title: Risk of adverse events among older adults following co-prescription of clarithromycin and statins not metabolized by cytochrome P450 3A4.
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.
  
  
  CONCLUSIONS
  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.
authors.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.
authors.forename: Daniel Q
authors.initials: DQ
authors.lastname: Li
authors.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.
authors.forename: Richard
authors.initials: R
authors.lastname: Kim
authors.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.
authors.forename: Eric
authors.initials: E
authors.lastname: McArthur
authors.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.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Fleet
authors.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.
authors.forename: David G
authors.initials: DG
authors.lastname: Bailey
authors.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.
authors.forename: David
authors.initials: D
authors.lastname: Juurlink
authors.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.
authors.forename: Salimah Z
authors.initials: SZ
authors.lastname: Shariff
authors.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.
authors.forename: Tara
authors.initials: T
authors.lastname: Gomes
authors.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.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Mamdani
authors.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.
authors.forename: Sonja
authors.initials: S
authors.lastname: Gandhi
authors.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.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dixon
authors.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. amit.garg@lhsc.on.ca.
authors.forename: Amit X
authors.initials: AX
authors.lastname: Garg
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced; D000368:Aged; D000369:Aged, 80 and over; D017291:Clarithromycin / Q000009:adverse effects*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects*; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005464:Fluorobenzenes / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism* / Q000627:therapeutic use*; D006947:Hyperkalemia / Q000139:chemically induced; D007211:Indoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors; D017035:Pravastatin / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D012189:Retrospective Studies; D012206:Rhabdomyolysis / Q000139:chemically induced; D000068718:Rosuvastatin Calcium; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D005229:Fatty Acids, Monounsaturated; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides; D000077340:Fluvastatin; D000068718:Rosuvastatin Calcium; D017291:Clarithromycin; D017035:Pravastatin