Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population-based study

Objective — To determine whether the prescription of co-trimoxazole with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death.

Design — Population-based, nested case-control study.

Setting — Ontario, Canada, from April 1, 1994 to January 1, 2012.

Participants — Ontario residents aged 66 years or older treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Within this group, cases were those who died of sudden death shortly after receiving an outpatient prescription for one of co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin or nitrofurantoin, antibiotics often prescribed for urinary tract infections. Each case was matched with up to 4 controls on age, sex, chronic kidney disease and diabetes.

Main Outcome Measure — Odds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, after adjustment for predictors of sudden death using a disease risk index.

Results — Of 39,879 patients who experienced sudden death, 1,027 occurred within 7 days of antibiotic exposure and were matched to 3,733 controls. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38; 95% confidence interval 1.09 to 1.76). The risk was marginally higher at 14 days (adjusted odds ratio 1.54; 95% confidence interval 1.29 to 1.84). This corresponds to approximately 3 sudden deaths per 1,000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was 3 also associated with an increased risk of sudden death (adjusted odds ratio 1.29; 95% confidence interval 1.03 to 1.62), but no such risk was observed with nitrofurantoin or norfloxacin.

Conclusions — In older patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, co-trimoxazole is associated with an increased risk of sudden death. The researchers speculate that unrecognized severe hyperkalemia underlies this finding. When appropriate, alternative antibiotics should be considered in such patients