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Impact of Age, CYP2C9 Genotype and Concomitant Medication on the Rate of Rise for Prothrombin Time During the First 30 Days of Warfarin Therapy

Russell A. Wilke, MD, PhD, Department of Internal Medicine, Marshfield Clinic, and Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin
Richard L. Berg, MS, Biostatistics and Bioinformatics Core, Marshfield Clinic Research Foundation, Marshfield, Wisconsin
Humberto J. Vidaillet, MD, Department of Cardiology, Marshfield Clinic, Marshfield, Wisconsin
Michael D. Caldwell, MD, PhD, Department of Surgery, Marshfield Clinic, Marshfield, Wisconsin
James K. Burmester, PhD, Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin
Michael A. Hillman, MD, MBA, Care Management, Marshfield Clinic, Marshfield, Wisconsin

Reprint Requests: Russell A. Wilke, MD, PhD, Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 North Oak Street, Marshfield, WI 54449, Tel: 715-387-9433, Fax: 715389-4950, Email: wilke.russell{at}mcrf.mfldclin.edu.

Objectives: To characterize the impact of several important clinical variables on the rate of anticoagulation during warfarin initiation (i.e., the first 30 days).

Design: Retrospective study.

Setting: An anticoagulation service of a large horizontally integrated, multispecialty group practice in central and northern Wisconsin.

Participants: Patients with sufficient laboratory data obtained during the initiation phase of warfarin treatment.

Methods: Patients were consented and genotyped for cytochrome P450 (CYP) 2C9 polymorphisms. Anticoagulation laboratory data were then electronically abstracted and fitted to a logistic growth model. Rate of anticoagulation was compared between groups.

Results: During warfarin initiation, the mean slope for rise in International Normalized Ratio (INR) of prothrombin time was significantly associated with age (p=0.03, n=166). Because a relationship between diabetes and warfarin dosing has been suggested previously, we assessed the impact of this comorbidity in our model as well. Diabetes showed relatively little impact, but concomitant treatment with an anti-diabetic sulfonylurea medication was associated with an increase in slope (3-fold, p<0.05). Since this drug interaction may occur at the level of CYP2C9, we also assessed the impact of CYP2C9 genotype in our model. The impact of CYP2C9 genotype was marginally significant (p=0.119, non-pooled dataset; p=0.053, data pooled for CYP2C9 *2/*2, *2/*3 and *3/*3).

Conclusions: Age and concomitant sulfonylurea therapy alter the rate of anticoagulation during the first 30 days of warfarin therapy.

Key Words: Pharmacogenetics • Pharmacokinetics • Drug interactions • Logistic modeling • Prothrombin time

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