Do case-only designs yield consistent results across design and different databases? A case study of hip fractures and benzodiazepines

Gema Requena, John Logie, Elisa Martin, Nada Boudiaf, Rocío González González, Consuelo Huerta, Arturo Alvarez, David Webb, Andrew Bate, Luis A. García Rodríguez, Robert Reynolds, Raymond Schlienger, Helga Gardarsdottir, Mark de Groot, Olaf H. Klungel, Fancisco de Abajo, Ian J. Douglas

Research output: Contribution to journalSpecial issueAcademicpeer-review


Background: The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in pharmacoepidemiology. In both, relative risk estimates are obtained within persons, implicitly controlling for time-fixed confounding variables. Objectives: To examine the consistency of relative risk estimates of hip/femur fractures (HFF) associated with the use of benzodiazepines (BZD) across case-only designs in two databases (DBs), when a common protocol was applied. Methods: CXO and SCCS studies were conducted in BIFAP (Spain) and CPRD (UK). Exposure to BZD was divided into non-use, current, recent and past use. For CXO, odds ratios (OR; 95%CI) of current use versus non-use/past were estimated using conditional logistic regression adjusted for co-medications (AOR). For the SCCS, conditional Poisson regression was used to estimate incidence rate ratios (IRR; 95%CI) of current use versus non/past-use, adjusted for age. To investigate possible event-exposure dependence the relative risk in the 30days prior to first BZD exposure was also evaluated. Results: In the CXO current use of BZD was associated with an increased risk of HFF in both DBs, AORBIFAP=1.47 (1.29-1.67) and AORCPRD=1.55 (1.41-1.70). In the SCCS, IRRs for current exposure was 0.79 (0.72-0.86) in BIFAP and 1.21 (1.13-1.30) in CPRD. However, when we considered separately the 30-day pre-exposure period, the IRR for current period was 1.43 (1.31-1.57) in BIFAP and 1.37 (1.27-1.47) in CPRD. Conclusions: CXO designs yielded consistent results across DBs, while initial SCCS analyses did not. Accounting for event-exposure dependence, estimates derived from SCCS were more consistent across DBs and designs.
Original languageEnglish
Pages (from-to)79–87
JournalPharmacoepidemiology and Drug Safety
Issue numberSuppl. S1
Publication statusPublished - 1 Apr 2016


  • Benzodiazepines
  • Case crossover (CXO)
  • Electronic healthcare records databases (DBs)
  • Hip fractures
  • Pharmacoepidemiology
  • Self-controlled case series (SCCS)
  • case study
  • confounding variable
  • data base
  • drug therapy
  • exposure
  • fracture
  • health care
  • hip fracture
  • human
  • incidence
  • logistic regression analysis
  • pharmacoepidemiology
  • risk
  • risk factor
  • Spain
  • benzodiazepine derivative


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