Migraine With Aura Doesn’t Hone CV Risk Prediction in Middle-aged Women

Adding migraine with aura to the mix doesn’t do much to improve standard scores for estimating CV risk in women, a new analysis suggests.

These severe headaches have a known association with cardiovascular disease that’s independent of other traditional risk factors, Pamela M. Rist, ScD (Brigham and Women’s Hospital, Boston, MA), and colleagues point out in a paper published online ahead of the June 13, 2023, issue of the Journal of the American College of Cardiology.

And similarly in their study, after adjustment for covariables in the Reynolds Risk Score and the American Heart Association/American College of Cardiology (AHA/ACC) pooled cohort equations, women who reported having migraines with aura were twice as likely to have a CVD-related event over the next decade as those who either had migraines without aura or had no migraines at all.

Even so, adding this risk factor to the tools did not help them go above and beyond their existing performance—perhaps because migraine with aura is relatively rare compared with things like high cholesterol and blood pressure, the investigators suggest.

Rist told TCTMD that, going into their analysis, they were on the fence as to what they’d find. Earlier research aimed at improving upon CV risk scores had demonstrated how hard that process can be.

“Those risk scores, they do have advantages, and it has been tricky to beat those risk scores. There’s a reason that they’ve been used for so long. So we actually weren’t sure: we knew that migraine was a strong risk factor, at least risk marker, but we weren’t sure if adding it would actually improve risk stratification on that population level, which is what these algorithms do,” she explained.

Those risk scores, they do have advantages, and it has been tricky to beat those risk scores. Pamela M. Rist

Dave L. Dixon, PharmD (Virginia Commonwealth University, Richmond), a member of the ACC’s Prevention of Cardiovascular Disease Council, agreed that this study mainly relates to the risk calculators themselves, not one-on-one interactions with patients. He suggested it may well be that migraine with aura is akin to the risk-enhancing factors listed in the 2018 cholesterol guidelines. “These are factors that are not included in the risk calculators for various reasons. But they’re certainly indicators of risk that we want to assess,” he noted, citing preeclampsia in women as an example.

Understanding the pathological mechanisms whereby migraine is linked to higher CV risk will be helpful, said Dixon, especially given that these headaches are more prevalent in women versus men, and that cardiovascular disease is often underrecognized in female patients.

Dixon said it’s useful to look at CV risk assessment at a population level as the researchers did here. “But at the end of the day, in day-to-day practice, it’s about the individual patient in front of you,” he commented. “This is where these risk calculators can be great to start conversations with patients, but they shouldn’t overrule clinical judgement.”

Women’s Health Study

For their analysis, the researchers turned to the Women’s Health Study for data, identifying 24,493 women (average age around 54 years) with self-reported migraine status. Among them, 5.1% reported migraines with aura at baseline; these individuals tended to be slightly younger and were more apt to have a family history of MI, higher C-reactive protein values, and no history of diabetes.

Over a median follow-up of 10.2 years, women who had migraine with aura experienced 45 CVD events (20 strokes, 17 MIs, and eight CVD deaths) and those without these headaches experienced 524 events (259 strokes, 197 MIs, and 68 CVD deaths).

Migraine with aura was linked to higher risk of incident CVD, whether calculated by accounting for covariables in the Reynolds Risk Score (HR 2.09; 95% CI 1.54-2.84) or those in the AHA/ACC pooled cohort equations (HR 2.10; 95% CI 1.55-2.85).

C-index improved when including migraine with aura in the Reynolds Risk Score model (from 0.792 to 0.797; P = 0.02) and the AHA/ACC score model (from 0.793 to 0.798; P = 0.01). There also were small but statistically significant gains in integrated discrimination improvement (IDI), but no changes in net reclassification improvement (NRI).

“Adding information on migraine with aura status to commonly used CVD risk prediction algorithms enhanced model fit but did not substantially improve risk stratification among women,” the authors conclude. “Despite the strong association of migraine with CVD risk, the relatively low prevalence of migraine with aura compared with other CV risk factors limits its usefulness in improving risk classification at the population level.”

Still, on an individual level, it would make sense to ask at least some patients—particularly women under age 45—about migraine status, as this analysis used data from the Women’s Health Study to reach its conclusions, Rist noted.

“So I wouldn’t necessarily exclude migraine as something to ask about if I had a younger woman in front of me. That was a question we weren’t able to answer here,” she said, pointing out that the link between migraine and stroke is stronger in this subgroup. Also ripe for research is whether there are sex differences.

“Another issue for us,” Rist added, “is that we used a coarser classification of migraine with aura: you either have it or you don’t.” It’s still to be determined whether the various migraine features would show differential effects when added to risk calculators.

And finally, it will be important to see if their current findings are “replicated in other populations, in more diverse settings. Hopefully, we’ll be able to look at that more in the future, to make a more-definitive statement on what people should be doing” in a clinical setting, she said.

Risk calculators can be great to start conversations with patients, but they shouldn’t overrule clinical judgement. Dave L. Dixon

Angela A. Stanton, PhD (Stanton Migraine Protocol Inc, Anaheim, CA), in an editorial accompanying the study, opens the door to the idea that there’s much left to be learned about what characteristics truly drive CVD risk and emphasizes the need to separate causation from association.

The finding that migraine with aura didn’t improve net reclassification, she writes, “is surprising, but the silver lining of this negative finding seemingly is that we can cross it off the list of risk factors that can predict CVD. Or can we?”

Like the authors, she notes that migraines aren’t monolithic. “Understanding the differences between migraine with aura and migraine without aura, and recognizing the underlying physiological differences that may be driving factors for CVD, would be important for better predictive models,” says Stanton. “There is no clear definition of what an aura is, how long it lasts, and if a headache starts during the aura or only after. And what to do with the cases when a headache does not follow the aura at all?”

But perhaps even more importantly, Stanton argues, the models for CV risk prediction may be flawed by being based on factors that are merely associated with CVD. Layering further variables on top of these will continue to magnify the underlying errors, she explains. “Looking at the literature for both migraine research and CVD, proper evaluations clearly have not always been done, which has a ripple effect on scientific studies using such ‘trusted’ predictors without factual proof that they had truly met the requirements when they were added to the risk prediction model.”

With this backdrop, the seemingly negative study by Rist et al is valuable, Stanton agrees. “There is gold in not finding what one is looking for, and publication of these results should be encouraged. They can help clear the field of the many distorted correlations treated as causal predictors.”