Comparison of CGRP-Targeting Treatments and OnabotulinumtoxinA Shows No Increased Cardiovascular Disease Risk

Seonkyeong Yang, MS, BS Pharm

A recently published retrospective, sequential cohort study comparing anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) vs onabotulinumtoxinA showed that treatment with the newer class of medications was not associated with an increased risk of cardiovascular disease (CVD), despite initial concerns.¹

Using Medicare administrative claims data from May 2018 to December 2020, findings revealed no increased risk of composite CVD events (adjusted HR [aHR], 0.88; 95% CI, 0.44-1.77), hypertensive crisis (aHR, 0.46; 95% CI, 0.14-1.55), peripheral revascularization (aHR, 1.50; 95% CI, 0.48-4.73) or Raynaud phenomenon (aHR, 0.75; 95% CI, 0.45-1.24) with anti-CGRP mAbs vs onabotulinumtoxinA. These data remained consistent across various subgroups, including individuals older than 65 years and those with established CVD.

"Clinical trials typically involve populations with fewer cardiovascular concerns, underscoring the importance of postapproval observational studies in broader populations using real-world data,” lead author Seonkyeong Yang, MS, BS Pharm, a pharmacoepidemiology intern at the University of Florida, and others, wrote. "These studies are crucial for obtaining a comprehensive understanding of relatively rare CVD events that require long- term follow-up to establish the safety profile of anti-CGRP mAbs. Future studies should leverage more recent data to assess the long-term safety of anti-CGRP mAbs in larger samples."

In total, the study comprised of 9153 Medicare beneficiaries with migraine who were on either anti-CGRP mAbs (n = 5153) or onabotulinumtoxinA (n = 4000). Among anti-CGRP mAb initiators, erenumab was the most commonly used (60.4%), followed by galcanezumab (29.5%), fremanezumab (9.8%), and eptinezumab (0.4%). Coming into the study, those on these newer class of medications were more likely to have disability status (67.6% vs 56.0%), full Part D LIS eligibility (54.9% vs 39.7%), and obesity (37.0% vs 30.4%) than those on onabotulinumtoxinA.

The median follow-up time of the composite myocardial infarction (MI) or stroke outcome was 4.3 (IQR, 2.0-9.5) months for anti-CGRP mAb inhibitors and 4.4 (IQR, 1.6-8.8) months for onabotulinumtoxinA users. In addition to showing no significant difference in the risk of composite CVD outcome, the study found no risk differences when assessing CVD outcomes separately, including MI (aHR, 0.86; 95% CI, 0.30-2.48) and stroke (aHR, 0.90; 95% CI, 0.35-2.27).

To the study authors knowledge, this was the first study to evaluate the comparative cardiovascular safety of anti-CGRP mAbs compared with onabotulinumtoxinA within the Medicare population. Subgroup analyses within the research showed a comparable risk of the composite CVD outcome when each group was stratified by age and the presence of established CVD. IN addition, all sensitivity analyses, including changes in the follow-up approach, weighting method, length of the gap between prescription fills, and operational definitions during cohort creation, yielded similar findings.

READ MORE: Atogepant Appears More Cost Effective and Efficacious Than Rimegepant, Indirect Comparison Data Suggests

This study has several limitations that should be considered. Anti-CGRP mAb exposure may be misclassified due to patient assistance programs, which have strict eligibility criteria. Claims data lacked detailed prescription information, meaning some onabotulinumtoxinA might not have been used solely for migraines, although this was addressed by requiring a migraine diagnosis near the index date. A limited sample size and the rarity of cardiovascular events led to imprecise risk estimates, and newer migraine treatments like gepants and lasmiditan were excluded due to minimal usage. While these factors limit the strength of conclusions, the findings provide valuable safety insights to guide clinical decision-making.

Prior to this study, previous research has linked anti-CGRP mAbs with CVD, including stroke, MI, RP, and exacerbation of cerebrovascular disease. Postmarketing surveillance has identified cardiovascular safety concerns with anti-CGRP mAbs. For instance, FAERS data revealed elevated blood pressure shortly after starting erenumab, sometimes requiring hospitalization or medication, leading to updated prescribing information that highlights hypertension risks.²

Postmarketing surveillance studies have suggested a potential link between erenumab use and hypertension.³ FAERS data also identified overlapping signals of palpitations and RP across the four anti-CGRP mAbs, along with rare cardiovascular events, such as coronary artery dissection with erenumab and supraventricular tachycardia with fremanezumab. While earlier case reports raised concerns about major events like MI and stroke, these passive studies did not show an excessive number of such incidents, likely due to their rarity. Given the limitations of case reports and passive surveillance, more rigorous real-world studies are needed to assess the cardiovascular safety of anti-CGRP mAbs.

REFERENCES
1. Yang S, Orlova Y, Park H, et al. Cardiovascular Safety of Anti-CGRP Monoclonal Antibodies in Older Adults or Adults With Disability With Migraine. JAMA Neurol. Published online January 6, 2025. doi:10.1001/jamaneurol.2024.4537
2. Erenumab.Packageinsert.Amgen;2018. Accessed January 21, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761077s000lbl.pdf
3. orbaraEE,BarbieriMA,RussoG,CicalaG, Spina E. Cardiovascular adverse drug reactions of anti-calcitonin gene-related peptide monoclonal antibodies for migraine prevention: an analysis from the European Spontaneous Adverse Event Reporting System. BioDrugs. 2024;38(2):275-285. doi:10.1007/s40259-024-00651-8