Outcomes of Intensive Systolic Blood Pressure Reduction in Patients With Intracerebral Hemorrhage and Excessively High Initial Systolic Blood Pressure: Post Hoc Analysis of a Randomized Clinical Trial

Key Points

Questions  What are the outcomes of intensive systolic blood pressure reduction in patients with intracerebral hemorrhage and excessively high initial systolic blood pressure (≥220 mm Hg)?

Findings  This post hoc analysis of a randomized clinical trial showed higher rates of neurological deterioration and no evidence of reducing hematoma expansion at 24 hours or death or severe disability at 90 days in those who underwent intensive systolic blood pressure reduction.

Meaning  The significantly higher rate of neurological deterioration associated with intensive treatment in patients with initial systolic blood pressure of 220 mm Hg or more warrants caution against broad recommendations for intensive systolic blood pressure reduction in patients with intracerebral hemorrhage.

Importance  The safety and efficacy of intensive systolic blood pressure reduction in patients with intracerebral hemorrhage who present with systolic blood pressure greater than 220 mm Hg appears to be unknown.

Objective  To evaluate the differential outcomes of intensive (goal, 110-139 mm Hg) vs standard (goal, 140-179 mm Hg) systolic blood pressure reduction in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more vs less than 220 mm Hg.

Design, Setting, and Participants  This post hoc analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage-II trial was performed in November 2019 on data from the multicenter randomized clinical trial, which was conducted between May 2011 to September 2015. Patients with intracerebral hemorrhage and initial systolic blood pressure of 180 mm Hg or more, randomized within 4.5 hours after symptom onset, were included.

Interventions  Intravenous nicardipine infusion titrated to goals.

Main Outcomes and Measures  Neurological deterioration and hematoma expansion within 24 hours and death or severe disability at 90 days, plus kidney adverse events and serious adverse events until day 7 or hospital discharge.

Results  A total of 8532 patients were screened, and 999 individuals (mean [SD] age, 62.0 [13.1] years; 620 men [62.0%]) underwent randomization and had an initial SBP value. Among 228 participants with initial systolic blood pressures of 220 mm Hg or more, the rate of neurological deterioration within 24 hours was higher in those who underwent intensive (vs standard) systolic blood pressure reduction (15.5% vs 6.8%; relative risk, 2.28 [95% CI, 1.03-5.07]; P = .04). The rate of death and severe disability (39.0% vs 38.4%; relative risk, 1.02 [95% CI, 0.73-1.78]; P = .92) was not significantly different between the 2 groups. There was a significantly higher rate of kidney adverse events in participants randomized to intensive systolic blood pressure reduction (13.6% vs 4.2%; relative risk, 3.22 [95% CI, 1.21-8.56]; P = .01), but no difference was observed in the rate of kidney serious adverse events.

Conclusions and Relevance  The higher rate of neurological deterioration within 24 hours associated with intensive treatment in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more, without any benefit in reducing hematoma expansion at 24 hours or death or severe disability at 90 days, warrants caution against generalization of recommendations for intensive systolic blood pressure reduction.

The guidelines¹ from the American Heart Association and American Stroke Association for the management of spontaneous intracerebral hemorrhage (ICH) recommend, “For ICH patients presenting with SBP [systolic blood pressure] between 150 and 220 mm Hg and without contraindication to acute blood pressure treatment, acute lowering of SBP to 140 mm Hg is safe (Class I; Level of Evidence A) and can be effective for improving functional outcome (Class IIa; Level of Evidence B)”^1(p2040) and “For ICH patients presenting with SBP >220 mm Hg, it may be reasonable to consider aggressive reduction of BP [blood pressure] with a continuous intravenous infusion and frequent BP monitoring (Class IIb; Level of Evidence C).”^1(p2040) Class IIb indicates that efficacy is less well established by evidence and additional studies with broad objectives and/or additional registry data will be helpful.

