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1 Anticoagulation 2014 Bruce Ritchie MD, FRCPC 3 Director VTE Clinic, UofA Hospital Director Comprehensive Bleeding Disorder Clinic Director Comprehensive Rare Blood Disorder Clinic Director Canadian BioSample Repository (CBSR) Mar-2014

2 Conflicts of Interest Principle Investigator in Pharmaceutical Trials including: Fragmin, Lovenox, XiMelagatran, Rivaroxaban, Dabigatran, Apixaban, Edoxaban Unpaid consulting advice to: Baxter, Bayer, Boehringer- Ingelheim, Canadian Blood Service, Canadian Hemophilia Society, Covidien, CSL Behring, Dyax, Leo Pharmaceuticals, Novartis, Novo Nordisk, Pharming, Pfizer, Sanofi, Talecris, Wyeth In lieu of Honoraria, I request that donations be made to the University of Alberta to fund summer students ($1300/month X 4 = $5200) I have received funding for Investigator Initiated studies (biobanking) from: Baxter, CSL Behring, Novartis, Novo Nordisk, Pfizer, Wyeth. Pending: Bayer, Boehringer-Ingelheim, Leo, Sanofi.

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4 Venous ThromboEmbolism: New Anticoagulant Drugs How do they work 2.How do we measure them 3.How do we reverse them 4.How do we manage elective Surgery Bruce Ritchie MD, FRCPC 3 Director VTE Clinic, UofA Hospital Director Comprehensive Bleeding Disorder Clinic Director Comprehensive Rare Blood Disorder Clinic Director Canadian BioSample Repository (CBSR)

5 Adapted from Wikipedia 9

6 Microparticles & Tissue Factor, green=tf, red=platelets, fibrin=blue, platelets/tf=yellow, platelets/fibrin=turquoise, platelets/tf/fibrin=white. 10

7 Thromboembolic Disease in Alberta Incidence 108 in 100, ,584,304 people in Alberta in 2011; 4 million (Mar, 2013) 3,871 new cases per year in Alberta; 4,320 (Mar 2013) Recurrence in 30% - 40% 2, recurrent cases per year in Alberta (Mar-2013) Severe Post thrombotic Syndrome 2,3,4 Severe PTS in 3% at 2 years 2 ( ), 6% at 10 years 3 ; ( ) Disability costs $5,500-7, % of symptomatic PE s are fatal within 1 hour 4,5, 40% at 30 days 6 1. Roger VL, et al. Heart disease and stroke statistics update: A report from the american heart association. Circulation. 2012;125:e2-e220 ; 2. Schulman S, et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost. 2006;4: ; 3. Kahn SR, et al. Determinants and time course of the post-thrombotic syndrome after acute deep venous thrombosis. Annals of Internal Medicine. 149(10): , 2008 Nov 18.

8 VTE Clinical Features Anderson FA Jr, et al. Incidence of VTE increases with age: Arch Intern Med. 1991;151: Fihn SD; Callahan CM; Martin DC; McDonell MB; Henikoff JG; White RH. The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Annals of Internal Medicine. 124(11):970-9, 1996 Heit JA, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: A population-based cohort study. Arch Intern Med. 2000;160: Schulman S, et al. Postthrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost. 2006;4:

9 Risk of VTE Recurrence Florent Boutitie, Laurent Pinede, Sam Schulman, Giancarlo Agnelli, Gary Raskob, Jim Julian, Jack Hirsh, Clive Kearon. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants data from seven trials. BMJ 2011;342:d3036. doi: /bmj.d3036

10 Long-term Prophylaxis Schulman S, Granqvist S, Holmström M, Carlsson A, Lindmarker P, Nicol P, Eklund SG, Nordlander S, Lärfars G, Leijd B, Linder O, Loogna E. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med Feb 6;336(6): Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med Mar 25;340(12): Erratum in: N Engl J Med 1999 Jul 22;341(4):298.

