Anticoagulation 2014 - University of Alberta · Anticoagulation Reversal Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal. Dowlatshahi

Anticoagulation 2014

Bruce Ritchie MD, FRCPC3

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

Bruce Ritchie MD, FRCPC3

Director VTE Clinic, UofA Hospital Director Comprehensive Bleeding Disorder Clinic

Director Comprehensive Rare Blood Disorder Clinic Director Canadian BioSample Repository (CBSR)

1.How do they work 2.How do we measure them 3.How do we reverse them 4.How do we manage elective Surgery

9

Adapted from Wikipedia – http://en.wikipedia.org/wiki/Coagulation

http://en.wikipedia.org/wiki/Coagulation

http://en.wikipedia.org/wiki/Coagulation

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

http://80-www.nature.com.login.ezproxy.library.ualberta.ca/nm/journal/v8/n10/suppinfo/nm782_S1.html

http://80-www.nature.com.login.ezproxy.library.ualberta.ca/nm/journal/v8/n10/suppinfo/nm782_S1.html

Thromboembolic Disease in Alberta • Incidence 108 in 100,0001

– 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 years2(116-130), 6% at 10 years3; (232-260) – Disability costs $5,500-7,6003

• 10% of symptomatic PE’s are fatal within 1 hour4,5, 40% at 30 days6

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.

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

VTE Clinical Features

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. 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

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.

25

Pulmonary Embolism: A Life-threatening Disease

Cumulative mortality following acute PE

25 PE=pulmonary embolism Goldhaber SZ et al; for ICOPER. Lancet. 1999;353:1386–1389.

0 10 20 30 40 50 60 70 80 90

4

0

2

6

8 10

12 14

16

Time from diagnosis (days)

Mor

talit

y ra

te (%

; exc

ludi

ng P

E

first

reco

gnis

ed a

t nec

rops

y)

N=2454

International Cooperative Pulmonary Embolism Registry

15.3% Mortality At 3 months

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


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.

New Oral Anticoagulants Drug Indication targ

et Peak T ½ Clearance Drug Interactions Antidote

Dabigatran A Fib DVT/PE Hip/Knee

II 1-4 h 12-17 h 85% renal Rifampin, quinidine, amiodarone, Potent P-gp inhibitor

aPCC

Rivaroxaban A Fib DVT/PE Hip/Knee

Xa 0.5-2 h

7-11 h 66% renal really 33%

Potent CYP3A4, P-gp inhibitor

PCC

Apixaban A Fib Hip/Knee

Xa 3-4 h 12 h 27% renal Potent CYP3A4 inhibitor

PCC

Edoxaban No Xa 1-2 h 6-11 h 35% renal Potent CYP3A4, P-gp inhibitor

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

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


Oral Rivaroxaban

for the Treatment of Symptomatic

Pulmonary Embolism


Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism

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.

Apixaban in Patients with Atrial Fibrillation

Thrombin Time Ratio Best

Approximates Dabigatran Plasma Levels

43

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 anticoagulant activity. Thrombosis and haemostasis [0340-6245] yr:2010 vol:103 iss:6 pg:1116-27

44

Standardized Hemoclot Thrombin Time


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

46

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

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%2FcU2ba23ZoNBF2cTx7FZlR4qrBObwvFcmhQ%3D%3D

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

Reversal of Rivaroxaban and 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

Effect of non-specific reversal agents on anticoagulant activity of dabigatran and

rivaroxaban Dabigatran

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

FEIBA monograph: http://www.baxter.ca/en/downloads/product_information/FEIBA%20NF_PM_May242013_EN.pdf

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_approved.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-

bl f ll df

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.

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

Alberta Health Services http://www.albertahealthservices.ca/3318.asp

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.

http://www.albertahealthservices.ca/3318.asp

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)

http://www.albertahealthservices.ca/3318.asp

FEIBA (aPCC) Monograph

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 actiity (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

aPCCs and thrombosis

Post-marketing surveillance: 1. the risk of thrombosis ranged from 0/4500 infusions4, 3.18/100,000

infusion in 18 years5, 8.24/100,000 infusions3, and 4.05/100,000 infusions2. Risk factors were overdose/frequent dosing in 30-80%

