The Science and Medicine of Thrombosis Management New Dimensions, Novel Approaches, and Landmark Practice Advances in Venous and Arterial Thrombosis Prevention

The Science and Medicine of The Science and Medicine of Thrombosis ManagementThrombosis Management

New Dimensions, Novel Approaches, and Landmark Practice New Dimensions, Novel Approaches, and Landmark Practice Advances in Venous and Arterial Thrombosis Prevention and Advances in Venous and Arterial Thrombosis Prevention and

Treatment: The Internal Medicine PerspectiveTreatment: The Internal Medicine Perspective


New Dimensions, Novel Approaches, and Landmark Practice New Dimensions, Novel Approaches, and Landmark Practice Advances in Venous and Arterial Thrombosis Prevention and Advances in Venous and Arterial Thrombosis Prevention and

Treatment: The Internal Medicine PerspectiveTreatment: The Internal Medicine Perspective

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDProgram Chairman and ModeratorProgram Chairman and Moderator

Cardiovascular DivisionCardiovascular DivisionBrigham and Women’s HospitalBrigham and Women’s Hospital

Professor of MedicineProfessor of MedicineHarvard Medical SchoolHarvard Medical School




National Experts Illuminate and DebateNational Experts Illuminate and Debate

CME-certified symposiumCME-certified symposium jointly sponsored by University of jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Massachusetts Medical Center, office of CME and CMEducation Resources, LLCResources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from Bristol-Myers Squibb/Pfizer Pharmaceuticals Partnership.from Bristol-Myers Squibb/Pfizer Pharmaceuticals Partnership.

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

CME-certified symposiumCME-certified symposium jointly sponsored by University of jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Massachusetts Medical Center, office of CME and CMEducation Resources, LLCResources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from Bristol-Myers Squibb/Pfizer Pharmaceuticals Partnership.from Bristol-Myers Squibb/Pfizer Pharmaceuticals Partnership.

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

Welcome and Program OverviewWelcome and Program Overview

Program Educational ObjectivesProgram Educational Objectives

As a result of this session: As a result of this session: ► Clinicians will learn how to apply current guidelines issued by national Clinicians will learn how to apply current guidelines issued by national

professional organizations and colleges—including the AHA, ACC, AAN, and professional organizations and colleges—including the AHA, ACC, AAN, and ACCP—mandating risk-directed prophylaxis against cerebral thromboembolic ACCP—mandating risk-directed prophylaxis against cerebral thromboembolic infarction in at risk patients with AF.infarction in at risk patients with AF.

► Clinicians will learn how to apply current guidelines issued by national Clinicians will learn how to apply current guidelines issued by national professional organizations and colleges, such as the ACCP, mandating risk-professional organizations and colleges, such as the ACCP, mandating risk-directed prophylaxis against DVT in at risk patients with medical and surgical directed prophylaxis against DVT in at risk patients with medical and surgical conditions.conditions.

► Clinicians will learn about the coagulation cascade, mechanisms involved in Clinicians will learn about the coagulation cascade, mechanisms involved in inhibition at various points in the clotting cascade, and the rationale for inhibition at various points in the clotting cascade, and the rationale for developing and investigating oral agents with predictable anticoagulation, in the developing and investigating oral agents with predictable anticoagulation, in the absence of clinical monitoring.absence of clinical monitoring.

► Clinicians will learn to risk stratify medical and surgical patients, assess their Clinicians will learn to risk stratify medical and surgical patients, assess their likelihood for incurring DVT, and be aware of prophylaxis measures that can likelihood for incurring DVT, and be aware of prophylaxis measures that can reduce the incidence of DVT in the patient populations.reduce the incidence of DVT in the patient populations.

As a result of this session: As a result of this session: ► Clinicians will learn how to apply current guidelines issued by national Clinicians will learn how to apply current guidelines issued by national

professional organizations and colleges—including the AHA, ACC, AAN, and professional organizations and colleges—including the AHA, ACC, AAN, and ACCP—mandating risk-directed prophylaxis against cerebral thromboembolic ACCP—mandating risk-directed prophylaxis against cerebral thromboembolic infarction in at risk patients with AF.infarction in at risk patients with AF.

► Clinicians will learn how to apply current guidelines issued by national Clinicians will learn how to apply current guidelines issued by national professional organizations and colleges, such as the ACCP, mandating risk-professional organizations and colleges, such as the ACCP, mandating risk-directed prophylaxis against DVT in at risk patients with medical and surgical directed prophylaxis against DVT in at risk patients with medical and surgical conditions.conditions.

► Clinicians will learn about the coagulation cascade, mechanisms involved in Clinicians will learn about the coagulation cascade, mechanisms involved in inhibition at various points in the clotting cascade, and the rationale for inhibition at various points in the clotting cascade, and the rationale for developing and investigating oral agents with predictable anticoagulation, in the developing and investigating oral agents with predictable anticoagulation, in the absence of clinical monitoring.absence of clinical monitoring.

► Clinicians will learn to risk stratify medical and surgical patients, assess their Clinicians will learn to risk stratify medical and surgical patients, assess their likelihood for incurring DVT, and be aware of prophylaxis measures that can likelihood for incurring DVT, and be aware of prophylaxis measures that can reduce the incidence of DVT in the patient populations.reduce the incidence of DVT in the patient populations.

Program FacultyProgram Faculty

Program Chair And ModeratorProgram Chair And ModeratorSamuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDProfessor of MedicineProfessor of MedicineCardiovascular DivisionCardiovascular DivisionHarvard Medical SchoolHarvard Medical SchoolDirector, Venous Thromboembolism Director, Venous Thromboembolism Research GroupResearch GroupDirector, Anticoagulation ServiceDirector, Anticoagulation ServiceBrigham and Women’s HospitalBrigham and Women’s HospitalPresident, North American Thrombosis President, North American Thrombosis Forum Forum Boston, MABoston, MA

Distinguished Faculty Distinguished Faculty Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHAssociate Professor of MedicineAssociate Professor of MedicineDepartment of MedicineDepartment of MedicineBoston University School of MedicineBoston University School of MedicineBoston, MABoston, MA

Program Chair And ModeratorProgram Chair And ModeratorSamuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDProfessor of MedicineProfessor of MedicineCardiovascular DivisionCardiovascular DivisionHarvard Medical SchoolHarvard Medical SchoolDirector, Venous Thromboembolism Director, Venous Thromboembolism Research GroupResearch GroupDirector, Anticoagulation ServiceDirector, Anticoagulation ServiceBrigham and Women’s HospitalBrigham and Women’s HospitalPresident, North American Thrombosis President, North American Thrombosis Forum Forum Boston, MABoston, MA

Distinguished Faculty Distinguished Faculty Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHAssociate Professor of MedicineAssociate Professor of MedicineDepartment of MedicineDepartment of MedicineBoston University School of MedicineBoston University School of MedicineBoston, MABoston, MA

Geno Merli, MD, FACPGeno Merli, MD, FACPDirector, Jefferson Center for Vascular Director, Jefferson Center for Vascular DiseaseDiseaseProfessor of MedicineProfessor of MedicineSenior Vice President and Chief Medical Senior Vice President and Chief Medical OfficerOfficerThomas Jefferson HospitalThomas Jefferson HospitalPhiladelphia, PAPhiladelphia, PA

Alexander G. G. Turpie, MD, Alexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPCFRCP, FACP, FACC, FRCPCProfessor of MedicineProfessor of MedicineDepartment of MedicineDepartment of MedicineHamilton Health Sciences - General Hamilton Health Sciences - General HospitalHospitalHamilton, Ontario Hamilton, Ontario CanadaCanada

Geno Merli, MD, FACPGeno Merli, MD, FACPDirector, Jefferson Center for Vascular Director, Jefferson Center for Vascular DiseaseDiseaseProfessor of MedicineProfessor of MedicineSenior Vice President and Chief Medical Senior Vice President and Chief Medical OfficerOfficerThomas Jefferson HospitalThomas Jefferson HospitalPhiladelphia, PAPhiladelphia, PA

Alexander G. G. Turpie, MD, Alexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPCFRCP, FACP, FACC, FRCPCProfessor of MedicineProfessor of MedicineDepartment of MedicineDepartment of MedicineHamilton Health Sciences - General Hamilton Health Sciences - General HospitalHospitalHamilton, Ontario Hamilton, Ontario CanadaCanada

Faculty COI Financial DisclosuresFaculty COI Financial Disclosures

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDResearch SupportResearch Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; Mitsubishi; : AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; Mitsubishi; Sanofi-Aventis Sanofi-Aventis Consultant:Consultant: Boehringer-Ingelheim; BMS; Eisai, Emisphere; Merck; Pfizer; Sanofi- Boehringer-Ingelheim; BMS; Eisai, Emisphere; Merck; Pfizer; Sanofi-AventisAventis

Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHResearch FundingResearch Funding: AstraZeneca, Bristol-Myers Squibb, Pfizer: AstraZeneca, Bristol-Myers Squibb, PfizerAdvisory Board:Advisory Board: Aton Pharma, Bristol-Myers Squibb, Vox Medica Aton Pharma, Bristol-Myers Squibb, Vox Medica

Geno Merli, MD, FACPGeno Merli, MD, FACPGrants/Research Support:Grants/Research Support: Boehringer Ingelheim GmbH, Bristol-Myers Squibb, sanofi- Boehringer Ingelheim GmbH, Bristol-Myers Squibb, sanofi-aventis U.S. aventis U.S. Consultant:Consultant: Bacchus Vascular, Inc., Bristol-Myers Squibb, sanofi-aventis U.S. Bacchus Vascular, Inc., Bristol-Myers Squibb, sanofi-aventis U.S. Speakers’ Bureau:Speakers’ Bureau: sanofi-aventis U.S sanofi-aventis U.S..

Alexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPCAlexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPCSpeaker's Bureau: Speaker's Bureau: GlaxoSmithKline, sanofi-aventis and PfizerGlaxoSmithKline, sanofi-aventis and PfizerGrant and/or Research Support: Grant and/or Research Support: Bayer PharmaceuticalsBayer Pharmaceuticals Consultation: Consultation: GlaxoSmithKline, Bayer Pharmaceuticals, sanofi-aventis and Astellas GlaxoSmithKline, Bayer Pharmaceuticals, sanofi-aventis and Astellas Pharma IncPharma Inc. .

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDResearch SupportResearch Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; Mitsubishi; : AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; Mitsubishi; Sanofi-Aventis Sanofi-Aventis Consultant:Consultant: Boehringer-Ingelheim; BMS; Eisai, Emisphere; Merck; Pfizer; Sanofi- Boehringer-Ingelheim; BMS; Eisai, Emisphere; Merck; Pfizer; Sanofi-AventisAventis

Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHResearch FundingResearch Funding: AstraZeneca, Bristol-Myers Squibb, Pfizer: AstraZeneca, Bristol-Myers Squibb, PfizerAdvisory Board:Advisory Board: Aton Pharma, Bristol-Myers Squibb, Vox Medica Aton Pharma, Bristol-Myers Squibb, Vox Medica

Geno Merli, MD, FACPGeno Merli, MD, FACPGrants/Research Support:Grants/Research Support: Boehringer Ingelheim GmbH, Bristol-Myers Squibb, sanofi- Boehringer Ingelheim GmbH, Bristol-Myers Squibb, sanofi-aventis U.S. aventis U.S. Consultant:Consultant: Bacchus Vascular, Inc., Bristol-Myers Squibb, sanofi-aventis U.S. Bacchus Vascular, Inc., Bristol-Myers Squibb, sanofi-aventis U.S. Speakers’ Bureau:Speakers’ Bureau: sanofi-aventis U.S sanofi-aventis U.S..

Alexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPCAlexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPCSpeaker's Bureau: Speaker's Bureau: GlaxoSmithKline, sanofi-aventis and PfizerGlaxoSmithKline, sanofi-aventis and PfizerGrant and/or Research Support: Grant and/or Research Support: Bayer PharmaceuticalsBayer Pharmaceuticals Consultation: Consultation: GlaxoSmithKline, Bayer Pharmaceuticals, sanofi-aventis and Astellas GlaxoSmithKline, Bayer Pharmaceuticals, sanofi-aventis and Astellas Pharma IncPharma Inc. .

Crisis in Thrombosis MedicineCrisis in Thrombosis Medicine

Current Successes and an Current Successes and an Even Brighter Future Even Brighter Future

Crisis in Thrombosis MedicineCrisis in Thrombosis Medicine

Current Successes and an Current Successes and an Even Brighter Future Even Brighter Future

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s HospitalProfessor of MedicineProfessor of Medicine

Harvard Medical SchoolHarvard Medical School

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s HospitalProfessor of MedicineProfessor of Medicine

Harvard Medical SchoolHarvard Medical School


Myocardial Infarction Myocardial Infarction Good and Bad NewsGood and Bad News

Inci

denc

e R

ate

per

100,

000

Inci

denc

e R

ate

per

100,

000

0

40

80

120

160

200

Q-Wave Non Q-Wave

1975/19781981/19841986/19881990/19911993/19951997

ICOPER Cumulative MortalityICOPER Cumulative MortalityM

orta

lity

(%)

Mor

talit

y (%

)

Days From DiagnosisDays From Diagnosis

17.5%17.5%

0

5

10

15

20

25

LancetLancet 1999;353:1386-1389 1999;353:1386-1389

7 14 30 60 90

Incidence of VTEIncidence of VTE

► 900,000 PEs/ DVTs in USA in 2002

► Estimated 296,000 PE deaths 7% treated, 34% sudden and fatal, and 59% undetected

(Heit J. ASH Abstract 2005)

► 762,000 PEs/ DVTs in EU in 2004(Thromb Haemostas 2007; 98: 756)

► 900,000 PEs/ DVTs in USA in 2002

► Estimated 296,000 PE deaths 7% treated, 34% sudden and fatal, and 59% undetected

(Heit J. ASH Abstract 2005)

► 762,000 PEs/ DVTs in EU in 2004(Thromb Haemostas 2007; 98: 756)

► The high death rate from PE (exceeding acute The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed MI!) and the high frequency of undiagnosed PE causing “sudden cardiac death” PE causing “sudden cardiac death” emphasize the need for emphasize the need for improved preventive improved preventive efforts.efforts.

► Failure to institute prophylaxis is a much Failure to institute prophylaxis is a much bigger problem with Medical Service patients bigger problem with Medical Service patients than Surgical Service patients.than Surgical Service patients.

► The high death rate from PE (exceeding acute The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed MI!) and the high frequency of undiagnosed PE causing “sudden cardiac death” PE causing “sudden cardiac death” emphasize the need for emphasize the need for improved preventive improved preventive efforts.efforts.

► Failure to institute prophylaxis is a much Failure to institute prophylaxis is a much bigger problem with Medical Service patients bigger problem with Medical Service patients than Surgical Service patients.than Surgical Service patients.

Incidence of VTEIncidence of VTE

Morbidity/Mortality of Pulmonary Embolism

Progression of Chronic Venous InsufficiencyProgression of Chronic Venous Insufficiency

From UpToDate 2006From UpToDate 2006

Danish 20-year Cohort:Danish 20-year Cohort:VTE, Subsequent CV EventsVTE, Subsequent CV Events

► Assessed risk of MI, StrokeAssessed risk of MI, Stroke

► 25,199 with DVT25,199 with DVT

► 16,925 with PE 16,925 with PE

► 163,566 population controls163,566 population controls

► Assessed risk of MI, StrokeAssessed risk of MI, Stroke

► 25,199 with DVT25,199 with DVT

► 16,925 with PE 16,925 with PE

► 163,566 population controls163,566 population controls

Sorensen HT. Lancet 2007; 370: 1773-1779Sorensen HT. Lancet 2007; 370: 1773-1779Sorensen HT. Lancet 2007; 370: 1773-1779Sorensen HT. Lancet 2007; 370: 1773-1779

Association Between VTE and Association Between VTE and Arterial Thrombotic EventsArterial Thrombotic Events

CV EventCV Event 1 Year RR1 Year RR 2-20 Year RR2-20 Year RR

Acute MIAcute MI 2.62.6 1.31.3

StrokeStroke 2.92.9 1.31.3

Sorensen HT. Lancet 2007; 370: 1773-1779

Relative Risk (RR) of CV Events in PE PatientsRelative Risk (RR) of CV Events in PE Patients

Cardiovascular Risk Factors and VTECardiovascular Risk Factors and VTEA Continuum of Shared RiskA Continuum of Shared Risk

Ageno W. Ageno W. CirculationCirculation 2008; 117: 93-102 2008; 117: 93-102

Risk FactorRisk Factor Relative RiskRelative Risk

ObesityObesity 2.32.3

HypertensionHypertension 1.51.5

DiabetesDiabetes 1.41.4

CigarettesCigarettes 1.21.2

High CholesterolHigh Cholesterol 1.21.2

N = 63,552 for this meta-analysisN = 63,552 for this meta-analysis

Risk Factors for VTE and Arterial Thrombosis Risk Factors for VTE and Arterial Thrombosis Implications of Meta-AnalysisImplications of Meta-Analysis

1.1. Risk factors for atherothrombosis are also Risk factors for atherothrombosis are also associated with VTEassociated with VTE

2.2. Cardiovascular risk factors may be involved Cardiovascular risk factors may be involved in pathogenesis of VTEin pathogenesis of VTE

3.3. Atherosclerosis and VTE are Atherosclerosis and VTE are not not completely completely distinct entities.distinct entities.

1.1. Risk factors for atherothrombosis are also Risk factors for atherothrombosis are also associated with VTEassociated with VTE

2.2. Cardiovascular risk factors may be involved Cardiovascular risk factors may be involved in pathogenesis of VTEin pathogenesis of VTE

3.3. Atherosclerosis and VTE are Atherosclerosis and VTE are not not completely completely distinct entities.distinct entities.

Ageno W. Ageno W. CirculationCirculation 2008; 117: 93-102 2008; 117: 93-102

Risk Factors Linking Venous and Risk Factors Linking Venous and Arterial ThromboembolismArterial Thromboembolism

1.1. Activation of platelets and coagulation Activation of platelets and coagulation proteinsproteins

2.2. Increased fibrin turnoverIncreased fibrin turnover

3.3. InflammationInflammation

4.4. Lipid profilesLipid profiles

1.1. Activation of platelets and coagulation Activation of platelets and coagulation proteinsproteins

2.2. Increased fibrin turnoverIncreased fibrin turnover

3.3. InflammationInflammation

4.4. Lipid profilesLipid profiles

Biologically Plausible MechanismsBiologically Plausible Mechanisms

Steffen LM. Steffen LM. Circulation Circulation 2007;115:188-1952007;115:188-195

Lowering VTE RiskLowering VTE Risk

Adjusted Hazard Ratios (Quintiles)Adjusted Hazard Ratios (Quintiles)

22 33 44 55 pp

Fruits, Fruits, veggieveggie 0.730.73 0.570.57 0.470.47 0.590.59 0.030.03

FishFish 0.580.58 0.600.60 0.550.55 0.700.70 0.300.30

Red MeatRed Meat 1.241.24 1.211.21 1.091.09 2.012.01 0.020.02

Eat Veggies and Be Careful with Red MeatEat Veggies and Be Careful with Red Meat

Persistent Stress and PEPersistent Stress and PEAn Evolving AssociationAn Evolving Association

1.1. Persistent stress increased the risk of Persistent stress increased the risk of PE by 80%PE by 80%

2.2. After multivariable adjustment, the risk After multivariable adjustment, the risk of PE increased by 66%of PE increased by 66%

1.1. Persistent stress increased the risk of Persistent stress increased the risk of PE by 80%PE by 80%

2.2. After multivariable adjustment, the risk After multivariable adjustment, the risk of PE increased by 66%of PE increased by 66%

Rosengren A, et al. Rosengren A, et al. JTHJTH 2008; 6: 558-564 2008; 6: 558-564

N=6,958 Swedish Men — N=6,958 Swedish Men — 23-Year Average Follow-Up23-Year Average Follow-UpN=6,958 Swedish Men — N=6,958 Swedish Men — 23-Year Average Follow-Up23-Year Average Follow-Up

Reversible Risk Factors Reversible Risk Factors

1.1. Nutrition: Eat fruits, veggies, fish; less red Nutrition: Eat fruits, veggies, fish; less red meatmeat

22.. Quit cigarettesQuit cigarettes

3.3. Lose weight and exerciseLose weight and exercise

4.4. Prevent DM and metabolic syndromePrevent DM and metabolic syndrome

5.5. Control hypertension Control hypertension

6.6. Lower cholesterolLower cholesterol

7.7. Stress reductionStress reduction

1.1. Nutrition: Eat fruits, veggies, fish; less red Nutrition: Eat fruits, veggies, fish; less red meatmeat

22.. Quit cigarettesQuit cigarettes

3.3. Lose weight and exerciseLose weight and exercise

4.4. Prevent DM and metabolic syndromePrevent DM and metabolic syndrome

5.5. Control hypertension Control hypertension

6.6. Lower cholesterolLower cholesterol

7.7. Stress reductionStress reduction

Trends In CV Disease IncidenceTrends In CV Disease Incidence A Success StoryA Success Story

Trends in Cigarette Smoking Incidence Trends in Cigarette Smoking Incidence A Success StoryA Success Story

Warfarin PharmacogenomicsWarfarin Pharmacogenomics

1.1. Cytochrome P450 2C9 genotyping can Cytochrome P450 2C9 genotyping can identify mutations associated with impaired identify mutations associated with impaired warfarin metabolism.warfarin metabolism.

