FormalPara Key Summary Points

Triptans are vasoconstrictors and have been associated with rare vascular adverse events, leading to contraindications for patients with cardiovascular conditions.

Lasmiditan does not cause vasoconstriction and does not have these contraindications.

The objective of this post hoc analysis was to evaluate the efficacy and safety of lasmiditan in patients with and without triptan contraindications. Pooled data were from randomized, double-blind, placebo-controlled trials SAMURAI, SPARTAN, MONONOFU, and CENTURION.

The efficacy and safety of lasmiditan appeared to be independent of whether patients had (n = 207) or did not have (n = 5497) a contraindication to triptans, supporting that lasmiditan may be a therapeutic option for patients with contraindications to triptans.

Introduction

Migraine is a chronic neurological disorder characterized by recurrent attacks of headache typically accompanied by additional symptoms such as nausea, vomiting, photophobia, or phonophobia [1]. As the leading cause of disability in those under 50 years old [2] and the second highest cause of disability worldwide, migraine imposes a significant global health burden [3]. Optimal migraine care depends on a careful, personalized analysis of individual needs. In the absence of contraindications, the triptan class of drugs has been a first-line approach for treating migraine acutely [4]. Triptans are serotonin 5-HT1B/1D/1F receptor agonists. These receptors are present predominantly on peripheral trigeminal sensory nerve endings, neurons in the trigeminal cervical complex, rostral brainstem, thalamus, and on blood vessels [5].

Based on the hypothesis that migraine attacks resulted from vasodilation [6], triptans were developed to selectively target cranial blood vessels and to produce vasoconstriction. This vasoconstrictive effect is mediated through 5-HT1B receptors [7, 8]. Preclinical and clinical studies have shown that triptans induce vasoconstriction in different intracranial and extracranial vessels, including the coronary arteries [7,8,9,10,11]. Consistent with this mechanism, triptans have been associated with rare vascular adverse events after dosing [12], leading to contraindications for patients with cardiovascular conditions [13]; these contraindications and precautions are present in the package insert for all triptans and are referred to as class labeling. Results from the 2009 American Migraine Prevalence and Prevention (AMPP) survey estimated that in the USA, there were roughly 2.6 million people with episodic migraine aged 22 years and older, living with one of more prior cardiovascular events, conditions, or procedures that were triptan contraindications; the prevalence of these contraindications increased with age [14]. Still more individuals have risk factor profiles that mandate caution in the use of triptans [15].

Lasmiditan is a selective 5-HT1F receptor agonist [16, 17] approved in the USA for the acute treatment of migraine, with or without aura, in adults. The efficacy and safety profile of lasmiditan in the treatment of acute migraine has been reported in phase 3 trials [18,19,20,21,22]. Like triptans, lasmiditan also works on the trigeminal system but has a low affinity for 5-HT1B receptors and does not cause vasoconstriction [16]. Lasmiditan aborts migraine attacks by decreasing neural transmission and inhibiting the release of neurotransmitters involved in migraine pathophysiology, including calcitonin gene-related peptide (CGRP) [23]. In experiments using sumatriptan as a positive control, lasmiditan did not cause vasoconstriction in human proximal or distal coronary, internal mammary, or middle meningeal arteries ex vivo, or in dog coronary or carotid arteries in vivo [24]. Additionally, the presence of cardiovascular risk factors has not been associated with differences in the efficacy or safety profile of lasmiditan based on two studies reported previously [25].

Because lasmiditan is free of the 5-HT1B agonism thought to mediate vasoconstriction associated with triptans, the drug was developed with the hope that it would be free of cardiovascular contraindications. Nonetheless, both lasmiditan and triptans are serotonergic agonists that have sufficient pharmacologic overlap to make shared adverse events possible. In addition, lasmiditan may be preferentially used in those with triptan contraindications. Therefore, the efficacy and tolerability of lasmiditan in people with triptan contraindications is especially relevant to clinical practice. Though prior work focused on those with cardiovascular risk factors [25], that group is much larger and may be less vulnerable to adverse events than those with firm contraindications.

The objective of this post hoc analysis was to evaluate the efficacy and safety of lasmiditan in patients with and without at least one triptan contraindication, and to assess whether the presence of cardiovascular contraindications could interfere with lasmiditan treatment outcomes, given its distinct mechanism of action.

