Reviews/Anti CGRP Antibodies/Cardiovascular safety of CGRP antibodies
Safety · CGRP-SAF-01 · v2
The question is whether these injectable migraine-prevention antibodies raise the risk of serious heart and stroke events. The strongest evidence designed to answer it directly points to no clear increase: a large insurance-based study tracking heart attack and stroke found no raised risk [14], pooled trial safety data matched placebo [19], and a treadmill study in people with existing heart disease found no worsening [10]. Against this, the single biggest dataset reported a modest but statistically real increase in combined heart-and-stroke events, driven by ischaemic stroke [29], and several studies show blood pressure can rise on treatment [26]. The reassuring studies are either small or not built to catch rare serious events, and the people most at risk were usually excluded from the trials. The panel concluded the evidence rules out a large increase but cannot confidently rule out a smaller one, especially for stroke.
The dedicated comparative evidence leans against an increase in hard events: a Medicare cohort with a first myocardial infarction or stroke endpoint found no raised risk versus onabotulinumtoxinA (aHR 0.88; 95% CI 0.44-1.77) [14], pooled erenumab data showed a vascular safety profile comparable to placebo [19], and erenumab did not worsen exercise-induced ischaemia in documented coronary artery disease [10]. Real-world and preclinical signals are also broadly reassuring in the short term [12, 17, 28, 32]. However, the largest dataset (900,370 beneficiaries) reported a significant increase in composite cardiovascular events (aHR 1.26; 95% CI 1.10-1.45) and ischaemic stroke (aHR 1.26; 95% CI 1.07-1.49) [29], and a prospective study documented systolic blood pressure rising by up to 5.2 mm Hg (95% CI 3.1-7.5) [26]. The efficacy trials [1-9, 22, 23] report only generic adverse-event similarity. The contested point: The evidence divides on direction and endpoint: the one comparative study powered for myocardial infarction and stroke is null but underpowered [14], while the far larger claims cohort reports a small, significant rise driven by ischaemic stroke [29]. Whether that stroke signal reflects a real antibody effect or confounding and drug-class mixing is the unresolved point.
All 36 papers behind this claim with their DOIs and what each does to it, the panel’s arbitration, the evidence gap map and the open research questions. Free, and sent to your inbox.
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One reviewer's only job is to attack the finding. The challenges below were weighed before the grade was set.
The largest study in the corpus [29] directly contradicts the claim, reporting a statistically significant increase in composite cardiovascular events (aHR 1.26, 95% CI 1.10-1.45) driven by ischaemic stroke across 900,370 patients. A null claim cannot stand unqualified against a significant positive signal of this size.
The only study measuring hard MACE in a comparative design [14] is underpowered: the confidence interval (0.44-1.77) is consistent with both a halving and a 77% increase in composite CV risk, so its null point estimate is reassuring but non-confirmatory.
Where it remains uncertain. The largest dataset reported a significant increase in composite cardiovascular events (aHR 1.26; 95% CI 1.10-1.45) and ischaemic stroke [29], and blood pressure demonstrably rose on treatment [26].
Aleatory
The only comparative MI/stroke cohort has few outcome events, producing a confidence interval (0.44-1.77) consistent with both benefit and substantial harm [14].
Epistemic
Trials ran 3-12 months and excluded patients with significant cardiovascular history [1-9, 22, 23, 15, 16]; long-term major-event data in high-risk populations are absent.
Inferential
Much of the safety corpus [16, 17, 18, 26] reports blood pressure rather than major cardiovascular events, and [26] shows it rises, so inferring MACE safety from it is indirect.
The load-bearing papers from a corpus of 36, each classified by what it does to the claim. Every DOI is taken from the corpus the claim was graded on.
Mechanistic reassurance in a documented coronary-disease population, though small (n=88) and a surrogate endpoint.
“Erenumab did not adversely affect exercise time in a high cardiovascular risk population of patients, supporting that inhibition of the canonical CGRP receptor does not worsen myocardial ischemia.”
Panel auditInternal validity: high · scope of inference: Acute effect of a single erenumab dose on exercise-induced ischemia in stable angina, not long-term MACE.Key limitations: small n=88 · single dose · ischemia surrogate not hard MACE · 12-week follow-up
Only dedicated hard-MACE comparative cohort; null point estimate supports the claim but the wide CI cannot exclude a substantial increase.
“Use of anti-CGRP mAbs was not associated with an increased risk of composite CVD events (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.44-1.77), hypertensive crisis (aHR, 0.46; 95% CI, 0.14-1.55), peripheral revascularization (aHR, 1.50; 95% CI, 0.48-4.73), or Raynaud phenomenon (aHR, 0.75; 95% CI, 0.45-1.24) compared with onabotulinumtoxinA.”
Panel auditInternal validity: high · scope of inference: MI or stroke risk in predominantly older Medicare migraine patients without baseline MI/stroke.Key limitations: wide confidence interval · excludes prior MI/stroke · short follow-up through 2020 · observational confounding
Pooled RCT vascular-safety analysis (n=2,443), Class II; supports no short-term increase in vascular AEs.
“Selective blockade of the canonical calcitonin gene-related peptide receptor with erenumab for migraine prevention had a vascular safety profile comparable to that of placebo over 12 weeks, with no increased emergence of events over time.”
Panel auditInternal validity: high · scope of inference: 12-week vascular safety of erenumab in chronic and episodic migraine trial populations.Key limitations: 12-week double-blind window · 4 adjudicated CV events all during open-label erenumab · trial-excluded high-risk patients
Real-world antibody cohort documenting serious CV events (stroke, SCAD, pericarditis); uncontrolled, so rate not comparative.
“We observed CV events in 1.6% of patients with 1.5-year follow-up of anti-CGRP(R)-mAbs treatment.”
Panel auditInternal validity: low · scope of inference: 1.5-year CV event occurrence in low-CV-risk migraine patients on erenumab or fremanezumab.Key limitations: no comparator · small sample · excluded CV-history patients · cannot attribute causation
4 of 36 papers shown. The full review lists all of them, with the panel’s arbitration →
Claims are graded at each quarterly release, and re-graded between releases only when a pivotal trial lands. Every change is a new version of the claim.
Conflicting primary evidence and sparse adequately powered long-term hard-outcome data keep the null claim below the Likely band.
Release 2026-q4 re-graded every claim from its corpus under protocol v0.19. An earlier release's grade is shown for the record; it came from an earlier protocol and is not a movement.
Assumptions that carry weight but are not themselves established.
The panel records the gap that would most move the claim, and the study that would close it.
Antibody-only hard-outcome study in high-CV-risk patients. The claim concerns antibodies specifically, yet the only significant signal pools gepants [29] and the trials excluded at-risk patients. The panel rates this the highest-importance open gap for the claim, and names the study design that would close it: A large, adequately powered cohort or pragmatic trial restricted to anti-CGRP antibodies, with first MI/stroke endpoints and long follow-up in patients with established vascular disease.
Open question: Do anti-CGRP antibodies increase ischaemic stroke risk specifically? Why it is still open: The only significant signal is driven by ischaemic stroke [29] but mixes gepants and is unadjudicated, while the comparative MI/stroke cohort [14] is underpowered for stroke alone.
Priors is a sceptical first reader, not peer review, and not medical advice.
Release 2026-q4 · graded 21 Oct 2026 · protocol v0.19