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

doi:10.1136/bmj.g6196

. 2014 Oct 30:349:g6196.

doi: 10.1136/bmj.g6196.

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

Michael Fralick¹, Erin M Macdonald², Tara Gomes³, Tony Antoniou⁴, Simon Hollands², Muhammad M Mamdani⁵, David N Juurlink⁶; Canadian Drug Safety and Effectiveness Research Network

Affiliations

¹ Department of Internal Medicine, University of Toronto, Toronto, ON, Canada, M5G 2C4.
² Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, M5N 4M5.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 25359996
PMCID: PMC4214638
DOI: 10.1136/bmj.g6196

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

Michael Fralick et al. BMJ. 2014.

. 2014 Oct 30:349:g6196.

doi: 10.1136/bmj.g6196.

Authors

Michael Fralick¹, Erin M Macdonald², Tara Gomes³, Tony Antoniou⁴, Simon Hollands², Muhammad M Mamdani⁵, David N Juurlink⁶; Canadian Drug Safety and Effectiveness Research Network

Affiliations

¹ Department of Internal Medicine, University of Toronto, Toronto, ON, Canada, M5G 2C4.
² Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, M5N 4M5.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 25359996
PMCID: PMC4214638
DOI: 10.1136/bmj.g6196

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.

Design: Population based nested case-control study.

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

Participants: 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.

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 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.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: support for the submitted work as described above; MMM has served on advisory boards and/or received honorariums from Astra Zeneca, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Hoffman La Roche, Novartis, Novo Nordisk, and Pfizer; no other relationships or activities that could appear to have influenced the submitted work.

Comment in

Antibiotics and sudden death in adults taking renin-angiotensin system blockers.
Etminan M, Brophy JM. Etminan M, et al. BMJ. 2014 Oct 30;349:g6242. doi: 10.1136/bmj.g6242. BMJ. 2014. PMID: 25360034 No abstract available.
Link between co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system could be due to confounding.
Scheper H, Lijfering WM. Scheper H, et al. BMJ. 2014 Nov 18;349:g6899. doi: 10.1136/bmj.g6899. BMJ. 2014. PMID: 25406143 No abstract available.
Authors' reply to Scheper and Lijfering.
Fralick M, Juurlink DN. Fralick M, et al. BMJ. 2014 Nov 18;349:g6906. doi: 10.1136/bmj.g6906. BMJ. 2014. PMID: 25406180 No abstract available.
[Cotrimoxazole plus ACE inhibitors or angiotensin receptor blockers and sudden cardiac death].
Steurer J. Steurer J. Praxis (Bern 1994). 2015 Jan 28;104(3):155-6. doi: 10.1024/1661-8157/a001907. Praxis (Bern 1994). 2015. PMID: 25626385 German. No abstract available.
Cotrimoxazole is associated with sudden death in older patients receiving inhibitors of renin-angiotensin system.
Kheirbek RE, Shara N. Kheirbek RE, et al. Evid Based Med. 2015 Jun;20(3):113. doi: 10.1136/ebmed-2014-110133. Epub 2015 Mar 18. Evid Based Med. 2015. PMID: 25786800 No abstract available.

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References

1. Health and Social Care Information Centre. Prescriptions disepensed in the community: England 2002-2012. 2013. www.hscic.gov.uk/catalogue/PUB11291.
1. IMS Institute for Healthcare Informatics. National prescription audit. IMS, 2012:46.
1. Izzo JL, Weir MR. Angiotensin-converting enzyme inhibitors. J Clin Hypertens (Greenwich) 2011;13:667-75. - PMC - PubMed
1. Reardon L, Macpherson D. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. Arch Intern Med 1999;158:26-32. - PubMed
1. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585-92. - PubMed

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[1] Health and Social Care Information Centre. Prescriptions disepensed in the community: England 2002-2012. 2013. www.hscic.gov.uk/catalogue/PUB11291.

[2] Health and Social Care Information Centre. Prescriptions disepensed in the community: England 2002-2012. 2013. www.hscic.gov.uk/catalogue/PUB11291.

[3] IMS Institute for Healthcare Informatics. National prescription audit. IMS, 2012:46.

[4] IMS Institute for Healthcare Informatics. National prescription audit. IMS, 2012:46.

[5] Izzo JL, Weir MR. Angiotensin-converting enzyme inhibitors. J Clin Hypertens (Greenwich) 2011;13:667-75. - PMC - PubMed

[6] Izzo JL, Weir MR. Angiotensin-converting enzyme inhibitors. J Clin Hypertens (Greenwich) 2011;13:667-75. - PMC - PubMed

[7] Reardon L, Macpherson D. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. Arch Intern Med 1999;158:26-32. - PubMed

[8] Reardon L, Macpherson D. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. Arch Intern Med 1999;158:26-32. - PubMed

[9] Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585-92. - PubMed

[10] Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585-92. - PubMed

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

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

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