Anticoagulant therapies: how do they work?

1. Anticoagulant therapies: how do they work? Mary Byrne, St James’s Hospital

2. Outline of presentation • Anticoagulants • Warfarin • Heparin • Dabigatran • Laboratory monitoring

3. Warfarin • Most widely used anticoagulant in world • 1% of UK population (8% of >80yrs) • 40,000 people on Warfarin in Ireland

4. Clinical indications • Treatment of venous thrombosis (VTE), pulmonary embolism(PE) and their extension. • Prophylaxis and treatment of thromboembolic complications associated with rheumatic heart disease, atrial fibrillation (AF) and/or prosthetic heart valve replacement. • Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolisation after myocardial infarction.

5. Aim of Warfarin therapy • Maintain a level of anticoagulation • Minimise the risk of thrombosis • Minimise the risk of haemorrhagic complication • Dependant on the length of time and extent that a persons INR stays outside the therapeutic range

6. History of Warfarin discovery

7. History of Warfarin discovery • 1920s: prairies of North America and Canada • Cattle dying of internal bleeding with no precipitating cause • Query dietary problem • “Sweet clover disease” • Farmers recommended not to feed cattle the mouldy sweet clover hay

8. History of Warfarin discovery • Karl Link experimented with “uncoagulated” blood from affected cattle • Team isolated compound • 3,3’-methylene-bis[4-hyfroxycoumarin] • Oxidised in mouldy hay to form dicoumarol.

9. History of Warfarin discovery • Research work funded by the: • Wisconsin Alumni Research Foundation • Patented in 1941 • Variation of dicoumarol (warfarin) patented as rat poison in 1948 • Transition to clinical application (Coumadin)

10. The need for anticoagulation • Why do thromboses occur? • How are they treated? • How are they prevented? • Thrombosis and haemostasis

11. Virchow’s Triad for thrombosis

12. What is haemostasis? Balance between four major components Vascular endothelium Platelets Coagulation pathway Procoagulant Anticoagulant Fibrinolysis

13. Coagulation pathway • Procoagulant proteins • Anticoagulant proteins • Balance between activation and control of coagulation

14. Coagulation pathway

15. Coagulation pathway

16. Mechanism of action of Warfarin • Interferes with the biochemistry of vitamin K dependant coagulation factors in the liver • Vitamin K dependant coagulation factors • Factor II VII IX X Protein C and Protein S • Involved in coagulation and anticoagulation pathways in haemostasis

17. Coagulation pathway Warfarin

18. Vitamin K cycle and warfarin Active coagulation factors Warfarin

19. Warfarin therapy • Inter-individual differences • Narrow therapeutic range • Bleeding risk • Outside anticoagulation range • Higher mortality • Increased risk of stroke • Increased rate of hospitalisation

20. Warfarin • Environmental factors • Vitamin K intake • Illness • Concurrent medication • Genetic variation (VKORC1 and CYP2C9)

21. Warfarin interactions • Pharmacokinetic interactions • Drugs which interfere with clearance • Antibiotics which affect intestinal flora • Pharmacodynamic interactions • Drugs which have anti-platelet effect (aspirin and NSAIDS) • Drugs associated with falls in the elderly

22. Drug interactions • Reduce anticoagulant effect • Reduce absorption (cholestyramine) • Potentiate anticoagulant effect • Inhibit clearance (metronidazole, amiodarone) • Inhibit anticoagulant effect • Enhance clearance (barbiturates)

23. Warfarin and bleeding • Major bleeding events 7.2/100 patient years • Fatal bleeding events 1.3/100 patient years • Bleeding • May be lower in specialised anticoagulation clinics • More likely within the first 90 days • Can occur when INR is raised or within the therapeutic range • Wadelius M and Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. The pharacogenetics Journal (2007) 7, 99-111