The lower levels of evidence for recommendations for patients with SBP greater than 220 mm Hg are based on the lack of data derived from the Second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2),² which only included patients with ICH with at least 2 SBP measurements greater than or equal to 150 mm Hg and less than or equal to 220 mm Hg.^2,3 The European Stroke Organisation–Karolinska Stroke Update Conference⁴ has also recommended lowering SBP to less than 140 mm Hg and greater than 110 mm Hg in patients with acute ICH (without recommendations stratified by initial SBP levels) but has recommended avoiding SBP reduction of more than 90 mm Hg to prevent acute kidney injury (grade B; supported by randomized clinical trials and statistical reviews). The guidelines¹ admit the lack of existing data regarding SBP reduction in patients with excessively high SBP. We performed a post hoc analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage–II (ATACH-II) trial (ClinicalTrials.gov Identifier: NCT01176565) to provide additional data on safety and efficacy of intensive SBP reduction in patients with excessively high initial SBP.

The ATACH-II trial was a multicenter, 2-group, open-label randomized clinical trial to determine the relative efficacy of intensive vs standard SBP reduction initiated within 4.5 hours of symptom onset and continued for the next 24 hours in patients with spontaneous supratentorial ICH. The details are provided in previous publications.^5-7 The flow diagram is presented in the Figure. In the initial protocol (version 1.0), finalized on January 20, 2010, SBP on admission greater than 180 mm Hg but less than 240 mm Hg on 2 measurements at least 5 minutes apart was used as a key inclusion criterion. A protocol modification (version 3.0-4.0) on September 23, 2011, removed the upper limit (less than 240 mm Hg).^8-10 At least 1 reading of SBP of 180 mm Hg or more between symptom onset and the initiation of intravenous antihypertensive treatment was required for eligibility.⁶ The protocol and consent forms were approved by the institutional review board or equivalent ethics committee at each participating site, and all participants or their legally authorized representatives provided written informed consent before randomization. An independent data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke monitored the trial.

The first SBP recorded in the emergency department was termed the initial SBP. Treatment could be initiated before randomization to lower the SBP to less than 180 mm Hg, which was consistent with the American Stroke Association Stroke Council guidelines,¹¹ but this was maintained at 140 mm Hg or more before randomization. The SBP immediately prior to randomization was termed the prerandomization SBP, which was different from the initial SBP.

The goal of treatment was to reduce and maintain the hourly minimum SBP in the ranges of 140 to 179 mm Hg in the standard SBP reduction group and 110 to 139 mm Hg in the intensive SBP group throughout the period of 24 hours after randomization. Baseline and 24-hour computed tomography scans were forwarded to the core image analysis center. All adverse events (AEs) were classified with the use of terminology from the Medical Dictionary for Regulatory Activities and systematically reported up to day 7 or hospital discharge, whichever came first. The kidney AEs were grouped as described previously.⁷ Serious AEs (SAEs) that met the regulatory definition of seriousness were systematically reported up to 3 months after randomization.¹² The degree of disability or dependence in daily activities was assessed at 90 days using the modified Rankin scale by an independent investigator unaware of the SBP reduction group. The SAEs were further classified as treatment-associated SAEs occurring within 72 hours after randomization that were considered by the site investigator to be associated with treatment.

The primary outcome was the proportion of participants who experienced death or severe disability (modified Rankin scale score, 4 to 6) at 90 days. Additional outcomes were neurologic deterioration, defined as a decrease from baseline of 2 or more points in Glasgow Coma Scale score or an increase of 4 or more points in the National Institutes of Health Stroke Scale score that was not associated with sedation or hypnotic agent use and was sustained for at least 8 hours within the 24 hours after randomization; hematoma expansion, defined as an increase of 33% or more in the hematoma volume from baseline to 24 hours; and hypotension within 72 hours, defined by a BP that was lower than 90/60 mm Hg.¹³

We compared demographic features; clinical characteristics and rates of hematoma expansion; neurological deterioration; SAEs, including those ascribed to treatment; serious hypotension; and 90-day death or severe disability between groups with initial SBP of 220 mm Hg or more and less than 220 mm Hg. We subsequently categorized the participants classified with initial SBP of 220 mm Hg or more and those with initial SBP of less than 220 mm Hg according to allocated treatment (intensive or standard SBP reduction) and compared the mentioned variables. We used χ² tests and analysis of Wilcoxon rank sum tests for categorical and continuous variables. We performed an exploratory analysis comparing the mentioned variables in participants with prerandomization SBP of 220 mm Hg or more and less than 220 mm Hg.

