Knight R A, Nagaraja T N, Li L, Jiang Q, Tundo K, Chopp M, Seyfried D M
Department of Neurology, Henry Ford Hospital, USA.
Department of Physics, Oakland University, Rochester, USA.
Austin J Cerebrovasc Dis Stroke. 2016;3(1). Epub 2016 Jul 20.
This study was designed to determine any rebleeding after atorvastatin treatment following spontaneous intracerebral hemorrhage (ICH) in a prospective safety trial.
Atorvastatin (80 mg/day) therapy was initiated in 6 patients with primary ICH with admission Glasgow Coma Score (GCS) >5 within 24 hours of ictus and continued for 7 days, with the dose tapered and treatment terminated over the next 5 days. Patients were studied longitudinally by multiparametric magnetic resonance imaging (MRI) at three time points: acute (3 to 5 days), subacute (4 to 6 weeks) and chronic (3 to 4 months). Imaging sequences included T, T-weighted imaging (TWI), diffusion tensor imaging (DTI) and contrast-enhanced MRI measures of cerebral perfusion, blood volume and blood-brain barrier (BBB) permeability. Susceptibility weighted imaging (SWI) was used to identify primary ICH and to check for secondary rebleeding. Final outcome was assessed using Glasgow Outcome Score (GOS) at 3-4 months.
Mean admission GCS was 13.2±4.0 and mean GOS at 3 months was 4.5±0.6. Hemorrhagic lesions were segmented into core and rim areas. Mean lesion volumes decreased significantly between the acute and chronic study time points (p=0.008). Average ipsilateral hemispheric tissue loss at 3 to 4 months was 11.4±4.6 cm. MRI showed acutely reduced CBF (p=0.004) and CBV (p=0.002) in the rim, followed by steady normalization. Apparent diffusion coefficient of water (ADC) in the rim demonstrated no alterations at any of the time points (p>0.2). The T values were significantly elevated in the rim acutely (p=0.02), but later returned to baseline. The ICH core showed sustained low CBF and CBV values concurrent with a small reduction in ADC acutely, but significant ADC elevation at the end suggestive of irreversible injury.
Despite the presence of a small, probably permanent, cerebral lesion in the ICH core, no patients exhibited post-treatment rebleeding. These data suggest that larger, Phase 2 trials are warranted to establish long term clinical safety of atorvastatin in spontaneous ICH.
本前瞻性安全性试验旨在确定阿托伐他汀治疗自发性脑出血（ICH）后是否存在再出血情况。
6例原发性ICH患者在发病24小时内且格拉斯哥昏迷评分（GCS）>5时开始接受阿托伐他汀（80毫克/天）治疗，并持续7天，随后剂量逐渐减少并在接下来5天内终止治疗。通过多参数磁共振成像（MRI）在三个时间点对患者进行纵向研究：急性期（3至5天）、亚急性期（4至6周）和慢性期（3至4个月）。成像序列包括T1加权成像（T1WI）、扩散张量成像（DTI）以及对比增强MRI对脑灌注、血容量和血脑屏障（BBB）通透性的测量。磁敏感加权成像（SWI）用于识别原发性ICH并检查是否有继发性再出血。在3至4个月时使用格拉斯哥预后评分（GOS）评估最终结局。
平均入院GCS为13.2±4.0，3个月时平均GOS为4.5±0.6。出血性病变被分为核心区和边缘区。在急性期和慢性期研究时间点之间，平均病变体积显著减小（p=0.008）。3至4个月时同侧半球平均组织损失为11.4±4.6立方厘米。MRI显示边缘区急性期脑血流量（CBF）（p=0.004）和脑血容量（CBV）（p=0.002）降低，随后逐渐恢复正常。边缘区水的表观扩散系数（ADC）在任何时间点均无变化（p>0.2）。边缘区T2值急性期显著升高（p=0.02），但随后恢复至基线。ICH核心区显示持续低CBF和CBV值，同时急性期ADC略有降低，但末期ADC显著升高，提示存在不可逆损伤。
尽管ICH核心区存在一个小的、可能为永久性的脑损伤，但没有患者出现治疗后再出血。这些数据表明，有必要开展更大规模的2期试验，以确定阿托伐他汀在自发性ICH中的长期临床安全性。
