Confounding by drug formulary restriction in pharmacoepidemiologic research

Pharmacoepidemiol Drug Saf. 2016 Mar;25(3):278-86. doi: 10.1002/pds.3923. Epub 2015 Dec 9.


Purpose: The potential consequences of confounding due to drug formulary restrictions in pharmacoepidemiologic research remain incompletely understood. Our objective was to illustrate this potential bias using the example of fluticasone/salmeterol combination therapy, an oral inhaler used to treat asthma and chronic obstructive pulmonary disease, whose use is restricted in the province of Quebec, Canada.

Methods: We identified all new users of fluticasone/salmeterol in Quebec's administrative databases and classified those who received their initial dispensing of fluticasone/salmeterol between 1 September 1999 and 30 September 2003 as users from the liberal period and those who received it between 1 January 2004 and 31 October 2006 as users from the restricted period. The primary outcome was time to first hospitalization for respiratory causes within 12 months of cohort entry.

Results: Our cohort included 72 154 new users from the liberal period and 5058 from the restricted period. Compared with use during the liberal period, use during the restricted period was associated with an increased rate of hospitalization for respiratory causes (crude hazard ratio [HR] = 1.41, 95% confidence interval [CI] = 1.32, 1.51). Subsequent adjustment for age, sex, and hospitalization for respiratory causes in the previous year attenuated the association (HR = 1.05, 95%CI = 0.98, 1.12). Further adjustment for other potential confounders resulted in a lower rate during the restricted period (HR = 0.78, 95%CI = 0.73, 0.83).

Conclusions: Formulary restrictions can result in substantial and unexpected confounding and should be considered during the design and analysis of pharmacoepidemiologic studies.

Keywords: bias; confounding; drug formulary restrictions; pharmacoepidemiology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asthma / drug therapy
  • Asthma / mortality
  • Bronchodilator Agents / administration & dosage*
  • Bronchodilator Agents / therapeutic use
  • Cohort Studies
  • Confounding Factors, Epidemiologic
  • Databases, Factual
  • Drug Utilization Review / statistics & numerical data*
  • Fluticasone-Salmeterol Drug Combination / administration & dosage*
  • Fluticasone-Salmeterol Drug Combination / therapeutic use
  • Formularies as Topic*
  • Hospitalization / statistics & numerical data*
  • Humans
  • Mortality / trends
  • Outcome Assessment, Health Care / statistics & numerical data
  • Pharmacoepidemiology / methods
  • Pharmacoepidemiology / standards*
  • Pharmacoepidemiology / statistics & numerical data
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Pulmonary Disease, Chronic Obstructive / mortality
  • Quebec
  • Retrospective Studies


  • Bronchodilator Agents
  • Fluticasone-Salmeterol Drug Combination