III. Management: INR variability

  1. See Coumadin Drug Interactions
  2. Vitamin K supplementation significantly helps stabilize INR levels
    1. Vitamin K 100-150 mcg orally daily
    2. (2007) Blood 109: 2419-33 [PubMed] (or open in [QxMD Read])
  3. Medical conditions that increase INR levels
    1. Hyperthyroidism
    2. Diarrhea
    3. Congestive Heart Failure
    4. Liver Disease
  4. Medical conditions that decrease INR levels
    1. Hypothyroidism

IV. Protocol: Starting Coumadin in elderly inpatients

  1. General
    1. Safe (no patient had an INR >4)
    2. Therapeutic INR achieved within 6-7 days
  2. Initial Dose: 4 mg daily for first 3 days
  3. Dosing protocol after day 3 based on daily INR
    1. INR <1.3: Warfarin 5 mg
    2. INR 1.3-1.4: Warfarin 4 mg
    3. INR 1.5-1.6: Warfarin 3 mg
    4. INR 1.7-1.8: Warfarin 2 mg
    5. INR 1.9-2.4: Warfarin 1 mg
    6. INR >2.4: Hold Warfarin, check INR daily
  4. References
    1. Siguret (2005) Am J Med 118:137 [PubMed] (or open in [QxMD Read])

V. Protocol: Starting Coumadin in general patients

  1. Indications for starting with concurrent Heparin
    1. Thrombophilic state (e.g. known Protein C Deficiency)
    2. Thromboembolism
  2. Indications for starting Warfarin without Heparin
    1. Chronic stable Atrial Fibrillation
  3. Starting dose of Warfarin
    1. Standard dose: 5 mg orally daily
      1. Anticipate therapeutic by day 4-5
    2. High Dose: 10 mg daily for 2 days, then drop to standard dosing
      1. Indicated for urgency to reach therapeutic level
        1. Consider for young patients with Thromboembolism
        2. Avoid in chronic Atrial Fibrillation (no urgency to get to level)
      2. Study: 10 mg start was therapeutic 1.4 days earlier
        1. Kovacs (2003) Ann Intern Med 138:714-9 [PubMed] (or open in [QxMD Read])
    3. Low dose: 2.5 to 4 mg orally daily
      1. Elderly
      2. Liver disease
      3. High risk of bleeding
  4. Protocol
    1. Monitor daily ProTime with INR
    2. Stop Heparin when 2 consecutive INRs therapeutic
    3. Monitor INR 2-3 times per week for 1-2 weeks
    4. Monitor INR every 2-4 weeks when stable
    5. Consider less frequent monitoring in stable patients
      1. Indications
        1. Stable INR without Warfarin dose change for 12 weeks
        2. Compliant patient, without other Bleeding Diathesis or serious comorbidity
      2. Protocol
        1. Consider spacing monitoring of INR to every 12 weeks
      3. References
        1. Schulman (2011) Ann Intern Med 155(10):653-9 [PubMed] (or open in [QxMD Read])
  5. INR 2.2 to 2.3 associated with lowest overall mortality
    1. Oden (2002) BMJ 325:1073-5 [PubMed] (or open in [QxMD Read])

VI. Protocol: Adjust Coumadin (based on INR 2 to 3)

  1. See Coumadin for other target INR indications
  2. INR less than 2
    1. Increase weekly Coumadin dose by 5 to 20%
  3. INR 3 to 3.5
    1. Decrease weekly Coumadin dose by 5 to 15% or
    2. Maintain same dose and recheck in 7 days
      1. Banet (2003) Chest 123:499-503 [PubMed] (or open in [QxMD Read])
  4. INR 3.6 to 5.0
    1. Consider withholding one Coumadin dose
    2. Decrease weekly Coumadin dose by 10 to 15%
  5. INR 5.0 to 10.0
    1. Withhold 1 to 2 Warfarin doses
    2. Decrease weekly Warfarin dose by 10 to 20%
    3. Indications for Vitamin K
      1. Bleeding or high bleeding risk: Vitamin K 1.0 to 2.5 mg orally for 1 dose
      2. Surgery in 24 hours: Vitamin K 2 to 4 mg orally x1 dose
  6. INR exceeds 10.0
    1. Hold Warfarin
    2. Vitamin K 2.5 to 5 mg orally for 1 dose
    3. Monitor INR daily and consider repeating Vitamin K
    4. Anticipate significantly lower INR within 24-48 hours

