II. Definitions

  1. Vitamin K Antagonist
    1. Agents that inhibit the intrahepatic intercoversion of Vitamin K to its reduced form
      1. Competitively block Vitamin K epoxide reductase (recycles Vitamin K)
    2. In the absence of Vitamin K, Clotting Factors/Proteins are not activated and Clotting Cascade does not occur
    3. Warfarin is the most commonly used Vitamin K Antagonist
    4. Other Vitamin K Antagonists include Dicoumarol, phenprocoumon and acenocoumarol
      1. Dicoumarol and coumarin are naturally occurring compounds found in plants

III. Mechanism

  1. Inhibits Vitamin K participation in factor synthesis (Vitamin K Antagonist)
    1. Clotting Factors (both pro-coagulant and Anticoagulant) are Vitamin K Dependent
    2. Vitamin K is required for carboxylation of terminal ends of coagulation Proteins
    3. Without carboxylation, Clotting Factors/Proteins are not activated and Clotting Cascade does not occur
    4. Warfarin inhibits the intrahepatic cyclic interconversion of Vitamin K to a reduced form
      1. Keeps Vitamin K and dependent factors inactive
  2. Vitamin K dependent coagulation Proteins
    1. Procoagulant Activity (Mnemonic: "1972")
      1. Factor 10 (36 hour half life)
      2. Factor 9 (24 hour half life)
      3. Factor 7 (8 hour half life)
      4. Factor 2 (50-72 hour half life)
    2. Anticoagulant Activity
      1. Protein C (8-14 hour half life)
      2. Protein S (30-42 hour half life)
  3. Coumadin has an initial paradoxical procoagulant effect
    1. Anticoagulant factors are depleted first
    2. Initially both Hypercoagulable and at increased risk for Warfarin skin necrosis
    3. Concurrently administer Heparin for first 4-5 days

IV. Indications: General

  1. DOACs are often preferred over Warfarin for most Anticoagulation indications (esp. Atrial Fibrillation, Venous Thromboembolism)
  2. However, Warfarin is preferred over DOACs in a few specific conditions
    1. Mechanical Heart Valve
      1. Pradaxa and Apixaban have both shown higher thrombosis risk than Warfarin
    2. Moderate to severe Mitral Stenosis and Atrial Fibrillation
      1. Higher mortality and stroke risk with Rivaroxaban compared with Warfarin
    3. Left Ventricular Assist Device (LVAD)
    4. Antiphospholipid Antibody Syndrome and Thrombosis history
    5. Breakthough stroke on DOAC
    6. Chronic Kidney Disease Stage 4-5 (most DOACs contraindicated in severe renal disease)
    7. DOAC Drug Interactions that decrease Anticoagulation efficacy
      1. Rifampin
      2. Carbamazepine
  3. References
    1. (2022) Presc Lett 29(11): 62

V. Indications: Standard INR between 2.0 and 3.0

  1. Precautions
    1. INR 2.2 to 2.3 associated with lowest overall mortality
      1. Oden (2002) BMJ 325:1073-5 [PubMed]
  2. Major orthopedic surgery
    1. Hip replacement or ORIF Fracture (for 28-35 days)
    2. Elective total knee arthroplasty (for 10-14 days)
  3. Atrial Fibrillation
    1. High CVA risk (CHADS Score 2 or higher)
    2. Persistent, paroxysmal Atrial Fibrillation, flutter
    3. Cardioversion (Warfarin for 3 weeks before, 4 weeks after)
    4. Mitral Stenosis
    5. Coronary Stent and high CVA risk (CHADS Score 2 or higher)
      1. Warfarin is continued indefinately AND
      2. Antiplatelet agents
        1. First - Immediately after stenting: Triple Therapy
          1. Clopidogrel AND Aspirin (and Warfarin)
          2. Continue triple therapy for 1 month following bare metal stent
          3. Continue triple therapy for 3-6 months following drug eluting stent
        2. Next - Following initial period of triple therapy: Dual Therapy
          1. Clopidogrel OR Aspirin (and Warfarin) until 12 months following stenting
        3. Next - Following first year of antiplatelet drugs
          1. Continue Warfarin alone
  4. Venous Thromboembolism (Deep Vein Thrombosis or Pulmonary Embolism)
    1. First episode with reversible risks: 3 months
    2. First episode and idiopathic: 6-12 months
    3. Cancer: LMWH x3-6 months, then Warfarin longterm
    4. Antiphospholipid Antibody (Lupus Anticoagulant): 12 months or longterm
    5. Two Thrombophilias: 12 months or longterm
    6. Clotting disorder related: 6-12 months or longterm
    7. Two or more episodes: Longterm
  5. Coronary Artery Disease
    1. High risk patients for Myocardial Infarction without stent
      1. Continue Warfarin for 3 months following Myocardial Infarction
      2. Continue with low dose Aspirin (e.g. 81 mg)
    2. High risk patients for Myocardial Infarction with bare metal stent
      1. First: Triple therapy (Warfarin AND Clopidogrel AND low dose Aspirin) for 1 month
      2. Next: Dual therapy (Warfarin AND Clopidogrel or low dose Aspirin) for 2 months
    3. High risk patients for Myocardial Infarction with drug eluting stent
      1. First: Triple therapy (Warfarin AND Clopidogrel AND low dose Aspirin) for 3-6 months
  6. Heart Valve Replacement
    1. Mechanical Aortic Valve Replacement with bileaflet or tilting disk valves
      1. Low dose Aspirin (e.g. 81 mg) is recommended with Warfarin if low bleeding risk
    2. Bioprosthetic Heart Valve in mitral position
      1. Warfarin for 3 months after insertion

VI. Indications: Target INR between 2.5 and 3.5

  1. Mechanical Heart Valves
    1. Ball and cage valve
    2. Comorbid Atrial Fibrillation, CHF, MI, LAE
    3. Mitral Valve Replacement

VII. Dosing

VIII. Drug Interactions

IX. Safety

  1. Pregnancy Category X in all trimesters (except if Mechanical Heart Valves)
  2. Considered safe in Lactation

X. Adverse Effects

  1. Major Bleeding (including gastrointestinal Hemorrhage)
    1. Highest risk on initiation and when INR elevated
    2. Other risks
      1. Variable INR
      2. Age over 65 years
      3. Gastrointestinal Bleeding history
      4. Hypertension
      5. Cerebrovascular Disease
      6. Malignancy
      7. Renal Insufficiency (Apixaban is preferred instead of GFR <30 ml/min)
  2. Warfarin Skin Necrosis
    1. Rare complication
  3. Gastrointestinal symptoms
    1. Nausea, Vomiting, Abdominal Pain and distention, Flatulence and Dysgeusia

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Cost: Medications

warfarin (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
WARFARIN SODIUM 1 MG TABLET Generic $0.09 each
WARFARIN SODIUM 10 MG TABLET Generic $0.12 each
WARFARIN SODIUM 2 MG TABLET Generic $0.09 each
WARFARIN SODIUM 2.5 MG TABLET Generic $0.09 each
WARFARIN SODIUM 3 MG TABLET Generic $0.11 each
WARFARIN SODIUM 4 MG TABLET Generic $0.09 each
WARFARIN SODIUM 5 MG TABLET Generic $0.11 each
WARFARIN SODIUM 6 MG TABLET Generic $0.12 each
WARFARIN SODIUM 7.5 MG TABLET Generic $0.12 each