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Original Investigation |

Warfarin Interactions With Antibiotics in the Ambulatory Care Setting

Nathan P. Clark, PharmD1,2; Thomas Delate, PhD1,2; Catherine S. Riggs, PharmD1; Daniel M. Witt, PharmD1,2; Elaine M. Hylek, MD3; David A. Garcia, MD4; Walter Ageno, MD5; Francesco Dentali, MD5; Mark A. Crowther, MD6 ; for the Warfarin-Associated Research Projects and Other Endeavors Consortium
[+] Author Affiliations
1Department of Clinical Pharmacy, Kaiser Permanente Colorado, Aurora
2Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver
3Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
4Division of Hematology, University of Washington, Seattle
5Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
6Division of Hematology and Thromboembolism, McMaster University, Hamilton, Ontario, Canada
JAMA Intern Med. 2014;174(3):409-416. doi:10.1001/jamainternmed.2013.13957.
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Importance  The effect of antibiotic coadministration on the international normalized ratio (INR) in a relatively stable, real-world warfarin population has not been adequately described. Case reports and studies of healthy volunteers do not account for the potential contribution of acute illness to INR variability.

Objective  To compare the risk of excessive anticoagulation among patients with stable warfarin therapy purchasing an antibiotic (antibiotic group) with the risk in patients purchasing a warfarin refill (stable controls) and patients with upper respiratory tract infection but not receiving an antibiotic (sick controls).

Design, Setting, and Participants  A retrospective, longitudinal cohort study evaluated patients receiving warfarin between January 1, 2005, and March 31, 2011, at Kaiser Permanente Colorado, an integrated health care delivery system. Continuous data were expressed as mean (SD) or median (interquartile range). Multivariable logistic regression analysis was used to identify factors independently associated with a follow-up INR of 5.0 or more. A total of 5857 (48.8%), 5579 (46.5%), and 570 (4.7%) patients were included in the antibiotic, stable control, and sick control groups, respectively. Mean age was 68.3 years, and atrial fibrillation was the most common (44.4%) indication for anticoagulation.

Exposures  Warfarin therapy with a medical visit for upper respiratory tract infection or coadministration of antibiotics.

Main Outcomes and Measures  Primary outcomes were the 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.

Results  The proportion of patients experiencing an INR of 5.0 or more was 3.2%, 2.6%, and 1.2% for the antibiotic, sick, and stable groups, respectively (P < .001, antibiotic vs stable control group; P < .017, sick vs stable control group; P = .44, antibiotic vs sick control group). Cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR of 5.0 or more. Among antibiotics, those interfering with warfarin metabolism posed the greatest risk for an INR of 5.0 or more.

Conclusions and Relevance  Acute upper respiratory tract infection increases the risk of excessive anticoagulation independent of antibiotic use. Antibiotics also increase the risk; however, most patients with previously stable warfarin therapy will not experience clinically relevant increases in INR following antibiotic exposure or acute upper respiratory tract infection.

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Timing of International Normalized Ratio (INR) Values During Inclusion and the Follow-up Period

The timing of INR values required for inclusion into the study groups is shown. Not every INR in the preindex period was between 2.0 and 3.5. Only the first INR in the follow-up period was included for analysis of outcomes.

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