title: Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation.
abstract: BACKGROUND
  Dabigatran etexilate is a prodrug whose absorption is opposed by intestinal P-glycoprotein and which is converted by carboxylesterase to its active form, dabigatran. Unlike other statins, simvastatin and lovastatin are potent inhibitors of P-glycoprotein and carboxylesterase, and might either increase the risk of hemorrhage with dabigatran etexilate or decrease its effectiveness.
  
  
  METHODS
  We conducted 2 population-based, nested case-control studies involving Ontario residents 66 years of age and older who started dabigatran etexilate between May 1, 2012, and Mar. 31, 2014. In the first study, cases were patients with ischemic stroke; in the second, cases were patients with major hemorrhage. Each case was matched with up to 4 controls by age and sex. All cases and controls received a single statin in the 60 days preceding the index date. We determined the association between each outcome and the use of simvastatin or lovastatin, relative to other statins.
  
  
  RESULTS
  Among 45 991 patients taking dabigatran etexilate, we identified 397 cases with ischemic stroke and 1117 cases with major hemorrhage. After multivariable adjustment, use of simvastatin or lovastatin was not associated with an increased risk of stroke (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.88 to 2.01). In contrast, use of simvastatin and lovastatin were associated with a higher risk of major hemorrhage (adjusted OR 1.46, 95% CI 1.17 to 1.82).
  
