Methodological challenges when evaluating potential off-label prescribing of drugs using electronic health care databases: A case study of dabigatran etexilate in Europe

Pharmacoepidemiol Drug Saf. 2018 Jul;27(7):713-723. doi: 10.1002/pds.4416. Epub 2018 Mar 23.


Purpose: To report and discuss estimated prevalence of potential off-label use and associated methodological challenges using a case study of dabigatran.

Methods: Observational, cross-sectional study using 3 databases with different types of clinical information available: Cegedim Strategic Data Longitudinal Patient Database (CSD-LPD), France (cardiologist panel, n = 1706; general practitioner panel, n = 2813; primary care data); National Health Databases, Denmark (n = 28 619; hospital episodes and dispensed ambulatory medications); and Clinical Practice Research Datalink (CPRD), UK (linkable to Hospital Episode Statistics [HES], n = 2150; not linkable, n = 1285; primary care data plus hospital data for HES-linkable patients).

Study period: August 2011 to August 2015. Two definitions were used to estimate potential off-label use: a broad definition of on-label prescribing using codes for disease indication (eg, atrial fibrillation [AF]), and a restrictive definition excluding patients with conditions for which dabigatran is not indicated (eg, valvular AF).

Results: Prevalence estimates under the broad definition ranged from 5.7% (CPRD-HES) to 34.0% (CSD-LPD) and, under the restrictive definition, from 17.4% (CPRD-HES) to 44.1% (CSD-LPD). For the majority of potential off-label users, no diagnosis potentially related to anticoagulant use was identified. Key methodological challenges were the limited availability of detailed clinical information, likely leading to overestimation of off-label use, and differences in the information available, which may explain the disparate prevalence estimates across data sources.

Conclusions: Estimates of potential off-label use should be interpreted cautiously due to limitations in available information. In this context, CPRD HES-linkable estimates are likely to be the most accurate.

Trial registration: NCT02240654.

Keywords: NOACs; atrial fibrillation; dabigatran; drug utilization; off-label; pharmacoepidemiology.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antithrombins / administration & dosage
  • Antithrombins / therapeutic use*
  • Cross-Sectional Studies
  • Dabigatran / administration & dosage
  • Dabigatran / therapeutic use*
  • Databases, Factual
  • Electronic Health Records*
  • Europe
  • Female
  • Humans
  • Male
  • Middle Aged
  • Off-Label Use*
  • Primary Health Care
  • Thrombosis / etiology
  • Thrombosis / prevention & control*


  • Antithrombins
  • Dabigatran

Associated data