We tested the modifying effect of an initial SBP of 220 mm Hg or more by entering the interaction between treatment group (intensive vs standard SBP reduction) and SBP level (excessively high [≥220 mm Hg] vs <220 mm Hg) using a logistic regression model that included all randomized participants, with 90-day death or severe disability as the primary end point. We also explored the association of race (African American vs others) by entering it as an interaction term with excessively higher SBP in the model. We adjusted for age, Glasgow Coma Scale score, and hematoma volume (all continuous variables). All results were analyzed using SAS Studio Software release 3.8 (Enterprise Edition [SAS Institute]) in November 2019.

Of a total of 999 participants with data on initial SBP, 228 had initial SBP of 220 mm Hg or more (mean [SD] age, 59.0 [13.2] years; 137 men [60.1%]; Table 1). The mean (SD) age of the group with initial SBP of 220 mm Hg or more was lower than the 771 individuals with initial SBP of less than 220 mm Hg (59.0 [13.2] years vs 62.8 [12.9] years; P < .001). There was a lower proportion of cerebral lobe ICHs in individuals with SBP of 220 mm Hg or more vs less than 220 mm Hg (17 of 228 [7.5%] vs 99 of 771 [12.8%]; P = .03). The mean (SD) minimum SBP measurements at 6 to 7 hours and 23 to 24 hours after randomization were significantly higher among the participants with SBP of 220 mm Hg or more (6-7 hours: 132.2 [17.9] mm Hg vs 128.9 [18.0] mm Hg; P = .01; 23-24 hours: 140.1 [19.0] mm Hg vs 135.8 [17.2] mm Hg; P = .002, respectively). The rate of 90-day death or severe disability was not different between groups (38.7% vs 38.1%; relative risk [RR], 1.02 [95% CI, 0.84-1.23]; P = .87). The rate of hematoma expansion (14.8% vs 25.0%; RR, 0.59 [95% CI, 0.42-0.83]; P = .001) was significantly lower among participants with SBP of 220 mm Hg or more. The neurological deterioration within 24 hours (11.0% vs 9.1%; RR, 1.21 [95% CI, 0.78-1.86]; P = .39) and SAEs (22.4% vs 22.8%; RR, 0.98 [95% CI, 0.74-1.29]; P = .93) were not different between groups. There were no significant differences in the rates of kidney AEs (8.8% vs 5.8%; RR, 1.50 [95% CI, 0.91-2.49]; P = .11) and kidney SAEs (1.3% vs 0.3%; RR, 5.07 [95% CI, 0.85-30.17]; P = .08) between the 2 groups.

Of a total of 228 randomized participants with SBP of 220 mm Hg or more, 110 were randomized to intensive SBP reductions. Compared with 118 participants with SBP of 220 mm Hg or more who were randomized to standard SBP reduction, there were no differences in the mean age or proportion of each sex (Table 2). The mean (SD) minimum SBP measurements at 2 to 3 hours, 6 to 7 hours, and 23 to 24 hours after randomization were all significantly lower in the intensive SBP reduction group than the standard SBP reduction group (2-3 hours: 121.7 [15.2] mm Hg vs 140.4 [19.2] mm Hg; P < .001; 6-7 hours: 122.1 [12.2] mm Hg vs 141.7 [17.3] mm Hg; P < .001; 23-24 hours: 127.1 [13.4] mm Hg vs 152.6 [14.8] mm Hg; P < .001). The rates of death or severe disability at 90 days showed no significant difference between groups (39.0% vs 38.4% for intensive and standard SBP reductions, respectively; RR, 1.02 [95% CI, 0.73-1.78]; P = .92; Table 3). Hematoma expansion within 24 hours (13.8% and 15.8% for intensive and standard SBP reductions, respectively; RR, 0.87 [95% CI, 0.46-1.64]; P = .67) was not different between the 2 groups. The rate of neurological deterioration within 24 hours (15.5% vs 6.8%; RR, 2.28 [95% CI, 1.03-5.07]; P = .04) was significantly higher in participants randomized to intensive SBP reduction. The percentage of participants with treatment-associated SAEs within 72 hours after randomization was 2.7% and 0.8% in the intensive and standard SBP reduction groups, respectively (RR, 3.22 [95% CI, 0.34-30.48]; P = .35). The percentage of participants with SAEs during the full study duration was 27.3% and 17.8% in the intensive and standard SBP reduction groups (RR, 1.53 [95% CI, 0.94-2.51]; P = .09). There was a significantly higher rate of kidney AEs in individuals randomized to intensive SBP reduction (13.6% vs 4.2%; RR, 3.22 [95% CI, 1.21-8.56]; P = .01).

