Co-trimoxazole Might Increase Risk of Sudden Death in Elderly Patients on ACE Inhibitors or Angiotensin Receptor Blockers

EBM Focus - Volume 9, Issue 44

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Reference: BMJ 2014 Oct 30;349:g6196 (level 2 [mid-level] evidence)

Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are commonly prescribed medications, often used for the treatment of hypertension, coronary artery disease, or chronic kidney disease. Both drug classes are associated with an increased risk of hyperkalemia (N Engl J Med 2004 Aug 5;351(6):585). Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole and at doses used in clinical practice, trimethoprim is known to impair renal potassium elimination. Previous case-control studies have demonstrated that co-trimoxazole, which is often prescribed for urinary tract infections (UTI), may further increase the risk of hyperkalemia in elderly patients taking ACE inhibitors or ARBs (Arch Intern Med 2010 Jun 28;170(12):1045 full-text). A new case-control study evaluated the risk of sudden death with various antibiotics commonly prescribed for UTIs in this population.

A total of 1,027 patients at least 66 years old who had sudden death and 3,733 matched controls who did not have sudden death were evaluated. All patients were being treated with an ACE inhibitor or ARB and had received an antibiotic prescription within the previous 7 days. The antibiotics included co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin, and matching was by age, sex, and presence of chronic kidney disease or diabetes. Relative to amoxicillin, co-trimoxazole and ciprofloxacin were associated with increased risk of sudden death within 7 days of treatment (adjusted odds ratio [adjusted OR] 1.38, 95% CI 1.09-1.76) and (adjusted OR 1.29, 95% CI 1.03-1.62 respectively), while nitrofurantoin was associated with a decreased risk of sudden death (adjusted OR 0.64, 95% CI 0.46-0.88). In addition, at 14 days, co-trimoxazole was still associated with a significantly increased risk (adjusted OR 1.54, 95% CI 1.29-1.84), while the risk with ciprofloxacin was no longer significant (adjusted OR 1.18, 95% CI 1-1.39). There were no significant differences between either norfloxacin or nitrofurantoin compared to amoxicillin within 14 days of treatment.

The findings of this study suggest that co-trimoxazole may increase the risk of sudden death in elderly patients on ACE inhibitors or ARBs. The increase in risk of sudden death within 14 days is reported to correspond to approximately 3 sudden deaths per 1,000 co-trimoxazole prescriptions. There may also be some risk with ciprofloxacin although this is more likely to be mediated by the known QT prolongation effects of fluoroquinolones rather than via increased risk of hyperkalemia (Am J Emerg Med. 2012 Jan;30(1):252). Although the case-control design is a limitation, these findings support previous observational data showing an increased risk of hyperkalemia associated with co-trimoxazole in this patient population. Collectively, these data suggest that increased care or monitoring may be warranted when prescribing co-trimoxazole or ciprofloxacin, and also suggest nitrofurantoin may be preferred in elderly patients receiving ACE inhibitors or ARBs.

For more information, see the Co-trimoxazole topic in DynaMed.