A randomized controlled trial of empiric warfarin dose reduction with the initiation of doxycycline therapy

When interacting medications, such as doxycycline, are initiated during warfarin therapy, one method to correct for non-therapeutic international normalized ratio (INR) is adjusting the warfarin dose, if necessary. Another approach is preemptive warfarin dose adjustment. This study's objective was to evaluate the utility of preemptive warfarin dose adjustment for preventing non-therapeutic INR following doxycycline-warfarin co-administration.

Patients were randomized to either a 10% to 20% preemptive warfarin dose reduction (intervention) or reactive warfarin dose adjustment (control) within 72 hours of warfarin-doxycycline co-administration. Subjects received a follow-up INR within 7 days (index INR). Primary outcome was the occurrence of index INR ≥ 1 point over the INR goal range upper limit. Secondary outcomes included INR control, purchases of prescription vitamin K, and warfarin-associated adverse events in the 30 days after doxycycline initiation.

Twenty and 17 patients comprised the intervention and control groups. The intervention group's warfarin dose was reduced by a median of 11%. More control patients (n=2) experienced an INR ≥ 1 point over the INR goal range upper limit compared to intervention (n=0); however, the difference (12% vs. 0%) was not statistically significant (p=0.20). A higher percentage of intervention patients had subtherapeutic index INRs compared to control (35% vs. 6%, p<0.05). One patient from each group experienced warfarin-associated bleeding. No thromboembolic complications or vitamin K use were observed.

For warfarin patients initiating doxycycline therapy, preemptive warfarin dose reduction did not result in supratherapeutic INRs but increased the likelihood of subtherapeutic INRs compared to INR monitoring with reactive warfarin dose adjustment.