2. Combining aPCC with tranexamic acid showed no excess thrombosis1.

Adapted from Kubitza et al., ISTH 2005; Lovenox Product Monograph, 2010

Enoxaparin has a half-life of 4-7 hours and can be dosed either OD or BID

Rivaroxaban and enoxaparin have similar effects on Anti-Factor Xa

activity beyond 24 hours

Questions

59

Questions

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

ClinicalTrials.gov

The future for DOAC reversal - Idarucizumab

Neal Shah. Reversal Agents for Anticoagulants: Focus on Andexanet Alfa. AMSRJ Spring 2014; 1, No. 1

The future for DOAC reversal - Andexanet Alfa

Discontinuation Before Elective Invasive or Surgical Procedures

Recommended

May be considered

Time to discontinue medication prior to procedure

Determine patients risk of

bleeding

Rivaroxaban Determine

patients risk of bleeding

Apixaban


bleeding

Dabigatran

2-3 days

At least 1 day

2-4 days

At least 1 day

At least 2 days

30-49 mL/min

50-79 mL/min

≥ 80 mL/min

2-3 days

1-2 days

1 day

4 days

2 days

2-3 days

Estimate CrCl

30-49 mL/min

50-79 mL/min

≥ 80 mL/min

Estimate CrCl

Standard risk High risk of bleeding or

major surgery


major surgery Standard risk High risk of bleeding or

major surgery

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
















Rivaroxaban Clinical Programme Overview: > 60,000 Patients Enrolled

Phase III Customized Dose VTE prevention after major orthopaedic surgery

RECORD1

RECORD2

RECORD3

RECORD4

10 mg od (2 weeks, knee; 5 weeks, hip)

VTE prevention in hospitalized medically ill patients

10 mg od (5 weeks)

VTE treatment

EINSTEIN-DVT

EINSTEIN-PE

EINSTEIN-EXT

15 mg bid for first 3 weeks

20 mg od 3, 6, or 12 months

Stroke prevention in atrial fibrillation

20 mg od

15 mg od for CrCl 30-49 mL/min

Secondary prevention of acute coronary syndromes

2.5 mg bid

5 mg bid

http://www.vein.co.uk/anatomy_page1.html

http://www.youtube.com/watch?v=qgkOgWV2Frk http://www.youtube.com/watch?v=rf_uuMX3NgE

http://www.youtube.com/watch?v=qgkOgWV2Frk

http://www.youtube.com/watch?v=rf_uuMX3NgE

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.

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

1 month observation

period

Rivaroxaban 20 mg od n~ 950

Rivaroxaban 10 mg od n~ 950 N~ 2,850

Patients with confirmed symptomatic DVT and/or PE who completed 6-12 months of anticoagulant treatment*

R

Day 1

ASA 100mg od n~ 950

12-month treatment duration

* Completed 6 to 12 months (± 1 month) with interruption of anticoagulation ≤ 1 week at randomisation

Primary endpoint: Fatal or non-fatal symptomatic recurrent VTE

www.clinicaltrials.gov/ct2/show/NCT02064439

Study Start Date: February 2014 Estimated Study Completion Date: December 2016

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)

www.clinicaltrials.gov/ct2/show/NCT01619007

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

Investigators to collect data at initial visit, at 1 month and then

quarterly*

Final assessment

Rivaroxaban for ≥3 months

SOC: e.g. initial treatment with LMWH or fondaparinux, followed by VKA for

≥3 months

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

(1 month after end of treatment)

N~2400

N~2400 *Protocol does not define exact referral dates for follow-up visits

Study Start Date: June 2012 Estimated Study Completion Date: March 2015

Last updated: February 2014

© 1996 American College of Physicians. 7

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

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.

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

http://www.wjgnet.com/1949-8454/full/v2/i2/WJBC-2-35-g002.htm



Factor X activation of Thrombin

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

http://www.accessmedicine.com

• 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

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 II

U/mL VII

U/mL IX

U/mL X

U/mL C

U/mL S

U/mL Z other

Octaplex, OctaPharma 500 U/20 mL

31 16 22 24 12 24 Yes Heparin added, low amnt FVIIa

Beriplex, CSL Behring 500 U/20mL

20-48 10-25 20-31 22-60 22-31 17-19 Yes Heparin, ATII added

FEIBA, Baxter 400-1200 U/20 mL 1750-3250 U/50ml Units reqd to correct pTT

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

FFP 1U/mL, 200-250 mL

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

a 52% higher probability of being compliant

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

0

20

40

60

80

100

Total Population ≥ 65 years old

OD BID

P=0.017

0

20

40

60

80

100

3 6 12 18

OD BID

P<0.001

Months since initiation of therapy

Com

plia

nt P

atie

nts

(%)

(med

icat

ion

poss

essi

on r

atio

, MPR

)

P<0.001 P<0.001

P<0.001 P<0.001

Com

plia

nt P

atie

nts

(%)

(pro

port

ion

of d

ays

cove

red,

PDC

)

aPTT variable among sites/reagents

88


aPTT variable among sites/reagents

89

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. Ann Pharmacother 2012;46:1627-36.

