The Science and Medicine of Thrombosis Management New Dimensions, Novel Approaches, and Landmark Practice Advances in Venous and Arterial Thrombosis Prevention and Treatment: The Internal Medicine Perspective Samuel Z. Goldhaber, MD Program Chairman and Moderator Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School Samuel Z. Goldhaber, MD Program Chairman and Moderator Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School National Experts Illuminate and Debate

CME-certified symposium jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Bristol-Myers Squibb/Pfizer Pharmaceuticals Partnership. Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview

Program Educational Objectives As a result of this session: Clinicians will learn how to apply current guidelines issued by national professional organizations and collegesincluding the AHA, ACC, AAN, and ACCPmandating risk-directed prophylaxis against cerebral thromboembolic infarction in at risk patients with AF. Clinicians will learn how to apply current guidelines issued by national professional organizations and collegesincluding the AHA, ACC, AAN, and ACCPmandating risk-directed prophylaxis against cerebral thromboembolic infarction in at risk patients with AF. Clinicians will learn how to apply current guidelines issued by national professional organizations and colleges, such as the ACCP, mandating risk- directed prophylaxis against DVT in at risk patients with medical and surgical conditions. Clinicians will learn how to apply current guidelines issued by national professional organizations and colleges, such as the ACCP, mandating risk- directed prophylaxis against DVT in at risk patients with medical and surgical conditions. Clinicians will learn about the coagulation cascade, mechanisms involved in inhibition at various points in the clotting cascade, and the rationale for developing and investigating oral agents with predictable anticoagulation, in the absence of clinical monitoring. Clinicians will learn about the coagulation cascade, mechanisms involved in inhibition at various points in the clotting cascade, and the rationale for developing and investigating oral agents with predictable anticoagulation, in the absence of clinical monitoring. Clinicians will learn to risk stratify medical and surgical patients, assess their likelihood for incurring DVT, and be aware of prophylaxis measures that can reduce the incidence of DVT in the patient populations. Clinicians will learn to risk stratify medical and surgical patients, assess their likelihood for incurring DVT, and be aware of prophylaxis measures that can reduce the incidence of DVT in the patient populations. As a result of this session: Clinicians will learn how to apply current guidelines issued by national professional organizations and collegesincluding the AHA, ACC, AAN, and ACCPmandating risk-directed prophylaxis against cerebral thromboembolic infarction in at risk patients with AF. Clinicians will learn how to apply current guidelines issued by national professional organizations and collegesincluding the AHA, ACC, AAN, and ACCPmandating risk-directed prophylaxis against cerebral thromboembolic infarction in at risk patients with AF. Clinicians will learn how to apply current guidelines issued by national professional organizations and colleges, such as the ACCP, mandating risk- directed prophylaxis against DVT in at risk patients with medical and surgical conditions. Clinicians will learn how to apply current guidelines issued by national professional organizations and colleges, such as the ACCP, mandating risk- directed prophylaxis against DVT in at risk patients with medical and surgical conditions. Clinicians will learn about the coagulation cascade, mechanisms involved in inhibition at various points in the clotting cascade, and the rationale for developing and investigating oral agents with predictable anticoagulation, in the absence of clinical monitoring. Clinicians will learn about the coagulation cascade, mechanisms involved in inhibition at various points in the clotting cascade, and the rationale for developing and investigating oral agents with predictable anticoagulation, in the absence of clinical monitoring. Clinicians will learn to risk stratify medical and surgical patients, assess their likelihood for incurring DVT, and be aware of prophylaxis measures that can reduce the incidence of DVT in the patient populations. Clinicians will learn to risk stratify medical and surgical patients, assess their likelihood for incurring DVT, and be aware of prophylaxis measures that can reduce the incidence of DVT in the patient populations.

Program Faculty Program Chair And Moderator Samuel Z. Goldhaber, MD Professor of Medicine Cardiovascular Division Harvard Medical School Director, Venous Thromboembolism Research Group Research Group Director, Anticoagulation Service Brigham and Womens Hospital President, North American Thrombosis Forum Forum Boston, MA Distinguished Faculty Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Boston University School of Medicine Boston, MA Program Chair And Moderator Samuel Z. Goldhaber, MD Professor of Medicine Cardiovascular Division Harvard Medical School Director, Venous Thromboembolism Research Group Research Group Director, Anticoagulation Service Brigham and Womens Hospital President, North American Thrombosis Forum Forum Boston, MA Distinguished Faculty Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Boston University School of Medicine Boston, MA Geno Merli, MD, FACP Director, Jefferson Center for Vascular Disease Disease Professor of Medicine Senior Vice President and Chief Medical Officer Officer Thomas Jefferson Hospital Philadelphia, PA Alexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPC Professor of Medicine Department of Medicine Hamilton Health Sciences - General Hospital Hospital Hamilton, Ontario Hamilton, Ontario Canada Geno Merli, MD, FACP Director, Jefferson Center for Vascular Disease Disease Professor of Medicine Senior Vice President and Chief Medical Officer Officer Thomas Jefferson Hospital Philadelphia, PA Alexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPC Professor of Medicine Department of Medicine Hamilton Health Sciences - General Hospital Hospital Hamilton, Ontario Hamilton, Ontario Canada

Faculty COI Financial Disclosures Samuel Z. Goldhaber, MD Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; Mitsubishi; Sanofi-Aventis Consultant: Boehringer-Ingelheim; BMS; Eisai, Emisphere; Merck; Pfizer; Sanofi- Aventis Elaine M. Hylek, MD, MPH Research Funding: AstraZeneca, Bristol-Myers Squibb, Pfizer Advisory Board: Aton Pharma, Bristol-Myers Squibb, Vox Medica Geno Merli, MD, FACP Grants/Research Support: Boehringer Ingelheim GmbH, Bristol-Myers Squibb, sanofi- aventis U.S. Consultant: Bacchus Vascular, Inc., Bristol-Myers Squibb, sanofi-aventis U.S. Speakers Bureau: sanofi-aventis U.S. Alexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPC Speaker's Bureau: GlaxoSmithKline, sanofi-aventis and Pfizer Grant and/or Research Support: Bayer Pharmaceuticals Consultation: GlaxoSmithKline, Bayer Pharmaceuticals, sanofi-aventis and Astellas Pharma Inc. Samuel Z. Goldhaber, MD Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; Mitsubishi; Sanofi-Aventis Consultant: Boehringer-Ingelheim; BMS; Eisai, Emisphere; Merck; Pfizer; Sanofi- Aventis Elaine M. Hylek, MD, MPH Research Funding: AstraZeneca, Bristol-Myers Squibb, Pfizer Advisory Board: Aton Pharma, Bristol-Myers Squibb, Vox Medica Geno Merli, MD, FACP Grants/Research Support: Boehringer Ingelheim GmbH, Bristol-Myers Squibb, sanofi- aventis U.S. Consultant: Bacchus Vascular, Inc., Bristol-Myers Squibb, sanofi-aventis U.S. Speakers Bureau: sanofi-aventis U.S. Alexander G. G. Turpie, MD, FRCP, FACP, FACC, FRCPC Speaker's Bureau: GlaxoSmithKline, sanofi-aventis and Pfizer Grant and/or Research Support: Bayer Pharmaceuticals Consultation: GlaxoSmithKline, Bayer Pharmaceuticals, sanofi-aventis and Astellas Pharma Inc.

Crisis in Thrombosis Medicine Current Successes and an Even Brighter Future Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School The Science and Medicine of Thrombosis Management

Myocardial Infarction Good and Bad News Incidence Rate per 100,000

ICOPER Cumulative Mortality Mortality (%) Days From Diagnosis 17.5% Lancet 1999;353:

Incidence 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 MI!) and the high frequency of undiagnosed PE causing sudden cardiac death emphasize the need for improved preventive efforts. The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed PE causing sudden cardiac death emphasize the need for improved preventive efforts. Failure to institute prophylaxis is a much bigger problem with Medical Service patients than Surgical Service patients. Failure to institute prophylaxis is a much bigger problem with Medical Service patients than Surgical Service patients. The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed PE causing sudden cardiac death emphasize the need for improved preventive efforts. The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed PE causing sudden cardiac death emphasize the need for improved preventive efforts. Failure to institute prophylaxis is a much bigger problem with Medical Service patients than Surgical Service patients. Failure to institute prophylaxis is a much bigger problem with Medical Service patients than Surgical Service patients. Incidence of VTE

Morbidity/Mortality of Pulmonary Embolism

Progression of Chronic Venous Insufficiency From UpToDate 2006

Danish 20-year Cohort: VTE, Subsequent CV Events Assessed risk of MI, Stroke Assessed risk of MI, Stroke 25,199 with DVT 25,199 with DVT 16,925 with PE 16,925 with PE 163,566 population controls 163,566 population controls Assessed risk of MI, Stroke Assessed risk of MI, Stroke 25,199 with DVT 25,199 with DVT 16,925 with PE 16,925 with PE 163,566 population controls 163,566 population controls Sorensen HT. Lancet 2007; 370:

Association Between VTE and Arterial Thrombotic Events CV Event 1 Year RR 2-20 Year RR Acute MI Stroke Sorensen HT. Lancet 2007; 370: Relative Risk (RR) of CV Events in PE Patients

Cardiovascular Risk Factors and VTE A Continuum of Shared Risk Ageno W. Circulation 2008; 117: Risk Factor Relative Risk Obesity2.3 Hypertension1.5 Diabetes1.4 Cigarettes1.2 High Cholesterol 1.2 N = 63,552 for this meta-analysis N = 63,552 for this meta-analysis

Risk Factors for VTE and Arterial Thrombosis Implications of Meta-Analysis Risk Factors for VTE and Arterial Thrombosis Implications of Meta-Analysis 1.Risk factors for atherothrombosis are also associated with VTE 2.Cardiovascular risk factors may be involved in pathogenesis of VTE 3.Atherosclerosis and VTE are not completely distinct entities. 1.Risk factors for atherothrombosis are also associated with VTE 2.Cardiovascular risk factors may be involved in pathogenesis of VTE 3.Atherosclerosis and VTE are not completely distinct entities. Ageno W. Circulation 2008; 117:

Risk Factors Linking Venous and Arterial Thromboembolism 1.Activation of platelets and coagulation proteins 2.Increased fibrin turnover 3.Inflammation 4.Lipid profiles 1.Activation of platelets and coagulation proteins 2.Increased fibrin turnover 3.Inflammation 4.Lipid profiles Biologically Plausible Mechanisms

Steffen LM. Circulation 2007;115: Lowering VTE Risk Adjusted Hazard Ratios (Quintiles) 2345p Fruits, veggie Fish Red Meat Eat Veggies and Be Careful with Red Meat

Persistent Stress and PE An Evolving Association 1.Persistent stress increased the risk of PE by 80% 2.After multivariable adjustment, the risk of PE increased by 66% 1.Persistent stress increased the risk of PE by 80% 2.After multivariable adjustment, the risk of PE increased by 66% Rosengren A, et al. JTH 2008; 6: N=6,958 Swedish Men 23-Year Average Follow-Up

Reversible Risk Factors 1.Nutrition: Eat fruits, veggies, fish; less red meat 2.Quit cigarettes 3.Lose weight and exercise 4.Prevent DM and metabolic syndrome 5.Control hypertension 6.Lower cholesterol 7.Stress reduction 1.Nutrition: Eat fruits, veggies, fish; less red meat 2.Quit cigarettes 3.Lose weight and exercise 4.Prevent DM and metabolic syndrome 5.Control hypertension 6.Lower cholesterol 7.Stress reduction

Trends In CV Disease Incidence A Success Story

Trends in Cigarette Smoking Incidence A Success Story

Warfarin Pharmacogenomics 1.Cytochrome P450 2C9 genotyping can identify mutations associated with impaired warfarin metabolism. 2.Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, or high doses of warfarin. 1.Cytochrome P450 2C9 genotyping can identify mutations associated with impaired warfarin metabolism. 2.Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, or high doses of warfarin. Schwartz UI. NEJM 2008; 358: 999

Incorporating routine genetic testing into warfarin dosing will result in an estimated: 85,000 fewer serious bleeds 85,000 fewer serious bleeds 17,700 fewer strokes 17,700 fewer strokes $1.1 billion saved $1.1 billion saved Incorporating routine genetic testing into warfarin dosing will result in an estimated: 85,000 fewer serious bleeds 85,000 fewer serious bleeds 17,700 fewer strokes 17,700 fewer strokes $1.1 billion saved $1.1 billion saved American Enterprise Institute The Brookings Report November, 2006

