WARFARIN

1. WARFARIN AN OVERVIEW

2. HEMOSTASIS • VASCULAR SPASM • PLATELET PLUG • BLOOD COAGULATION • GROWTH OF FIBROUS TISSUE IN CLOT

3. WHEN DOES BLOOD COAGULATE? • Procoagulants > Anticoagulants • Injury to blood vessel • Blood stasis

4. INITIATION OF BLOOD COAGULATION Extrinsic Pathway Intrinsic Pathway Tissue trauma Leakage of Tissue Factor Blood trauma/ contact with collagen Activation of factor XII, IX, VIII Ca+2, factor VII XXa XXa Ca+2 Ca+2 Prothrombin activator Prothrombin activator Ca+2 Prothrombin Thrombin (factor II) Prothrombin Thrombin (factor II) Activation of certain factors (VII, II, X and protein C and S) is essential for coagulation. This activation requires vit K (reduced form)

5. BLOOD COAGULATION Thrombin Fibrin Monomers Fibrinogen Ca+2, factor XIII Fibrin threads

6. ANTICOAGULANTS Three classes • Heparin and Low Molecular Weight Heparins (e.g. enoxaparin, dalteparin) • Coumarin Derivatves e.g. Warfarin, Acenocoumarol • Indandione Derivatves e.g. Phenindione, Anisindione

7. WARFARIN: MECHANISM OF ACTION Vitamin K epoxide WARFARIN Vitamin K reduced Inactive factors II, VII, IX, and X Proteins S and C Active factors II, VII, IX, and X Proteins S and C • Prevents the reduction of vitamin K, which is essential for activation of certain factors • Has no effect on previously formed thrombus

8. PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS Peak anticoagulant effect may be delayed by 72 to 96 hours

9. INDICATIONS • Prophylaxis and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) • Prophylaxis and treatment of Atrial fibrillation • Valvular stenosis • Heart valve replacement • Myocardial infarction

10. WHY TO MONITOR WARFARIN THERAPY? • Narrow therapeutic range • Can increase risk of bleeding

11. MONITORING OF WARFARIN THERAPY • Prothrombin time • PT ratio • INR (International Normalized Ratio)

12. PROTHROMBIN TIME (PT) • Time required for blood to coagulate is called PT • Performed by adding a mixture of calcium and thromboplastin to citrated plasma • As a control, a normal blood sample is tested continuously • PT ratio (PTR) = Patient’s PT Control PT

13. PROBLEMS WITH PT/PTR • Thromboplastins are extracts from brain, lung or placenta of animals • Thromboplastins from various manufacturers differ in their sensitivity to prolong PT • May result in erratic control of anticoagulant therapy

14. INTERNATIONAL NORMALISED RATIO (INR) INR = [PTpt] ISI [PTRef] PTpt – prothrombin time of patient PTRef – prothrombin time of normal pooled sample ISI – International Sensitivity Index

15. OPTIMIZING WARFARIN THERAPY • Dosage to be individualized according to patient’s INR response. • Use of large loading dose may lead to hemorrhage and other complications. • Initial dose: 2-5 mg once daily • Maintenance dose: 2-10 mg once daily • Immediate anticoagulation required: Start heparin along with loading dose of warfarin 10 mg. Heparin is usually discontinued after 4-5 days. Before discontinuing, ensure INR is in therapeutic range for 2 consecutive days • Monitor daily until INR is in therapeutic range, then 3 times weekly for 1-2 weeks, then less often (every 4 to 6 weeks)

16. OPTIMAL THERAPEUTIC RANGE

17. FACTORS INFLUENCING DOSE RESPONSE • Inaccurate lab testing • Poor patient compliance • Concomitant medications • Levels of dietary vitamin K • Alcohol • Hepatic dysfunction • Fever

18. DURATION OF THERAPY • Venous thromboembolism: Minimum 3 months, usually 6 months • AMI: During initial 10-14 days of hospitalization or until patient is ambulatory • Mitral valve disease/Mechanical heart valves: Lifelong • Bioprosthetic heart valves: 3 months • Atrial fibrillation: Lifelong • Prevention of cerebral embolism: 3-6 months

19. CONTARINDICATIONS AND PRECAUTIONS • Hypersensitivity to warfarin • Condition with risk of hemorrhage • Hemorrhagic tendency • Inadequate laboratory techniques • Protein C & S deficiency • Vitamin K deficiency • Intramuscular injections

20. SIDE EFFECTS • Hemorrhage • Skin necrosis • Purple toe syndrome • Microembolization • Teratogenecity Agranulocytosis, leukopenia, diarrhoea, nausea, anorexia.

21. SWITCHOVER FROM ONE BRAND OF WARFARIN TO ANOTHER/ ACENOCOUMAROL • Check patient’s INR • Start with dose of 2 mg; increase dose slowly as required

22. COMPARISON WITH ACENOCOUMAROL

23. THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER WITH WARFARIN AS COMPARED TO ACENOCOUMAROL 72% 72% 70% 67% 68% % Responders 66% 64% Warfarin Acenocoumarol Thrombosis And Haemostasis 1994; 71(2): 188-191

24. RECENT TRIALS ON WARFARIN

25. ANTICOAGULATION FOR VTE PROVOKED BY TRANSIENT RISK FACTORS (SURGERY etc) SHOULD BE CONTINUED FOR 3 MONTHS There were no major bleeds in either groups Follow-up=11 mths J Thromb Haemost. 2004; 2(5): 743-749

26. THE PREVENTION OF RECURRENT VENOUS THROMBOEMBOLISM (PREVENT) TRIAL Long-term use of low-intensity warfarin, prevents venous thromboembolism without increasing the risk of hemorrhage INCIDENCE OF VTES IN THE TWO TREATMENT GROUPS N= 508 Target INR 1.5-2.0 NEJM 2003; 348 (15): 1425-1434

27. Warfarin Reduced the Risk of Recurrent Venous Thromboembolism, Major Hemorrhage, or Death From Any Cause 0.25 P=0.02 Placebo 0.20 48% ) % ( s t n e v Low-intensity E 0.15 warfarin f o e t a R e v 0.10 i t a l u m u C 0.05 0.00 0 1 2 3 4 Years of Follow-up NEJM 2003; 348 (15): 1425-1434