AGE-DEPENDENT DIFFERENCES IN THE ANTICOAGULANT EFFECT OF PHENPROCOUMON IN PATIENTS AFTER HEART-VALVE SURGERY

Objective: An enhanced response to warfarin and an increased risk of m ajor bleeding has been observed in older patients. The reason for this increase in sensitivity remains unknown. It could be due to pharmacod ynamic reasons, pharmacokinetic reasons, or both. Methods: We therefor e followed an anticoagulant regimen with phenprocoumon in 19 older (76 years) and 19 younger patients (50 years) following heart valve repla cement. INR values were determined frequently. At the 4th and around t he 24th day after starting treatment with phenprocoumon, we also measu red the total and unbound plasma concentration of phenprocoumon. Resul ts: The dose requirement to obtain the desired anticoagulant effect wa s significantly lower in the older patients than in the younger patien ts (26.3 vs. 37.3 mu g.kg(-1).day(-1)). The total plasma concentration (2.19 vs. 2.43 mu g.ml(-1)), the percentage unbound drug in the plasm a (0.61 vs. 0.64%) and the unbound plasma concentration (13.8 vs. 15.1 ng.ml(-1)) did not differ significantly between older and younger pat ients. The dose-adjusted INR (INR/dose) was higher in the older patien ts (110 vs. 67) but the INR adjusted for the unbound plasma concentrat ion (INR/C-uss) which reflects the intrinsic sensitivity to the drug, was not significantly different (192 vs. 173). However, the older pati ents had an about 30% significantly lower metabolic clearance based on unbound drug (84 vs. 115 ml.kg(-1).h(-1)). Conclusions: Older patient s (> 70 years) require a dose approximately 30% lower than younger pat ients (< 160 years). Pharmacokinetic reasons (reduced metabolic cleara nce) are mainly responsible for the lower dose requirement of the olde r patients after heart valve surgery.