24. Warfarin and bleeding

25. Reversal of warfarin • Discontinue warfarin • Vitamin K • Prothrombin complex concentrates

26. Monitoring Warfarin therapy • Laboratory testing • Point of care testing • Self testing • Test = INR (International Normalised Ratio)

27. INR PT (Prothrombin Time) • INR calculated from the Prothrombin Time (PT) • Reported as time (sec), INR • Sensitive to factor II V VII X fibrinogen • Normal range variations • PT: • Measures the plasma clotting time in the presence of a highly sensitive activating reagent

28. INR • Surrogate measure of the effectiveness of Warfarin therapy • Different reagent and analytical systems are widely used

29. INR • ISI: International Sensitivity Index • Compares local reagent with international reference preparation

30. Coagulation pathway PT

31. Delivery of Warfarin monitoring • In-patient • Out-patient • Warfarin clinic (SJH: 1500 active patients) • Primary Care Team • Warfarin clinic

32. Delivery of Warfarin monitoring • Point of care / self testing • Coagucheck XS Plus • Hemosense INRatio • Protime 3 (ITC)

33. Published 2009 • 162 patients recruited • Crossover study • Self selected group • On long tem anticoagulant

35. Other anticoagulants • Indirect Xa inhibitors (Heparin) • Direct thrombin inhibitors (Dabigitran, Argatroban) • Direct Xa inhibitors • Different modes of action on coagulation cascade

36. Other anticoagulants Indirect Xa inhibitors (Heparin) Direct thrombin inhibitors (Dabigatran, Argatroban) Different modes of action on coagulation cascade

37. Indirect Xa inhibitors • Enhance action of antithrombin • Heparin • unfractionated UFH • low molecular weight LMWH

38. Heparin • Discovered in 1916 • Utilised when there is need for rapid anticoagulant effect • Prevention of VTE and treatment of DVT and PE • Early treatment of unstable angina and MI • Cardiac surgery, bypass, vascular surgery, and coronary angioplasty • Selected patients with disseminated intravascular coagulation • Heparin and Low-Molecular-Weight Heparin, Mechanisms of Action, Pharmacokinetics,Dosing, Monitoring, Efficacy, and Safety Hirsh J et al CHEST 2001; 119:64S–94S

39. Low Molecular Weight Heparin • Prevention of VTE and treatment of DVT and PE • Early treatment of unstable angina and MI

40. Heparin: mechanism of action • Mechanism is mediated through antithrombin in the coagulation cascade • Inhibits platelet function

41. Coagulation pathway Heparin Antithrombin 1000X

42. Unfractionated heparin • Continuous IV route • Low molecular weight heparin • SC route • enoxaparin (Clexane) • tinzaparin (Innohep)

43. Heparin and bleeding The risk of heparin-associated bleeding increases with Dose Concomitant thrombolytic therapy or other drugs Recent surgery Trauma Invasive procedures Concomitant haemostatic defects

44. Heparin and bleeding • Reversal of heparin • Stop treatment (Half life = 90 minutes) • Protamine Sulphate

45. Osteopoenia Heparin Induced Thrombocytopoenia Limitations of heparin

46. Monitoring heparin therapy • Relationship between heparin dose, efficacy and safety • Need for laboratory monitoring • APTT (Unfractionated heparin) • Anti Xa assay (Low molecular weight heparin)

47. APTT • Activated Partial Thromboplastin Time • APTT ratio calculated from the APTT • Sensitive to factor VIII IX XI XII • Normal range variations • APTT: • Measures the clotting time of plasma after the activation of the coagulation cascade with Silica.

48. Coagulation pathway APTT Heparin Antithrombin 1000X

49. Direct Thrombin Inhibitors (DTI) • Dabigatran • Inhibits thrombin directly, no cofactor required as in heparin • Predictable anticoagulant response • Dabigatran etexilate, oral prodrug that is converted to dabigatran

50. Dabigatran • Rapid onset of action • Lack of interaction with food and drugs • No need for routine monitoring • Broad therapeutic window • Fixed dose administration • Renal excretion