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ANTICOAGULATION

Optimal Initial Dose Adjustment of Warfarin in Orthopedic Patients

Research Statistician, Washington University in St. Louis, St. Louis, MO

Gloria R Grice, PharmD BCPS

Assistant Professor, Saint Louis College of Pharmacy, St. Louis

Paul E Milligan, PharmD

Clinical Pharmacist, Washington University in St. Louis

Susan K Gatchel, CCRC

Research Patient Assistant, Washington University in St. Louis

Elena Deych, MS

Research Statistician, Washington University in St. Louis

Charles S Eby, MD

Associate Professor of Pathology and Immunology, Washington University in St. Louis

R Stephen J Burnett, MD FRCS(C)

Orthopaedic Surgeon, Vancouver Island Health Authority, Division of Orthopaedic Surgery, Adult Reconstructive Surgery, Vancouver, British Columbia, Canada

John C Clohisy, MD

Associate Professor of Orthopaedic Surgery, Washington University in St. Louis

Robert L Barrack, MD

C & J Knight Distinguished Professor of Orthopaedic Surgery, Department of Orthopaedic Surgery, Washington University in St. Louis

Brian F Gage, MD MS

Associate Professor of Medicine, Department of Medicine, Washington University in St. Louis

Reprints: Dr. Gage, Department of Medicine, Washington University in St. Louis, Campus Box 8005, 660 South Euclid Ave., St. Louis, MO 63110, fax 314/454-5554, bgage{at}im.wustl.edu

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.

Key Words: anticoagulants, orthopedics, warfarin

Published Online, October 2, 2007. www.theannals.com, DOI 10.1345/aph.1K197

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