Despite the widespread challenges of providing optimal anticoagulation during infection and interactions with antibiotics, there is little guidance to inform clinical practice as to which warfarin interactions with antibiotics are most important, what monitoring should be undertaken, and how the interactions should be managed.
The purpose of this retrospective cohort study was to determine whether antibiotics co-prescribed to patients receiving long-term warfarin therapy are more likely to result in clinically significant INR increases compared with patients receiving long-term warfarin therapy who are not ill (stable controls) and those who are acutely ill but do not receive concomitant antibiotics (sick controls).
Researchers identified subjects, treatments and outcomes using medical, pharmacy, and laboratory records and an anticoagulation database. A total of 12,006 patients (mean age, 68 years; 49.9% male; median pre-index INR was 2.5; most common indication, atrial fibrillation) receiving long-term warfarin therapy were eligible for study inclusion and were stratified into the following groups:
• Antibiotic group (n=5,857; 48.8%): These patients had purchased a prescription for an oral antibiotic and had at least 1 INR measured 3 to 15 days after the purchase.
• Stable group (n= 5, 579; 46.5%): These patients had purchased a warfarin refill and had a follow-up INR measured within the next 3 to 30 days.
• Sick control group (n= 570; 4.7%): These patients had to have either purchased guaifenesin with codeine or have a coded provider visit for upper respiratory tract infection and a follow-up INR measured within 15 days.
The primary outcome, proportion of patients experiencing a follow-up INR of 5.0 or more and change between the last INR measured before the index date and the follow-up INR, was 3.2%, 2.6%, and 1.2% for the antibiotic, sick, and stable groups, respectively (P < 0.001, antibiotic vs stable control group; P < 0.017, sick vs stable control group; P = 0.44, antibiotic vs sick control group).
Factors associated with a follow-up INR of 5.0 or more included cancer diagnosis, elevated baseline INR, and female sex. Among antibiotics, those interfering with warfarin metabolism (8.6%; metronidazole and trimethoprim-sulfamethoxazole) posed the greatest risk for an INR of 5.0 or more than those disrupting vitamin K synthesis (3.1%) or not known to interact with warfarin (2.1%) (P < 0.001).
Overall, the authors concluded that acute upper respiratory tract infection increases the risk of excessive anticoagulation independent of antibiotic use but this increase is not clinically relevant. Possible reasons for increased INR include reduced oral intake and resultant decreased consumption of vitamin K–rich foods, the effect of paracetamol-containing cough and cold remedies that can increase the INR, or increased clotting factor catabolism associated with fever. Antibiotics also increase the risk; however, most patients with previously stable warfarin therapy did not experience clinically relevant increases in INR following antibiotic exposure. The authors suggest that timely INR monitoring may be particularly important when factors such as female sex, active cancer and elevated baseline INR are present.