Rapid turnaround CYP2C9 and VKORC1 testing vs. empiric Rapid turnaround CYP2C9 and VKORC1 testing vs. empiric Primary endpoint: TTR Primary endpoint: TTR Smaller and fewer dosing changes with genetic testing Smaller and fewer dosing changes with genetic testing No difference in TTR No difference in TTR Rapid turnaround CYP2C9 and VKORC1 testing vs. empiric Rapid turnaround CYP2C9 and VKORC1 testing vs. empiric Primary endpoint: TTR Primary endpoint: TTR Smaller and fewer dosing changes with genetic testing Smaller and fewer dosing changes with genetic testing No difference in TTR No difference in TTR Genotype vs Standard Warfarin Dosing A Provocative Clinical Trial Coumadin-Genotype Trial (N=206) Coumadin-Genotype Trial (N=206) Circulation 2007; 116:

Can routine genetic testing reduce the Guessing Game and Play of Chance in warfarin dosing? Can routine genetic testing reduce the Guessing Game and Play of Chance in warfarin dosing? Is this approach ready for Prime Time? Is this approach ready for Prime Time? Can routine genetic testing reduce the Guessing Game and Play of Chance in warfarin dosing? Can routine genetic testing reduce the Guessing Game and Play of Chance in warfarin dosing? Is this approach ready for Prime Time? Is this approach ready for Prime Time? Shurin SB, Nabel EG. NEJM 2008; 358: Genotype vs Standard Warfarin Dosing

Novel Oral Anticoagulants 1.Apixaban: Direct factor Xa inhibitor (hepatic clearance)twice daily fixed dose 2.Rivaroxaban: direct factor Xa inhibitor (renal clearance)once daily fixed dose 3.Dabigatran: An oral DTItwice daily fixed dose (renal clearance) 1.Apixaban: Direct factor Xa inhibitor (hepatic clearance)twice daily fixed dose 2.Rivaroxaban: direct factor Xa inhibitor (renal clearance)once daily fixed dose 3.Dabigatran: An oral DTItwice daily fixed dose (renal clearance) Gross PL, Weitz JI; ATVB 2008; 28: 380

Take Home Points 1.Lump, dont split, venous and arterial TE risk factors. They are not separate silos. Risk factors are shared. 2.VTE and Atherosclerosis are linked: VTE may herald arterial event. 3.Lifestyle/reversible risk factors provide foundation for prevention. 4.Novel drugs, genetics, and decreased CV incidence trends promise a brighter future. 1.Lump, dont split, venous and arterial TE risk factors. They are not separate silos. Risk factors are shared. 2.VTE and Atherosclerosis are linked: VTE may herald arterial event. 3.Lifestyle/reversible risk factors provide foundation for prevention. 4.Novel drugs, genetics, and decreased CV incidence trends promise a brighter future.

Alexander G. G. Turpie Department of Medicine HHS-General Hospital Hamilton, Canada Alexander G. G. Turpie Department of Medicine HHS-General Hospital Hamilton, Canada The Emerging Role of Factor Xa Inhibition Mechanisms and Applications Across the Arteriovenous Spectrum The Science and Medicine of Thrombosis Management

The Demise of Warfarin Ecstatic or or Dead Dead

Antithrombotics That Have Changed Clinical Practice Anticoagulants Low-molecular-weight heparin Low-molecular-weight heparin Antiplatelet Drugs Thienopyridines Thienopyridines Glycoprotein IIb/IIIa Inhibitors Glycoprotein IIb/IIIa InhibitorsAnticoagulants Low-molecular-weight heparin Low-molecular-weight heparin Antiplatelet Drugs Thienopyridines Thienopyridines Glycoprotein IIb/IIIa Inhibitors Glycoprotein IIb/IIIa Inhibitors

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

Oral Anticoagulants are Recommended for Venous and Arterial Thrombosis Venous thrombosis Prevention Prevention After orthopaedic surgery After orthopaedic surgery After general surgery After general surgery In cancer patients In cancer patients Treatment Treatment Venous thrombosis Prevention Prevention After orthopaedic surgery After orthopaedic surgery After general surgery After general surgery In cancer patients In cancer patients Treatment Treatment Arterial thrombosis Arterial thrombosis Prevention Prevention Stroke in patients with AF Stroke in patients with AF MI in patients with ACS MI in patients with ACS ACCP guidelines, Chest 2004

Venous Thromboembolism Deep vein thrombosis Pulmonary embolism PROPHYLAXIS

VTE in Orthopaedic Surgery

ACCP 2004 Summary of Recommendations Geerts WH et al. Chest. 2004;126(3 suppl):338S-400S. THR = total hip replacement; TKR = total knee replacement; HFS = hip fracture surgery. THRTKRHFS Extended Use in HFS Extended Use in THR Fondaparinux1A1A1A1A1C+ LMWH1A1A1C+1C+1A Warfarin1A1A2B1C+1A

Venous Thromboembolism Deep vein thrombosis Pulmonary embolism Treatment

Confirmed VTE Continue LMWH or UFH for 5 days Monitor UFH with APTT and adjust dose Start warfarin 5mg, target INR 2.5 ( ) Overlap minimum 4-5 days and until INR >2.0 for 2 days Daily platelet count with UFH; x 1 for LMWH Suspected VT SC LMWH or IV heparin bolus (5000u) Confirm diagnosis Guidelines for Antithrombotic Therapy Treatment of Venous Thromboembolism ACCP Chest 2001

Treatment of Venous Thromboembolism Cochrane Library 4, 2002 Heparin(%)LMWH(%)RR (95% CI) Recurrent VTE 98/ %73/ %0.76( ) Major Bleeding 51/ %30/ %0.60( ) Death172/ %135/ %0.78( )

Recurrent Venous Thrombosis is Common Following a First Episode of Symptomatic DVT Cumulative Cumulative Incidence (%) Years Prandoni et al, Ann Intern Med 1996;125:

Long-term Treatment of VTE First episode of VTE secondary to a transient (reversible) risk factor First episode of VTE secondary to a transient (reversible) risk factor VKA for at least 3 months VKA for at least 3 months (Grade 1A) (Grade 1A) First episode of VTE First episode of VTE VKA at least 6 to 12 months VKA at least 6 to 12 months (Grade 1A) (Grade 1A) First episode idiopathic VTE First episode idiopathic VTE Consider indefinite anticoagulant therapy Consider indefinite anticoagulant therapy (Grade 2A) (Grade 2A) Second episode of VTE Second episode of VTE Indefinite anticoagulant therapy Indefinite anticoagulant therapy (Grade 1A) (Grade 1A) First episode of VTE secondary to a transient (reversible) risk factor First episode of VTE secondary to a transient (reversible) risk factor VKA for at least 3 months VKA for at least 3 months (Grade 1A) (Grade 1A) First episode of VTE First episode of VTE VKA at least 6 to 12 months VKA at least 6 to 12 months (Grade 1A) (Grade 1A) First episode idiopathic VTE First episode idiopathic VTE Consider indefinite anticoagulant therapy Consider indefinite anticoagulant therapy (Grade 2A) (Grade 2A) Second episode of VTE Second episode of VTE Indefinite anticoagulant therapy Indefinite anticoagulant therapy (Grade 1A) (Grade 1A)

Atrial Fibrillation (AF) AF – The most common significant cardiac arrhythmia AF – The most common significant cardiac arrhythmia Estimated to affect 4.5 million people in the EU and 2.2 million people in the US Estimated to affect 4.5 million people in the EU and 2.2 million people in the US Incidence of 9.9 per 1000 person-years in a large European study (N=6432) Incidence of 9.9 per 1000 person-years in a large European study (N=6432) Incidence of AF strongly age dependent – prevalence ~10% in those aged >80 years Incidence of AF strongly age dependent – prevalence ~10% in those aged >80 years AF increases the risk of stroke 5-fold AF increases the risk of stroke 5-fold AF is directly responsible for 15–20% of strokes AF is directly responsible for 15–20% of strokes AF is also a significant risk factor for stroke recurrence and severity AF is also a significant risk factor for stroke recurrence and severity The population is aging … The population is aging … AF – The most common significant cardiac arrhythmia AF – The most common significant cardiac arrhythmia Estimated to affect 4.5 million people in the EU and 2.2 million people in the US Estimated to affect 4.5 million people in the EU and 2.2 million people in the US Incidence of 9.9 per 1000 person-years in a large European study (N=6432) Incidence of 9.9 per 1000 person-years in a large European study (N=6432) Incidence of AF strongly age dependent – prevalence ~10% in those aged >80 years Incidence of AF strongly age dependent – prevalence ~10% in those aged >80 years AF increases the risk of stroke 5-fold AF increases the risk of stroke 5-fold AF is directly responsible for 15–20% of strokes AF is directly responsible for 15–20% of strokes AF is also a significant risk factor for stroke recurrence and severity AF is also a significant risk factor for stroke recurrence and severity The population is aging … The 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 US Assuming no further increase in age-adjusted AF incidence Miyasaka et al. Circulation Year Projected number of persons with AF (millions)

AF Guidelines – ACC/AHA/ESC 2006 Risk stratification Therapy High risk of stroke Prior thromboembolism (stroke, TIA, systemic embolism) Prior thromboembolism (stroke, TIA, systemic embolism) Rheumatic mitral stenosis Rheumatic mitral stenosis More than one of: age 75 years, hypertension, heart failure, impaired LV systolic function, or diabetes mellitus More than one of: age 75 years, hypertension, heart failure, impaired LV systolic function, or diabetes mellitus Oral VKA Moderate risk of stroke Only one of: age 75 years, hypertension, heart failure, impaired LV systolic function, or diabetes mellitus Only one of: age 75 years, hypertension, heart failure, impaired LV systolic function, or diabetes mellitus Oral VKA or aspirin Low risk of stroke Lone AF (no other risk factors) Lone AF (no other risk factors)Aspirin Oral VKA target INR is 2.5 (range 2–3); aspirin is recommended at 81–325 mg/day Fuster et al., Circulation 2006

Vitamin K Antagonists – Limitations Unpredictable pharmacokinetics and pharmacodynamics, which are affected by : Unpredictable pharmacokinetics and pharmacodynamics, which are affected by : Genetic factors (CYP 2C9 mutation) Genetic factors (CYP 2C9 mutation) Drug–drug interactions Drug–drug interactions Consumption of alcohol and foods containing vitamin K Consumption of alcohol and foods containing vitamin K Monitoring and frequent dose adjustment required to maintain INR within therapeutic window Monitoring and frequent dose adjustment required to maintain INR within therapeutic window Monitoring is costly, and a burden on patients and society Monitoring is costly, and a burden on patients and society Slow onset and offset of action (e.g. if patient requires surgery), requiring bridging with heparin or LMWH Slow onset and offset of action (e.g. if patient requires surgery), requiring bridging with heparin or LMWH Unpredictable pharmacokinetics and pharmacodynamics, which are affected by : Unpredictable pharmacokinetics and pharmacodynamics, which are affected by : Genetic factors (CYP 2C9 mutation) Genetic factors (CYP 2C9 mutation) Drug–drug interactions Drug–drug interactions Consumption of alcohol and foods containing vitamin K Consumption of alcohol and foods containing vitamin K Monitoring and frequent dose adjustment required to maintain INR within therapeutic window Monitoring and frequent dose adjustment required to maintain INR within therapeutic window Monitoring is costly, and a burden on patients and society Monitoring is costly, and a burden on patients and society Slow onset and offset of action (e.g. if patient requires surgery), requiring bridging with heparin or LMWH Slow onset and offset of action (e.g. if patient requires surgery), requiring bridging with heparin or LMWH Ansell et al., Chest 2004

Narrow Therapeutic Window of Vitamin K Antagonists Dose (µmol/kg/day) Thrombus size Total bleeding time (min) Effect Bleeding Warfarin New drug

Acetylsalicylacid Allopurinol Alufibrat Amiodarone Ammoidine Amoxapine Anabolika Androsteron Anthranilacis deriveratives Azapropazone Bezafibrate Benziodarone Broad spectrum antibiotics Cephalosporins Chinidinpräparate Chloralhydrate Chloramphenicole Cimetidine Clofihrate Clonipramine Cloxacilline Desipramin Dextrans Disulfirame Doxepins Erythromycins Ethacrynic acid Fenoprofene Fluconazole Glucagone Immunsuppressants Indomethacin Itraconazol Lofepramin Lokalanästhetika Mefenaminsäure Methylandrostenolon Metronidazol Monoaminoxidasehemmer Mutterkornalkaloide Nalidixinsäure Naproxen Nifluminsäure Nicotinsäurederivate Nortryptiline Oxyphenbutazon Paraaminosalicylsäure Penicilline Phenotiazinpräparate Phenylbutazone (in Rheuma-, Gicht-, Grippemitteln) Piroxicame Rauwolfiapräparate Salicylats Steroide, anabole Sulfinpyrazon Sulfisoxazol Sulfonamide Sulfonylurea Testosterone Thiobarbiturate Thyroxin Tienilinsäure Acetylcholine ACTH Adrenaline Amitriptyline Athinyl-Ostradiol Atropine Barbiturate Carbamacep~n Cholestyramine Corticosteroids, systemic Digitalis Diphenylhydantoine Diuretics Ganglion blocking agents Gluthetimide Griseofulvine Haloperidole Laxanzien Mercaptogurine Neuroleptika Ovulationshemmer Phenytoin Purinderivate Pyrithyldion Rifampicine Strophantine Thiouracile Thyreostatics Vitamin K Preparations Vitamin supplements Drug Interactions with VKAs Increased Effect Decreased Effect Close INR monitoring is required with EVERY change in medication !

