Conflicts of Interest

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

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.

Venous ThromboEmbolism: New Anticoagulant Drugs 2014 1.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)

Adapted from Wikipedia http://en.wikipedia.org/wiki/coagulation 9

Microparticles & Tissue Factor, green=tf, red=platelets, fibrin=blue, platelets/tf=yellow, platelets/fibrin=turquoise, platelets/tf/fibrin=white. http://80- www.nature.com.login.ezproxy.library.ualberta.ca/nm/journal/v8/n10/suppinfo/nm782_s1.html 10

Thromboembolic Disease in Alberta Incidence 108 in 100,000 1 3,584,304 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% 2,6 1161-1548 recurrent cases per year in Alberta 1296-1728 (Mar-2013) Severe Post thrombotic Syndrome 2,3,4 Severe PTS in 3% at 2 years 2 (116-130), 6% at 10 years 3 ; (232-260) Disability costs $5,500-7,600 3 10% 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--2012 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;4:734-742; 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):698-707, 2008 Nov 18.

VTE Clinical Features Anderson FA Jr, et al. Incidence of VTE increases with age: Arch Intern Med. 1991;151:933-938. 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;160:761-768 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;4:734-742

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:10.1136/bmj.d3036

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. 1997 Feb 6;336(6):393-8. 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. 1999 Mar 25;340(12):901-7. Erratum in: N Engl J Med 1999 Jul 22;341(4):298.

Pulmonary Embolism: A Life-threatening Disease Cumulative mortality following acute PE Mortality rate (%; excluding PE first recognised at necropsy) 16 14 12 10 8 6 4 2 0 15.3% Mortality At 3 months International Cooperative Pulmonary Embolism Registry N=2454 0 10 20 30 40 50 60 70 80 90 Time from diagnosis (days) PE=pulmonary embolism Goldhaber SZ et al; for ICOPER. Lancet. 1999;353:1386 1389. 25 2

Kahn SR, et al. Determinants and time course of the post-thrombotic syndrome after acute deep venous thrombosis. Annals of Internal Medicine. 149(10):698-707, 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;4:734-742 Post Thrombotic Syndrome in Canada

Warfarin & Intracranial Hemorrhage in Finland 1993 to 2008

Warfarin & Intracranial Hemorrhage in Finland 1993 to 2008 2004, introduction of PCC

Reversal of Coumadin - PCC Nitzki-George D. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47:841-55.

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;43:1812-1817.

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 12-17 h 85% renal Rifampin, quinidine, amiodarone, Potent P-gp inhibitor Xa 0.5-2 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

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;43:1511-7. doi: 10.1161/STROKEAHA.112.650614 2. 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;123:2363-2372, published online before print May 16 2011, doi:10.1161/circulationaha.110.004747

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;123:2363-2372, published online before print May 16 2011, doi:10.1161/circulationaha.110.004747

Southworth MR, Reichman ME, Unger EF. Dabigatran and Postmarketing Reports of Bleeding. NEJM Online 13-Mar- 2013 DOI: 10.1056/NEJMp1302834

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;366:1287-97.

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;366:1287-97.

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;366:1287-97.

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;364:806-17.

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 [0340-6245] yr:2010 vol:103 iss:6 pg:1116-27

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 [0340-6245] yr:2010 vol:103 iss:6 pg:1116-27

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

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) 32:183 187 46

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

http://www.medscape.com/viewarticle/827433?pa=8izenlu7llvhv32clyf10l32j6kmwg0mkicysjdylifpszrevsz%2fcu2ba2 3ZoNBF2cTx7FZlR4qrBObwvFcmhQ%3D%3D

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

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: 217 224

FEIBA monograph: http://www.baxter.ca/en/downloads/product_information/feiba%20nf_pm_may242013_en.p df Reversing NOACs: FEIBA (Activated PCC) Contains Factors II, IX, and X, mainly non-activated, and Factor VII mainly in the activated form. Dose: 50-100 IU/kg