2.2. Vitamin K receptor polymorphism testing Vitamin K receptor polymorphism testing can identify whether patients require low, can identify whether patients require low, intermediate, or high doses of warfarin.intermediate, or high doses of warfarin.

1.1. Cytochrome P450 2C9 genotyping can Cytochrome P450 2C9 genotyping can identify mutations associated with impaired identify mutations associated with impaired warfarin metabolism.warfarin metabolism.

2.2. Vitamin K receptor polymorphism testing Vitamin K receptor polymorphism testing can identify whether patients require low, can identify whether patients require low, intermediate, or high doses of warfarin.intermediate, or high doses of warfarin.

Schwartz UI. Schwartz UI. NEJMNEJM 2008; 358: 999 2008; 358: 999

Incorporating routine genetic testing into Incorporating routine genetic testing into warfarin dosing will result in an estimated:warfarin dosing will result in an estimated:

► 85,000 fewer serious bleeds85,000 fewer serious bleeds

► 17,700 fewer strokes17,700 fewer strokes

► $1.1 billion saved$1.1 billion saved

Incorporating routine genetic testing into Incorporating routine genetic testing into warfarin dosing will result in an estimated:warfarin dosing will result in an estimated:

► 85,000 fewer serious bleeds85,000 fewer serious bleeds

► 17,700 fewer strokes17,700 fewer strokes

► $1.1 billion saved$1.1 billion saved

American Enterprise InstituteAmerican Enterprise InstituteThe Brookings ReportThe Brookings Report

November, 2006November, 2006

► Rapid turnaround CYP2C9 and VKORC1 Rapid turnaround CYP2C9 and VKORC1 testing vs. “empiric”testing vs. “empiric”

► Primary endpoint: TTR Primary endpoint: TTR

► Smaller and fewer dosing changes with Smaller and fewer dosing changes with genetic testing genetic testing

► No difference in TTRNo difference in TTR

► Rapid turnaround CYP2C9 and VKORC1 Rapid turnaround CYP2C9 and VKORC1 testing vs. “empiric”testing vs. “empiric”

► Primary endpoint: TTR Primary endpoint: TTR

► Smaller and fewer dosing changes with Smaller and fewer dosing changes with genetic testing genetic testing

► No difference in TTRNo difference in TTR

Genotype vs Standard Warfarin DosingGenotype vs Standard Warfarin DosingA Provocative Clinical TrialA Provocative Clinical Trial

Coumadin-Genotype Trial (N=206)Coumadin-Genotype Trial (N=206) Coumadin-Genotype Trial (N=206)Coumadin-Genotype Trial (N=206)

CirculationCirculation 2007; 116: 2563-2570 2007; 116: 2563-2570

► Can routine genetic testing reduce the Can routine genetic testing reduce the “Guessing Game” and “Play of Chance” in “Guessing Game” and “Play of Chance” in warfarin dosing?warfarin dosing?

► Is this approach ready for “Prime Time?”Is this approach ready for “Prime Time?”

► Can routine genetic testing reduce the Can routine genetic testing reduce the “Guessing Game” and “Play of Chance” in “Guessing Game” and “Play of Chance” in warfarin dosing?warfarin dosing?

► Is this approach ready for “Prime Time?”Is this approach ready for “Prime Time?”

Shurin SB, Nabel EG. Shurin SB, Nabel EG. NEJMNEJM 2008; 358: 1061-1063 2008; 358: 1061-1063

Genotype vs Standard Warfarin DosingGenotype vs Standard Warfarin Dosing

Novel Oral AnticoagulantsNovel Oral Anticoagulants

1.1. ApixabanApixaban: Direct factor Xa inhibitor (hepatic : Direct factor Xa inhibitor (hepatic clearance)—twice daily fixed doseclearance)—twice daily fixed dose

2.2. RivaroxabanRivaroxaban: direct factor Xa inhibitor (renal : direct factor Xa inhibitor (renal clearance)—once daily fixed doseclearance)—once daily fixed dose

3.3. DabigatranDabigatran: An oral DTI—twice daily fixed : An oral DTI—twice daily fixed dose (renal clearance)dose (renal clearance)

1.1. ApixabanApixaban: Direct factor Xa inhibitor (hepatic : Direct factor Xa inhibitor (hepatic clearance)—twice daily fixed doseclearance)—twice daily fixed dose

2.2. RivaroxabanRivaroxaban: direct factor Xa inhibitor (renal : direct factor Xa inhibitor (renal clearance)—once daily fixed doseclearance)—once daily fixed dose

3.3. DabigatranDabigatran: An oral DTI—twice daily fixed : An oral DTI—twice daily fixed dose (renal clearance)dose (renal clearance)

Gross PL, Weitz JI; ATVB 2008; 28: 380

““Take Home” PointsTake Home” Points

1.1. ““Lump,” don’t “split”, venous and arterial TE risk Lump,” don’t “split”, venous and arterial TE risk factors. They are not separate silos. Risk factors factors. They are not separate silos. Risk factors are shared.are shared.

2.2. VTE and Atherosclerosis are linked: VTE may VTE and Atherosclerosis are linked: VTE may herald arterial event.herald arterial event.

3.3. Lifestyle/reversible risk factors provide foundation Lifestyle/reversible risk factors provide foundation for prevention.for prevention.

4.4. Novel drugs, genetics, and decreased CV Novel drugs, genetics, and decreased CV incidence trends promise a brighter future.incidence trends promise a brighter future.

1.1. ““Lump,” don’t “split”, venous and arterial TE risk Lump,” don’t “split”, venous and arterial TE risk factors. They are not separate silos. Risk factors factors. They are not separate silos. Risk factors are shared.are shared.

2.2. VTE and Atherosclerosis are linked: VTE may VTE and Atherosclerosis are linked: VTE may herald arterial event.herald arterial event.

3.3. Lifestyle/reversible risk factors provide foundation Lifestyle/reversible risk factors provide foundation for prevention.for prevention.

4.4. Novel drugs, genetics, and decreased CV Novel drugs, genetics, and decreased CV incidence trends promise a brighter future.incidence trends promise a brighter future.

Alexander G. G. TurpieAlexander G. G. TurpieDepartment of MedicineDepartment of MedicineHHS-General HospitalHHS-General Hospital

Hamilton, Canada Hamilton, Canada

Alexander G. G. TurpieAlexander G. G. TurpieDepartment of MedicineDepartment of MedicineHHS-General HospitalHHS-General Hospital

Hamilton, Canada Hamilton, Canada

The Emerging Role of The Emerging Role of Factor Xa InhibitionFactor Xa Inhibition

Mechanisms and Applications Across the Mechanisms and Applications Across the Arteriovenous SpectrumArteriovenous Spectrum

The Emerging Role of The Emerging Role of Factor Xa InhibitionFactor Xa Inhibition

Mechanisms and Applications Across the Mechanisms and Applications Across the Arteriovenous SpectrumArteriovenous Spectrum


The Demise of WarfarinThe Demise of Warfarin

EcstaticEcstatic

oror

DeadDead

Antithrombotics That Have Antithrombotics That Have Changed Clinical PracticeChanged Clinical Practice

AnticoagulantsAnticoagulants

► Low-molecular-weight heparinLow-molecular-weight heparin

Antiplatelet DrugsAntiplatelet Drugs

► ThienopyridinesThienopyridines

► Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors

AnticoagulantsAnticoagulants

► Low-molecular-weight heparinLow-molecular-weight heparin

Antiplatelet DrugsAntiplatelet Drugs

► ThienopyridinesThienopyridines

► Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors

But…But…

For oral anticoagulation, Vitamin K For oral anticoagulation, Vitamin K antagonists (warfarin) remain the antagonists (warfarin) remain the only available optiononly available option

For oral anticoagulation, Vitamin K For oral anticoagulation, Vitamin K antagonists (warfarin) remain the antagonists (warfarin) remain the only available optiononly available option

Oral Anticoagulants are Recommended for Oral Anticoagulants are Recommended for Venous and Arterial ThrombosisVenous and Arterial Thrombosis

Venous thrombosisVenous thrombosis

► PreventionPrevention● After After

orthopaedic orthopaedic surgerysurgery

● After general After general surgerysurgery

● In cancer In cancer patientspatients

► Treatment Treatment

Venous thrombosisVenous thrombosis

► PreventionPrevention● After After

orthopaedic orthopaedic surgerysurgery

● After general After general surgerysurgery

● In cancer In cancer patientspatients

► Treatment Treatment

Arterial thrombosisArterial thrombosis

► Prevention Prevention ● Stroke in patients Stroke in patients

with AFwith AF● MI in patients with MI in patients with

ACSACS

Arterial thrombosisArterial thrombosis

► Prevention Prevention ● Stroke in patients Stroke in patients

with AFwith AF● MI in patients with MI in patients with

ACSACS

ACCP guidelines, Chest 2004

Venous Thromboembolism Venous Thromboembolism

Deep vein thrombosisDeep vein thrombosis

Pulmonary embolismPulmonary embolism

PROPHYLAXIS

PROPHYLAXIS

VTE in Orthopaedic SurgeryVTE in Orthopaedic Surgery

ACCP 2004 ACCP 2004 Summary of RecommendationsSummary of Recommendations

Geerts WH et al. Geerts WH et al. Chest.Chest. 2004;126(3 suppl):338S-400S. 2004;126(3 suppl):338S-400S.

THR = total hip replacement; TKR = total knee replacement; HFS = hip fracture surgery.

THRTHR TKRTKR HFSHFSExtended Extended

Use in Use in HFSHFS

Extended Extended Use in Use in THRTHR

FondaparinuxFondaparinux 1A1A 1A1A 1A1A 1A1A 1C+1C+

LMWHLMWH 1A1A 1A1A 1C+1C+ 1C+1C+ 1A1A

WarfarinWarfarin 1A1A 1A1A 2B2B 1C+1C+ 1A1A

Venous ThromboembolismVenous Thromboembolism

Deep vein thrombosis Pulmonary embolism

Treatment

Treatment

Confirmed VTEConfirmed VTE

Continue LMWH or UFH for 5 daysContinue LMWH or UFH for 5 days

Monitor UFH with APTT and adjust doseMonitor UFH with APTT and adjust dose

Start warfarin 5mg, target INR 2.5 (2.0-3.0)Start warfarin 5mg, target INR 2.5 (2.0-3.0)

Overlap minimum 4-5 days and until INR >2.0 for 2 daysOverlap minimum 4-5 days and until INR >2.0 for 2 days

Daily platelet count with UFH; x 1 for LMWHDaily platelet count with UFH; x 1 for LMWH

Suspected VTSuspected VT

SC LMWH or IV heparin bolus (5000u)SC LMWH or IV heparin bolus (5000u)

Confirm diagnosisConfirm diagnosis

Guidelines for Antithrombotic TherapyGuidelines for Antithrombotic TherapyTreatment of Venous ThromboembolismTreatment of Venous Thromboembolism

ACCP Chest 2001

Treatment of Venous ThromboembolismTreatment of Venous Thromboembolism

Cochrane Library 4, 2002

Heparin Heparin (%)(%)

LMWH LMWH (%)(%)

RR RR (95% CI)(95% CI)

Recurrent VTERecurrent VTE 98/191898/19185.1%5.1%

73/189773/18973.8%3.8%

0.760.76(0.57-1.01)(0.57-1.01)

Major BleedingMajor Bleeding 51/240151/24012.1%2.1%

30/235330/23531.3%1.3%

0.600.60(0.39-0.93)(0.39-0.93)

DeathDeath 172/2137172/21378.0%8.0%

135/2108135/21086.4%6.4%

0.780.78(0.62-0.99)(0.62-0.99)

Recurrent Venous Thrombosis is Common Recurrent Venous Thrombosis is Common Following a First Episode of Symptomatic DVTFollowing a First Episode of Symptomatic DVT

CumulativeCumulativeIncidence (%)Incidence (%)

YearsYears

Prandoni et al, Ann Intern Med 1996;125:1-7

00

55

1010

1515

2020

2525

3030

00 11 22 33 44 55 66 77 88

Long-term Treatment of VTELong-term Treatment of VTE

► First episode of VTE secondary to a transient (reversible) risk First episode of VTE secondary to a transient (reversible) risk factorfactor

VKA for at least 3 monthsVKA for at least 3 months (Grade 1A)(Grade 1A)

► First episode of VTEFirst episode of VTE VKA at least 6 to 12 monthsVKA at least 6 to 12 months (Grade 1A)(Grade 1A)

► First episode idiopathic VTEFirst episode idiopathic VTE Consider indefinite anticoagulant therapyConsider indefinite anticoagulant therapy (Grade 2A)(Grade 2A)

► Second episode of VTESecond episode of VTE Indefinite anticoagulant therapy Indefinite anticoagulant therapy (Grade 1A)(Grade 1A)

► First episode of VTE secondary to a transient (reversible) risk First episode of VTE secondary to a transient (reversible) risk factorfactor

VKA for at least 3 monthsVKA for at least 3 months (Grade 1A)(Grade 1A)

► First episode of VTEFirst episode of VTE VKA at least 6 to 12 monthsVKA at least 6 to 12 months (Grade 1A)(Grade 1A)

► First episode idiopathic VTEFirst episode idiopathic VTE Consider indefinite anticoagulant therapyConsider indefinite anticoagulant therapy (Grade 2A)(Grade 2A)

► Second episode of VTESecond episode of VTE Indefinite anticoagulant therapy Indefinite anticoagulant therapy (Grade 1A)(Grade 1A)

Atrial Fibrillation (AF)Atrial Fibrillation (AF)

► AF – The most common significant cardiac arrhythmiaAF – The most common significant cardiac arrhythmia● Estimated to affect 4.5 million people in the EU and 2.2 Estimated to affect 4.5 million people in the EU and 2.2

million people in the USmillion people in the US● Incidence of 9.9 per 1000 person-years in a large Incidence of 9.9 per 1000 person-years in a large

European study (N=6432) European study (N=6432) ► Incidence of AF strongly age dependentIncidence of AF strongly age dependent – prevalence – prevalence

~10% in those aged >80 years~10% in those aged >80 years► AF increases the risk of stroke 5-foldAF increases the risk of stroke 5-fold

● AF is directly responsible for 15–20% of strokesAF is directly responsible for 15–20% of strokes► AF is also a significant risk factor for stroke recurrence AF is also a significant risk factor for stroke recurrence

and severityand severity► The population is agingThe population is aging … …

► AF – The most common significant cardiac arrhythmiaAF – The most common significant cardiac arrhythmia● Estimated to affect 4.5 million people in the EU and 2.2 Estimated to affect 4.5 million people in the EU and 2.2

million people in the USmillion people in the US● Incidence of 9.9 per 1000 person-years in a large Incidence of 9.9 per 1000 person-years in a large

European study (N=6432) European study (N=6432) ► Incidence of AF strongly age dependentIncidence of AF strongly age dependent – prevalence – prevalence

~10% in those aged >80 years~10% in those aged >80 years► AF increases the risk of stroke 5-foldAF increases the risk of stroke 5-fold

● AF is directly responsible for 15–20% of strokesAF is directly responsible for 15–20% of strokes► AF is also a significant risk factor for stroke recurrence AF is also a significant risk factor for stroke recurrence

and severityand severity► The population is agingThe population is aging … …

Singer et al., Chest 2004; Fuster et al., Circulation 2006; Heeringa et al., Eur Heart J 2006

Projected Prevalence of AF in the USProjected Prevalence of AF in the US

Assuming no further increase in age-adjusted AF incidence Miyasaka et al. Circulation 2006

5.1 5.66.1

6.87.5

8.49.4

10.311.1

11.7 12.1

2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

YearYear

Pro

ject

ed n

umbe

r of

Pro

ject

ed n

umbe

r of

per

sons

with

AF

(m

illio

ns)

per

sons

with

AF

(m

illio

ns)

16

14

12

10

8

6

4

2

0

AF Guidelines – ACC/AHA/ESC 2006AF Guidelines – ACC/AHA/ESC 2006

Risk stratificationRisk stratification TherapyTherapy

High risk of strokeHigh risk of stroke► Prior thromboembolism (stroke, TIA, systemic embolism)Prior thromboembolism (stroke, TIA, systemic embolism)

► Rheumatic mitral stenosisRheumatic mitral stenosis

► More than one of:More than one of: age ≥75 years, hypertension, heart failure, impaired age ≥75 years, hypertension, heart failure, impaired LV systolic function, or diabetes mellitusLV systolic function, or diabetes mellitus

Oral VKAOral VKA

Moderate risk of strokeModerate risk of stroke► Only one of:Only one of: age ≥75 years, hypertension, heart failure, impaired LV age ≥75 years, hypertension, heart failure, impaired LV

systolic function, or diabetes mellitussystolic function, or diabetes mellitusOral VKA Oral VKA oror aspirin aspirin

Low risk of strokeLow risk of stroke► ‘‘Lone’ AF (no other risk factors)Lone’ AF (no other risk factors)

AspirinAspirin

Oral VKA target INR is 2.5 (range 2–3); aspirin is recommended at 81–325 mg/dayFuster et al., Circulation 2006

Vitamin K Antagonists – LimitationsVitamin K Antagonists – Limitations

► Unpredictable pharmacokinetics and pharmacodynamics, Unpredictable pharmacokinetics and pharmacodynamics, which are affected bywhich are affected by::

● Genetic factors (CYP 2C9 mutation)Genetic factors (CYP 2C9 mutation)● Drug–drug interactionsDrug–drug interactions● Consumption of alcohol and foods containing vitamin KConsumption of alcohol and foods containing vitamin K

► Monitoring and frequent dose adjustment required to Monitoring and frequent dose adjustment required to maintain INR within therapeutic windowmaintain INR within therapeutic window

● Monitoring is costly, and a burden on patients and societyMonitoring is costly, and a burden on patients and society

► Slow onset and offset of action (e.g. if patient requires Slow onset and offset of action (e.g. if patient requires surgery), requiring bridging with heparin or LMWHsurgery), requiring bridging with heparin or LMWH

► Unpredictable pharmacokinetics and pharmacodynamics, Unpredictable pharmacokinetics and pharmacodynamics, which are affected bywhich are affected by::

● Genetic factors (CYP 2C9 mutation)Genetic factors (CYP 2C9 mutation)● Drug–drug interactionsDrug–drug interactions● Consumption of alcohol and foods containing vitamin KConsumption of alcohol and foods containing vitamin K

► Monitoring and frequent dose adjustment required to Monitoring and frequent dose adjustment required to maintain INR within therapeutic windowmaintain INR within therapeutic window

● Monitoring is costly, and a burden on patients and societyMonitoring is costly, and a burden on patients and society

► Slow onset and offset of action (e.g. if patient requires Slow onset and offset of action (e.g. if patient requires surgery), requiring bridging with heparin or LMWHsurgery), requiring bridging with heparin or LMWH

Ansell et al., Chest 2004

Narrow Therapeutic Window ofNarrow Therapeutic Window ofVitamin K Antagonists Vitamin K Antagonists

00

55

1010

1515

2020

0.010.01 0.10.1 11 1010Dose (µmol/kg/day)Dose (µmol/kg/day)

Thrombus sizeThrombus size

00

1010

2020

3030

4040

5050

Total bleeding time (min)Total bleeding time (min)

EffectEffect

BleedingBleeding

WarfarinWarfarinNew drugNew drug

AcetylsalicylacidAllopurinolAlufibratAmiodaroneAmmoidineAmoxapineAnabolikaAndrosteronAnthranilacis deriverativesAzapropazoneBezafibrateBenziodaroneBroad spectrum antibioticsCephalosporinsChinidinpräparateChloralhydrateChloramphenicoleCimetidineClofihrateClonipramineCloxacillineDesipraminDextransDisulfirameDoxepinsErythromycinsEthacrynic acidFenoprofeneFluconazoleGlucagone

ImmunsuppressantsIndomethacin

ItraconazolLofepramin

LokalanästhetikaMefenaminsäure

MethylandrostenolonMetronidazol

MonoaminoxidasehemmerMutterkornalkaloide

NalidixinsäureNaproxen

NifluminsäureNicotinsäurederivate

NortryptilineOxyphenbutazon

ParaaminosalicylsäurePenicilline

PhenotiazinpräparatePhenylbutazone

(in Rheuma-, Gicht-, Grippemitteln)Piroxicame

RauwolfiapräparateSalicylats

Steroide, anaboleSulfinpyrazon

SulfisoxazolSulfonamideSulfonylurea

TestosteroneThiobarbiturate

ThyroxinTienilinsäure

AcetylcholineACTHAdrenalineAmitriptylineAthinyl-OstradiolAtropineBarbiturateCarbamacep~nCholestyramineCorticosteroids, systemicDigitalisDiphenylhydantoineDiureticsGanglion blocking agents

GluthetimideGriseofulvineHaloperidole

LaxanzienMercaptogurine

NeuroleptikaOvulationshemmer

PhenytoinPurinderivate

PyrithyldionRifampicine

StrophantineThiouracile

ThyreostaticsVitamin K Preparations

Vitamin supplements

Drug Interactions with VKAsDrug Interactions with VKAs

Increased Effect Decreased Effect

Close INR monitoring is requiredClose INR monitoring is requiredwith EVERY change in medicationwith EVERY change in medication!!

Do We Need Do We Need New Anticoagulants?New Anticoagulants?

Current Anticoagulants are Suboptimal—Current Anticoagulants are Suboptimal—What are Evolving Options and What Do CurrentWhat are Evolving Options and What Do Current

Trials Suggest?Trials Suggest?

