Migraine With Aura Linked to Increased Mortality From Stroke and Heart Disease

Migraine, particularly migraine with aura, is associated with an increased risk for death from cardiovascular disease and hemorrhagic stroke, according to the findings of 2 large prospective cohort studies.But, the researchers emphasize, the individual risk for those with migraine is low. The reports, which add more weight to previous data suggesting this link, were published online August 25 in the BMJ.

Reykjavik Study

In the first study, Larus S. Gudmundsson, a doctoral student from the University of Iceland in Reykjavik, and colleagues assessed the impact of midlife migraine episodes in 18,725 men and women born between 1907 and 1935.

The study cohort was part of the Reykjavik Study, which was started in 1967 by the Icelandic Heart Association to prospectively study cardiovascular disease in Iceland. Participants were followed up for up to 40 years, until the end of 2007. The median follow-up was 25.9 years. In total, the researchers assessed 470,990 person-years of data and used questionnaires to assess migraine with and without aura.

Overall, there were 10,358 deaths, 4323 from cardiovascular disease and 6035 from other causes.

After adjusting for baseline risk factors, age, and sex, the study found that people with migraine with aura were at increased risk for all-cause mortality and mortality from cardiovascular disease compared with people with no headache. No increased risk was found for people with migraine without aura and people with nonmigraine headache.

A closer look at death from cardiovascular disease revealed that people with migraine with aura were at increased risk for mortality from coronary heart disease and stroke.

Table. Mortality Risk for Migraine With Aura vs No Headache

CI = confidence interval

The study also showed that women with migraine with aura were at increased risk for mortality from noncardiovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.06 – 1.35).

Explaining the clinical significance of the findings, Gudmundsson told Medscape Medical News, “Although our study shows that migraine and in particular migraine with aura is an independent risk factor for all-cause and cardiovascular disease mortality, the risk is low compared to conventional modifiable risk factors, such as smoking, adverse blood lipid profile, and hypertension. Having migraine with aura should be an additional reason for monitoring your modifiable risk factors and keeping them in check, and this applies to both men and women.”

He added that future studies will determine whether reducing migraine or aura frequency with medication or other interventions will lower the risk for cardiovascular disease in these individuals.

Women’s Health Study

In the second study, Tobias Kurth, MD, from Harvard Medical School, Boston, Massachusetts, and colleagues, used data from the Women’s Health Study to examine the association between migraine and migraine with aura and the risk for hemorrhagic stroke.

The study included 27,860 women 45 years or older who were free from stroke or other major disease at study entry. The women were asked about migraine headaches with and without aura on questionnaires.

Overall, 5130 women (18%) reported having a history of migraine. Of this number, 3612 reported having a migraine in the previous year and were classified as having active migraine, and 40% of the women with active migraine reported having migraine with aura.

During a mean of 13.6 years of follow-up (377,711 patient years), 85 confirmed hemorrhagic strokes occurred.

The study showed that, compared with women with no history of migraine, the women with active migraine with aura had more than twice the risk for hemorrhagic stroke (adjusted hazard ratio, 2.25; 95% confidence interval, 1.11 – 4.54; P = .024).

The study authors add that 4 additional hemorrhagic stroke events were attributable to migraine with aura per 10,000 women per year. Women who reported active migraine without aura or migraine in the more distant past had no increased risk for hemorrhagic stroke.

“It is very important to understand that, although we see this link and the relative risk measure indicates about a 2-fold increased risk, that the risk for an individual woman with migraine with aura is considerably low,” Dr. Kurth told Medscape Medical News. “So even if we have this link, having a woman with migraine with aura in front of us will not allow us to tell whether this specific woman has a very high risk of hemorrhagic stroke or not.”

Dr. Kurth added that until more is known about whether different treatments of migraine would lead to a reduced risk, traditional risk factors for stroke, such as hypertension and smoking, should be addressed.

“I’m not saying you should not worry about hemorrhagic stroke; it could still happen, but it is very, very difficult to say you are the one who is going to get it,” he stressed. “Rather, these results reemphasize the need to modify traditional risk factors, so if you have increased blood pressure, lower it; if you smoke, stop smoking.”

Expert Diagnosis of Aura

In an accompanying editorial, Klaus Berger, MD, from the University of Muenster, and Stefan Evers, from University Hospital Muenster, in Germany, stress the importance of distinguishing whether aura is actually present in a patient with migraine and suggest that this should be done by an expert.

But once the diagnosis is made, the next question is whether the clinician should inform the patient about the increased risk.

“For many people the information will cause an unwarranted amount of anxiety, although others may use the opportunity to modify their lifestyle and risk factors accordingly,” they write. “Future research will have to assess whether prophylactic drug treatment of migraine not only reduces the number and severity of migraine attacks but also reduces subsequent cardiovascular and cerebrovascular events.

“However,” they conclude, “because this will require long follow-up, in the meantime clinicians must carefully weigh the decision whether or not to discuss the risks related to this condition.”

Link With Hemorrhagic Stroke Surprising

Asked to comment on these studies, Tudor Jovin, MD, from University of Pittsburgh Medical Center in Pennsylvania, told Medscape Medical News that the association between hemorrhagic stroke and migraine with aura was surprising.

“The number of events in this large group of individuals is actually very low,” he said. “Certainly, the signals are all there that there may be an association but I think that needs to be confirmed, and the association is not that strong.”

Dr. Jovin agrees that patients should not be alarmed. Instead, clinicians should urge them to control modifiable risk factors.

“I don’t think that migraineurs should now rush to the emergency department and seek to be checked out for signs of stroke. But people with migraine should be more careful about controlling the risk factors that they can do something about,” he said. “There is probably a genetic predisposition to migraine with aura, and this can make things worse, but there are much more potent risk factors that we can influence, such as blood pressure control, cholesterol control, quitting smoking, diabetes control, and lifestyle changes, so for these people we should step up efforts to control these modifiable risk factors.”

