Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients

P. A. Lenzini, G. R. Grice, P. E. Milligan, M. B. Dowd, S. Subherwal, E. Deych, C. S. Eby, C. R. King, R. M. Porche-sorbet, C. V. Murphy, R. Marchand, E. A. Millican, R. L. Barrack, J. C. Clohisy, K. Kronquist, S. K. Gatchel, Brian F. Gage

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

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 R2 was 82% in a derivation cohort (n=86) and 70% when used prospectively (n=146). The R2 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 1month 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.

Original languageEnglish
Pages (from-to)1655-1662
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume6
Issue number10
DOIs
StatePublished - 2008

Keywords

  • Anticoagulants
  • Dosing algorithm
  • Orthopedic surgery
  • Pharmacogenetics
  • Warfarin

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