title: Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study.
abstract: OBJECTIVE
  To determine whether the prescription of co-trimoxazole with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death.
  
  
  METHODS
  Population based nested case-control study.
  
  
  METHODS
  Ontario, Canada, from 1 April 1994 to 1 January 2012.
  
  
  METHODS
  Ontario residents aged 66 years or older treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. Cases were those who died suddenly shortly after receiving an outpatient prescription for one of co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes.
  
  
  METHODS
  Odds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, after adjustment for predictors of sudden death according to a disease risk index.
  
  
  RESULTS
  Of 39,879 sudden deaths, 1027 occurred within seven days of exposure to an antibiotic and were matched to 3733 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, 1.29 to 1.84). This corresponds to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was also associated with an increased risk of sudden death (adjusted odds ratio 1.29, 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. Unrecognized severe hyperkalemia may underlie this finding. When appropriate, alternative antibiotics should be considered in such patients.
authors.affiliation: Department of Internal Medicine, University of Toronto, Toronto, ON, Canada, M5G 2C4.
authors.forename: Michael
authors.initials: M
authors.lastname: Fralick
authors.affiliation: Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, M5N 4M5.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Macdonald
authors.affiliation: Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, M5N 4M5 Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada, M5B 1W8 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada, M5T 3M7.
authors.forename: Tara
authors.initials: T
authors.lastname: Gomes
authors.affiliation: Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, M5N 4M5 Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada, M5B 1W8 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada, M5T 3M7 Department of Family and Community Medicine, St Michael's Hospital, Toronto.
authors.forename: Tony
authors.initials: T
authors.lastname: Antoniou
authors.affiliation: Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, M5N 4M5.
authors.forename: Simon
authors.initials: S
authors.lastname: Hollands
authors.affiliation: Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, M5N 4M5 Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada, M5B 1W8 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada, M5T 3M7 Applied Health Research Centre, St Michael's Hospital, Toronto King Saud University, Riyadh, Saudi Arabia.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Mamdani
authors.affiliation: Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, M5N 4M5 Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada, M5B 1W8 Sunnybrook Research Institute, Toronto, ON, Canada, M4N 3M5 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada, M5T 3M7 dnj@ices.on.ca.
authors.forename: David N
authors.initials: DN
authors.lastname: Juurlink
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000892:Anti-Infective Agents, Urinary / Q000009:adverse effects*; D016022:Case-Control Studies; D003645:Death, Sudden / Q000453:epidemiology*; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced / Q000401:mortality; D008297:Male; D016017:Odds Ratio; D009864:Ontario / Q000453:epidemiology; D012307:Risk Factors; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000892:Anti-Infective Agents, Urinary; D015662:Trimethoprim, Sulfamethoxazole Drug Combination