Do We Need Do We Need New Anticoagulants?New Anticoagulants?

Current Anticoagulants are Suboptimal—Current Anticoagulants are Suboptimal—What are Evolving Options and What Do CurrentWhat are Evolving Options and What Do Current

Trials Suggest?Trials Suggest?

The Science and Medicine of Thrombosis Management

The Science and Medicine of Thrombosis Management

New AnticoagulantsNew Anticoagulants

TFPI (tifacogin)TFPI (tifacogin)

FondaparinuxFondaparinuxIdraparinuxIdraparinux

RivaroxabanRivaroxabanApixabanApixabanLY517717LY517717YM150YM150DU-176bDU-176bBetrixabanBetrixabanTAK 442TAK 442

DabigatranDabigatran

ORALORAL PARENTERALPARENTERAL

DX-9065a DX-9065a

XaXa

IIaIIa

TF/VIIa

XX IXIX

IXaIXaVIIIaVIIIa

VaVa

IIII

FibrinFibrinFibrinogenFibrinogen

ATAT

APC (drotrecogin alfa)APC (drotrecogin alfa)sTM (ART-123)sTM (ART-123)

Adapted from Weitz & Bates,Adapted from Weitz & Bates, J Thromb Haemost J Thromb Haemost 20072007

TTP889TTP889

VIIaVIIa

XaXa

IXaIXa

XIaXIa

XIIaXIIa

Direct Thrombin InhibitionDirect Thrombin Inhibition

Tissue Tissue factorfactor

Factor IIaFactor IIa(thrombin)(thrombin)


IIII

××

Dabigatran for Prevention of VTE After Major Dabigatran for Prevention of VTE After Major Orthopaedic Surgery: Phase III StudiesOrthopaedic Surgery: Phase III Studies

► Dabigatran doses of 150 and 220 mg once daily Dabigatran doses of 150 and 220 mg once daily (od) were investigated in all three studies(od) were investigated in all three studies

► Dabigatran doses of 150 and 220 mg once daily Dabigatran doses of 150 and 220 mg once daily (od) were investigated in all three studies(od) were investigated in all three studies

TKR: total knee replacement; THR: total hip replacement Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

StudyStudy Type of Type of surgerysurgery ComparatorComparator Number of Number of

patientspatients

Time to 1st Time to 1st administration administration of dabigatranof dabigatran

Treatment Treatment durationduration

RE-MODELRE-MODEL TKRTKR

Enoxaparin Enoxaparin 40 mg od, starting 40 mg od, starting evening before evening before surgerysurgery

20102010 1–4 hours 1–4 hours post-surgerypost-surgery 6–10 days6–10 days

RE-MOBILIZERE-MOBILIZE TKRTKR

Enoxaparin Enoxaparin 30 mg bid, starting 30 mg bid, starting 12–24 hours post-12–24 hours post-surgerysurgery


RE-NOVATERE-NOVATE THRTHR

Enoxaparin Enoxaparin 40 mg od, starting 40 mg od, starting evening before evening before surgerysurgery


Dabigatran for Prevention of VTE After Major Dabigatran for Prevention of VTE After Major Orthopaedic Surgery: ResultsOrthopaedic Surgery: Results

EnoxaparinEnoxaparin Dabigatran Dabigatran (150 mg)(150 mg)

Dabigatran Dabigatran (220 mg)(220 mg)

DVT, PE and all-cause mortality (%)DVT, PE and all-cause mortality (%)

RE-NOVATERE-NOVATE 6.76.7 8.6 8.6 pp<0.0001*<0.0001*

6.06.0pp<0.0001*<0.0001*

RE-MOBILIZERE-MOBILIZE 25.325.3 33.733.7pp=0.0009=0.0009††

31.131.1pp=0.02=0.02††

RE-MODELRE-MODEL 37.737.7 40.540.5pp=0.0005*=0.0005*

36.436.4pp=0.0345*=0.0345*

Major bleeding (%)Major bleeding (%)

RE-NOVATERE-NOVATE 1.61.6 1.31.3 2.02.0

RE-MOBILIZERE-MOBILIZE 1.41.4 0.60.6 0.60.6

RE-MODELRE-MODEL 1.31.3 1.31.3 1.51.5

*Non-inferior to enoxaparin; †inferior to enoxaparin Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

Dabigatran: Phase III StudiesDabigatran: Phase III Studies

► RE-LY (stroke prevention in patients with AF)RE-LY (stroke prevention in patients with AF)● Planned enrolment 15,000 patientsPlanned enrolment 15,000 patients● Dabigatran 110 and 150 mg bid compared with Dabigatran 110 and 150 mg bid compared with warfarinwarfarin● Treatment duration up to 3 yearsTreatment duration up to 3 years

► RE-SOLVE, RE-COVER and RE-MEDYRE-SOLVE, RE-COVER and RE-MEDY● Ongoing studies in treatment and secondary prevention Ongoing studies in treatment and secondary prevention

of VTEof VTE

► RE-LY (stroke prevention in patients with AF)RE-LY (stroke prevention in patients with AF)● Planned enrolment 15,000 patientsPlanned enrolment 15,000 patients● Dabigatran 110 and 150 mg bid compared with Dabigatran 110 and 150 mg bid compared with warfarinwarfarin● Treatment duration up to 3 yearsTreatment duration up to 3 years

► RE-SOLVE, RE-COVER and RE-MEDYRE-SOLVE, RE-COVER and RE-MEDY● Ongoing studies in treatment and secondary prevention Ongoing studies in treatment and secondary prevention

of VTEof VTE

New AnticoagulantsNew Anticoagulants

TFPI (tifacogin)TFPI (tifacogin)

FondaparinuxFondaparinuxIdraparinuxIdraparinux

RivaroxabanRivaroxabanApixabanApixabanLY517717LY517717YM150YM150DU-176bDU-176bBetrixabanBetrixabanTAK 442TAK 442


ORALORAL PARENTERALPARENTERAL

DX-9065aDX-9065a

XaXa

IIa

TF/VIIa

XX IXIX

IXaIXaVIIIaVIIIa

VaVa

IIII

FibrinFibrinFibrinogenFibrinogen

ATAT

APC (drotrecogin alfa)APC (drotrecogin alfa)sTM (ART-123)sTM (ART-123)

Adapted from Weitz & Bates,Adapted from Weitz & Bates, J Thromb Haemost J Thromb Haemost 20072007

TTP889TTP889

VIIaVIIa

XaXa

IXaIXa

XIaXIa

XIIaXIIa

Direct Factor Xa inhibitionDirect Factor Xa inhibition

Tissue Tissue factorfactor

FibrinogenFibrinogen Fibrin clotFibrin clot

Factor IIFactor II(prothrombin)(prothrombin)

RivaroxabanRivaroxabanApixabanApixabanYM150YM150

DU-176b DU-176b LY517717LY517717BetrixabanBetrixabanTAK 442TAK 442

××

Oral Factor Xa InhibitorsOral Factor Xa Inhibitors Clinical DevelopmentClinical Development

Rivaroxaban (Bayer/J&J)Rivaroxaban (Bayer/J&J)

Phase III Phase III

Apixaban (BMS/Pfizer)Apixaban (BMS/Pfizer)

Phase IIPhase II

YM150 (Astellas)YM150 (Astellas)

Phase IIb Phase IIb

DU-176b (Daiichi)DU-176b (Daiichi)

Phase IIb Phase IIb

LY517717 (Lilly)LY517717 (Lilly)

Phase IIb Phase IIb

Betrixaban (Portola) Betrixaban (Portola)

Phase IIPhase II

TAK 442 (Takeda) TAK 442 (Takeda)

Phase IIPhase II

Rivaroxaban (Bayer/J&J)Rivaroxaban (Bayer/J&J)

Phase III Phase III

Apixaban (BMS/Pfizer)Apixaban (BMS/Pfizer)

Phase IIPhase II

YM150 (Astellas)YM150 (Astellas)

Phase IIb Phase IIb

DU-176b (Daiichi)DU-176b (Daiichi)

Phase IIb Phase IIb

LY517717 (Lilly)LY517717 (Lilly)

Phase IIb Phase IIb

Betrixaban (Portola) Betrixaban (Portola)

Phase IIPhase II

TAK 442 (Takeda) TAK 442 (Takeda)

Phase IIPhase II

Apixaban — Factor Xa InhibitorApixaban — Factor Xa Inhibitor

► Oral, direct, selective factor Xa inhibitorOral, direct, selective factor Xa inhibitor

► Produces concentration-dependent Produces concentration-dependent anticoagulationanticoagulation

► No formation of reactive intermediatesNo formation of reactive intermediates

► No organ toxicity or LFT abnormalities in No organ toxicity or LFT abnormalities in chronic toxicology studies chronic toxicology studies

► Low likelihood of drug interactions or QTc Low likelihood of drug interactions or QTc prolongationprolongation

► Good oral bioavailability Good oral bioavailability

► No food effect No food effect

► Balanced elimination (~25% renal) Balanced elimination (~25% renal)

► Half-life ~12 hrsHalf-life ~12 hrs

► Oral, direct, selective factor Xa inhibitorOral, direct, selective factor Xa inhibitor


► No formation of reactive intermediatesNo formation of reactive intermediates

► No organ toxicity or LFT abnormalities in No organ toxicity or LFT abnormalities in chronic toxicology studies chronic toxicology studies

► Low likelihood of drug interactions or QTc Low likelihood of drug interactions or QTc prolongationprolongation


► No food effect No food effect

► Balanced elimination (~25% renal) Balanced elimination (~25% renal)


He et al., ASH, 2006, Lassen, et al ASH, 2006He et al., ASH, 2006, Lassen, et al ASH, 2006

N

N

NO

N O

NH2

O

O

Apixaban: Phase II StudiesApixaban: Phase II Studies

► APROPOS – Orthopaedic surgeryAPROPOS – Orthopaedic surgery

► Botticelli – Treatment Botticelli – Treatment

► ADAPT – Advanced cancer ADAPT – Advanced cancer ► APPRAISE 1 – ACSAPPRAISE 1 – ACS

► APROPOS – Orthopaedic surgeryAPROPOS – Orthopaedic surgery

► Botticelli – Treatment Botticelli – Treatment

► ADAPT – Advanced cancer ADAPT – Advanced cancer ► APPRAISE 1 – ACSAPPRAISE 1 – ACS

Apixaban Phase 2 StudiesApixaban Phase 2 Studies

APROPOSAPROPOSCV185010CV185010completedcompleted

Phase 2 dose-ranging study for VTE prevention in Phase 2 dose-ranging study for VTE prevention in patients undergoing total knee replacement. 1238 patients undergoing total knee replacement. 1238 patients randomized. 10-14 day treatmentpatients randomized. 10-14 day treatment::

Apixaban 2.5, 5, 10 mg BID, 5, 10, 20 QD, enoxaparin Apixaban 2.5, 5, 10 mg BID, 5, 10, 20 QD, enoxaparin 30 mg BID, warfarin30 mg BID, warfarin

BOTTICELLIBOTTICELLICV185017CV185017completedcompleted

Phase 2 dose-ranging study for treatment of DVT; Phase 2 dose-ranging study for treatment of DVT; 520 patients randomized. 3 month treatment with: 520 patients randomized. 3 month treatment with:

Apixaban 5, 10 mg BID, 20 mg QD, or LMWH/warfarinApixaban 5, 10 mg BID, 20 mg QD, or LMWH/warfarin

ADVOCATEADVOCATECV185027CV185027

Phase 2 pilot study for VTE prevention in patients Phase 2 pilot study for VTE prevention in patients with advanced cancer (planned 160 subjects)with advanced cancer (planned 160 subjects)

Apixaban 5, 10, 20 mg QD vs. placeboApixaban 5, 10, 20 mg QD vs. placebo

APPRAISE-1APPRAISE-1CV185023CV185023

Phase 2 study in patients with recent acute Phase 2 study in patients with recent acute coronary syndromes; randomization completedcoronary syndromes; randomization completed

6 month treatment with apixaban 2.5 mg BID, 10 mg 6 month treatment with apixaban 2.5 mg BID, 10 mg QD, 10 mg BID, 20 mg QD vs. placebo on top of QD, 10 mg BID, 20 mg QD vs. placebo on top of standard-of-care (aspirin or aspirin + clopidogrel)standard-of-care (aspirin or aspirin + clopidogrel)

Lassen et al. Blood 2006

Total VTE and All-Cause Mortality (%)Total VTE and All-Cause Mortality (%) Major Bleeding (%)Major Bleeding (%)

Enoxaparin(30mg bid)

Apixaban for Prevention of VTE Apixaban for Prevention of VTE After Major Orthopaedic SurgeryAfter Major Orthopaedic Surgery

► Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patientsand warfarin, in 1,217 patients

20mg

Apixaban Apixaban (Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin (INR

1.8-3.0)

Enoxaparin(30mg bid)

20mg

Apixaban Apixaban (Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin (INR

1.8-3.0)

Per

cen

t

Per

cen

t10.6

8.66.8

26.6

15.6

0

5

10

15

20

25

30

1.3 1.63.0

0 00

5

10

15

20

25

30

Büller, Eur Heart J 2006

Composite of Symptomatic Composite of Symptomatic Recurrent VTE and Deterioration of Recurrent VTE and Deterioration of

Thrombotic Burden (%)Thrombotic Burden (%)

Composite of Symptomatic Composite of Symptomatic Recurrent VTE and Deterioration of Recurrent VTE and Deterioration of

Thrombotic Burden (%)Thrombotic Burden (%)Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)

Apixaban for the Treatment of DVT: Apixaban for the Treatment of DVT: The Botticelli-DVT StudyThe Botticelli-DVT Study

► Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight heparin (LMWH) or fondaparinux followed by VKA, in 520 patientsheparin (LMWH) or fondaparinux followed by VKA, in 520 patients

20mg bid

ApixabanApixaban

10mg bid

5mg bid

LMWH/ fondaparinux

+ VKA

20mg bid

Apixaban Apixaban

10mg bid

5mg bid

LMWH/ fondaparinux

+ VKA

Per

cen

t

Per

cen

t

6.0 5.6

2.6

4.2

0

2

4

6

8

10

0.80

0.80

0

2

4

6

8

10

Apixaban Phase 3 Clinical Development Apixaban Phase 3 Clinical Development VTE PreventionVTE Prevention

ADVANCE-1ADVANCE-1CV185034CV185034

VTE prevention after knee replacement surgery (N ~ VTE prevention after knee replacement surgery (N ~ 3000)3000)

• 12d vs. enoxaparin 30mg BID (superiority)12d vs. enoxaparin 30mg BID (superiority)


VTE prevention after knee replacement surgery (N ~ VTE prevention after knee replacement surgery (N ~ 3000)3000)

• 12d vs. enoxaparin 40mg QD (superiority)12d vs. enoxaparin 40mg QD (superiority)


VTE prevention after hip replacement surgery (N ~ 4000)VTE prevention after hip replacement surgery (N ~ 4000)• 35d vs. enoxaparin 40mg QD (noninferiority)35d vs. enoxaparin 40mg QD (noninferiority)

ADOPTADOPTCV185036CV185036

VTE prevention in acutely ill medical patients (N ~ 6500)VTE prevention in acutely ill medical patients (N ~ 6500)•30d vs. ~6d enoxaparin 40mg QD followed by placebo 30d vs. ~6d enoxaparin 40mg QD followed by placebo post-discharge (superiority)post-discharge (superiority)

Apixaban Phase 3 Apixaban Phase 3 Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation

ARISTOTLEARISTOTLECV185030CV185030

Stroke prevention in patients with atrial Stroke prevention in patients with atrial fibrillation fibrillation (N ~ 15,000)(N ~ 15,000)

Treatment for up to two years with 5 mg Treatment for up to two years with 5 mg BID apixaban vs. warfarin (INR 2 -3)BID apixaban vs. warfarin (INR 2 -3)

AVERROESAVERROESCV185048CV185048

Stroke prevention in patients with atrial Stroke prevention in patients with atrial fibrillation not able to receive warfarin fibrillation not able to receive warfarin (N ~ 5,600)(N ~ 5,600)

Treatment for up to two years with 5 mg Treatment for up to two years with 5 mg BID apixaban vs. aspirinBID apixaban vs. aspirin

Rivaroxaban: Oral Direct Factor Xa InhibitorRivaroxaban: Oral Direct Factor Xa Inhibitor

► Predictable Predictable pharmacologypharmacology

► High bioavailability High bioavailability

► Low risk of drug–Low risk of drug–drug interactionsdrug interactions

► Fixed doseFixed dose

► No requirement for No requirement for monitoringmonitoring

► Predictable Predictable pharmacologypharmacology

► High bioavailability High bioavailability

► Low risk of drug–Low risk of drug–drug interactionsdrug interactions

► Fixed doseFixed dose

► No requirement for No requirement for monitoringmonitoring

Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

Rivaroxaban® – rivaroxaban

N NO

NH

O

SCl

O

O

O

RivaroxabanRivaroxaban

► Specific, competitive, direct Specific, competitive, direct FXa inhibitor FXa inhibitor

► Inhibits free and clot-Inhibits free and clot-associated FXa activity, associated FXa activity, and prothrombinase activityand prothrombinase activity

► Inhibits thrombin generation Inhibits thrombin generation via inhibition of FXa activity via inhibition of FXa activity

● Prolongs time to thrombin Prolongs time to thrombin generationgeneration

● Inhibits peak thrombin Inhibits peak thrombin generationgeneration

● Reduces the total amount Reduces the total amount of thrombin generatedof thrombin generated

► Does not require a cofactorDoes not require a cofactor

► Specific, competitive, direct Specific, competitive, direct FXa inhibitor FXa inhibitor

► Inhibits free and clot-Inhibits free and clot-associated FXa activity, associated FXa activity, and prothrombinase activityand prothrombinase activity

► Inhibits thrombin generation Inhibits thrombin generation via inhibition of FXa activity via inhibition of FXa activity

● Prolongs time to thrombin Prolongs time to thrombin generationgeneration

● Inhibits peak thrombin Inhibits peak thrombin generationgeneration

● Reduces the total amount Reduces the total amount of thrombin generatedof thrombin generated

► Does not require a cofactorDoes not require a cofactor

Perzborn et al. J Thromb Haemost 2005; ICT 2004; Depasse et al. ISTH 2005; Kubitza et al. Clin Pharmacol Ther 2005; Br J Clin Pharmacol, 2007; Graff et al. In press

Rivaroxaban (nM)0.01 0.1 1 10 100 1000

Inh

ibit

ion

of

Fa

cto

r X

a a

cti

vit

y (

%)

0

20

40

60

80

100

Free FXaProthrombinase activityClot-associated FXa

Study BackgroundStudy Background

► ACCP guidelines: grade 1A ACCP guidelines: grade 1A recommendation for up to 35 days’ recommendation for up to 35 days’ prophylaxis after elective hip prophylaxis after elective hip replacement surgery replacement surgery

► ACCP guidelines: grade 1A ACCP guidelines: grade 1A recommendation for up to 35 days’ recommendation for up to 35 days’ prophylaxis after elective hip prophylaxis after elective hip replacement surgery replacement surgery

Geerts et al., 2004

20042004

Oral rivaroxaban compared with subcutaneous enoxaparin for extended

thromboprophylaxis after total hip arthroplasty

Oral rivaroxaban compared with subcutaneous enoxaparin for extended

thromboprophylaxis after total hip arthroplasty

Factor Xa InhibitionFactor Xa Inhibition

Enoxaparin 40 mg odEnoxaparin 40 mg od

Rivaroxaban 10 mg odRivaroxaban 10 mg od

RECORD 1— Study DesignRECORD 1— Study Design

Mandatorybilateral

venographyR

SURGERY

FOLLOW

UP

Evening before surgery

6–8 hours post-surgery

6–8 hours post-surgery

Day 1 Day 36±4

Double blind

Last dose, daybefore venography

Up to Day 65

Inclusion criteriaInclusion criteria Patients aged ≥18 years, scheduled Patients aged ≥18 years, scheduled

to undergo elective THR to undergo elective THR


to undergo elective THR to undergo elective THR

Major exclusion criteriaMajor exclusion criteria Active bleeding or high risk of bleedingActive bleeding or high risk of bleeding

Significant liver diseaseSignificant liver disease

Anticoagulant therapy that could not be stoppedAnticoagulant therapy that could not be stopped

Use of HIV-protease inhibitorsUse of HIV-protease inhibitors





RECORD 1 — SummaryRECORD 1 — SummaryIn

cide

nce

(%)

Inci

denc

e (%

)

Total VTETotal VTE

Major bleedingMajor bleeding

Enoxaparin 40 mg once dailyEnoxaparin 40 mg once dailyRivaroxaban 10 mg once dailyRivaroxaban 10 mg once daily

00

11

22

33

44

55

0.5%0.3%0.3%

0.1%0.1% 0.3%0.3%

Symptomatic VTESymptomatic VTE

RRR 70%RRR 70%

2.0%

0.2%0.2%

Major VTEMajor VTE

RRR 88%RRR 88%

1.1%

3.7%

Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis

with low molecular weight heparin after total hip arthroplasty

Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis

with low molecular weight heparin after total hip arthroplasty


Rivaroxaban 10 mg odRivaroxaban 10 mg odMandatoryMandatory

bilateralbilateralvenographyvenography

RECORD 2 — Study DesignRECORD 2 — Study Design


to undergo elective THRto undergo elective THR

Day 65Day 65+5+5

RR

SSUURRGGEERRYY

FFOOLLLLOOWW

UUPP

Evening before surgeryEvening before surgery

6–8 hours post-surgery6–8 hours post-surgery


Day 1Day 1

Double blindDouble blind





Day 36Day 36±±44

EnoxaparinEnoxaparin40 mg od40 mg od

Oral placeboOral placebo

RECORD 2 — SummaryRECORD 2 — Summary

Total VTETotal VTETotal VTETotal VTE

Major bleedingMajor bleedingMajor bleedingMajor bleeding

Major VTEMajor VTE

Inci

denc

e (%

)

