarin. Am J Emerg Med. • 6. Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016. 2017;35:871–4. doi:10.1016/j.ajem.2017.01.049.

• 7. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009. • 31. Tornkvist M, Smith JG, Labaf A. Current evidence of oral anticoagulant reversal: A systematic review. Thromb Res. 2018;162 December 2017:22–31. doi:10.1016/j.thromres.2017.12.003. • 8. Giugliano RP, Ruff CT, Braunwald E, Murphy S a, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013. • 32. Burnett A, Siegal D, Crowther M. Specific antidotes for bleeding associated with direct oral anticoagulants. BMJ. 2017;357:1–8. • 9. Granger CB, Alexander JH, McMurray JJ V, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011. • 33. Almegren M. Reversal of direct oral anticoagulants. Vasc Health Risk Manag. 2017;13:287–92. • 10. Hu TY, Vaidya VR, Asirvatham SJ. Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab. Vasc Health Risk Manag. 2016. • 34. Pollack C V., Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. N Engl J Med. 2017;:NEJMoa1707278. doi:10.1056/NEJMoa1707278. • 11. Investigators* TE. Oral Rivaroxaban for Symptomatic Venous Thromboembolism — NEJM. N Engl J Med. 2010. • 35. Swinkels BM, de Mol BA, Kelder JC, Vermeulen FE, Ten Berg JM. Long-term bleeding events after mechanical aortic valve replacement in patients under the age of 60. Netherlands Hear J. 2015;23:111–5. • 12. Investigators TH-V. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. N Engl J Med. 2013.

• 36. Kuramatsu JB, Sembill JA, Gerner ST, Sprügel MI, Hagen M, Roeder SS, et al. Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and • 13. Jones GM, Erdman MJ, Smetana KS, Mohrien KM, Vandigo JE, Elijovich L. 3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe mechanical heart valves. Eur Heart J. 2018;39:1709–23. Bleeding: A Multicenter, Retrospective, Propensity-Matched Pilot Study. J Thromb Thrombolysis. 2016.

• 37. Douxfils J, Ageno W, Samama C-M, Lessire S, ten Cate H, Verhamme P, et al. Laboratory Testing In Patients Treated With Direct Oral Anticoagulants: A Practical Guide For • 14. Majeed A, Ågren A, Holmström M, Bruzelius M, Chaireti R, Odeberg J, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex Clinicians. J Thromb Haemost. 2017;:209–19. doi:10.1111/jth.13912. concentrates: A cohort study. Blood. 2017.

• 38. Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA. Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review. Chest. • 15. Makaryus JN, Halperin JL, Lau JF. Oral anticoagulants in the management of venous thromboembolism. Nature Reviews Cardiology. 2013. 2017;151:127–38. doi:10.1016/j.chest.2016.08.1462.

• 16. Mangram A, Oguntodu OF, Dzandu JK, Hollingworth AK, Hall S, Cung C, et al. Is there a difference in efficacy, safety, and cost-effectiveness between 3-factor and 4-factor • 39. Kaatz S, Bhansali H, Gibbs J, Lavender R, Mahan C, Paje D. Reversing factor Xa inhibitors – clinical utility of andexanet alfa. J Blood Med. 2017;Volume 8:141–9. prothrombin complex concentrates among trauma patients on oral anticoagulants? J Crit Care. 2016. doi:10.2147/JBM.S121550.

• 17. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, et al. Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents. N Engl J Med. 2014. • 40. Pollack C V., Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. N Engl J Med. 2017;:NEJMoa1707278. doi:10.1056/NEJMoa1707278. • 18. Murthy SB, Gupta A, Merkler AE, Navi BB, Mandava P, Iadecola C, et al. Restarting Anticoagulant Therapy after Intracranial Hemorrhage: A Systematic Review and Meta- Analysis. Stroke. 2017. • 41. Sarode R, Milling TJ, Refaai MA, Mangione A, Schneider A, Durn BL, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: A randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128:1234–43. • 19. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011. • 42. Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. • 20. Poli L, Grassi M, Zedde M, Marcheselli S, Silvestrelli G, Sessa M, et al. Anticoagulants Resumption after Warfarin-Related Intracerebral Haemorrhage: The Multicenter Study 2016;375:1131–41. doi:10.1056/NEJMoa1607887. on Cerebral Hemorrhage in Italy (MUCH-Italy). Thromb Haemost. 2018. • 43. Heo YA. Andexanet Alfa: First Global Approval. Drugs. 2018;78:1049–55. doi:10.1007/s40265-018-0940-4. • 21. Pollack Jr. C V, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal. NEnglJMed. 2015. • 44. Goldstein JN, Refaai MA, Milling TJ, Lewis B, Goldberg-Alberts R, Hug BA, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist • 22. Proietti M, Romiti GF, Romanazzi I, Farcomeni A, Staerk L, Nielsen PB, et al. Restarting oral anticoagulant therapy after major bleeding in atrial fibrillation: A systematic reversal in patients needing urgent surgical or invasive interventions: A phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385:2077–87. doi:10.1016/S0140- review and meta-analysis. Int J Cardiol. 2018. 6736(14)61685-8.

• 23. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. • 45. Shih AW, Crowther MA. Reversal of direct oral anticoagulants: a practical approach. ASH Educ Progr B. 2016;2016:612–9. doi:10.1182/asheducation-2016.1.612. 2009. • 46. Serebruany VL, Malinin AI, Eisert RM, Sane DC. Risk of Bleeding Complications with Antiplatelet Agents: Meta-Analysis of 338,191 Patients Enrolled in 50 Randomized • 24. Schulman S, Ritchie B, Nahirniak S, Gross PL, Carrier M, Majeed A, et al. Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: A Controlled Trials. Am J Hematol. 2004;75:40–7. prospective cohort study. Thromb Res. 2017. • 47. Warfarin and Aspirin after Heart-Valve Replacement. N Engl J Med. 1994;330:507–9. doi:10.1056/NEJM199402173300717. • 25. Scott MJ, Veitch A, Thachil J. Reintroduction of anti-thrombotic therapy after a gastrointestinal haemorrhage: if and when? British Journal of Haematology. 2017.