Amit M. Patel, MD; Salimah Shariff, PhD; David G. Bailey, BScPhm, PhD; David N. Juurlink, MD, PhD; Sonja Gandhi, BSc; Muhammad Mamdani, PharmD, MPH; Tara Gomes, MHSc; Jamie Fleet, BSc; Y. Joseph Hwang, BMSc; Amit X. Garg, MD, PhD
Acknowledgment: The authors thank IMS Brogan (Ottawa, Ontario, Canada), for use of their Drug Product and Therapeutic Class Database; the late Dr. Milton Haines, Ms. Barbara Jones, Mr. Jeff Lamond, and others from Gamma Dynacare for use of their outpatient laboratory database; and Mr. Glen Kearns from the London Health Sciences Centre who facilitated the use of linked hospital laboratory databases.
Financial Support: The investigators received grant support from the Academic Medical Organization of Southwestern Ontario to conduct this research. This project was conducted at the Institute for Clinical Evaluative Sciences site at Western University. The Institute for Clinical Evaluative Sciences is funded by an annual grant from the Ontario Ministry of Health and Long-term Care. The Institute for Clinical Evaluative Sciences site at Western University is funded by an operating grant from the Academic Medical Organization of Southwestern Ontario. Dr. Garg was supported by a Canadian Institutes of Health Research Clinician Scientist Award.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1300.
Reproducible Research Statement: Study protocol, statistical code, and data set: Portions are available to approved individuals through written agreements with Dr. Garg (e-mail, email@example.com).
Requests for Single Reprints: Amit Garg, MD, PhD, London Kidney Clinical Research Unit, Room ELL-101, Westminster, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Patel, Shariff, and Garg; Ms. Gandhi; Ms. Fleet; and Mr. Hwang: London Kidney Clinical Research Unit, Room ELL-101, Westminster, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada.
Dr. Bailey: University Hospital, Room B3-264, London Health Sciences Centre, 339 Windermere Road, London, Ontario N6G 2K3, Canada.
Dr. Juurlink and Ms. Gomes: Sunnybrook Health Sciences Centre, Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Dr. Mamdani: Keenan Research Centre, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.
Author Contributions: Conception and design: A.M. Patel, S. Shariff, D.G. Bailey, D.N. Juurlink, S. Gandhi, M. Mamdani, T. Gomes, J. Fleet, Y.J. Hwang, A.X. Garg.
Analysis and interpretation of the data: A.M. Patel, S. Shariff, D.G. Bailey, D.N. Juurlink, S. Gandhi, M. Mamdani, T. Gomes, J. Fleet, Y.J. Hwang, A.X. Garg.
Drafting of the article: A.M. Patel, D.G. Bailey, A.X. Garg.
Critical revision of the article for important intellectual content: A.M. Patel, S. Shariff, D.G. Bailey, D.N. Juurlink, S. Gandhi, M. Mamdani, T. Gomes, J. Fleet, Y.J. Hwang, A.X. Garg.
Final approval of the article: A.M. Patel, S. Shariff, D.G. Bailey, D.N. Juurlink, S. Gandhi, M. Mamdani, T. Gomes, J. Fleet, Y.J. Hwang, A.X. Garg.
Provision of study materials or patients: A.X. Garg.
Statistical expertise: S. Shariff, D.N. Juurlink, M. Mamdani, T. Gomes, A.X. Garg.
Obtaining of funding: A.X. Garg.
Administrative, technical, or logistic support: A.M. Patel, S. Shariff, T. Gomes, J. Fleet, A.X. Garg.
Collection and assembly of data: S. Shariff.
Patel AM, Shariff S, Bailey DG, Juurlink DN, Gandhi S, Mamdani M, et al. Statin Toxicity From Macrolide Antibiotic Coprescription: A Population-Based Cohort Study. Ann Intern Med. 2013;158:869-876. doi: 10.7326/0003-4819-158-12-201306180-00004
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Published: Ann Intern Med. 2013;158(12):869-876.
Clarithromycin and erythromycin, but not azithromycin, inhibit cytochrome P450 isoenzyme 3A4 (CYP3A4), and inhibition increases blood concentrations of statins that are metabolized by CYP3A4.
To measure the frequency of statin toxicity after coprescription of a statin with clarithromycin or erythromycin.
Population-based cohort study.
Ontario, Canada, from 2003 to 2010.
Continuous statin users older than 65 years who were prescribed clarithromycin (n = 72 591) or erythromycin (n = 3267) compared with those prescribed azithromycin (n = 68 478).
The primary outcome was hospitalization with rhabdomyolysis within 30 days of the antibiotic prescription.
Atorvastatin was the most commonly prescribed statin (73%) followed by simvastatin and lovastatin. Compared with azithromycin, coprescription of a statin with clarithromycin or erythromycin was associated with a higher risk for hospitalization with rhabdomyolysis (absolute risk increase, 0.02% [95% CI, 0.01% to 0.03%]; relative risk [RR], 2.17 [CI, 1.04 to 4.53]) or with acute kidney injury (absolute risk increase, 1.26% [CI, 0.58% to 1.95%]; RR, 1.78 [CI, 1.49 to 2.14]) and for all-cause mortality (absolute risk increase, 0.25% [CI, 0.17% to 0.33%]; RR, 1.56 [CI, 1.36 to 1.80]).
Only older adults were included in the study. The absolute risk increase for rhabdomyolysis may be underestimated because the codes used to identify it were insensitive.
In older adults, coprescription of clarithromycin or erythromycin with a statin that is metabolized by CYP3A4 increases the risk for statin toxicity.
Academic Medical Organization of Southwestern Ontario.
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Cardiology, Infectious Disease, Dyslipidemia, Coronary Risk Factors.
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