VII. Protocol: Mild to moderate bleeding risk (INR >5-10)

  1. Hold Warfarin per protocols above
  2. Vitamin K
    1. Mild bleeding: Vitamin K 2.5 mg orally
    2. Moderate-severe bleeding: Vitamin K 5-10 mg orally or IV

VIII. Protocol: Serious or Life-threatening bleeding (esp. INR >20)

  1. Replace Clotting Factors (first-line)
    1. Prothrombin Complex Concentrate 4 (PCC4, Kcentra or outside U.S. Octaplex, Beriplex)
      1. Preferred if available
      2. FFP-like serum extract that is 25 fold more potent than FFP
      3. Formulation in United States was PCC3 (without Factor 7) until 2013
      4. Cost is 20 times that of the $250 FFP dose (but faster acting and fewer reactions than FFP)
      5. Avoid in DIC
      6. Dose: 50 Units/kg
    2. Fresh Frozen Plasma (FFP)
      1. Indicated if PCC is not available
      2. Fresh Frozen Plasma (FFP) 15 ml/kg (roughly 1 to 1.5 liters for most patients) or a typical empiric adult dose of 4 units
      3. INR of Fresh Frozen Plasma is 1.7 and hence do not expect INR to drop below 1.6 following FFP administration
      4. Each FFP unit replaces 5% of Clotting Factors
      5. Anticipate 45 minutes to thaw FFP and 6 hours to completely transfuse the full 4 unit dose
    3. Factor Eight Inhibitor Bypass Activity (FEIBA)
      1. Similar Mechanism and components to PCC
    4. Older regimens (not recommended)
      1. Factor VIIa replacement is no longer recommended
  2. Reverse Warfarin effect
    1. Vitamin K 5-10 mg by slow IV infusion (do not use subcutaneous dosing due to inconsistent absorption)
    2. Anticipate Warfarin resistance after dose
    3. Avoid in valve replacement
    4. Anaphylaxis risk to IV Vitamin K is reduced with newer preparations from prior 3 events per 100,000
    5. Anticipate 16 hour delay in effect
      1. Consider repeat INR at that time
      2. Consider repeating Vitamin K at 12 hours
  3. References
    1. (2013) Presc Lett 20(10): 57
    2. Lex and Orman in Majoewsky (2013) EM:Rap 13(4): 4-5

IX. Dosing Adjustment: Decreased Dosing

  1. Decrease Dosing by 20% (27.5 mg per week)
    1. Coumadin 2.5 mg PO on Monday, Wednesday, Friday
    2. Coumadin 5 mg PO all other days
  2. Decrease Dosing by 15% (30 mg per week)
    1. Coumadin 2.5 mg PO on Monday and Friday
    2. Coumadin 5 mg PO all other days
  3. Decrease Dosing by 5% (32.5 mg per week)
    1. Coumadin 2.5 mg PO on Monday
    2. Coumadin 5 mg PO all other days

X. Dosing Adjustments: Standard Dosing

  1. Coumadin 5 mg PO qd (35 mg per week)

XI. Dosing Adjustments: Increased Dosing

  1. Increase Dosing by 5% (37.5 mg per week)
    1. Coumadin 7.5 mg PO on Monday
    2. Coumadin 5 mg PO all other days
  2. Increase Dosing by 15% (40 mg per week)
    1. Coumadin 7.5 mg PO on Monday and Friday
    2. Coumadin 5 mg PO all other days
  3. Increase Dosing by 20% (42.5 mg per week)
    1. Coumadin 7.5 mg PO on Monday, Wednesday, Friday
    2. Coumadin 5 mg PO all other days

XII. Resources

  1. Point of Care Guide by Mark Ebell, MD
    1. http://www.aafp.org/20050515/pocform.html

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