Evolocumab Cuts First-Stroke Risk, Shows MACE Benefit Up to 8 Years

Adding the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab (Repatha; Amgen) to optimized lipid-lowering therapy reduced the risk of a first stroke by 24% among high-risk patients with no history of stroke or myocardial infarction (MI), according to a prespecified analysis of the VESALIUS-CV (NCT03872401) trial presented at the American Heart Association (AHA) Scientific Sessions 2026 in Chicago, Illinois.¹

In addition to the stroke data on evolocumab, there was an effectiveness study drawing on the FOURIER (NCT01764633) open-label extension (OLE).

Stroke Risk Fell 24% in Patients Without Prior MI or Stroke

VESALIUS-CV randomized 12,257 patients with qualifying atherosclerosis or high-risk diabetes, no prior stroke or MI, and a low-density lipoprotein cholesterol (LDL-C) level of at least 90 mg/dL to evolocumab or placebo on top of background optimized lipid-lowering therapy. The trial's primary results, published in the New England Journal of Medicine, showed that evolocumab lowered the risk of coronary heart disease death, MI, or ischemic stroke by 25% (HR, 0.75; 95% CI, 0.65-0.86; P < .001).²

In the new analysis, 306 patients (2.5%) had a stroke over a median follow-up of 4.6 years, and 85% of strokes were ischemic.¹ In a lipid substudy of 2014 patients, median LDL-C at 48 weeks was 45 mg/dL with evolocumab vs 109 mg/dL with placebo.

At 5 years, any stroke had occurred in 2.6% of the evolocumab group vs 3.2% of the placebo group (HR, 0.76; 95% CI, 0.61-0.95; P = .018), with an apparent early divergence of the curves. Nonhemorrhagic stroke was also less frequent (2.4% vs 2.9%; HR, 0.77; 95% CI, 0.61-0.98; P = .030), with consistent effects for ischemic stroke (2.3% vs 2.7%; HR, 0.79; 95% CI, 0.62-1.01) and stroke of undetermined type (0.1% vs 0.3%; HR, 0.46; 95% CI, 0.19-1.13), although the CIs for both subtypes crossed 1.

The ischemic stroke benefit was particularly pronounced in patients without baseline atrial fibrillation (HR, 0.71; 95% CI, 0.54-0.94), in whom strokes are less likely to be cardioembolic. There was no excess in hemorrhagic stroke, which occurred in 11 patients (0.2%) in the evolocumab arm and 17 (0.3%) in the placebo arm (HR, 0.64; 95% CI, 0.30-1.37). Results for any stroke were consistent across key subgroups.

Evolocumab Tied to 29% Lower MACE Risk vs External Control

Unlike FOURIER, the original randomized outcomes trial, its OLE had no concurrent placebo arm. To estimate long-term treatment effects, investigators from Amgen, the TIMI Study Group, and other institutions built an external control arm (ECA) of 56,490 patients before weighting from the UK Clinical Practice Research Datalink Aurum database, applying FOURIER's eligibility criteria and enrollment period.³ After weighting, ECA event rates were comparable with the FOURIER placebo arm for 3-point major adverse cardiovascular events (MACE; MI, stroke, or cardiovascular [CV] death) and its components. They were not comparable for coronary revascularization, which meant the 4-point MACE (3-point MACE plus coronary revascularization) could not be compared either.

In this nonrandomized comparison, over a median follow-up of 6.6 years (maximum, 8.1 years), patients treated with evolocumab in FOURIER and its OLE had a 29% lower risk of 3-point MACE than the ECA (HR, 0.71; 95% CI, 0.65-0.79). HRs were 0.63 (95% CI, 0.55-0.72) for MI, 0.77 (95% CI, 0.64-0.93) for stroke, and 0.75 (95% CI, 0.63-0.88) for CV death. The authors concluded the findings support evolocumab's long-term effectiveness relative to placebo, although the comparison was with a weighted external control.

"In the US, every 40 seconds someone has a heart attack and 3 out of 4 of those are first-time events. With more than a decade of clinical research with Repatha and growing evidence supporting earlier LDL-C lowering, no one should have to wait for a first heart attack or stroke to take more aggressive action against cardiovascular risk," said Murdo Gordon, executive vice president of Global Markets and Policy at Amgen, in a statement.⁴ "For high-risk patients with a guideline recommended LDL-C goal below 55 mg/dL, we need to help make reaching that goal sooner a reality. That means pairing strong clinical data with continued efforts to address barriers to care. We've taken actions to make Repatha more affordable and accessible, and these findings add to the evidence of its benefit to patients."

References

1. Bohula E, Giugliano R, Saver JL, et al. Evolocumab for stroke prevention in patients at high CV risk without a prior stroke or MI in VESALIUS-CV. Presented at: American Heart Association Scientific Sessions 2026; November 6-9, 2026; Chicago, IL. Abstract 14174.
2. Bohula EA, Marston NA, Bhatia AK, et al. Evolocumab in patients without a previous myocardial infarction or stroke. N Engl J Med. 2026;394(2):117-127. doi:10.1056/NEJMoa2514428
3. Sakhuja S, Walsh E, Brookhart M, et al. Long-term effectiveness of evolocumab in reducing the risk for major adverse cardiovascular events: comparing FOURIER OLE data to external control using a principled approach. Presented at: American Heart Association Scientific Sessions 2026; November 6-9, 2026; Chicago, IL. Abstract 6839.
4. New data at AHA 2026 demonstrates the value of treatment with Repatha earlier in the cardiovascular risk continuum. News release. Amgen. November 9, 2026. Accessed November 9, 2026. https://www.prnewswire.com/news-releases/new-data-at-aha-2026-demonstrates-the-value-of-treatment-with-repatha-earlier-in-the-cardiovascular-risk-continuum-302932775.html