Do We Need New Anticoagulants? Current Anticoagulants are Suboptimal What are Evolving Options and What Do Current Trials Suggest? The Science and Medicine of Thrombosis Management

New Anticoagulants TFPI (tifacogin) Fondaparinux Idraparinux Rivaroxaban Apixaban LY517717YM150DU-176bBetrixaban TAK 442 Dabigatran ORAL PARENTERAL DX-9065a DX-9065a Xa IIa TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen AT APC (drotrecogin alfa) sTM (ART-123) Adapted from Weitz & Bates, J Thromb Haemost 2007 TTP889

VIIa Xa IXa XIa XIIa Direct Thrombin Inhibition Tissue factor Factor IIa (thrombin) Dabigatran II ×

Dabigatran for Prevention of VTE After Major Orthopaedic Surgery: Phase III Studies Dabigatran doses of 150 and 220 mg once daily (od) were investigated in all three studies Dabigatran doses of 150 and 220 mg once daily (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 Study Type of surgery Comparator Number of patients Time to 1st administration of dabigatran Treatment duration RE-MODELTKR Enoxaparin 40 mg od, starting evening before surgery –4 hours post-surgery 6–10 days RE-MOBILIZETKR Enoxaparin 30 mg bid, starting 12–24 hours post- surgery –12 hours post-surgery 12–15 days RE-NOVATETHR Enoxaparin 40 mg od, starting evening before surgery –4 hours post-surgery 28–35 days

Dabigatran for Prevention of VTE After Major Orthopaedic Surgery: Results Enoxaparin Dabigatran (150 mg) Dabigatran (220 mg) DVT, PE and all-cause mortality (%) RE-NOVATE p<0.0001* 6.0 p<0.0001* RE-MOBILIZE p= p= p= p=0.02 RE-MODEL p=0.0005* 36.4 p=0.0345* Major bleeding (%) RE-NOVATE RE-MOBILIZE RE-MODEL *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 Studies RE-LY (stroke prevention in patients with AF) RE-LY (stroke prevention in patients with AF) Planned enrolment 15,000 patients Planned enrolment 15,000 patients Dabigatran 110 and 150 mg bid compared with warfarin Dabigatran 110 and 150 mg bid compared with warfarin Treatment duration up to 3 years Treatment duration up to 3 years RE-SOLVE, RE-COVER and RE-MEDY RE-SOLVE, RE-COVER and RE-MEDY Ongoing studies in treatment and secondary prevention of VTE Ongoing studies in treatment and secondary prevention of VTE RE-LY (stroke prevention in patients with AF) RE-LY (stroke prevention in patients with AF) Planned enrolment 15,000 patients Planned enrolment 15,000 patients Dabigatran 110 and 150 mg bid compared with warfarin Dabigatran 110 and 150 mg bid compared with warfarin Treatment duration up to 3 years Treatment duration up to 3 years RE-SOLVE, RE-COVER and RE-MEDY RE-SOLVE, RE-COVER and RE-MEDY Ongoing studies in treatment and secondary prevention of VTE Ongoing studies in treatment and secondary prevention of VTE

New Anticoagulants TFPI (tifacogin) Fondaparinux Idraparinux Rivaroxaban Apixaban LY517717YM150DU-176bBetrixaban TAK 442 Dabigatran ORALPARENTERAL DX-9065a Xa IIa TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen AT APC (drotrecogin alfa) sTM (ART-123) Adapted from Weitz & Bates, J Thromb Haemost 2007 TTP889

VIIa Xa IXa XIa XIIa Direct Factor Xa inhibition Tissue factor Fibrinogen Fibrin clot Factor II (prothrombin) RivaroxabanApixabanYM150DU-176bLY517717Betrixaban TAK 442 ×

Oral Factor Xa Inhibitors Clinical Development Rivaroxaban (Bayer/J&J) Phase III Apixaban (BMS/Pfizer)Phase II YM150 (Astellas) Phase IIb DU-176b (Daiichi) Phase IIb LY (Lilly) Phase IIb Betrixaban (Portola) Phase II TAK 442 (Takeda) Phase II Rivaroxaban (Bayer/J&J) Phase III Apixaban (BMS/Pfizer)Phase II YM150 (Astellas) Phase IIb DU-176b (Daiichi) Phase IIb LY (Lilly) Phase IIb Betrixaban (Portola) Phase II TAK 442 (Takeda) Phase II

Apixaban Factor Xa Inhibitor Oral, direct, selective factor Xa inhibitor Oral, direct, selective factor Xa inhibitor Produces concentration-dependent anticoagulation Produces concentration-dependent anticoagulation No formation of reactive intermediates No formation of reactive intermediates No organ toxicity or LFT abnormalities in chronic toxicology studies No organ toxicity or LFT abnormalities in chronic toxicology studies Low likelihood of drug interactions or QTc prolongation Low likelihood of drug interactions or QTc prolongation Good oral bioavailability Good oral bioavailability No food effect No food effect Balanced elimination (~25% renal) Balanced elimination (~25% renal) Half-life ~12 hrs Half-life ~12 hrs Oral, direct, selective factor Xa inhibitor Oral, direct, selective factor Xa inhibitor Produces concentration-dependent anticoagulation Produces concentration-dependent anticoagulation No formation of reactive intermediates No formation of reactive intermediates No organ toxicity or LFT abnormalities in chronic toxicology studies No organ toxicity or LFT abnormalities in chronic toxicology studies Low likelihood of drug interactions or QTc prolongation Low likelihood of drug interactions or QTc prolongation Good oral bioavailability Good oral bioavailability No food effect No food effect Balanced elimination (~25% renal) Balanced elimination (~25% renal) Half-life ~12 hrs Half-life ~12 hrs He et al., ASH, 2006, Lassen, et al ASH, 2006

Apixaban: Phase II Studies APROPOS – Orthopaedic surgery APROPOS – Orthopaedic surgery Botticelli – Treatment Botticelli – Treatment ADAPT – Advanced cancer ADAPT – Advanced cancer APPRAISE 1 – ACS APPRAISE 1 – ACS APROPOS – Orthopaedic surgery APROPOS – Orthopaedic surgery Botticelli – Treatment Botticelli – Treatment ADAPT – Advanced cancer ADAPT – Advanced cancer APPRAISE 1 – ACS APPRAISE 1 – ACS

Apixaban Phase 2 Studies APROPOSCV185010completed Phase 2 dose-ranging study for VTE prevention in patients undergoing total knee replacement patients randomized day treatment : Apixaban 2.5, 5, 10 mg BID, 5, 10, 20 QD, enoxaparin 30 mg BID, warfarin BOTTICELLICV185017completed Phase 2 dose-ranging study for treatment of DVT; 520 patients randomized. 3 month treatment with: Apixaban 5, 10 mg BID, 20 mg QD, or LMWH/warfarin ADVOCATECV Phase 2 pilot study for VTE prevention in patients with advanced cancer (planned 160 subjects) Apixaban 5, 10, 20 mg QD vs. placebo APPRAISE-1CV Phase 2 study in patients with recent acute coronary syndromes; randomization completed 6 month treatment with apixaban 2.5 mg BID, 10 mg QD, 10 mg BID, 20 mg QD vs. placebo on top of standard-of-care (aspirin or aspirin + clopidogrel)

Lassen et al. Blood 2006 Total VTE and All-Cause Mortality (%) Major Bleeding (%) Enoxaparin (30mg bid) Apixaban for Prevention of VTE After Major Orthopaedic Surgery Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patients Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patients 20mg Apixaban (Total Daily Dose) 10mg5mg Warfarin (INR ) Enoxaparin (30mg bid) 20mg Apixaban (Total Daily Dose) 10mg5mg Warfarin (INR ) Percent

Büller, Eur Heart J 2006 Composite of Symptomatic Recurrent VTE and Deterioration of Thrombotic Burden (%) Major Bleeding (%) Apixaban for the Treatment of DVT: The Botticelli-DVT Study Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight heparin (LMWH) or fondaparinux followed by VKA, in 520 patients Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight heparin (LMWH) or fondaparinux followed by VKA, in 520 patients 20mg bid Apixaban 10mg bid 5mg bid LMWH/ fondaparinux + VKA 20mg bid Apixaban 10mg bid 5mg bid LMWH/ fondaparinux + VKA Percent

Apixaban Phase 3 Clinical Development VTE Prevention ADVANCE-1CV VTE prevention after knee replacement surgery (N ~ 3000) 12d vs. enoxaparin 30mg BID (superiority) 12d vs. enoxaparin 30mg BID (superiority) ADVANCE-2CV VTE prevention after knee replacement surgery (N ~ 3000) 12d vs. enoxaparin 40mg QD (superiority) 12d vs. enoxaparin 40mg QD (superiority) ADVANCE-3CV VTE prevention after hip replacement surgery (N ~ 4000) 35d vs. enoxaparin 40mg QD (noninferiority) 35d vs. enoxaparin 40mg QD (noninferiority) ADOPTCV VTE prevention in acutely ill medical patients (N ~ 6500) 30d vs. ~6d enoxaparin 40mg QD followed by placebo post-discharge (superiority) 30d vs. ~6d enoxaparin 40mg QD followed by placebo post-discharge (superiority)

Apixaban Phase 3 Stroke Prevention in Atrial Fibrillation ARISTOTLECV Stroke prevention in patients with atrial fibrillation (N ~ 15,000) Treatment for up to two years with 5 mg BID apixaban vs. warfarin (INR 2 -3) AVERROESCV Stroke prevention in patients with atrial fibrillation not able to receive warfarin (N ~ 5,600) Treatment for up to two years with 5 mg BID apixaban vs. aspirin

Rivaroxaban: Oral Direct Factor Xa Inhibitor Predictable pharmacology Predictable pharmacology High bioavailability High bioavailability Low risk of drug– drug interactions Low risk of drug– drug interactions Fixed dose Fixed dose No requirement for monitoring No requirement for monitoring Predictable pharmacology Predictable pharmacology High bioavailability High bioavailability Low risk of drug– drug interactions Low risk of drug– drug interactions Fixed dose Fixed dose No requirement for monitoring No requirement for monitoring Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005 Rivaroxaban ® – rivaroxaban

Rivaroxaban Specific, competitive, direct FXa inhibitor Specific, competitive, direct FXa inhibitor Inhibits free and clot- associated FXa activity, and prothrombinase activity Inhibits free and clot- associated FXa activity, and prothrombinase activity Inhibits thrombin generation via inhibition of FXa activity Inhibits thrombin generation via inhibition of FXa activity Prolongs time to thrombin generation Prolongs time to thrombin generation Inhibits peak thrombin generation Inhibits peak thrombin generation Reduces the total amount of thrombin generated Reduces the total amount of thrombin generated Does not require a cofactor Does not require a cofactor Specific, competitive, direct FXa inhibitor Specific, competitive, direct FXa inhibitor Inhibits free and clot- associated FXa activity, and prothrombinase activity Inhibits free and clot- associated FXa activity, and prothrombinase activity Inhibits thrombin generation via inhibition of FXa activity Inhibits thrombin generation via inhibition of FXa activity Prolongs time to thrombin generation Prolongs time to thrombin generation Inhibits peak thrombin generation Inhibits peak thrombin generation Reduces the total amount of thrombin generated Reduces the total amount of thrombin generated Does not require a cofactor Does 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

Study Background ACCP guidelines: grade 1A recommendation for up to 35 days prophylaxis after elective hip replacement surgery ACCP guidelines: grade 1A recommendation for up to 35 days prophylaxis after elective hip replacement surgery Geerts et al.,

Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprophylaxis after total hip arthroplasty Factor Xa Inhibition

