| 18662264 |
Lenzini PA, Grice GR, Milligan PE, Dowd MB, Subherwal S, Deych E, Eby CS, King CR, Porche-Sorbet RM, Murphy CV, Marchand R, Millican EA, Barrack RL, Clohisy JC, Kronquist K, Gatchel SK, Gage BF: Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients. J Thromb Haemost. 2008 Oct;6(10):1655-62. Epub 2008 Jul 24.
BACKGROUND: Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common. METHODS: In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy. RESULTS: The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, peri-operative blood loss, liver disease, INR values and dose history to predict the therapeutic dose. The R (2) was 82% in a derivation cohort (n = 86) and 70% when used prospectively (n = 146). The R (2) of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (n = 178) and 48% in a prospective validation cohort (n = 146). In 1 month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7-11.7) in the pharmacogenetic cohort. The risk of a laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.30-0.97). CONCLUSIONS: Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, http://www.WarfarinDosing.org. |
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