Kidney function influences warfarin responsiveness and hemorrhagic complications

Abstract

Although management of warfarin is challenging for patients with chronic kidney disease (CKD), no prospective studies have compared response to warfarin among patients with minimal, moderate, and severe CKD. This secondary analysis of a prospective cohort of 578 patients evaluated the influence of kidney function on warfarin dosage, anticoagulation control, and risk for hemorrhagic complications. We adjusted all multivariable regression and proportional hazard analyses for clinical and genetic factors. Patients with severe CKD (estimated GFR <30 ml/min per 1.73 kg/m2) required significantly lower warfarin dosages (P = 0.0002), spent less time with their international normalized ratio within the target range (P = 0.049), and were at a higher risk for overanticoagulation (international normalized ratio >4; P = 0.052), compared with patients with no, mild, or moderate CKD. Patients with severe CKD had a risk for major hemorrhage more than double that of patients with lesser degrees of renal dysfunction (hazard ratio 2.4, 95% confidence interval 1.1 to 5.3). In conclusion, patients with reduced kidney function require lower dosages of warfarin, have poorer control of anticoagulation, and are at a higher risk for major hemorrhage. These observations suggest that warfarin may need to be initiated at a lower dosage and monitored more closely in patients with moderate or severe CKD compared with the general population. Diminished renal function may have implications for a larger proportion of warfarin users than previously estimated.

Figure 1.

Average warfarin dosage (mg/d) by CKD stages 1 and 2 (no/mild) versus stage 3 (moderate) versus stages 4 and 5 (severe) stratified by CYP2C9 and VKORC1 genotype. Least square means of back-transformed log-dosage adjusted for VKORC1-1173, CYP2C9, GFR, age, race, gender, BMI, vitamin K intake, alcohol, education, insurance, income, smoking, number of comorbid conditions, and concomitant therapy with CYP2C9 inhibitors and HMG-CoA inhibitors. Values given for a 60-yr-old white man with BMI 30, consuming two servings of vitamin K–rich foods per week, nondrinker, nonsmoker, with no other comorbid conditions, no CYP2C9 inhibitors or HMG-CoA reductase inhibitors. Wt, wild-type; v, variant. CYP2C9 variant genotype includes *2 and *3 alleles among European Americans and *2, *3, *5, *6, and *11 alleles among African Americans. Variant VKORC1-1173C/T includes TT or CT.

Figure 2.

(A and B) Time to major (A) and minor (B) hemorrhage stratified by CKD stages 1 and (no/mild) versus stage 3 (moderate) versus stages 4 and 5 (severe). Estimated survival curve from Cox PH model adjusted for age, race, warfarin dosage, gender, BMI, INR, alcohol intake, smoking, vitamin K intake, number of comorbid conditions, drug interactions, and CYP2C9 and VKORC1 genotype.