11 Pulmonary Embolism: A Life-threatening Disease Cumulative mortality following acute PE Mortality rate (%; excluding PE first recognised at necropsy) % Mortality At 3 months International Cooperative Pulmonary Embolism Registry N= Time from diagnosis (days) PE=pulmonary embolism Goldhaber SZ et al; for ICOPER. Lancet. 1999;353:

12 Kahn SR, et al. Determinants and time course of the post-thrombotic syndrome after acute deep venous thrombosis. Annals of Internal Medicine. 149(10): , 2008 Nov 18. Schulman S, et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost. 2006;4: Post Thrombotic Syndrome in Canada

13 Warfarin & Intracranial Hemorrhage in Finland 1993 to 2008

14 Warfarin & Intracranial Hemorrhage in Finland 1993 to , introduction of PCC

15 Reversal of Coumadin - PCC Nitzki-George D. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47:

16 Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal. Dowlatshahi D et al; on behalf of the Canadian PCC Registry (CanPro) Investigators* Stroke. 2012;43:

17 Drug New Oral Anticoagulants Indication targ et Peak T ½ Clearance Drug Interactions Antidote Dabigatran Rivaroxaban Apixaban A Fib DVT/PE Hip/Knee A Fib DVT/PE Hip/Knee A Fib Hip/Knee II 1-4 h h 85% renal Rifampin, quinidine, amiodarone, Potent P-gp inhibitor Xa h 7-11 h 66% renal really 33% Potent CYP3A4, P-gp inhibitor Xa 3-4 h 12 h 27% renal Potent CYP3A4 inhibitor Edoxaban No Xa 1-2 h 6-11 h 35% renal Potent CYP3A4, P-gp inhibitor apcc PCC PCC PCC Betrixaban No Xa 3-4 h 20 h <8% renal Fonda Hip/Knee Abd Surg Xa 2 h 17 h 100% renal protamine

18 Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial 1. Hart RG, Diener HC, Yang S, etal. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: The RELY trial. Stroke 2012;43: doi: /STROKEAHA Eikelboom JW, et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial Circulation. 2011;123: , published online before print May , doi: /circulationaha

19 Eikelboom JW, et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial Circulation. 2011;123: , published online before print May , doi: /circulationaha

20 Southworth MR, Reichman ME, Unger EF. Dabigatran and Postmarketing Reports of Bleeding. NEJM Online 13-Mar DOI: /NEJMp

21 Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism The EINSTEIN PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012;366:

22 Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism The EINSTEIN PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012;366:

23 Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism The EINSTEIN PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012;366:

24 Apixaban in Patients with Atrial Fibrillation Connolly SJ, Eikelboom J, Joyner C, Diener H-C, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser S, Rafael Diaz, M.D., Talajic M, Zhu J, Pais P, M.B, Budaj A, Parkhomenko A, Jansky A, Commerford P, Tan RS, Sim K-H, Lewis BS, Van Mieghem W, Lip GJY, Kim JH, Lanas- Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O Donnell M, Lawrence J, Lewis G, Afzal, R, and Yusuf S, for the AVERROES Steering Committee and Investigators. Apixaban in Patients with Atrial Fibrillation. N Engl J Med 2011;364:

25 Thrombin Time Ratio Best Approximates Dabigatran Plasma Levels van Ryn J; Stangier J; Haertter S; Liesenfeld K-H; Wienen W; Feuring M; Clemens A. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of 43 anticoagulant activity. Thrombosis and haemostasis [ ] yr:2010 vol:103 iss:6 pg:

26 Standardized Hemoclot Thrombin Time van Ryn J; Stangier J; Haertter S; Liesenfeld K-H; Wienen W; Feuring M; Clemens A. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of 44 anticoagulant activity. Thrombosis and haemostasis [ ] yr:2010 vol:103 iss:6 pg:

27 Effect of Rivaroxaban On Coagulation Parameters: aptt Ratio 45 Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundamental & Clinical Pharmacology 26 (2012) 27 32

