Bleeding Management in the NOAC era

1. Bleeding Management in the NOAC era Eddy Lang Senior Researcher Alberta Health Services Associate Professor University of Calgary

2. Disclosures • Member of Thrombosis Interest Group of Canada • Sponsored presentations BoeringherIngleheim / Bayer • Research support BI – studentship grant • Failed heme exam in med school

3. Objectives(Q’s you will be able to answer) • What should my approach be to NOAC related bleeding? • How can I tell if the drug’s on board? • What do I do when the patient is spiralling?

4. Key Points

5. Key Points

6. Pharmacological advantages of the new OAC compared with warfarin include: More rapid onset & offset of action Easily reversible anticoagulant effect No need for routine laboratory monitoring All of the above 1 and 3

7. Case Scenario • 82 year old female • Rivaroxaban 20 mg OD • Started 3 mos ago for AF, CHADs 2 • Syncope, melena this am • No liver disease • BP 90/60; HR 115 • OB +ve; BUN 16; Hgb 95 (145) • GI: Stabilize first

9. New OACs: Advantages vs. VKAs

10. New OACs: Disadvantages vs. VKAs *dabigatran and apixaban

11. Pharmacology of New OACs

12. Three new drugs have been studied in AF (dabigatran, rivaroxaban, apixaban)… All 3 are as efficacious as warfarin to reduce stroke/SE All 3 are associated with less overall bleeding All 3 are associated with less intracranial bleeding All of above 1 and 3 are correct

14. Pharmacokinetics Douketis JD. Curr Pharm Des 2010;16:3436

15. Dabigatran and the aPTT - non-linear dose-response - median peak aPTT is approximately 2-fold of control - 12 hrs after the last dose (trough level), median aPTT 1.5-fold of control

16. Measuring Anticoagulant Effect of Dabigatran: INR? - dose-dependent and short-lived (1-4 hrs after dose) prolongation of INR

17. Thrombin Time • linear dose-response over therapeutic concentrations of dabigatran • directly measures plasma thrombin activity

18. Laboratory Monitoring of Dabigatran PT (INR) Dabigatranhas MINIMAL or NO EFFECT on effect on PT Apixiban and Rivaroxibando effect PT not reliable to measure anticoagulant effect aPTT dabigatranHAS EFFECT on aPTT Apix and Dabi no effect on aPTT trough level (10-16 hrs post-ingestion) >80 sec = ABNORMAL trough level >1.5-times control aPTT = EXPECTED prolongation reflects thrombin (factor II) inhibition NOT factor deficiency

19. Laboratory Monitoring of Dabigatran Thrombin clotting time (TCT) normal TCT (<30 sec) likely reflects absence of significant anticoagulant effect too sensitive for routine monitoring (to distinguish different levels of anticoagulation) but determines if any dabigatran present Dilute thrombin clotting time (Hemoclot assay) 1/16th dilution of TCT peak (2 hr post-ingestion levels): 125-175 ng/mL trough (10-16 hrs post-ingestion levels): 65-90 ng/mL

20. Laboratory Monitoring of Dabigatran: Use in Practice Step 1: aPTT qualitative test (for screening) if elevated aPTT (and no other cause), likely some dabigatran effect if normal aPTT, no clinically significant dabigatran effect for extra reassurance that no residual anticoagulant effect… Step 2: TCT (or Hemoclot test) quantitative test if normal TCT (<30 sec) or if normal Hemoclot test, no detectable dabigatran anticoagulant effect

21. Laboratory Monitoring of Rivaroxaban (and Apixaban) Step 1: PT qualitative test (for screening) if elevated PT (and no other cause), likely some rivaroxaban effect BUT, highly assay-dependent if normal PT, no clinically significant rivaroxaban effect for extra reassurance that no residual anticoagulant effect… Step 2: anti-factor Xa assay ‘LMWH-calibrated’ anti-factor Xa assay can develop rivaroxaban (apixaban) – calibrated assays

23. General Management • Stop offending drug + general supportive measures • Baseline tests: CBC, aPTT, INR, TCT, creat • Investigate and treat bleeding: ulcer electrocautery, polyp clipping, embolization, etc. • Antidote - vitamin K for VKAs - others for new anticoagulants in development

24. General Management Crowther M, et al. Blood 2008 • Transfuse pRBCs as required - dilutional coagulopathy after 8 units pRBCs - consider cryoprecipitate (especially if low fibrinogen) • Use non-specific “blood thickeners” ??? - DDAVP - Amicar/Tranexamic acid - platelet transfusion • Consider dialysis to remove drug (dabigatran) • By the time all this is done…most drugs will have been cleared