Methods

Statement of Ethics Compliance

All studies were conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice guideline, and local regulatory requirements. The study protocols were approved by an independent ethics committee or institutional review board at each study site. All participants provided written consent before the start of the study. All studies were registered at ClinicalTrials.gov (SAMURAI, NCT:02439320; SPARTAN, NCT:02605174; CENTURION, NCT:03670810; and MONONOFU, NCT:03962738).

Study Design

This post hoc analysis examined pooled data from four randomized, double-blind, placebo-controlled trials (SAMURAI, SPARTAN, CENTURION, and MONONOFU). All trials had a common design. Participants were asked to treat a single migraine attack (SAMURAI, SPARTAN, and MONONOFU) or four migraine attacks (CENTURION; first attack data only included). Participants were randomized 1:1:1 to placebo, lasmiditan 100 mg, or lasmiditan 200 mg (SAMURAI and CENTURION first attack), 1:1:1:1 to placebo, lasmiditan 50 mg, lasmiditan 100 mg, or lasmiditan 200 mg (SPARTAN), and 7:3:7:6 to placebo, lasmiditan 50 mg, lasmiditan 100 mg, or lasmiditan 200 mg (MONONOFU). Full details of each trial’s study design can be found in the primary report for each trial [18, 19, 22, 26].

Trial Population and Definition of Cardiovascular Contraindications to TRIPTANS

Eligibility criteria were similar across all studies with the exception that SAMURAI excluded patients with known coronary artery disease, clinically significant arrhythmia, and uncontrolled hypertension [18]. Participants were aged 18 years or older, with a diagnosis of migraine with or without aura fulfilling the criteria of the International Classification of Headache Disorders (ICHD). Criteria were from ICHD-2 for SAMURAI, SPARTAN, and MONONOFU [1], and ICHD-3 for CENTURION [27]. Participants were required to have a history of 3 to 8 migraine attacks per month, a history of disabling migraine for at least 1 year, and a Migraine Disability Assessment (MIDAS) score of ≥ 11.

For this analysis, participants from the four trials were pooled and then separated into two distinct patient subpopulations: patients with at least one triptan contraindication and patients with no triptan contraindications. The definition of triptan contraindications was based on a previous report [5]. In this research, a team of headache specialists, cardiologists, and health economics and outcomes researchers identified triptan contraindications by reviewing labels and then identified current procedural terminology (CPT) diagnostic codes corresponding to these contraindications in some or all of the triptan labels. Because medical conditions are coded in Medical Dictionary for Regulatory Activities (MedDRA) terms in clinical trials, each of the CPT diagnostic codes was converted to MedDRA codes to generate a comprehensive list of triptan contraindications (see supplementary material, including number of patients with each contraindication in the safety population). Medical histories were then reviewed to identify study participants who did and did not have at least one of the triptan contraindications.

Outcomes/Endpoints/Assessments

Patient-reported efficacy outcomes were recorded by the patient in an electronic diary at baseline and at 0.5, 1, 1.5, 2, 3, 4, 24, and 48 h after treatment or at baseline, 0.5, 1, 2, 4, 6, 24, and 48 h after treatment (CENTURION only). For the efficacy analysis, only the time points up to 2 h post treatment were evaluated because rescue medications were permitted after the assessment at 2 h. At the designated time points, patients recorded their level of headache pain as “none”, “mild”, “moderate”, or “severe.” Headache pain freedom is defined as a reduction in headache severity from mild, moderate, or severe at baseline to none at the indicated assessment time. A subject is not counted as being pain-free at a specific time point if she or he used rescue or recurrence medication at or before the specific time point. Sustained pain-free is defined as experiencing headache pain-free at 2 h after dosing and at the indicated assessment time, having not used any medications after the first dose. Patients also indicated the presence or absence of migraine-associated symptoms, including nausea, vomiting, photophobia, or phonophobia. At baseline, patients identified their most bothersome symptom (MBS) from choices, including nausea, phonophobia, or photophobia. At each time point, patients indicated their level of migraine-related disability by responding to the following question: “How much is your migraine interfering with your normal activities?” with response options “none”, “mild interference”, “marked interference”, or “need complete bed rest.” At 2 h post treatment, patients indicated their global impression of change (PGIC) in response to the following question: “How do you feel after taking study medication?” with seven response options ranging from ”very much better” to ”very much worse.”

