WARFARINWARFARIN

AN OVERVIEWAN OVERVIEW

HEMOSTASISHEMOSTASIS

VASCULAR SPASMVASCULAR SPASM

PLATELET PLUGPLATELET PLUG

BLOOD COAGULATIONBLOOD COAGULATION

GROWTH OF FIBROUS TISSUE IN CLOTGROWTH OF FIBROUS TISSUE IN CLOT

WHEN DOES BLOOD COAGULATE?WHEN DOES BLOOD COAGULATE?

Procoagulants > AnticoagulantsProcoagulants > Anticoagulants Injury to blood vesselInjury to blood vessel Blood stasisBlood stasis

INITIATION OF BLOOD COAGULATIONINITIATION OF BLOOD COAGULATION

Extrinsic PathwayExtrinsic Pathway

Tissue traumaTissue trauma

Leakage of Tissue FactorLeakage of Tissue Factor

XX XaXa

Prothrombin activatorProthrombin activator

CaCa+2+2,, factor VII factor VII

CaCa+2+2

Prothrombin Prothrombin ThrombinThrombin(factor II)(factor II)

CaCa+2+2

Intrinsic PathwayIntrinsic Pathway

Blood trauma/ contact with collagenBlood trauma/ contact with collagen

Activation of factor Activation of factor XII, IX, VIIIXII, IX, VIII

XX XaXa

CaCa+2+2

ProthrombinProthrombin activatoractivator

Prothrombin Prothrombin Thrombin Thrombin(factor II)(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 COAGULATIONBLOOD COAGULATION

ThrombinThrombin

FibrinogenFibrinogen Fibrin MonomersFibrin Monomers

Fibrin threadsFibrin threads

CaCa+2+2, factor XIII, factor XIII

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparin and Low Molecular Weight Heparins (Heparins (e.g. enoxaparin, dalteparin)e.g. enoxaparin, dalteparin)

Coumarin Derivatves Coumarin Derivatves e.g. Warfarin, e.g. Warfarin, AcenocoumarolAcenocoumarol

Indandione Derivatves Indandione Derivatves e.g. Phenindione, e.g. Phenindione, AnisindioneAnisindione

Three classes

WARFARIN: MECHANISM OF ACTIONWARFARIN: MECHANISM OF ACTION

Inactive factors II, VII, IX, and X

Proteins S and C

Active factors II, VII, IX, and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K, which is essential for Prevents the reduction of vitamin K, which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

PLASMA HALF-LIVES OF VITAMIN K-PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINSDEPENDENT PROTEINS

Factor IIFactor II 72h72h

Factor VIIFactor VII 6h6h

Factor IXFactor IX 24h24h

Factor XFactor X 36h36h

Peak anticoagulant effect may be delayed by 72 to 96 hoursPeak anticoagulant effect may be delayed by 72 to 96 hours

INDICATIONSINDICATIONS

Prophylaxis and treatment of venous Prophylaxis and treatment of venous thromboembolism thromboembolism (deep vein thrombosis and (deep vein thrombosis and pulmonary embolism)pulmonary embolism)

Prophylaxis and treatment of Atrial fibrillationProphylaxis and treatment of Atrial fibrillation Valvular stenosisValvular stenosis Heart valve replacementHeart valve replacement Myocardial infarction Myocardial infarction

WHY TO MONITOR WARFARIN THERAPY?WHY TO MONITOR WARFARIN THERAPY?

Narrow therapeutic rangeNarrow therapeutic range Can increase risk of bleedingCan increase risk of bleeding

MONITORING OF WARFARIN MONITORING OF WARFARIN THERAPYTHERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate is called PTTime required for blood to coagulate is called PT Performed by adding a mixture of calcium and Performed by adding a mixture of calcium and

thromboplastin to citrated plasmathromboplastin to citrated plasma As a control, a normal blood sample is tested As a control, a normal blood sample is tested

continuouslycontinuously PT ratio (PTR) = PT ratio (PTR) = Patient’s PTPatient’s PT

Control PTControl PT

PROBLEMS WITH PT/PTRPROBLEMS WITH PT/PTR

Thromboplastins are extracts from brain, Thromboplastins are extracts from brain, lung or placenta of animalslung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their sensitivity to manufacturers differ in their sensitivity to prolong PTprolong PT

May result in erratic control of May result in erratic control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt – prothrombin time of patient– prothrombin time of patient

PTPTRef Ref – prothrombin time of normal pooled sample– prothrombin time of normal pooled sample

ISI – International Sensitivity IndexISI – International Sensitivity Index

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Dosage to be individualized according to patient’s INR Dosage to be individualized according to patient’s INR response. response. Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complications.other complications.