25. Prothrombin complex concentrates Contain all vitamin K-dependent coagulation factors Non-activated: • ‘4-factor-concentrates’ contain Factors II, VII, IX, and X (e.g. Beriplex, Octaplex, Proplex T, Cofact) • ‘3-factor-concentrates’ contain lower amounts of Factor VII(e.g. Prothrombinex-HT, Profilnine and BEBULIN) Activated: • FEIBA VH contains Factors II, IX, X and protein C mainly in non-activated forms and Factor VII mainly in the activated form Van Ryn J et al. ThrombHemost 2010;103:1116–27 • Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph • The content of this slide may contain information not reviewed by Health Canada

26. Studies evaluating reversal with new oral anticoagulants ICH = intracranial haemorrhage; OAC = oral anticoagulant; PCC = prothrombin complex concentrate1. van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2009;114;Abs 1065; 2. Warkentin TE et al. Blood 2012;119:2172–4; 3. Zhou W et al. Stroke 2011;42:3594–9; 4. van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2011;118:Abs 2316; 5. van Ryn J et al. PathophysiolHaemostThromb 2010;37:A94–P486; 6. Eerenberg ES et al. Circulation 2011;124:1573–9; 7. Perzborn A et al. J Thromb Haemost 2009;7(suppl 2):Abs PP-MO-183; 8. Gruber A et al. Haematologica 2009;94(suppl 2):181 Abs 0449; 9. Godier A et al. Anesthesiology 2012;116:94–102. 10. Wang X et al. Clin Pharmacol Ther 2012;91(suppl 1):Abs PI-90; 11. Martin A-C et al. ACC 2012; 24-27 March, Chicago, IL, USA: Abs 904-8; 12. Fukuda T et al. Thromb Haemost 2012;107:253–9 • Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph • The content of this slide may contain information not reviewed by Health Canada

27. Administer antidote…? 27 There are no “antidotes” for dabigatran or rivaroxaban (apixaban) Hemodialysis (…and patience!) are the only methods to remove dabigatran Hemodialysis does NOT work for rivaroxaban (apixaban) since these are highly protein-bound (…can’t dialyse out) No blood product (FFP, PCC) has been shown to reverse the anticoagulant effect of the new agents in bleedingpatients

29. Administer coagulation factor replacement…? • Replacement of clotting factors • does NOT reverse effect of dabigatran or rivaroxaban • existing drug will simply inhibit ADDED clotting factors…BUT • adding factor II (or X) may ‘overwhelm’ this inhibitory effect • No agent has been shown to reverse the anticoagulant effect of the new agents in bleeding patients • ? 4-factor PCC (contains: II, VII, IX, X) – Octaplex, Beriplex • ? activated 4-factor PCC – Feiba • ? recombinant (activated) factor VII – Novoseven

30. Reversal of dabigatran activity by coagulation factor concentrates: van Ryn et al. Dabigatran etexilate 30 mg/kg + Beriplex 35 U/kg + Octaplex 40 U/kg + FEIBA 100 U/kg + NovoSeven 500 µg/kg 500 Bleeding time prolonged with dabigatran (vscontrol) 400 Mean (standard error) bleeding time, seconds 300 Effect of dabigatran reversed by concentrate administration 200 Control 0 5 15 30 120 Time post concentrate addition (min) Prolonged bleeding time induced by dabigatran was rapidly reversed within 5 min of concentrate administration • Effect maintained during study period (120 min) n=4van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2011;118:Abs 2316 • Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph • The content of this slide may contain information not reviewed by Health Canada

31. Reversal of rivaroxaban and dabigatran activity by PCC in healthy subjects: Eerenberg et al. Rivaroxaban 20 mg BID(n=6) Rivaroxaban 20 mg BID(n=6) PCC or placebo PCC or placebo Dabigatran150 mg BID(n=6) Dabigatran150 mg BID(n=6) 2.5 days Washout period(11 days) 2.5 days Effects of a single dose of concentrate were assessed in a randomized, double-blind, placebo-controlled, crossover trial • Healthy male volunteers (n=12) • Single dose of PCC (Cofact*50 U/kg) Assessments were coagulation parameters only *Non-activated PCC derived from human plasma containing a high concentration of the procoagulation Factors II, VII, IX, and X, as well as the natural anticoagulants protein C and S and antithrombin BID = twice daily; PCC = prothrombin complex concentrate Eerenberg ES et al. Circulation 2011;124:1573–9 • Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph • The content of this slide may contain information not reviewed by Health Canada

32. Reversal of rivaroxaban and dabigatran activity by PCC in healthy subjects: Eerenberg et al. Effect of rivaroxaban Effect of rivaroxaban Effect of subsequent PCC or placebo infusion Effect of subsequent PCC or placebo infusion 18 200 Placebo Placebo PCC PCC 16 150 14 PT (seconds) ETP (%) 100 12 50 10 0 0 1 h 2 h 4 h 6 h 24 h 1 h 2 h 4 h 6 h 24 h 30 min 30 min Baseline T=0 15 min Baseline T=0 15 min Time Time Data are mean ± standard deviationETP = endogenous thrombin potential; PCC = prothrombin complex concentrate; PT = prothrombin timeEerenberg ES et al. Circulation 2011;124:1573–9 Rivaroxaban significantly prolonged PT and significantly decreased ETP Effects were normalized by subsequent PCC infusion • Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph • The content of this slide may contain information not reviewed by Health Canada

33. Reversal of rivaroxaban and dabigatran activity by PCC in healthy subjects: Eerenberg et al. Effect of dabigatran Effect of dabigatran Effect of dabigatran Effect of subsequent PCC or placebo infusion Effect of subsequent PCC or placebo infusion Effect of subsequent PCC or placebo infusion 100 >120 150 100 80 80 100 60 aPTT (seconds) TT (seconds) ECT (seconds) 60 40 40 50 20 20 0 0 0 1 h 2 h 4 h 6 h 24 h 1 h 2 h 4 h 6 h 24 h 1 h 2 h 4 h 6 h 24 h Baseline T=0 15 min 30 min Baseline T=0 15 min 30 min Baseline T=0 15 min 30 min Time Time Time Dabigatran significantly prolonged aPTT, TT, and ECT Effects not reversed by subsequent infusion of PCC Data are mean ± standard deviation aPTT = activated partial thromboplastin time; ECT = ecarin clotting time; PCC = prothrombin complex concentrate; TT = thrombin timeEerenberg ES et al. Circulation 2011;124:1573–9 • Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph • The content of this slide may contain information not reviewed by Health Canada

34. Reversing the effects of dabigatran by coagulation factor concentrates: summary Patient with bleeding on dabigatran therapy Moderate to severe bleeding Life-threatening bleeding Mild bleeding • Symptomatic treatment • Mechanical compression • Surgical intervention • Fluid replacement and haemodynamic support • Blood product transfusion • Oral charcoal application* (if dabigatran etexilate ingested <2 hrs before) • Haemodialysis • Consideration of rFVlla or PCC* • Charcoal filtration* Delay next dose or discontinue treatment as appropriate van Ryn J et al. ThrombHaemost2010;103:1116-1127. There is some experimental evidence to support the role of coagulation factor concentrates in reversing the anticoagulant effect of dabigatran However, limited clinical evidence is available • Guidance regarding reversal of dabigatran activity (e.g. in cases of overdose or major bleeding) highlights that the usefulness of CFCs in clinical settings has not yet been demonstrated *Recommendation based only on limited non-clinical data; there is no experience in volunteers or patientsCFCs = coagulation factor concentrates; PCC = prothrombin complex concentrate; rFVIIa = recombinant activated Factor VIIa • Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph • The content of this slide may contain information not reviewed by Health Canada

35. Reversal of rivaroxaban activity by coagulation factor concentrates: Perzborn et al. Baseline After treatment 1400 * U/kg 1200 * 1000 800 Bleeding time (seconds) 600 400 200 0 Rivaroxaban 2 mg/kg+ vehicle Rivaroxaban 2 mg/kg+ PCC 25 U/kg Rivaroxaban 2 mg/kg+ PCC 50 U/kg *P<0.01 vs baseline PCC = prothrombin complex concentrate; PT = prothrombin time Perzborn E et al. ISTH XXII Congress, July 11–16 2009, Boston, MA, USA: PP-MO-183 Rivaroxaban significantly increased bleeding time vs baseline PCC reversed rivaroxaban-induced bleeding (dose-dependent)

36. Take-home Messages • New OACs use increasing but warfarin will remain • warfarin in users with good results and INR monitoring • patients with impaired renal function

37. …more Take-home Messages • Laboratory monitoring • rivaroxaban/apixaban: PT (screen), anti-Xa (quantitative) • dabigatran: aPTT (screen), TT (more sensitive) • Bleeding in patients receiving new OACs • supportive care (fluids, pRBCs) is most relevant • FFP and PCC do NOT eliminate anticoagulant effect • no full antidotes yet BUT short drug half-lives • HD for dabigatran but NOT rivaroxaban/apixaban • Fab for Dabigitran

38. Case Scenario • 82 year old female • Rivaroxaban 20 mg QD • Started 3 mos ago for AF, CHADs 2 • Syncope, melena this am • No liver disease • BP 90/60; HR 115 • OB +ve; BUN 16; Hgb 95 (145) • GI: Stabilize first

39. Q and A…