Dose and Intensity of Warfarin Therapy are Associated with Coronary Artery Calcification in a Low-Risk Cohort

Background: Warfarin inhibits activation of vitamin K-dependent proteins, including matrix Gla protein (MGP), a potent vascular calcification inhibitor. Effects of warfarin dose and intensity of anticoagulation on coronary artery calcium (CAC) in individuals without traditional cardiovascular risk factors are unclear. Methods: We conducted a retrospective matched cohort study of 100 patients on long-term warfarin treatment (≥1 year) and 100 sex- and age-matched (±2 years) controls without anticoagulant exposure. CAC was assessed by non-contrast computed tomography. We analyzed associations of CAC scores with warfarin dose, international normalized ratio (INR), and clinical variables using multivariate linear regression. Results: Warfarin treated group exhibited statistically significantly higher median CAC scores than the matched controls (387.5 [IQR 215.6 - 598.4] vs. 25.0 [IQR 0.0 - 64.8], p<0.001). Multivariable analysis in warfarin group identified mean INR (β=152.67, 95% CI 75.76 – 229.58; p<0.001), average daily warfarin dose (β=45.32, 95% CI 20.83 – 69.81; p<0.001), and treatment duration (β=29.50 per year, 95% CI 10.80 – 48.20; p=0.002) as independent predictors of higher CAC score, after adjustment for age, sex, and prosthetic valve position. Male sex and dual mechanical valve replacement were also independently associated with higher CAC scores. Conclusion: In this low-risk cohort, the dose, intensity and duration of warfarin therapy were independently associated with the severity of coronary artery calcification. These findings point to a potential vascular trade-off of long-term vitamin K antagonism and necessitate investigation into calcification-sparing anticoagulation strategies in these patients.