Alternative: PCC and rfviia + Octaplex/Beriplex 40 IU/kg NovoSeven (rfviia) 1 mg 1. Octaplex monograph: http://www.octapharma.com/index.php?eid=tx_nawsecuredl&u=0&file=uploads/media/20120613_pm_octaplex_app roved.pdf&t=1384711575&hash=0ab78e2e273f669f418af3633c86b3bf07ab3da4 2. Beriplex monograph: http://www.cslbehring.ca/docs/921/921/2013-08-14_e_beriplex_pm.pdf 3. NovoSeven monograph: http://www.novonordisk.com/images/haemostasis/pdf/n7-monograph-eu-room-

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 50-100 U/kg or PCC+rFVIIa Rivaroxaban Reverse with PCC 20-40 U/kg Nitzki-George D, Wozniak I, Caprini J. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47:841-55. 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: 1116-27.

Availability of PCCs (Octaplex. Beriplex) in Alberta http://www.albertahealthservices.ca/3318.asp 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 http://www.albertahealthservices.ca/3318.asp

Availability of apccs (FEIBA) in Alberta http://www.albertahealthservices.ca/3318.asp 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 http://www.albertahealthservices.ca/3318.asp

FEIBA (apcc) Monograph

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 1. 1. 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, 544 549 DOI: 10.1111/j.1365-2516.2012.02748.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, 83 90 3. ALEDORT LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. Journal of Thrombosis and Haemostasis, 2: 1700 1708 4. DIMICHELE D, & NEGRIER C. A retrospective post licensure survey of FEIBA efficacy and safety. Haemophilia (2006), 12, 352 362 DOI: 10.1111/j.1365-2516.2006.01284.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

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

Questions 59

Questions FOTOS DE LAURENT SCHWEBEL: http://www.slideshare.net/halffast/fotos-de-laurentschwebel1-16369767?from_search=1 60

ClinicalTrials.gov The future for DOAC reversal - Idarucizumab

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

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 30-49 ml/min Estimate CrCl 50-79 ml/min 80 ml/min 30-49 ml/min Estimate CrCl 50-79 ml/min 80 ml/min At least 1 day At least 2 days 2-3 2-3 days days 1-2 days 1 day 4 days 2-3 days 2 days Recommended May be considered

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 2014. Circulation DOI: 10.1161/CIRCULATIONAHA.114.008828 Xarelto PM, July 18, 2012; Eliquis PM November 27, 2012; Pradaxa PM November 12, 2012

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 2014. Circulation DOI: 10.1161/CIRCULATIONAHA.114.008828 Xarelto PM, July 18, 2012; Eliquis PM November 27, 2012; Pradaxa PM November 12, 2012

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 2014. Circulation DOI: 10.1161/CIRCULATIONAHA.114.008828 Xarelto PM, July 18, 2012; Eliquis PM November 27, 2012; Pradaxa PM November 12, 2012

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 2014. Circulation DOI: 10.1161/CIRCULATIONAHA.114.008828 Xarelto PM, July 18, 2012; Eliquis PM November 27, 2012; Pradaxa PM November 12, 2012

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 2014. PM Circulation November 27, DOI: 2012; 10.1161/CIRCULATIONAHA.114.008828 Pradaxa PM November 12, 2012

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 2014. PM Circulation November 27, DOI: 2012; 10.1161/CIRCULATIONAHA.114.008828 Pradaxa PM November 12, 2012

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 30-49 ml/min 2.5 mg bid 5 mg bid

http://www.youtube.com/watch?v=qgkogwv2frk http://www.youtube.com/watch?v=rf_uumx3nge http://www.vein.co.uk/anat omy_page1.html

Bleeding with NOACs

Bleeding with NOACs

Bleeding with NOACs

Bleeding with NOACs

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. 1999 Mar 25;340(12):901-7. Erratum in: N Engl J Med 1999 Jul 22;341(4):298.