Enoxaparin 40 mg od Rivaroxaban 10 mg od RECORD 1 Study Design Mandatory bilateral venography R S U R G E R Y F O L L O W U P Evening before surgery 6–8 hours post-surgery Day 1 Day 36±4 Double blind Last dose, day before venography Up to Day 65 Inclusion criteria Patients aged 18 years, scheduled to undergo elective THR Patients aged 18 years, scheduled to undergo elective THR Inclusion criteria Patients aged 18 years, scheduled to undergo elective THR Patients aged 18 years, scheduled to undergo elective THR Major exclusion criteria Active bleeding or high risk of bleeding Active bleeding or high risk of bleeding Significant liver disease Significant liver disease Anticoagulant therapy that could not be stopped Anticoagulant therapy that could not be stopped Use of HIV-protease inhibitors Use of HIV-protease inhibitors Major exclusion criteria Active bleeding or high risk of bleeding Active bleeding or high risk of bleeding Significant liver disease Significant liver disease Anticoagulant therapy that could not be stopped Anticoagulant therapy that could not be stopped Use of HIV-protease inhibitors Use of HIV-protease inhibitors

RECORD 1 Summary Incidence (%) Total VTE Major bleeding Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily % 0.3% 0.1% 0.3% Symptomatic VTE RRR 70% 2.0% 0.2% Major VTE 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 Inhibition

Rivaroxaban 10 mg od Mandatorybilateralvenography RECORD 2 Study Design Inclusion criteria Patients aged 18 years, scheduled to undergo elective THR Patients aged 18 years, scheduled to undergo elective THR Day 65+5 R S U R G E R Y FO L L O W U P Evening before surgery 6–8 hours post-surgery Day 1 Double blind Major exclusion criteria Active bleeding or high risk of bleeding Active bleeding or high risk of bleeding Significant liver disease Significant liver disease Anticoagulant therapy that could not be stopped Anticoagulant therapy that could not be stopped Use of HIV-protease inhibitors Use of HIV-protease inhibitors Day 36±4 Enoxaparin 40 mg od Oral placebo

RECORD 2 Summary Total VTE Major bleeding Major VTE Incidence (%) % RRR 78.9% 2.0% 5.1%0.1%0.1%0.6% RRR 87.8% RRR 80.1% 1.2% 0.2% Symptomatic VTE Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily

Rivaroxaban – An oral, direct Factor Xa inhibitor: For the prevention of venous thromboembolism in total knee arthroplasty surgery Factor Xa Inhibition

Enoxaparin 40 mg od Rivaroxaban 10 mg od Mandatorybilateralvenography RECORD 3 Study Design Inclusion criteria Patients aged 18 years, scheduled to undergo elective, total knee replacement (TKR) surgery Patients aged 18 years, scheduled to undergo elective, total knee replacement (TKR) surgery Day 42+5 R S U R G E R Y FO L L O W U P Evening before surgery 6–8 hours post-surgery Day 1 Day 13±2 Double blind Last dose, 1 day before venography Major exclusion criteria Active bleeding or high risk of bleeding Active bleeding or high risk of bleeding Significant liver disease Significant liver disease Anticoagulant therapy that could not be stopped Anticoagulant therapy that could not be stopped Use of HIV-protease inhibitors Use of HIV-protease inhibitors R S U R G E R Y

RECORD 3 Summary Total VTE Major bleeding 20 Incidence (%) 0 Major VTE NS RRR 49% RRR 62% Symptomatic VTE Rivaroxaban 10 mg od Enoxaparin 40 mg od RRR 65% 0.5% 0.6% 18.9%9.6% 2.6% 1.0% 2.0% 0.7%

Rivaroxaban Clinical Trials ~50,000 patients

Properties of an Ideal Anticoagulant PropertiesBenefits Orally active Ease of administration Rapid onset of action Obviates need for overlap with a parenteral anticoagulant No food or drug interactions Simplified dosing Predictable anticoagulant effect No routine coagulation monitoring Extra-renal clearance Safe in patients with renal insufficiency Rapid offset of action Simplifies management in case of bleed or need for intervention Safe antidote Useful in case of major bleed Favourable net clinical benefit Treatment benefit outweighs risk

Beyond Vitamin K Antagonists The Future of Oral Anticoagulation New anticoagulants that do not require monitoring or dose adjustment are in development New anticoagulants that do not require monitoring or dose adjustment are in development Drugs that inhibit thrombin or FXa are attractive options Drugs that inhibit thrombin or FXa are attractive options Rivaroxaban, dabigatran and apixaban are in phase III development Rivaroxaban, dabigatran and apixaban are in phase III development Over the next 5 years, we could see a paradigm shift in the anticoagulant management of thromboembolic disease Over the next 5 years, we could see a paradigm shift in the anticoagulant management of thromboembolic disease New anticoagulants that do not require monitoring or dose adjustment are in development New anticoagulants that do not require monitoring or dose adjustment are in development Drugs that inhibit thrombin or FXa are attractive options Drugs that inhibit thrombin or FXa are attractive options Rivaroxaban, dabigatran and apixaban are in phase III development Rivaroxaban, dabigatran and apixaban are in phase III development Over the next 5 years, we could see a paradigm shift in the anticoagulant management of thromboembolic disease Over the next 5 years, we could see a paradigm shift in the anticoagulant management of thromboembolic disease

Challenges of Stroke Prevention in Atrial Fibrillation Achieving the Balance between Thromboprophylaxis and Hemorrhage Challenges of Stroke Prevention in Atrial Fibrillation Achieving the Balance between Thromboprophylaxis and Hemorrhage The Science and Medicine of Thrombosis Management Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Boston University School of Medicine Boston, MA Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Boston University School of Medicine Boston, MA

Miyasaka, Y. et al. Circulation 2006;114: Projected Number of Persons with AF in the U.S. Between 2000 and 2050 Assumes no further increase in age-adjusted AF incidence (yellow curve) and assumes a continued increase in incidence rate as evident in 1980 to 2000 (orange curve) Projected number of persons with AF (millions)

Prevalence of AF at Various Ages Chest 1995;108:352S FraminghamCHSRochester Western Australia Prevalence (%) Age

The Epidemic of Atrial Fibrillation Increasing prevalence of risk factors for AF Older age Older age Systemic hypertension Systemic hypertension Heart failure Heart failure Valvular heart disease Valvular heart disease Diabetes mellitus Diabetes mellitus Obesity Obesity Increasing prevalence of risk factors for AF Older age Older age Systemic hypertension Systemic hypertension Heart failure Heart failure Valvular heart disease Valvular heart disease Diabetes mellitus Diabetes mellitus Obesity Obesity

LAA Thrombus

Cardiac Embolism to a Cerebral Artery

Atrial 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% per year Risk of stroke in untreated AF patients averages ~ 5% per year Risk of stroke in AF patients by age group Risk of stroke in AF patients by age group 1.5% in 50 to 59 year age group 1.5% in 50 to 59 year age group 23.5% in 80 to 89 year age group 23.5% in 80 to 89 year age group AF is associated with a 50 to 90% increase in risk of death after adjustment for coexisting CV conditions AF is associated with a 50 to 90% increase in risk of death after adjustment for coexisting CV conditions ~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% per year Risk of stroke in untreated AF patients averages ~ 5% per year Risk of stroke in AF patients by age group Risk of stroke in AF patients by age group 1.5% in 50 to 59 year age group 1.5% in 50 to 59 year age group 23.5% in 80 to 89 year age group 23.5% in 80 to 89 year age group AF is associated with a 50 to 90% increase in risk of death after adjustment for coexisting CV conditions AF is associated with a 50 to 90% increase in risk of death after adjustment for coexisting CV conditions Wolf PA, et al. Stroke 1991; 22: Benjamin EB, et al. Circulation 1998;98: American Heart Association. Heart Disease and Stroke Statistics-2006 Update. Dallas, TX: American Heart Association;2006. ©2006 American Heart Association

Global Impact of Stroke 3 rd most common cause of death in developed countries 3 rd most common cause of death in developed countries 15 million strokes occur each year worldwide 15 million strokes occur each year worldwide 5.5 million deaths from stroke 5.5 million deaths from stroke Stroke is a leading cause of serious, long-term disability Stroke is a leading cause of serious, long-term disability 5 million people permanently disabled each year 5 million people permanently disabled each year Disability-adjusted life years projected to reach 61 million years per 1000 population by the year 2020 (38 million in 1990 ) Disability-adjusted life years projected to reach 61 million years per 1000 population by the year 2020 (38 million in 1990 ) 3 rd most common cause of death in developed countries 3 rd most common cause of death in developed countries 15 million strokes occur each year worldwide 15 million strokes occur each year worldwide 5.5 million deaths from stroke 5.5 million deaths from stroke Stroke is a leading cause of serious, long-term disability Stroke is a leading cause of serious, long-term disability 5 million people permanently disabled each year 5 million people permanently disabled each year Disability-adjusted life years projected to reach 61 million years per 1000 population by the year 2020 (38 million in 1990 ) Disability-adjusted life years projected to reach 61 million years per 1000 population by the year 2020 (38 million in 1990 ) World Health Organization. The Atlas of Heart Disease and Stroke American Heart Association. Heart Disease and Stroke Statistics-2006 Update. Dallas, TX: American Heart Association;2006. ©2006 American Heart Association

Efficacy of Warfarin in Atrial Fibrillation Five Randomized Trials in Non-Valvular AF *Stopped early due to published positive results 68% overall risk reduction for stroke Study Value Warfarin (Number Pts.) Control INRRRp-Value AFASAK %0.027 SPAF %0.01 BAATAF %<0.05 CAFA* %0.25 SPINAF %0.001

Underutilization of Anticoagulation Therapy in AF (Jan Dec 2002) Waldo et al. JACC 2005;46(9): Approximately half of high-risk patients with atrial fibrillation receive warfarin therapy 53% 53% 47% 47% 13 Community Hospitals 21 Academic Hospitals Warfarin Therapy No Warfarin Therapy

Approximately half of high-risk patients with atrial fibrillation receive warfarin therapy 13 Community Hospitals21 Academic Hospitals Age >80 and perceived bleeding risk were negative predictors of warfarin use. Age >80 and perceived bleeding risk were negative predictors of warfarin use. Underutilization of Anticoagulation Therapy in Atrial Fibrillation (Jan Dec 2002) 53% 53% 47% 47% 13 Community Hospitals 21 Academic Hospitals Warfarin Therapy No Warfarin Therapy

Warfarin Use Among Ohio Medicaid Patients Retrospective analysis using claims data Only 11.9% of patients without contraindications filled prescriptions for warfarin Most prevalent potential contraindications: * Barriers to compliance-30% * Predisposition to falls-24% * Prior Bleed-13 % Retrospective analysis using claims data Only 11.9% of patients without contraindications filled prescriptions for warfarin Most prevalent potential contraindications: * Barriers to compliance-30% * Predisposition to falls-24% * Prior Bleed-13 % Johnston JA, et al. Arch Intern Med 2003;163: (n=11,699)

Effectiveness of Warfarin Among Different Patient Populations: FeaturesWhiteN=16,007BlackN=797HispanicN=468 CHADS 2 Score, mean (SD) 2.6 (1.4) 3.1 (1.4) 2.9 (1.3) Warfarin at discharge (%) Monitored < 90 days (%) Lost to Monitoring (%) Stroke Rate per 100 yr (95% CI) 5.2( )12.2( )10.6( ) Birman-Deych et al; Stroke. 2006;37: A State-Stratified Random Sample of Medicare Beneficiaries Jan 1998 – Dec 1999

Major Hemorrhage Rates Randomized Trials INR Target ICHMajorAge AFI SPAF II AFFIRM Observational INR Target ICHMajorAge Van der Meer,et al (1993) Palareti, et al (1996) Go, et al

Caveats Relating to Published Data on Hemorrhage Randomized trials - Enrolled few patients 80 years - Highly selected, closely monitored - Vitamin K antagonist at entry Prospective cohort studies - Predominantly non-inception cohort studies of prevalent warfarin use (survivor bias) - Enrolled few patients 80 years - Varying definitions of bleeding - Most conducted within anticoagulation clinic setting setting Randomized trials - Enrolled few patients 80 years - Highly selected, closely monitored - Vitamin K antagonist at entry Prospective cohort studies - Predominantly non-inception cohort studies of prevalent warfarin use (survivor bias) - Enrolled few patients 80 years - Varying definitions of bleeding - Most conducted within anticoagulation clinic setting setting

Cumulative Incidence of Major Bleeding in the First Year Among Patients Newly Starting Warfarin by Age Hylek EM et al, Circulation 2007;115(21): Days on Warfarin Age 80 Cumulative Proportion with Major Hemorrhage

