THROMBOTIC DISORDERS: The Final Frontier

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1 THROMBOTIC DISORDERS: The Final Frontier Jeffrey I. Weitz, MD, FRCP(C), FACP Professor of Medicine and Biochemistry McMaster University Canada Research Chair in Thrombosis Heart & Stroke Foundation/ J.F. Mustard Chair in Cardiovascular Research

2 Overview Arterial and venous thrombosis Antithrombotic therapy Which drugs for which patients

3 Thrombosis Blood clot formation

4

5 Thrombosis Arterial Venous Stroke (AF) DVT MI PE PAD

6 Burden of Thrombotic Disease Each year in the USA: 75,000 diagnosed with AF 900,000 suffer VTE 800,000 have a stroke Cost of care enormous; $74 billion annually for care of stroke victims

7 Pathogenesis of Thrombosis

8 Thrombosis Threshold Thrombosis + Intrinsic Thrombosis Risk Environmental Factors Surgery Immobilization Pregnancy Estrogens + + Genetic Risk Factors Acquired Risk Factors Loss of function AT deficiency PC deficiency PS deficiency Gain of function FV Leiden FIIG20210A Increased procoagulants Dysfibrinogenemia Age Previous Thrombosis Cancer Obesity

9 Arterial and Venous Thrombosis Mackman, Nature 2008;451:

10 Thrombin Generation at Sites of Vascular Injury Platelet activation Thrombin Fibrinogen Prothrombin Plasma clotting factors Tissue factor Fibrin Platelet aggregation Collagen Vessel Injury

11 Vascular injury Contact activation Extrinsic tenase TF IX VIIa X IXa VIIIa L VIIIa M IXa X Intrinsic tenase Xa Xa Va L Va M Xa II Prothrombinase IIa Fibrinogen Fibrin

12 Constituents of Thrombi Platelets Fibrin Trapped cells

13 Antithrombotic Drugs Antiplatelet Drugs ASPIRIN Clopidogrel Prasugrel Ticagrelor Anticoagulant Drugs Heparin LMWH Warfarin Dabigatran RIVAROXABAN Apixaban Edoxaban Fibrinolytic Agents Activase Reteplase Tenecteplase

14 Major Components of Arterial versus Venous Thrombi Type Major Component Arterial Venous Platelets Fibrin

15 Antithrombotic Drug Strategies Disorder Drugs Arterial thrombosis Antiplatelet drugs Venous thrombosis Arterial and venous thrombosis Anticoagulants Fibrinolytic drugs

16 Thrombosis versus Hemostasis Occlusive thrombus obstructs blood flow Hemostatic plug stops bleeding

17 Implications of Thrombosis versus Hemostasis Need to find the optimal balance between efficacy and safety

18 Anticoagulants Parenteral Heparin LMWH Fondaparinux Oral Warfarin Dabigatran RIVAROXABAN Apixaban Edoxaban

19 Use of Parenteral versus Oral Anticoagulants Delivery Route Indication Parenteral Oral Short-term Long-term

20 Limitations of Warfarin Limitation Consequence Slow onset of action Genetic variation in metabolism Overlap with a parenteral anticoagulant Variable dose requirements Multiple food and drug Frequent coagulation interactions monitoring Narrow therapeutic index Frequent coagulation monitoring

21 Worldwide Utilization of Oral Anticoagulation in AF: Results from a Global Registry Based on 15,174 patients with AF between Jan and Apr OAC in CHADS 2 2 TTR* *Based on 3 most recent INR values Healey et al. ESC 2011 Appropriate use of OAC remains low. When used, INR control is suboptimal.

22 New Oral Anticoagulants Direct inhibitors of factor Xa or thrombin

23 Due to legal restrictions, the content of this slide has been deleted.

24 Advantages of New Oral Anticoagulants Over Warfarin Feature Warfarin New Orals Onset Slow Rapid Dosing Variable Fixed Food effect Yes No Interactions Many Few Monitoring Yes No Offset Long Short

25 What Have We Learned From Studies With New Oral Anticoagulants? At least as effective and safe as LMWH for VTE prevention after knee or hip arthroplasty At least as effective as warfarin for stroke prevention in AF and associated with less ICH At least as effective and safe as conventional anticoagulation for VTE treatment

26 Where Are We Going With New Agents? Replacing LMWH for VTE prevention after hip or knee replacement surgery Increasing use in place of warfarin for stroke prevention in AF Facilitate treatment of VTE

27 Conclusions Thrombotic diseases are the major cause of morbidity and mortality worldwide New oral anticoagulants represent a major advance for the prevention and treatment of thrombotic disorders