Diluted Thrombin Time to Measure Dabigatran

90

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

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

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.

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

Hemodialysis for removal of Dabigatran

93

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

ATAN (Alberta Thromboembolism and Anticoagulation Network)

Accreditation Canada http://www.accreditation.ca/uploadedFiles/ROP%20Handbook.pdf Page 54

http://www.accreditation.ca/uploadedFiles/ROP Handbook.pdf



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

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.

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

Reversal of Coumadin - rFVIIa


Discontinuation Before Elective Invasive or Surgical Procedures

Recommended

May be considered

Time to discontinue medication prior to procedure


bleeding

Rivaroxaban Determine

patients risk of bleeding

Apixaban


bleeding

Dabigatran

2-3 days

At least 1 day

2-4 days

At least 1 day

At least 2 days

30-49 mL/min

50-79 mL/min

≥ 80 mL/min

2-3 days

1-2 days

1 day

4 days

2 days

2-3 days

Estimate CrCl

30-49 mL/min

50-79 mL/min

≥ 80 mL/min

Estimate CrCl


major surgery


major surgery Standard risk High risk of bleeding or

major surgery

Xarelto® PM, June 2013, 2012; Eliquis® PM November, 2012; Pradaxa ® PM November, 2012

EINSTEIN Extension Outcomes

102

0

1

2

3

4

5

6

7

8

9

10

Placebo Rivaroxaban 20 mg OD

0

1

2

3

4

5

6

7

8

9

10

Placebo Rivaroxaban 20 mg OD

NS

p<0.0001

0% 0.7%

7.1%

1.3%

Symptomatic recurrent VTE Major Bleeding

82% RRR

The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510

Rivaroxaban Currently Has Three Indications

Xarelto® PM, June 2013

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)

Treatment of venous thromboembolic events (deep vein thrombosis [DVT], pulmonary embolism [PE]) and prevention of recurrent DVT and PE.

VTE-OS

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

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.”

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 II

U/mL VII

U/mL IX

U/mL X

U/mL C

U/mL S

U/mL Z other

Octaplex, OctaPharma 500 U/20 mL

31 16 22 24 12 24 Yes Heparin added, low amnt FVIIa

Beriplex, CSL Behring 500 U/20mL

20-48 10-25 20-31 22-60 22-31 17-19 Yes Heparin, ATII added

FEIBA, Baxter 400-1200 U/20 mL 1750-3250 U/50ml Units reqd to correct pTT

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

FFP 1U/mL, 200-250 mL

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


EINSTEIN DVT: Safety Outcomes Rivaroxaban

(n=1,718) Enox/VKA (n=1,711) HR (95% CI)

n (%) n (%) p value First major or clinically relevant non-major bleeding

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 10 (0.6) 12 (0.7)

Clinically relevant non-major bleeding

126 (7.3) 119 (7.0)

Safety population The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510

EINSTEIN PE: Safety Outcomes Rivaroxaban

(N=2412) Enoxaparin/VKA

(N=2405) HR (95% CI) p-value n (%) n (%)

First major or non-major clinically relevant bleeding event

249 (10.3) 274 (11.4) 0.90 (0.76–1.07) p=0.23

Major bleeding 26 (1.1) 52 (2.2) 0.49 (0.31–0.80) p=0.0032

Contributing to death 2 (<0.1) 3 (0.1)

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

18 (0.7) 26 (1.1)

Non-major clinically relevant bleeding 228 (9.5) 235 (9.8)

Safety population The EINSTEIN–PE Investigators. N Engl J Med 2012; 366:1287-1297

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

Effect of non-specific reversal agents on anticoagulant activity of dabigatran and

rivaroxaban Rivaroxaban

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

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

Hemodialysis for removal of Dabigatran

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.

