Calcitonin gene-related peptide-targeting drugs and Raynaud’s phenomenon: a real-world potential safety signal from the WHO pharmacovigilance database

Abstract

Background Migraine is responsible for significant disability and societal burden. Recently, drugs targeting the calcitonin gene-related peptide (CGRP) pathway raised new hopes. CGRP, a potent vasodilator, plays a key role in the pathogenesis of migraine attacks. The deficiency of CGRP is involved in Raynaud’s phenomenon, which consists of abnormal vasoconstriction of the digits. We aimed to assess the potential association of Raynaud’s phenomenon with CGRP-targeting drugs, analyzing real-world data from the World Health Organization (VigiBase®). Methods We queried all reports of Raynaud’s phenomenon involving a CGRP-targeting drug. We sought disproportionate reporting of Raynaud’s phenomenon with these drugs. For this purpose, we relied on the calculation of the Information Component (IC). A positive lower end of the 95% confidence interval (CI) of the IC defines a statistically significant association. As migraine patients are prone to Raynaud’s phenomenon, we also calculated the IC of Raynaud’s phenomenon with CGRP-targeting drugs compared to 5HT1B/D agonists (triptans), and beta-blockers used in the treatment of migraine. Results Overall, 99 reports of Raynaud’s phenomenon involving CGRP-targeting drugs have been yielded in VigiBase®. The most reported CGRP-targeting drug was erenumab, with 56 reports (56.6%). The median time to onset was 84 days. No fatality was notified, but one patient suffered from gangrene and extremity necrosis. As a whole, CGRP-targeting drugs were significantly associated with Raynaud’s phenomenon, with an IC of 3.3 (95%CI: 3.0–3.5). There was a disproportionate reporting of Raynaud’s phenomenon with CGRP-targeting drugs compared to triptans (IC 0.4; 95%CI: 0.1–0.6) and to beta-blockers (IC 0.5; 95%CI: 0.2–0.7) as well. Conclusions There is a significant disproportionality signal of Raynaud’s phenomenon with CGRP-targeting. This signal stands out when CGRP-targeting drugs are compared to other drugs used in patients with migraine. This study is limited by missing data in pharmacovigilance reports. CGRP-targeting drugs may be subject to Weber effect and reporting bias. Nonetheless, CGRP blockade might be the last straw that disrupts the physiological balance of vascular response in patients at-risk of Raynaud’s phenomenon. Pending further data regarding vascular safety of CGRP-targeting drugs, caution is warranted in these patients.

Adverse event reporting of four anti-Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: a real-world study based on the FDA adverse event reporting system

“…Therefore, while anti-CGRP drugs can reduce the release of CGRP and relieve migraine attacks, they also can induce Raynaud’s phenomenon in some cases. A real-world study showed that anti-CGRP drugs could induce or aggravate Raynaud’s phenomenon with a significantly stronger signal than triphenylamine, which is a migraine drug that can induce the Raynaud phenomenon ( Gerard et al, 2022 ). Although the Raynaud phenomenon was rare and the use of anti-CGRP mAbs in patients with the Raynaud phenomenon had a low incidence of microvascular complications, this was still considered worthy of attention in clinical practice ( Breen et al, 2021 ).…”

Myocardial infarction associated with erenumab: A case report

“…Patient imaging suggested a vasospasm mechanism and erenumab was suspected in the absence of any other evident etiologies 12 . Recent study‐based pharmacovigilance data from the World Health Organization (VigiBase®) warned about vascular safety owing to a significant disproportionality signal of Raynaud's phenomenon with CGRP‐targeting drugs, especially erenumab 13 . However, the safety profile of CGRP‐mabs could be different for molecules that target the CGRP receptor or ligand.…”

“…12 Recent study-based pharmacovigilance data from the World Health Organization (VigiBase®) warned about vascular safety owing to a significant disproportionality signal of Raynaud's phenomenon with CGRP-targeting drugs, especially erenumab. 13 However, the safety profile of CGRP-mabs could be different for molecules that target the CGRP receptor or ligand. Such is the case for the risk of hypertension, which has been related only with erenumab.…”

Consenso sobre anticuerpos monoclonales en migraña del Grupo de Estudio de Cefaleas de la Asociación Madrileña de Neurología

“…-Enfermedad coronaria o ictus reciente e hipertensión arterial sin control adecuado. -Antecedentes de fenómeno de Raynaud, especialmente cuando es secundario 58 . -Historia de estreñimiento grave y uso de erenumab 59 .…”