Severe-to-occluded intracranial atherosclerotic disease independently increased the risk of ischemic events and mortality, and coexisting cerebral small vessel disease burden further increased the risk of all outcomes including hemorrhagic events.
Key Findings
Results
Severe-to-occluded ICAD independently increased the risk of any ischemic event and all-cause mortality.
Adjusted hazard ratio for any ischemic event with severe-to-occluded ICAD: 1.39 (95% CI: 1.03–1.86)
Adjusted hazard ratio for all-cause mortality with severe-to-occluded ICAD: 2.01 (95% CI: 1.48–2.74)
ICAD was classified as normal-to-mild in 3781 (72%), moderate in 571 (11%), and severe-to-occluded in 894 (17%) of 5250 patients
Associations were adjusted for SVD burden and assessed via Cox regression and mediation analyses
Results
Coexisting SVD burden further increased the risk of all outcomes in patients with ICAD.
SVD burden was defined as SVD score >2 and was observed in 1400 (27%) of patients
Coexisting SVD burden increased risk beyond ICAD alone for any ischemic event, ischemic stroke, major bleeding, intracranial hemorrhage, and all-cause mortality
Mortality was mainly driven by the additive interaction between ICAD and SVD burden
ICAD directly affected ischemic events, while hemorrhagic events were associated with the combination of ICAD and SVD
Results
ICAD was associated with a higher frequency of non-lacunar infarcts and a lower frequency of enlarged perivascular spaces.
Non-lacunar infarcts were more frequent in patients with more severe ICAD
Enlarged perivascular spaces (PVS) were less frequent in patients with ICAD
There was no graded association between ICAD severity and overall SVD burden score
SVD markers assessed included white matter hyperintensities, cerebral microbleeds, lacunes, and enlarged perivascular spaces
Results
During a median follow-up of 2 years, substantial rates of ischemic, hemorrhagic, and fatal events occurred in the study cohort.
278 ischemic events, 197 ischemic strokes, 97 major bleedings, 55 intracranial hemorrhages, and 217 deaths occurred
Median follow-up was 2 years across 5250 patients
Mean patient age was 71 ± 11 years; 33% were women
3947 (75%) received antiplatelets and 1304 (25%) received anticoagulants at baseline
Results
The effect of ICAD on mortality was mainly mediated through its additive interaction with SVD burden rather than a direct effect.
Mediation analyses were used to distinguish direct effects of ICAD from indirect effects involving SVD
ICAD directly affected ischemic events
Mortality risk was primarily driven by the additive interaction of ICAD with SVD burden
This finding suggests distinct mechanistic pathways for ischemic versus fatal outcomes in patients with ICAD
Methods
The study was a prospective, multicenter, observational study using baseline brain MRI to characterize both ICAD and SVD.
5250 patients were enrolled across multiple centers
Baseline brain MRI assessed white matter hyperintensities, cerebral microbleeds, lacunes, enlarged perivascular spaces, non-lacunar infarcts, and ICAD
ICAD was classified into three categories: normal-to-mild, moderate, and severe stenosis-to-occlusion
Outcomes tracked were any ischemic event, ischemic stroke, major bleeding, intracranial hemorrhage, and all-cause mortality
What This Means
This research suggests that patients receiving blood-thinning medications who also have significant narrowing or blockage of arteries inside the brain (intracranial atherosclerotic disease, or ICAD) face meaningfully higher risks of strokes and death compared to those with less arterial disease. The study followed over 5,000 patients for about two years, finding that those with the most severe arterial narrowing were about 40% more likely to have an ischemic (clot-related) event and twice as likely to die compared to those with minimal arterial disease, even after accounting for other risk factors.
The research also found that when patients had both severe ICAD and a high burden of cerebral small vessel disease—a separate condition involving damage to the brain's tiny blood vessels—their risks were even greater across all outcomes, including bleeding in the brain. Interestingly, the two conditions appeared to contribute to risk through somewhat different mechanisms: ICAD directly drove ischemic strokes, while the elevated mortality risk was largely explained by the combination of both diseases together rather than either one alone.
This research matters because it highlights that two different types of brain vascular disease commonly occur together and interact to worsen patient outcomes beyond what either condition causes alone. This suggests that evaluating patients for both ICAD and small vessel disease simultaneously, rather than treating them as separate concerns, may be important for better understanding and managing stroke and mortality risk in people already on antithrombotic therapy.
Miwa K, Koga M, Tanaka K, Yakushiji Y, Sasaki M, Kudo K, et al.. (2026). Impact of Intracranial Atherosclerosis and Cerebral Small Vessel Disease on Overt Vascular Events During Antithrombotic Therapy.. European journal of neurology. https://doi.org/10.1111/ene.70635