28 Effect of Apixaban on anti Xa assays Becker RC, Yang H, Barrett Y, Mohan P, Wang J, Wallentin L, Alexander JH. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis (2011) 32:

29 Reversal of Rivaroxaban and Dabigatran Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate : A Randomized, Placebo- Controlled, Crossover Study in Healthy Subjects Elise S. Eerenberg, Pieter W. Kamphuisen, Meertien K. Sijpkens, Joost C. Meijers, Harry R. Buller and Marcel Levi. Circulation October 4, 2011

30 3ZoNBF2cTx7FZlR4qrBObwvFcmhQ%3D%3D

31 Reversal of Rivaroxaban and Dabigatran Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate : A Randomized, Placebo- Controlled, Crossover Study in Healthy Subjects Elise S. Eerenberg, Pieter W. Kamphuisen, Meertien K. Sijpkens, Joost C. Meijers, Harry R. Buller and Marcel Levi. Circulation October 4, 2011

32 Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban Dabigatran Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban A randomised crossover ex vivo study in healthy volunteers. Raphael Marlu; Enkelejda Hodaj; Adeline Paris; Pierre Albaladejo; Jean Luc Crackowski; Gilles Pernod. Thromb Haemost 2012; 108:

33 FEIBA monograph: df Reversing NOACs: FEIBA (Activated PCC) Contains Factors II, IX, and X, mainly non-activated, and Factor VII mainly in the activated form. Dose: IU/kg

34 Alternative: PCC and rfviia + Octaplex/Beriplex 40 IU/kg NovoSeven (rfviia) 1 mg 1. Octaplex monograph: roved.pdf&t= &hash=0ab78e2e273f669f418af3633c86b3bf07ab3da4 2. Beriplex monograph: 3. NovoSeven monograph:

35 Strategies for treating bleeding on NOACs Minor or Moderate bleeding: hold NOAC; measure creatinine, PTT/PT; local measures Severe/Life-threatening bleeding: hold NOAC; measure creatinine, PTT/PT; local measures, PLUS Dabigatran Activated charcoal suspension if less then 2 hrs Consider dialysis Reverse with FEIBA U/kg or PCC+rFVIIa Rivaroxaban Reverse with PCC U/kg Nitzki-George D, Wozniak I, Caprini J. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47: van Ryn J, et al. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:

36 Availability of PCCs (Octaplex. Beriplex) in Alberta North Zone: 37 hospitals, not LaCrete (RHIg), Vilna Edmonton Zone: 12 hospitals, not CCI (IVIg), East Edmonton Health, Gibbons Central Zone: 29 hospitals (all) Calgary: 13 hospitals (all) South: 12 hospitals, not Coaldale, Oyen (rbcs & RhIg) Total: 103 hospitals in Alberta almost all the hospitals that carry blood products. Alberta Health Services

37 Availability of apccs (FEIBA) in Alberta PCC availability, includes most stroke sites (?Canmore, Medicine Hat), & FVIII Inhibitor patients Peace River Community Health Centre Queen Elizabeth II Hospital (Grande Prairie) Sturgeon Hospital (St. Albert) University of Alberta Hospital Royal Alexandra Hospital Misericordia Hospital Grey Nuns Hospital Hinton Healthcare Centre Westlock Healthcare Centre Red Deer Hospital Foothills Hospital Alberta Children s Hospital Chinook Regional Hospital (Lethbridge) Alberta Health Services