Safe Use of Hemodialysis for Dabigatran Removal Before Cardiac Surgery

Apixaban in Medically Ill Patients







• 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 118 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 Haemostasis 103.6/2010 1116-1127

Dabigatran etexilate: a direct thrombin inhibitor (Wikipedia)

Esterase-mediated hydrolysis

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 glycoprotein1

•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

Rivaroxaban Is Structurally Similar To Linezolid (Wikipedia)

119 Graphics from Ganfyd and Wikipedia: http://www.ganfyd.org/index.php?title=Image:Linezolid.png http://en.wikipedia.org/wiki/File:Rivaroxaban.png

http://www.ganfyd.org/index.php?title=Image:Linezolid.png

http://en.wikipedia.org/wiki/File:Rivaroxaban.png

• 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]

120

• 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 England Journal of Medicine 365.doi:10.1056/NEJMoa1107039.

Apixaban: a direct Factor Xa inhibitor (Wikipedia)

http://en.wikipedia.org/wiki/Direct_factor_Xa_inhibitor

http://en.wikipedia.org/wiki/Pfizer

http://en.wikipedia.org/wiki/Bristol-Myers_Squibb

http://en.wikipedia.org/wiki/Apixaban

http://en.wikipedia.org/wiki/Digital_object_identifier

http://dx.doi.org/10.1111/j.1538-7836.2007.02764.x

http://en.wikipedia.org/wiki/PubMed_Identifier

http://www.ncbi.nlm.nih.gov/pubmed/17868430


http://dx.doi.org/10.1056/NEJMoa1006885







http://en.wikipedia.org/w/index.php?title=Template:Cite_doi/10.1056.2FNEJMoa1007432&action=edit&editintro=Template:Cite_doi/editintro2





http://clinicaltrials.gov/ct2/show/study/NCT00412984?term=apixaban+aristotle&rank=1



• Edoxaban, is a direct factor Xa inhibitor undergoing phase III trials • Mostly liver clearance, • Daichi (Japan)

121

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/TH10-01-0066.PMID 20694273

Edoxaban: a direct Factor Xa inhibitor (Wikipedia)



http://dx.doi.org/10.1111/j.1538-7836.2008.03064.x




http://dx.doi.org/10.1055/s-0029-1234147




http://dx.doi.org/10.1160/TH10-02-0142



http://en.wikipedia.org/wiki/Edoxaban


http://dx.doi.org/10.1160/TH10-01-0066

http://dx.doi.org/10.1160/TH10-01-0066



• Betrixaban, is a direct factor Xa inhibitor undergoing phase III trials • Mostly liver clearance, • Portola

122

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 Hemostasis 35 (5): 515–24. doi:10.1055/s-0029-1234147. PMID 19739042.

Betrixaban: a direct Factor Xa inhibitor (Wikipedia)


• 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.

123 https://ash.confex.com/ash/2013/webprogram/Paper56863.html http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle&ID=1874725&highlight=

Andexanet Alfa (PRT4445*): a Factor Xa analogue (Portola

Pharmaceuticals)


http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle&ID=1874725&highlight


http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle&ID=1874725&highlight=

• 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).

124 https://ash.confex.com/ash/2013/webprogram/Paper56863.html http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle&ID=1874725&highlight=

Andexanet Alfa (PRT4445*): a Factor Xa analogue (Portola Pharmaceuticals)

















• 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

125

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.

Andexanet Alfa (PRT4445*): a Factor Xa analogue




Caribbean Drug Registration/Licensing Sources: • Lise Jantzon, Canadian National Sales Mgr. BioPharm, Baxter Corporation Biopharmaceutical, [email protected] • • Sri Adapa, President, Octapharma Canada Inc., [email protected]

• Joseph Andolfatto, Canadian National Manager Coagulation and Critical Care, CSL Behring Biotherapies for Life, [email protected]

mailto:[email protected]




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, [email protected] • Sri Adapa, President, Octapharma Canada Inc., [email protected] • Joseph Andolfatto, Canadian National Manager Coagulation and Critical Care, CSL Behring Biotherapies for Life, [email protected]




VTE Clinical Features

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. 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

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

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


• Subjects with first 1o 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 warfarin-

related ICHs (P0.002) decreased. • Admission INR >therapeutic decreased 1993-2008.


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, [email protected] • • Sri Adapa, President, Octapharma Canada Inc., [email protected]

• Joseph Andolfatto, Canadian National Manager Coagulation and Critical Care, CSL Behring Biotherapies for Life, [email protected]





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 (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

CLOTS 3

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Anticoagulation 2014 - University of Alberta · Anticoagulation Reversal Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal. Dowlatshahi