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~ 950 12-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 2016 www.clinicaltrials.gov/ct2/show/nct02064439 * Completed 6 to 12 months (± 1 month) with interruption of anticoagulation 1 week at randomisation

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 www.clinicaltrials.gov/ct2/show/nct01619007

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 1 1996 American College of Physicians. 7

Factor VII, Tissue Factor & Factor X http://www.wjgnet.com/1949-8454/full/v2/i2/wjbc-2-35- g002.htm Pedersen LG. Lee Pedersen s work in theoretical and computational chemistry and biochemistry. World J Biol Chem. 2011 February 26; 2(2): 35-38. doi: 10.4331/wjbc.v2.i2.35. 80

Factor X activation of Thrombin 81 Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, and Prcahl JT: Williams Hematology, 8 th Ed: http://www.accessmedicine.com

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

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 17-21 hr renal apcc, Txa

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: 447 52. 2. 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: 1593 601. 3. 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: 191 202. 4. Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecular-weight-heparin compared with intravenous heparin for treatment of pulmonary embolism. Ann Intern Med 2004;140:175 83.

Thromboembolic complications of a subtherapeutic INR 501 patients with INR 0.5 1 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. 87:384 387, 2012

Prothrombin Complex Concentrates vs apcc Octaplex, OctaPharma 500 U/20 ml Beriplex, CSL Behring 500 U/20mL FEIBA, Baxter 400-1200 U/20 ml 1750-3250 U/50ml Units reqd to correct ptt FFP 1U/mL, 200-250 ml II U/mL VII U/mL IX U/mL X U/mL C U/mL S U/mL Z other 31 16 22 24 12 24 Yes Heparin added, low amnt FVIIa 20-48 10-25 20-31 22-60 22-31 17-19 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 1 1 1 1 1 1 1 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;47:841-55. 2. 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

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 100 80 60 40 20 0 P<0.001 OD Total Population 65 years old 1. Laliberté F et al. Adv Ther 2012; 29: 675-90 2. Laliberté F et al. Patient (2013) 6:213 224. DOI 10.1007/s40271-013-0020-5 BID P=0.017 Compliant Patients (%) (proportion of days covered, PDC) 100 80 60 40 20 0 P<0.001 OD P<0.001 BID P<0.001 P<0.001 3 6 12 18 Months since initiation of therapy

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 [0340-6245] yr:2010 vol:103 iss:6 pg:1116-27

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;46:1627-36.

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;137:572-574. DOI: 10.1309/AJCPAU7OQM0SRPZQ 90

Activated Charcoal for removal of Dabigatran Dabigatran etixilate is lipophilic, & binds to Activated Charcoal Dabigatran etexilate in water (ph 2.4 2.7) + 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: 1116-27. doi: 10.1160/TH09-11-0758

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; 119:2172-4. doi: 10.1182/blood-2011-11-393587 2. 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: 10.1345/aph.1R081 3. Chang DN, Dager WE, Chin AI. Removal of dabigatran by hemodialysis. Am J Kidney Dis 2013;61:487-9. doi: 10.1053/j.ajkd.2012.08.047

ATAN (Alberta Thromboembolism and Anticoagulation Network) Unanswered Questions Early death from PE can we prevent it with TPA on-site Recurrence of DVT can we prevent it with anticoagulant strategies, D-dimers Post-phlebitic syndrome can we prevent or minimize this Unquestioned Answers Start coumadin immediately Stop treatment at 3, 6, 12 months Abandon patients to follow-up 93

Accreditation Canada http://www.accreditation.ca/ uploadedfiles/rop%20hand book.pdf Page 54

AHS Pocket Card

AHS Pocket Card

Catheter Directed Thrombolysis Enden T, lva Haig Y, Kløw N-E, Slagsvold C-E, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen LA, Njaastad AM, Sandbæk G, Sandset PM, on behalf of the CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012; 379: 31 38

Reversal of Coumadin FEIBA vs PCC Retrospective analysis of 141 patients treated with FEIBA (72) vs PCC (69) FEIBA significantly better then PCC for reversing INR No difference in clinical outcomes AE with FEIBA include: 1 fatal v fib, chest pain, troponin bump, MI, DVT Wójcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med 2009;2:217-25.

Reversal of Coumadin - rfviia Nitzki-George D. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47:841-55.