Risk of Stopping Therapy in the First Year Among Patients Newly Starting Warfarin by Age Hylek EM et al, Circulation 2007;115(21): Days on Warfarin Age 80 Risk of Stopping Warfarin

CHADS 2 Score N Major Bleed (N) Bleeding Rates % Taken Off Therapy (N) Taken Off Rates % Total Major Hemorrhagic Events and Warfarin Terminations by CHADS 2 Score Hylek EM et al, Circulation 2007;115(21):

Challenges to Use of Vitamin K Antagonists Challenges to Use of Vitamin K Antagonists Challenges to Managing AF

Drug interference Drug interference Amiodarone (inhibits R- and S-); Amiodarone (inhibits R- and S-); Acetaminophen (enzymes vitamin K cycle) Acetaminophen (enzymes vitamin K cycle) Dietary vitamin K Dietary vitamin K Genetic polymorphisms: Genetic polymorphisms: Cytochrome P450 CYP2C9 and VKORC1 (vitamin K epoxide reductase complex 1) Cytochrome P450 CYP2C9 and VKORC1 (vitamin K epoxide reductase complex 1) Disease States, e.g., CHF, malignancy Disease States, e.g., CHF, malignancy Pharmacodynamic changes with aging Pharmacodynamic changes with aging Drug interference Drug interference Amiodarone (inhibits R- and S-); Amiodarone (inhibits R- and S-); Acetaminophen (enzymes vitamin K cycle) Acetaminophen (enzymes vitamin K cycle) Dietary vitamin K Dietary vitamin K Genetic polymorphisms: Genetic polymorphisms: Cytochrome P450 CYP2C9 and VKORC1 (vitamin K epoxide reductase complex 1) Cytochrome P450 CYP2C9 and VKORC1 (vitamin K epoxide reductase complex 1) Disease States, e.g., CHF, malignancy Disease States, e.g., CHF, malignancy Pharmacodynamic changes with aging Pharmacodynamic changes with aging Variable Dose Response

Maintenance warfarin dose by age INR target 2-3 Derived from two independent ambulatory populations Garcia D, et al. Chest ;127:

Challenges of Warfarin Use Variable dose response Variable dose response Narrow therapeutic window Narrow therapeutic window Need for frequent monitoring Need for frequent monitoring Long half-life Long half-life Variable dose response Variable dose response Narrow therapeutic window Narrow therapeutic window Need for frequent monitoring Need for frequent monitoring Long half-life Long half-life

Fuster, V. et al. Circulation 2006;114: Adjusted Odds Ratios for Ischemic Stroke and Intracranial Bleeding in Relation to Intensity of Anticoagulation

Hylek, et al. NEJM

Challenges of Warfarin Use Variable dose response Variable dose response Narrow therapeutic window Narrow therapeutic window Need for frequent monitoring Need for frequent monitoring Long half-life Long half-life Variable dose response Variable dose response Narrow therapeutic window Narrow therapeutic window Need for frequent monitoring Need for frequent monitoring Long half-life Long half-life

Hylek, EM (unpublished data) Patient with Low INR Variability

Hylek, EM (unpublished data) Patient with High INR Variability

Challenges of Warfarin Use Variable dose response Variable dose response Narrow therapeutic window Narrow therapeutic window Need for frequent monitoring Need for frequent monitoring Long half-life Long half-life Variable dose response Variable dose response Narrow therapeutic window Narrow therapeutic window Need for frequent monitoring Need for frequent monitoring Long half-life Long half-life

Hylek et al, Ann Intern Med. 2001;135: Interval (days) INR 1b Index INR (n = 235) Median INR half life = 2.3 days Interquartile Range = (1.7,3.8) Median days to INR < 4: 1.5 days Interquartile Range = (1.1,2.5)

Risk factors for INR 4.0 After Holding Two Doses of Warfarin Warfarin dose, weekly per 10 mg 0.87 ( )Warfarin dose, weekly per 10 mg 0.87 ( ) Age, per decade 1.18 ( )Age, per decade 1.18 ( ) Decompensated heart failure 2.79 ( )Decompensated heart failure 2.79 ( ) Active malignancy 2.48 ( )Active malignancy 2.48 ( ) Index INR, per unit 1.25 ( )Index INR, per unit 1.25 ( ) Adjusted Odds Ratio

Strategies to Optimize Benefit Improve anticoagulation control Improve anticoagulation control ? Lower target intensity-NO ? Lower target intensity-NO ? Use antiplatelet therapy-NO ? Use antiplatelet therapy-NO Aggressive control of blood pressure Aggressive control of blood pressure Improve risk stratification Improve risk stratification New antithrombotic therapies (Factor Xa Inhibitors?) New antithrombotic therapies (Factor Xa Inhibitors?) ? Cure AF ? Cure AF Improve anticoagulation control Improve anticoagulation control ? Lower target intensity-NO ? Lower target intensity-NO ? Use antiplatelet therapy-NO ? Use antiplatelet therapy-NO Aggressive control of blood pressure Aggressive control of blood pressure Improve risk stratification Improve risk stratification New antithrombotic therapies (Factor Xa Inhibitors?) New antithrombotic therapies (Factor Xa Inhibitors?) ? Cure AF ? Cure AF

Summary 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 VTE Current Strategies and Emerging Role of Xa Inhibition for DVT Prevention and Treatment The Science and Medicine of Thrombosis Management Samuel Z. Goldhaber, MD Program Chairman and Moderator Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School Samuel Z. Goldhaber, MD Program Chairman and Moderator Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School

EPIDEMIOLOGY Scope of the Problem Prophylaxis of VTE

Annual At-Risk Population for VTE 7.7 million Medical Service inpatients 7.7 million Medical Service inpatients 3.4 million Surgical Service inpatients 3.4 million Surgical Service inpatients Based upon ACCP guidelines for VTE prophylaxis Based upon ACCP guidelines for VTE prophylaxis 7.7 million Medical Service inpatients 7.7 million Medical Service inpatients 3.4 million Surgical Service inpatients 3.4 million Surgical Service inpatients Based upon ACCP guidelines for VTE prophylaxis Based upon ACCP guidelines for VTE prophylaxis Anderson FA Jr, et al. Am J Hematol; 2007; 82: U.S. Hospitals

ENDORSE A Worldwide Study 68,183 patients; 32 countries; 358 sites First patient enrolled August 2, 2006;Last patient enrolled January 4, 2007 Lancet 2008; 371:

Worldwide Prophylaxis Status for 68,183 Patients 52% at risk for VTE (50% received ACCP recommended prophylaxis) Surgical 64% at risk for VTE 59% received ACCP recommended prophylaxis Medical 42% at risk for VTE 40% received ACCP recommended prophylaxis

Outpatient and Inpatient VTE are Linked 74% of VTEs present in outpatients. 74% of VTEs present in outpatients. 42% of outpatient VTE patients have had recent surgery or hospitalization. 42% of outpatient VTE patients have had 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 recent surgery or hospitalization. 42% of outpatient VTE patients have had 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:

Problems with Warfarin in the Setting of VTE Prophylaxis Challenges of Long-Term VTE Prophylaxis

The Delicate and Problematic Balance Between Thrombosis Prevention and Hemorrhage Avoidance Elevated INR is a surrogate for increased risk Elevated INR is a surrogate for increased risk of intracranial hemorrhage and other major of intracranial hemorrhage and other major bleeding complications. bleeding complications. Subtherapeutic INR is a surrogate for Subtherapeutic INR is a surrogate for thrombotic complications. thrombotic complications. The Delicate and Problematic Balance Between Thrombosis Prevention and Hemorrhage Avoidance Elevated INR is a surrogate for increased risk Elevated INR is a surrogate for increased risk of intracranial hemorrhage and other major of intracranial hemorrhage and other major bleeding complications. bleeding complications. Subtherapeutic INR is a surrogate for Subtherapeutic INR is a surrogate for thrombotic complications. thrombotic complications. Challenges of Long-Term VTE Prophylaxis

Therapeutic Range for Warfarin INR Values at Stroke or ICH Odds Ratio INR Stroke 1.0 Fuster et al. J Am Coll Cardiol. 2001;38: Intracranial Hemorrhage

Hylek, EM et al. N Engl J Med. 2003;349: Warfarin in Nonvalvular Atrial Fibrillation

Risk Factors for an Elevated INR (Its not all Genetics) Advanced Age (one-third dose) Advanced Age (one-third dose) Abnormal Liver Function Abnormal Liver Function Decreased Vitamin K Intake (NPO, Decreased Vitamin K Intake (NPO, diarrhea, antibiotics) Concomitant Medications Concomitant Medications Alcohol in Binges Alcohol in Binges Change in Warfarin Preparation Change in Warfarin Preparation Drug-drug and drug-food interactions Drug-drug and drug-food interactions Advanced Age (one-third dose) Advanced Age (one-third dose) Abnormal Liver Function Abnormal Liver Function Decreased Vitamin K Intake (NPO, Decreased Vitamin K Intake (NPO, diarrhea, antibiotics) Concomitant Medications Concomitant Medications Alcohol in Binges Alcohol in Binges Change in Warfarin Preparation Change in Warfarin Preparation Drug-drug and drug-food interactions Drug-drug and drug-food interactions

FDA Adds Black Box Warning/Precaution for Warfarin Therapy October 6, 2006 WARNING: BLEEDING RISK August 16, 2007 Precaution: Consider a lower initial warfarin dose for patients with certain genetic variations.

FDA 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)…

ED 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:

First Month Warfarin Has High Bleeding Rate Bleeding Type Head Bleed Major Non-Head Bleed 1 st Month Warfarin 0.92% (annualized) 1.2% (annualized) Subsequent Warfarin 0.46% per year 0.61% per year Fang MC. J Am Geriatr Soc 2006; 54:

Novel Anticoagulants What Do Published Trials and Clinical Trial Programs Tell Us? Solutions and Emerging Strategies

Properties of an Ideal Anticoagulant PropertiesBenefits Orally active Ease of administration Rapid onset of action Obviates need for overlap with a parenteral anticoagulant No food or drug interactions Simplified dosing Predictable anticoagulant effect No routine coagulation monitoring Extra-renal clearance Safe in patients with renal insufficiency Rapid offset of action Simplifies management in case of bleed or need for intervention Safe antidote Useful in case of major bleed Favorable net clinical benefit Treatment benefit outweighs risk

New Oral Anticoagulants: Advantages 1.No coagulation lab monitoring 2.No dose adjustment 3.No drug-food interactions 4.Rare drug-drug interactions 5.No bridging needed prior to invasive procedures or surgery 1.No coagulation lab monitoring 2.No dose adjustment 3.No drug-food interactions 4.Rare drug-drug interactions 5.No bridging needed prior to invasive procedures or surgery

Targets of New Oral Anticoagulants in the Most Advances Stages of Development Bates SM and Weitz JI. Drugs of the Future 2008, 33 TF/VIIaTF/VIIa XX IXIX IXaIXa VIIIaVIIIa VaVa XaXa IIII IIaIIa FibrinogenFibrinogenFibrinFibrin RivaroxabanApixabanRivaroxabanApixaban DabigatranDabigatran

Comparison of Novel Oral Anticoagulants with Warfarin Eikelboom JW, Weitz JI. Circulation 2007; 116: *Includes ketoconazole, macrolides (eg, clarithromycin), and protease inhibitors (eg, atazanavir) DrugTargetDosing Coag monitoring Half life (h) Renal cleared (%) Interacts Rivaroxa- ban Factor Xa Fixed, once daily No965 Potent CYP3A4 inhibitors* Apixaban Factor Xa Fixed, twice daily No9–1425 Potent CYP3A4 inhibitors* Dabigatran Factor IIa (thrombin) Fixed, twice daily No14–17100 Proton pump inhibitors Warfarin Vitamin K Variable, once daily Yes400 Multiple drugs, dietary vitamin K

Features of Apixaban Oral, direct, highly selective Factor Xa inhibitor Oral, direct, highly selective Factor Xa inhibitor Produces concentration-dependent anticoagulation Produces concentration-dependent anticoagulation No reactive intermediates No reactive intermediates No LFT abnormalities in chronic toxicology studies No LFT abnormalities in chronic toxicology studies Low likelihood of drug interactions Low likelihood of drug interactions Good oral bioavailability Good oral bioavailability No food effect No food effect Balanced elimination (~25% renal) Balanced elimination (~25% renal) Half-life ~12 hrs Half-life ~12 hrs Oral, direct, highly selective Factor Xa inhibitor Oral, direct, highly selective Factor Xa inhibitor Produces concentration-dependent anticoagulation Produces concentration-dependent anticoagulation No reactive intermediates No reactive intermediates No LFT abnormalities in chronic toxicology studies No LFT abnormalities in chronic toxicology studies Low likelihood of drug interactions Low likelihood of drug interactions Good oral bioavailability Good oral bioavailability No food effect No food effect Balanced elimination (~25% renal) Balanced elimination (~25% renal) Half-life ~12 hrs Half-life ~12 hrs He et al, ASH, 2006, Lassen, et al ASH, 2006