38 FEIBA (apcc) Monograph

39 apccs and thrombosis Post-marketing surveillance: 1. the risk of thrombosis ranged from 0/4500 infusions 4, 3.18/100,000 infusion in 18 years 5, 8.24/100,000 infusions 3, and 4.05/100,000 infusions 2. Risk factors were overdose/frequent dosing in 30-80% 2. Combining apcc with tranexamic acid showed no excess thrombosis HOLMSTROM M, TRAN HTT, HOLME PA.Combined treatment with APCC (FEIBAÒ) and tranexamic acid in patients with haemophilia A with inhibitors and in patients with acquired haemophilia A a two-centre experience. Haemophilia (2012), 18, DOI: /j x 2. EHRLICH HJ, HENZL MJ, GOMPERTS ED. Safety of factor VIII inhibitor bypass activity(feibaò): 10-year compilation of thrombotic adverse events. Haemophilia (2002), 8, ALEDORT LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. Journal of Thrombosis and Haemostasis, 2: DIMICHELE D, & NEGRIER C. A retrospective post licensure survey of FEIBA efficacy and safety. Haemophilia (2006), 12, DOI: /j x 5. Evaluating the Thrombotic Safety Profile of Factor VIII Bypassing Activity (FEIBA). Adams J, Lee D, Yoon BS. Poster, WFH World Congress 02-Jun-2008

40 Rivaroxaban and enoxaparin have similar effects on Anti-Factor Xa activity beyond 24 hours Enoxaparin has a half-life of 4-7 hours and can be dosed either OD or BID Adapted from Kubitza et al., ISTH 2005; Lovenox Product Monograph, 2010

41 Questions 59

42 Questions FOTOS DE LAURENT SCHWEBEL: 60

43 ClinicalTrials.gov The future for DOAC reversal - Idarucizumab

44 The future for DOAC reversal - Andexanet Alfa Neal Shah. Reversal Agents for Anticoagulants: Focus on Andexanet Alfa. AMSRJ Spring 2014; 1, No. 1

45 Xarelto PM, July 18, 2012; Eliquis PM November 27, 2012; Pradaxa PM November 12, 2012 Rivaroxaban Determine patients risk of bleeding Discontinuation Before Elective Invasive or Surgical Procedures Time to discontinue medication prior to procedure Dabigatran Determine patients risk of bleeding Apixaban Determine patients risk of bleeding Standard risk High risk of bleeding or major surgery Standard risk High risk of bleeding or major surgery Standard risk High risk of bleeding or major surgery At least 1 day 2-4 days ml/min Estimate CrCl ml/min 80 ml/min ml/min Estimate CrCl ml/min 80 ml/min At least 1 day At least 2 days days days 1-2 days 1 day 4 days 2-3 days 2 days Recommended May be considered

46 ASA for VTE prophylaxis after unprovoked VTE Aspirin for the Prevention of Recurrent Venous Thromboembolism: The INSPIRE Collaboration. John Simes, Cecilia Becattini, Giancarlo Agnelli, John W. Eikelboom, Adrienne C. Kirby, Rebecca Mister, Paolo Prandoni, Timothy A. Brighton, for the INSPIRE Study Investigators*. Published online before print August Circulation DOI: /CIRCULATIONAHA Xarelto PM, July 18, 2012; Eliquis PM November 27, 2012; Pradaxa PM November 12, 2012

47 ASA for VTE prophylaxis after unprovoked VTE Aspirin for the Prevention of Recurrent Venous Thromboembolism: The INSPIRE Collaboration. John Simes, Cecilia Becattini, Giancarlo Agnelli, John W. Eikelboom, Adrienne C. Kirby, Rebecca Mister, Paolo Prandoni, Timothy A. Brighton, for the INSPIRE Study Investigators*. Published online before print August Circulation DOI: /CIRCULATIONAHA Xarelto PM, July 18, 2012; Eliquis PM November 27, 2012; Pradaxa PM November 12, 2012

48 ASA for VTE prophylaxis after unprovoked VTE Aspirin for the Prevention of Recurrent Venous Thromboembolism: The INSPIRE Collaboration. John Simes, Cecilia Becattini, Giancarlo Agnelli, John W. Eikelboom, Adrienne C. Kirby, Rebecca Mister, Paolo Prandoni, Timothy A. Brighton, for the INSPIRE Study Investigators*. Published online before print August Circulation DOI: /CIRCULATIONAHA Xarelto PM, July 18, 2012; Eliquis PM November 27, 2012; Pradaxa PM November 12, 2012