Xarelto PM, June 2013, 2012; Eliquis PM November, 2012; Pradaxa PM November, 2012 Discontinuation Before Elective Invasive or Surgical Procedures Time to discontinue medication prior to procedure Rivaroxaban Dabigatran Apixaban Determine patients risk of bleeding Determine patients risk of bleeding 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 30-49 ml/min Estimate CrCl 50-79 ml/min 80 ml/min 30-49 ml/min Estimate CrCl 50-79 ml/min 80 ml/min At least 1 day At least 2 days 2-3 2-3 days days 1-2 days 1 day 4 days 2-3 days 2 days Recommended May be considered

The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510 EINSTEIN Extension Outcomes 10 Symptomatic recurrent VTE 10 Major Bleeding 9 8 7 7.1% p<0.0001 9 8 7 6 6 5 4 82% RRR 5 4 3 2 1 1.3% 3 2 1 NS 0% 0.7% 0 Placebo Rivaroxaban 20 mg OD 0 Placebo Rivaroxaban 20 mg OD 102

Xarelto PM, June 2013 Rivaroxaban Currently Has Three Indications SPAF (Stroke Prevention in Atrial Fibrillation) Prevention of stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation is appropriate. VTE (Venous thromboembolic events) VTE-OS Treatment of venous thromboembolic events (deep vein thrombosis [DVT], pulmonary embolism [PE]) and prevention of recurrent DVT and PE. Prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement (THR) or total knee replacement (TKR) surgery.

Larsen TB, Rasmussen LV, Skjøth F, Due KM, Callréus T, Rosenzweig M, Lip GYH. Efficacy and Safety of Dabigatran Etexilate and Warfarin in Real-World Patients With Atrial Fibrillation, A Prospective Nationwide Cohort Study. Journal of the American College of Cardiology Vol. 61, No. 22, 2013 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.03.020 Danish Registry of Medicinal Product Statistics: Dabigatran vs warfarin-treated group, 4,978 vs 8,936. Comparisons on efficacy & safety based on Cox-proportional hazards models. Stroke & systemic embolism NOT significantly different between warfarin and dabigatran. Adjusted mortality significantly lower with both dabigatran doses (110 mg bid [ahr]: 0.79, 95% confidence interval [CI]: 0.65 to 0.95; 150 mg bid, ahr: 0.57, 95% CI: 0.40 to 0.80), vs warfarin. Pulmonary embolism lower with both doses of dabigatran. MI lower with both dabigatran doses (110 mg b.i.d., ahr: 0.309; 150 mg b.i.d., ahr: 0.40. Less intracranial bleeding seen with dabigatran (110 mg bid, ahr: 0.24; 150 mg bid, ahr: 0.08. Less gastrointestinal bleeding with dabigatran (110 mg bid ahr: 0.60 vs warfarin but not dabigatran 150 mg bid.

European Medicines Agency, 23 August 2012, EMA/556143/2012, Committee for Medicinal Products for Human Use (CHMP), Assessment report: Pradaxa dabigatran etexilate; Procedure No.: EMEA/H/C/000829/II/0031 Pg 19, The MAH concluded and the CHMP agreed that the post-marketing bleeding rates for dabigatran etexilate are substantially less than the respective rates seen in the RE-LY groups for both doses of dabigatran etexilate. If the reporting rate in the post-marketing phase had been higher than in the RE- LY study, there would clearly have been a safety concern. The fact that reporting rate in the post- marketing phase is lower gives some reassurance as to the safety profile of the product. Following further explanation the CHMP agreed with the MAH that the results from the RE-LY study on the frequency of MI in warfarin-treated patients with or without VHD lacked biological/clinical plausibility and were not readily explainable other than as a spurious finding. European Medicines Agency, 23 August 2012, EMA/556143/2012, Committee for Medicinal Products for Human Use (CHMP), Assessment report: Pradaxa dabigatran etexilate; Procedure No.: EMEA/H/C/000829/II/0031

Who am I Born Edmonton 1954 Father from Nelson, BC; Mother born in Edmonton 1954 Census Edmonton 209,353; Calgary 168,840; Alberta 1,061,859 2012 Census Edmonton 817,498; Calgary 1,120,225; Alberta 3,699,939 BMedSc 1974, MD 1978, Post-graduate training NZ 1978-83; Calgary 1983-86; Vancouver 1986-91; Post-doctoral Fellowship 1987-91 FRCPC: Internal Medicine 1985, Oncology 1987, Hematology 1988 Clinical work: Bleeding Disorder Clinic, Rare Blood Disorder Clinic, Thromboembolism Clinic Research Work: Clinical Trials in VTE, Hemophilia, Hereditary Angioedema, Primary Immunodeficiency, Basic Research Work: Blood Borne Pathogens Iron Metabolism BioBanking