00

22

4

6

10

8

9.3%

RRR 78.9%RRR 78.9%

2.0% 5.1% 0.1%0.1% 0.1%0.1%0.6%

RRR 87.8%RRR 87.8%RRR 80.1%RRR 80.1%

1.2% 0.2%0.2%


Enoxaparin 40 mg once daily

Rivaroxaban 10 mg once daily

Rivaroxaban – An oral, direct Factor Xa Rivaroxaban – An oral, direct Factor Xa inhibitor: For the prevention of venous inhibitor: For the prevention of venous

thromboembolism in total knee arthroplasty thromboembolism in total knee arthroplasty surgerysurgery

Rivaroxaban – An oral, direct Factor Xa Rivaroxaban – An oral, direct Factor Xa inhibitor: For the prevention of venous inhibitor: For the prevention of venous

thromboembolism in total knee arthroplasty thromboembolism in total knee arthroplasty surgerysurgery



Rivaroxaban 10 mg odRivaroxaban 10 mg odMandatoryMandatory

bilateralbilateralvenographyvenography

RECORD 3 — Study DesignRECORD 3 — Study Design

Inclusion criteriaInclusion criteria Patients aged ≥18 years, Patients aged ≥18 years,

scheduled to undergo elective, scheduled to undergo elective, total knee replacement (TKR) total knee replacement (TKR) surgerysurgery

Day 42Day 42+5+5

RR

SSUURRGGEERRYY

FFOOLLLLOOWW

UUPP

Evening before surgeryEvening before surgery



Day 1Day 1 Day 13Day 13±±22

Double blindDouble blind

Last dose, 1 dayLast dose, 1 daybefore venographybefore venography





RR

SSUURRGGEERRYY

RECORD 3 — SummaryRECORD 3 — Summary

Total VTETotal VTETotal VTETotal VTE

Major bleedingMajor bleedingMajor bleedingMajor bleeding

2020

Inci

denc

e (%

)In

cide

nce

(%)

00

Major VTEMajor VTE

55

1010

1515

NSNS

RRR 49%RRR 49%

RRR 62%RRR 62%


Rivaroxaban 10 mg odRivaroxaban 10 mg od


RRR 65%RRR 65%

0.5%0.5% 0.6%0.6%18.9% 9.6%

2.6%2.6%

1.0%1.0%

2.0%2.0%

0.7%0.7%

Rivaroxaban Clinical TrialsRivaroxaban Clinical Trials

~50,000 patients~50,000 patients~50,000 patients~50,000 patients

Properties of an Ideal AnticoagulantProperties of an Ideal Anticoagulant

PropertiesProperties BenefitsBenefitsOrally activeOrally active Ease of administrationEase of administration

Rapid onset of actionRapid onset of action Obviates need for overlap with a Obviates need for overlap with a parenteral anticoagulantparenteral anticoagulant

No food or drug interactionsNo food or drug interactions Simplified dosingSimplified dosing

Predictable anticoagulant effectPredictable anticoagulant effect No routine coagulation monitoringNo routine coagulation monitoring

Extra-renal clearanceExtra-renal clearance Safe in patients with renal Safe in patients with renal insufficiencyinsufficiency

Rapid offset of actionRapid offset of action Simplifies management in case of Simplifies management in case of bleed or need for interventionbleed or need for intervention

Safe antidoteSafe antidote Useful in case of major bleedUseful in case of major bleed

Favourable net clinical benefitFavourable net clinical benefit Treatment benefit outweighs riskTreatment benefit outweighs risk

Beyond Vitamin K Antagonists — Beyond Vitamin K Antagonists — The Future of Oral AnticoagulationThe Future of Oral Anticoagulation

► New anticoagulants that do not require monitoring New anticoagulants that do not require monitoring or dose adjustment are in developmentor dose adjustment are in development

► Drugs that inhibit thrombin or FXa are attractive Drugs that inhibit thrombin or FXa are attractive optionsoptions

► Rivaroxaban, dabigatran and apixaban are in Rivaroxaban, dabigatran and apixaban are in phase III developmentphase III development

► Over the next 5 years, we could see a paradigm Over the next 5 years, we could see a paradigm shift in the anticoagulant management of shift in the anticoagulant management of thromboembolic diseasethromboembolic disease

► New anticoagulants that do not require monitoring New anticoagulants that do not require monitoring or dose adjustment are in developmentor dose adjustment are in development

► Drugs that inhibit thrombin or FXa are attractive Drugs that inhibit thrombin or FXa are attractive optionsoptions

► Rivaroxaban, dabigatran and apixaban are in Rivaroxaban, dabigatran and apixaban are in phase III developmentphase III development

► Over the next 5 years, we could see a paradigm Over the next 5 years, we could see a paradigm shift in the anticoagulant management of shift in the anticoagulant management of thromboembolic diseasethromboembolic disease

Challenges of Stroke Prevention Challenges of Stroke Prevention in Atrial Fibrillationin Atrial Fibrillation

Achieving the Balance between Achieving the Balance between Thromboprophylaxis and Hemorrhage Thromboprophylaxis and Hemorrhage

Challenges of Stroke Prevention Challenges of Stroke Prevention in Atrial Fibrillationin Atrial Fibrillation

Achieving the Balance between Achieving the Balance between Thromboprophylaxis and Hemorrhage Thromboprophylaxis and Hemorrhage


Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHAssociate Professor of MedicineAssociate Professor of Medicine

Department of MedicineDepartment of MedicineBoston University School of MedicineBoston University School of Medicine

Boston, MABoston, MA

Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHAssociate Professor of MedicineAssociate Professor of Medicine

Department of MedicineDepartment of MedicineBoston University School of MedicineBoston University School of Medicine

Boston, MABoston, MA

Miyasaka, Y. et al. Circulation 2006;114:119-125

Projected Number of Persons with AF in the Projected Number of Persons with AF in the U.S. Between 2000 and 2050 U.S. Between 2000 and 2050

Assumes no further increase in age-adjusted AF incidence (Assumes no further increase in age-adjusted AF incidence (yellow curveyellow curve) and assumes a ) and assumes a continued increase in incidence rate as evident in 1980 to 2000 (continued increase in incidence rate as evident in 1980 to 2000 (orange curveorange curve))

Pro

ject

ed n

umbe

r of

P

roje

cted

num

ber

of

pers

ons

with

AF

(m

illio

ns)

pers

ons

with

AF

(m

illio

ns)

5.15.9

6.77.7

15.915.214.3

13.111.7

10.28.9

5.1 5.66.1

12.111.711.1

10.39.4

8.47.5

6.8

0

2

4

6

8

10

12

14

16

2000 2010 2020 2030 2040 2050

Prevalence of AF at Various AgesPrevalence of AF at Various Ages

Chest 1995;108:352SChest 1995;108:352S

FraminghamFramingham

CHSCHS

RochesterRochester

Western AustraliaWestern Australia

Pre

vale

nce

(%)

Pre

vale

nce

(%)

AgeAge

2020

1616

1414

1212

1010

88

66

44

22

004040 50 50 60 60 70 70 80 80 90 90

The Epidemic of Atrial Fibrillation The Epidemic of Atrial Fibrillation

Increasing prevalence of risk factors for AFIncreasing prevalence of risk factors for AF

► Older ageOlder age

► Systemic hypertensionSystemic hypertension

► Heart failureHeart failure

► Valvular heart diseaseValvular heart disease

► Diabetes mellitusDiabetes mellitus

► ObesityObesity

Increasing prevalence of risk factors for AFIncreasing prevalence of risk factors for AF

► Older ageOlder age

► Systemic hypertensionSystemic hypertension

► Heart failureHeart failure

► Valvular heart diseaseValvular heart disease

► Diabetes mellitusDiabetes mellitus

► ObesityObesity

LAA ThrombusLAA Thrombus

Cardiac Embolism to a Cerebral ArteryCardiac Embolism to a Cerebral Artery

Atrial Fibrillation: Morbidity and MortalityAtrial Fibrillation: Morbidity and Mortality

► ~15% of all strokes occur in people with AF~15% of all strokes occur in people with AF

► Risk of stroke in untreated AF patients averages ~ 5% Risk of stroke in untreated AF patients averages ~ 5% per yearper year

► Risk of stroke in AF patients by age groupRisk of stroke in AF patients by age group● 1.5% in 50 to 59 year age group1.5% in 50 to 59 year age group● 23.5% in 80 to 89 year age group23.5% in 80 to 89 year age group

► AF is associated with a 50 to 90% increase in AF is associated with a 50 to 90% increase in risk of death after adjustment for coexisting CV risk of death after adjustment for coexisting CV conditionsconditions

► ~15% of all strokes occur in people with AF~15% of all strokes occur in people with AF

► Risk of stroke in untreated AF patients averages ~ 5% Risk of stroke in untreated AF patients averages ~ 5% per yearper year

► Risk of stroke in AF patients by age groupRisk of stroke in AF patients by age group● 1.5% in 50 to 59 year age group1.5% in 50 to 59 year age group● 23.5% in 80 to 89 year age group23.5% in 80 to 89 year age group

► AF is associated with a 50 to 90% increase in AF is associated with a 50 to 90% increase in risk of death after adjustment for coexisting CV risk of death after adjustment for coexisting CV conditionsconditions

Wolf PA, et al. Wolf PA, et al. StrokeStroke 1991; 22: 983-988 1991; 22: 983-988 Benjamin EB, et al. Benjamin EB, et al. CirculationCirculation 1998;98:946-952. 1998;98:946-952. American Heart Association. American Heart Association. Heart Disease and Stroke Statistics-2006 UpdateHeart Disease and Stroke Statistics-2006 Update . . Dallas, TX: American Heart Association;2006. ©2006 American Heart Dallas, TX: American Heart Association;2006. ©2006 American Heart AssociationAssociation

Global Impact of StrokeGlobal Impact of Stroke

► 33rdrd most common cause of death in developed most common cause of death in developed countriescountries ● 15 million strokes occur each year worldwide15 million strokes occur each year worldwide● 5.5 million deaths from stroke5.5 million deaths from stroke

► Stroke is a leading cause of serious, long-term Stroke is a leading cause of serious, long-term disabilitydisability ● 5 million people permanently disabled each year5 million people permanently disabled each year● Disability-adjusted life years projected to reach 61 million Disability-adjusted life years projected to reach 61 million

years per 1000 population by the year 2020 (38 million in years per 1000 population by the year 2020 (38 million in 19901990))

► 33rdrd most common cause of death in developed most common cause of death in developed countriescountries ● 15 million strokes occur each year worldwide15 million strokes occur each year worldwide● 5.5 million deaths from stroke5.5 million deaths from stroke

► Stroke is a leading cause of serious, long-term Stroke is a leading cause of serious, long-term disabilitydisability ● 5 million people permanently disabled each year5 million people permanently disabled each year● Disability-adjusted life years projected to reach 61 million Disability-adjusted life years projected to reach 61 million

years per 1000 population by the year 2020 (38 million in years per 1000 population by the year 2020 (38 million in 19901990))

World Health Organization. The Atlas of Heart Disease and Stroke 2004. World Health Organization. The Atlas of Heart Disease and Stroke 2004. American Heart Association. American Heart Association. Heart Disease and Stroke Statistics-2006 UpdateHeart Disease and Stroke Statistics-2006 Update . Dallas, TX: American Heart Association;2006. . Dallas, TX: American Heart Association;2006. ©2006 American Heart Association©2006 American Heart Association

Efficacy of Warfarin in Atrial FibrillationEfficacy of Warfarin in Atrial Fibrillation

Five Randomized Trials in Non-Valvular AFFive Randomized Trials in Non-Valvular AF

*Stopped early due to published positive results

68% overall risk reduction for stroke68% overall risk reduction for stroke

Study Study ValueValue

WarfarinWarfarin(Number Pts.)(Number Pts.)

Control Control (Number Pts.)(Number Pts.)

INRINR RRRR p-Valuep-Value

AFASAKAFASAK 335335 336336 2.8-4.22.8-4.2 60%60% 0.0270.027

SPAFSPAF 210210 211211 2.0-4.52.0-4.5 67%67% 0.010.01

BAATAFBAATAF 212212 208208 1.5-2.71.5-2.7 86%86% <0.05<0.05

CAFA*CAFA* 187187 191191 2.0-3.02.0-3.0 45%45% 0.250.25

SPINAFSPINAF 260260 265265 1.4-2.81.4-2.8 79%79% 0.0010.001

Underutilization of Anticoagulation Therapy in Underutilization of Anticoagulation Therapy in AF (Jan 2002 - Dec 2002)AF (Jan 2002 - Dec 2002)

Waldo et al. JACC 2005;46(9):1729-1736 Waldo et al. JACC 2005;46(9):1729-1736 Waldo et al. JACC 2005;46(9):1729-1736 Waldo et al. JACC 2005;46(9):1729-1736

Approximately half of high-risk patients with Approximately half of high-risk patients with atrial fibrillation receive warfarin therapy atrial fibrillation receive warfarin therapy

Approximately half of high-risk patients with Approximately half of high-risk patients with atrial fibrillation receive warfarin therapy atrial fibrillation receive warfarin therapy

53%53% 53%53%47%47% 47%47%

13 Community Hospitals13 Community Hospitals 21 Academic 21 Academic HospitalsHospitals

Warfarin TherapyWarfarin TherapyWarfarin TherapyWarfarin Therapy

No Warfarin TherapyNo Warfarin TherapyNo Warfarin TherapyNo Warfarin Therapy

Approximately half of high-risk patients with Approximately half of high-risk patients with atrial fibrillation receive warfarin therapyatrial fibrillation receive warfarin therapy

Approximately half of high-risk patients with Approximately half of high-risk patients with atrial fibrillation receive warfarin therapyatrial fibrillation receive warfarin therapy

13 Community Hospitals 21 Academic Hospitals

Age >80 and perceived bleeding risk were Age >80 and perceived bleeding risk were negative predictors of warfarin use.negative predictors of warfarin use.

Age >80 and perceived bleeding risk were Age >80 and perceived bleeding risk were negative predictors of warfarin use.negative predictors of warfarin use.

Underutilization of Anticoagulation Therapy in Underutilization of Anticoagulation Therapy in Atrial Fibrillation (Jan 2002 - Dec 2002)Atrial Fibrillation (Jan 2002 - Dec 2002)

53%53% 53%53%47%47% 47%47%

13 Community Hospitals13 Community Hospitals 21 Academic 21 Academic HospitalsHospitals

Warfarin TherapyWarfarin TherapyWarfarin TherapyWarfarin Therapy

No Warfarin TherapyNo Warfarin TherapyNo Warfarin TherapyNo Warfarin Therapy

Warfarin Use Among Ohio Medicaid PatientsWarfarin Use Among Ohio Medicaid Patients

Retrospective analysis using claims data 1998-2000Retrospective analysis using claims data 1998-2000

Only Only 11.911.9%% of patients without of patients without contraindications contraindications

filled prescriptions for warfarin filled prescriptions for warfarin

Most prevalent potential contraindications:Most prevalent potential contraindications:

* Barriers to compliance-30% * Barriers to compliance-30% * Predisposition to falls-24%* Predisposition to falls-24%

* Prior Bleed-13* Prior Bleed-13%%

Retrospective analysis using claims data 1998-2000Retrospective analysis using claims data 1998-2000

Only Only 11.911.9%% of patients without of patients without contraindications contraindications

filled prescriptions for warfarin filled prescriptions for warfarin

Most prevalent potential contraindications:Most prevalent potential contraindications:

* Barriers to compliance-30% * Barriers to compliance-30% * Predisposition to falls-24%* Predisposition to falls-24%

* Prior Bleed-13* Prior Bleed-13%%

Johnston JA, et al. Arch Intern Med 2003;163:1705-1710.

(n=11,699)(n=11,699)

Effectiveness of Warfarin Among Effectiveness of Warfarin Among Different Patient Populations: Different Patient Populations:

FeaturesFeatures WhiteWhiteN=16,007N=16,007

BlackBlackN=797N=797

HispanicHispanicN=468N=468

CHADSCHADS22 Score, mean (SD) Score, mean (SD) 2.6 (1.4)2.6 (1.4) 3.1 (1.4)3.1 (1.4) 2.9 (1.3)2.9 (1.3)

Warfarin at discharge (%)Warfarin at discharge (%) 49.749.7 43.243.2 40.240.2

Monitored < 90 days (%)Monitored < 90 days (%) 7.97.9 17.917.9 13.613.6

Lost to Monitoring (%)Lost to Monitoring (%) 9.79.7 21.321.3 16.716.7

Stroke Rate per 100 yrStroke Rate per 100 yr(95% CI)(95% CI)

5.2 5.2 (4.6-5.8)(4.6-5.8)

12.2 12.2 (8.0-18.5)(8.0-18.5)

10.6 10.6 (6.0-18.7)(6.0-18.7)

Birman-Deych et al; Stroke. 2006;37:1070-1074

A State-Stratified Random Sample of Medicare BeneficiariesA State-Stratified Random Sample of Medicare Beneficiaries Jan 1998 – Dec 1999Jan 1998 – Dec 1999

Major Hemorrhage RatesMajor Hemorrhage Rates

Randomized TrialsRandomized Trials INR TargetINR Target ICHICH MajorMajor AgeAge

AFIAFI 1.5-4.51.5-4.5 0.30.3 1.01.0 6969

SPAF IISPAF II 2.0-4.52.0-4.5 0.90.9 1.41.4 7070

AFFIRMAFFIRM 2.0-3.02.0-3.0 -------- 2.02.0 7.07.0

ObservationalObservational INR TargetINR Target ICHICH MajorMajor AgeAge

Van der Meer,et al (1993)Van der Meer,et al (1993) 2.8-4.82.8-4.8 0.60.6 2.02.0 6666

Palareti, et al (1996)Palareti, et al (1996) 2.0-4.52.0-4.5 0.50.5 0.90.9 6262

Go, et alGo, et al 2.0-3.02.0-3.0 0.50.5 1.01.0 7171

Caveats Relating to Published Caveats Relating to Published Data on HemorrhageData on Hemorrhage

Randomized trialsRandomized trials- Enrolled few patients - Enrolled few patients ≥≥ 80 years 80 years- Highly selected, closely monitored- Highly selected, closely monitored- Vitamin K antagonist at entry- Vitamin K antagonist at entry

Prospective cohort studiesProspective cohort studies- Predominantly non-inception cohort studies of - Predominantly non-inception cohort studies of

prevalent warfarin use (survivor bias)prevalent warfarin use (survivor bias)- Enrolled few patients - Enrolled few patients ≥≥ 80 years 80 years- Varying definitions of bleeding- Varying definitions of bleeding- Most conducted within anticoagulation clinic - Most conducted within anticoagulation clinic

settingsetting

Randomized trialsRandomized trials- Enrolled few patients - Enrolled few patients ≥≥ 80 years 80 years- Highly selected, closely monitored- Highly selected, closely monitored- Vitamin K antagonist at entry- Vitamin K antagonist at entry

Prospective cohort studiesProspective cohort studies- Predominantly non-inception cohort studies of - Predominantly non-inception cohort studies of

prevalent warfarin use (survivor bias)prevalent warfarin use (survivor bias)- Enrolled few patients - Enrolled few patients ≥≥ 80 years 80 years- Varying definitions of bleeding- Varying definitions of bleeding- Most conducted within anticoagulation clinic - Most conducted within anticoagulation clinic

settingsetting

Cumulative Incidence of Major Bleeding in the First Cumulative Incidence of Major Bleeding in the First Year Among Patients Newly Starting Warfarin by AgeYear Among Patients Newly Starting Warfarin by Age

Hylek EM et al, Circulation 2007;115(21):2689-2696.

00 100 100 200 200 300300 400400

Days on WarfarinDays on Warfarin

Age < 80 Age Age < 80 Age >> 80 80

Cum

ulat

ive

Pro

port

ion

with

Maj

or H

emor

rhag

eC

umul

ativ

e P

ropo

rtio

n w

ith M

ajor

Hem

orrh

age

0.00

0.0

2

0.0

4

0.0

6

0.08

0

.10

0.00

0.0

2

0.0

4

0.0

6

0.08

0

.10

Risk of Stopping Therapy in the First Year Among Risk of Stopping Therapy in the First Year Among Patients Newly Starting Warfarin by AgePatients Newly Starting Warfarin by Age


00 100 100 200 200 300300 400400Days on WarfarinDays on Warfarin

Age < 80 Age Age < 80 Age >> 80 80

Ris

k of

Sto

ppin

g W

arfa

rinR

isk

of S

topp

ing

War

farin

0

.00

05

.

001

.001

5

.0

020

.