Of a total of 771 randomized participants with initial SBP less than 220 mm Hg, 390 and 381 participants were randomized to intensive and standard SBP reduction, respectively (Table 2). The rate of hematoma expansion within 24 hours was significantly lower in those randomized to intensive SBP reduction than those randomized to standard SBP reduction (20.9% vs 29.2%; RR, 0.72 [95% CI, 0.56-0.92]; P = .009; Table 4). There was a significantly higher rate of kidney AEs in participants randomized to intensive SBP reduction (7.7% vs 3.9%; RR, 1.95 [95% CI, 1.07-3.57]; P = .03).

Of a total of 1000 randomized participants with complete data on prerandomization SBP, 48 had a prerandomization SBP of 220 mm Hg or more. Among those with a prerandomization SBP of 220 mm Hg of more, the rate of death or severe disability at 90 days was significantly higher for individuals randomized to intensive SBP reduction (66.7% vs 29.2%; RR, 2.29 [95% CI, 1.15-4.53]; P = .009). The rate of hematoma expansion (33.3% vs 26.1%; RR, 1.28 [95% CI, 0.52-3.11]; P = .59) was similar between the 2 treatment groups. The rate of neurological deterioration within 24 hours was 20.8% and 4.2% for the intensive and standard SBP reduction treatment groups (RR, 5.00 [95% CI, 0.63-39.67]; P = .19).

In the first multivariate model including all randomized participants (n = 960) with data available on modified Rankin scale scores at 90 days, neither intensive SBP reduction nor an initial SBP of 220 mm Hg or more was associated with death or severe disability at 90 days. The interaction between treatment group (intensive vs standard SBP reduction) and initial SBP (≥220 mm Hg vs <220 mm Hg) was not significant. The interaction between race and initial SBP was not significant. In the second analysis, the interaction between treatment groups and prerandomization SBP was significant (SBP ≥220 mm Hg with intensive treatment: RR, 4.8 [95% CI, 1.8-12.7]; SBP ≥220 mm Hg with standard treatment: RR, 0.9 [95% CI, 0.3-2.6]; intensive treatment with SBP ≥220 mm Hg: RR, 4.8 [95% CI, 1.2-18.6]; intensive treatment with SBP <220 mm Hg: RR, 0.9 [95% CI, 0.7-1.3]; P = .02).

Intensive SBP reduction was associated with a higher rate of neurological deterioration within 24 hours compared with standard SBP reduction among individuals with initial SBP of 220 mm Hg or more (and this was not seen in those with initial SBP <220 mm Hg). Although hematoma expansion is an important cause of early neurological deterioration,¹⁴ we did not identify any difference in the rate of hematoma expansion within 24 hours between participants randomized to intensive vs standard SBP reduction. Another possibility is that intensive SBP reduction resulted in cerebral ischemia among participants with initial SBP of 220 mm Hg or more. A previous study¹⁵ found that minimum SBP of 120 mm Hg or less over 72 hours was associated with restricted diffusion lesions (suggestive of ischemia) on magnetic resonance imaging (MRI) in patients with ICH. Garg et al¹⁶ found that patients with restricted diffusion lesions on MRI had higher SBP on emergency department admission. However, no differences were identified in SBP changes from intensive care unit admission until MRI completion between patients who did vs did not have restricted diffusion lesions on MRI. Presence of restricted diffusion lesions on MRI was associated with higher rates of death or severe disability at 3 months.

