Antibiotic associated with increased risk for sudden death in patients taking ACE inhibitors or ARBs

Trimethoprim/sulfamethoxazole (or co-trimoxazole) was associated with an increased risk of sudden death in older patients receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), a study found.

Researchers conducted a population-based, nested, case-control study in Ontario, Canada, from April 1994 to January 2012 among patients age 66 years or older taking an ACE inhibitor or ARB. Cases of patients who died suddenly shortly after receiving an outpatient prescription for either co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin were matched with up to 4 control patients for age, sex, comorbid chronic kidney disease, or diabetes. Results were published online Oct. 30 by BMJ.

Of 39,879 sudden deaths, 1,027 occurred within 7 days of exposure to an antibiotic. They were matched to 3,733 controls. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death within 7 days (adjusted odds ratio [OR], 1.38; 95% CI, 1.09 to 1.76). The relatively increased risk with co-trimoxazole was marginally higher when the period was extended to 14 days (adjusted OR, 1.54; 95% CI, 1.29 to 1.84). This corresponds to approximately 3 sudden deaths within 14 days per 1,000 co-trimoxazole prescriptions.

Ciprofloxacin, a known cause of QT interval prolongation, was also associated with an increased risk of sudden death compared to amoxicillin in the week after a prescription (adjusted OR, 1.29; 95% CI, 1.03 to 1.62), but no such risk was observed with norfloxacin (adjusted OR, 0.74; 95% CI, 0.53 to 1.02), and a decreased risk was associated with nitrofurantoin (adjusted OR, 0.64; 95% CI, 0.46 to 0.88).

The authors suggested that, when clinically appropriate, clinicians either choose alternate antibiotics or limit the dose and duration of co-trimoxazole in patients on an ACE or ARB and also closely monitor serum potassium levels in susceptible patients.

“We speculate that this association reflects sudden death from co-trimoxazole induced hyperkalemia in a vulnerable group of patients,” the authors wrote. “The importance of our findings is underscored by the fact that co-trimoxazole is prescribed to millions of patients taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Sudden death in these patients is likely to be misattributed to underlying cardiovascular disease, rather than hyperkalemia.”

An editorial noted that the clinical implications of the current study will remain unclear until further studies confirm the results.

“In the absence of higher quality evidence, some doctors may choose to prescribe alternative antibiotics for uncomplicated community acquired infections in patients taking RASBs [renin-angiotensin-system blockers],” the editorial stated. “Alternatively, given that co-trimoxazole is an established antibiotic with a broad spectrum of antibacterial activity and is well tolerated, others may continue prescribing co-trimoxazole with RASBs but monitor potassium concentrations until either drug is stopped. Finally, still other doctors, perhaps more concerned about the quality and interpretation of observational studies in general, and pharmacoepidemiology studies in particular, with their occasionally conflicting conclusions, may prefer to wait for other studies before modifying their practice.”