0005

.00

1

.0

015

.002

CHADSCHADS22

ScoreScoreNN

Major Major Bleed Bleed

(N)(N)

Bleeding Bleeding RatesRates

%%

Taken Off Taken Off Therapy (N)Therapy (N)

Taken Off Taken Off RatesRates

%%

00 4242 11 3.173.17 55 15.8415.84

11 121121 44 4.354.35 1616 17.3917.39

22 181181 33 2.082.08 1919 13.1613.16

33 9494 1212 19.719.7 2020 32.8432.84

≥≥44 3434 66 23.6323.63 99 35.4435.44

TotalTotal 472472 2626 6969

Major Hemorrhagic Events and Warfarin Major Hemorrhagic Events and Warfarin Terminations by CHADSTerminations by CHADS22 Score Score


Challenges to Use of Challenges to Use of Vitamin K AntagonistsVitamin K AntagonistsChallenges to Use of Challenges to Use of Vitamin K AntagonistsVitamin K Antagonists

Challenges to Managing AFChallenges to Managing AF

• Drug interferenceDrug interference • Amiodarone (inhibits R- and S-);Amiodarone (inhibits R- and S-);• Acetaminophen (enzymes vitamin K cycle)Acetaminophen (enzymes vitamin K cycle)

• Dietary vitamin KDietary vitamin K• Genetic polymorphisms:Genetic polymorphisms:

• Cytochrome P450 CYP2C9 and VKORC1 Cytochrome P450 CYP2C9 and VKORC1 (vitamin K epoxide reductase complex 1)(vitamin K epoxide reductase complex 1)

• Disease States, e.g., CHF, malignancyDisease States, e.g., CHF, malignancy• Pharmacodynamic changes with agingPharmacodynamic changes with aging

• Drug interferenceDrug interference • Amiodarone (inhibits R- and S-);Amiodarone (inhibits R- and S-);• Acetaminophen (enzymes vitamin K cycle)Acetaminophen (enzymes vitamin K cycle)

• Dietary vitamin KDietary vitamin K• Genetic polymorphisms:Genetic polymorphisms:

• Cytochrome P450 CYP2C9 and VKORC1 Cytochrome P450 CYP2C9 and VKORC1 (vitamin K epoxide reductase complex 1)(vitamin K epoxide reductase complex 1)

• Disease States, e.g., CHF, malignancyDisease States, e.g., CHF, malignancy• Pharmacodynamic changes with agingPharmacodynamic changes with aging

Variable Dose ResponseVariable Dose Response

2025

3035

4045

50W

arfa

rin

Wee

kly

Dos

e, m

g

<50 50-59 60-69 70-79 80-89 >=90Age

Female Male

2025

3035

4045

50W

arfa

rin

Wee

kly

Dos

e, m

g<50 50-59 60-69 70-79 80-89 >=90

Age

Female Male

Maintenance warfarin dose by age Maintenance warfarin dose by age INR target 2-3INR target 2-3

Derived from two independent ambulatory populationsDerived from two independent ambulatory populations

Garcia D, et al. Chest 2005 2005;127:2049-2056Garcia D, et al. Chest 2005 2005;127:2049-2056

Challenges of Warfarin Use Challenges of Warfarin Use

► Variable dose responseVariable dose response

► Narrow therapeutic windowNarrow therapeutic window

► Need for frequent monitoringNeed for frequent monitoring

► Long half-lifeLong half-life





Hylek EM, Singer DE. Ann Int Med 1994;120:897-902.Hylek EM, et al. N Engl J Med 1996;335:540-546.

PTR above 2.0 (INR of 3.7 to 4.3) PTR above 2.0 (INR of 3.7 to 4.3) increases the risk of bleedingincreases the risk of bleeding

1.61.61.41.400 1.81.8 22 2.32.3 2.72.7

Prothrombin Time RatioProthrombin Time Ratio

00

22

44

66

88

1010

18.218.211.211.2

Odd

s R

atio

for

ICH

Odd

s R

atio

for

ICH

Optimal Intensity for Warfarin Therapy Optimal Intensity for Warfarin Therapy InIn Atrial FibrillationAtrial Fibrillation

INRINR Odds RatioOdds Ratio

2.02.0 1.01.0

1.71.7 2.02.0

1.51.5 3.33.3

1.31.3 6.06.0

1.01.0 1.51.5 3.03.0 4.04.0 7.07.0

11

33

55

1010

1515

INRINR

2.02.0O

dds

Rat

io fo

r S

trok

eO

dds

Rat

io fo

r S

trok

e

Odds Ratio of stroke by INROdds Ratio of stroke by INR

Fuster, V. et al. Circulation 2006;114:700-752

Adjusted Odds Ratios for Ischemic Stroke and Intracranial Adjusted Odds Ratios for Ischemic Stroke and Intracranial Bleeding in Relation to Intensity of AnticoagulationBleeding in Relation to Intensity of Anticoagulation

Hylek, et al. NEJM. 2003. Days Since AdmissionDays Since Admission

Sur

viva

l Pro

bab

ility

Sur

viva

l Pro

bab

ility

0.6

0.6

0.7

0.7

0.8

0.8

0.9

0.9

1.0

1.0

00 55 1010 1515 2020 2525 3030

NoneAspirinWarfarin, INR< 2Warfarin, INR>=2

p = 0.002p = 0.002










Hylek, EM (unpublished data)

Patient with Low INR VariabilityPatient with Low INR Variability

Hylek, EM (unpublished data)Hylek, EM (unpublished data)

Patient with High INR VariabilityPatient with High INR Variability










Hylek et al, Ann Intern Med. 2001;135:393-400Hylek et al, Ann Intern Med. 2001;135:393-400

0.000.00 0.250.25 0.500.50 0.750.75 1.001.00 1.251.25 1.501.50 1.751.75 2.002.00

Interval (days)Interval (days)

11

22

33

44

66

1010

INR

INR

1b1b

Index INR 7 - 9 (n = 235)Index INR 7 - 9 (n = 235)Median INR half life = 2.3 daysMedian INR half life = 2.3 daysInterquartile Range = (1.7,3.8)Interquartile Range = (1.7,3.8)

Median days to INR < 4: 1.5 daysMedian days to INR < 4: 1.5 daysInterquartile Range = (1.1,2.5)Interquartile Range = (1.1,2.5)

Risk factors for INR Risk factors for INR 4.0 After Holding Two 4.0 After Holding Two Doses of WarfarinDoses of Warfarin

• Warfarin dose, weekly per 10 mg Warfarin dose, weekly per 10 mg 0.87 (0.79-0.97) 0.87 (0.79-0.97)

• Age, per decadeAge, per decade 1.18 (1.01- 1.18 (1.01-1.38)1.38)

• Decompensated heart failureDecompensated heart failure 2.79 (1.30- 2.79 (1.30-5.98)5.98)

• Active malignancyActive malignancy 2.48 (1.11- 2.48 (1.11-5.57)5.57)

• Index INR, per unitIndex INR, per unit 1.25 (1.14-1.37) 1.25 (1.14-1.37)

Adjusted Odds RatioAdjusted Odds Ratio

Strategies to Optimize BenefitStrategies to Optimize Benefit

► Improve anticoagulation controlImprove anticoagulation control

► ? Lower target intensity-NO? Lower target intensity-NO

► ? Use antiplatelet therapy-NO ? Use antiplatelet therapy-NO

► Aggressive control of blood pressureAggressive control of blood pressure

► Improve risk stratificationImprove risk stratification

► New antithrombotic therapies (Factor Xa Inhibitors?)New antithrombotic therapies (Factor Xa Inhibitors?)

► ? Cure AF? Cure AF

► Improve anticoagulation controlImprove anticoagulation control

► ? Lower target intensity-NO? Lower target intensity-NO

► ? Use antiplatelet therapy-NO ? Use antiplatelet therapy-NO

► Aggressive control of blood pressureAggressive control of blood pressure

► Improve risk stratificationImprove risk stratification

► New antithrombotic therapies (Factor Xa Inhibitors?)New antithrombotic therapies (Factor Xa Inhibitors?)

► ? Cure AF? Cure AF

SummarySummary

► Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage.

► 30-day mortality of AF-related stroke is approximately 24%.

► Rates of ischemic stroke significantly exceed rates of ICH on OAC.

► Intensive efforts to optimize OAC in this age group will help to minimize major bleeding.

► There is a pressing clinical need for alternatives to warfarin.

► Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage.

► 30-day mortality of AF-related stroke is approximately 24%.

► Rates of ischemic stroke significantly exceed rates of ICH on OAC.

► Intensive efforts to optimize OAC in this age group will help to minimize major bleeding.

► There is a pressing clinical need for alternatives to warfarin.

Prophylaxis Of VTEProphylaxis Of VTE

Current Strategies and Emerging Role of Xa Current Strategies and Emerging Role of Xa Inhibition for DVT Prevention and TreatmentInhibition for DVT Prevention and Treatment

Prophylaxis Of VTEProphylaxis Of VTE

Current Strategies and Emerging Role of Xa Current Strategies and Emerging Role of Xa Inhibition for DVT Prevention and TreatmentInhibition for DVT Prevention and Treatment








EPIDEMIOLOGYEPIDEMIOLOGYScope of the ProblemScope of the Problem

EPIDEMIOLOGYEPIDEMIOLOGYScope of the ProblemScope of the Problem

Prophylaxis of VTEProphylaxis of VTE

Annual At-Risk Population for VTE Annual At-Risk Population for VTE

► 7.7 million Medical Service inpatients7.7 million Medical Service inpatients

► 3.4 million Surgical Service inpatients 3.4 million Surgical Service inpatients

► Based upon ACCP guidelines for VTE Based upon ACCP guidelines for VTE prophylaxisprophylaxis

► 7.7 million Medical Service inpatients7.7 million Medical Service inpatients

► 3.4 million Surgical Service inpatients 3.4 million Surgical Service inpatients

► Based upon ACCP guidelines for VTE Based upon ACCP guidelines for VTE prophylaxisprophylaxis

Anderson FA Jr, et al. Am J Hematol; 2007; 82: 777-782Anderson FA Jr, et al. Am J Hematol; 2007; 82: 777-782

U.S. HospitalsU.S. Hospitals

ENDORSE — A Worldwide StudyENDORSE — A Worldwide Study

68,183 patients; 32 countries; 358 sites68,183 patients; 32 countries; 358 sitesFirst patient enrolled August 2, 2006;Last patient enrolled January 4, 2007First patient enrolled August 2, 2006;Last patient enrolled January 4, 2007

LancetLancet 2008; 371: 387-394 2008; 371: 387-394

Worldwide Prophylaxis Status Worldwide Prophylaxis Status for 68,183 Patientsfor 68,183 Patients

52% at risk for VTE52% at risk for VTE

(50% (50% received ACCPreceived ACCPrecommended prophylaxis)recommended prophylaxis)

SurgicalSurgical64% at risk for VTE64% at risk for VTE

59% received ACCP59% received ACCPrecommended prophylaxisrecommended prophylaxis

MedicalMedical42% at risk for VTE42% at risk for VTE

40% received ACCP40% received ACCPrecommended prophylaxisrecommended prophylaxis

Outpatient and Inpatient VTE are LinkedOutpatient and Inpatient VTE are Linked

► 74% of VTEs present in outpatients.74% of VTEs present in outpatients.

► 42% of outpatient VTE patients have had 42% of outpatient VTE patients have had recent surgery or hospitalization. recent surgery or hospitalization.

► Only 40% had received VTE prophylaxis.Only 40% had received VTE prophylaxis.

► 74% of VTEs present in outpatients.74% of VTEs present in outpatients.

► 42% of outpatient VTE patients have had 42% of outpatient VTE patients have had recent surgery or hospitalization. recent surgery or hospitalization.

► Only 40% had received VTE prophylaxis.Only 40% had received VTE prophylaxis.

Spencer FA, et al. Arch Intern Med 2007; 167: 1471-1475Spencer FA, et al. Arch Intern Med 2007; 167: 1471-1475

Problems with Warfarin in theProblems with Warfarin in theSetting of VTE ProphylaxisSetting of VTE Prophylaxis

Challenges of Long-Term VTE Prophylaxis

The Delicate and Problematic Balance The Delicate and Problematic Balance Between Thrombosis Prevention and Between Thrombosis Prevention and

Hemorrhage AvoidanceHemorrhage Avoidance

Elevated INRElevated INR is a surrogate for increased risk is a surrogate for increased risk of intracranial hemorrhage and other major of intracranial hemorrhage and other major bleeding complications. bleeding complications.

Subtherapeutic INRSubtherapeutic INR is a surrogate for is a surrogate for thrombotic complications.thrombotic complications.

The Delicate and Problematic Balance The Delicate and Problematic Balance Between Thrombosis Prevention and Between Thrombosis Prevention and

Hemorrhage AvoidanceHemorrhage Avoidance

Elevated INRElevated INR is a surrogate for increased risk is a surrogate for increased risk of intracranial hemorrhage and other major of intracranial hemorrhage and other major bleeding complications. bleeding complications.

Subtherapeutic INRSubtherapeutic INR is a surrogate for is a surrogate for thrombotic complications.thrombotic complications.

Challenges of Long-Term VTE Prophylaxis

Therapeutic Range for WarfarinTherapeutic Range for WarfarinINR Values at Stroke or ICHINR Values at Stroke or ICH

Odd

s R

atio

Odd

s R

atio

005.05.0 6.06.0 8.08.0

INRINR1.01.0 2.02.0 3.03.0 4.04.0 7.07.0

5.05.0

15.015.0

10.010.0

StrokeStroke

1.01.0

Fuster et al. Fuster et al. J Am Coll CardiolJ Am Coll Cardiol. 2001;38:1231-1266.. 2001;38:1231-1266.

Intracranial Intracranial HemorrhageHemorrhage

Hylek, EM Hylek, EM et alet al. . N Engl J MedN Engl J Med. 2003;349:1019-26. 2003;349:1019-26

Warfarin in Nonvalvular Atrial Fibrillation

Risk Factors for an Elevated INRRisk Factors for an Elevated INR(It’s not all Genetics)(It’s not all Genetics)

► Advanced Age (one-third dose)Advanced Age (one-third dose)► Abnormal Liver FunctionAbnormal Liver Function► Decreased Vitamin K Intake (NPO,Decreased Vitamin K Intake (NPO,

diarrhea, antibiotics)diarrhea, antibiotics)► Concomitant MedicationsConcomitant Medications► Alcohol in BingesAlcohol in Binges► Change in Warfarin PreparationChange in Warfarin Preparation► Drug-drug and drug-food interactionsDrug-drug and drug-food interactions

► Advanced Age (one-third dose)Advanced Age (one-third dose)► Abnormal Liver FunctionAbnormal Liver Function► Decreased Vitamin K Intake (NPO,Decreased Vitamin K Intake (NPO,

diarrhea, antibiotics)diarrhea, antibiotics)► Concomitant MedicationsConcomitant Medications► Alcohol in BingesAlcohol in Binges► Change in Warfarin PreparationChange in Warfarin Preparation► Drug-drug and drug-food interactionsDrug-drug and drug-food interactions

FDA Adds “Black Box” Warning/Precaution FDA Adds “Black Box” Warning/Precaution for Warfarin Therapyfor Warfarin Therapy

October 6, 2006October 6, 2006

WARNING: BLEEDING RISKWARNING: BLEEDING RISK

August 16, 2007August 16, 2007

Precaution:Precaution: “Consider a lower initial “Consider a lower initial warfarin dose for patients with certain warfarin dose for patients with certain genetic variations.”genetic variations.”

FDA “Black Box” WarningFDA “Black Box” Warning

“Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR)…”

“Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR)…”

ED Visits for Adverse Drug EventsED Visits for Adverse Drug Events

► Estimated 701,547 ADEs per year.

► 17% require hospitalization.

► Insulin (8%) or warfarin (6%): implicated in 14% of ADEs treated in ED.

► Patients > 65 years were more than twice as susceptible.

► Estimated 701,547 ADEs per year.

► 17% require hospitalization.

► Insulin (8%) or warfarin (6%): implicated in 14% of ADEs treated in ED.

► Patients > 65 years were more than twice as susceptible.

JAMA 2006; 296: 1858-1866JAMA 2006; 296: 1858-1866

First Month Warfarin Has High Bleeding RateFirst Month Warfarin Has High Bleeding Rate

Bleeding TypeBleeding Type Head BleedHead Bleed Major Non-Head Major Non-Head BleedBleed

11stst Month Warfarin Month Warfarin 0.92% (annualized) 0.92% (annualized) 1.2% (annualized)1.2% (annualized)

Subsequent Subsequent WarfarinWarfarin 0.46% per year0.46% per year 0.61% per year0.61% per year

Fang MC. J Am Geriatr Soc 2006; 54: 1231-1236

Novel AnticoagulantsNovel Anticoagulants

What Do Published Trials and Clinical Trial What Do Published Trials and Clinical Trial Programs Tell Us?Programs Tell Us?

Solutions and Emerging StrategiesSolutions and Emerging Strategies

Properties of an Ideal AnticoagulantProperties of an Ideal Anticoagulant

PropertiesProperties BenefitsBenefits

Orally activeOrally active Ease of administrationEase of administration

Rapid onset of actionRapid onset of action Obviates need for overlap with a Obviates need for overlap with a parenteral anticoagulantparenteral anticoagulant

No food or drug interactionsNo food or drug interactions Simplified dosingSimplified dosing

Predictable anticoagulant effectPredictable anticoagulant effect No routine coagulation monitoringNo routine coagulation monitoring

Extra-renal clearanceExtra-renal clearance Safe in patients with renal Safe in patients with renal insufficiencyinsufficiency

Rapid offset of actionRapid offset of action Simplifies management in case of Simplifies management in case of bleed or need for interventionbleed or need for intervention

Safe antidoteSafe antidote Useful in case of major bleedUseful in case of major bleed

Favorable net clinical benefitFavorable net clinical benefit Treatment benefit outweighs riskTreatment benefit outweighs risk

New Oral Anticoagulants: AdvantagesNew Oral Anticoagulants: Advantages

1.1. No coagulation lab monitoringNo coagulation lab monitoring

2.2. No dose adjustmentNo dose adjustment

3.3. No drug-food interactionsNo drug-food interactions

4.4. Rare drug-drug interactionsRare drug-drug interactions

5.5. No “bridging” needed prior to invasive No “bridging” needed prior to invasive procedures or surgeryprocedures or surgery

1.1. No coagulation lab monitoringNo coagulation lab monitoring

2.2. No dose adjustmentNo dose adjustment

3.3. No drug-food interactionsNo drug-food interactions

4.4. Rare drug-drug interactionsRare drug-drug interactions

5.5. No “bridging” needed prior to invasive No “bridging” needed prior to invasive procedures or surgeryprocedures or surgery

Targets of New Oral Anticoagulants in the Targets of New Oral Anticoagulants in the Most Advances Stages of Development Most Advances Stages of Development

Bates SM and Weitz JI. Drugs of the Future 2008, 33Bates SM and Weitz JI. Drugs of the Future 2008, 33Bates SM and Weitz JI. Drugs of the Future 2008, 33Bates SM and Weitz JI. Drugs of the Future 2008, 33

TF/VIIaTF/VIIaTF/VIIaTF/VIIa

XXXX IXIXIXIX

IXaIXaIXaIXa

VIIIaVIIIaVIIIaVIIIa

VaVaVaVa

XaXaXaXa

IIIIIIII IIaIIaIIaIIa

FibrinogenFibrinogenFibrinogenFibrinogen FibrinFibrinFibrinFibrin

RivaroxabanRivaroxabanApixabanApixaban

RivaroxabanRivaroxabanApixabanApixaban

DabigatranDabigatran DabigatranDabigatran

Comparison of Novel Oral Comparison of Novel Oral Anticoagulants with WarfarinAnticoagulants with Warfarin

Eikelboom JW, Weitz JI. Eikelboom JW, Weitz JI. CirculationCirculation 2007; 2007; 116: 131-133 116: 131-133

*Includes ketoconazole, macrolides (eg, clarithromycin), and protease inhibitors (eg, *Includes ketoconazole, macrolides (eg, clarithromycin), and protease inhibitors (eg, atazanavir)atazanavir)

*Includes ketoconazole, macrolides (eg, clarithromycin), and protease inhibitors (eg, *Includes ketoconazole, macrolides (eg, clarithromycin), and protease inhibitors (eg, atazanavir)atazanavir)

DrugDrug TargetTarget DosingDosing Coag Coag monitoring monitoring

Half Half life (h)life (h)

Renal Renal cleared cleared

(%)(%)Interacts Interacts

Rivaroxa-Rivaroxa-banban Factor XaFactor Xa

Fixed, Fixed, once once dailydaily

NoNo 99 6565Potent Potent

CYP3A4 CYP3A4 inhibitors*inhibitors*

ApixabanApixaban Factor XaFactor XaFixed, Fixed, twice twice dailydaily

NoNo 9–149–14 2525Potent Potent

CYP3A4 CYP3A4 inhibitors*inhibitors*

DabigatranDabigatran Factor IIa Factor IIa (thrombin)(thrombin)

Fixed, Fixed, twice twice dailydaily

No No 14–1714–17 100100 Proton pump Proton pump inhibitorsinhibitors

WarfarinWarfarin Vitamin K Vitamin K Variable, Variable,

once once dailydaily

YesYes 4040 00

Multiple Multiple drugs, drugs, dietary dietary

vitamin Kvitamin K

Features of ApixabanFeatures of Apixaban

► Oral, direct, highly selective Factor Xa inhibitorOral, direct, highly selective Factor Xa inhibitor


► No reactive intermediatesNo reactive intermediates

► No LFT abnormalities in chronic toxicology No LFT abnormalities in chronic toxicology studiesstudies

► Low likelihood of drug interactionsLow likelihood of drug interactions


► No food effectNo food effect

► Balanced elimination (Balanced elimination (~~25% renal)25% renal)


► Oral, direct, highly selective Factor Xa inhibitorOral, direct, highly selective Factor Xa inhibitor


► No reactive intermediatesNo reactive intermediates

► No LFT abnormalities in chronic toxicology No LFT abnormalities in chronic toxicology studiesstudies

► Low likelihood of drug interactionsLow likelihood of drug interactions


► No food effectNo food effect

► Balanced elimination (Balanced elimination (~~25% renal)25% renal)


He et al, ASH, 2006, Lassen, et al ASH, 2006He et al, ASH, 2006, Lassen, et al ASH, 2006

Comparison of the Antithrombotic Effects of Warfarin or Apixaban in a Rabbit DVT ModelComparison of the Antithrombotic Effects of Warfarin or Apixaban in a Rabbit DVT Model

Wong et al, ASH, 2006Wong et al, ASH, 2006

WarfarinWarfarin* P< 0.05 vs. vehicle* P< 0.05 vs. vehicle

WarfarinWarfarin* P< 0.05 vs. vehicle* P< 0.05 vs. vehicle

ApixabanApixabanApixabanApixaban

Warfarin (mg/kg PO)Warfarin (mg/kg PO)Warfarin (mg/kg PO)Warfarin (mg/kg PO) Apixaban (mg/kg/h IV)Apixaban (mg/kg/h IV)Apixaban (mg/kg/h IV)Apixaban (mg/kg/h IV)

**-33%-33%

**-33%-33%

**-51%-51%

**-51%-51%

**-74%-74%

**-74%-74% **

-384-384**

-384-384

**-16%-16%

**-16%-16%

**-55%-55%

**-55%-55%

**-73%-73%

**-73%-73% **

-83%-83%**

-83%-83%

0

1020

3040

50

6070

80

Vehicl

e0.

