DARWIN EU® - Assessing the feasibility of conducting a causal study on the potential association between beta-blockers and breast cancer

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Drug utilisation
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Population studied

• Short description of the study population:
  Study population: ; Objectives 1, 2, and 4: Newly initiating an index treatment during the study period (At least 1 prescription/dispensation of an index treatment; when both are available, prescription data will be prioritised).; Inclusion criteria; • Female individuals aged ≥18 years; • ≥365 days of prior observation; • Hypertension diagnosis on or before the index date[JN1.1]; Exclusion criteria; • Breast cancer diagnosis (including in situ breast cancer) or bilateral preventive mastectomy any time before the index date.; Washout: Infinite washout [-inf, -1] will be applied for prior use of the index treatment class. For any beta-blocker cohorts, washout will be applied across all beta-blockers. For any CCBs cohorts, washout will be applied across all CCBs; ; For objective 3, a different cohort (general female population) will be defined: ; Inclusion criteria; • Female individuals aged ≥18 years; • ≥365 days of prior observation; Exclusion criteria; • Breast cancer diagnosis (including in situ) or bilateral preventive mastectomy any time before index date.;
• Age groups:
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)

Study design details

• Study design:
  A cohort study will be conducted using routinely collected health data from 5 data sources from 5 countries across Europe and in 3 European Union (EU) member states.
• Main study objective:
  1. To describe baseline demographic, clinical characteristics, the potential indications, as well as previous and baseline antihypertensive medication use in female individuals newly initiating the following distinct antihypertensive classes: Β1-selective beta-blockers, non-selective beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), non-dihydropyridines calcium channel blockers (CCBs), dihydropyridines CCBs.; 2. To describe the number, proportion, and time-to-event distribution of the following events among female individuals newly initiating Β1-selective beta-blockers, non-selective beta-blockers, ACE inhibitors, ARBs, non-dihydropyridines CCBs, dihydropyridines CCBs during 5 and 10 years of follow-up: 1) all cause death, 2) loss to follow-up, and 3) discontinuation of index treatment.; 3. To estimate the yearly incidence of primary breast cancer in the general adult (≥18 years) female population overall and by age group (18–40, 41–50, >50 years).; 4. Based on the size of each cohort, assess whether the study size provides adequate precision to support a causal analysis.
• Setting:
  This study will be conducted using routinely collected data from five primary/secondary care data sources in the DARWIN EU® network of data partners from five European countries (Table 1 and ANNEX I). All data were a priori mapped to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM). Information on data sources included and a rationale for their inclusion in terms of ability to capture the relevant data is described in ANNEX II.
• Outcomes:
  Objective 1: ; Not applicable. ; Objective 2: ; • Discontinuation of index treatment: discontinuation will be defined as a gap of >90 days without a subsequent prescription/dispensation of index treatment. The date of discontinuation will be the last prescription/dispensation + days of supply, where available. More detailed information about days of supply data and how the end of each prescription is estimated in each data source can be found in Annex II. ; • All-cause death ; • Loss to follow-up: defined as the end of an individual’s observation period in the data source, which ; may reflect deregistration, disenrollment, or emigration. ; Objective 3: ; The outcome will be defined as the occurrence of incident breast cancer recorded in the data sources. Breast cancer codes are available in SNOMED and ICDO3. The preliminary concept sets used for the identification of outcomes are described in Annex IV. These codes will be refined during the study execution following the DARWIN EU® phenotyping standard processes, which involve the review of code lists by clinical experts and the review of phenotypes after their execution in the participating data sources.[7]