Warfarin (coumadin)

Warfarin half-life approximately 48hrs

Inhibits vitamin K dependent factors (II, VII, IX, X)

  • Decline in factor II most important for efficacy (half-life 72hrs)
  • Decline in factor VII most important for INR measurement (half-life 6 days)

Adverse event most likely in the first 30 days of Rx

Antidote:

  • Vitamin K
    • IV – 6hrs to onset, risk of anaphylaxis
    • SC, or PO – 12hrs to onset
    • in a non-bleeding patient with INR 4-10:
      • 1 mg po Vitamin K will bring INR down to normal range about 1 day sooner
      • no decreased risk of bleeding
  • FFP/factors if emergency

Elevated INR:

  • >4.0 – risk of major bleed increased
  • >5.0 – risk of intracranial hemorrhage
  • >6.0 – 4% risk of life-threatening bleed within the next 2 weeks
    • hold warfarin until INR 4.0
    • consider administering 1-2.5mg of Vitamin K

Age vs average warfarin dose:

  • < 50 years – 6.4mg
  • 50 to 59 years – 5.1mg
  • 60 to 69 years – 4.2mg
  • >70 years – 3.6mg

Initiation

  • for VTE: 5-10mg (use 5mg nomogram for less acute indications and elderly patients, and the 10mg nomogram for VTE and mechanical heart valves)
  • 10mg nomogram for dose adjustments
  • for atrial fibrillation in elderly patients (Siguret V et al. Am J Med 2005; 118:137-42):
    • Warfarin 4 mg once daily for 3 days in the evening (6pm)
    • INR the morning of day 4:
      • 1.0 to 1.2 – 5mg warfarin
      • 1.3 to 1.5 – 4mg warfarin
      • 1.6 to 1.7 – 3mg warfarin
      • 1.8 to 2.0 – 2mg warfarin
      • 1.9 to 2.5 – 1mg warfarin
      • > 2.5 – hold warfarin until INR < 2.5, then 1mg warfarin

Establishing therapy:

  • Short-acting antithrombotic until INR above 2.0
  • INR daily for at least 5 consecutive days
  • INR above 2.0 for at least 2 days
  • Then INR twice weekly for 2 weeks
  • If stable, can increase interval to a maximum of q4weeks

Follow-up Algorithm, based on number of INRs consecutively in range:

  • 1: 5-10 days
  • 2: 2 weeks
  • 3: 3 weeks
  • 4-6: 4 weeks
  • 7: 6 weeks
  • 8: 8 weeks
  • 9: 10 weeks
  • 10: 12 weeks
  • Note:for any F/U that is longer than 6 weeks, patient education about RTC is critical

Absolute risk of thromboembolism, and reduction of that risk via warfarin therapy:

  • VTE (target INR 2.0-3.0)
    • acute
      • 1st month – 40%/month, 80% risk reduction
      • 2-3rd months – 10%/2 months, 80% risk reduction
    • recurrent – 15%/year – 90% risk reduction
    • initiation: at least 5 days with fast-acting thrombolytics and at least 2 days with an INR >2.0
    • F/U with FD: 2x week for 2 weeks, weekly for 2 weeks, all with INR
  • atrial fibrillation (target INR 2.0-3.0)
    • 4.5%/year, 66% risk reduction
    • with prior 12%/year, 66% risk reduction, 2-3% per year risk of major bleed
    • with ASA instead: ~20% risk reduction, 1% per year risk of major bleed
  • Mechanical heart valve (target INR 2.5-3.5)
    • 8%/year, 75% risk reduction

Risk factors for bleed with anticoagulation

  • Advanced age
  • Uncontrolled hypertension
  • History of myocardial infarction, ischemic heart disease, cerebrovascular disease, anaemia or bleeding
  • Concomitant use of other drugs such as antiplatelet agents

If INR has been stable and is between 1.7-3.3, consider making no changes to the warfarin, otherwise:

  • 5 to 10% of weekly dose if +/- 0.5 units
  • 10 to 20% of weekly dose if > 0.5 units
  • effect of any dose change will be seen at days 3-4

Common factors causing a change in INR (only about ~50% of the time is a cause identified):

  • change in medications (addition or deletion, Abx, vitamins)
  • acute illness
  • Dietary habits and/or changes in nutritional status
  • lifestyle habits (EtOH, exercise, travel, etc)
  • inaccurate INR determination
  • compliance

Drug interactions so numerous, mechanisms are more important

  • inhibition of platelet function
  • reduced vitamin K from gut flora
  • alteration of warfarin metabolism
  • injury to gut mucosa
  • interference with vitamin K cycle
  • Well-known medications that cause INR changes
    • fluconazole
    • cotrimoxazole
    • amiodarone
    • sertraline
    • fluvastatin
    • fenofibrate
    • levothyroxine
    • acetaminophen