Migraine prophylaxis may increase CV, cerebrovascular, and mortality risks

Liz Meszaros, MDLinx | June 25, 2019

Migraine prophylaxis may be associated with increased risk for several negative outcomes—including cardiovascular events, cerebrovascular events, and death—but underlying conditions may play a role in their origin and progression as well, according to results from a recent study published in Cephalalgia.


Exposure to anticonvulsants, SNRIs, beta blockers, antihypertensives, tricyclic antidepressants, and other prophylactic treatments was associated with increased risks of cardiovascular and cerebrovascular events, and mortality.

The study researchers added, however, that most of the prophylactic treatments they assessed were likely markers for risk factors that developed and progressed independently of prophylactic migraine treatment, and stressed that clinicians consider other factors—including migraine severity, frequency, and other treatment indications—when assessing safety in these patients.

“Migraine is associated with the development of cardiovascular and cerebrovascular diseases, particularly among young women with migraine with aura. More frequent migraines may be associated with increased risk of ischemic stroke in women. Associations between migraine and mortality due to cardiovascular and cerebrovascular or other causes have also been observed. The risk of these outcomes among patients with migraines who use prophylactic treatments to reduce migraine frequency and severity is unclear,” noted the authors, led by Veena Hoffman, Optum Epidemiology, Ann Arbor, MI.

Prophylactic treatments such as topiramate, valproate, valproic acid, beta blockers, calcium channel blockers, tricyclic antidepressants, and botulinum toxics have multiple primary indications, but are frequently used in patients with migraine.

To assess the risk of cardiovascular events, cerebrovascular events, and mortality in migraineurs treated with these agents, Hoffman et al used administrative claims data to identify 119,243 patients aged 18 to 65 years (mean age: 42 years; 82.2% female) with migraine.

Prophylactic treatments included the following:

  • Anticonvulsants: valproate, valproic acid, divalproex, pregabalin, gabapentin, levetiracetam, zonisamide, and carbamazepine
  • Beta blockers
  • Tricyclic antidepressants
  • Serotonin norepinephrine reuptake inhibitors (SNRIs)
  • Calcium channel blockers
  • Antihypertensives: lisinopril and candesartan
  • Other prophylactic treatments: botulinum toxins, cyproheptadine, methysergide, memantine, carisoprodol, clonidine, and guanfacine

Hoffman and colleagues used four logistic regression models to estimate propensity scores predicting initiation of topiramate compared with initiation of cardiovascular treatment, other anticonvulsants (other than topiramate), antidepressants, and other treatments. Patients who initiated treatment with topiramate were propensity score-matched to users of other prophylactic treatments, including anticonvulsants, cardiovascular treatment, and antidepressants.

Researchers found that patients treated with topiramate as prophylaxis had lower mortality risk compared with two other groups—those treated with antidepressants (HR: 0.44; 95% CI: 0.24-0.83) and those treated with anticonvulsants (HR: 0.45; 95% CI: 0.25-0.84).

Upon case-controlled analysis, researchers observed that—compared with non-use of these treatments—all prophylactic treatments increased the risks of several outcomes, except topiramate and calcium channel blockers.

Upon multivariate odds ratio (OR) adjustment, Hoffman and colleagues found that exposure to anticonvulsants, SNRIs, beta blockers, antihypertensives, tricyclic antidepressants, and other prophylactic treatments was associated with increased risks of all three outcomes: cardiovascular and cerebrovascular events, and mortality.

They also observed that patients treated with anticonvulsant medications had the highest overall mortality risk (adjusted OR [AOR]: 5.83; 95% CI: 4.49-7.58), as well as the highest risk for cardiovascular and cerebrovascular mortality (AOR: 5.47; 95% CI: 2.53-11.83), unstable angina (AOR: 1.77; 95% CI: 1.02-3.09), ischemic stroke (AOR: 2.38; 95% CI: 1.85-3.07), and transient ischemic attack (AOR: 1.60; 95% CI: 087-2.93).

According to Hoffman and colleagues, depression, hypertension, hypercholesterolemia, obesity, and opioid use were independent risk factors for several outcomes.

They concluded, however, that although they found risks for several outcomes with certain prophylactic agents, all of these treatments—with the exception of topiramate—were markers for outcome risks that either developed or progressed after the initiation of their study. These treatments, therefore, could not be classified as directly affecting these risks.

“This study provides an initial assessment of the influence of prophylactic treatments on the estimated effect between migraine and cardiovascular and cerebrovascular disease and mortality. Additional risk factors, including migraine type, severity, frequency, and other treatment indications should be   considered in future migraine prophylactic treatment safety assessments,” concluded Hoffman and colleagues.

This study was funded with a research contract between Optum and Amgen, Inc.