Lasmiditan for acute treatment of migraine in patients with cardiovascular risk factors: post-hoc analysis of pooled results from 2 randomized, double-blind, placebo-controlled, phase 3 trials

Abstract

BackgroundIn addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs.MethodsSAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200 mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects.ResultsIn this pooled analysis, a total of 4439 patients received ≥1 dose of study drug. A total of 3500 patients (78.8%) had ≥1 CVRF, and 1833 patients (41.3%) had ≥2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2 h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations.ConclusionsWhen analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, the lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Future studies are needed to assess long-term efficacy and safety.Trial registrationClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.Electronic supplementary materialThe online version of this article (10.1186/s10194-019-1044-6) contains supplementary material, which is available to authorized users.

Evaluation of 2‐Hour Post‐Dose Efficacy of Lasmiditan for the Acute Treatment of Difficult‐to‐Treat Migraine Attacks

“…These findings suggest that the efficacy of lasmiditan is generally consistent across many patient subgroups, indicating that lasmiditan may be beneficial in treating migraine headaches in a wide range of patients or attack characteristics. These data extend previous findings that the efficacy of lasmiditan was not compromised in patients who had an insufficient response to triptans, were currently using migraine preventive medications, or had the presence of cardiovascular risk factors/comorbidities 33‐35 …”

Lasmiditan: Its Development and Potential Use

“…Additionally (from pooled data trials), lasmiditan's efficacy and cardiovascular adverse events were similar in patients with cardiovascular risk factors and those without. Cardiovascular adverse events were rare in patients with cardiovascular risk factors (lastmiditan, 0.9%; placebo, 0.4%), and only benign arrythmias reached statistical significance to be more common (palpitations, tachycardia, etc) . Dizziness is the most commonly reported AE with lasmiditan .…”

“…This is due to the results of 2 trials assessing the effect of lasmiditan on simulated driving performance in healthy participants . Trials compared different doses of lasmiditan to either alprazolam or diphenhydramine and placebo. The results of these trials have not yet been published.…”

“…Cardiovascular adverse events were rare in patients with cardiovascular risk factors (lastmiditan, 0.9%; placebo, 0.4%), and only benign arrythmias reached statistical significance to be more common (palpitations, tachycardia, etc). 17 Dizziness is the most commonly reported AE with lasmiditan. [8][9][10][11] Pooled data from SPARTAN and SAMURAI confirm this, with 8.6% to 16.8% of patients (50 to 200 mg lasmiditan) experiencing mild to moderate dizziness over about 2 hours.…”

The Risks or Lack Thereof of Migraine Treatments in Vascular Disease

“…Novel acute treatment medications for migraine that do not have vasoconstrictive properties have been FDA approved in late 2019, including the calcitonin-generelated peptide (CGRP) antagonist ubrogepant 30 and the 5-HT 1F agonist, lasmiditan. 31,32 More small molecule CGRP receptor antagonists or gepants are in development (rimegepant, vazegepant, atogepant). They are therefore suitable for this patient population with CAD.…”