  
  CONCLUSIONS
  In patients receiving dabigatran etexilate, simvastatin and lovastatin were associated with a higher risk of major hemorrhage relative to other statins. Preferential use of the other statins should be considered in these patients.
authors.affiliation: Department of Family and Community Medicine (Antoniou), St. Michael's Hospital and University of Toronto; Li Ka Shing Knowledge Institute (Gomes) and Li Ka Shing Centre for Healthcare Analytics Research and Training (Mamdani), St. Michael's Hospital; Leslie Dan Faculty of Pharmacy (Gomes, Tadrous, Mamdani) and Department of Medicine (Juurlink), University of Toronto; Institute for Clinical Evaluative Sciences (Antoniou, Macdonald, Yao, Hollands, Gomes, Tadrous, Mamdani, Juurlink); Applied Health Research Centre (Tadrous), St. Michael's Hospital; Sunnybrook Research Institute (Juurlink), Toronto, Ont. tantoniou@smh.ca.
authors.forename: Tony
authors.initials: T
authors.lastname: Antoniou
authors.affiliation: Department of Family and Community Medicine (Antoniou), St. Michael's Hospital and University of Toronto; Li Ka Shing Knowledge Institute (Gomes) and Li Ka Shing Centre for Healthcare Analytics Research and Training (Mamdani), St. Michael's Hospital; Leslie Dan Faculty of Pharmacy (Gomes, Tadrous, Mamdani) and Department of Medicine (Juurlink), University of Toronto; Institute for Clinical Evaluative Sciences (Antoniou, Macdonald, Yao, Hollands, Gomes, Tadrous, Mamdani, Juurlink); Applied Health Research Centre (Tadrous), St. Michael's Hospital; Sunnybrook Research Institute (Juurlink), Toronto, Ont.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Macdonald
authors.affiliation: Department of Family and Community Medicine (Antoniou), St. Michael's Hospital and University of Toronto; Li Ka Shing Knowledge Institute (Gomes) and Li Ka Shing Centre for Healthcare Analytics Research and Training (Mamdani), St. Michael's Hospital; Leslie Dan Faculty of Pharmacy (Gomes, Tadrous, Mamdani) and Department of Medicine (Juurlink), University of Toronto; Institute for Clinical Evaluative Sciences (Antoniou, Macdonald, Yao, Hollands, Gomes, Tadrous, Mamdani, Juurlink); Applied Health Research Centre (Tadrous), St. Michael's Hospital; Sunnybrook Research Institute (Juurlink), Toronto, Ont.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Family and Community Medicine (Antoniou), St. Michael's Hospital and University of Toronto; Li Ka Shing Knowledge Institute (Gomes) and Li Ka Shing Centre for Healthcare Analytics Research and Training (Mamdani), St. Michael's Hospital; Leslie Dan Faculty of Pharmacy (Gomes, Tadrous, Mamdani) and Department of Medicine (Juurlink), University of Toronto; Institute for Clinical Evaluative Sciences (Antoniou, Macdonald, Yao, Hollands, Gomes, Tadrous, Mamdani, Juurlink); Applied Health Research Centre (Tadrous), St. Michael's Hospital; Sunnybrook Research Institute (Juurlink), Toronto, Ont.
authors.forename: Simon
authors.initials: S
authors.lastname: Hollands
authors.affiliation: Department of Family and Community Medicine (Antoniou), St. Michael's Hospital and University of Toronto; Li Ka Shing Knowledge Institute (Gomes) and Li Ka Shing Centre for Healthcare Analytics Research and Training (Mamdani), St. Michael's Hospital; Leslie Dan Faculty of Pharmacy (Gomes, Tadrous, Mamdani) and Department of Medicine (Juurlink), University of Toronto; Institute for Clinical Evaluative Sciences (Antoniou, Macdonald, Yao, Hollands, Gomes, Tadrous, Mamdani, Juurlink); Applied Health Research Centre (Tadrous), St. Michael's Hospital; Sunnybrook Research Institute (Juurlink), Toronto, Ont.
authors.forename: Tara
authors.initials: T
authors.lastname: Gomes
authors.affiliation: Department of Family and Community Medicine (Antoniou), St. Michael's Hospital and University of Toronto; Li Ka Shing Knowledge Institute (Gomes) and Li Ka Shing Centre for Healthcare Analytics Research and Training (Mamdani), St. Michael's Hospital; Leslie Dan Faculty of Pharmacy (Gomes, Tadrous, Mamdani) and Department of Medicine (Juurlink), University of Toronto; Institute for Clinical Evaluative Sciences (Antoniou, Macdonald, Yao, Hollands, Gomes, Tadrous, Mamdani, Juurlink); Applied Health Research Centre (Tadrous), St. Michael's Hospital; Sunnybrook Research Institute (Juurlink), Toronto, Ont.
authors.forename: Mina
authors.initials: M
authors.lastname: Tadrous
authors.affiliation: Department of Family and Community Medicine (Antoniou), St. Michael's Hospital and University of Toronto; Li Ka Shing Knowledge Institute (Gomes) and Li Ka Shing Centre for Healthcare Analytics Research and Training (Mamdani), St. Michael's Hospital; Leslie Dan Faculty of Pharmacy (Gomes, Tadrous, Mamdani) and Department of Medicine (Juurlink), University of Toronto; Institute for Clinical Evaluative Sciences (Antoniou, Macdonald, Yao, Hollands, Gomes, Tadrous, Mamdani, Juurlink); Applied Health Research Centre (Tadrous), St. Michael's Hospital; Sunnybrook Research Institute (Juurlink), Toronto, Ont.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Mamdani
authors.affiliation: Department of Family and Community Medicine (Antoniou), St. Michael's Hospital and University of Toronto; Li Ka Shing Knowledge Institute (Gomes) and Li Ka Shing Centre for Healthcare Analytics Research and Training (Mamdani), St. Michael's Hospital; Leslie Dan Faculty of Pharmacy (Gomes, Tadrous, Mamdani) and Department of Medicine (Juurlink), University of Toronto; Institute for Clinical Evaluative Sciences (Antoniou, Macdonald, Yao, Hollands, Gomes, Tadrous, Mamdani, Juurlink); Applied Health Research Centre (Tadrous), St. Michael's Hospital; Sunnybrook Research Institute (Juurlink), Toronto, Ont.
authors.forename: David N
authors.initials: DN
authors.lastname: Juurlink
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins / Q000008:administration & dosage / Q000009:adverse effects*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D016022:Case-Control Studies; D016001:Confidence Intervals; D000069604:Dabigatran / Q000008:administration & dosage / Q000009:adverse effects*; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D016017:Odds Ratio; D009864:Ontario / Q000453:epidemiology; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced* / Q000453:epidemiology
chemical_list: D000991:Antithrombins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069604:Dabigatran