Comparison of the Antithrombotic Effects of Warfarin or Apixaban in a Rabbit DVT Model Wong et al, ASH, 2006 Warfarin * P< 0.05 vs. vehicle Warfarin ApixabanApixaban Warfarin (mg/kg PO) Apixaban (mg/kg/h IV) *-33%*-33% *-51%*-51% *-74%*-74% *-384*-384 *-16%*-16% *-55%*-55% *-73%*-73% *-83%*-83%

Comparison of the Effects of Warfarin or Apixaban on Cuticle Bleeding Time in Rabbits Wong et al, ASH, 2006 WarfarinWarfarin ApixabanApixaban Warfarin (mg/kg PO) Apixaban (mg/kg/h IV) Vehicle13

Lassen MR, et al. J Thromb Haemost 2007; 5: 2368–75. Incidence of VTE plus Death for QD and BID Doses of Apixaban and Comparators Apixaban Incidence of VTE and all causes death (%)

Lassen MR, et al. J Thromb Haemost 2007; 5: 2368–75. Incidence of Bleeding Events for QD and BID Doses of Apixaban and Comparators Apixaban Incidence of bleeding events (%) QD2.5 BID 10 QD5 BID20 QD10 BID EnoxWarf MajorMinor

Apixaban Clinical Development Program IndicationStatus VTE Prevention in Major Orthopedic Surgery Phase III VTE Prevention in Acutely Ill Medical Patients Phase III Stroke Prevention in Atrial Fibrillation Phase III Acute and Extended VTE Treatment Planning Phase III Prevention of Thrombotic Events in Patients with Recent ACS Phase II VTE Prevention in Cancer Patients Phase II

Eriksson B. ASH; December 8-11, 2007; Atlanta, GA. RECORD-1 (THR 5 weeks Rx) (N=4,541) Outcome Rivaroxaban % (n) Enoxaparin % (n) Relative risk reduction, % (95% CI) p DVT, nonfatal PE, all-cause mortality 1.1 (18/1595) 3.7 (58/1558) 70 (49–82) <0.001 Major VTE 0.2 (4/1686) 2.0 (33/1678) 88 (66–96) <0.001 Major bleed 0.3 (6/2209) 0.1 (2/2224) 0.178

Optimizing Implementation of VTE Prophylaxis Front Lines of Internal Medicine Practice

We have initiated trials with electronic alerts to modify MD behavior and improve implementation of VTE prophylaxis. Front Lines of Internal Medicine Practice

Definition Of High Risk VTE risk score 4 points: Cancer3(ICD codes) Cancer3(ICD codes) Prior VTE3(ICD codes) Prior VTE3(ICD codes) Hypercoagulability3(Leiden, ACLA) Hypercoagulability3(Leiden, ACLA) Major surgery2(> 60 minutes) Major surgery2(> 60 minutes) Bed rest1(bed rest order) Bed rest1(bed rest order) Advanced age1(> 70 years) Advanced age1(> 70 years) Obesity1(BMI > 29 kg/m 2 ) Obesity1(BMI > 29 kg/m 2 ) HRT/OC1(order entry) HRT/OC1(order entry) VTE risk score 4 points: Cancer3(ICD codes) Cancer3(ICD codes) Prior VTE3(ICD codes) Prior VTE3(ICD codes) Hypercoagulability3(Leiden, ACLA) Hypercoagulability3(Leiden, ACLA) Major surgery2(> 60 minutes) Major surgery2(> 60 minutes) Bed rest1(bed rest order) Bed rest1(bed rest order) Advanced age1(> 70 years) Advanced age1(> 70 years) Obesity1(BMI > 29 kg/m 2 ) Obesity1(BMI > 29 kg/m 2 ) HRT/OC1(order entry) HRT/OC1(order entry)

Patient Randomization Kucher N, et al. NEJM 2005;352: VTE risk score > 4 No prophylaxis N = 2506 VTE risk score > 4 No prophylaxis N = 2506 INTERVENTION Single Alert n = 1255 INTERVENTION Single Alert n = 1255 CONTROL No Computer Alert n = 1251 CONTROL No Computer Alert n = 1251

90-Day Primary Endpoint Kucher N, et al. NEJM 2005;352: Interventionn=1255ControlN=1251 Hazard Ratio (95% CI) P Total VTE 61 (4.9) 103 (8.2) 0.59 ( ) Acute PE 14 (1.1) 35 (2.8) 0.40 ( ) Proximal DVT 10 (0.8) 23 (1.8) 0.47 ( ) 0.08 Distal DVT 5 (0.4) 12 (1.0) 0.42 ( ) 0.10 UE DVT 32 (2.5) 33 (2.6) 0.97 ( ) 0.90

Primary End Point Intervention Control Number at risk Intervention Control Time (days) %Freedom from DVT/ PE Kucher N, et al. NEJM 2005;352:

eALERT Cohort (N=866) 18% high risk patients were not prophylaxed in the NEJM eAlert RCT 18% high risk patients were not prophylaxed in the NEJM eAlert RCT After turning off randomization, 9% high risk patients were not prophylaxed in the cohort study After turning off randomization, 9% high risk patients were not prophylaxed in the cohort study 82% were Medical Service patients 82% 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 the NEJM eAlert RCT 18% high risk patients were not prophylaxed in the NEJM eAlert RCT After turning off randomization, 9% high risk patients were not prophylaxed in the cohort study After turning off randomization, 9% high risk patients were not prophylaxed in the cohort study 82% were Medical Service patients 82% 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 11/17/2007

DVT Alert Screen

Conclusions 1.VTE causes CVI, pulmonary hypertension, disability, and death. 2.Prophylaxis against PE and DVT is crucial. 3.Novel drugs promise fixed dosing, no laboratory coagulation monitoring, minimal drug-drug and drug-food interactions 4.Factors Xa inhibition is emerging as an effective and safe anticoagulation strategy. 5.Alerting MDs that their patients are at high risk for VTE may modify behavior, decrease symptomatic PE and DVT rate. 1.VTE causes CVI, pulmonary hypertension, disability, and death. 2.Prophylaxis against PE and DVT is crucial. 3.Novel drugs promise fixed dosing, no laboratory coagulation monitoring, minimal drug-drug and drug-food interactions 4.Factors Xa inhibition is emerging as an effective and safe anticoagulation strategy. 5.Alerting MDs that their patients are at high risk for VTE may modify behavior, decrease symptomatic PE and DVT rate.

The Challenge of Optimizing Anticoagulation Management in the Setting of Venous Thrombosis and Cardiovascular Disease The Internists Perspective Geno J Merli, MD, FACP Professor of Medicine Director: Jefferson Center for Vascular Diseases Senior Vice President and Chief Medical Officer Jefferson Medical College Jefferson University Hospitals Geno J Merli, MD, FACP Professor of Medicine Director: Jefferson Center for Vascular Diseases Senior Vice President and Chief Medical Officer Jefferson Medical College Jefferson University Hospitals Science and Medicine of Thrombosis Management

Deep Vein Thrombosis Pulmonary Embolism Venous Thromboembolism

IVUFH SCUFHSCUFH 1.Etiology of VTE 2.Duration of Warfarin Therapy 3.Maintaining Therapeutic Range 5-7 days 3-6 months orIndefinite VTE Management Options VTE UFH LMWH Warfarin

RegimenOutpatient N = 2725 Inpatient N = 2726 SC LMWH to warfarin 1244 (46%) 899 (33%) IV UFH to warfarin 1071 (39%) 855 (31%) UFH monotherapy 96 (4%) 230 (8%) LMWH monotherapy 152 (6%) 364 (13%) DVT FREE Database Goldhaber S, et al, Am J Card 2004;93:

Standard and Weight-Based UFH Bolus 5000 units then Bolus 5000 units then Infusion 1200 units per hour Infusion 1200 units per hour Target aPTT therapeutic range of the hospital Target aPTT therapeutic range of the hospital Check aPTT in 6 hours and adjust upward or downward by 200 units Check aPTT in 6 hours and adjust upward or downward by 200 units aPTT should be checked every 6 hours for the first 24 hours then aPTT should be checked every 6 hours for the first 24 hours then Daily or more frequently as indicated by the need to achieve the therapeutic range Daily or more frequently as indicated by the need to achieve the therapeutic range Check platelet count on days 3 and 5 Check platelet count on days 3 and 5 Initiate warfarin 5 mg on day 1 Initiate warfarin 5 mg on day 1 Continue unfractionated heparin until the INR is between 2 and 3 for 2 consecutive days Continue unfractionated heparin until the INR is between 2 and 3 for 2 consecutive days Bolus 5000 units then Bolus 5000 units then Infusion 1200 units per hour Infusion 1200 units per hour Target aPTT therapeutic range of the hospital Target aPTT therapeutic range of the hospital Check aPTT in 6 hours and adjust upward or downward by 200 units Check aPTT in 6 hours and adjust upward or downward by 200 units aPTT should be checked every 6 hours for the first 24 hours then aPTT should be checked every 6 hours for the first 24 hours then Daily or more frequently as indicated by the need to achieve the therapeutic range Daily or more frequently as indicated by the need to achieve the therapeutic range Check platelet count on days 3 and 5 Check platelet count on days 3 and 5 Initiate warfarin 5 mg on day 1 Initiate warfarin 5 mg on day 1 Continue unfractionated heparin until the INR is between 2 and 3 for 2 consecutive days Continue unfractionated heparin until the INR is between 2 and 3 for 2 consecutive days Infusion 18 IU/kg/hr Infusion 18 IU/kg/hr Target aPTT therapeutic range of the hospital Target aPTT therapeutic range of the hospital Check aPTT in 6 hours and adjust via the schedule Check aPTT in 6 hours and adjust via the schedule Check platelet count on days 3 and 5 Check platelet count on days 3 and 5 Initiate warfarin 5 mg on day 1 Initiate warfarin 5 mg on day 1 Continue unfractionated heparin until the INR is between 2 and 3 for 2 consecutive days Continue unfractionated heparin until the INR is between 2 and 3 for 2 consecutive days Jefferson University Hospitals has adopted a dosing schedule of bolus 70 IU/kg then Infusion 15 IU/kg/hr Jefferson University Hospitals has adopted a dosing schedule of bolus 70 IU/kg then Infusion 15 IU/kg/hr Raschke RA, et al. Ann Intern Med. 1993;119:

Unfractionated Heparin Subcutaneous Dosing FIDO Investigators Initial Dose 333 U/kg, SC Initial Dose 333 U/kg, SC Maintenance 250 U/kg, SC, Q12hrs Maintenance 250 U/kg, SC, Q12hrs Galilei 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, Q12hrs 50 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 dosing Step Adjustment of UFH dosing Pini Method 250 u / kg, Q12hrs 250 u / kg, Q12hrs Adjust dose 6 hours after the AM dose and adjust upward or downward based on aPTT of 1.5 x baseline aPTT Adjust dose 6 hours after the AM dose and adjust upward or downward based on aPTT of 1.5 x baseline aPTT FIDO Investigators Initial Dose 333 U/kg, SC Initial Dose 333 U/kg, SC Maintenance 250 U/kg, SC, Q12hrs Maintenance 250 U/kg, SC, Q12hrs Galilei 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, Q12hrs 50 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 dosing Step Adjustment of UFH dosing Pini Method 250 u / kg, Q12hrs 250 u / kg, Q12hrs Adjust dose 6 hours after the AM dose and adjust upward or downward based on aPTT of 1.5 x baseline aPTT Adjust dose 6 hours after the AM dose and adjust upward or downward based on aPTT of 1.5 x baseline aPTT Kearon C, et al JAMA 2006;296: Galilei Investigators. Arch Intern Med 2004;164: Buller H, et al Chest 2004;126:401S-428S ACCP Recommendation Adjusted Dose Unfractionated Heparin can be used as an adequate alternative to IV Unfractionated Heparin [1A]

