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Trimethoprim-sulfamethoxazole and risk of sudden death among patients taking spironolactone


Background — Trimethoprim-sulfamethoxazole increases the risk of hyperkalemia when used with spironolactone. The extent to which this drug combination increases the risk of sudden death, a consequence of severe hyperkalemia, is not known.

Methods — The researchers conducted a population-based nested case-control study of Ontario residents aged 66 years or older receiving spironolactone between April 1, 1994 and December 31, 2011. Within this group, cases were patients who died of sudden death within 14 days of receiving a prescription for one of trimethoprim-sulfamethoxazole, amoxicillin, ciprofloxacin, norfloxacin or nitrofurantoin. For each case, we identified up to four controls matched on age and sex. The researchers determined the odds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, adjusted for predictors of sudden death using a disease risk index.

Results — During the 17-year study period, the researchers identified 11,968 patients who died of sudden death while receiving spironolactone. Of these, 328 occurred within 14 days of antibiotic exposure. Compared with amoxicillin, trimethoprim-sulfamethoxazole was associated with a more than two-fold increase in the risk of sudden death (adjusted odds ratio 2.46; 95% confidence interval: 1.55 to 3.90). Ciprofloxacin (adjusted odds ratio 1.55; 95% confidence interval: 1.02 to 2.38) and nitrofurantoin (adjusted odds ratio 1.70; 95% confidence interval 1.03 to 2.27) were also 3 associated with an increased risk of sudden death, although the risk associated with nitrofurantoin was not apparent in a sensitivity analysis.

Interpretation — Trimethoprim-sulfamethoxazole is associated with sudden death in older patients taking spironolactone. When clinically appropriate, alternative antibiotics should be considered in these patients.



Antoniou T, Hollands S, Macdonald EM, Gomes T, Mamdani MM, Juurlink DN; Canadian Drug Safety and Effectiveness Research Network (CDSERN). CMAJ. 2015; 187(4):E138-43. Epub 2015 Feb 2.

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