European non-interventional post-authorization safety study related to serious cardiovascular events of myocardial infarction and stroke, and all-cause mortality for romosozumab by the EU-ADR Alliance

Study type

• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness

  Drug utilisation

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Name of medicine:
  EVENITY
• Study drug International non-proprietary name (INN) or common name:
  ROMOSOZUMAB
• Anatomical Therapeutic Chemical (ATC) code:
  (M05BX) Other drugs affecting bone structure and mineralization

  Other drugs affecting bone structure and mineralization
• Medical condition to be studied:
  Osteoporosis postmenopausal

Population studied

• Age groups:
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

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

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)
• Estimated number of subjects:
  337200

Study design details

• Main study objective:
  The overarching objective of this study is to characterize the risk of serious cardiovascular events of myocardial infarction and stroke, and all-cause mortality including cardiovascular death associated with the use of romosozumab, in comparison with other available osteoporosis medications in routine clinical practice in Europe
• Outcomes:
  MACE-2 (first occurrence of death all cause including cardiovascular (CV) death, Myocardial Infarction (MI), or stroke), - Myocardial Infarction (MI)- Stroke- Death due to cardiovascular (CV) causes, ie, MI or stroke- All-cause mortality- First occurrence of death (CV causes), MI, or stroke (MACE-1)
• Data analysis plan:
  Incidence rates and 95 % confidence intervals for each outcome will be calculated for each study drug cohort using a Poisson model. These will be reported for prespecified intervals of 6, 12, 18, and 24 months after treatment indexes, and will be stratified by several factors including age, prior use of osteoporosis medication, and previous history of cardiovascular event. For comparative safety studies, propensity score matching will be used to match patients using romosozumab to up to 3 users of alendronate. Cox regression models stratified by matched sets will be used to calculate hazard ratios and 95 % CIs for each of the safety endpoints (MI, stroke, MACE-1, and MACE-2) according to drug exposure in the propensity-matched cohorts. The pooled estimates of the incidence rate for the databases will be calculated using the random or fixed effects meta-analysis depending on heterogeneity detected using an I^2 threshold of >40 %.