FIDO Investigators Fixed Dose UFH OutcomesUFH(n=345)LMWH(n=352) Risk Difference VTE (10 days) 1 (0.3%) 2 (0.6%) -0.3 (-1.8 – 1.1) VTE (3 months) 13 (3.8%) 12 (3.5%) 0.4 (-2.6 – 3.3) Major Bleeding (10 days) 4 (1.14%) 5 (1.4%) -0.3 (-2.3 – 1.7) Major Bleeding (3 months) 6 (1.7%) 12 (3.4%) -1.7 (-4.3 – 0.8) Kearon C, et al JAMA 2006;296:

Recurrent VTE: 1st 24 Hours 23% 5% 6% Hull RD, et al. Arch Intern Med. 1997;157: % 5% 10% 15% 20% 25% Recurrent VTE SubtherapeuticTherapeutic Supratherapeutic

Outcomes with UFH Standard vs Weight-Based Dosing Outcomes Standard UFH Weight-based UFH P Value 1st aPTT > 1.5* 32%86% < aPTT > 1.5 in 24 hrs 77%97%0.002 aPTT therapeutic in 24 hrs 75%89%0.08 Minor bleeding 2/522/631 Major bleeding 1/ RVTE 8/32 (25%) 2/41 (5%) 0.02 *aPTT > 1.5 times control Raschke RA, et al. Ann Intern Med. 1993;119:

Hylek, E. M. et al. Arch Intern Med 2003;163: P =.002 Number of aPTT Achieving Therapeutic Range Achieving Therapeutic Range Proportion of aPTTs > 55 s >5 aPTT Measurements 4-5 aPTT Measurements <3 aPTT Measurements Heparin Therapy, d

VTE Treatment ACCP Recommendations Unfractionated Heparin IV UFH adjustment dose to achieve a plasma heparin level from 0.3 to 0.7 IU/mL anti-Xa activity (1C+) IV UFH adjustment dose to achieve a plasma heparin level from 0.3 to 0.7 IU/mL anti-Xa activity (1C+) UFH with large doses: measure anti-Xa to adjust dose (1B) UFH with large doses: measure anti-Xa to adjust dose (1B) SC UFH at a dose of 35,000 U/24hrs, SC with adjustment to achieve a therapeutic aPTT (1C+) SC UFH at a dose of 35,000 U/24hrs, SC with adjustment to achieve a therapeutic aPTT (1C+) Unfractionated Heparin IV UFH adjustment dose to achieve a plasma heparin level from 0.3 to 0.7 IU/mL anti-Xa activity (1C+) IV UFH adjustment dose to achieve a plasma heparin level from 0.3 to 0.7 IU/mL anti-Xa activity (1C+) UFH with large doses: measure anti-Xa to adjust dose (1B) UFH with large doses: measure anti-Xa to adjust dose (1B) SC UFH at a dose of 35,000 U/24hrs, SC with adjustment to achieve a therapeutic aPTT (1C+) SC UFH at a dose of 35,000 U/24hrs, SC with adjustment to achieve a therapeutic aPTT (1C+) Buller H, et al Chest 2004;126:401S-428S

Challenges Using UFH in Acute VTE Achieving a therapeutic aPTT in the first 24 hours to prevent recurrent disease Achieving a therapeutic aPTT in the first 24 hours to prevent recurrent disease UFH must be adjusted daily to maintain a therapeutic range UFH must be adjusted daily to maintain a therapeutic range Platelets checked during the course of UFH use Platelets checked during the course of UFH use Achieving a therapeutic aPTT in the first 24 hours to prevent recurrent disease Achieving a therapeutic aPTT in the first 24 hours to prevent recurrent disease UFH must be adjusted daily to maintain a therapeutic range UFH must be adjusted daily to maintain a therapeutic range Platelets checked during the course of UFH use Platelets checked during the course of UFH use

Venographic Assessment Efficacy and Safety LMWH vs UFH Simonneau G, et al. Arch Intern Med. 1993;153: % Patients 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: % Patients Venographic Assessment Efficacy and Safety LMWH vs UFH 200 U/kg/Q24hrs

% Patients Merli G, et al. Ann Intern Med. 2001;134: Enoxaparin 1.5 mg/kg, SC, Qday Clinical Outcomes Efficacy and Safety of LMWH vs UFH Enoxaparin 1mg/kg, SC, Q12hrs UFH 0% 1% 2% 3% 4% 5% RVTEMajor Bleed

Obesity 3/122 (2.5%)10/137(7.3%)5/146 (3.4%) Cancer3/ 45 (6.7%)6/ 49 (12.2%)3/ 47 (6.4%) Iliac Vein Thrombosis0/223/23 (13%)0/21 PE at baseline4/88 (4.5%)5/94 (5.3%)5/105 (4.8%) UFH Enoxaparin Qday Qday Inpatient Treatment of DVT Results: Recurrences of Thromboembolism Enoxaparin Q12h Q12h Other subgroups analyzed: h/o VTE, prolonged immobilization, varicose veins, CHF, COPD, estrogen use, thrombophilia, recent chemotherapy/radiation therapy, recent surgery, recent trauma Merli G, et al. Ann Intern Med 2001;134:

VTE Clinical Outcomes Efficacy of LMWH 1/31 3/24 37/948 39/974 5/119 3/109 Fondaparinux 5 mg: < 50kg 7.5 mg: 50 – 100kg 10 mg: > 100 kg Buller H, et al Ann Intern Med 2004;140:

Outpatient Treatment of DVT % Levine et al Koopman et al Enoxaparin (N = 247) UFH (N = 253) Nadroparin (N = 202) UFH (N = 198) Recurrent TE Major bleeding Death Hospital days 1.1* Levine M, et al. N Engl J Med. 1996;334: Levine M, et al. N Engl J Med. 1996;334: Koopman MM, et al. N Engl J Med. 1996;334: *120 (48%) were exclusively treated in the outpatient setting.

ACCP Recommendations Low Molecular Weight Heparin SC LMWH once or twice daily over UFH as an outpatient if possible (1C) or as an inpatient (1A) SC LMWH once or twice daily over UFH as an outpatient if possible (1C) or as an inpatient (1A) Recommend against monitoring with anti-Xa levels (1A) Recommend against monitoring with anti-Xa levels (1A) Severe renal failure suggest IV UFH over LMWH (2C) Severe renal failure suggest IV UFH over LMWH (2C) Low Molecular Weight Heparin SC LMWH once or twice daily over UFH as an outpatient if possible (1C) or as an inpatient (1A) SC LMWH once or twice daily over UFH as an outpatient if possible (1C) or as an inpatient (1A) Recommend against monitoring with anti-Xa levels (1A) Recommend against monitoring with anti-Xa levels (1A) Severe renal failure suggest IV UFH over LMWH (2C) Severe renal failure suggest IV UFH over LMWH (2C) Buller H, et al Chest 2004;126:401S-428S

Challenges Using LMWH in VTE Appropriate dosing of LMWH in obesity Appropriate dosing of LMWH in obesity actual body weight dosing actual body weight dosing Appropriate dosing in renal insufficiency Appropriate dosing in renal insufficiency Appropriate dosing of LMWH in obesity Appropriate dosing of LMWH in obesity actual body weight dosing actual body weight dosing Appropriate dosing in renal insufficiency Appropriate dosing in renal insufficiency

IVUFH SCUFHSCUFH 1.Etiology of VTE 2.Duration of Warfarin Therapy 3.Maintaining Therapeutic Range 5-7 days 3-6 months orIndefinite VTE Management UFHLMWHWarfarin VTE

IVUFH SCUFHSCUFH 5-7 days VTE Management Patient Factors 1.Thrombophilia 2.Age Co-morbid Factors 1.Temporary Risk Factors 2.Malignancy / Chemotherapy 3.Idiopathic Thrombosis Factors 1.DVT vs PE 2.DVT (proximal vs distal) UFHLMWHWarfarin VTE

IVUFH SCUFHSCUFH 5-7 days VTE Management Recurrent VTE Major Bleeding UFHLMWHWarfarin VTE

Hylek EM. Ann Intern Med 1994; 120:897. Hylek EM. N Engl J Med 1996; 335:540. Odds Ratio INR RecurrentVTE Intracranial Bleeding 1.0 Therapeutic Range for Warfarin Balancing Safety and Efficacy Therapeutic Range for Warfarin Balancing Safety and Efficacy

Outpatient Bleeding Risk Warfarin Therapy Risk Factors (1 point for each risk factor) Age > 65 yrs Age > 65 yrs History of GI Bleed History of GI Bleed Recent MI, Recent MI, HCT < 30% HCT < 30% Cr > 1.5 mg/dl Cr > 1.5 mg/dl History DM History DM Months Low Risk (RF 0) Intermediate Risk (RF 1-2) High Risk (RF 3-4) 3 months 2%5%23% 12 months 3%12%48% Beyth R, et al Am J Med 1998;105(2):91-99

Risk of Major Bleeding on Warfarin Factors Relative Risk (95% CI) (95% CI) P value Sex (women vs men) 1.26 ( ) Age (> 70 vs 70 vs < 70 yrs) 1.69 ( ) <0.001 Target INR ( 2.8) 0.83 ( ) Indication (arterial vs other) 1.72 ( ) <0.001 Actual INR (> 4.5 vs 4.5 vs < 4.5) 5.96 ( ) < Coumarin type (acenocoumarol vs warfarin) 1.20 ( ) Timing of event ( 90 days) 2.50 ( ) < Parlareti G et al Lancet 1996;348:

Time Spent in Therapeutic Range Outcomes Study No Pts Target INR TTREvent Incidence of Events 95% CI Hylek 13,559 AF < NSStroke OR 7.7 (CI ) OR 0.9 (CI ) Sarawate 614 AF %Stroke OR 1.68 ( ) Witt 6,645 AF/S/VTE % (UC) VTE3% 63.5% (CCPS) 1.2% Veeger 2,614 AF %VTE OR 1.7 ( CI ) Jones 2,223 AF 2-368%S OR 1.10 (P = 0.006) VTE OR 1.12 (P = < 0.001) Schmidt- Lucke 248 AF 2-330%VTE/D/B80%

ACCP Recommendations Recommend adjusted INR to 2 – 3 range for all 2° prevention [1A] Recommend adjusted INR to 2 – 3 range for all 2° prevention [1A] Recommend against low-intensity warfarin at INR of 1.5 – 1.9 [1A] Recommend against low-intensity warfarin at INR of 1.5 – 1.9 [1A] Patients should be assessed periodically during anticoagulation to evaluated risk benefit [1C] Patients should be assessed periodically during anticoagulation to evaluated risk benefit [1C] Recommend adjusted INR to 2 – 3 range for all 2° prevention [1A] Recommend adjusted INR to 2 – 3 range for all 2° prevention [1A] Recommend against low-intensity warfarin at INR of 1.5 – 1.9 [1A] Recommend against low-intensity warfarin at INR of 1.5 – 1.9 [1A] Patients should be assessed periodically during anticoagulation to evaluated risk benefit [1C] Patients should be assessed periodically during anticoagulation to evaluated risk benefit [1C] Buller H, et al. Chest. 2004;126:401S-428S

Challenges with Warfarin Maintaining INR in therapeutic range by regular monitoring Maintaining INR in therapeutic range by regular monitoring Vigilance for drug interaction with warfarin Vigilance 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 medical status or new onset illness Instruction to seek medical care with any change in medical status or new onset illness Undertreatment: Physicians aversion of the risk of bleed lead them to under-dosing Undertreatment: Physicians aversion of the risk of bleed lead them to under-dosing Poor and inconsistent patient follow-up and monitoring Poor and inconsistent patient follow-up and monitoring Maintaining INR in therapeutic range by regular monitoring Maintaining INR in therapeutic range by regular monitoring Vigilance for drug interaction with warfarin Vigilance 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 medical status or new onset illness Instruction to seek medical care with any change in medical status or new onset illness Undertreatment: Physicians aversion of the risk of bleed lead them to under-dosing Undertreatment: Physicians aversion of the risk of bleed lead them to under-dosing Poor and inconsistent patient follow-up and monitoring Poor and inconsistent patient follow-up and monitoring

IVUFH SCUFHSCUFH 5-7 days VTE Management Recurrent VTE Malignancy/ChemoHereditary/AcquiredThrombophiliaIdiopathicTemporary Risk Factor UFHLMWHWarfarin VTE

Management of VTE 3 months warfarin 8 years DVT 355 patients LMWH or UFH + Warfarin 78 recurrent VTE 35 (44.9%) ipsilateral leg 35 (44.9%) ipsilateral leg 28 (35.9%) contralateral leg 28 (35.9%) contralateral leg 15 (19.2%) PE (9 fatal) 15 (19.2%) PE (9 fatal) Prandoni P, et al. Ann Intern Med. 1996;125:1-7. Recurrent 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 recurrence Increased risk: Cancer: 1.72 Cancer: 1.72 Thrombophilia: 1.44 Thrombophilia: 1.44 Decreased risk: Trauma/fracture: 0.51 Trauma/fracture: 0.51 Surgery: 0.36 Surgery: 0.36

