CGRP-Targeted Migraine Therapies in Patients With Vascular Risk Factors or Stroke

Abstract

Calcitonin gene-related peptide (CGRP)–targeted therapies, including monoclonal antibodies (mAbs) and gepants, represent a major advancement in migraine prevention, offering greater efficacy and improved tolerability compared with traditional treatments. These agents selectively inhibit the CGRP pathway, a key mediator in migraine pathophysiology, and are increasingly used even as first-line options in selected patients. While clinical trials and real-world data suggest a favorable cardiovascular (CV) safety profile, particularly in patients without major risk factors, evidence remains limited for those with established vascular disease or recent vascular events. Concerns persist regarding long-term effects and the safety of CGRP blockade in high-risk populations. This narrative review focuses on the CV and cerebrovascular safety of CGRP-targeted migraine treatments—an area of growing clinical relevance. We compare these newer agents with traditional migraine preventives and highlight the paucity of data in patients with previous stroke, subarachnoid hemorrhage, myocardial infarction, or significant CV comorbidities. In addition, we discuss the emerging topic of dual CGRP pathway blockade (mAbs plus gepants), which has not previously been reviewed in the context of vascular risk. Based on currently available scientific evidence, we offer structured clinical considerations to guide the use of CGRP-targeted therapies in patients with vascular risk or cerebrovascular disease. Our aim is to support informed decision making in a population that has often been excluded from clinical trials but is becoming increasingly important in clinical practice.

CGRP: A Key Player in Migraine Pathogenesis and Potential Stroke Protector

Migraine is the second most prevalent debilitating disorder among young individuals.¹ Although its exact pathophysiology remains unclear, calcitonin gene-related peptide (CGRP) has been identified as a key player in the development of migraine. CGRP is a 37-amino acid peptide that exists in 2 forms: alpha-CGRP and beta-CGRP. While alpha-CGRP is predominantly expressed in the nervous system, beta-CGRP has its primary effect at the site of the gastrointestinal system. This indicates a primary role of alpha-CGRP in the pathogenesis of migraine.² CGRP has been demonstrated to exert its effects by binding to the canonical CGRP receptor. The canonical CGRP receptor is composed of 2 subunits: the calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1).³ As an endogenous agonist, CGRP enables CLR to heterodimerize with RAMP, forming a biological active receptor that accumulates cyclic adenosine-monophosphate and subsequently activates multiple pathways.³ CGRP is not the only peptide acting on the CGRP receptor family as adrenomedullin (AM) and amylin also have affinity to the canonical CGRP receptor. Especially, AM showed vasodilative potential comparably with CGRP.³ A high density of canonical CGRP receptors has been identified in the trigeminal ganglion, in the dura mater, and throughout the trigeminal nociceptive axis in general.⁴ In the context of nociception, CGRP has been demonstrated to sensitize trigeminal neurons, rendering them more responsive to stimuli. This phenomenon has been linked to the development of allodynia and migraine headaches where normal stimuli can lead to nociceptive sensitizations.⁵ CGRP plays a significant role in the pathophysiology of migraine as evidenced by elevated CGRP levels in the blood and saliva of individuals experiencing an acute migraine attack, compared with those without migraine history.⁶ Furthermore, in individuals with chronic migraine, CGRP levels were elevated even during interictal periods.⁷ These findings are supported by CGRP's potential to induce migraine headaches in people with migraine if infused IV. In nonmigraine patients, only unspecific tension-type headache like headaches have been reported by CGRP's IV infusion.⁸

Stroke is the second leading cause of death worldwide and the leading cause of long-term disability. Approximately two-thirds of all strokes are ischemic, and one-third is hemorrhagic.⁹ CGRP's vasodilative potential may provide perfusion in critical circumstances and potentially allow for the rescue of the penumbra, which is defined as tissue at risk in ischemic conditions.¹⁰ CGRP has been demonstrated to exert beneficial effects not only through its vasodilative potential but also by preventing damage to the blood-brain barrier (BBB)¹¹; antioxidative effects¹²; anti-inflammatory effects^13,14; antiapoptotic effects by stabilization of the mitochondrial membrane, by upregulating antiapoptotic cellular pathways^13,14; and potential protective effects in subarachnoid hemorrhage (SAH) such as prevention of vasospasm.¹⁵ It has been well established that migraine and stroke have multiple pathophysiologic mechanisms in common. Table 1 provides a summary of shared pathophysiologic conditions between migraine and stroke. The Figure illustrates the potential role of CGRP in stroke.

Table 1.

Shared Risk Factors of Stroke and Migraine

Shared risk factor	Migraine impact	Stroke impact	Mechanism connecting migraine and stroke
PFO16	More common in migraine with aura (in up to 80%)	PFO allows clots to bypass the lungs leading to stroke (paradoxical embolism)	PFO may explain the elevated risk of stroke in some people with migraine with aura due to embolic events
Endothelial dysfunction17,18	People with migraine, particularly with aura, show evidence of endothelial dysfunction	Endothelial dysfunction is a known cause of stroke due to impaired blood vessel function	Both conditions involve poor vascular control and inflammation, increasing stroke likelihood
Proinflammatory state19	Elevated CRP and cytokines (IL-1, IL-6) in patients with migraine, especially with aura	Inflammation contributes to atherosclerosis and clot formation, increasing stroke risk	Chronic inflammation weakens blood vessel walls and promotes clot formation in both conditions
Platelet activation and hypercoagulation17,18	People with migraine, especially women with aura, have higher platelet activation and clotting factors	Stroke is often caused by clot formation blocking blood flow to the brain	Increased platelet activation and clotting in people with migraine heighten the risk of thrombotic strokes
CSD20,21	Underlies migraine aura and shares features with ischemic stroke mechanisms	CSD may exacerbate brain damage in ischemic stroke by increasing energy demand and excitotoxicity	CSD leads to increased risk of cell death in energy-compromised areas, similar to ischemic stroke conditions
Vasoconstrictive medications (ergotamines, triptans)22	Used to treat migraines, can cause blood vessel constriction, especially ergotamines	Excessive vasoconstriction may trigger stroke in susceptible individuals	Vasoconstriction from these medications can compromise blood flow, increasing the risk of stroke
Sex and hormonal factors23	Women are more prone to experiencing migraines during periods of hormonal fluctuation (i.e., menstrual migraine)	Female sex and hormonal contraceptives are known stroke risk factors	Hormonal changes may affect vascular function and inflammation, contributing to both conditions

Abbreviations: CRP = C-reactive protein; CSD = cortical spreading depression; IL = interleukin; PFO = patent foramen ovale.

Figure. Potential Role of Calcitonin Gene-Related Peptide in Stroke.

Methods

A comprehensive search was conducted on MEDLINE using the terms “stroke,” “CGRP,” “gepants,” and “monoclonal antibodies,” combined with the linking word “AND.” Abstracts were then screened for relevance to the topic, and full-text articles were reviewed to extract relevant information and for relevant references. All recommendations in the discussion are the consensus of the authors, based on current evidence.

New CGRP Pathway–Targeting Drugs and Traditional Migraine Medications: Risk and Benefit Ratio

Currently, 2 types of CGRP pathway–targeting medications are available: monoclonal antibodies (mAbs) and gepants. For episodic and chronic migraine treatment, 4 mAbs are approved: eptinezumab, erenumab, fremanezumab, and galcanezumab. The migraine preventive effect of erenumab is caused by the mAb's binding affinity to the extracellular canonical CGRP receptor, whereas eptinezumab, fremanezumab, and galcanezumab bind to the endogenous CGRP ligand, respectively.²⁴

Given their half-life of approximately 28–32 days, the administration of erenumab, fremanezumab, and galcanezumab requires a monthly subcutaneous application. By contrast, eptinezumab is administered IV at 3-month intervals, and for high-dose fremanezumab, every 3-month subcutaneous application is possible.^24,25 Most common adverse reactions reported in randomized clinical trials (RCTs) include injection site pain, injection site erythema, and more frequently regarding erenumab, constipation and alopecia.²⁶

The orally or nasally administered gepants directly interact with the CGRP receptor by binding one of the subunits of the canonical CGRP receptor. In comparison with mAbs, gepants show a by far shorter half-life (from 5 to 11 hours) and can be used for acute migraine treatment and/or preventative migraine treatment.²⁵

Atogepant and rimegepant are approved for preventive migraine treatment. Notably, rimegepant can be used as acute migraine and preventive migraine medication. Rimegepant for preventive use is taken every other day while atogepant is taken daily. Ubrogepant and rimegepant for acute migraine use should be taken similar to triptans. Zavegepant is the first gepant that is applied nasally for acute migraine attack termination.^25,27 Most common adverse reactions include nausea, constipation, fatigue, and, for zavegepant, dysgeusia.^25,28

In healthy participants, mAbs cannot penetrate the BBB to a relevant amount, which is due to their high molecular weight.²⁹ However, for small molecular receptor antagonists as gepants are, a small fraction may pass the BBB with yet unknown effects.³⁰ An experimental study demonstrated mAbs exerting effects within the vessel wall or indirectly influencing cerebral vasomotor function.³¹

In summary, CGRP-targeting migraine therapies have been demonstrated to exhibit a significantly reduced side-effect profile and higher efficacy in reducing MHDs in comparison with conventional migraine preventatives. This assertion is substantiated by the findings of the randomized, double-blind HERMES trial, which conducted a comparative analysis between erenumab and topiramate. They also have a much favorable benefit-risk ratio, especially in the largest migraine patient group: young women of childbearing age.²⁴ A recently published observational cohort study compared erenumab with other non-CGRP pathway–acting migraine preventive drugs and found no difference in cerebrovascular and cardiovascular (CV) events.³²

CGRP-Targeted Therapies: What Do We Know About CV Safety?

The use of mAbs and gepants targeting the CGRP system has proven to be an effective, safe, and well-tolerated approach for reducing migraine attacks.²⁴ However, clinical trials for migraine therapies typically enroll patients in good health. Although initial concerns about CV effects were raised, evidence suggests that mAbs do not induce CV disease (CVD) in the short term. A meta-analysis involving 5,817 participants reported no serious CV-related adverse events (AEs).³³ Despite these findings, the trials have limitations, including short follow-up periods (under 6 months), exclusion of patients with preexisting CV conditions, and an age cap of 65 years. In addition, some studies included only patients not using migraine preventive drugs while others allowed participants on medications that could affect the CV system.

Recent studies have extended follow-up periods beyond 2 years and included patients with CV risk factors. For example, an analysis of AEs associated with erenumab showed low incidences of ischemic CV and cerebrovascular events, with similar rates across different 10-year CV risk categories.³⁴ Another study of 162 patients aged 65–87 years (74.1% women), 42% with dyslipidemia and 40.3% with hypertension, reported mild AEs in 25.3% of patients, with only 2 cases of increased blood pressure and no significant CV events.³⁵ However, small group sizes across treatment arms limit the statistical power and the generalizability of such findings.

A recent study³⁶ focused on AEs in both, healthy patients with migraine and those with preexisting CV conditions. The goal was to enroll 6,000 patients in each cohort (fremanezumab and controls). However, only 1,077 participants enrolled over 30 months, particularly few in the CV-compromised group, leading to the study's termination. In the fremanezumab cohort, with a mean follow-up of around 397 days, no new safety concerns were observed.

In a double-blind, placebo-controlled study, 88 participants with stable angina received either an IV infusion of erenumab (140 mg) or placebo, followed by an exercise treadmill test.³⁷ Results showed no significant difference in total exercise time between groups. However, the study analyzed a nonmigraine population, and female patients with migraine, who face higher CV risks, were underrepresented because only 20% of participants were women. Minimal effects on cerebral hemodynamics were observed in mAb recipients, although a small sample size limits conclusions.³⁸ Vasomotor reactivity and brachial flow-mediated dilation measured in a clinical trial involving 60 patients with migraine receiving 70 mg of erenumab subcutaneously every 4 weeks showed no significant differences in cerebral or systemic vasomotor activity compared with a control group of healthy participants.³⁹

An observational cohort study assessed the CV safety of erenumab and fremanezumab over at least 1 year.⁴⁰ Of 193 patients (erenumab = 101, fremanezumab = 92), 3.1% developed abnormal ECGs or CV AEs. Moderate-to-severe events, such as stroke, coronary artery dissection, and pericarditis, occurred in 1.6% of patients. Another 1.6% experienced nonthreatening ECG abnormalities without symptoms. While comparisons with a control group were unavailable, the findings emphasize the need for robust CV monitoring during CGRP-targeted therapy. Another observational study involving 155 patients (42.5% with hypertension) showed no significant impact on blood pressure, even among those on antihypertensive medications (39%).⁴¹ A retrospective cohort study evaluated the safety of mAbs and gepants in patients with Raynaud phenomenon (RP) with nonsignificant findings of microvascular complications (worsening of RP, gangrenous necrosis, or digital ulcerations). However, still 5.3% of patients showed significant microvascular complications.⁴²

