Optimal initial dose adjustment of warfarin in orthopedic patients

Ann Pharmacother. 2007 Nov;41(11):1798-804. doi: 10.1345/aph.1K197. Epub 2007 Oct 2.


Background: Warfarin sodium is commonly prescribed for the prophylaxis and treatment of venous thromboembolism. Dosing algorithms have not been widely adopted because they require a fixed initial warfarin dose (eg, 5 mg) and are not tailored to other factors that may affect the international normalized ratio (INR).

Objective: To develop an algorithm that could predict a therapeutic warfarin dose based on drug interactions, INR response after the initial warfarin doses, and other clinical factors.

Methods: We used stepwise regression to quantify the relationship between these factors in patients beginning prophylactic warfarin therapy immediately prior to joint replacement. In the derivation cohort (n = 271), we separately modeled the therapeutic dose after 2 and 3 initial doses. We prospectively validated these 2 models in an independent cohort (n = 105).

Results: About half of the therapeutic dose variability was predictable after 3 days of therapy: R2 was 53% in the derivation cohort and 42% in the validation cohort. INR response after 3 warfarin doses (INR3) inversely correlated with therapeutic dose (p < 0.001). Intraoperative blood loss transiently, but significantly, elevated the postoperative INR values. Other significant (p < 0.03) predictors were the first and second warfarin doses (+7% and +6%, respectively, per 1 mg), and statin use (-15.0%). The model derived after 2 warfarin doses explained 32% of the variability in therapeutic dose.

Conclusions: We developed and validated algorithms that estimate therapeutic warfarin doses based on clinical factors and INR response available after 2-3 days of warfarin therapy. The algorithms are implemented online at www.WarfarinDosing.org.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Algorithms
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Anticoagulants / therapeutic use
  • Arthroplasty, Replacement, Hip*
  • Arthroplasty, Replacement, Knee*
  • Blood Loss, Surgical / prevention & control
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • International Normalized Ratio
  • Male
  • Middle Aged
  • Prospective Studies
  • Pulmonary Embolism / prevention & control
  • Venous Thrombosis / prevention & control
  • Warfarin / administration & dosage*
  • Warfarin / adverse effects
  • Warfarin / therapeutic use


  • Anticoagulants
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Warfarin