8 August, 2016: 

Long ago it was perceived that migraineurs have a higher risk for ischemic stroke, mainly because of short-term pro-thrombotic alterations during attacks [1, 2]. Migraine with aura confers a lifelong 2–2.5-fold elevated risk of stroke. Frequency of migraine directly correlates with higher stroke risk, but only minimal evidence supports reducing migraine frequency with medications to reduce stroke risk. Women suffering from migraine with aura who smoke have a 9-fold increased risk of stroke. There are several potential mechanisms for the increased risk of ischemic stroke in migraineurs. Migraine may increase ischemic stroke risk via vasospasm-induced cerebrovascular hypoperfusion, platelet activation, increased platelet aggregation, and increased concentrations and activity of various vascular pro-coagulant factors. Still, the absolute risk of migraine-associated stroke in women is relatively low.

In the Women's Health Study (prospective, n = 27,840, age 45 or older, mean age 54, mean follow-up 10 years) [3], the multivariable-adjusted hazard ratio for ischemic stroke among women suffering from migraine with aura was 1.91 (95% CI 1.17–3.10; p = 0.01). However, in terms of absolute risk, there were four additional ischemic stroke cases per 10,000 women per year when migraine with aura was the assumed underlying cause of stroke. In contrast, women who reported active migraine without aura did not have significantly increased risk for any ischemic vascular event. The Women's Health Study addressed a range of other cardiovascular events as well [3]. After adjusting for age, there were 18 additional major cardiovascular events attributable to migraine with aura per 10,000 women per year. Women who reported active migraine with aura had multivariable-adjusted hazard ratios of 2.15 (95% CI 1.58–2.92; p < 0.001) for major cardiovascular disease, 2.08 (95% CI 1.30–3.31; p = 0.002) for myocardial infarction, 1.74 (95% CI 1.23–2.46; p = 0.002) for coronary revascularization, 1.71 (95% CI 1.16–2.53; p = 0.007) for angina, and 2.33 (95% CI 1.21–4.51; p = 0.01) for ischemic cardiovascular death.

A recent publication of data from the Nurses' Health Study II demonstrated similar trends [4]. This large, prospective cohort study of 115,541 female nurses, aged 25–42 years at inclusion, recruited women who were free of cardiovascular disease at baseline. In the current analysis, 17,531 (15.2%) women reported a physician's diagnosis of migraine. Over 20 years of follow-up, 1329 major cardiovascular disease events occurred and 223 women died from cardiovascular disease. After adjustment for potential confounding factors, migraine was associated with an increased risk for major cardiovascular disease (hazard ratio (HR) 1.50; 95% CI 1.33–1.69), myocardial infarction (HR 1.39; 95% CI 1.18–1.64), stroke (HR 1.62; 95% CI 1.37–1.92), and angina/coronary revascularization procedures (HR 1.73; 95% CI 1.29–2.32), compared with women without migraine. Furthermore, migraine was associated with a significantly increased risk for cardiovascular disease mortality (HR 1.37; 95% CI 1.02–1.83). Associations were similar across subgroups of women, including by age (< 50/≥ 50), smoking status (current/past/never), hypertension (yes/no), postmenopausal hormone therapy (current/not current), and oral contraceptive use (current/not current).

It seems that the association of migraine with ischemic stroke is more robust than that with cardiovascular events in general. As always in medicine, the biology behind this association is very complex. Several studies, including the Nurses' Health Study [4], showed that women with migraine also have a higher prevalence of vascular risk factors, such as hypertension, higher body mass index, and hypercholesterolemia. The Nurses' Health Study investigators concluded that no clear mechanisms have been identified that could explain the increased risk of cardiovascular disease and mortality among patients with migraine, and no data exist on whether prevention of migraine attacks reduces these risks. Nevertheless, existing data support consideration of a history of migraine as a marker for increased risk of any cardiovascular disease event. A recent review in the Medical Clinics of North America includes migraine in young women as a potential risk factor for future vascular thrombosis [5]. Women with frequent migraines should be evaluated for other cardiovascular risk factors, and risk reduction strategies should be implemented whenever appropriate. When postmenopausal hormone replacement (HT) is considered, and in view of the higher risk for stroke related to HT, especially in women with migraine and aura, perhaps the lower effective doses and the less thrombogenic hormonal preparations, i.e. transdermal estrogen, should be preferred.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1.  Spector JT, Kahn SR, Jones MR, et al: Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med 2010;123:612-24
   http://www.ncbi.nlm.nih.gov/pubmed/20493462
2. Kurth T, Diener HC. Migraine and stroke: perspectives for stroke physicians. Stroke 2012;43:3421–26
   http://www.ncbi.nlm.nih.gov/pubmed/22996957
3. Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE. Migraine and risk of cardiovascular disease in women. JAMA 2006;296:283-91
   http://www.ncbi.nlm.nih.gov/pubmed/16849661
4. Kurth T, Winter AC, Eliassen AH, et al. Migraine and risk of cardiovascular disease in women: prospective cohort study. BMJ 2016;353:i2610
   http://www.ncbi.nlm.nih.gov/pubmed/27247281
5. Gill SK. Cardiovascular risk factors and disease in women. Med Clin North Am 2015;99:535-52
   http://www.ncbi.nlm.nih.gov/pubmed/25841599