Citation

Li DQ, Kim R, McArthur E, Fleet JL, Bailey DG, Juurlink D, Shariff SZ, Gomes T, Mamdani M, Gandhi S, Dixon S, Garg AX. CMAJ 2014; 187(3): 174-180.

Affiliation

Divisions of Nephrology (Li, McArthur, Fleet, Shariff, Gandhi, Dixon, Garg) and Clinical Pharmacology (Kim), Department of Medicine, Western University, London, Ont.; Institute for Clinical Evaluative Sciences (ICES) Western (McArthur, Juurlink, Shariff, Gomes, Dixon, Garg), London, Ont.; Lawson Health Research Institute (Bailey), London Health Sciences Centre, London, Ont.; Sunnybrook Health Sciences Centre (Juurlink), Toronto, Ont.; Li Ka Shing Knowledge Institute (Gomes, Mamdani), St. Michael's Hospital, Toronto, Ont.; Institute of Health Policy, Management and Evaluation (Mamdani), University of Toronto, Toronto, Ont.; Department of Epidemiology and Biostatistics (Gandhi), Western University, London, Ont.

Copyright

(Copyright © 2014, Canadian Medical Association)

DOI

10.1503/cmaj.140950

PMID

25534598

Abstract

BACKGROUND: The cytochrome P450 3A4 (CYP3A4) inhibitor clarithromycin may also inhibit liver-specific organic anion-transporting polypeptides (OATP1B1 and OATP1B3). We studied whether concurrent use of clarithromycin and a statin not metabolized by CYP3A4 was associated with an increased frequency of serious adverse events.

METHODS: Using large health care databases, we studied a population-based cohort of older adults (mean age 74 years) who were taking a statin not metabolized by CYP3A4 (rosuvastatin [76% of prescriptions], pravastatin [21%] or fluvastatin [3%]) between 2002 and 2013 and were newly prescribed clarithromycin (n = 51 523) or azithromycin (n = 52 518), the latter an antibiotic that inhibits neither CYP3A4 nor OATP1B1 and OATP1B3. Outcomes were hospital admission with a diagnostic code for rhabdomyolysis, acute kidney injury or hyperkalemia, and allcause mortality. All outcomes were assessed within 30 days after co-prescription.

RESULTS: Compared with the control group, patients co-prescribed clarithromycin and a statin not metabolized by CYP3A4 were at increased risk of hospital admission with acute kidney injury (adjusted relative risk [RR] 1.65, 95% confidence interval [CI] 1.31 to 2.09), admission with hyperkalemia (adjusted RR 2.17, 95% CI 1.22 to 3.86) and all-cause mortality (adjusted RR 1.43, 95% CI 1.15 to 1.76). The adjusted RR for admission with rhabdomyolysis was 2.27 (95% CI 0.86 to 5.96). The absolute increase in risk for each outcome was small and likely below 1%, even after we considered the insensitivity of some hospital database codes.

INTERPRETATION: Among older adults taking a statin not metabolized by CYP3A4, co-prescription of clarithromycin versus azithromycin was associated with a modest but statistically significant increase in the 30-day absolute risk of adverse outcomes.

Language: en