49 ASA for VTE prophylaxis after unprovoked VTE Aspirin for the Prevention of Recurrent Venous Thromboembolism: The INSPIRE Collaboration. John Simes, Cecilia Becattini, Giancarlo Agnelli, John W. Eikelboom, Adrienne C. Kirby, Rebecca Mister, Paolo Prandoni, Timothy A. Brighton, for the INSPIRE Study Investigators*. Published online before print August Circulation DOI: /CIRCULATIONAHA Xarelto PM, July 18, 2012; Eliquis PM November 27, 2012; Pradaxa PM November 12, 2012

50 ASA for VTE prophylaxis after unprovoked VTE Aspirin for the Prevention of Recurrent Venous Thromboembolism: The INSPIRE Collaboration. John Simes, Cecilia Becattini, Giancarlo Agnelli, John W. Eikelboom, Adrienne C. Kirby, Rebecca Mister, Paolo Prandoni, Timothy A. Brighton, for the INSPIRE Study Investigators*. Published Xarelto online before PM, July print 18, 2012; August Eliquis PM Circulation November 27, DOI: 2012; /CIRCULATIONAHA Pradaxa PM November 12, 2012

51 ASA for VTE prophylaxis after unprovoked VTE Aspirin for the Prevention of Recurrent Venous Thromboembolism: The INSPIRE Collaboration. John Simes, Cecilia Becattini, Giancarlo Agnelli, John W. Eikelboom, Adrienne C. Kirby, Rebecca Mister, Paolo Prandoni, Timothy A. Brighton, for the INSPIRE Study Investigators*. Published Xarelto online before PM, July print 18, 2012; August Eliquis PM Circulation November 27, DOI: 2012; /CIRCULATIONAHA Pradaxa PM November 12, 2012

52 Rivaroxaban Clinical Programme Overview: > 60,000 Patients Enrolled VTE prevention after major orthopaedic surgery VTE prevention in hospitalized medically ill patients VTE treatment Stroke prevention in atrial fibrillation Secondary prevention of acute coronary syndromes Phase III RECORD1 RECORD2 RECORD3 RECORD4 EINSTEIN-DVT EINSTEIN-PE EINSTEIN-EXT Customized Dose 10 mg od (2 weeks, knee; 5 weeks, hip) 10 mg od (5 weeks) 15 mg bid for first 3 weeks 20 mg od 3, 6, or 12 months 20 mg od 15 mg od for CrCl ml/min 2.5 mg bid 5 mg bid

53 omy_page1.html

54 Bleeding with NOACs

55 Bleeding with NOACs

56 Bleeding with NOACs

57 Bleeding with NOACs

58 Long-term Prophylaxis Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med Mar 25;340(12): Erratum in: N Engl J Med 1999 Jul 22;341(4):298.

59 Last updated: February 2014 Einstein Choice- Study Design Randomized, double-blind, event-driven, superiority study Objective of the study: Demonstrate that both rivaroxaban 20 mg or 10 mg are superior in the long term secondary prevention of recurrent VTE to ASA 100 mg with comparable rates of major bleeding Patients with confirmed symptomatic DVT and/or PE who completed 6-12 months of anticoagulant treatment* Day 1 N~ 2,850 R Rivaroxaban 20 mg od n~ 950 Rivaroxaban 10 mg od n~ 950 ASA 100mg od n~ month treatment duration 1 month observation period Primary endpoint: Fatal or non-fatal symptomatic recurrent VTE Study Start Date: February 2014 Estimated Study Completion Date: December * Completed 6 to 12 months (± 1 month) with interruption of anticoagulation 1 week at randomisation