10.

3 1 3

Vehicl

e0.

03 0.1

0.3 1

Comparison of the Effects of Warfarin or Apixaban on Cuticle Bleeding Time in Rabbits

Comparison of the Effects of Warfarin or Apixaban on Cuticle Bleeding Time in Rabbits

Wong et al, ASH, 2006Wong et al, ASH, 2006

WarfarinWarfarinWarfarinWarfarin ApixabanApixabanApixabanApixaban

Warfarin (mg/kg PO)Warfarin (mg/kg PO)Warfarin (mg/kg PO)Warfarin (mg/kg PO) Apixaban (mg/kg/h IV)Apixaban (mg/kg/h IV)Apixaban (mg/kg/h IV)Apixaban (mg/kg/h IV)

1

2

3

4

5

6

7

0.1 0.3 1 3 Vehicle 1 3

Lassen MR, et al. J Thromb Haemost 2007; 5: 2368–75.Lassen MR, et al. J Thromb Haemost 2007; 5: 2368–75.

Incidence of VTE plus Death for QD and BID Incidence of VTE plus Death for QD and BID Doses of Apixaban and ComparatorsDoses of Apixaban and Comparators

ApixabanApixaban

Inci

denc

e of

VT

E a

nd a

ll ca

uses

dea

th (

%)

Inci

denc

e of

VT

E a

nd a

ll ca

uses

dea

th (

%)

0

5

10

15

20

25

30

35

5 QD 2.5BID

10QD

5 BID 20QD

10BID

Enox Warf

Lassen MR, et al. J Thromb Haemost 2007; 5: 2368–75.Lassen MR, et al. J Thromb Haemost 2007; 5: 2368–75.

Incidence of Bleeding Events for QD and BID Incidence of Bleeding Events for QD and BID Doses of Apixaban and ComparatorsDoses of Apixaban and Comparators

ApixabanApixaban

Inci

denc

e of

ble

edin

g ev

ents

(%

)In

cide

nce

of b

leed

ing

even

ts (

%)

-4

-2

0

2

4

6

8

10

12

14

16

18

5 QD 2.5BID

10 QD 5 BID 20 QD 10BID

Enox Warf

Major Minor

Apixaban Clinical Development ProgramApixaban Clinical Development Program

IndicationIndication StatusStatus

VTE Prevention in Major Orthopedic VTE Prevention in Major Orthopedic SurgerySurgery Phase IIIPhase III

VTE Prevention in Acutely Ill Medical VTE Prevention in Acutely Ill Medical PatientsPatients Phase IIIPhase III

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation Phase IIIPhase III

Acute and Extended VTE TreatmentAcute and Extended VTE Treatment Planning Phase IIIPlanning Phase III

Prevention of Thrombotic Events in Prevention of Thrombotic Events in Patients with Recent ACSPatients with Recent ACS Phase IIPhase II

VTE Prevention in Cancer PatientsVTE Prevention in Cancer Patients Phase IIPhase II

Eriksson B. ASH; December 8-11, 2007; Atlanta, GA. Eriksson B. ASH; December 8-11, 2007; Atlanta, GA.

RECORD-1 RECORD-1 (THR—5 weeks Rx) (N=4,541)(THR—5 weeks Rx) (N=4,541)

OutcomeOutcome Rivaroxaban Rivaroxaban % (n)% (n)

Enoxaparin Enoxaparin % (n) % (n)

Relative Relative risk risk

reduction, reduction, % (95% CI) % (95% CI)

pp

DVT, nonfatal DVT, nonfatal PE, all-cause PE, all-cause

mortalitymortality1.1 (18/1595)1.1 (18/1595) 3.7 (58/1558)3.7 (58/1558) 70 (49–82)70 (49–82) <0.001<0.001

Major VTEMajor VTE 0.2 (4/1686)0.2 (4/1686) 2.0 (33/1678)2.0 (33/1678) 88 (66–96)88 (66–96) <0.001<0.001

Major bleedMajor bleed 0.3 (6/2209)0.3 (6/2209) 0.1 (2/2224)0.1 (2/2224) —— 0.1780.178

Optimizing Implementation ofOptimizing Implementation ofVTE ProphylaxisVTE Prophylaxis

Front Lines of Internal Medicine PracticeFront Lines of Internal Medicine Practice

We have initiated trials with We have initiated trials with electronic alerts to electronic alerts to modify MD modify MD

behaviorbehavior and improve and improve implementationimplementation of VTE of VTE

prophylaxis.prophylaxis.

We have initiated trials with We have initiated trials with electronic alerts to electronic alerts to modify MD modify MD

behaviorbehavior and improve and improve implementationimplementation of VTE of VTE

prophylaxis.prophylaxis.

Front Lines of Internal Medicine PracticeFront Lines of Internal Medicine Practice

Definition Of “High Risk”Definition Of “High Risk”

VTE risk score ≥ 4 points:VTE risk score ≥ 4 points:► CancerCancer 33 (ICD codes)(ICD codes)► Prior VTEPrior VTE 33 (ICD codes)(ICD codes)► HypercoagulabilityHypercoagulability 33 (Leiden, ACLA)(Leiden, ACLA)► Major surgeryMajor surgery 22 (> 60 minutes)(> 60 minutes)► Bed restBed rest 11 (“bed rest” order)(“bed rest” order)► Advanced ageAdvanced age 11 (> 70 years)(> 70 years)► ObesityObesity 11 (BMI > 29 kg/m(BMI > 29 kg/m22))► HRT/OCHRT/OC 11 (order entry)(order entry)

VTE risk score ≥ 4 points:VTE risk score ≥ 4 points:► CancerCancer 33 (ICD codes)(ICD codes)► Prior VTEPrior VTE 33 (ICD codes)(ICD codes)► HypercoagulabilityHypercoagulability 33 (Leiden, ACLA)(Leiden, ACLA)► Major surgeryMajor surgery 22 (> 60 minutes)(> 60 minutes)► Bed restBed rest 11 (“bed rest” order)(“bed rest” order)► Advanced ageAdvanced age 11 (> 70 years)(> 70 years)► ObesityObesity 11 (BMI > 29 kg/m(BMI > 29 kg/m22))► HRT/OCHRT/OC 11 (order entry)(order entry)

Patient RandomizationPatient Randomization

Kucher N, et al. NEJM 2005;352:969-977Kucher N, et al. NEJM 2005;352:969-977

VTE risk score > 4No prophylaxis

N = 2506

VTE risk score > 4No prophylaxis

N = 2506

INTERVENTIONSingle Alert

n = 1255

INTERVENTIONSingle Alert

n = 1255

CONTROL No Computer Alert

n = 1251

CONTROL No Computer Alert

n = 1251

90-Day Primary Endpoint90-Day Primary Endpoint

Kucher N, et al. NEJM 2005;352:969-977Kucher N, et al. NEJM 2005;352:969-977

InterventionInterventionn=1255n=1255

ControlControlN=1251N=1251

Hazard RatioHazard Ratio(95% CI)(95% CI) PP

Total VTETotal VTE 61 (4.9)61 (4.9) 103 (8.2)103 (8.2) 0.590.59 (0.43-0.81) (0.43-0.81) 0.0010.001

Acute PEAcute PE 14 (1.1)14 (1.1) 35 (2.8)35 (2.8) 0.400.40 (0.21-0.74) (0.21-0.74) 0.0040.004

Proximal DVTProximal DVT 10 (0.8)10 (0.8) 23 (1.8)23 (1.8) 0.470.47 (0.20-1.09) (0.20-1.09) 0.080.08

Distal DVTDistal DVT 5 (0.4)5 (0.4) 12 (1.0)12 (1.0) 0.42 (0.15-1.18)0.42 (0.15-1.18) 0.100.10

UE DVTUE DVT 32 (2.5)32 (2.5) 33 (2.6)33 (2.6) 0.97 (0.60-1.58)0.97 (0.60-1.58) 0.900.90

Primary End PointPrimary End Point

Intervention

Control

Number at risk1255 977 900 853

1251 976 893 839

Intervention

Control

Time (days)0 30 60 90

%F

reed

om f

rom

DV

T/

PE

90

92

94

96

98

100

Kucher N, et al. NEJM 2005;352:969-977

eALERT Cohort (N=866)eALERT Cohort (N=866)

► 18% high risk patients were not prophylaxed in 18% high risk patients were not prophylaxed in the NEJM eAlert RCTthe NEJM eAlert RCT

► After “turning off” randomization, 9% high risk After “turning off” randomization, 9% high risk patients were not prophylaxed in the cohort patients were not prophylaxed in the cohort studystudy

► 82% were Medical Service patients82% were Medical Service patients

► Symptomatic VTE at 90 days occurred in 5.1%Symptomatic VTE at 90 days occurred in 5.1%

► 18% high risk patients were not prophylaxed in 18% high risk patients were not prophylaxed in the NEJM eAlert RCTthe NEJM eAlert RCT

► After “turning off” randomization, 9% high risk After “turning off” randomization, 9% high risk patients were not prophylaxed in the cohort patients were not prophylaxed in the cohort studystudy

► 82% were Medical Service patients82% were Medical Service patients

► Symptomatic VTE at 90 days occurred in 5.1%Symptomatic VTE at 90 days occurred in 5.1%

J Thromb Thrombolysis; epub 11/17/2007J Thromb Thrombolysis; epub 11/17/2007

DVT Alert ScreenDVT Alert Screen



ConclusionsConclusions

1.1. VTE causes CVI, pulmonary hypertension, disability, and VTE causes CVI, pulmonary hypertension, disability, and death.death.

2.2. Prophylaxis against PE and DVT is crucial.Prophylaxis against PE and DVT is crucial.

3.3. Novel drugs promise fixed dosing, no laboratory coagulation Novel drugs promise fixed dosing, no laboratory coagulation monitoring, minimal drug-drug and drug-food interactionsmonitoring, minimal drug-drug and drug-food interactions

4.4. Factors Xa inhibition is emerging as an effective and safe Factors Xa inhibition is emerging as an effective and safe anticoagulation strategy.anticoagulation strategy.

5.5. Alerting MDs that their patients are at high risk for VTE may Alerting MDs that their patients are at high risk for VTE may modify behavior, decrease symptomatic PE and DVT rate.modify behavior, decrease symptomatic PE and DVT rate.

1.1. VTE causes CVI, pulmonary hypertension, disability, and VTE causes CVI, pulmonary hypertension, disability, and death.death.

2.2. Prophylaxis against PE and DVT is crucial.Prophylaxis against PE and DVT is crucial.

3.3. Novel drugs promise fixed dosing, no laboratory coagulation Novel drugs promise fixed dosing, no laboratory coagulation monitoring, minimal drug-drug and drug-food interactionsmonitoring, minimal drug-drug and drug-food interactions

4.4. Factors Xa inhibition is emerging as an effective and safe Factors Xa inhibition is emerging as an effective and safe anticoagulation strategy.anticoagulation strategy.

5.5. Alerting MDs that their patients are at high risk for VTE may Alerting MDs that their patients are at high risk for VTE may modify behavior, decrease symptomatic PE and DVT rate.modify behavior, decrease symptomatic PE and DVT rate.

The Challenge of Optimizing The Challenge of Optimizing Anticoagulation Management in the Setting Anticoagulation Management in the Setting

of Venous Thrombosis and of Venous Thrombosis and Cardiovascular Disease Cardiovascular Disease

The Internist’s PerspectiveThe Internist’s Perspective

The Challenge of Optimizing The Challenge of Optimizing Anticoagulation Management in the Setting Anticoagulation Management in the Setting

of Venous Thrombosis and of Venous Thrombosis and Cardiovascular Disease Cardiovascular Disease

The Internist’s PerspectiveThe Internist’s Perspective

Geno J Merli, MD, FACPGeno J Merli, MD, FACPProfessor of MedicineProfessor of Medicine

Director: Jefferson Center for Vascular DiseasesDirector: Jefferson Center for Vascular Diseases

Senior Vice President and Chief Medical Officer Senior Vice President and Chief Medical Officer

Jefferson Medical CollegeJefferson Medical College

Jefferson University HospitalsJefferson University Hospitals

Geno J Merli, MD, FACPGeno J Merli, MD, FACPProfessor of MedicineProfessor of Medicine

Director: Jefferson Center for Vascular DiseasesDirector: Jefferson Center for Vascular Diseases

Senior Vice President and Chief Medical Officer Senior Vice President and Chief Medical Officer

Jefferson Medical CollegeJefferson Medical College

Jefferson University HospitalsJefferson University Hospitals

Science and Medicine of Thrombosis Management

Deep Vein ThrombosisDeep Vein Thrombosis

Pulmonary EmbolismPulmonary Embolism

Venous ThromboembolismVenous Thromboembolism

IV IV UFHUFH

SC SC UFHUFH

SC SC UFHUFH

1.1. Etiology of VTEEtiology of VTE2.2. Duration of Warfarin TherapyDuration of Warfarin Therapy3.3. Maintaining Therapeutic RangeMaintaining Therapeutic Range

5-7 days5-7 days

3-6 months3-6 monthsororIndefiniteIndefinite

VTE Management — OptionsVTE Management — Options

VTEVTE

UFH LMWH

Warfarin

RegimenRegimen OutpatientOutpatientN = 2725 N = 2725

InpatientInpatientN = 2726N = 2726

SC LMWH to warfarinSC LMWH to warfarin 1244 (46%)1244 (46%) 899 (33%)899 (33%)

IV UFH to warfarinIV UFH to warfarin 1071 (39%)1071 (39%) 855 (31%)855 (31%)

UFH monotherapyUFH monotherapy 96 (4%)96 (4%) 230 (8%)230 (8%)

LMWH monotherapyLMWH monotherapy 152 (6%)152 (6%) 364 (13%)364 (13%)

DVT FREE DatabaseDVT FREE Database

Goldhaber S, et al, Am J Card 2004;93:259-262Goldhaber S, et al, Am J Card 2004;93:259-262

Standard and Weight-Based UFHStandard and Weight-Based UFH

Bolus 5000 units thenBolus 5000 units then Infusion 1200 units per hourInfusion 1200 units per hour Target aPTT therapeutic range of Target aPTT therapeutic range of

the hospitalthe hospital Check aPTT in 6 hours and Check aPTT in 6 hours and

adjust upward or downward by adjust upward or downward by 200 units200 units

aPTT should be checked every 6 aPTT should be checked every 6 hours for the first 24 hours thenhours for the first 24 hours then

Daily or more frequently as Daily or more frequently as indicated by the need to achieve indicated by the need to achieve the therapeutic rangethe therapeutic range

Check platelet count on days 3 Check platelet count on days 3 and 5and 5

Initiate warfarin 5 mg on day 1Initiate warfarin 5 mg on day 1 Continue unfractionated heparin Continue unfractionated heparin

until the INR is between 2 and 3 until the INR is between 2 and 3 for 2 consecutive daysfor 2 consecutive days

Bolus 5000 units thenBolus 5000 units then Infusion 1200 units per hourInfusion 1200 units per hour Target aPTT therapeutic range of Target aPTT therapeutic range of

the hospitalthe hospital Check aPTT in 6 hours and Check aPTT in 6 hours and

adjust upward or downward by adjust upward or downward by 200 units200 units

aPTT should be checked every 6 aPTT should be checked every 6 hours for the first 24 hours thenhours for the first 24 hours then

Daily or more frequently as Daily or more frequently as indicated by the need to achieve indicated by the need to achieve the therapeutic rangethe therapeutic range

Check platelet count on days 3 Check platelet count on days 3 and 5and 5

Initiate warfarin 5 mg on day 1Initiate warfarin 5 mg on day 1 Continue unfractionated heparin Continue unfractionated heparin

until the INR is between 2 and 3 until the INR is between 2 and 3 for 2 consecutive daysfor 2 consecutive days

Infusion 18 IU/kg/hrInfusion 18 IU/kg/hr Target aPTT therapeutic range Target aPTT therapeutic range

of the hospitalof the hospital Check aPTT in 6 hours and Check aPTT in 6 hours and

adjust via the scheduleadjust via the schedule Check platelet count on days 3 Check platelet count on days 3

and 5and 5 Initiate warfarin 5 mg on day 1Initiate warfarin 5 mg on day 1 Continue unfractionated Continue unfractionated

heparin until the INR is heparin until the INR is between 2 and 3 for 2 between 2 and 3 for 2 consecutive daysconsecutive days

Jefferson University Hospitals Jefferson University Hospitals has adopted a dosing schedule has adopted a dosing schedule of bolus 70 IU/kg then Infusion of bolus 70 IU/kg then Infusion 15 IU/kg/hr15 IU/kg/hr

Infusion 18 IU/kg/hrInfusion 18 IU/kg/hr Target aPTT therapeutic range Target aPTT therapeutic range

of the hospitalof the hospital Check aPTT in 6 hours and Check aPTT in 6 hours and

adjust via the scheduleadjust via the schedule Check platelet count on days 3 Check platelet count on days 3

and 5and 5 Initiate warfarin 5 mg on day 1Initiate warfarin 5 mg on day 1 Continue unfractionated Continue unfractionated

heparin until the INR is heparin until the INR is between 2 and 3 for 2 between 2 and 3 for 2 consecutive daysconsecutive days

Jefferson University Hospitals Jefferson University Hospitals has adopted a dosing schedule has adopted a dosing schedule of bolus 70 IU/kg then Infusion of bolus 70 IU/kg then Infusion 15 IU/kg/hr15 IU/kg/hr

Raschke RA, et al. Raschke RA, et al. Ann Intern MedAnn Intern Med. 1993;119:874-881.. 1993;119:874-881.

Unfractionated HeparinUnfractionated HeparinSubcutaneous DosingSubcutaneous Dosing

FIDO InvestigatorsFIDO Investigators► Initial Dose 333 U/kg, SCInitial Dose 333 U/kg, SC► Maintenance 250 U/kg, SC, Q12hrsMaintenance 250 U/kg, SC, Q12hrs

Galilei InvestigatorsGalilei Investigators► < 50 kg: 4,000 U, IV then 12,500 U, SC, Q12hrs< 50 kg: 4,000 U, IV then 12,500 U, SC, Q12hrs► 50 kg: 70 kg : 5,000 U, IV then 15,000 U, SC, Q12hrs50 kg: 70 kg : 5,000 U, IV then 15,000 U, SC, Q12hrs► > 70 kg : 6,000 U, IV then 17,500 U, SC, Q12hrs> 70 kg : 6,000 U, IV then 17,500 U, SC, Q12hrs► Step Adjustment of UFH dosingStep Adjustment of UFH dosing

Pini MethodPini Method► 250 u / kg, Q12hrs250 u / kg, Q12hrs► Adjust dose 6 hours after the AM dose and adjust upward or Adjust dose 6 hours after the AM dose and adjust upward or

downward based on aPTT of 1.5 x baseline aPTTdownward based on aPTT of 1.5 x baseline aPTT

FIDO InvestigatorsFIDO Investigators► Initial Dose 333 U/kg, SCInitial Dose 333 U/kg, SC► Maintenance 250 U/kg, SC, Q12hrsMaintenance 250 U/kg, SC, Q12hrs

Galilei InvestigatorsGalilei Investigators► < 50 kg: 4,000 U, IV then 12,500 U, SC, Q12hrs< 50 kg: 4,000 U, IV then 12,500 U, SC, Q12hrs► 50 kg: 70 kg : 5,000 U, IV then 15,000 U, SC, Q12hrs50 kg: 70 kg : 5,000 U, IV then 15,000 U, SC, Q12hrs► > 70 kg : 6,000 U, IV then 17,500 U, SC, Q12hrs> 70 kg : 6,000 U, IV then 17,500 U, SC, Q12hrs► Step Adjustment of UFH dosingStep Adjustment of UFH dosing

Pini MethodPini Method► 250 u / kg, Q12hrs250 u / kg, Q12hrs► Adjust dose 6 hours after the AM dose and adjust upward or Adjust dose 6 hours after the AM dose and adjust upward or

downward based on aPTT of 1.5 x baseline aPTTdownward based on aPTT of 1.5 x baseline aPTT

Kearon C, et al JAMA 2006;296:935-942Galilei Investigators. Arch Intern Med 2004;164:1077-1083Buller H, et al Chest 2004;126:401S-428S

ACCP RecommendationACCP RecommendationAdjusted Dose Unfractionated Heparin can be used as an Adjusted Dose Unfractionated Heparin can be used as an

adequate alternative to IV Unfractionated Heparin [1A]adequate alternative to IV Unfractionated Heparin [1A]

FIDO InvestigatorsFIDO InvestigatorsFixed Dose UFHFixed Dose UFH

OutcomesOutcomes UFHUFH(n=345)(n=345)

LMWHLMWH(n=352)(n=352)

Risk Risk DifferenceDifference

VTE (10 days)VTE (10 days) 1 (0.3%)1 (0.3%) 2 (0.6%)2 (0.6%) -0.3 (-1.8 – 1.1)-0.3 (-1.8 – 1.1)

VTE (3 months)VTE (3 months) 13 (3.8%)13 (3.8%) 12 (3.5%)12 (3.5%) 0.4 (-2.6 – 3.3)0.4 (-2.6 – 3.3)

Major BleedingMajor Bleeding(10 days)(10 days) 4 (1.14%)4 (1.14%) 5 (1.4%)5 (1.4%) -0.3 (-2.3 – 1.7)-0.3 (-2.3 – 1.7)

Major BleedingMajor Bleeding(3 months)(3 months) 6 (1.7%)6 (1.7%) 12 (3.4%)12 (3.4%) -1.7 (-4.3 – 0.8)-1.7 (-4.3 – 0.8)

Kearon C, et al JAMA 2006;296:935-942Kearon C, et al JAMA 2006;296:935-942

Recurrent VTE: 1st 24 HoursRecurrent VTE: 1st 24 Hours

23%23%

5%5%6%6%

Hull RD, et al. Hull RD, et al. Arch Intern Med.Arch Intern Med. 1997;157:2562-2568. 1997;157:2562-2568.