Initial dose: 2-5 mg once dailyInitial dose: 2-5 mg once daily Maintenance dose: 2-10 mg once dailyMaintenance dose: 2-10 mg once daily Immediate anticoagulation required:Immediate anticoagulation required: Start heparin Start heparin

along with loading dose of warfarin 10 mg. Heparin is along with loading dose of warfarin 10 mg. Heparin is usually discontinued after 4-5 days. usually discontinued after 4-5 days. Before discontinuing, Before discontinuing, ensure INR is in therapeutic range for 2 consecutive daysensure INR is in therapeutic range for 2 consecutive days

Monitor daily until INR is in therapeutic range, then 3 Monitor daily until INR is in therapeutic range, then 3 times weekly for 1-2 weeks, then less often (every 4 to times weekly for 1-2 weeks, then less often (every 4 to 6 weeks) 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

2.0-3.02.0-3.0

Treatment of venous Treatment of venous thromboembolismthromboembolism

2.0-3.02.0-3.0

Atrial fibrillationAtrial fibrillation 2.0-3.02.0-3.0

Mitral valve stenosisMitral valve stenosis 2.0-3.02.0-3.0

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

2.0-3.02.0-3.0

2.5-3.52.5-3.5

Myocardial infarctionMyocardial infarction 2.0-3.02.0-3.0

2.5-3.5 2.5-3.5 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Inaccurate lab testingInaccurate lab testing Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Alcohol Hepatic dysfunctionHepatic dysfunction FeverFever

DURATION OF THERAPYDURATION OF THERAPY

Venous thromboembolism: Minimum 3 months, Venous thromboembolism: Minimum 3 months, usually 6 monthsusually 6 months

AMI: During initial 10-14 days of hospitalization AMI: During initial 10-14 days of hospitalization or until patient is ambulatoryor until patient is ambulatory

Mitral valve disease/Mechanical heart valves: Mitral valve disease/Mechanical heart valves: LifelongLifelong

Bioprosthetic heart valves: 3 monthsBioprosthetic heart valves: 3 months Atrial fibrillation: LifelongAtrial fibrillation: Lifelong Prevention of cerebral embolism: 3-6 monthsPrevention of cerebral embolism: 3-6 months

CONTARINDICATIONS AND CONTARINDICATIONS AND PRECAUTIONSPRECAUTIONS

Hypersensitivity to warfarinHypersensitivity to warfarin Condition with risk of hemorrhageCondition with risk of hemorrhage Hemorrhagic tendencyHemorrhagic tendency Inadequate laboratory techniquesInadequate laboratory techniques Protein C & S deficiencyProtein C & S deficiency Vitamin K deficiencyVitamin K deficiency Intramuscular injectionsIntramuscular injections

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity

Agranulocytosis, leukopenia, diarrhoea,Agranulocytosis, leukopenia, diarrhoea,

nausea, anorexia.nausea, anorexia.

SWITCHOVER FROM ONE BRAND OF SWITCHOVER FROM ONE BRAND OF WARFARIN TO ANOTHER/ WARFARIN TO ANOTHER/ ACENOCOUMAROLACENOCOUMAROL

Check patient’s INRCheck patient’s INR Start with dose of 2 mg; increase dose Start with dose of 2 mg; increase dose

slowly as requiredslowly as required

COMPARISON WITH COMPARISON WITH ACENOCOUMAROLACENOCOUMAROL

THE OVERALL ANTICOAGULATION QUALITY THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER WITH WARFARIN IS SIGNIFICANTLY BETTER WITH WARFARIN AS COMPARED TO ACENOCOUMAROLAS COMPARED TO ACENOCOUMAROL

72%

67%

64%

66%

68%

70%

72%

% R

espo

nder

s

Warfarin Acenocoumarol

Thrombosis And Haemostasis 1994; 71(2): 188-191

RECENT TRIALS ON RECENT TRIALS ON WARFARINWARFARIN

ANTICOAGULATION FOR VTE PROVOKED BY ANTICOAGULATION FOR VTE PROVOKED BY TRANSIENT RISK FACTORS (SURGERY etc) SHOULD TRANSIENT RISK FACTORS (SURGERY etc) SHOULD BE CONTINUED FOR 3 MONTHSBE CONTINUED FOR 3 MONTHS

GroupGroup Incidence (%) per yearIncidence (%) per year

Warfarin for 1 monthWarfarin for 1 month 6.8%6.8%

Warfarin for 3 monthsWarfarin for 3 months 3.2%3.2%

Follow-up=11 mths

There were no major bleeds in either groups

J Thromb Haemost. 2004; 2(5): 743-749

THE THE PPREVENTION OF REVENTION OF RERECURRENT CURRENT VENVENOUS OUS TTHROMBOEMBOLISM (PREVENT) TRIALHROMBOEMBOLISM (PREVENT) TRIAL

Long-term use of low-intensity warfarin, prevents Long-term use of low-intensity warfarin, prevents venous thromboembolism without increasing the risk venous thromboembolism without increasing the risk of hemorrhageof hemorrhage

NEJM 2003; 348 (15): 1425-1434NEJM 2003; 348 (15): 1425-1434

INCIDENCE OF VTES IN THE TWO TREATMENT GROUPSINCIDENCE OF VTES IN THE TWO TREATMENT GROUPS

Drug Warfarin Placebo

Events per 100 person-years

2.6 7.2

Bleeding requiring hospitalization

0.9 0.40.4

N= 508508

Target INR Target INR 1.5-2.01.5-2.0

Warfarin Reduced the Risk of Recurrent Venous Thromboembolism, Major Hemorrhage, or Death From Any Cause

0 1 2 3 4

Years of Follow-up

0.00

0.05

0.10

0.15

0.20

0.25 P=0.02

Placebo

Low-intensitywarfarin

Cum

ulat

ive

Rat

e of

Eve

nts

(%) 48%

NEJM 2003; 348 (15): 1425-1434NEJM 2003; 348 (15): 1425-1434