What is the proper dosing for warfarin (Coumadin) therapy?

Warfarin Dosing Protocol

For outpatients, initiate warfarin therapy with 10 mg daily for the first 2 days followed by dosing based on INR measurements rather than starting with the estimated maintenance dose. 1

Initial Dosing Strategy

• For patients who are sufficiently healthy to be treated as outpatients, a loading dose of 10 mg daily for the first 2 days is recommended, followed by INR-guided dosing 1
• For elderly patients (≥65 years), those at increased risk of bleeding, or patients expected to have heightened sensitivity to warfarin, use a lower initial dose of 2-5 mg daily 1, 2
• When rapid anticoagulation is required, heparin should be given concurrently with warfarin for at least 4 days until the INR has been in the therapeutic range for 2 consecutive days 1
• For non-urgent anticoagulation (e.g., atrial fibrillation), warfarin can be started at 4-5 mg daily without heparin, which typically produces a satisfactory anticoagulant effect within 6 days 1

Monitoring Protocol

• Check INR daily until the therapeutic range has been reached and sustained for 2 consecutive days 1
• After initial stabilization, monitor INR 2-3 times weekly for 1-2 weeks 1
• As INR stability improves, gradually reduce monitoring frequency to intervals as long as 4 weeks for stable patients 1
• When dose adjustments are required, resume more frequent monitoring 1
• Most patients are satisfactorily maintained on a dose of 2-10 mg daily 2

Dose Adjustment

• Adjust dosing based on INR results to maintain the target INR appropriate for the indication:
  • Venous thromboembolism: target INR 2.5 (range 2.0-3.0) 2
  • Atrial fibrillation: target INR 2.5 (range 2.0-3.0) 2
  • Mechanical heart valves: target INR varies by valve type (2.5-3.5) 2
• When adjusting doses, change the total weekly dose by 5-20% based on INR values 3
• For patients with unexpected fluctuations in dose-response, consider factors such as changes in diet, medication changes, poor compliance, or alcohol consumption 1

Special Populations

• Elderly patients (≥60 years) exhibit greater than expected PT/INR response to warfarin and generally require lower doses 2
• Asian patients may require lower initiation and maintenance doses (mean daily requirement of 3.3 ± 1.4 mg in one study) 2
• Patients with genetic variations in CYP2C9 and VKORC1 enzymes require lower doses:
  • CYP2C9*2 carriers: 17% lower mean daily dose 2
  • CYP2C9*3 carriers: 37% lower mean daily dose 2
• Patients with hepatic dysfunction may have potentiated response to warfarin through impaired synthesis of clotting factors and decreased warfarin metabolism 2

Management of Elevated INR

• For INR above therapeutic range but <5 without bleeding: reduce or omit next dose and resume at lower dose when INR approaches desired range 1
• For INR 5-9 without bleeding: omit 1-2 doses and reinstate at lower dose when INR returns to therapeutic range; alternatively, omit next dose and give 1-2.5 mg oral vitamin K if patient has increased bleeding risk 1
• For INR >9 without bleeding: give 3-5 mg oral vitamin K 1
• For serious bleeding with any INR: administer 5-10 mg IV vitamin K 1, 4
• For life-threatening bleeding: administer 4-factor prothrombin complex concentrate (PCC) plus 10 mg IV vitamin K 4

Common Pitfalls and Caveats

• Avoid excessive loading doses that can raise the INR excessively and increase bleeding risk 3
• The risk of bleeding increases exponentially with INR values above 3.0 and becomes clinically significant when INR exceeds 5.0 4
• Elderly patients have higher bleeding risk at any given INR level 4
• After high-dose vitamin K administration, warfarin resistance may occur, potentially requiring bridging with heparin until vitamin K effects subside 4
• Fluctuations in vitamin K intake from diet can affect INR stability 1
• Numerous drug interactions can potentiate or inhibit warfarin's effect, requiring more frequent monitoring when starting or stopping other medications 1