Despite a higher rate of neurological deterioration within 24 hours of randomization in participants with initial SBP of 220 mm Hg or more, the rate of death or severe disability at 90 days was not higher in those randomized to intensive SBP reduction. In an analysis of INTERACT2 that limited inclusion to those with SBP less than 220 mm Hg, participants with higher SBP were at higher risk of early and late neurological deterioration (via an incremental risk for each 10 mm Hg of SBP greater than 150 mm Hg).¹⁷ Both early and late neurological deteriorations were associated with death or major disability at 90 days. The goal for individuals with initial SBP of 220 mm Hg or more in ATACH-II was to reduce SBP to less than 180 mm Hg until randomization was performed, leading to stepwise SBP reductions. One possible explanation of lack of association of neurological deterioration with 90-day death or severe disability rates could be that treating physicians may have responded to neurological deterioration by adjustment in the rate of (or avoidance of any further) SBP decline, which could have prevented irreversible ischemia and long-term adverse outcomes. There was a higher rate of kidney AEs but not kidney SAEs in participants randomized to intensive SBP reduction, which may explain the lack of association with 90-day death or severe disability. Intensive SBP reduction was associated with a higher rate of death or severe disability at 90 days in individuals with prerandomization SBP of 220 mm Hg or more, and a significant modifying interaction of prerandomization SBP of 220 mm Hg or more was seen on the association with SBP reduction in an exploratory analysis.

Patients with excessively high initial SBP represent a unique group of patients with ICH. Earlier studies have suggested that this group of patients are at higher risk of hematoma expansion¹⁸ and higher mortality.¹⁹ The ATACH-II trial was uniquely poised to study patients with excessively high SBP on presentation because of a higher proportion of patients who presented with SBP of 220 mm Hg or more. The mean SBP at presentation in participants in ATACH-II was 200 mm Hg, compared with 170 to 182 mm Hg in INTERACT1,²⁰ INTERACT2,² the Recombinant Activated Factor VII trial,²¹ the Factor Seven for Acute Hemorrhagic Stroke trial,²² and the Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial.²³ Some previous studies have found a higher rate of hematoma expansion,¹⁸ hospital mortality,¹⁹ and 28-day mortality²⁴ with very high SBP or mean arterial pressure measured in the initial period of presentation to the hospital. Contrary to such studies,^18,19 patients with excessively high initial SBP did not have higher rates of hematoma expansion, death, or disability compared with those with initial SBP less than 220 mm Hg in the ATACH-II trial. Some other studies^25,26 have reported that higher rates of hematomata expansion or mortality in patients with ICH and high initial mean arterial pressure or SBP are associated with differences in initial Glasgow Coma Scale scores, hematoma volume, and presence of intraventricular hemorrhage. We did not identify any differences in initial neurological status or hematoma volumes in patients with excessively high initial SBP compared with those with initial SBP less than 220 mm Hg. It is possible that excessively high initial SBP were the result of poorly controlled baseline hypertension and not associated with acute neurological events in some patients.

The American Heart Association and American Stroke Association guidelines in 2015 were based on the results of the INTERACT2 trial.^2,3,27 The trial included 2794 patients, of whom 47% had initial SBP of 180 mm Hg or more. The rate of death or dependency at 90 days was slightly higher among patients with initial SBP of 180 mm Hg or more (56%) compared with those with initial SBP less than 180 mm Hg (52%). However, the outcomes associated with intensive SBP reduction did not differ according to initial SBP groups (<180 mm Hg and ≥180 mm Hg) in a prespecified analysis. In the absence of additional data, the guidelines considered it reasonable to aggressively reduce BP with a continuous intravenous infusion and frequent BP monitoring for patients with ICH who present with excessively high SBP (>220 mm Hg), with the clear understanding that usefulness or efficacy is not well established by evidence and based on consensus of opinion. Our data provide additional insight and perhaps evidence for caution and the need for further studies in this unique patient population. It is possible that the modest benefit seen with intensive SBP reduction in the INTERACT2 trial may not be reproducible in patients with initial SBP of 220 mm Hg or more.

We acknowledge the limitations of post hoc analysis.^28-30 Post hoc or subgroup analysis is reserved for the examination of data subsets accrued in the setting of a clinical trial to answer clinically relevant questions that were not addressed in the prespecified data analysis plan. Our analysis can identify a group of patients who may respond differently to treatment than other groups. We acknowledge that the subgroup hypothesis or the direction of outcome was not prespecified.^29,30 There was biologic plausibility of different outcomes and perhaps treatment effects in the patients with initial SBP of 220 mm Hg or more as described. The small number of patients with initial SBP of 220 mm Hg or more may not have allowed identification of smaller differences in outcome between the subgroups, such as those based on hematoma location (a type II error).³¹ Patients with severe neurological injury, high intracranial pressure, or compression of the brainstem were excluded in the ATACH-II study. Therefore, the analysis may not be reflective of patients who have high SBP secondary to intracranial hypertension or brainstem compression.