0%

5%

10%

15%

20%

25%

Recurrent VTE

Subtherapeutic Therapeutic Supratherapeutic

Outcomes with UFHOutcomes with UFHStandard vs Weight-Based DosingStandard vs Weight-Based Dosing

OutcomesOutcomes Standard UFHStandard UFH Weight-based Weight-based UFHUFH PP Value Value

1st aPTT > 1.5*1st aPTT > 1.5* 32%32% 86%86% < 0.001< 0.001

aPTT > 1.5 aPTT > 1.5 in 24 hrsin 24 hrs 77%77% 97%97% 0.0020.002

aPTT therapeutic in aPTT therapeutic in 24 hrs24 hrs 75%75% 89%89% 0.080.08

Minor bleedingMinor bleeding 2/522/52 2/632/63 11

Major bleedingMajor bleeding 1/521/52 00 0.450.45

RVTERVTE 8/32 (25%)8/32 (25%) 2/41 (5%)2/41 (5%) 0.020.02

*aPTT > 1.5 times control*aPTT > 1.5 times control

Raschke RA, et al. Raschke RA, et al. Ann Intern Med.Ann Intern Med. 1993;119:874-881. 1993;119:874-881.

Hylek, E. M. et al. Arch Intern Med 2003;163:621-627.Hylek, E. M. et al. Arch Intern Med 2003;163:621-627.

P = .002P = .002

Number of aPTT Number of aPTT Achieving Therapeutic RangeAchieving Therapeutic Range

11 22 33 44

1.001.00

0.800.80

0.600.60

0.400.40

0.200.20

0.000.00

Pro

port

ion

of a

PT

Ts

Pro

port

ion

of a

PT

Ts

>> 5

5 s

55

s

>5 aPTT Measurements>5 aPTT Measurements4-5 aPTT Measurements4-5 aPTT Measurements<3 aPTT Measurements<3 aPTT Measurements

Heparin Therapy, dHeparin Therapy, d

VTE TreatmentVTE TreatmentACCP RecommendationsACCP Recommendations

Unfractionated HeparinUnfractionated Heparin► IV UFH adjustment dose to achieve a plasma IV UFH adjustment dose to achieve a plasma

heparin level from 0.3 to 0.7 IU/mL anti-Xa heparin level from 0.3 to 0.7 IU/mL anti-Xa activity (1C+)activity (1C+)

► UFH with large doses: measure anti-Xa to adjust UFH with large doses: measure anti-Xa to adjust dose (1B)dose (1B)

► SC UFH at a dose of 35,000 U/24hrs, SC with SC UFH at a dose of 35,000 U/24hrs, SC with adjustment to achieve a therapeutic aPTT (1C+)adjustment to achieve a therapeutic aPTT (1C+)

Unfractionated HeparinUnfractionated Heparin► IV UFH adjustment dose to achieve a plasma IV UFH adjustment dose to achieve a plasma

heparin level from 0.3 to 0.7 IU/mL anti-Xa heparin level from 0.3 to 0.7 IU/mL anti-Xa activity (1C+)activity (1C+)

► UFH with large doses: measure anti-Xa to adjust UFH with large doses: measure anti-Xa to adjust dose (1B)dose (1B)

► SC UFH at a dose of 35,000 U/24hrs, SC with SC UFH at a dose of 35,000 U/24hrs, SC with adjustment to achieve a therapeutic aPTT (1C+)adjustment to achieve a therapeutic aPTT (1C+)

Buller H, et al Chest 2004;126:401S-428SBuller H, et al Chest 2004;126:401S-428S

Challenges Challenges Using UFH in Acute VTEUsing UFH in Acute VTE

► Achieving a therapeutic aPTT in the first 24 Achieving a therapeutic aPTT in the first 24 hours to prevent recurrent diseasehours to prevent recurrent disease

► UFH must be adjusted daily to maintain a UFH must be adjusted daily to maintain a therapeutic rangetherapeutic range

► Platelets checked during the course of UFH Platelets checked during the course of UFH useuse

► Achieving a therapeutic aPTT in the first 24 Achieving a therapeutic aPTT in the first 24 hours to prevent recurrent diseasehours to prevent recurrent disease

► UFH must be adjusted daily to maintain a UFH must be adjusted daily to maintain a therapeutic rangetherapeutic range

► Platelets checked during the course of UFH Platelets checked during the course of UFH useuse

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

Total VTE DVT PE Major Bleed

UFH Enoxaparin

Venographic AssessmentVenographic AssessmentEfficacy and Safety LMWH vs UFHEfficacy and Safety LMWH vs UFH

Simonneau G, et al. Simonneau G, et al. Arch Intern Med.Arch Intern Med. 1993;153:1541-1546. 1993;153:1541-1546.

% P

a tie

nts

All patients had bilateral leg venography and lung scanning on day 1 and 10.

No warfarin started until day 11.

Lindmarker P, Holmstrom M. J Intern Med. 1996;240:395-401.

% P

a tie

nts



200 U/kg/Q24hrs200 U/kg/Q24hrs

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Total VTE DVT PE Major Bld

UFH Dalteparin

% P

ati

ent s

Merli G, et al. Merli G, et al. Ann Intern Med.Ann Intern Med. 2001;134:191-202. 2001;134:191-202.

Enoxaparin 1.5 mg/kg, SC, QdayEnoxaparin 1.5 mg/kg, SC, Qday

Clinical OutcomesClinical OutcomesEfficacy and Safety of LMWH vs UFHEfficacy and Safety of LMWH vs UFH

Clinical OutcomesClinical OutcomesEfficacy and Safety of LMWH vs UFHEfficacy and Safety of LMWH vs UFH

Enoxaparin 1mg/kg, SC, Q12hrsEnoxaparin 1mg/kg, SC, Q12hrs

UFHUFH

0%

1%

1%

2%

2%

3%

3%

4%

4%

5%

RVTE Major Bleed

ObesityObesity 3/122 (2.5%) 3/122 (2.5%) 10/137(7.3%)10/137(7.3%) 5/146 (3.4%)5/146 (3.4%)

CancerCancer 3/ 45 (6.7%)3/ 45 (6.7%) 6/ 49 (12.2%)6/ 49 (12.2%) 3/ 47 (6.4%)3/ 47 (6.4%)

Iliac Vein ThrombosisIliac Vein Thrombosis 0/220/22 3/23 (13%)3/23 (13%) 0/210/21

PEPE at baseline at baseline 4/88 (4.5%)4/88 (4.5%) 5/94 (5.3%)5/94 (5.3%) 5/105 (4.8%)5/105 (4.8%)

UFHUFHEnoxaparinEnoxaparin

QdayQday

Inpatient Treatment of DVTInpatient Treatment of DVTResults: Recurrences of ThromboembolismResults: Recurrences of Thromboembolism

EnoxaparinEnoxaparin Q12h Q12h

Other subgroups analyzed: h/o VTE, prolonged immobilization,Other subgroups analyzed: h/o VTE, prolonged immobilization,varicose veins, CHF, COPD, estrogen use, thrombophilia, recentvaricose veins, CHF, COPD, estrogen use, thrombophilia, recentchemotherapy/radiation therapy, recent surgery, recent traumachemotherapy/radiation therapy, recent surgery, recent trauma

Merli G, et al. Ann Intern Med 2001;134:191-202.Merli G, et al. Ann Intern Med 2001;134:191-202.

VTE Clinical OutcomesVTE Clinical Outcomes Efficacy of LMWHEfficacy of LMWH

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

14.00%

< 50 kg 50-100 kg > 100 kg

Fondaparinux Enoxaparin

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

14.00%

< 50 kg 50-100 kg > 100 kg

Fondaparinux Enoxaparin

1/311/31 3/243/24 37/94837/948 39/97439/974 5/1195/119 3/1093/109Fondaparinux Fondaparinux 5 mg: < 50kg5 mg: < 50kg7.5 mg: 50 – 100kg7.5 mg: 50 – 100kg10 mg: > 100 kg10 mg: > 100 kg

Buller H, et al Ann Intern Med 2004;140:867-873Buller H, et al Ann Intern Med 2004;140:867-873

Outpatient Treatment of DVTOutpatient Treatment of DVT

%%

Levine et alLevine et al Koopman et alKoopman et al

EnoxaparinEnoxaparin(N = 247)(N = 247)

UFHUFH(N = 253)(N = 253)

Nadroparin Nadroparin (N = 202)(N = 202)

UFHUFH(N = 198)(N = 198)

Recurrent TERecurrent TE 5.35.3 6.76.7 6.96.9 8.68.6

Major bleedingMajor bleeding 2.02.0 1.21.2 0.50.5 2.02.0

DeathDeath 4.44.4 6.76.7 6.96.9 8.18.1

Hospital daysHospital days 1.1*1.1* 6.56.5 2.72.7 8.18.1

Levine M, et al. Levine M, et al. N Engl J Med. N Engl J Med. 1996;334:677-681.1996;334:677-681.Koopman MM, et al. Koopman MM, et al. N Engl J Med.N Engl J Med. 1996;334:682-687. 1996;334:682-687.

*120 (48%) were exclusively treated in the outpatient setting.*120 (48%) were exclusively treated in the outpatient setting.

ACCP RecommendationsACCP Recommendations

Low Molecular Weight HeparinLow Molecular Weight Heparin► SC LMWH once or twice daily over SC LMWH once or twice daily over

UFH as an outpatient if possible (1C) UFH as an outpatient if possible (1C) or as an inpatient (1A)or as an inpatient (1A)

► Recommend against monitoring with Recommend against monitoring with anti-Xa levels (1A)anti-Xa levels (1A)

► Severe renal failure suggest IV UFH Severe renal failure suggest IV UFH over LMWH (2C)over LMWH (2C)

Low Molecular Weight HeparinLow Molecular Weight Heparin► SC LMWH once or twice daily over SC LMWH once or twice daily over

UFH as an outpatient if possible (1C) UFH as an outpatient if possible (1C) or as an inpatient (1A)or as an inpatient (1A)

► Recommend against monitoring with Recommend against monitoring with anti-Xa levels (1A)anti-Xa levels (1A)

► Severe renal failure suggest IV UFH Severe renal failure suggest IV UFH over LMWH (2C)over LMWH (2C)

Buller H, et al Chest 2004;126:401S-428SBuller H, et al Chest 2004;126:401S-428S

ChallengesChallengesUsing LMWH in VTEUsing LMWH in VTE

► Appropriate dosing of LMWH in obesityAppropriate dosing of LMWH in obesity● actual body weight dosing actual body weight dosing

► Appropriate dosing in renal insufficiencyAppropriate dosing in renal insufficiency

► Appropriate dosing of LMWH in obesityAppropriate dosing of LMWH in obesity● actual body weight dosing actual body weight dosing

► Appropriate dosing in renal insufficiencyAppropriate dosing in renal insufficiency

IV IV UFHUFH

SC SC UFHUFH

SC SC UFHUFH

1.1. Etiology of VTEEtiology of VTE2.2. Duration of Warfarin TherapyDuration of Warfarin Therapy3.3. Maintaining Therapeutic RangeMaintaining Therapeutic Range

5-7 days5-7 days

3-6 months3-6 monthsororIndefiniteIndefinite

VTE ManagementVTE Management

UFH LMWH

Warfarin

VTEVTE

IV IV UFHUFH

SC SC UFHUFH

SC SC UFHUFH

5-7 days


Patient FactorsPatient Factors1.1. ThrombophiliaThrombophilia2.2. AgeAge

Co-morbid FactorsCo-morbid Factors1.1. Temporary Risk FactorsTemporary Risk Factors2.2. Malignancy / ChemotherapyMalignancy / Chemotherapy3.3. IdiopathicIdiopathic

Thrombosis FactorsThrombosis Factors1.1. DVT vs PEDVT vs PE2.2. DVT (proximal vs distal)DVT (proximal vs distal)

UFH LMWH

Warfarin

VTEVTE

IV IV UFHUFH

SC SC UFHUFH

SC SC UFHUFH

5-7 days5-7 days


Recurrent VTERecurrent VTEMajor BleedingMajor Bleeding

UFH LMWH

Warfarin

VTEVTE

Hylek EM. Ann Intern Med 1994; 120:897.Hylek EM. N Engl J Med 1996; 335:540.

Od

ds

Ra

tioO

dd

s R

atio

005.05.0 6.06.0 8.08.0

INRINR

1.01.0 2.02.0 3.03.0 4.04.0 7.07.0

5.05.0

15.015.0

10.010.0RecurrentRecurrent

VTEVTEIntracranial BleedingIntracranial Bleeding

1.01.0

Therapeutic Range for WarfarinTherapeutic Range for WarfarinBalancing Safety and EfficacyBalancing Safety and Efficacy

Outpatient Bleeding RiskOutpatient Bleeding RiskWarfarin TherapyWarfarin Therapy

Risk Factors (1 point for each risk factor)Risk Factors (1 point for each risk factor)► Age > 65 yrsAge > 65 yrs► History of GI BleedHistory of GI Bleed► Recent MI, Recent MI, ► HCT < 30%HCT < 30%► Cr > 1.5 mg/dlCr > 1.5 mg/dl► History DMHistory DM

Risk Factors (1 point for each risk factor)Risk Factors (1 point for each risk factor)► Age > 65 yrsAge > 65 yrs► History of GI BleedHistory of GI Bleed► Recent MI, Recent MI, ► HCT < 30%HCT < 30%► Cr > 1.5 mg/dlCr > 1.5 mg/dl► History DMHistory DM

MonthsMonths Low Risk Low Risk (RF 0)(RF 0)

Intermediate Intermediate Risk (RF 1-2)Risk (RF 1-2)

High Risk High Risk (RF 3-4)(RF 3-4)

3 months3 months 2%2% 5%5% 23%23%

12 months12 months 3%3% 12%12% 48%48%

Beyth R, et al Am J Med 1998;105(2):91-99Beyth R, et al Am J Med 1998;105(2):91-99

Risk of Major Bleeding on WarfarinRisk of Major Bleeding on Warfarin

FactorsFactors Relative RiskRelative Risk (95% CI)(95% CI)

P P valuevalue

Sex (women vs men)Sex (women vs men) 1.26 (0.86-1.70)1.26 (0.86-1.70)

Age (> 70 vs < 70 yrs)Age (> 70 vs < 70 yrs) 1.69 (1.21-2.37)1.69 (1.21-2.37) <0.001<0.001

Target INR (< 2.8 vs > 2.8)Target INR (< 2.8 vs > 2.8) 0.83 (0.56-1.22)0.83 (0.56-1.22)

Indication (arterial vs other)Indication (arterial vs other) 1.72 (1.17-2.54)1.72 (1.17-2.54) <0.001<0.001

Actual INR (> 4.5 vs < 4.5)Actual INR (> 4.5 vs < 4.5) 5.96 (3.68-9.62)5.96 (3.68-9.62) <0.0001<0.0001

Coumarin type (acenocoumarol vs warfarin)Coumarin type (acenocoumarol vs warfarin) 1.20 (0.85-1.69)1.20 (0.85-1.69)

Timing of event (< 90 vs > 90 days)Timing of event (< 90 vs > 90 days) 2.50 (1.4-3.3)2.50 (1.4-3.3) < 0.001< 0.001

Parlareti G et al Lancet 1996;348:423-428Parlareti G et al Lancet 1996;348:423-428

Time Spent in Therapeutic RangeTime Spent in Therapeutic RangeOutcomesOutcomes

StudyStudy No PtsNo PtsTarget Target

INRINRTTRTTR EventEvent

Incidence of EventsIncidence of Events95% CI95% CI

HylekHylek 13,559 AF13,559 AF< 1.5< 1.5

2.6-3.02.6-3.0NSNS StrokeStroke

OR 7.7 (CI 5.7-10.4)OR 7.7 (CI 5.7-10.4)

OR 0.9 (CI 0.6-0.9)OR 0.9 (CI 0.6-0.9)

SarawateSarawate 614 AF614 AF 2-32-3 28.6%28.6% StrokeStroke OR 1.68 (1.04-2.73)OR 1.68 (1.04-2.73)

WittWitt 6,645 6,645 AF/S/VTEAF/S/VTE 2-3.52-3.5 55.2% 55.2%

(UC)(UC) VTEVTE 3%3%

63.5% 63.5% (CCPS)(CCPS) 1.2%1.2%

VeegerVeeger 2,614 AF2,614 AF 2.5-3.52.5-3.5 42%42% VTEVTE OR 1.7 ( CI 1.2-2.3)OR 1.7 ( CI 1.2-2.3)

JonesJones 2,223 AF2,223 AF 2-32-3 68%68% SS OR 1.10 (P = 0.006)OR 1.10 (P = 0.006)

VTEVTE OR 1.12 (P = < 0.001)OR 1.12 (P = < 0.001)

Schmidt-Schmidt-LuckeLucke 248 AF248 AF 2-32-3 30%30% VTE/D/BVTE/D/B 80%80%


► Recommend adjusted INR to 2 – 3 range for all 2Recommend adjusted INR to 2 – 3 range for all 2°° prevention [1A]prevention [1A]

► Recommend Recommend against low-intensity warfarinagainst low-intensity warfarin at INR of 1.5 at INR of 1.5 – 1.9 [1A]– 1.9 [1A]

► Patients should be assessed periodically during Patients should be assessed periodically during anticoagulation to evaluated risk benefit [1C]anticoagulation to evaluated risk benefit [1C]

► Recommend adjusted INR to 2 – 3 range for all 2Recommend adjusted INR to 2 – 3 range for all 2°° prevention [1A]prevention [1A]

► Recommend Recommend against low-intensity warfarinagainst low-intensity warfarin at INR of 1.5 at INR of 1.5 – 1.9 [1A]– 1.9 [1A]

► Patients should be assessed periodically during Patients should be assessed periodically during anticoagulation to evaluated risk benefit [1C]anticoagulation to evaluated risk benefit [1C]

Buller H, et al. Buller H, et al. ChestChest. 2004;126:401S-428S. 2004;126:401S-428S

Challenges with WarfarinChallenges with Warfarin

► Maintaining INR in therapeutic range by regular Maintaining INR in therapeutic range by regular monitoringmonitoring

► Vigilance for drug interaction with warfarinVigilance for drug interaction with warfarin

► Patient education on Vitamin K reduced diet Patient education on Vitamin K reduced diet

► Instruction to seek medical care with any change in Instruction to seek medical care with any change in medical status or new onset illness medical status or new onset illness

► Undertreatment: Physicians’ aversion of the risk of Undertreatment: Physicians’ aversion of the risk of bleed lead them to under-dosingbleed lead them to under-dosing

► Poor and inconsistent patient follow-up and Poor and inconsistent patient follow-up and monitoringmonitoring

► Maintaining INR in therapeutic range by regular Maintaining INR in therapeutic range by regular monitoringmonitoring

► Vigilance for drug interaction with warfarinVigilance for drug interaction with warfarin

► Patient education on Vitamin K reduced diet Patient education on Vitamin K reduced diet

► Instruction to seek medical care with any change in Instruction to seek medical care with any change in medical status or new onset illness medical status or new onset illness

► Undertreatment: Physicians’ aversion of the risk of Undertreatment: Physicians’ aversion of the risk of bleed lead them to under-dosingbleed lead them to under-dosing

► Poor and inconsistent patient follow-up and Poor and inconsistent patient follow-up and monitoringmonitoring

IV IV UFHUFH

SC SC UFHUFH

SC SC UFHUFH

5-7 days5-7 days


Recurrent VTERecurrent VTE

Malignancy/ChemoMalignancy/Chemo Hereditary/Acquired Hereditary/Acquired ThrombophiliaThrombophilia

IdiopathicIdiopathicTemporaryTemporaryRisk FactorRisk Factor

UFH LMWH

Warfarin

VTEVTE

Management of VTEManagement of VTE

3 months3 monthswarfarinwarfarin

8 years8 years

DVTDVT355 patients355 patients

LMWH or UFH + WarfarinLMWH or UFH + Warfarin

78 recurrent VTE78 recurrent VTE 35 (44.9%) ipsilateral leg35 (44.9%) ipsilateral leg 28 (35.9%) contralateral leg28 (35.9%) contralateral leg 15 (19.2%) PE (9 fatal)15 (19.2%) PE (9 fatal)

Prandoni P, et al. Prandoni P, et al. Ann Intern Med.Ann Intern Med. 1996;125:1-7. 1996;125:1-7.