Prothrombin Complex Concentrates vs apcc Octaplex, OctaPharma 500 U/20 ml Beriplex, CSL Behring 500 U/20mL FEIBA, Baxter 400-1200 U/20 ml 1750-3250 U/50ml Units reqd to correct ptt FFP 1U/mL, 200-250 ml II U/mL VII U/mL IX U/mL X U/mL C U/mL S U/mL Z other 31 16 22 24 12 24 Yes Heparin added, low amnt FVIIa 20-48 10-25 20-31 22-60 22-31 17-19 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 1 1 1 1 1 1 1 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;47:841-55. 2. 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

Reversal of Coumadin - PCC Nitzki-George D. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47:841-55.

The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510 EINSTEIN DVT: Safety Outcomes First major or clinically relevant non-major bleeding Rivaroxaban (n=1,718) Enox/VKA (n=1,711) HR (95% CI) n (%) n (%) p value 139 (8.1) 138 (8.1) 0.97 (0.76 1.22) p=0.77 Major bleeding 14 (0.8) 20 (1.2) 0.65 (0.33-1.30) p=0.21 Contributing to death 1 (<0.1) 5 (0.3) In a critical site 3 (0.2) 3 (0.2) Associated with fall in Hb 2 g/dl and/or transfusion of 2 units Clinically relevant non-major bleeding 10 (0.6) 12 (0.7) 126 (7.3) 119 (7.0) Safety population

Safety population The EINSTEIN PE Investigators. N Engl J Med 2012; 366:1287-1297 EINSTEIN PE: Safety Outcomes First major or non-major clinically relevant bleeding event Rivaroxaban (N=2412) Enoxaparin/VKA (N=2405) n (%) n (%) 249 (10.3) 274 (11.4) HR (95% CI) p-value 0.90 (0.76 1.07) p=0.23 Major bleeding 26 (1.1) 52 (2.2) Contributing to death 2 (<0.1) 3 (0.1) 0.49 (0.31 0.80) p=0.0032 In a critical site 6 (0.2) 27 (1.1) ICH 1 (<0.1) 10 (0.4) Associated with fall in haemoglobin 2 g/dl and/or transfusion of 2 units Non-major clinically relevant bleeding 18 (0.7) 26 (1.1) 228 (9.5) 235 (9.8)

Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban Rivaroxaban 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: 217 224

Catheter Directed Thrombolysis Enden T, lva Haig Y, Kløw N-E, Slagsvold C-E, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen LA, Njaastad AM, Sandbæk G, Sandset PM, on behalf of the CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012; 379: 31 38

Hemodialysis for removal of Dabigatran 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; 119:2172-4. doi: 10.1182/blood-2011-11-393587

Safe Use of Hemodialysis for Dabigatran Removal Before Cardiac Surgery Safe Use of Hemodialysis for Dabigatran Removal Before Cardiac Surgery. Matthew R Wanek, Edward T Horn, Subbarao Elapavaluru, Samuel C Baroody, and George Sokos. Ann Pharmacother 2012;46:e21.

Apixaban in Medically Ill Patients

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;43:1812-1817.

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;43:1812-1817.

Dabigatran etexilate: a direct thrombin inhibitor (Wikipedia) Esterase-mediated hydrolysis Half life of 12-17 h ~ 80% renally excreted & 6.5% bioavailability Predictable and consistent anticoagulant effects Low potential for drug-drug interactions (p Glycoprotein Inhibitor Effect), no drug-food interactions No requirement for routine coagulation monitoring Rapid onset of action (1-4 hrs) Twice daily treatment van Ryn J; Stangier J; Haertter S; Liesenfeld K-H; WienenW; Feuring M; Clemens A. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thrombosis and 118 Haemostasis 103.6/2010 1116-1127

