Evaluating dual calcitonin gene‐related peptide antagonists for chronic migraine prevention

Abstract Objectives/Background To explore the safety and effectiveness of using two preventive calcitonin gene‐related peptide (CGRP) antagonists in patients with chronic migraine. Although the literature supports concurrent use of CGRP antagonists for acute and preventive treatment of chronic migraine, it is unknown whether two concurrent preventive CGRP agents are safe and effective. Methods Adults with chronic migraine who were prescribed two preventive CGRP antagonists, one monoclonal antibody (e.g., eptinezumab, erenumab, fremanezumab, galcanezumab) and one oral agent (gepant) (e.g., atogepant, rimegepant) were included in this retrospective cohort study. Patients served as their own controls in a pre–post analysis completed at the University of Vermont Health Network, including data from January 1, 2020 through December 31, 2024. Demographic, clinical, and medication data were recorded at baseline (immediately prior to the addition of a second CGRP antagonist) and after a minimum of 3 months of dual therapy. The primary outcome was the change in patient‐reported headache in days per month. Secondary outcomes included changes in severe headache or migraine in days per month, adverse events, and the rate and reasons for discontinuation of dual preventive therapy. Results Of the 37 patients who were included, the average age was 54 years, and the population was primarily female (86%), White (94%), and commercially insured (57%). There was a significant decrease in headache days (median = 0; interquartile range = −5 to 0; p = 0.031) while on two CGRP antagonists, including 8 patients (22%) who achieved at least a 50% reduction in reported headache days. There was also a significant reduction in severe headache or migraine days (median = −2; interquartile range = −6 to 0; p < 0.001). There was no significant increase in adverse events with two CGRP antagonists ( p = 0.219 sign test, p = 0.103 McNemar test). However, a single case of ischemic stroke was reported in a patient with multiple risk factors. Half of all patients (19, 51%) discontinued at least one CGRP antagonist by the end of the study period, primarily due to insurance restrictions or lack of perceived benefit. No patients discontinued due to reported side effects. Conclusion Trialing two preventive CGRP antagonists may be an effective approach for some patients with chronic migraine who have exhausted other preventive treatment options, with some patients in this study experiencing a significant reduction in headache frequency and severity. Prospective studies with larger, more diverse populations should be completed to confirm these findings and investigate any potential stroke risks.