6th Edition of Neurology World Conference 2026

Abstract

Background: Calcitonin gene–related peptide (CGRP) pathway inhibitors are widely used for migraine prevention and acute treatment, yet concerns persist regarding potential stroke risk given CGRP’s role in cerebral vasodilation. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate stroke risk associated with CGRP inhibitors and to contextualize findings with post-marketing safety signals. Methods: RCTs enrolling adults (≥18 years) with episodic or chronic migraine comparing CGRP monoclonal antibodies or Gepants with placebo or alternative therapies were identified. The prespecified primary outcome was incident stroke (ischemic or hemorrhagic); secondary outcomes included transient ischemic attack (TIA) and composite arterial thrombotic events. Given the rarity of cerebrovascular events, Mantel– Haenszel pooled risk difference (random effects) was the primary analytic method, allowing inclusion of double-zero studies, with generalized linear mixed models and Peto odds ratios used for sensitivity analyses. Results: Thirteen RCTs comprising 14 safety comparisons (N = 21,002; active n = 12,080; placebo n = 8,922) evaluating Eptinezumab, Erenumab, Fremanezumab, and Galcanezumab were included, with follow-up ranging from 12 to 56 weeks. Stroke events were exceedingly rare and inconsistently reported, precluding reliable pooled estimates. TIA analysis demonstrated no increased risk (risk difference 0.00079, 95% CI −0.00099 to 0.00257; I² = 0%). Absolute risk differences across cerebrovascular endpoints were near zero with no heterogeneity, and subgroup analyses by agent and dose revealed no strokespecific safety signals. These findings contrast with post-marketing pharmacovigilance analyses (WHO VigiBase, EudraVigilance) reporting disproportionate cerebrovascular signals, particularly with Erenumab; however, such data are signal-generating and limited by reporting and detection biases. Conclusions: In randomized evidence involving over 21,000 patients, CGRP pathway inhibitors were not associated with an increased short-term risk of stroke or TIA, providing reassuring cerebrovascular safety data while underscoring the importance of continued post-marketing surveillance.