By Dara G. Jamieson, MD
Synopsis: The presence of traditional vascular risk factors does not explain the increased incidence of ischemic stroke and myocardial infarction in patients with migraine. The use of nonsteroidal anti-inflammatory drugs does not increase the risk of ischemic stroke or myocardial infarction in migraineurs.
Sources: Bonnesen K, Fuglsang CH, Schmidt M. Impact of nonsteroidal anti-inflammatory drug use on the migraine-associated risk of myocardial infarction and ischemic stroke: A population-based cohort study. Neurology. 2024;103(12):e210034.
Al-Hassany L, Acarsoy C, Ikram MK, et al. Sex-specific association of cardiovascular risk factors with migraine: The population-based Rotterdam Study. Neurology. 2024;103(4):e209700.
Bonnesen et al acknowledged that migraine, a debilitating primary headache disorder that affects about 1 billion people worldwide, increases the risk of myocardial infarction and ischemic stroke. However, Al-Hassany et al, in a cohort study of vascular risk factors in 1,085 middle-aged and older adult participants with migraine from Rotterdam, concluded that despite the established link between migraine and cardiovascular events, in our current study, most traditional cardiovascular risk factors are not associated with an increased migraine prevalence in middle-aged and older adult participants. Only an elevated diastolic blood pressure was associated with a higher migraine prevalence in older females.
The link between migraine and an increase in vascular risk is complicated and multifactorial, deviating from the traditional vascular risk factors of current smoking, obesity, hypercholesterolemia, hypertension, and diabetes mellitus. In an effort to explain this association, other potential vascular risk factors have been explored. Bonnesen et al noted that nonsteroidal anti-inflammatory drugs (NSAIDs) are a first-line treatment for acute migraine. They are associated with a lower risk of medication-overuse headache, as compared to other acute migraine treatments (e.g., opioids, barbiturates, or triptans). However, Bonnesen et al reported that NSAIDs may be associated with an increase in vascular risk. The authors considered whether NSAIDs could factor in the established vascular risk associated with migraine. This study from Denmark examined the risk of myocardial infarction and ischemic stroke associated with migraine, as a function of the migraineur’s long-term use of NSAIDs.
This population-based matched cohort study was based on prospectively and routinely collected data from nationwide Danish health registries. The data were accumulated from 1995 through 2021. Migraine cohorts had a hospital diagnosis of migraine (n = 46,647) or two filled prescriptions for migraine medication as primary care-diagnosed migraine (n = 288,529).
Each individual with migraine was randomly matched with four individuals from the general population based on age and sex. Incident events of fatal or nonfatal myocardial infarction and ischemic stroke were identified from first-time primary or secondary inpatient diagnoses in the Danish National Patient Registry.
The study results confirmed the known association of migraine with vascular events, without indicating a link to NSAID use in patients with migraine. Hospital-diagnosed migraine was associated with a higher incidence rate of myocardial infarction and ischemic stroke. The 20-year risk of myocardial infarction was 3.3% for hospital-diagnosed migraine (controls, 2.2%) and 2.6% for primary care-diagnosed migraine (controls, 2.6%). The 20-year risk of ischemic stroke was 4.5% for hospital-diagnosed migraine (controls, 2.4%) and 3.0% for primary care-diagnosed migraine (controls, 2.9%).
The increased risk of ischemic stroke in individuals with hospital-diagnosed migraine seemed higher during time without NSAID use (adjusted hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.82-2.13) than with NSAID use (adjusted HR, 1.49; 95% CI, 1.13-1.97). Primary care-diagnosed migraine was not associated with an increased risk of myocardial infarction or ischemic stroke as compared with the general population comparisons, independent of NSAID use.
Bonnesen et al found that, over a 20-year period of observation, hospital-diagnosed migraine was associated with an increased risk of myocardial infarction and ischemic stroke regardless of NSAID use. The increased risk of myocardial infarction did not change as a function of NSAID use. The risk of ischemic stroke seemed higher during the time without NSAID use than with NSAID use. The conclusion of the cohort study was that NSAID-associated vascular risk could not explain the observed increased risks of myocardial infarction and ischemic stroke associated with migraine.
Commentary
Attributing the increased vascular risk of migraine to the use of NSAIDs simplifies the pathophysiology of a complex disease with both cerebrovascular (i.e., brain) and cardiovascular (i.e., heart) involvement. Since the two studies noted earlier examined the risk of ischemic stroke, the shared risk factors should be described as vascular since they are not only heart-related risk factors. An imprecise description of risk factors is one of the multiple criticisms of the Danish cohort study.
The study of the use of NSAIDs conflates two disparate ischemic events in different vascular territories. Assuming that all vascular risk factors are interchangeable, equally assigning them to ischemic stroke and myocardial infarction ignores the non-traditional vascular risk factors (e.g., dissection, vasculitis, embolization) that are more commonly associated with ischemic stroke than with myocardial infarction. I believe that the mechanisms and risk factors associated with an ischemic stroke are more complex and diverse than those associated with myocardial infarction.
Migraines with and without aura are known to have different vascular risks. Cerebrovascular and cardiovascular risk are assigned to migraine with aura, as opposed to migraine without aura, which has significantly less vascular risk. Since the focal neurological deficits of an aura may lead to hospitalization because of concern about a cerebrovascular event, the increased vascular risk attributed to hospital-diagnosed migraine may be the result of an increased incidence of migraine with aura in the hospitalized cohort.
In the analysis of NSAID data, Bonnesen et al makes the incorrect assumption that the cardiovascular and the cerebrovascular risks of NSAIDs are the same. An increased risk of ischemic stroke with the use of NSAIDs has not been established. The single reference cited by Bonnesen et al to support the premise that there is an increased cerebrovascular risk with NSAIDs found that there was no evidence that any NSAID significantly increased the risk of stroke.1 The meta-analysis found no significant increase in the risk of ischemic stroke for any of the specific NSAIDs studied, including selective COX-2 inhibitors, diclofenac, ibuprofen, and naproxen.
The Coxib and traditional NSAID Trialists’ Collaboration also concluded that there was a different degree of cardiovascular risk with specific NSAIDs. Bonnesen et al combined all NSAIDs in assessing their myocardial infarction risk in migraine. The lack of individual analysis of these medications may conceal cardiovascular risk associated with specific NSAIDs with different mechanisms of action.
The vascular risk associated with migraine with aura has been recognized for decades. However, our understanding of the mechanisms that explain this association has been elusive. Migraine is more than just a headache. Some of the processes involved in migraine pathophysiology have been revealed over time; however, migraine’s association with vascular events is not the result of a single, easily identifiable mechanism. Both ischemic stroke and migraine are too complicated to be linked by a simple hypothesis. There are many more puzzle pieces yet to be discovered.
Dara G. Jamieson, MD, is Clinical Associate Professor of Neurology, Weill Cornell Medical College.
Reference
- Coxib and traditional NSAID Trialists (CNT) Collaboration; Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769-779.