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

Date of Approval: 
2020-12-08 00:00:00
Lay Summary: 
Osteoporosis weakens bones, making them more likely to break (fracture). Romosozumab is a new medication used to treat patients at high risk of fractures (severe osteoporosis). Whilst effective at preventing further fractures in patients, there are concerns about the side effects of this drug, one of which is its effect on heart health. This study, combined with 2 other projects (assessing the effect on serious infection, and whether prescribing guidelines are followed), will use data from 7 countries in Europe to assess whether it is safe to use romosozumab in patients in clinical practice. This application includes the UK assessment of the medication for risk of heart disease. This project has two components. First to assess the number of heart events in both romosozumab users and users of other osteoporosis medications, then, to assess the risk of heart events in romosozumab users compared to users of the most common osteoporosis medication used in the UK, alendronate. This study will be undertaken in women aged 50+ with severe osteoporosis. The results of this study, along with the other two projects, will be sent to the European Medicines Agency, and based on the results, the continued availability of romosozumab in Europe and the UK may be affected.
Technical Summary: 
Objective The aim of this study is to characterize the risk of serious cardiovascular (CV) events of myocardial infarction (MI) and stroke, and all-cause mortality including CV death associated with the use of romosozumab, in comparison with other available osteoporosis medications in routine clinical practice in the UK as part of a study using 7 databases from Europe. This will be achieved by meeting three objectives: 1) assessing the incidence of cardiovascular outcomes in romosozumab patients; 2) assessing the incidence of cardiovascular outcomes in patients using other osteoporosis medications and 3) assess the comparative risk of cardiovascular outcomes between patients using romosozumab and alendronate. Population The population for this study is women aged 50+ with severe osteoporosis who are prescribed one of the below osteoporotic medications. Severe osteoporosis is identified by the presence of 1 or more fractures of any skeletal sites except face/skull/digit/s fractures recorded in the year prior to therapy initiation. Exposure The exposure of interest is romosozumab. Comparator exposures are alendronate (primary comparator); ibandronate (oral and intravenous); risedronate; zoledronate; denosumab; and teriparatide. Outcome The primary outcome of interest is MACE-2 (first occurrence of death [all cause including cardiovascular (CV) death], MI, or stroke) whilst secondary outcomes are MI; stroke ; death due to CV causes, i.e., MI or stroke; all-cause mortality; MACE-1 (First occurrence of death (CV causes), MI, or stroke). Methods This will be designed using a cohort study with incidence rates of each outcome for each osteoporosis medication calculated using a Poisson model. Meanwhile, cox proportional hazards with propensity score matching will be used for the comparative risk assessment. Multiple sensitivity analyses including negative controls, self-controlled case series (SCCS), and instrumental variable analysis will assess the results for confounding.
Health Outcomes to be Measured: 
Primary: MACE-2 (first occurrence of death [all cause including cardiovascular (CV) death], myocardial infarction (MI), or stroke) Secondary: MI; Stroke; Death due to CV causes, i.e., MI or stroke; All-cause mortality; MACE-1 (First occurrence of death (CV causes), MI, or stroke).
Application Number: 
20_000063
Collaborators: 

Alireza Moayyeri - Chief Investigator - UCB Pharma SA - UK
Danielle Robinson - Corresponding Applicant - University of Oxford
Annika Jodicke - Collaborator - University of Oxford
Antonella Delmestri - Collaborator - University of Oxford
Chao Lu - Collaborator - UCB BioSciences, Inc.
Daniel Prieto-Alhambra - Collaborator - University of Oxford
Eng Hooi Tan - Collaborator - University of Oxford
Victoria Y Strauss - Collaborator - University of Oxford

Linkages: 
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation