Increased sensitivity to warfarin (W) with aging-a pharmacokinetic (PK) or pharmacodynamic (PD) phenomenon?

Background: Increased sensitivity to W, has been demonstrated in the elderly. Evidence is conflicting on the relative contribution of PK changes vs increased intrinsic sensitivity to W to this phenomenon. We sought to determine whether age affects the anticoagulant response to W by PK or PD changes. Methods: In 178 patients on stable W doses and INRs, steady state plasma W and vitamin K concentrations were measured, W Sensitivity Index (WSI=INR/warfarin daily dose per m² BSA) and average W clearance were calculated. Results: Mean INR was 2.6±0.53 with no significant differences among the 4 age groups: <50 (n=34), 51-65 (n=44), 66-75 (n=47) and 76< (n=35). Mean W dose (mg/day) decreased with increasing age: 7.9±3.6, 6.7±3.7, 5.0±2.1 and 5.2±2.3 respectively (p<.0001). Steady-state plasma W concentrations (mg/L) did not differ among the groups: 2.2±0.9, 2.0±1.0, 1.9±0.9 and 1.9±0.7 respectively, indicating decreased W clearance with advancing age: 2.8±1.4 ml/min, 2.5±1.2, 2.0±1.4 and 2.0±0.8 (p<.002). Serum vitamin K concentrations did not differ significantly among the groups. Multivariate analysis revealed that only serum W concentrations (r²=0.21) and age (r²=0.03) are significant independent predictors for the WSI. Conclusions: Advanced age is associated with increased sensitivity to W mostly due to diminished W clearance. A possible age-related increase in intrinsic sensitivity to W is of borderline significance.