Intensive Blood Pressure Reduction in Deep Intracerebral Hemorrhage

自发性脑出血占所有卒中的10%至15%，构成最具破坏性的卒中亚型， 40%的死亡率和大多数幸存者经历了严重的残疾。这是一种毁灭性的负担 疾病是由于缺乏有效的治疗方法，正如几个治疗脑出血的大型临床试验所述 已经开展了一些活动，但未能改善结果。其中一种疗法是强化降压， 这被认为可以减少血肿的扩大。最近的两项大型试验，ATACH-2和INTERACT2 证明了强化降压是可行和安全的，但没有明确的临床表现 利益。然而，这些试验招募的受试者与脑出血的位置无关，这是众所周知的相关因素。 具有不同的潜在病理生理过程：大叶性脑出血主要与脑淀粉样蛋白有关 血管病变、深部脑出血主要与长期高血压引起的小血管疾病有关。 推动目前这一提议的是越来越多的证据表明，不同的生物途径 深部和叶状脑出血的潜在发展不仅决定了脑出血的风险，而且还决定了脑出血的体积 一旦出血发生，就会出血。这个想法告诉我们的中心假设， 高血压相关的脑出血对急性血压波动更敏感。通过对HIGH的重新分析， NINDS资助的高质量数据，我们将测试ICH位置是否改变候选疗法的效果 中间端点和功能结果。我们将对ATACH-2试验进行二次分析 深度高血压相关脑出血的受试者，以确定从强化治疗中受益的患者亚群 血压治疗，随后在观察中复制我们的发现，种族/民族多样化 ERICH研究，以减轻随机临床试验二次分析固有的局限性的影响。 我们将解决以下目标：(1)确定强化血压治疗是否与 减少深部脑出血的血肿扩张和水肿扩张，以及这种影响是否被 脑出血的特定深部位置(丘脑与基底节)；以及(2)确定是否有强烈的血压 治疗与改善深部脑出血的预后有关，以及这种影响是否会被 脑出血的特定深部位置(丘脑与基底节)。这一建议的可行性取决于：(1)开放 NINDS临床研究提供的可获得的、表型良好的临床试验和观察数据 档案；(2)PIs在流行病学、神经影像特征、遗传学方面的广泛研究经验 结果的基础和决定因素；和(3)有希望的初步分析，评估 这项提议中正在探索的假设。总而言之，这项工作将确定一个重要的患者亚群 这可能受益于强化的血压治疗，而且将为脑出血的使用提供证据。 在未来试验的设计和分析中定位，以更快地为这一毁灭性的疾病转化新疗法 疾病。

Spontaneous ICH comprises 10% to 15% of all strokes and constitutes the most devastating stroke subtype, with 40% mortality and the majority of survivors experiencing severe disability. The devastating burden of this disease is due to the lack of effective treatments, as several large clinical trials of therapies for ICH have been conducted but have failed to improve outcomes. One of these therapies is intensive blood pressure reduction, which is thought to reduce hematoma expansion. Two large trials, ATACH-2 and INTERACT2, recently demonstrated that intensive blood pressure reduction is feasible and safe but failed to show a definitive clinical benefit. However, these trials enrolled subjects without regard to ICH location, a factor well-known to correlate with different underlying pathophysiological processes: while lobar ICH is mainly related to cerebral amyloid angiopathy, deep ICH is mainly linked to small vessel disease caused by long-standing hypertension. Motivating the current proposal is mounting evidence suggesting that the different biological pathways underlying the development of deep and lobar ICHs not only determine ICH risk, but also the volume of bleeding once the hemorrhage has taken place. This idea informs our central hypothesis that deep, hypertension-related ICH is more sensitive to acute blood pressure fluctuations. Through re-analyses of high- quality NINDS-funded data, we will test whether ICH location modifies the effect of candidate therapies on intermediate endpoints and functional outcome. We will perform a secondary analysis of the ATACH-2 trial in subjects with deep, hypertension-related ICH to identify a subgroup of patients that benefit from intensive blood pressure treatment, followed by replication of our findings in the observational, racially/ethnically diverse ERICH study to mitigate the impact of limitations inherent to secondary analyses of randomized clinical trials. We will address the following aims: (1) To determine if intensive blood pressure treatment is associated with reduced hematoma expansion and edema expansion in deep ICH, and whether this effect is modified by the specific deep location of the ICH (thalamus vs basal ganglia); and (2) To determine if intensive blood pressure treatment is associated with improved outcomes among deep ICH, and whether this effect is modified by the specific deep location of the ICH (thalamus vs basal ganglia). This proposal's feasibility rests on: (1) open access, well-phenotyped clinical trial and observational data available from the NINDS Clinical Research Archives; (2) the PIs' extensive research experience in epidemiology, neuroimaging characteristics, genetic underpinnings and determinants of outcomes in ICH; and (3) promising preliminary analyses evaluating the hypotheses being explored in this proposal. In total, this work will identify an important subgroup of patients that may benefit from intensive blood pressure treatment, and furthermore, will provide evidence for use of ICH location in design and analysis of future trials to more rapidly translate new therapies for this devastating disease.