Statistical Analyses

The patient demographics and baseline migraine attack characteristics were summarized using descriptive statistics for patients with and without triptan contraindications. All efficacy analyses were conducted in the efficacy population defined as all randomized patients who used at least 1 dose of study drug to treat an attack of at least mild pain severity and had any non-missing post-dose pain severity assessment at or before 2 h after dose. Mantel–Haenszel odds ratio with 95% confidence intervals and general association p values at 2 h post treatment, stratified by study, were calculated for two distinct patient subpopulations: “Triptan contraindication” versus “Triptan no contraindication.” Additionally, p values for treatment-by-triptan contraindicated status interaction were calculated based on a logistic regression model with treatment-by-triptan contraindicated status interaction term and study, treatment group, and triptan contraindicated status as covariates.

The safety population (all patients who were randomized and received at least one dose of study medication) was used for all safety analyses. Treatment-emergent adverse events were defined as new or worsening adverse events within 48 h of dosing.

Due to the post hoc nature of these analyses, the analyses were not corrected for multiplicity. Subgroup tests for interaction were considered statistically significant based on a p value of 0.10; otherwise, p values less than 0.05 were used to define statistical significance.

Results

Patient Demographics and Baseline Characteristics

A total of 5704 patients in the efficacy population, pooled from the SAMURAI, SPARTAN, MONONOFU, and CENTURION trials, were included in this analysis. Of the 5704 patients, 207 (3.6%) patients had at least one contraindication to triptans. The patient demographics and baseline disease characteristics for the efficacy population are summarized in Table 1. In comparison to patients free of triptan contraindications, those with a triptan contraindication were older, more likely to be White, more likely to have a family history of coronary artery disease, more likely to take a migraine preventive agent, and more likely to have a history of migraine with aura (Table 1).

Table 1 Patient demographics and baseline characteristics
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Efficacy Outcomes

The subgroup analysis revealed that the effects of lasmiditan on the study co-primary endpoints of headache pain freedom at 2 h post-dose (2hPF) and freedom from MBS at 2 h post-dose (2hMBS) were not statistically different in patients with and without triptan contraindications (interaction p values > 0.1; Fig. 1). For example, for the 100-mg dose, 2hPF rates were 31.7% in the group with triptan contraindications and 30.3% in the group without contraindications, and odds ratios relative to placebo had overlapping confidence intervals (Fig. 1A). For the 100-mg dose, 2hMBS freedom rates were 47.1% in the group with triptan contraindications and 45.6% in the group without contraindications, and odds ratios relative to placebo had overlapping confidence intervals (Fig. 1B). Figure 2 shows that the magnitude of the treatment effect for 2-h headache pain relief, PGIC, and migraine-associated disability were similar, the confidence intervals for the odds ratios relative to placebo overlapped, and again the interaction p values were > 0.1. These outcomes generally showed a similar pattern of benefit for lasmiditan in both subgroups, with all results being statistically significant in the larger subgroup of patients without contraindications, and the results for pain relief being statistically significant in the smaller subgroup of patients with contraindications (Figs. 1 and 2).

Fig. 1
figure 1

Headache pain freedom (A) and freedom from MBS (B) in patients with and without a contraindication to triptans, 2 h following treatment with placebo, lasmiditan 100 or 200 mg. Comparisons of lasmiditan effect in the group of patients with triptan contraindications versus those without were not significant for any treatment group for either pain freedom or freedom from MBS (all interaction p values > 0.1). Odds ratio compared to patients who received placebo in the same subgroup. ***p < 0.001 vs. placebo. CI confidence interval, LTN lasmiditan, MBS most bothersome symptom, N number of patients, PBO placebo

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Fig. 2
figure 2

Headache pain relief (A), Patient Global Impression of Change (B), and patient-reported freedom from migraine-related disability (C) in patients with and without a contraindication to triptans, 2 h following treatment with placebo, lasmiditan 100 or 200 mg. Comparisons of lasmiditan effect in the group of patients with triptan contraindications versus those without were not significant for any treatment group for either headache pain relief (percentage of patients with a reduction in pain severity from “moderate” or “severe” at baseline to “mild” or “none” at 2 h), PGIC (percentage of patients with responses “very much better” or “much better”), or freedom from migraine-related disability (percentage of patients with response option “none”) (all interaction p values > 0.1). Odds ratio compared to patients who received placebo in the same subgroup. *p < 0.05, ***p < 0.001 vs. placebo. CI confidence interval, LTN lasmiditan, N number of patients, PBO placebo, PGIC Patient Global Impression of Change

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The proportion of patients achieving headache pain freedom over the 2 h post treatment is shown in Table 2. This time course was similar in patients with and without triptan contraindications.

