Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study.
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.
Fischer
Hadas D
HD
Department of Health Policy Management and Evaluation, University of Toronto, Toront, Ontario, Canada. Hadas.fischer@ices.on.ca
Juurlink
David N
DN
Mamdani
Muhammad M
MM
Kopp
Alexander
A
Laupacis
Andreas
A
D000368:Aged; D000369:Aged, 80 and over; D000658:Amoxicillin / Q000009:adverse effects; D000667:Ampicillin / Q000009:adverse effects; D000892:Anti-Infective Agents, Urinary / Q000009:adverse effects; D000925:Anticoagulants / Q000009:adverse effects; D016022:Case-Control Studies; D016208:Databases, Factual; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced*; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D009864:Ontario; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects*; D014552:Urinary Tract Infections / Q000188:drug therapy*; D014859:Warfarin / Q000009:adverse effects*
D000892:Anti-Infective Agents, Urinary; D000925:Anticoagulants; D014859:Warfarin; D000667:Ampicillin; D000658:Amoxicillin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination