A new real-world study published in the Journal of Neurology by Alessia Bellotti of the Neurocenter of Southern Switzerland and colleagues now offers some of the most direct long-term evidence to date. Drawing on a prospective registry of migraine patients treated at a tertiary Headache Centre, the team identified every patient treated with CGRP pathway inhibitors who also carried a documented history of ischemic stroke, transient cerebral ischemic attack, or ischemic heart disease. Out of 420 consecutive patients in the registry, 17 individuals, roughly 4 percent, met these criteria and formed the study cohort. The number is small, but the clinical stakes are not, because each of these patients represents the exact scenario in which prescribing decisions have historically been made with the least data and the greatest uncertainty.

The biology behind the concern is worth unpacking. CGRP is not exclusively a migraine molecule; it is a potent vasodilator and neuropeptide distributed throughout the peripheral and central nervous systems, including the cerebral and coronary vasculature. Under physiological conditions it contributes to the regulation of vascular tone, and experimental work has suggested that CGRP may even play a protective role during cerebral ischemia and reperfusion injury. Blocking this pathway with a monoclonal antibody or a receptor antagonist could, in theory, blunt these protective mechanisms, particularly in vessels already compromised by atherosclerosis or prior infarction. This theoretical risk is amplified in patients whose brains have already demonstrated vulnerability to ischemia, since recurrent stroke carries a substantial cumulative risk, and cardiovascular guidelines emphasize aggressive secondary prevention in exactly this group.

Epidemiology deepens the dilemma rather than resolving it. Large prospective cohort studies have shown that migraine, particularly migraine with aura, is associated with an elevated risk of ischemic stroke in middle-aged and elderly populations, and neuroimaging research has linked migraine to deep white matter lesions and subclinical posterior circulation infarcts. Genetic studies reinforce the connection between migraine and stroke biology. In other words, the migraine patients most likely to have suffered a prior vascular event are not an incidental subgroup; they are the population in whom the migraine-vascular relationship is most pronounced. Denying them the most effective preventive therapies available would leave them exposed to the disabling consequences of chronic migraine, while prescribing without safety data would constitute an uncontrolled experiment. The Swiss registry study was designed to begin filling precisely this evidentiary gap.

The cohort itself reflects the clinical reality of severe, treatment-resistant migraine. The 17 patients had a median age of 54.5 years, 76 percent were women, and 82 percent suffered from chronic migraine, the most disabling form of the disorder, defined by headache on 15 or more days per month. The group accumulated a total of 31 patient-years of exposure to CGRP pathway inhibitors, with individual follow-up extending up to five years. Importantly, the median interval between the original ischemic event and the start of CGRP-targeted treatment was 5.0 years, with an interquartile range of 4.5 years, meaning that most patients were not treated in the immediate aftermath of a stroke or cardiac event but at a point when their vascular disease had been medically stabilized.

The efficacy findings were striking. Thirteen of the 17 patients, 76 percent, achieved a reduction of at least 50 percent in their monthly migraine days, a threshold widely regarded as a clinically meaningful response. Among the 14 patients with chronic migraine, 10 reached this benchmark, and remarkably, all three patients with episodic migraine did so as well. These response rates compare favorably with those reported in broader real-world cohorts of migraine patients without vascular comorbidity, suggesting that a history of stroke or ischemic heart disease does not blunt the therapeutic benefit of CGRP blockade. For patients who had often exhausted multiple conventional preventives, the magnitude of improvement represents a transformation in daily functioning and quality of life.

On the safety side, the results were equally notable for what the investigators did not find. Across the entire follow-up period, no recurrent cerebrovascular events were observed, and no worsening of underlying cardiac disease was documented. In a subset of patients, serial neuroimaging was performed, and dedicated neuroradiological assessment revealed no new ischemic lesions. This combination of clinical and radiological surveillance is significant, because silent ischemic lesions can occur without overt symptoms, and their absence on imaging provides a more sensitive measure of cerebrovascular integrity than clinical history alone. The involvement of a dedicated neuroradiologist, who assessed ischemic lesions using specialized software, adds technical rigor to the imaging component of the study.

The authors are careful, and rightly so, to frame these findings as exploratory and hypothesis-generating rather than definitive. Seventeen patients and 31 patient-years of exposure cannot exclude a modest increase in vascular risk, and the absence of a control group means that the background rate of recurrent events in comparable untreated patients cannot be formally compared. Registry data from a single tertiary center may also be subject to selection effects, since patients considered for CGRP therapy after a stroke are likely to have been judged clinically stable by their treating physicians. Nevertheless, the study aligns with a growing body of real-world evidence, including multicenter safety evaluations of CGRP-targeting antibodies in patients with comorbidities excluded from trials, analyses of cardiovascular safety in older adults, and large pharmacoepidemiological studies examining cardiovascular events among migraine patients exposed to these drugs.

The report also touches on one of the most debated corner cases in the field: CADASIL, a hereditary small-vessel disease characterized by subcortical infarcts and leukoencephalopathy, in which CGRP has been hypothesized to play a protective vascular role. The Swiss registry included a CADASIL case among its patients, and prior case reports have described long-term treatment with the receptor antagonist erenumab in CADASIL without apparent harm, even as commentators have warned about the potential danger of blocking CGRP in such patients. By contributing longitudinal, imaging-verified data from this rare and theoretically highest-risk scenario, the study adds a valuable data point to an ongoing conversation about whether CGRP inhibition is safe in small-vessel cerebrovascular disease.

For clinicians, the practical message is one of cautious reassurance. In patients with prior ischemic stroke, transient ischemic attack, or ischemic heart disease whose vascular disease is stable, CGRP pathway inhibitors appear, on current real-world evidence, to deliver their expected efficacy without detectable clinical or radiological ischemic consequences over follow-up periods of up to five years. This does not eliminate the need for individualized risk assessment, coordination with vascular specialists, and continued surveillance, particularly in the early years after an ischemic event, where the evidence remains sparse. But it does shift the default conversation from whether these drugs can be used at all to how best to monitor them. For the large population of migraine patients living with the dual burden of severe headache and established vascular disease, that shift, however incremental, is genuinely good news, and it underscores the value of prospective registries in answering the safety questions that randomized trials were never designed to address.

Subject of Research: Long-term cerebrovascular and cardiovascular safety of CGRP pathway inhibitors in migraine patients with prior ischemic events

Article Title: Long-term safety of CGRP pathway inhibitors in migraine patients with prior cerebrovascular or cardiovascular disease

Article References: Long-term safety of CGRP pathway inhibitors in migraine patients with prior cerebrovascular or cardiovascular disease. (n.d.). https://doi.org/10.1007/s00415-026-14099-z

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14099-z

Keywords: CGRP, migraine, stroke, ischemic heart disease, monoclonal antibodies, cerebrovascular safety, CADASIL, real-world registry, neuroimaging, preventive treatment, transient ischemic attack, Journal of Neurology