Table 2 Pain freedom at time points up to 2 h in patient subgroups
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Safety Outcomes

Proportions of patients with treatment-emergent adverse events (TEAEs) were generally similar in the triptan contraindicated and triptan not contraindicated population. There were no deaths in either group, and the proportions of patients experiencing adverse events (AEs) or serious AEs (SAEs) were similar between the two groups. There were no cardiovascular events in either subgroup suggesting vasoconstriction. The proportion of patients with triptan contraindications reporting SAEs was 0% (0/67) in the placebo group and 1.5% (2/138) in the lasmiditan group. The reported SAEs (menorrhagia, somatic symptom disorder) were not treatment-emergent (new or worsening within 48 h after dosing) and were not considered related to study drug. TEAEs with at least 2% frequency are reported in Table 3 and were similar in the subgroups, with dizziness in 18.3–22.8% and somnolence in 7.9–9.9% of patients at the highest lasmiditan dose.

Table 3 Treatment-emergent adverse events in patient subgroups
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Discussion

The results of this post hoc analysis show that the effects of lasmiditan in terms of efficacy and safety appeared to be independent of whether patients had or did not have a contraindication to triptans. Because lasmiditan is not a vasoconstrictor, these results support that lasmiditan may be a therapeutic option for patients with contraindications to triptans.

The four clinical trials included in the current analysis shared a common design. No upper age limit was applied, and patients were not excluded on the basis of having cardiovascular risk factors or disease, with the exception that SAMURAI excluded patients with known coronary artery disease, clinically significant arrhythmia, and uncontrolled hypertension [18].

As expected, patients with triptan contraindications were older, more likely to have a family history of coronary artery disease, use medications for migraine prevention, and have a history of migraine with aura. Efficacy data were similar among patients with and without triptan contraindications, as defined by all interaction p values being greater than 0.37. For pain freedom, pain relief, and PGIC at 2 h, and the time course of pain freedom, the results were similar visually and in terms of odds ratios for patients with and without contraindications. For MBS at 2 h, responses for patients treated with lasmiditan and those having contraindications versus not having contraindications were similar, but the placebo response was higher in triptan contraindicated patients, leading to odds ratios of 1.2 for patients treated with lasmiditan and having a contraindication compared to 1.7–1.8 for patients not having a contraindication. For migraine-related disability, the odds ratios for lasmiditan versus placebo were 1.2–1.8 in the contraindicated group compared with 1.7–1.9 in the not contraindicated group. Statistical testing of lasmiditan versus placebo within the subset of patients with contraindications to triptans showed statistical significance only for pain relief; these statistical tests not showing statistical significance should be considered within the context of the limited sample size and power in the subset of triptan contraindicated patients.

Safety data revealed that the proportions of patients with TEAEs were generally similar in the triptan contraindicated and triptan not contraindicated population. There were no deaths in either group, and the proportions of patients experiencing AEs or SAEs were similar between the two groups. TEAEs also displayed a similar profile across the subgroups, including dizziness in 18.3–22.8% and somnolence in 7.9–9.9% of patients at the highest lasmiditan dose. There were no cardiovascular events in either subgroup suggesting vasoconstriction.

Lasmiditan is a highly selective 5-HT1F receptor agonist distinct from triptans in chemical structure and in pharmacology and was developed to have a neurological mechanism of action [16]. Importantly, lasmiditan lacks significant activity at the vasoconstrictive 5-HT1B receptor and so is not vasoconstrictive. Patients who have contraindications to triptans might be candidates for lasmiditan therapy, and the results from the current analysis suggest that these patients may benefit from lasmiditan therapy.

A strength of this analysis is that results from four similarly conducted clinical trials with similar inclusion and exclusion criteria were pooled to maximize the available patients with triptan contraindications.

There are limitations to consider when interpreting the results of this report. The first limitation is that all analyses were completed post-hoc and that the studies were not powered to detect treatment-by-triptan contraindicated status interaction. The relatively small sample size of patients with triptan contraindications limits the power to detect significant changes within this subset and to detect differences in effects between patients having versus not having triptan contraindications (subset effects). Prior efforts to enroll patients with cardiovascular disease into migraine studies have proven challenging. For example, a study of telcagepant in patients with stable coronary artery disease and migraine enrolled 165 of the planned 400 patients and was stopped for futility due to enrollment difficulties (28).

Conclusions

In conclusion, the efficacy and safety findings for lasmiditan appeared to be independent of whether patients had or did not have contraindications to triptans. Lasmiditan may be a therapeutic option in patients unable to take triptans because of contraindications.