PDF: CGRP-CV
(2026)Objective
To examine whether CGRP inhibitor use is associated with an increased risk of cardiovascular events in patients with migraine
Study Summary
• MI, revascularization, CRAO, and intracranial hemorrhage not significantly elevated; results considered hypothesis-generating (Class II evidence)
Intervention
CGRP inhibitor initiation vs non-initiation in migraine patients (MarketScan claims registry)
Inclusion Criteria
MarketScan beneficiaries with at least one migraine diagnosis claim and ≥12 months continuous coverage prior to diagnosis
Study Design
Arms: CGRP Inhibitor Initiators vs Non-Initiators
Patients per Arm: CGRP Initiators: 58,679, Non-Initiators: 841,691
Outcome
• Ischemic stroke: aHR 1.26 (95% CI 1.07-1.49)
• MI, revascularization, CRAO, intracranial hemorrhage: not significantly elevated
Bottom Line
In a large MarketScan cohort of 900,370 beneficiaries with migraine, CGRP inhibitor initiation was associated with a modest 26% increase in composite cardiovascular events (aHR 1.26, 95% CI 1.10-1.45), driven primarily by ischemic stroke. The absolute risk increase remains small (8.77 vs 6.76 per 1,000 person-years), and results are hypothesis-generating rather than practice-changing.
Major Points
- Retrospective, observational cohort study using MarketScan (Merative) proprietary insurance-based claims registry to evaluate cardiovascular safety of CGRP inhibitors in migraine.
- 900,370 beneficiaries with migraine (median age 41, 77.8% female); 58,679 initiated a CGRP inhibitor and 841,691 did not initiate one.
- CGRP inhibitor initiation associated with increased composite CV risk in overlap-weighted analysis: aHR 1.26 (95% CI 1.10-1.45); 8.77 vs 6.76 events per 1,000 person-years.
- Primary composite endpoint: MI, cerebral ischemic stroke, revascularization, peripheral arterial disease, and central retinal artery occlusion (CRAO).
- Composite increase driven by ischemic stroke: aHR 1.26 (95% CI 1.07-1.49).
- MI, revascularization, CRAO, and intracranial hemorrhage not significantly elevated as secondary endpoints.
- CGRP inhibitor initiators had a greater degree of baseline cardiovascular morbidity than noninitiators.
- Analysis used a sequential trial framework with propensity score overlap-weighted cohorts to reduce confounding.
- Humeral fracture used as a falsification (negative control) endpoint.
- Class II evidence per AAN classification: initiation of CGRP inhibitor associated with modestly increased composite CV risk in migraine patients.
Study Design
- Study Type
- Retrospective, observational cohort study
- Randomization
- No
- Blinding
- N/A (observational)
- Sample Size
- 900370
Primary Outcome
Definition: Composite cardiovascular events (MI, cerebral ischemic stroke, revascularization, peripheral arterial disease, CRAO)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | 1.26 (1.10-1.45) | - |
Limitations & Criticisms
- Observational design cannot establish causation
- Confounding by indication: CGRP initiators had greater baseline CV morbidity, potentially reflecting more severe or refractory migraine with inherently higher CV risk
- Claims data may miss clinical detail, migraine severity, and unmeasured confounders
- Absolute risk increase is small despite statistical significance; results considered hypothesis-generating
Citation
Lusk JB et al. Neurology. 2026;106(3):e214479. DOI: 10.1212/WNL.0000000000214479