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Background & Purpose: Although statin pretreatment (SP) is associated with better early outcomes in acute ischemic stroke (AIS) patients, there are limited data regarding the underlying mechanism of this beneficial effect. We sought to evaluate the potential association between SP and microembolic signal (MES) burden in patients with acute cerebral ischemia (ACI) due to large-artery atherosclerosis (LAA).Methods: We prospectively evaluated consecutive patients admitted with first-ever ACI due to LAA in three tertiary stroke centers over a two-year period. LAA was diagnosed according to TOAST criteria. LAA location (extracranial vs. intracranial, posterior vs. anterior) was confirmed using CT or MR angiography. All patients underwent continuous 1-hour TCD monitoring of affected vessel at baseline (≤24 hrs from symptom onset) to identify both the presence and number of MES (MES burden). SP was recorded and dichotomized as high (rosuvastatin 40mg or atorvastatin 80mg) or low-to-moderate dose (HD &LMD). Functional outcome (FO) at 1 month was evaluated using the modified Rankin Scale (mRS).Results: SP was documented in 43 (41%) out of 106 LAA patients (mean age 65±10 years; 72% men; median NIHSS-score: 2, interquartile range: 0-4; LMD 32%, HD 8%). There was a significant (p=0.022) dose-dependent effect between SP and prevalence of MES on TCD: no SP (37%), SP with LMD (18%) and SP with HD (0%). Similarly, a significant (p=0.045) dose-dependent effect was documented between SP and MES burden: no SP (1.1±1.8), SP with LMD (0.7±1.6) and SP with HD (0±0). Patients with SP had better FO (median mRS-score: 1, interquartile range: 0-2) than patients without SP (median mRS-score:0, interquartile range: 0-2, p=0.004 by Cochran-Mantel-Haenszel test). In multivariable logistic regression analysis adjusting for demographics, vascular risk factors, LAA location, stroke severity, and other prevention therapies (antiplatelets, antihypertensives, antidiabetics) only SP (OR=0.29, 95%CI: 0.09-0.92, p=0.036) and current smoking (OR=3.09, 95%CI: 1.05-9.07, p=0.040) were associated with MES presence.Conclusion: SP in patients with acute LAA is associated with reduced MES presence and lower MES burden. This effect appears to be dose-dependent.