Efficacy and cardiovascular safety of lasmiditan in patients with cardiovascular risk factors: A systematic review and meta-analysis with updated synthesis of triptan safety data.

Abstract

Objective: This study was conducted to evaluate lasmiditan efficacy and cardiovascular (CV) safety in patients with CV risk factors, and provide an updated synthesis of observational evidence on long-term triptan-related CV outcomes.

Background: Approximately 20% of patients with migraine have CV contraindications to triptans. Lasmiditan, a selective 5-hydroxytryptamine (5-HT)₁F receptor agonist without vasoconstrictive properties, may offer a safer alternative to triptans for these patients.

Methods: In this systematic review and meta-analysis, we systematically searched MEDLINE, Embase, Scopus, and Cochrane CENTRAL from inception to June 2025 following a retrospectively registered International Prospective Register of Systematic Reviews protocol (CRD420251208584). Primary outcomes were pain freedom at 2 h (efficacy; randomized controlled trials) and major adverse CV events (observational studies). Random-effects meta-analyses used odds ratios (ORs) for binary efficacy outcomes and hazard ratios for time-to-event safety data. Rare cardiac adverse events were analyzed using Peto ORs. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework.

Results: Sixteen studies were included (six lasmiditan studies involving three randomized controlled trials [two phase 3 and one phase 2] enrolling 5126 participants, two post hoc analyses, one open-label extension, and 10 triptan CV safety studies). In the meta-analysis of three independent randomized controlled trials (eight dose-specific comparisons), lasmiditan significantly increased pain freedom at 2 h versus placebo (OR, 2.09; 95% confidence interval [CI], 1.66-2.63, p < 0.001; heterogeneity statistic (I²) = 58.9%; GRADE: high certainty), with clear dose-dependent effects (50 mg OR ≈ 1.50; 100 mg OR ≈ 2.0; 200 mg OR ≈ 2.60; subgroup p < 0.001) and number needed to treat of 4.1-15.4. Most bothersome symptom freedom was similarly improved (OR, 1.79; 95% CI, 1.45-2.22, p < 0.001; I² = 54.5%; GRADE: high certainty). Observational triptan safety data (14 comparisons from 10 studies) showed apparent CV protection (hazard ratio, 0.82; 95% CI, 0.73-0.92), although certainty was very low due to confounding by indication, inconsistency (I² = 82.4%), and comparator indirectness. Cardiac treatment-emergent adverse events were rare with lasmiditan (<1%; Peto OR, 3.14; 95% CI, 1.10-8.98, based on 14 total events; GRADE: low certainty), with zero vasoconstrictive CV events across all trials. Common adverse events included dizziness (risk ratio [relative risk] [RR], 5.71), somnolence (RR, 2.68), and paresthesia (RR, 5.02), all dose-dependent.

Conclusions: Lasmiditan demonstrated efficacy and favorable CV safety in CV-risk populations, with no vasoconstrictive events detected across 5126 participants. Common central nervous system adverse effects, particularly dizziness, require careful patient counseling. The recent voluntary market withdrawal of lasmiditan underscores the need for continued development and evaluation of non-vasoconstrictive acute migraine treatments for patients with CV contraindications to triptans.