Daniel Q Li1, Richard Kim1, Eric McArthur1, Jamie L Fleet1, David G Bailey1, David Juurlink1, Salimah Z Shariff1, Tara Gomes1, Muhammad Mamdani1, Sonja Gandhi1, Stephanie Dixon1, Amit X Garg2. 1. 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. 2. 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. amit.garg@lhsc.on.ca.
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 all-cause 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.
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 all-cause 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.
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Authors: Mai H Trac; Eric McArthur; Racquel Jandoc; Stephanie N Dixon; Danielle M Nash; Daniel G Hackam; Amit X Garg Journal: CMAJ Date: 2016-02-22 Impact factor: 8.262
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Authors: Daniel Q Li; Richard B Kim; Eric McArthur; Jamie L Fleet; Robert A Hegele; Baiju R Shah; Matthew A Weir; Amber O Molnar; Stephanie Dixon; Jack V Tu; Sonia Anand; Amit X Garg Journal: PLoS One Date: 2016-03-08 Impact factor: 3.240