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 gt 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
Ca2, factor VII
X Xa
X Xa
Ca2
Ca2
Prothrombin activator
Prothrombin activator
Ca2
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)
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BLOOD COAGULATION
Thrombin
Fibrin Monomers
Fibrinogen
Ca2, factor XIII
Fibrin threads
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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

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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

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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
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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

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WHY TO MONITOR WARFARIN THERAPY?

• Narrow therapeutic range
• Can increase risk of bleeding

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MONITORING OF WARFARIN THERAPY

• Prothrombin time
• PT ratio
• INR (International Normalized Ratio)

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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) Patients PT
• Control PT

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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

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INTERNATIONAL NORMALISED RATIO (INR)
INR PTpt ISI PTRef PTpt
prothrombin time of patient PTRef prothrombin
time of normal pooled sample ISI International
Sensitivity Index
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OPTIMIZING WARFARIN THERAPY

• Dosage to be individualized according to
  patients 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)

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

• Inaccurate lab testing
• Poor patient compliance
• Concomitant medications
• Levels of dietary vitamin K
• Alcohol
• Hepatic dysfunction
• Fever

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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

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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

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SIDE EFFECTS

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

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SWITCHOVER FROM ONE BRAND OF WARFARIN TO ANOTHER/
ACENOCOUMAROL

• Check patients INR
• Start with dose of 2 mg increase dose slowly as
  required

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COMPARISON WITH ACENOCOUMAROL
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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
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RECENT TRIALS ON WARFARIN
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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-up11 mths
J Thromb Haemost. 2004 2(5) 743-749
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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
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Warfarin Reduced the Risk of Recurrent Venous
Thromboembolism, Major Hemorrhage, or Death From
Any Cause
0.25
P0.02
Placebo
0.20
48
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Years of Follow-up
NEJM 2003 348 (15) 1425-1434