ACCP Recommendations First DVT with transient risk factors: 3 months with INR 2 – 3 [1A] First DVT with transient risk factors: 3 months with INR 2 – 3 [1A] DVT with antiphospholipid antibodies, lupus anticoagulant, or 2 thrombophilic conditions: 12 months warfarin (INR 2 – 3) [1C+] or indefinite treatment [2C] DVT with antiphospholipid antibodies, lupus anticoagulant, or 2 thrombophilic conditions: 12 months warfarin (INR 2 – 3) [1C+] or indefinite treatment [2C] DVT with AT, protein C, protein S, factor V Leiden, prothrombin gene mutation, hyperhomocysteinemia, factor VIII > 90 th percentile: 6 – 12 months [1A] or indefinite therapy [2C] DVT with AT, protein C, protein S, factor V Leiden, prothrombin gene mutation, hyperhomocysteinemia, factor VIII > 90 th percentile: 6 – 12 months [1A] or indefinite therapy [2C] First DVT with transient risk factors: 3 months with INR 2 – 3 [1A] First DVT with transient risk factors: 3 months with INR 2 – 3 [1A] DVT with antiphospholipid antibodies, lupus anticoagulant, or 2 thrombophilic conditions: 12 months warfarin (INR 2 – 3) [1C+] or indefinite treatment [2C] DVT with antiphospholipid antibodies, lupus anticoagulant, or 2 thrombophilic conditions: 12 months warfarin (INR 2 – 3) [1C+] or indefinite treatment [2C] DVT with AT, protein C, protein S, factor V Leiden, prothrombin gene mutation, hyperhomocysteinemia, factor VIII > 90 th percentile: 6 – 12 months [1A] or indefinite therapy [2C] DVT with AT, protein C, protein S, factor V Leiden, prothrombin gene mutation, hyperhomocysteinemia, factor VIII > 90 th percentile: 6 – 12 months [1A] or indefinite therapy [2C] Buller H, et al. Chest. 2004;126:401S-428S

VTE Increased with Warfarin Treatment in Cancer Patients Time (months) Cumulative proportion recurrent VTE (%) Cancer No cancer 20.7% vs 6.8%; HR 3.2 at 1 year Warfarin to maintain INR 2–3 Major bleeding 12.4% vs 4.9%; HR 2.2 VTE and bleeding not predicted by INR Number of patients Cancer No cancer Prandoni P, et al. Blood. 2002;100:

LMWH in Cancer Patient CANTHANOX Warfarin (n = 71) INR 2 – 3 x 3 months Warfarin major bleeding = 8% LMWH (n = 67) enoxaparin 1.5 mg/kg SC QD x 3 months LMWH major bleeding = 0% Recurrent VTE (%) Meyer G, et al. Arch Intern Med. 2002;162:

LMWH in Cancer Patients CLOT Warfarin (n = 336) INR 2 – 3 x 6 months Warfarin major bleeding = 4% LMWH (n = 336) dalteparin 200 IU/kg SC QD x 1 month, then 150 IU/kg SC QD x 5 months LMWH major bleeding = 6% Recurrent VTE (%) Lee A, et al. N Engl J Med. 2003;349:

ACCP Recommendations Cancer Patients VTE and Cancer LMWH for 3 – 6 months [1A] then LMWH for 3 – 6 months [1A] then Warfarin Warfarin (INR 2 – 3) for indefinite period [1C] (INR 2 – 3) for indefinite period [1C] VTE and Cancer LMWH for 3 – 6 months [1A] then LMWH 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. Chest. 2004;126:401S-428S

NCCN VTE Treatment Guidelines 2007 NCCN. Venous Thromboembolic Disease: Version Available at: physician_gls/PDF/vte.pdf. Accessed October 19, 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 [ 100 kg] SC OD)Fondaparinux (5.0 mg [ 100 kg] SC OD) UFH (IV) weight-basedUFH (IV) weight-based 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 and prevention of recurrent VTE in patients with advanced or metastatic cancerLMWH is preferred as monotherapy without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer Warfarin (2.5–5 mg every day initially, subsequent dosing based on INR value; target INR 2.0–3.0)Warfarin (2.5–5 mg every day initially, subsequent dosing based on INR value; target INR 2.0–3.0) Stage 3 Chronic: Completion time period as recommended by guideline: LMWH or warfarin per therapeutic guidelines (warfarin adjusted for INR 2.0–3.0)LMWH or warfarin per therapeutic guidelines (warfarin adjusted for INR 2.0–3.0) Minimum time of 3–6 months for DVT and 6–12 months for PEMinimum time of 3–6 months for DVT and 6–12 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 and for 1-3 months after catheter removalFor catheter associated thrombosis, anticoagulate as long as catheter is in place and for 1-3 months after catheter removal Stage 1 Immediate: Concomitant with diagnosis or while diagnosis and risk being assessed (heparin phase):

Ridker PM, et al. N Engl J Med. 2003;348: Warfarin 4 yrs INR Idiopathic DVT 14/ /100 person-yr 37/ /100 person-yr 6 mo Warfarin INR 2-3 Placebo No./100 person-yr PlaceboWarfarinP Major bleeding 2 (0.4) 5 (0.9) 0.25 Deaths 8 (1.4) 4 (0.7) 0.26 Idiopathic VTE

Cumulative Event Rate Years of Follow-Up PREVENT: Composite Endpoint (Recurrent VTE, Major Bleed, or Death) Placebo Low-IntensityWarfarin Hazard Ratio = 0.52, 95% CI 0.31 to 0.87, P = % Ridker PM for the PREVENT investigators. N Eng J Med 2003;348:

Kearon C, et al. N Engl J Med. 2003;349: Warfarin 2.4 yrs INR 1.5 – 1.9 IdiopathicDVT 16/ /100 person-yr 6/ /100 person-yr 3 mo Warfarin INR 2-3 No Events(No./100 person- yr) Warfarin2-3Warfarin P Major bleeding 8 (0.9) 9 (1.1) 0.25 Deaths 8 (0.9) 16 (1.9) 0.26 Warfarin 2.4yrs INR 2-3

ELATE: Primary Endpoint Recurrent VTE Conventional-intensity therapy group Years Since Randomization Cumulative Probability of Recurrent Thromboembolism Low-intensity therapy group Kearon C for the ELATE Investigators. N Engl J Med. 2003;349: P=0.03

Cumulative Event Rate, % Years of Follow-Up PREVENT & ELATE Recurrent VTE INR – PREVENT Placebo - PREVENT INR – ELATE INR – ELATE 01

ACCP Recommendations Idiopathic VTE First VTE idiopathic: First VTE idiopathic: 6 – 12 months INR 2 – 3 [1A] First DVT idiopathic: First DVT idiopathic: 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] First VTE idiopathic: First VTE idiopathic: 6 – 12 months INR 2 – 3 [1A] First DVT idiopathic: First DVT idiopathic: 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] Buller H, et al. Chest. 2004;126:401S-428S

Clinical Challenges Complex special groups of VTE patients Cancer Patients Cancer Patients Idiopathic VTE Patients Idiopathic VTE Patients Risks of long-term anticoagulation with either warfarin or LMWH Risks of long-term anticoagulation with either warfarin or LMWH Complex special groups of VTE patients Cancer Patients Cancer Patients Idiopathic VTE Patients Idiopathic VTE Patients Risks of long-term anticoagulation with either warfarin or LMWH Risks of long-term anticoagulation with either warfarin or LMWH

Triple Therapy ASA, Clopidogrel, Warfarin 127 patients with Atrial Fibrillation undergoing cardiac stent placement 127 patients with Atrial Fibrillation undergoing cardiac stent placement Drug eluting stents and are metal stents Drug eluting stents and are metal stents 67% of bleeding occurred in the first 30 days 67% of bleeding occurred in the first 30 days 127 patients with Atrial Fibrillation undergoing cardiac stent placement 127 patients with Atrial Fibrillation undergoing cardiac stent placement Drug eluting stents and are metal stents Drug eluting stents and are metal stents 67% of bleeding occurred in the first 30 days 67% of bleeding occurred in the first 30 days Stent Group Major Bleeding Bleeding & Mortality Drug Eluting 5.6%5.6% Bare Metal 3.6%1.8% 6/127 pts = 4.7% overall major bleeding Rogacka R et al JACC Intl 2008;1:56-61

Combination Therapy Cardiac Prevention GroupsCombinationMonotherapyOutcome Anticoagulation Related Major Hemorrhage 2%0.9% P= < Adjusted Odds Ratio Anticoagulation Related Hemorrhage % CI Johnson S, et al Chest 2008;133;

Clinical Challenges Complex special groups of VTE patients Antiplatelet therapy with warfarin in cardiac prevention Antiplatelet therapy with warfarin in cardiac prevention Antiplatelet therapy with warfarin in coronary stent placement Antiplatelet therapy with warfarin in coronary stent placement Complex special groups of VTE patients Antiplatelet therapy with warfarin in cardiac prevention Antiplatelet therapy with warfarin in cardiac prevention Antiplatelet therapy with warfarin in coronary stent placement Antiplatelet therapy with warfarin in coronary stent placement

Contaminated Heparin Oversulfated Chondroitin Sulfate (OSCS) Oversulfated Chondroitin Sulfate (OSCS) Direct activation of Kinin- Kallikrein pathway Direct activation of Kinin- Kallikrein pathway Generation of bradykinin, potent vasoactive mediator Generation of bradykinin, potent vasoactive mediator Induces C3a and C5a Induces C3a and C5a Potent anaphylatoxins derived from complement proteins Potent anaphylatoxins derived from complement proteins Oversulfated Chondroitin Sulfate (OSCS) Oversulfated Chondroitin Sulfate (OSCS) Direct activation of Kinin- Kallikrein pathway Direct activation of Kinin- Kallikrein pathway Generation of bradykinin, potent vasoactive mediator Generation of bradykinin, potent vasoactive mediator Induces C3a and C5a Induces C3a and C5a Potent anaphylatoxins derived from complement proteins Potent anaphylatoxins derived from complement proteins Kishimoto T, et al N Engl J Med 2008;358

Kishimoto T et al. N Engl J Med 2008; /NEJMoa OSCS Generation Complement-Derived C5a Anaphylatoxin

Kishimoto T et al. N Engl J Me2008; /NEJMoa Effect of OSCS on Kallikrein Activity

Summary and Conclusions Achieving optimal anticoagulation is difficult Achieving optimal anticoagulation is difficult Limitations to attaining and maintaining optimal anticoagulation with all available agents: UFH, LMWH, warfarin, and antiplatelet agents Limitations to attaining and maintaining optimal anticoagulation with all available agents: UFH, LMWH, warfarin, and antiplatelet agents Multiple, combined antiplatelet plus anticoagulation strategies present special challenges Multiple, combined antiplatelet plus anticoagulation strategies present special challenges The need to monitor anticoagulation represents a major barrier and cost for long-term management The need to monitor anticoagulation represents a major barrier and cost for long-term management Achieving optimal anticoagulation is difficult Achieving optimal anticoagulation is difficult Limitations to attaining and maintaining optimal anticoagulation with all available agents: UFH, LMWH, warfarin, and antiplatelet agents Limitations to attaining and maintaining optimal anticoagulation with all available agents: UFH, LMWH, warfarin, and antiplatelet agents Multiple, combined antiplatelet plus anticoagulation strategies present special challenges Multiple, combined antiplatelet plus anticoagulation strategies present special challenges The need to monitor anticoagulation represents a major barrier and cost for long-term management The need to monitor anticoagulation represents a major barrier and cost for long-term management

Summary and Conclusions Balancing antithrombotic effects with bleeding safety is paramount Balancing antithrombotic effects with bleeding safety is paramount Factor Xa inhibition offers the possibility of better outcomes with oral, non-monitored anticoagulation and equivalent safety Factor Xa inhibition offers the possibility of better outcomes with oral, non-monitored anticoagulation and equivalent safety The landscape is evolving and may soon change The landscape is evolving and may soon change Balancing antithrombotic effects with bleeding safety is paramount Balancing antithrombotic effects with bleeding safety is paramount Factor Xa inhibition offers the possibility of better outcomes with oral, non-monitored anticoagulation and equivalent safety Factor Xa inhibition offers the possibility of better outcomes with oral, non-monitored anticoagulation and equivalent safety The landscape is evolving and may soon change The landscape is evolving and may soon change