the science and medicine of thrombosis management new dimensions, novel approaches, and landmark...
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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
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
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
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
The Science and Medicine of The Science and Medicine of Thrombosis ManagementThrombosis Management
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 Science and Medicine of The Science and Medicine of Thrombosis ManagementThrombosis Management
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)
DabigatranDabigatran
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
26152615 6–12 hours 6–12 hours post-surgerypost-surgery 12–15 days12–15 days
RE-NOVATERE-NOVATE THRTHR
Enoxaparin Enoxaparin 40 mg od, starting 40 mg od, starting evening before evening before surgerysurgery
34943494 1–4 hours 1–4 hours post-surgerypost-surgery 28–35 days28–35 days
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
DabigatranDabigatran
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
► 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
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)
ADVANCE-2ADVANCE-2CV185047CV185047
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)
ADVANCE-3ADVANCE-3CV185035CV185035
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
Inclusion criteriaInclusion criteria Patients aged ≥18 years, scheduled Patients aged ≥18 years, scheduled
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
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
Factor Xa InhibitionFactor Xa Inhibition
Rivaroxaban 10 mg odRivaroxaban 10 mg odMandatoryMandatory
bilateralbilateralvenographyvenography
RECORD 2 — Study DesignRECORD 2 — Study Design
Inclusion criteriaInclusion criteria Patients aged ≥18 years, scheduled Patients aged ≥18 years, scheduled
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
6–8 hours post-surgery6–8 hours post-surgery
Day 1Day 1
Double blindDouble blind
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
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%
Symptomatic VTESymptomatic VTE
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
Factor Xa InhibitionFactor Xa Inhibition
Enoxaparin 40 mg odEnoxaparin 40 mg od
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
6–8 hours post-surgery6–8 hours post-surgery
6–8 hours post-surgery6–8 hours post-surgery
Day 1Day 1 Day 13Day 13±±22
Double blindDouble blind
Last dose, 1 dayLast dose, 1 daybefore venographybefore venography
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
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%
Symptomatic VTESymptomatic VTE
Rivaroxaban 10 mg odRivaroxaban 10 mg od
Enoxaparin 40 mg odEnoxaparin 40 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
The Science and Medicine of The Science and Medicine of Thrombosis ManagementThrombosis Management
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
Hylek EM et al, Circulation 2007;115(21):2689-2696.
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
Hylek EM et al, Circulation 2007;115(21):2689-2696.
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
► 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
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
► Variable dose responseVariable dose response
► Narrow therapeutic windowNarrow therapeutic window
► Need for frequent monitoringNeed for frequent monitoring
► Long half-lifeLong half-life
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
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
► Variable dose responseVariable dose response
► Narrow therapeutic windowNarrow therapeutic window
► Need for frequent monitoringNeed for frequent monitoring
► Long half-lifeLong half-life
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
The Science and Medicine of The Science and Medicine of Thrombosis ManagementThrombosis Management
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
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
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
► Produces concentration-dependent Produces concentration-dependent anticoagulationanticoagulation
► 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
► Good oral bioavailability Good oral bioavailability
► No food effectNo food effect
► Balanced elimination (Balanced elimination (~~25% renal)25% renal)
► Half-life ~12 hrsHalf-life ~12 hrs
► Oral, direct, highly selective Factor Xa inhibitorOral, direct, highly selective Factor Xa inhibitor
► Produces concentration-dependent Produces concentration-dependent anticoagulationanticoagulation
► 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
► Good oral bioavailability Good oral bioavailability
► No food effectNo food effect
► Balanced elimination (Balanced elimination (~~25% renal)25% renal)
► Half-life ~12 hrsHalf-life ~12 hrs
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
DVT Alert ScreenDVT Alert Screen
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
Venographic AssessmentVenographic AssessmentEfficacy and Safety LMWH vs UFHEfficacy and Safety LMWH vs UFH
Venographic AssessmentVenographic AssessmentEfficacy and Safety LMWH vs UFHEfficacy and Safety LMWH vs UFH
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
VTE ManagementVTE Management
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
VTE ManagementVTE Management
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%
ACCP RecommendationsACCP Recommendations
► 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
VTE ManagementVTE Management
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
ACCP RecommendationsACCP Recommendations
► 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]
Buller H, et al. Buller H, et al. ChestChest. 2004;126:401S-428S. 2004;126:401S-428S
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]
Buller H, et al. Buller H, et al. ChestChest. 2004;126:401S-428S. 2004;126:401S-428S
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]
Buller H, et al. Buller H, et al. ChestChest. 2004;126:401S-428S. 2004;126:401S-428S
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
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
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
Complex special groups of VTE patientsComplex special groups of VTE patients
► 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
Complex special groups of VTE patientsComplex special groups of VTE patients
► 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