Intensive Blood Pressure Reduction in Deep Intracerebral Hemorrhage

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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.