WARFARIN AN OVERVIEW

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

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

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 X Xa X Xa 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)

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

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

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

PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS Factor II 72h Factor VII 6h Factor IX 24h Factor X 36h Peak anticoagulant effect may be delayed by 72 to 96 hours

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

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

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

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

Thromboplastins are extracts from brain, lung or placenta of animals 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

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

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)

OPTIMAL THERAPEUTIC RANGE Indication INR Prophylaxis of venous thromboembolism 2.0-3.0 Treatment of venous thromboembolism Atrial fibrillation Mitral valve stenosis Heart valve replacement Bioprosthetic valve Mechanical valve 2.5-3.5 Myocardial infarction 2.5-3.5 (high risk patients)

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

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

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

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

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

COMPARISON WITH ACENOCOUMAROL

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

RECENT TRIALS ON WARFARIN

There were no major bleeds in either groups ANTICOAGULATION FOR VTE PROVOKED BY TRANSIENT RISK FACTORS (SURGERY etc) SHOULD BE CONTINUED FOR 3 MONTHS Group Incidence (%) per year Warfarin for 1 month 6.8% Warfarin for 3 months 3.2% There were no major bleeds in either groups Follow-up=11 mths J Thromb Haemost. 2004; 2(5): 743-749

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 Drug Warfarin Placebo Events per 100 person-years 2.6 7.2 Bleeding requiring hospitalization 0.9 0.4 N= 508 Target INR 1.5-2.0 NEJM 2003; 348 (15): 1425-1434

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 f warfarin o e t a R e v t i 0.10 a l u m u C 0.05 0.00 1 2 3 4 Years of Follow-up NEJM 2003; 348 (15): 1425-1434