Rationale and background
Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month. The safety of atogepant in patients with significant cardiovascular (CV) or cerebrovascular (CeV) disease has not been evaluated in clinical trials. The implications of the use of atogepant in this population are unknown, therefore further characterisation in a real-world population is needed.
Research question and objectives
This study aims to evaluate the utilisation and safety of atogepant among patients diagnosed with migraine and significant CV or CeV disease.
The first phase of the study is descriptive and will evaluate the following objectives:
Objective 1: Among patients with migraine and significant CV or CeV disease who initiate atogepant, the first objective is to:
– Describe utilisation of atogepant;
– Describe patient characteristics (including demographics, comorbidities, comedications) at the time of atogepant initiation; and
– Estimate the incidence rate of CV and CeV events after initiating atogepant.
Objective 2: The second objective of this study is to determine the feasibility of a comparative safety study among patients with migraine and significant CV or CeV disease who initiate atogepant compared to a suitable comparator population, including:
– Evaluate proposed comparator population to inform feasibility of a comparative safety study; and – Examine accuracy and completeness of information on potential confounders.
The second phase of the study is comparative and will be conducted if deemed according to the Phase 1 results. The following objective will be investigated:
Objective 3: If feasible, a comparative safety analysis will be conducted to compare the incidence of CV and CeV events among patients with migraine and significant CV or CeV disease who are exposed to atogepant with users of a suitable comparator.
The scope and design of the comparative analysis will be determined as part of the interim report based on the results of the Phase 1 analyses.
Study design
This will be an observational, non-interventional study using data from population-based healthcare databases in four European countries.
Population
The study will include a cohort of all patients diagnosed with migraine with at least one dispensing of atogepant in population-based healthcare databases from four proposed countries in Europe, including Denmark, The Netherlands, Spain, and Sweden. Patients with migraine who initiate treatment with a comparator migraine preventive product during the study period will also be evaluated. The study period will start at the launch date of atogepant in each country (estimated by end of 2024 in all countries). The study population will include patients with migraine and a history of significant CV or CeV disease.
Variables
Exposure
The primary exposure of interest will include treatment with atogepant, defined as at least one dispensing or prescription for atogepant. Exposure to comparator migraine preventive products will be evaluated similarly and defined as at least one dispensing (or prescription) of the comparator. Dispensing data will be prioritised over prescription data, and the latter will be used only if dispensing data is not available or incomplete
Outcomes
The primary outcome is a composite of all CV and CeV events of interest (i.e., nonfatal myocardial infarction [MI], ischaemic heart disease, unstable angina, nonfatal ischaemic stroke, transient ischaemic attack [TIA], coronary revascularisation [percutaneous coronary intervention, coronary artery bypass grafting], and CV or CeV death [includes fatal MI, fatal ischaemic stroke, etc.]). The secondary outcomes are: nonfatal CV events (i.e., nonfatal MI, ischaemic heart disease, unstable angina, or coronary revascularisation), nonfatal CeV events (i.e., nonfatal ischaemic stroke or TIA event), and CV or CeV death (i.e., cardiovascular or CeV death). As cause of death is not available, a proxy will be used.
Covariates
Demographic and clinical characteristics will be included to describe the main cohort of patients diagnosed with migraine and significant CV or CeV disease and as confounders in the potential comparative study. All available data prior to treatment will be used, with a minimum of 12 months, to assess baseline and clinical covariates.
Data sources
Data will be obtained from the following proposed European databases: Danish Health Registers (DHR; Denmark), PHARMO Data Network (The Netherlands), Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP; Spain), and Swedish Health Registers (SHR; Sweden). The suitability of these databases for the comparative analysis will be evaluated as part of the feasibility assessment (Phase 1, Objective 2). Each database will be evaluated individually and included in the comparative analysis (Phase 2) if deemed suitable.
Study size
The number of atogepant-exposed patients included in this study will depend on the uptake of atogepant in the countries of interest. The descriptive outcomes will be presented in the final report regardless of the size of the study population (note: results for population sizes with N < 5 will not be presented due to privacy restrictions) and incidence rates for the primary and secondary outcomes will also be presented. Full comparative analyses will only be performed if the results of the interim study report confirm the ability to produce a valid analysis.
One criterion for the feasibility of the comparative analyses (see other criteria outlined in Section 9.7.6. Comparative safety analyses) is to determine adequate sample size, specifically to have a sample size that will allow detection of at least a 2-fold difference in the primary outcome of composite CV and CeV events.
Assuming a power of 80%, a 2-sided significance level of 0.05, propensity score matching, and a matching ratio of 1:1 of atogepant vs. comparator users is used, at least 10,388 person-years of follow-up in atogepant-exposed patients will be required in each database.
Data analysis
Descriptive statistics will be used for demographic and clinical characteristics at baseline. The incidence rate for the primary outcome will be presented for atogepant users, as well as the incidence rates for the secondary outcomes. The interim study report results will inform the design of the final study report and will determine if each database is suitable for the comparative analysis including (but not limited to): if the proposed data source has adequate atogepant uptake, whether confounding can be adequately addressed,
whether the number of observed events during the follow-up is sufficient, final inclusion/exclusion criteria, comparator drug, study design (e.g., new user or prevalent new user study design), and analysis approach (e.g., matching or inverse probability of treatment weighting [IPTW], inclusion of a negative control, sensitivity analyses). Assuming atogepant uptake and number of events are adequate, appropriate adjustment for confounding and matching/IPTW feasible, and a suitable comparator identified, a comparative analysis will be conducted to compare the incidence of CV and CeV events among patients with migraine and significant CV or CeV disease that are atogepant-exposed with users of a comparator. Relative risks for the outcomes of interest will be estimated as hazard ratios (HRs). A sensitivity analysis will be performed to examine the association between atogepant use and the safety outcomes of interest while excluding those with epilepsy.