Dr. Jovin added that migraine, and particularly migraine with aura, is a very complex disease. “We have a poor understanding of it, but it is very clear that migraine does not mean just a headache, whether it is with or without aura. Probably, migraine with aura is more complex in the spectrum of migraine, and it is most likely a systemic disease; it affects other vessels in the brain and the body in ways that we still need to learn a lot about. These 2 studies are a step in the right direction.”

Weighing in with her opinion, Sheena Aurora, MD, director of the Swedish Headache Center, Swedish Medical Center, Seattle, Washington, and a spokesperson for the American Academy of Neurology, commented that these studies continue to show the risk for increased vascular mortality associated with migraine with aura.

Dr. Aurora, who herself has migraines, said she would tell her patients to take care of their vascular risk profile, particularly if they have migraine with aura.

“I would say that you really need to try and control other contributors that increase vascular risk, particularly those that are in your control, like cigarette smoking and exercise, eating right, controlling cholesterol and blood pressure. I talk to patients like that because this is something tangible that they can do,” she added. “These patients often have anxiety and depression, and the cardiovascular risk profile is known to be higher in these people, so it is important not to alarm patients.”

Dr. Gudmundsson, Dr. Berger, Dr. Evers, Dr. Jovin, and Dr. Aurora have disclosed no relevant financial relationships. Dr. Kurth  has received funding from the French National Research Agency, the National Institutes of Health, Merck, and the Migraine Research Foundation and a consultant to i3 Drug Safety and World Health Information Science Consultants.

BMJ. Published online August 25, 2010.

Guidelines on diagnosis and management of headache issued in 2008 are available online

Clinical Context

Study Highlights

• Gudmundsson and colleagues
  • 18,725 subjects (9044 men and 968 women) born in 1907 to 1935 were enrolled.
  • Questionnaires and measures were completed at a mean age of 53 years (age range, 33 – 81 years).
  • Median follow-up period was 25.9 years.
  • Categories were no headache (headache < once a month), migraine without aura, migraine with aura, and nonmigraine.
  • 2023 participants (11%) reported migraines: 3% without aura and 8% with aura.
  • The main outcome measures were mortality from cardiovascular disease, noncardiovascular disease, and all causes.
  • 10,358 deaths occurred: 4323 from cardiovascular disease and 6035 from other causes.
  • Cardiovascular deaths included 2810 from coronary heart disease, 927 from stroke, and 586 from other forms of cardiovascular disease.
  • Analysis adjusted for sex, age, body mass index, education, smoking, and blood pressure.
  • Migraine headache vs no headache was linked with an increased risk for all-cause mortality (HR, 1.15) and cardiovascular mortality (HR, 1.22), specifically death from coronary heart disease (HR, 1.22).
  • Migraine with aura vs no headache was linked with an increased risk for all-cause mortality (HR, 1.21) and cardiovascular disease mortality (HR, 1.27).
  • Migraine with aura was also linked with a greater risk for mortality from coronary heart disease (HR, 1.28).and stroke (HR, 1.40).
  • Women with migraine with aura had an increased risk for noncardiovascular disease mortality (HR, 1.19).
  • Migraine without aura and nonmigraine headache vs no headache were not linked with the risk for all-cause mortality or cardiovascular disease mortality.
  • Study limitations included no adjustment for vascular risk factors that might have developed later and lack of data on migraine treatment in use.
• Kurth and colleagues
  • In the Women’s Health Study, 39,876 female health professionals 45 years or older were randomly assigned to receive aspirin, vitamin E, both aspirin and vitamin E, or neither.
  • Eligibility criteria were no cardiovascular disease, cancer, or other major illnesses.
  • Women self-reported cardiovascular risk factors and variables at baseline, twice in the first year, and then annually.
  • Mean follow-up was 13.6 years.
  • 27,860 women reported migraine information.
  • 5130 (18%) had any history of migraine.
  • Of 3612 with active migraine in the previous year, 1435 (40%) reported an aura.
  • The main outcome measures were time to first hemorrhagic stroke and subtypes of hemorrhagic stroke.
  • Nonfatal stroke was defined as a new focal neurologic deficit of sudden onset that was attributed to a cerebrovascular event lasting for more than 24 hours.
  • Fatal stroke was confirmed by death certificate, hospital records, or relatives.
  • Stroke subtypes were assessed by clinical information and brain imaging studies.
  • Hemorrhagic stroke occurred in 85 women: 44 had intracerebral hemorrhages, 36 had subarachnoid hemorrhages, and 5 had unclear subtype.
  • The age-adjusted incidence of hemorrhagic stroke per 10,000 women per year was 6.3 for active migraine with aura, 2.5 for any migraine history, 2.3 for no migraine, 1.3 for previous migraine, and 0.8 for active migraine without aura.
  • Multivariable analysis adjusted for age, hypertension, smoking, body mass index, alcohol intake, and total cholesterol level.
  • Women with active migraine with aura vs those with no migraine history had an increased risk for hemorrhagic stroke (adjusted hazard ratio [HR], 2.25).
  • The age-adjusted risk for hemorrhagic stroke was higher for intracerebral vs subarachnoid hemorrhage (adjusted HR, 2.78) and for fatal vs nonfatal events (adjusted HR, 3.56).
  • Active migraine without aura and previous migraine were not linked with the risk for hemorrhagic stroke.
  • Study limitations included the low number of events and the need for confirmatory studies.

Clinical Implications

• According to the Gudmundsson study, men and women with migraine with aura have an increased risk for cardiovascular and all-cause mortality.
• According to the prospective

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