anticoagulation 2014 - university of alberta · anticoagulation reversal poor prognosis in...
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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
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Conflicts of Interest • Principle Investigator in Pharmaceutical Trials
including: Fragmin, Lovenox, XiMelagatran, Rivaroxaban, Dabigatran, Apixaban, Edoxaban
• Unpaid consulting advice to: Baxter, Bayer, Boehringer-Ingelheim, Canadian Blood Service, Canadian Hemophilia Society, Covidien, CSL Behring, Dyax, Leo Pharmaceuticals, Novartis, Novo Nordisk, Pharming, Pfizer, Sanofi, Talecris, Wyeth
• In lieu of Honoraria, I request that donations be made to the University of Alberta to fund summer students ($1300/month X 4 = $5200)
• I have received funding for Investigator Initiated studies (biobanking) from: Baxter, CSL Behring, Novartis, Novo Nordisk, Pfizer, Wyeth. Pending: Bayer, Boehringer-Ingelheim, Leo, Sanofi.
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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
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9
Adapted from Wikipedia – http://en.wikipedia.org/wiki/Coagulation
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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
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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.
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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
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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
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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.
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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
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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
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Warfarin & Intracranial Hemorrhage in Finland 1993 to 2008
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Warfarin & Intracranial Hemorrhage in Finland 1993 to 2008
2004, introduction of PCC
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Reversal of Coumadin - PCC
Nitzki-George D. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47:841-55.
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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.
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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
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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
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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
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Southworth MR, Reichman ME, Unger EF. Dabigatran and Postmarketing Reports of Bleeding. NEJM Online 13-Mar-2013 DOI: 10.1056/NEJMp1302834
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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
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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
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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
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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
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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
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44
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 anticoagulant activity. Thrombosis and haemostasis [0340-6245] yr:2010 vol:103 iss:6 pg:1116-27
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Effect of Rivaroxaban On Coagulation Parameters: apTT Ratio
45 Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundamental & Clinical Pharmacology 26 (2012) 27–32
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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
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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
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http://www.medscape.com/viewarticle/827433?pa=8IzEnLu7lLVhv32cLYf10L32J6KMWG0MkICySjDylifPSzREvSZ%2FcU2ba23ZoNBF2cTx7FZlR4qrBObwvFcmhQ%3D%3D
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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
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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
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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
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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
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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
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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.
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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)
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FEIBA (aPCC) Monograph
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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.
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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
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Questions
59
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Questions
60 FOTOS DE LAURENT SCHWEBEL: http://www.slideshare.net/halffast/fotos-de-laurentschwebel1-16369767?from_search=1
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ClinicalTrials.gov
The future for DOAC reversal - Idarucizumab
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Neal Shah. Reversal Agents for Anticoagulants: Focus on Andexanet Alfa. AMSRJ Spring 2014; 1, No. 1
The future for DOAC reversal - Andexanet Alfa
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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
Determine patients risk of
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
Standard risk High risk of bleeding or
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
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ASA for VTE prophylaxis after unprovoked VTE
Xarelto® PM, July 18, 2012; Eliquis® PM November 27, 2012; Pradaxa ® PM November 12, 2012
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
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ASA for VTE prophylaxis after unprovoked VTE
Xarelto® PM, July 18, 2012; Eliquis® PM November 27, 2012; Pradaxa ® PM November 12, 2012
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
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ASA for VTE prophylaxis after unprovoked VTE
Xarelto® PM, July 18, 2012; Eliquis® PM November 27, 2012; Pradaxa ® PM November 12, 2012
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
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ASA for VTE prophylaxis after unprovoked VTE
Xarelto® PM, July 18, 2012; Eliquis® PM November 27, 2012; Pradaxa ® PM November 12, 2012
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
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ASA for VTE prophylaxis after unprovoked VTE
Xarelto® PM, July 18, 2012; Eliquis® PM November 27, 2012; Pradaxa ® PM November 12, 2012
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
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ASA for VTE prophylaxis after unprovoked VTE
Xarelto® PM, July 18, 2012; Eliquis® PM November 27, 2012; Pradaxa ® PM November 12, 2012
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
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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
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http://www.vein.co.uk/anatomy_page1.html
http://www.youtube.com/watch?v=qgkOgWV2Frk http://www.youtube.com/watch?v=rf_uuMX3NgE
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Bleeding with NOACs
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Bleeding with NOACs
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Bleeding with NOACs
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Bleeding with NOACs
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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.
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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
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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
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© 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.
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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
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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
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• 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
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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
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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.
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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
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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
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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
)
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aPTT variable among sites/reagents
88
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
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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.
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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
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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.
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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
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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)
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Accreditation Canada http://www.accreditation.ca/uploadedFiles/ROP%20Handbook.pdf Page 54
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AHS Pocket Card
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AHS Pocket Card
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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
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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
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Reversal of Coumadin - rFVIIa
Nitzki-George D. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47:841-55.
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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
Determine patients risk of
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
Standard risk High risk of bleeding or
major surgery Standard risk High risk of bleeding or
major surgery
Xarelto® PM, June 2013, 2012; Eliquis® PM November, 2012; Pradaxa ® PM November, 2012
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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
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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.
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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.
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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.”
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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
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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
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Reversal of Coumadin - PCC
Nitzki-George D. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann Pharmacother 2013;47:841-55.
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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
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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
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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
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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
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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
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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
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Apixaban in Medically Ill Patients
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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.
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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.
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• 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
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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
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• 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)
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• 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)
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• 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)
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• 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)
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• 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)
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• 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
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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]
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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]
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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
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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
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Warfarin & Intracranial Hemorrhage in Finland 1993 to 2008
• 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.
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Warfarin & Intracranial Hemorrhage in Finland 1993 to 2008
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Warfarin in the Real World
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Warfarin in the Real World
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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.
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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]
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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.
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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