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Original Investigation
April 12, 2010

Hemorrhage During Warfarin Therapy Associated With Cotrimoxazole and Other Urinary Tract Anti-infective Agents: A Population-Based Study

Author Affiliations

Author Affiliations: Department of Health Policy Management and Evaluation, University of Toronto (Drs Fischer, Juurlink, and Laupacis), Institute for Clinical Evaluative Sciences (Drs Fischer, Juurlink, Mamdani, and Laupacis and Mr Kopp) and Department of Medicine (Dr Juurlink), Sunnybrook Health Sciences Centre, and Keenan Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital (Drs Mamdani and Laupacis), Toronto, Ontario, Canada; and Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia (Dr Mamdani).

Arch Intern Med. 2010;170(7):617-621. doi:10.1001/archinternmed.2010.37

Background  Some antibiotic agents, including cotrimoxazole, inhibit the metabolism of warfarin sodium and possibly increase the risk of hemorrhage. We examined the risk of upper gastrointestinal (UGI) tract hemorrhage in older patients receiving warfarin in combination with antibiotics commonly used to treat urinary tract infection, with a focus on cotrimoxazole.

Methods  This population-based, nested case-control study using health care databases in Ontario, Canada, between April 1, 1997, and March 31, 2007, identified residents 66 years or older who were continuously treated with warfarin. Cases were hospitalized with UGI tract hemorrhage. For each case, we selected up to 10 age- and sex-matched control subjects. We calculated adjusted odds ratios (aORs) for exposure to cotrimoxazole, amoxicillin trihydrate, ampicillin trihydrate, ciprofloxacin hydrochloride, nitrofurantoin, and norfloxacin within 14 days before the UGI tract hemorrhage.

Results  We identified 134 637 patients receiving warfarin, of whom 2151 cases were hospitalized for UGI tract hemorrhage. Cases were almost 4 times more likely than controls to have recently received cotrimoxazole (aOR, 3.84; 95% confidence interval [CI], 2.33-6.33). Treatment with ciprofloxacin was also associated with increased risk (aOR, 1.94; 95% CI, 1.28-2.95), but no significant association was observed with amoxicillin or ampicillin (1.37; 0.92-2.05), nitrofurantoin (1.40; 0.71-2.75), or norfloxacin (0.38; 0.12-1.26). Compared with amoxicillin or ampicillin, cotrimoxazole prescription was associated with an almost 3-fold risk (ratio of ORs, 2.80; 95% CI, 1.48-5.32).

Conclusions  Among older patients receiving warfarin, cotrimoxazole is associated with a significantly higher risk of UGI tract hemorrhage than other commonly used antibiotics. Whenever possible, clinicians should prescribe alternative antibiotics in patients receiving warfarin.