Impact of Body Mass Index and Genetics on Warfarin Major Bleeding Outcomes in a Community Setting.
Several studies have demonstrated an association between body mass index (BMI) and warfarin therapeutic dose, but none evaluated the association of BMI with the clinically important outcome of major bleeding in a community setting. To address this evidence gap, we conducted a case-control study to evaluate the association between BMI and major bleeding risk among patients receiving warfarin.



We used a case-control study design to evaluate the association between obesity (BMI >30.0 kg/m2) and major bleeding risk among 265 cases and 305 controls receiving warfarin at Group Health, an integrated healthcare system in Washington State. Multivariate logistic regression was used to adjust for potential confounders derived from health plan records and a self-report survey. In exploratory analyses we evaluated the interaction between genetic variants potentially associated with warfarin bleeding (CYP2C9, VKORC1, and CYP4F2) and obesity on the risk of major bleeding.



Overall, the sample was 55% male, 94% Caucasian, and mean age was 70 years. Cases and controls had an average of 3.4 and 3.7 years of warfarin use, respectively. Obese patients had significantly lower major bleeding risk relative to non-obese patients (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.39-0.92). The OR was 0.56 (95% CI 0.35-0.90) in patients with ≥1 year of warfarin use, and 0.78 (95% CI 0.40-1.54) in patients with <1 year of warfarin use. An exploratory analysis indicated a statistically significant interaction between CYP4F2*3 genetic status and obesity (P = .049), suggesting a protective effect of obesity on the risk of major bleeding among those wild type for CYP4F2*3, but not among variants.



Our findings suggest that BMI is an important clinical factor in assessing and managing warfarin therapy. Future studies should confirm the major bleeding associations, including the interaction between obesity and CYP4F2*3 status identified in this study, and evaluate potential mechanisms.
Institute for Public Health Genetics, University of Washington, Seattle, Wash.
Ragan
R
Hart
Institute for Public Health Genetics, University of Washington, Seattle, Wash; Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, Wash.
David L
DL
Veenstra
Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, Wash; Group Health Research Institute, Group Health, Seattle, Wash.
Denise M
DM
Boudreau
Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, Wash; Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, Seattle, Wash. Electronic address: jroth@fredhutch.org.
Joshua A
JA
Roth
D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects*; D015992:Body Mass Index; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D000072470:Cytochrome P450 Family 4 / Q000235:genetics; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced* / Q000209:etiology / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008297:Male; D009765:Obesity / Q000150:complications; D012307:Risk Factors; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000009:adverse effects*
D000925:Anticoagulants; D014859:Warfarin; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
Body mass index; CYP2C9; CYP4F2; Gene–environment interaction; Major bleeding; VKORC1; Warfarin