In Europe, the EudraVigilance database confirmed that CV adverse drug reactions linked to anti-CGRP therapies align with existing literature.⁴³ However, events such as hypertension with erenumab, atrial fibrillation, and myocardial infarction with galcanezumab and unspecific symptoms with fremanezumab were not reported in large RCTs. In the United States, VigiAccess and FAERS databases revealed AEs associated with gepants between 2020 and 2024.⁴⁴ Rimegepant showed the highest incidence of gastrointestinal AEs (14.98%) while atogepant was more strongly linked to constipation (4.07%). Skin-related AEs, such as rash and pruritus, were common with rimegepant and ubrogepant, and alopecia emerged as a novel AE, especially with rimegepant. As for mAbs, RP was also reported as a rare adverse reaction.

Because gepants represent the latest approved targeted migraine therapies, study data beyond comprehensive approval studies are scarce. In a randomized, placebo-controlled, double-blind crossover study with 22 healthy male volunteers, no vasoconstrictive effect of telcagepant was identified, when the participants were orally administered 500 mg of telcagepant (representing the second highest dose of telcagepant studied in RCTs) or placebo.⁴⁵

In phase 3 trials for atogepant, rimegepant, and ubrogepant, no increase in CV AEs among treated patients have been reported.²⁵ However, these studies generally excluded or underrepresented individuals older than 65 and those with previous CVD. A recent controlled, open-label study evaluated rimegepant's safety for up to once daily intake in 735 participants with CV risk factors over 1 year and found no CV issues.⁴⁶ Notably, patients with previous CV events or uncontrolled CVD were excluded from this study. Research in mice demonstrated that gepants, specifically olcegepant and rimegepant, doubled infarct size, increased infarct occurrence, and worsened functional outcomes after cerebral ischemia.⁴⁷ However, it should be noted that these findings were established using a mouse stroke or TIA model and the dosage of gepants used was 10–100 times higher than the approved human dose. Table 2 provides an overview of selected studies.

Table 2.

Selected Meta-Analyses and Clinical and Preclinical Trials Evaluating the Efficacy and Safety of Monoclonal Antibodies and Gepants in Migraine Treatment

Study	Findings	Limitations
Meta-analyses/systematic review
Xu et al., 201933 5,723 participants randomized in mAb RCTs (eptinezumab/placebo n = 163; erenumab/placebo n = 1,990; fremanezumab/placebo n = 1,170; galcanezumab/placebo n = 2,400)	No CV-related AEs	Mean age around 40 y, participants with previous CVD excluded; follow-up periods were short (3–6 mo)
Messina et al., 202325 14,584 participants randomized in mAb RCTs (eptinezumab/placebo n = 2,019; erenumab/placebo n = 2,939; fremanezumab/placebo n = 3,771; galcanezumab/placebo n = 3,364) and gepant RCTs (atogepant/placebo = 1,744 and rimegepant/placebo = 747)	No CV-related AEs	Mean age 38–46 y, participants with previous CVD excluded; follow-up periods were short (3–6 mo)
(R)CTs
Depre et al., 201837 88 participants with stable angina, treadmill test after single erenumab 140 mg or placebo infusion	No significant difference in exercise treadmill performance between erenumab and placebo groups	Underrepresentation of female participants (20% of participants); nonmigraine population; small sample size; administration of erenumab was IV
Van der Schueren et al., 201145 22 healthy male participants, telcagepant 500 mg or placebo single dose, nitroglycerine administration 1.5 h later	No alteration in nitroglycerine induced vasodilation	Only healthy male participants, nonmigraine population; small sample size
Altamura et al., 202139 85 participants with migraine without aura, erenumab 70 mg or 140 mg or placebo, monthly subcutaneous treatment	No alteration in cerebral VMR and brachial FMD between erenumab and placebo groups	Mean age 49.3 y, follow-up period was short (4.5 mo); small sample size
Open-label/RWS
True et al., 202446 735 patients with CV risk factors, rimegepant 75 mg up to once daily for 52 wk	No CV-related AEs	Mean age of 47.2 y, participants with previous CVD excluded; follow-up of 1 y
Muñoz-Vendrell et al., 202335 162 participants with migraine under mAb therapy (erenumab, fremanezumab, galcanezumab); participants aged 65 y or older with CV comorbidities	No CV-related AEs	Follow-up of 6 mo; small sample size
Preclinical
Mulder et al., 202047 Olcegepant and rimegepant in mice in single and repeated dose; TIA or stroke model	More severe stroke or TIA in gepant pretreated mice	Dosage of rimegepant 10–100 times higher than the approved human dose

Abbreviations: AE = adverse event; CV = cardiovascular; CVD = cardiovascular disease; FMD = flow-mediated dilation; mAb = monoclonal antibody; RCT = randomized controlled trial; VMR = vasomotor reactivity.

