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
Application Number
20_000063
Technical Summary

Objective
The aim of this study is to characterize the risk of serious cardiovascular (CV) events of myocardial infarction (MI), stroke, and arrhythmia 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), cardiac arrhythmias and atrial fibrillation.
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), cardiac arrhythmias and atrial fibrillation.

Collaborators

Alireza Moayyeri - Chief Investigator - UCB Pharma SA - UK
Annika Jodicke - Corresponding Applicant - 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
Maria Sanchez - 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