Study Explores Warfarin-Antibiotic Interactions

Antibiotics are associated with an increased risk of excessive anticoagulation among previously stable warfarin patients with upper respiratory tract infections, according to the results of a recent retrospective, longitudinal cohort study. An increased risk was also observed among warfarin patients with upper respiratory tract infections who were not taking antibiotics. The absolute risk of harm, however, was low.

“Overall, the mean international normalized ratio (INR) change in the antibiotic group was negligible (<0.1 units), which argues against preemptive warfarin dose reduction,” lead author Nathan P. Clark, PharmD, Kaiser Permanente Colorado, Aurora, and University of Colorado, Denver, told Consultant360.

Clark explained that warfarin interactions with antibiotics are commonly encountered in clinical practice. “Our findings can assist clinicians in selecting patients at greater risk for additional INR monitoring,” he said.

“This study also helps to normalize expectations regarding the scope of warfarin-antibiotic interactions in practice,” he added. “Although this is a widely reported issue, the reality is that most patients taking warfarin who are prescribed an antibiotic will not develop excessive anticoagulation or bleeding problems.”    

According to Clark, most of our understanding about the interactions between warfarin and antibiotics has come from case reports or studies recruiting healthy volunteers. “Although important, these findings do not help us understand the frequency with which these interactions result in excessive anticoagulation in our own patients,” he said.

“Ours is the first study to describe a sick control population to compare to the antibiotic group,” he continued. “Experts have suspected for some time that illness itself contributes to excessive anticoagulation during warfarin therapy, and we have confirmed this association. Although antibiotic-receiving patient had a numerically higher risk for a follow-up INR ≥5.0 than sick controls, the results were not significant.”  

Approximately 12,000 patients (mean age, 68.3 years) taking warfarin between 2005 and 2011 were evaluated for the study. Participants were divided into the following three groups: antibiotic (ie, patients with upper respiratory tract infections taking warfarin and antibiotics; n=5857); stable control (ie, patients taking warfarin; n=5579); and sick control (ie, patients with upper respiratory tract infections taking warfarin but not antibiotics; n=570). The risk of excessive anticoagulation (INR ≥5.0) was compared between the groups.

Researchers found that 3.2%, 2.6%, and 1.2% of patients in the antibiotic, sick, and stable groups, respectively, had an INR of 5.0 or higher.

“Although antibiotics increased the risk of excessive anticoagulation, the overall risk was 3.2%,” said Clark. “This result might be surprising to some given the hundreds of published case reports of warfarin interactions in literature.”

It was determined that patients taking antibiotics that interfere with warfarin metabolism (trimethoprim-sulfamethoxazole and metronidazole), women, those with a cancer diagnosis, and those with elevated baseline INR are at higher risk for excessive anticoagulation. These patients should receive close INR monitoring, according to Clark.

A limitation of the study is the fact that it was observational. “There may have been unmeasured factors that influenced outcomes,” said Clark. In addition, researchers did not control for infection type or location. “The risk for excessive anticoagulation might be different for a warfarin-treated patient receiving ciprofloxacin for an uncomplicated urinary tract infection compared to pyelonephritis, for example,” he explained.

Clark noted that the next step in terms of future research is to confirm which antibiotics can be used in which patients taking warfarin without the need for close INR surveillance. “More research is also needed examining the typical onset and effect of coadministration of cytochrome P450 enzyme–inducing drugs during warfarin therapy,” he added.

See JAMA Internal Medicine for the full study.

-Meredith Edwards White

Reference

Clark NP, Delate T, Riggs CS, et al; for the Warfarin-Associated Research Projects and Other Endeavors Consortium. Warfarin interactions with antibiotics in the ambulatory care setting. JAMA Intern Med. 2014 Jan 20. doi: 10.1001/jamainternmed.2013.13957. [Epub ahead of print]