Rivaroxaban Is Structurally Similar To Linezolid (Wikipedia) Linelzolid (Antibiotic) Rivaroxaban (Antibiotic) No Antimicrobial Activity, No Observed Mitochondrial Toxicity Primarily renal elimination (66% - only half of this is active drug), remainder feces potent inhibitor of p glycoprotein 1 T1/2 7-11 hr (5-9 hr in young, 11-13 hr in elderly) No laboratory monitoring required No dosage adjustment for gender, age, extreme body weight Once daily dosing 80% bioavailability Graphics from Ganfyd and Wikipedia: http://www.ganfyd.org/index.php?title=image:linezolid.png http://en.wikipedia.org/wiki/file:rivaroxaban.png 119

Apixaban: a direct Factor Xa inhibitor (Wikipedia) Apixaban, tradename Eliquis, is a direct factor Xa inhibitor Available today for hip/knee prophylaxis 2.5 mg bid at 24 hr post-op. Mostly liver clearance, 27% renalt1/2 12 hours Assay Rotachrom anti-fxa Joint venture by Pfizer and Bristol-Myers Squibb. [2][3] Lassen MR, et al. "The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement". J. Thromb. Haemost. 5 (12): 2368 75. doi:10.1111/j.1538-7836.2007.02764.x. PMID 17868430. Lassen MR, and the ADVANCE-3 Investigators (December 2010). "Apixaban versus enoxaparin for thromboprophylaxis after hip replacement". N. Engl. J. Med. 363 (26): 2487 98.doi:10.1056/NEJMoa1006885. PMID 21175312. Connolly SJ, et al. (March 2011). "Apixaban in patients with atrial fibrillation". N. Engl. J. Med.364 (9): 806 17. doi:10.1056/nejmoa1007432.pmid 21309657. edit Alexander JH, et al. (August 2011). "Apixaban with antiplatelet therapy after acute coronary syndrome". N. Engl. J. Med. 365 (8): 699 708.doi:10.1056/NEJMoa1105819. PMID 21780946. "Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE)". NCT00412984. ClinicalTrials.gov. Retrieved 2011-06-23. Granger CB, Alexander JH, McMurray JJV, et al. (August 2011). "Apixaban versus Warfarin in Patients with Atrial Fibrillation". New 120 England Journal of Medicine 365.doi:10.1056/NEJMoa1107039.

Edoxaban: a direct Factor Xa inhibitor (Wikipedia) Edoxaban, is a direct factor Xa inhibitor undergoing phase III trials Mostly liver clearance, Daichi (Japan) Furugohri T, er al (September 2008). "DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles". Journal of Thrombosis and Haemostasis : JTH 6 (9): 1542 9. doi:10.1111/j.1538-7836.2008.03064.x. PMID 18624979. Sobieraj-Teague M, O'Donnell M, Eikelboom J (July 2009). "New anticoagulants for atrial fibrillation". Seminars in Thrombosis and Hemostasis 35 (5): 515 24. doi:10.1055/s-0029-1234147. PMID 19739042. Raskob G, et al. (2010). "Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement". Thrombosis and Haemostasis 104 (3): 642 649.doi:10.1160/TH10-02-0142. PMID 20589317. ^ Weitz JI, et al. (2010). "Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation". Thrombosis and Haemostasis 104 (3): 633 641. doi:10.1160/th10-01- 121 0066.PMID 20694273

Betrixaban: a direct Factor Xa inhibitor (Wikipedia) Betrixaban, is a direct factor Xa inhibitor undergoing phase III trials Mostly liver clearance, Portola Eriksson BI, Quinlan DJ, Weitz JI (2009). "Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development". Clinical Pharmacokinetics 48 (1): 1 22. PMID 19071881. Zhang P, Huang W, Wang L, Bao L, Jia ZJ, Bauer SM, Goldman EA, Probst GD, Song Y, Su T, Fan J, Wu Y, Li W, Woolfrey J, Sinha U, Wong PW, Edwards ST, Arfsten AE, Clizbe LA, Kanter J, Pandey A, Park G, Hutchaleelaha A, Lambing JL, Hollenbach SJ, Scarborough RM, Zhu BY (April 2009). "Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor".bioorganic & Medicinal Chemistry Letters 19 (8): 2179 85. doi:10.1016/j.bmcl.2009.02.111. PMID 19297154. Turpie AG, Bauer KA, Davidson BL, Fisher WD, Gent M, Huo MH, Sinha U, Gretler DD (January 2009). "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT)". Thrombosis and Haemostasis 101 (1): 68 76. PMID 19132191. Piccini, J. P.; Lopes, R. D.; Mahaffey, K. W. (2010). "Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation".current Opinion in Cardiology 25 (4): 312. doi:10.1097/hco.0b013e32833a524f. PMID 20520539. edit Sobieraj-Teague, M.; O donnell, M.; Eikelboom, J. (2009). "New Anticoagulants for Atrial Fibrillation". Seminars in Thrombosis and 122 Hemostasis 35 (5): 515 24. doi:10.1055/s-0029-1234147. PMID 19739042.