60 Last updated: February 2014 Non-interventional study: Xarelto (XALIA) study design Prospective, non-interventional cohort field study Objective: To collect real-life data on adverse events (AEs), bleeding, thromboembolic events and mortality in patients diagnosed with actue DVT treated with rivaroxaban or standard of care (SOC) Study population: Patients (N~4800) with diagnosis of acute DVT (not PE) and with an indication for anticoagulant therapy for 3 months Type, dose and duration of drug used at discretion of attending physician *Protocol does not define exact referral dates for follow-up visits Rivaroxaban for 3 months N~2400 Investigators to collect data at initial visit, at 1 month and then quarterly* SOC: e.g. initial treatment with LMWH or fondaparinux, followed by VKA for 3 months N~2400 Study Start Date: June 2012 Estimated Study Completion Date: March 2015 (1 month after end of treatment) Final assessment Primary outcomes: Major bleeding events, symptomatic recurrent venous thromboembolic events, all-cause mortality DVT, deep vein thrombosis; LMWH, low molecular weight heparin; PE, pulmonary embolism; SOC, standard of care; VKA, vitamin K antagonist

61 Figure 1. Adjusted relative risks for bleeding complications and 95% Cls according to age category. Relative risks were obtained by Cox regression using combined retrospective and prospective cohorts with adjustment for intensity of warfarin therapy and deviation in prothrombin time ratio. Fihn SD; Callahan CM; Martin DC; McDonell MB; Henikoff JG; White RH. The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Annals of Internal Medicine. 124(11):970-9, 1996 Jun American College of Physicians. 7

62 Factor VII, Tissue Factor & Factor X g002.htm Pedersen LG. Lee Pedersen s work in theoretical and computational chemistry and biochemistry. World J Biol Chem February 26; 2(2): doi: /wjbc.v2.i

63 Factor X activation of Thrombin 81 Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, and Prcahl JT: Williams Hematology, 8 th Ed:

64 Low Molecular Weight Heparins Rapid onset of action - Peak 4-6 hr Half life 3-4 h 100% renal excretion & 100% bioavailability Predictable and consistent anticoagulant effects No requirement for routine coagulation monitoring can do anti-xa Reversible w protamine 1mg/100u, but only 60% reversible and protamine is a potent anticoagulant when you overdose. Avearge size (60%) less then 8,000 daltons (vs UFH 3-4 kdaltons) 82

65 Low Molecular Weight Heparins Drug Mol Wt target Peak T ½ Clearance Antidote UF Heparin 15 kda II, Xa 1-4 hr 3-4 hr Endothelial / renal Protamine Dalteparin 4.5 kda Xa 4-6 hr 3-4 hr renal Protamine 60% Enoxaparin 4.5 kda Xa 4-6 hr 3-4 hr renal Protamine 60% Tinzaparin 4.5 kda Xa 4-6 hr 3-4 hr renal Protamine 60% Fondaparinux 1.7 kda Xa 2 hr hr renal apcc, Txa

66 Enoxaparin significantly reduces major ischaemic events when compared with UFH in the treatment of thromboembolic diseases 1. Cohen M, Demers C, Gurfinkel E, Turpie A, Fromell G, Goodman S, Langer A, Califf R, Fox K, Premmereur J, Bigonzi F, Stephens J, Weatherley B. A comparison of low molecular weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997; 337: Antman EM, McCabe C, Gurfinkel E, Turpie A, Alexander G, Bernink P, Salein D, de Luna A, Fox K, LaBlanche J-M, Radley D, Premmereur J, Braunwald E. Enoxaparin prevents death and cardiac ischaemic events in unstable angina/non-q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999; 100: Merli G, Spiro T, Olsson C, Abildgaard U, Davidson B, Eldor A, Elias D, Grigg A, Musset D, Rodgers G, Trowbridge A, Yusen R, Zawilska K. Subcutaneous enoxaparin once or twice daily compared with intravenous heparin for the treatment of venous thromboembolic disease. Ann Intern Med 2001; 134: Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecular-weight-heparin compared with intravenous heparin for treatment of pulmonary embolism. Ann Intern Med 2004;140:

67 Thromboembolic complications of a subtherapeutic INR 501 patients with INR INR units below lower limit of target INR included (280 with MHV, 221 with AF and CHADS2 score 3). LMWH was prescribed for 64 patients (12.8%). Seven patients had a TE (1.40%; 95% confidence interval 0.68, 2.86%; 5.58 events for 100 patients year). All occurred within 14 days. If only patients not bridged, incidence of TE was 1.14% (5 of 437 patients; 95% confidence interval 0.49, 2.64%; 4.58 events for 100 patients year). There were no major bleeding events. Dentali F, et al. Incidence of thromboembolic complications in patients with atrial fibrillation or mechanical heart valves with a subtherapeutic international normalized ratio: A prospective multicenter cohort study. Am. J. Hematol. 87: , 2012

68 Prothrombin Complex Concentrates vs apcc Octaplex, OctaPharma 500 U/20 ml Beriplex, CSL Behring 500 U/20mL FEIBA, Baxter U/20 ml U/50ml Units reqd to correct ptt FFP 1U/mL, ml II U/mL VII U/mL IX U/mL X U/mL C U/mL S U/mL Z other Yes Heparin added, low amnt FVIIa Yes Heparin, ATII added 28-38, Trace IIa 20-40, 89-98% FVIIa= 50U= 37 mcg 17-44, Trace IXa 24-28, Trace Xa Activated Protein C (APC) Activated Protein C, FVIII 0.1U/U CPD, ABO compatible 1. Diane Nitzki-George, Izabela Wozniak, Joseph A Caprini. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47: FEIBA NF monograph 3. Luu H, Ewenstein B. FEIBA safety profile in multiple modes of clinical and home-therapy application. Haemophilia 2004;10(suppl 2):10-6

69 Once-Daily Dosing Associated With Higher Adherence 10,697 adult AF patients with full insurance drug coverage, newly initiated on diabetes or antihypertensive medication Those (n=8,256) on once daily regimens had a 26% higher adherence than those (n=2,441) on twice daily regimens Among those aged 65 years, once daily medication was associated with Compliant Patients (%) (medication possession ratio, MPR) a 52% higher probability of being compliant P<0.001 OD Total Population 65 years old 1. Laliberté F et al. Adv Ther 2012; 29: Laliberté F et al. Patient (2013) 6: DOI /s BID P=0.017 Compliant Patients (%) (proportion of days covered, PDC) P<0.001 OD P<0.001 BID P<0.001 P< Months since initiation of therapy

70 aptt variable among sites/reagents van Ryn J; Stangier J; Haertter S; Liesenfeld K-H; Wienen W; Feuring M; Clemens A. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of 88 anticoagulant activity. Thrombosis and haemostasis [ ] yr:2010 vol:103 iss:6 pg:

71 aptt variable among sites/reagents Dabigatran Effects on the International Normalized Ratio, Activated Partial Thromboplastin Time, Thrombin Time, and Fibrinogen: A Multicenter, In Vitro Study. Dager WE, Gosselin RC, Kitchen S, and Dwyre D. 89 Ann Pharmacother 2012;46:

72 Diluted Thrombin Time to Measure Dabigatran Avecilla ST, Ferrell C, Chandler WL, Reyes M. Plasma-Diluted Thrombin Time to Measure Dabigatran Concentrations During Dabigatran Etexilate Therapy. Am J Clin Pathol 2012;137: DOI: /AJCPAU7OQM0SRPZQ 90

73 Activated Charcoal for removal of Dabigatran Dabigatran etixilate is lipophilic, & binds to Activated Charcoal Dabigatran etexilate in water (ph ) + Activated charcoal, Dabigatran etexilate could not be detected, > 99.99% adsorbed Dabigatran in human plasma pool at 470 and 940 ng/ml + Active charcoal (125 mg/ ml) or a 1:11 dilution. Dabigatran levels to <1.01 ng/ml. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103: doi: /TH

74 Hemodialysis for removal of Dabigatran 1. Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombinant factor VIIa (rfviia) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012; 119: doi: /blood Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 2012;46:e21. doi: /aph.1R Chang DN, Dager WE, Chin AI. Removal of dabigatran by hemodialysis. Am J Kidney Dis 2013;61: doi: /j.ajkd

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