title: Limited impact of drug exposure misclassification from non-benefit thiazolidinedione drug use on mortality and hospitalizations from Saskatchewan, Canada: a cohort study.
abstract: OBJECTIVE
  Our purpose was to measure the effect of non-benefit drug use on observed associations between exposure and outcome, thereby documenting an empirical example of the potential magnitude of biases introduced when exposure status is misclassified from a restrictive drug coverage policy.
  
  
  METHODS
  New users of antidiabetic agents were identified with a 1-year washout period between January 1, 1995, and December 31, 2005, in Saskatchewan, Canada, and were followed until December 31, 2008. Within this population-based cohort, persons were classified as users of benefit or non-benefit thiazolidinediones (TZDs) according to their first prescription record between January 1, 2006, and December 31, 2006 (non-benefit prescription records were not captured before 2006). An intention-to-treat approach was used to categorize TZD exposure over time. We evaluated the potential bias introduced by drug exposure misclassification by evaluating bootstrapped differences in hazard ratio (HR) estimates of all-cause hospitalization or death between users and nonusers of TZDs obtained from analyses that contained complete drug use (non-benefit and benefit drug use) versus benefit drug use only (non-benefit drug use was misclassified as unexposed). All analyses were replicated within the same cohort of new users of antidiabetic agents for clopidogrel and β-blocker (bisoprolol or carvedilol) users versus nonusers because these agents were also subject to exposure misclassification from non-benefit drug use during the period of the study.
  
  
  RESULTS
  Among 27,333 new users of antidiabetic agents, we identified 5759 TZD users (28% non-benefit) and 21,574 nonusers of TZDs. The crude HR for hospitalization or death among TZD users versus nonusers was higher in a database that contained benefit-only prescriptions than in a database that contained all prescriptions (HR = 1.11 [95% CI, 1.05-1.18] vs HR = 0.99 [95% CI, 0.94-1.04]). However, the differences in HRs after adjustment for demographic characteristics, health care utilization, comorbidities, and medications suggested minimal bias was introduced when TZD exposure was misclassified in the benefit-only database (adjusted HR [aHR] = 1.04 [95% CI. 0.98-1.10] vs aHR = 0.99 [95% CI, 0.94-1.04]; bootstrapped aHR difference = +0.05 [95% CI, 0.02-0.08]). Minimal differences in aHRs were also observed within analyses of clopidogrel (1551 users [24% non-benefit]; bootstrapped aHR difference = +0.01 [95% CI, -0.04 to 0.06]) and β-blocker users (351 users [42% non-benefit]; bootstrapped aHR difference = +0.06 [95% CI, -0.09 to 0.20]) versus nonusers.
  
  
  CONCLUSIONS
  Although patient characteristics and outcomes differed between users of non-benefit and benefit drugs, misclassification of drug exposure did not meaningfully bias estimates of all-cause mortality and hospitalization after covariate adjustment in our study.
authors.affiliation: School of Pharmacy, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada; Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD), University of Alberta, Edmonton, Alberta, Canada. Electronic address: jgamble@mun.ca.
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Gamble
authors.affiliation: Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD), University of Alberta, Edmonton, Alberta, Canada; School of Public Health, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD), University of Alberta, Edmonton, Alberta, Canada; Division of General Internal Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.
authors.forename: Finlay A
authors.initials: FA
authors.lastname: McAlister
authors.affiliation: Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD), University of Alberta, Edmonton, Alberta, Canada; School of Public Health, University of Alberta, Edmonton, Alberta, Canada; Division of General Internal Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sumit R
authors.initials: SR
authors.lastname: Majumdar
authors.affiliation: Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD), University of Alberta, Edmonton, Alberta, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Scot H
authors.initials: SH
authors.lastname: Simpson
authors.affiliation: Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD), University of Alberta, Edmonton, Alberta, Canada; School of Public Health, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Dean T
authors.initials: DT
authors.lastname: Eurich
mesh_terms: D000368:Aged; D000077144:Clopidogrel; D015331:Cohort Studies; D016208:Databases, Factual; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012525:Saskatchewan; D045162:Thiazolidinediones / Q000627:therapeutic use*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077144:Clopidogrel; C089946:2,4-thiazolidinedione; D013988:Ticlopidine
keywords: bias; cohort study; health outcomes; mortality; pharmaceutical policy; pharmacoepidemiology