Case Reports of Patients With Monoclonal Therapies and Stroke or Reversible Cerebral Vasoconstriction Syndrome

A case report describes a 41-year-old woman with episodic migraine without aura who received preventive mAb therapy with erenumab 70 mg.⁴⁸ The report notes an acute right-sided thalamic infarction in MRI 34 days after the first dose of erenumab. A CT angiography detected a right-sided near-occlusion of the posterior cerebral artery P1 segment, with a large right posterior communicating artery. It is worth noting that the erenumab injection was only administered on one occasion and the subsequent stroke occurred after the half-life was exceeded. In addition, the patient had been on an estrogen-containing oral contraceptive for approximately 10 years and had taken a triptan to treat her acute migraine attack just before the stroke, which raises the possibility that erenumab may not have been the sole contributing factor.

Two case reports have described reversible cerebral vasoconstriction syndrome (RCVS) in women who were undergoing preventive therapy with fremanezumab⁴⁹ and erenumab.⁵⁰ The diagnostic workup did not identify any causality for RCVS except for the newly initiated therapies with mAbs.

Discussion

The results of the large RCTs, which enrolled more than 10,000 patients with migraine, did not indicate any relevant increase in CV risk in patients who received mAbs or gepants. This is a significant finding, given that RCTs represent the highest level of evidence in medicine. In addition, the combination of CGRP-targeting therapies with potentially vasoconstrictive triptans or nonsteroidal anti-inflammatory drugs (NSAIDs) is safe in RCTs and in real-world data. However, preclinical studies have indicated an elevated risk for individuals under CGRP-targeted therapies and acute vascular events, such as stroke, at least in animal models. Because these treatments have been emerging over the past 5 years and might become the first-line treatment in patients with migraine, careful evaluation of CV safety in patients need to be studied further.⁵¹ For patients aged 65 years or younger and no relevant CV comorbidities, these new and targeted medications are superior compared with the efficacy and tolerability profile of traditional standard oral migraine preventives.⁵² Even more, in patients with chronic and episodic migraine, these novel therapies show a beneficial cost ratio for the public health system.⁵³

CGRP Targeted Treatment and Stroke: A Risk Worth Considering?

The 3 case reports described above do not prove direct causality between stroke or RCVS and CGRP-interfering treatment. However, it is crucial to consider the implications for patients using these migraine preventive therapies in acute stroke settings.

It has been proposed that CGRP blockage may affect cerebral hemodynamics in clinical responders to mAb preventive treatment, with lower cerebral blood-flow velocity (a marker for decreased CBF) observed in this subgroup.³⁸ This suggests that clinical responders to mAbs may be at an increased risk of insufficient collateral blood flow predominantly in the event of ischemic conditions such as a stroke. Furthermore, trigeminovascular vasodilation plays an important role in acute stroke and is at least partly mediated by CGRP. It is released by trigeminal nerves in ischemic conditions and shows a protective role by interfering with the microvasculature and providing additional mitochondrial membrane stabilization with resulting antiapoptotic effects. Yet, the exact role of CGRP in acute ischemic CV events remains unclear. Other neuropeptides such as AM, which have also been found to have vasodilative and antiapoptotic effects, may compensate for CGRP's part in acute ischemic stroke.³ In light of the available evidence and expert opinion, it may be advisable to refrain from using CGRP mAbs or antagonists in patients experiencing an acute or short-term postacute stroke.

Should CGRP Targeted Treatments Be Used in People With Stroke?

This leads us to consider how we might best approach the treatment of stroke patients who are currently receiving CGRP-targeted therapies. It seems prudent to suggest that treatment with CGRP pathway mAbs or gepants should be paused immediately. After (ischemic) stroke, the reintroduction of CGRP pathway–targeted therapies may be reconsidered after a thorough evaluation of the potential benefits and harms in each individual patient. Establishing a precise time frame for discontinuing CGRP pathway–targeting drugs after stroke is challenging because poststroke remodeling is an individual and dynamic process. Motor recovery after stroke typically occurs within the first 3 months, whereas other remodeling processes can last up to 1 year.⁵⁴ Owing to the long half-life of mAbs, short-term recovery could be jeopardized. Although mAbs and gepants have not been shown to cross the BBB in significant amounts, their potential direct or indirect effects on cerebrovascular function cannot be entirely ruled out.³¹ Younger patients generally have a greater capacity for recovery, and poststroke remodeling occurs more rapidly in younger individuals, making an earlier reinitiation of mAbs or gepants potentially justifiable.⁵⁵ However, we recommend observing a minimum pause of 3 months to allow for full motor recovery. The underlying cause of the stroke should also be carefully considered because CGRP primarily exerts its vasodilative effects on small vessels and the microvasculature.⁵⁶ We recommend that patients with small vessel disease or distal/intracerebral stenosis should avoid CGRP-targeted treatments. In poststroke patients aged 65 years or older, a reinitiation of previous mAb or gepant treatment should be critically reviewed because many mAbs and gepants are not approved for use in patients aged 65–75 years or older. Especially in patients with coexisting hypertension, traditional migraine preventives such as beta-blockers or ARBs offer a safer alternative. However, if targeted CGRP pathway therapy is necessary, we recommend gepants with a shorter half-life. For acute migraine treatment, gepants could also provide a safer alternative compared with NSAIDs or triptans.⁴⁶

Should CGRP-Targeted Treatments Be Used in Patients Who Are at Risk of Stroke or Other CV Events?

Based on existing data, it can be assumed that patients aged 65 years or younger without relevant CVD will not exhibit an increased risk of stroke due to CGRP-interfering drugs per se. This assumption is based on > 10,000 patients in phase 1–3 RCTs, postmarketing studies, long-term observational studies, and large migraine registries. However, as society in industrialized countries ages, an increasing number of people with migraine will face CVD. Various tools, such as the atherosclerotic CVD (ASCVD) score, have been developed to estimate a patient's risk of experiencing a CV event within the next 10 years. This score considers factors such as age; sex; ethnicity; cholesterol levels; blood pressure; smoking status; diabetes mellitus; and current use of hypertension, statin, and aspirin therapies.

Despite these variables, determining whether a patient can safely undergo CGRP-targeted therapy cannot be conclusively answered based on the ASCVD score alone. The (patho)physiology of CGRP is complex, presenting a challenging decision-making process. Nonetheless, we agree that there are certain groups of patients who should avoid CGRP-targeted therapies, including those with small vessel disease, distal artery stenosis, and uncontrolled hypertension and patients having RP.⁴² Table 3 gives a clinical guidance based on current evidence.

Table 3.

Clinical Guidance Suggested in Patients With Acute and Postacute Stroke and Patients Facing Stroke Risk

Patient condition/scenario	Recommendation for CGRP-targeted therapy	Notes
Patients with an acute stroke or short-term postacute stroke	Pause treatment with CGRP mAbs or gepants immediately	Reconsider reintroduction after a thorough benefit-risk evaluation. Avoid during early poststroke recovery (e.g., 3 mo)
Patients with acute SAH or short-term postacute SAH	Pause treatment with CGRP mAbs or gepants immediately	Because CGRP preserves beneficial mechanism in SAH (e.g., prevention of vasospasm), the blockage of the CGRP-dependent pathway should be avoided for at least > 1 mo
Patients with stroke history	Starting CGRP-targeted treatment should be evaluated thoroughly	Especially important for patients aged 65 y or older and with stroke history. Evaluate based on patient's stroke cause (e.g., small vessel disease or stenosis)
Patients aged 65 y or younger with no significant cardiovascular disease	CGRP-targeted therapies are generally safe, with no increased stroke risk from CGRP inhibition based on current data	Safety is based on findings from large RCTs, postmarketing studies, and observational studies
Patients aged 65 y or older or those with CVD	Avoid reinitiating CGRP-targeted therapies unless benefits significantly outweigh risks. If so, consider gepants cautiously	While monoclonal antibodies are not explicitly contraindicated in many countries for patients with a history of CV events, some caution is still advised in such cases, and gepants, with their shorter half-life, may represent a safer alternative
Patients with small vessel disease or distal stenosis or RP	Avoid CGRP-targeted therapies, including both mAbs and gepants	CGRP primarily affects small vessels and microvasculature, which may exacerbate conditions such as small vessel disease or RP
Patients with a high ASCVD score	Assess CV risk carefully before continuing or initiating CGRP-targeted therapy	ASCVD score alone cannot determine safety; however, patients with an ASCVD score of <10%–20% should avoid CGRP-targeted therapy
Acute migraine treatment in patients with relevant stroke risk or poststroke patients	Gepants or ditans may be used as a safer alternative compared with NSAIDs or triptans for acute migraine	Gepants do not have a vasoconstrictive potential compared with triptans. CV safety may be superior compared with NSAIDs (and triptans)

Abbreviations: ASCVD = atherosclerotic cardiovascular disease; CGRP = calcitonin gene-related peptide; CV = cardiovascular; CVD = cardiovascular disease; mAb = monoclonal antibody; NSAID = nonsteroidal inflammatory drug; RCT = randomized controlled trial; RP = Raynaud phenomenon; SAH = subarachnoid hemorrhage.

It would be beneficial for future investigations to comprise animal and human data on a multidisciplinary level to gain a deeper understanding of the safe use of CGRP-targeting therapies. It is also important to recognize the vital role that neurologists play in diagnosing and treating migraine patients effectively over time.

Dual CGRP Blockade: An Additional Risk of Stoke Severity?

Although evidence about a dual blockade of the CGRP pathway with mAbs for preventive treatment and gepants for acute migraine treatment is scarce, increasing numbers of people with migraine have been using this kind of therapy. Because dual CGRP blockade represents the latest possibility in migraine prevention and acute treatment, only a handful of studies exist evaluating the efficacy and safety of this combination. Erenumab or galcanezumab for preventive use and ubrogepant for acute use were evaluated in an open-label label study with a follow-up of 45 days with no reported CV concerns.⁵⁷ In patients with combined use of mAbs and rimegepant or ubrogepant, no CV AEs could be collected.⁵⁸ The threshold of CGRP-induced vasodilation was elevated in the combined use of erenumab and rimegepant compared with erenumab alone.⁵⁹ This could lead to the question whether cerebral tissue in acute stroke patients with a compromised BBB is at risk of an affection of the microvasculature.²⁰ As AM and amylin also bind to the CGRP receptor family and are not further blocked by gepants, these peptides could guide as a compensatory process.⁵⁹

Conclusion

In summary, CGRP has been found to play a profound role in migraine pathogenesis but also covers beneficial tissue-protecting roles in CVD, especially in stroke. Current data of large RCTs do not suggest any elevation in stroke risk per se; however, data of people with preexisting CVD receiving CGRP-targeted treatment are scarce. As mAb preventive migraine treatment might become first-line treatment, evidence-based data of older patients (≥65 years) and people facing comorbidities need to be established. Based on current data, we suggest the following approach for 3 different scenarios:

1. In patients with acute stroke or SAH, all CGRP-targeted treatments should be paused immediately.

2. Reinitiation of CGRP-targeted treatment needs to be evaluated particularly by the patients' stroke etiology and other CV comorbidities. A treatment pause of a minimum of 3 months needs to be respected, and patients with small vessel disease should not undergo CGRP-targeted treatment.

3. In older patients with preexisting CV comorbidities, traditional migraine preventives (e.g., beta-blockers) should be preferred. If CGRP-targeted treatment is still considered, gepants should be preferred because of their shorter half-life. mAbs or gepants should not be used in patients with small vessel disease or RP at all.

Glossary

AE

adverse event

AM

adrenomedullin

ASCVD

atherosclerotic CVD

BBB

blood-brain barrier

CGRP

calcitonin gene-related peptide

CLR

calcitonin receptor-like receptor

CV

cardiovascular

CDV

CV disease

mAb

monoclonal antibody

NSAID

nonsteroidal anti-inflammatory drug

RAMP1

receptor activity-modifying protein 1

RCT

randomized clinical trial

RCVS

reversible cerebral vasoconstriction syndrome

RP

Raynaud phenomenon

SAH

subarachnoid hemorrhage

Author Contributions

M.T. Eller: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. K. Schwarzová: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design. L. Gufler: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design. A. Karisik: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design. K. Kaltseis: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. F. Frank: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. G. Broessner: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design.

Study Funding

No targeted funding reported.

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.