Andexanet Alfa (PRT4445*): a Factor Xa analogue (Portola Pharmaceuticals) Andexanet, is a factor Xa analogue, similar to native Factor Xa, but modified to restrict ability to cleave thrombin Acts as a Factor Xa decoy to bind & sequester direct Factor Xa inhibitors in the blood. https://ash.confex.com/ash/2013/webprogram/paper56863.html http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsarticle&id=1874725&highlight= 123

Andexanet Alfa (PRT4445*): a Factor Xa analogue (Portola Pharmaceuticals) Methods: Randomized, placebo-controlled, double-blind, cohort dose-escalation, Phase 2 Healthy volunteers loaded with oral XARELTO, 20 mg qd for 6 days Randomized in a 6:3 ratio to andexanet alfa in different dosing cohorts. First two cohorts received single IV bolus of andexanet alfa, 210 mg or 420 mg. Results: Within two minutes following completion of the 210 mg and 420 mg bolus of andexanet alfa, anti-factor Xa activity decreased dose-dependently by 20% & 53%. AND plasma concentrations of unbound riva were decreased by 32% & 51%, AND molar ratio of AnXa to total plasma riva was 0.8 for the 210 mg dose (1.2 µm/1.6 µm,) and 1.2 for the 420 mg dose (2.6 µm/2.1 µm, respectively) AND showed dose-dependent reversal of XARELTO -induced: inhibition of thrombin generation and prolongation of protxhrombin time and activated clotting time Serious Adverse Events: No thrombotic events, SAEs reported. Adverse events: infusion-related reaction (n = 3, all mild) & post-procedural hematoma, headache, or postural dizziness (n = 2 each). https://ash.confex.com/ash/2013/webprogram/paper56863.html http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsarticle&id=1874725&highlight= 124

Andexanet Alfa (PRT4445*): a Factor Xa analogue Andexanet, is a factor Xa analogue undergoing phase III trials Andexanet is similar to native Factor Xa, but has been modified to restrict its biological activity, such as its ability to cleave thrombin, an enzyme involved in the clotting cascade. Andexanet alfa acts as a Factor Xa decoy that binds and sequesters direct Factor Xa inhibitors in the blood. Portola Pharmaceuticals http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsarticle&id=1874725&highlight= Zhang P, Huang W, Wang L, Bao L, Jia ZJ, Bauer SM, Goldman EA, Probst GD, Song Y, Su T, Fan J, Wu Y, Li W, Woolfrey J, Sinha U, Wong PW, Edwards ST, Arfsten AE, Clizbe LA, Kanter J, Pandey A, Park G, Hutchaleelaha A, Lambing JL, Hollenbach SJ, Scarborough RM, Zhu BY (April 2009). "Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor".bioorganic & Medicinal Chemistry Letters 19 (8): 2179 85. doi:10.1016/j.bmcl.2009.02.111. PMID 19297154. Turpie AG, Bauer KA, Davidson BL, Fisher WD, Gent M, Huo MH, Sinha U, Gretler DD (January 2009). "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT)". Thrombosis and Haemostasis 101 (1): 68 76. PMID 19132191. Piccini, J. P.; Lopes, R. D.; Mahaffey, K. W. (2010). "Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation".current Opinion in Cardiology 25 (4): 312. doi:10.1097/hco.0b013e32833a524f. PMID 20520539. edit Sobieraj-Teague, M.; O donnell, M.; Eikelboom, J. (2009). "New Anticoagulants for Atrial Fibrillation". Seminars in Thrombosis and Hemostasis 35 (5): 515 24. doi:10.1055/s-0029-1234147. PMID 19739042. 125

