Novel Migraine Drug Safe, Effective in Patients With CV Risk Factors

Pauline Anderson

July 02, 2019

Robert E. Shapiro,

OSLO, Norway — A new migraine drug appears to be safe and effective in patients at increased cardiovascular (CV) risk, new research shows.  

Investigators found risk factors such as high cholesterol or cigarette smoking did not significantly affect the efficacy or safety of the novel agent lasmiditan (Eli Lilly).

However, a post-hoc pooled analysis of the phase 3 SAMURAI and SPARTAN trials showed a small but significant increase in cardiac arrhythmia in patients taking lasmiditan that was likely due to increased tachycardia, the investigators report.

"The results indicate that cardiovascular risk factors likely don't have an effect on the safety and efficacy of this drug," study author Robert E. Shapiro, MD, PhD, professor, Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, told Medscape Medical News.

The findings were presented here at the Congress of the European Academy of Neurology (EAN) 2019.

Substantial Need

Patients with migraine, especially those who experience auras, have a higher risk for a variety of CV events, including myocardial infarction and stroke. Yet drugs commonly used to treat migraine, including triptans and nonsteroidal anti-inflammatories (NSAIDs), are contraindicated in many patients with cardiovascular disease (CVD).

"There is a need to develop and have accessible medications that may not have these kinds of limitations," Shapiro said.

Lasmiditan is an agonist of 5-HT1F receptors, which occur both centrally and peripherally. The molecule decreases neuropeptide release and affects pain pathways without causing vasoconstriction.

The drug is the first "ditan," a new category of agents for the treatment of migraine. However, the drug is not yet approved by the US Food and Drug Administration (FDA).

The new analysis included a subpopulation of patients with CV risk factors pooled from SPARTAN and SAMURAI, two randomized, double-blind, placebo-controlled phase 3 trials. These studies compared lasmiditan at 50 mg, 100 mg, and 200 mg to placebo during a single migraine attack.

Overall, both studies met their primary endpoints of freedom from pain and from most bothersome symptoms (MBS), and had comparable safety outcomes.

The two trials were very closely matched but not identical. For example, SAMURAI did not have a 50-mg lasmiditan arm and excluded patients with coronary artery disease, clinically significant arrhythmias, and uncontrolled hypertension, whereas these patients were not excluded in SPARTAN.

Shapiro emphasized that participants were not recruited to these trials based on whether or not they had CV risk factors, in contrast to the triptan trials of the 1980s and early 1990s, which did exclude these patients.

Six Risk Factors

The new subgroup analysis looked at the following six CV risk factors:

  • Age > 40 years;

  • Diabetes at baseline;

  • Current smoker;

  • Baseline total cholesterol ≥ 240 mg/dL;

  • Baseline high-density lipoprotein (HDL) cholesterol < 40 mg/dL for men and < 50 mg/dL for women; and

  • Baseline systolic blood pressure ≥ 140 mmHg or a self-reported history of high blood pressure.

"The question was: If patients have more of these risk factors does that increase their likelihood of developing cardiovascular treatment-emergent adverse events (TEAEs)?" said Shapiro.

He noted that about 55% of the participants were at least 40 years old. As in similar studies, about 84% were women.

The two efficacy endpoints of the current analysis were the proportion of patients achieving migraine-pain freedom and freedom from MBS 2 hours after the first treatment dose.

Researchers divided participants into those with zero to one CV risk factors and those with two or more such risk factors.

The analysis showed that the presence of CV risk factors did not affect efficacy.

There was no significant difference between those with one or less and those with two or more CV risk factors in terms of 2-hour headache pain freedom (P = .637) or 2-hour MBS freedom (P = .343)

For the safety analyses, investigators assessed CV TEAEs in patients who did and did not have aura. "Aura is thought to be a significant risk factor for cardiovascular disease," noted Shapiro.

The presence of CV risk factors was well balanced between those who received placebo (n = 1262) and those who received lasmiditan (n = 3177) across all groups.

In patients taking lasmiditan, there was a small but significant increase in cardiac arrhythmias compared with those taking placebo (0.9% vs 0.2%, respectively; odds ratio, 3.59; 95% CI, 1.09 - 11.79; P = .02)

Closer analysis determined that the cardiac arrhythmias were entirely due to increased palpitations or tachycardia, said Shapiro.

It is unclear whether these palpitations represent a direct CV effect or are signs of anxiety or other conditions, "and their potential importance to future patients or prescribing providers remains to be seen," he noted.

Potential Advantages

Overall, however, the presence of CV risk factors did not affect the likelihood of reporting any CV TEAEs, Shapiro said.

"Even the presence of multiple risk factors did not actually lead to a statistically significant elevation in reported cardiovascular TEAEs," he said.

Likewise, the presence of migraine aura did not affect whether or not CV TEAEs were reported. Shapiro added that this is "another potential advantage" of the drug.

"From these two phase 3 trials, the only cardiovascular TEAE that was reported was increased palpitations, or increased heart rate, and it was a very small number of subjects that reported this. So it's a low proportion but statistically higher than was seen for people who received placebo," he said.

If the drug is safe for people with a history of CVD or related risk factors, "there would be a potentially significant advantage for a sizeable population of people with migraine who don't have good treatment options at this time," he added.

A limitation of the analysis was that the original trials looked only at a single migraine attack and the review of potential cardiac TEAEs was unblinded.

"Subjects were treated at home, so there was no information on specific vital signs or cardiograms at the time of treatment," Shapiro reported.

He emphasized that identifying rare potential AEs requires post-hoc and pharmaco-surveillance studies.

Still Scared?

After the presentation, session cochair Hugh S. Markus, MD, PhD, professor, Department of Clinical Neurosciences, University of Cambridge, United Kingdom, asked whether clinicians should continue to be "very scared" about using triptans in patients with CVD.

According to FDA prescribing information, triptans are contraindicated in patients with a significant CV history or risk factors, but whether significant adverse outcomes occur in real-life practice is a "debatable point," Shapiro said.

He noted results of an independent marketing survey suggesting that more than 70% of US patients taking a triptan have some degree of CV risk factors or contraindications to use; for example, a family history of early heart disease.

"This would potentially preclude them from taking these medications, which is kind of a stunning thing," said Shapiro.

"If triptans really were as hazardous as most people are concerned about, I suspect that we would have a greater public health menace than we do. So I think the jury is still out on how much risk there really is with triptans and what really is the nature and origin of cardiovascular risks in people with migraine to begin with," he said.

"Very Promising"

Also commenting on the findings for Medscape Medical News, Erling Andreas Tronvik, MD, PhD, associate professor at the Norwegian University of Science and Technology, Trondheim, said so far, the data look "very promising."

Tronvik, who was not involved with the research, added he is very optimistic that this new drug option, which is the first of its kind that exclusively targets the receptor subtype, may be available to treat migraine in patients with CV risk factors.

"We have not been able to use the old triptans in this patient group, so we are very happy to have a drug that is similar to other triptans but without this concern," he said.

The study was funded by Eli Lilly. Shapiro has reported receiving consultant honoraria as a member of an Eli Lilly galcanezumab clinical trials data monitoring committee.

Congress of the European Academy of Neurology (EAN) 2019: Abstract 609. Presented June 30, 2019.

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