Recurrent VTERecurrent VTE After 3 months: 4.9%After 3 months: 4.9% After 6 months: 8.6%After 6 months: 8.6% After 2 years: 17.5%After 2 years: 17.5% After 5 years: 24.6%After 5 years: 24.6% After 8 years: 30.3%After 8 years: 30.3%

Risk factors for recurrenceRisk factors for recurrence

Increased risk:Increased risk:

► Cancer: 1.72Cancer: 1.72

► Thrombophilia: 1.44Thrombophilia: 1.44

Decreased risk:Decreased risk:

► Trauma/fracture: 0.51Trauma/fracture: 0.51

► Surgery: 0.36Surgery: 0.36


► First DVT with transient risk factors:First DVT with transient risk factors: 3 months with INR 2 – 3 [1A]3 months with INR 2 – 3 [1A]

► DVT with antiphospholipid antibodies, lupus DVT with antiphospholipid antibodies, lupus anticoagulant, or ≥ 2 thrombophilic conditions:anticoagulant, or ≥ 2 thrombophilic conditions: 12 12 months warfarin (INR 2 – 3) [1C+] or indefinite months warfarin (INR 2 – 3) [1C+] or indefinite treatment [2C]treatment [2C]

► DVT with AT, protein C, protein S, factor V Leiden, DVT with AT, protein C, protein S, factor V Leiden, prothrombin gene mutation, hyperhomocysteinemia, prothrombin gene mutation, hyperhomocysteinemia, factor VIII > 90factor VIII > 90thth percentile: percentile: 6 – 12 months [1A] or 6 – 12 months [1A] or indefinite therapy [2C]indefinite therapy [2C]

► First DVT with transient risk factors:First DVT with transient risk factors: 3 months with INR 2 – 3 [1A]3 months with INR 2 – 3 [1A]

► DVT with antiphospholipid antibodies, lupus DVT with antiphospholipid antibodies, lupus anticoagulant, or ≥ 2 thrombophilic conditions:anticoagulant, or ≥ 2 thrombophilic conditions: 12 12 months warfarin (INR 2 – 3) [1C+] or indefinite months warfarin (INR 2 – 3) [1C+] or indefinite treatment [2C]treatment [2C]

► DVT with AT, protein C, protein S, factor V Leiden, DVT with AT, protein C, protein S, factor V Leiden, prothrombin gene mutation, hyperhomocysteinemia, prothrombin gene mutation, hyperhomocysteinemia, factor VIII > 90factor VIII > 90thth percentile: percentile: 6 – 12 months [1A] or 6 – 12 months [1A] or indefinite therapy [2C]indefinite therapy [2C]


VTE Increased with Warfarin Treatment VTE Increased with Warfarin Treatment in Cancer Patientsin Cancer Patients

20

0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 11 11 1212

Time (months)Time (months)

30

00

10

Cum

ulat

ive

prop

ortio

n C

umul

ativ

e pr

opor

tion

recu

rren

t VT

E (

%)

recu

rren

t VT

E (

%)

Cancer

No cancer

20.7% vs 6.8%; HR 3.2 at 1 year

Warfarin to maintain INR 2Warfarin to maintain INR 2––33Major bleeding 12.4% vs 4.9%; HR 2.2Major bleeding 12.4% vs 4.9%; HR 2.2VTE and bleeding not predicted by INR VTE and bleeding not predicted by INR

Number ofNumber ofpatientspatientsCancer Cancer 181 181 160 160 129 129 92 92 73 73 6464No cancer No cancer 661 661 631 631 602 602 161 161 120 120 115115

Prandoni P, et al. Prandoni P, et al. Blood. Blood. 2002;100:3484-3488. 2002;100:3484-3488.

LMWH in Cancer PatientLMWH in Cancer PatientCANTHANOXCANTHANOX

Warfarin (n = 71) INR 2 – 3 x 3 monthsWarfarin (n = 71) INR 2 – 3 x 3 monthsWarfarin major bleeding = 8%Warfarin major bleeding = 8%LMWH (n = 67) enoxaparin 1.5 mg/kg SC QD x 3 monthsLMWH (n = 67) enoxaparin 1.5 mg/kg SC QD x 3 monthsLMWH major bleeding = 0%LMWH major bleeding = 0%

Re c

u rr e

n t V

TE

( %

)R

ecu r

ren t

VT

E

(%)

Meyer G, et al. Meyer G, et al. Arch Intern Med.Arch Intern Med. 2002;162:1729-1735 2002;162:1729-1735

21.1

10.6

0

5

10

15

20

25

Warfarin LMWH

LMWH in Cancer PatientsLMWH in Cancer PatientsCLOTCLOT

Warfarin (n = 336) INR 2 – 3 x 6 monthsWarfarin (n = 336) INR 2 – 3 x 6 monthsWarfarin major bleeding = 4%Warfarin major bleeding = 4%LMWH (n = 336) dalteparin 200 IU/kg SC QD x 1 month,LMWH (n = 336) dalteparin 200 IU/kg SC QD x 1 month,then 150 IU/kg SC QD x 5 monthsthen 150 IU/kg SC QD x 5 monthsLMWH major bleeding = 6%LMWH major bleeding = 6%

Rec

urre

n t V

TE

( %

)R

ecu r

ren t

VT

E

(%)

Lee A, et al. N Engl J Med. 2003;349:146-1153

17

9

0

4

8

12

16

20

Warfarin LMWH

ACCP RecommendationsACCP RecommendationsCancer PatientsCancer Patients

VTE and CancerVTE and Cancer

► LMWH for 3 – 6 months [1A] thenLMWH for 3 – 6 months [1A] then

► Warfarin Warfarin

(INR 2 – 3) for indefinite period [1C](INR 2 – 3) for indefinite period [1C]

VTE and CancerVTE and Cancer

► LMWH for 3 – 6 months [1A] thenLMWH for 3 – 6 months [1A] then

► Warfarin Warfarin

(INR 2 – 3) for indefinite period [1C](INR 2 – 3) for indefinite period [1C]


NCCN VTE Treatment Guidelines 2007NCCN VTE Treatment Guidelines 2007

NCCN. Venous Thromboembolic Disease: Version 2.2007.Available at: http://www.nccn.org/professionals/ physician_gls/PDF/vte.pdf. Accessed October 19, 2007.

• LMWHLMWH• Dalteparin (200 U/kg SC OD)Dalteparin (200 U/kg SC OD)• Enoxaparin (1 mg/kg SC BID)Enoxaparin (1 mg/kg SC BID)• Tinzaparin (175 U/kg SC OD)Tinzaparin (175 U/kg SC OD)• Fondaparinux (5.0 mg [<50 kg]; 7.5 mg [50Fondaparinux (5.0 mg [<50 kg]; 7.5 mg [50––100 kg]; 10 mg [> 100 kg] SC OD)100 kg]; 10 mg [> 100 kg] SC OD)

• UFH (IV) weight-basedUFH (IV) weight-based

Stage 2 Acute: Short-term, during transition to chronic phase:Stage 2 Acute: Short-term, during transition to chronic phase:• If UFH, pentasaccharide/Factor Xa antagonist, transition to LMWH or warfarinIf UFH, pentasaccharide/Factor Xa antagonist, transition to LMWH or warfarin• LMWH is preferred as monotherapy without warfarin in patients with proximal DVT or PE LMWH is preferred as monotherapy without warfarin in patients with proximal DVT or PE

and prevention of recurrent VTE in patients with advanced or metastatic cancerand prevention of recurrent VTE in patients with advanced or metastatic cancer• Warfarin (2.5Warfarin (2.5––5 mg every day initially, subsequent dosing based on INR value; target INR 5 mg every day initially, subsequent dosing based on INR value; target INR

2.02.0––3.0)3.0)

Stage 3 Chronic: Completion time period as recommended by guideline:Stage 3 Chronic: Completion time period as recommended by guideline:• LMWH or warfarin per therapeutic guidelines (warfarin adjusted for INR 2.0LMWH or warfarin per therapeutic guidelines (warfarin adjusted for INR 2.0––3.0)3.0)• Minimum time of 3Minimum time of 3––6 months for DVT and 66 months for DVT and 6––12 months for PE12 months for PE• Consider indefinite anticoagulation if active cancer or persistent risk factorsConsider indefinite anticoagulation if active cancer or persistent risk factors• For catheter associated thrombosis, anticoagulate as long as catheter is in place For catheter associated thrombosis, anticoagulate as long as catheter is in place

and for 1-3 months after catheter removaland for 1-3 months after catheter removal

Stage 1 Immediate: Concomitant with diagnosis or while diagnosis and risk being assessed Stage 1 Immediate: Concomitant with diagnosis or while diagnosis and risk being assessed (heparin phase):(heparin phase):

Ridker PM, et al. Ridker PM, et al. N Engl J Med.N Engl J Med. 2003;348:1425-1434. 2003;348:1425-1434.

Warfarin 4 yrsINR 1.5 - 2

IdiopathicDVT

14/25514/2552.6 /100 person-yr2.6 /100 person-yr

37/25337/2537.2/100 person-yr7.2/100 person-yr

6 mo6 moWarfarinWarfarinINR 2-3INR 2-3

PlaceboPlacebo

No./100 person-yrNo./100 person-yr

PlaceboPlacebo WarfarinWarfarin PP

Major bleedingMajor bleeding 2 (0.4)2 (0.4) 5 (0.9)5 (0.9) 0.250.25

DeathsDeaths 8 (1.4)8 (1.4) 4 (0.7)4 (0.7) 0.260.26

Idiopathic VTEIdiopathic VTE

Cumulative Cumulative Event RateEvent Rate

Years of Follow-UpYears of Follow-Up

PREVENT: Composite Endpoint PREVENT: Composite Endpoint (Recurrent VTE, Major Bleed, or Death)(Recurrent VTE, Major Bleed, or Death)

PlaceboPlacebo

Low-IntensityLow-IntensityWarfarinWarfarin

0.250.25

0.200.20

0.150.15

0.100.10

0.050.05

0.000.00

00 11 22 33 44

Hazard Ratio = 0.52, 95% CI 0.31 to 0.87, P = 0.01

48 %

Ridker PM for the PREVENT investigators. N Eng J Med 2003;348: 1425-34.

Kearon C, et al. Kearon C, et al. N Engl J Med.N Engl J Med. 2003;349:631-639. 2003;349:631-639.

Warfarin 2.4 yrsINR 1.5 – 1.9

IdiopathicIdiopathicDVTDVT

16/36916/3691.9 /100 person-yr1.9 /100 person-yr

6/3696/3690.7/100 person-yr0.7/100 person-yr

3 moWarfarinINR 2-3

No Events(No./100 person-No Events(No./100 person-yr)yr)

WarfarinWarfarin2-32-3

WarfarinWarfarin1.5-1.91.5-1.9 PP

Major bleedingMajor bleeding 8 (0.9)8 (0.9) 9 (1.1)9 (1.1) 0.250.25

DeathsDeaths 8 (0.9)8 (0.9) 16 (1.9)16 (1.9) 0.260.26

Warfarin 2.4yrsWarfarin 2.4yrsINR 2-3INR 2-3

ELATE: ELATE: Primary Endpoint Recurrent VTEPrimary Endpoint Recurrent VTE

Conventional-intensity Conventional-intensity −− therapy group therapy group

0.00

0.0 1.0 2.0 3.0 4.0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

Years Since RandomizationYears Since Randomization

Cum

ulat

ive

Pro

babi

lity

of R

ecur

rent

Cum

ulat

ive

Pro

babi

lity

of R

ecur

rent

Thr

ombo

embo

lism

Thr

ombo

embo

lism

Low-intensity − therapy group

Kearon C for the ELATE Investigators. Kearon C for the ELATE Investigators. N Engl J Med.N Engl J Med. 2003;349:631-9. 2003;349:631-9.

P=0.03

Cu m

ula t

i ve

Eve

n t R

a te ,

%C

umu l

a tiv

e E

vent

Rat

e, %

0.250.25

0.200.20

0.150.15

0.100.10

0.050.05

0.000.00

00 11 22 33 44

Years of Follow-UpYears of Follow-Up

PREVENT & ELATE PREVENT & ELATE Recurrent VTERecurrent VTE

INR 1.5-2.0 – PREVENTINR 1.5-2.0 – PREVENT

Placebo - PREVENTPlacebo - PREVENT

INR 1.5-2.0 – ELATEINR 1.5-2.0 – ELATE

INR 2.0-3.0 – ELATEINR 2.0-3.0 – ELATE

00 11

ACCP RecommendationsACCP RecommendationsIdiopathic VTEIdiopathic VTE

► First VTE idiopathic:First VTE idiopathic: 6 – 12 months INR 2 – 3 [1A]6 – 12 months INR 2 – 3 [1A]

► First DVT idiopathic:First DVT idiopathic:Indefinite treatment at INR 2 – 3 [2A]Indefinite treatment at INR 2 – 3 [2A]

► Patients with ≥ 2 episodes of DVT:Patients with ≥ 2 episodes of DVT:Indefinite treatment INR 2 – 3 [2A]Indefinite treatment INR 2 – 3 [2A]

► First VTE idiopathic:First VTE idiopathic: 6 – 12 months INR 2 – 3 [1A]6 – 12 months INR 2 – 3 [1A]

► First DVT idiopathic:First DVT idiopathic:Indefinite treatment at INR 2 – 3 [2A]Indefinite treatment at INR 2 – 3 [2A]

► Patients with ≥ 2 episodes of DVT:Patients with ≥ 2 episodes of DVT:Indefinite treatment INR 2 – 3 [2A]Indefinite treatment INR 2 – 3 [2A]


Clinical ChallengesClinical Challenges

Complex special groups of VTE patientsComplex special groups of VTE patients

► Cancer Patients Cancer Patients

► Idiopathic VTE PatientsIdiopathic VTE Patients

► Risks of long-term anticoagulation with either Risks of long-term anticoagulation with either warfarin or LMWHwarfarin or LMWH


► Cancer Patients Cancer Patients

► Idiopathic VTE PatientsIdiopathic VTE Patients

► Risks of long-term anticoagulation with either Risks of long-term anticoagulation with either warfarin or LMWHwarfarin or LMWH

Triple TherapyTriple TherapyASA, Clopidogrel, WarfarinASA, Clopidogrel, Warfarin

► 127 patients with Atrial Fibrillation undergoing 127 patients with Atrial Fibrillation undergoing cardiac stent placementcardiac stent placement

► Drug eluting stents and are metal stentsDrug eluting stents and are metal stents

► 67% of bleeding occurred in the first 30 days67% of bleeding occurred in the first 30 days

► 127 patients with Atrial Fibrillation undergoing 127 patients with Atrial Fibrillation undergoing cardiac stent placementcardiac stent placement

► Drug eluting stents and are metal stentsDrug eluting stents and are metal stents

► 67% of bleeding occurred in the first 30 days67% of bleeding occurred in the first 30 days

Stent GroupStent Group Major BleedingMajor Bleeding Bleeding & Bleeding & MortalityMortality

Drug ElutingDrug Eluting 5.6%5.6% 5.6%5.6%

Bare Metal Bare Metal 3.6%3.6% 1.8%1.8%

6/127 pts = 4.7% overall major bleeding6/127 pts = 4.7% overall major bleeding

Rogacka R et al JACC Intl 2008;1:56-61Rogacka R et al JACC Intl 2008;1:56-61

Combination TherapyCombination TherapyCardiac PreventionCardiac Prevention

GroupsGroups CombinationCombination MonotherapyMonotherapy OutcomeOutcome

Anticoagulation Anticoagulation Related Major Related Major HemorrhageHemorrhage

2%2% 0.9%0.9% P= < 0.003P= < 0.003

Adjusted Odds Ratio Adjusted Odds Ratio Anticoagulation Anticoagulation

Related HemorrhageRelated Hemorrhage2.062.06 1.001.00

95% CI95% CI

1.01-4.31.01-4.3

Johnson S, et al Chest 2008;133;948-954Johnson S, et al Chest 2008;133;948-954

Clinical ChallengesClinical Challenges


► Antiplatelet therapy with warfarin in Antiplatelet therapy with warfarin in cardiac preventioncardiac prevention

► Antiplatelet therapy with warfarin in Antiplatelet therapy with warfarin in coronary stent placementcoronary stent placement


► Antiplatelet therapy with warfarin in Antiplatelet therapy with warfarin in cardiac preventioncardiac prevention

► Antiplatelet therapy with warfarin in Antiplatelet therapy with warfarin in coronary stent placementcoronary stent placement

Contaminated HeparinContaminated Heparin

► Oversulfated Chondroitin Oversulfated Chondroitin Sulfate (OSCS)Sulfate (OSCS)

► Direct activation of Kinin-Direct activation of Kinin-Kallikrein pathwayKallikrein pathway Generation of bradykinin, Generation of bradykinin,

potent vasoactive mediatorpotent vasoactive mediator

► Induces C3a and C5aInduces C3a and C5a Potent anaphylatoxins Potent anaphylatoxins

derived from complement derived from complement proteinsproteins

► Oversulfated Chondroitin Oversulfated Chondroitin Sulfate (OSCS)Sulfate (OSCS)

► Direct activation of Kinin-Direct activation of Kinin-Kallikrein pathwayKallikrein pathway Generation of bradykinin, Generation of bradykinin,

potent vasoactive mediatorpotent vasoactive mediator

► Induces C3a and C5aInduces C3a and C5a Potent anaphylatoxins Potent anaphylatoxins

derived from complement derived from complement proteinsproteins

Kishimoto T, et al N Engl J Med 2008;358Kishimoto T, et al N Engl J Med 2008;358

Kishimoto T et al. N Engl J Med 2008;10.1056/NEJMoa0803200Kishimoto T et al. N Engl J Med 2008;10.1056/NEJMoa0803200

OSCS Generation OSCS Generation Complement-Derived C5a AnaphylatoxinComplement-Derived C5a Anaphylatoxin

Kishimoto T et al. N Engl J Me2008;10.1056/NEJMoa0803200Kishimoto T et al. N Engl J Me2008;10.1056/NEJMoa0803200

Effect of OSCS on Kallikrein ActivityEffect of OSCS on Kallikrein Activity

Summary and ConclusionsSummary and Conclusions

► Achieving optimal anticoagulation is difficultAchieving optimal anticoagulation is difficult

► Limitations to attaining and maintaining optimal Limitations to attaining and maintaining optimal anticoagulation with all available agents: UFH, anticoagulation with all available agents: UFH, LMWH, warfarin, and antiplatelet agentsLMWH, warfarin, and antiplatelet agents

► Multiple, combined antiplatelet plus Multiple, combined antiplatelet plus anticoagulation strategies present special anticoagulation strategies present special challengeschallenges

► The need to monitor anticoagulation represents a The need to monitor anticoagulation represents a major barrier and cost for long-term managementmajor barrier and cost for long-term management

► Achieving optimal anticoagulation is difficultAchieving optimal anticoagulation is difficult

► Limitations to attaining and maintaining optimal Limitations to attaining and maintaining optimal anticoagulation with all available agents: UFH, anticoagulation with all available agents: UFH, LMWH, warfarin, and antiplatelet agentsLMWH, warfarin, and antiplatelet agents

► Multiple, combined antiplatelet plus Multiple, combined antiplatelet plus anticoagulation strategies present special anticoagulation strategies present special challengeschallenges

► The need to monitor anticoagulation represents a The need to monitor anticoagulation represents a major barrier and cost for long-term managementmajor barrier and cost for long-term management

Summary and ConclusionsSummary and Conclusions

► Balancing antithrombotic effects with Balancing antithrombotic effects with bleeding safety is paramountbleeding safety is paramount

► Factor Xa inhibition offers the possibility of Factor Xa inhibition offers the possibility of better outcomes with oral, non-monitored better outcomes with oral, non-monitored anticoagulation and equivalent safetyanticoagulation and equivalent safety

► The landscape is evolving and may soon The landscape is evolving and may soon changechange

► Balancing antithrombotic effects with Balancing antithrombotic effects with bleeding safety is paramountbleeding safety is paramount

► Factor Xa inhibition offers the possibility of Factor Xa inhibition offers the possibility of better outcomes with oral, non-monitored better outcomes with oral, non-monitored anticoagulation and equivalent safetyanticoagulation and equivalent safety

► The landscape is evolving and may soon The landscape is evolving and may soon changechange

Documents

The Science and Medicine of Thrombosis Management New Dimensions, Novel Approaches, and Landmark Practice Advances in Venous and Arterial Thrombosis Prevention