Caribbean Drug Registration/Licensing Sources: Lise Jantzon, Canadian National Sales Mgr. BioPharm, Baxter Corporation Biopharmaceutical, Lise_Jantzon@baxter.com Sri Adapa, President, Octapharma Canada Inc., Sri.Adapa@octapharma.ca Joseph Andolfatto, Canadian National Manager Coagulation and Critical Care, CSL Behring Biotherapies for Life, Joseph.Andolfatto@cslbehring.co m

PCC Registration in the Caribbean Octaplex Netherland Antilles, Dominican Republic Beriplex Netherlands FEIBA Netherlands Sources: Lise Jantzon, Canadian National Sales Mgr. BioPharm, Baxter Corporation Biopharmaceutical, Lise_Jantzon@baxter.com Sri Adapa, President, Octapharma Canada Inc., Sri.Adapa@octapharma.ca Joseph Andolfatto, Canadian National Manager Coagulation and Critical Care, CSL Behring Biotherapies for Life, Joseph.Andolfatto@cslbehring.com

VTE Clinical Features Anderson FA Jr, et al. Incidence of VTE increases with age: Arch Intern Med. 1991;151:933-938. 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;160:761-768 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;4:734-742

Anticoagulation control in Sweden 18 391 patients in 67 different centres in Sweden analysed. (Mean age 70 years) main indications : A fib (64%), VTE (19%), valve (13%). Time in therapeutic range 76.2%. warfarin dose decreased, TTR increased with age. In 4273 patients from two centres in AuriculA, 2.6% major bleedings 1.7% venous/arterial thrombo-embolism were and per treatment year. correlation of age and the risk of major bleeding (P, 0.001), but not thrombo-embolic complications (P ¼ 0.147), was seen. Wieloch M et al. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. European Heart Journal (2011) 32, 2282 2289

Warfarin & Intracranial Hemorrhage in Finland 1993 to 2008 Subjects with first 1 o ICH during 1993 (pop 356 026 ) to 2008 (389 671) in N Ostrobothnia, Finland. Warfarin users increased 3.6-fold, 0.68% in 1993 to 2.28% in 2008. 982 patients with ICH, 182 (18.5%) warfarin. One-year survival rate after onset of stroke 35.2% in warfarin users & 67.9% in nonusers. Incidence (P0.062) and 28-day fatality of warfarinrelated ICHs (P0.002) decreased. Admission INR >therapeutic decreased 1993-2008.

Warfarin & Intracranial Hemorrhage in Finland 1993 to 2008

Warfarin in the Real World

Warfarin in the Real World

Effectiveness of Warfarin in Patients with Cancer 95 patients undergoing treatment for cancer matched to 283 patients without cancer. Cancer group spent less time in the target INR range (54 vs 66%, P<.001) and had more variable INR values (standard deviation around the mean INR value 1.30 vs 0.71, P<.001). More thrombotic events in the cancer group than control group (5 vs 0 events, P<.001). Rose AJ, et al. Effectiveness of Warfarin among Patients with Cancer.

Caribbean Drug Registration/Licensing Sources: Lise Jantzon, Canadian National Sales Mgr. BioPharm, Baxter Corporation Biopharmaceutical, Lise_Jantzon@baxter.com Sri Adapa, President, Octapharma Canada Inc., Sri.Adapa@octapharma.ca Joseph Andolfatto, Canadian National Manager Coagulation and Critical Care, CSL Behring Biotherapies for Life, Joseph.Andolfatto@cslbehring.co m

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: 447 52. 2. 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: 1593 601. 3. 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: 191 202. 4. Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecular-weight-heparin compared with intravenous heparin for treatment of pulmonary embolism. Ann Intern Med 2004;140:175 83.

CLOTS 3 CLOTS (Clots in Legs Or stockings after Stroke) Trials Collaboration. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet 2013, 382: 516 24