Impact of Intracranial Atherosclerosis and Cerebral Small Vessel Disease on Overt Vascular Events During Antithrombotic Therapy

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Abstract
Introduction: To investigate the association of intracranial atherosclerotic disease (ICAD), alone and comorbid with cerebral small vessel disease (SVD), with ischemic or hemorrhagic events in patients receiving antithrombotic therapy. Patients and Methods: In this prospective, multicenter, observational study, baseline brain MRI was performed to assess SVD (white matter hyperintensities, cerebral microbleeds, lacunes, enlarged perivascular spaces [PVS]), nonlacunar infarcts, and ICAD. SVD burden was defined as SVD score > 2. ICAD was classified as normal‐to‐mild, moderate, and severe stenosis‐to‐occlusion. The outcomes were any ischemic event, ischemic stroke, major bleeding, intracranial hemorrhage, and all‐cause mortality. We assessed associations of ICAD with outcomes via Cox regression and mediation analyses, adjusting for SVD burden. Results: Among 5250 patients (mean age: 71 ± 11 years, 33% women), 3947 (75%) received antiplatelets and 1304 (25%) anticoagulants at baseline. ICAD was normal‐to‐mild in 3781 (72%), moderate in 571 (11%), and severe‐to‐occluded in 894 (17%). SVD burden was observed in 1400 (27%). ICAD was associated with a higher frequency of non‐lacunar infarcts and a lower frequency of PVS. There was no graded association between ICAD severity and SVD burden. During a median follow‐up of 2 years, 278 ischemic events, 197 ischemic strokes, 97 major bleedings, 55 intracranial hemorrhages, and 217 deaths occurred. Severe‐to‐occluded ICAD independently increased the risk of any ischemic event (adjusted hazard ratio: 1.39 [1.03–1.86]) and mortality (2.01 [1.48–2.74]); coexisting SVD burden further increased the risk of all outcomes. ICAD directly affected ischemic events, while mortality was mainly driven by its additive interaction with SVD. Conclusions: ICAD increases the risk of any ischemic events and, with comorbid SVD, contributes to hemorrhagic events and excess mortality.
Funding Information
  • Japan Agency for Medical Research and Development (JP18ek0210055)
  • Japan Agency for Medical Research and Development (JP24lk0221171)
  • Japan Agency for Medical Research and Development (JP24lk0221186)
  • Japan Society for the Promotion of Science (19 K17023)
  • Japan Society for the Promotion of Science (JP23K27522)

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