In the ATACH-II trial, intensive SBP reduction resulted in disproportionately higher rates of neurological deterioration in patients with initial SBP of 220 mm Hg or more and higher rates of death or severe disability at 90 days in patients with prerandomization SBP of 220 mm Hg or more. This post hoc analysis of the ATACH-II data suggests that caution and avoidance of intensive SBP reduction is warranted in patients with initial SBP of 220 mm Hg or more.

Accepted for Publication: June 12, 2020.

Corresponding Author: Iryna Lobanova, MD, Zeenat Qureshi Stroke Institute, Department of Neurology, University of Missouri, One Hospital Drive, CE507, Columbia, MO 65212 (lobanovanmu@gmail.com).

Published Online: September 8, 2020. doi:10.1001/jamaneurol.2020.3075

Correction: This article was corrected on October 5, 2020, to update the short title to match the article title.

Author Contributions: Ms Huang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Qureshi, Hsu, Steiner, Suarez.

Acquisition, analysis, or interpretation of data: Huang, Lobanova, Barsan, Hanley, Lin, Silbergleit, Toyoda, Yamamoto.

Drafting of the manuscript: Qureshi, Hsu, Lin, Suarez.

Critical revision of the manuscript for important intellectual content: Huang, Lobanova, Barsan, Hanley, Silbergleit, Steiner, Suarez, Toyoda, Yamamoto.

Statistical analysis: Huang, Lobanova, Lin.

Obtained funding: Qureshi.

Administrative, technical, or material support: Huang, Barsan, Hanley, Silbergleit, Toyoda.

Supervision: Hsu, Steiner, Suarez, Yamamoto.

Conflict of Interest Disclosures: Dr Barsan reported grants from the National Institute of Neurological Disease and Stroke during the conduct of the study. Dr Hanley reported personal fees from BrainScope, Neurotrope, Op2Lysis, and Portola Pharmaceuticals and grants from the National Institutes of Health outside the submitted work. Dr Silbergleit reported grants from the National Institutes of Health during the conduct of the study. Dr Suarez reported serving as the chair of a data safety and monitoring board for the INTREPID study, which was funded by Bard; Dr Suarez received no compensation for his participation. Dr Toyoda reported personal fees from Daiichi-Sankyo, Bayer Yakuhin, Bristol-Myers Squibb, and Nippon Boehringer outside the submitted work. No other disclosures were reported.

Funding/Support: The study is supported by the National Institute of Neurological Disorders and Stroke (grants U01-NS062091 [Dr Qureshi] and U01-NS056975 [Dr Barsan]) and the Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center (grant H23-4-3 [Dr Toyoda]).

Role of the Funder/Sponsor: The funders provided oversight of the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The clinical sites and site investigators were National Cerebral and Cardiovascular Center, Osaka, Japan (79): Kazunori Toyoda, MD, PhD (principal investigator); Kazuyuki Nagatsuka, MD, PhD (investigator); and Kanae Hirase, RN, CCRC (primary coordinator). Beijing Tiantan Hospital, Beijing, China (72): Yongjun Wang, MD, PhD (principal investigator) and Zeyu Ding, MD, PhD (primary coordinator). Kobe City Medical Center General Hospital, Kobe City, Hyogo, Japan (53): Nobuyuki Sakai, MD, DMSc (principal investigator); Kenichi Todo, MD, PhD (investigator); and Sakina Yoshihira (primary coordinator). Toranomon Hospital, Tokyo, Japan (38): Takayuki Hara, MD (principal investigator) and Mihoko Matsukami (primary coordinator). Taizhou First People's Hospital, Taizhou City, Zhejiang Province, China (37): Zhimin Wang, MD (principal investigator) and Jie Chen, MD (primary coordinator). National Taiwan University Hospital, Taipei, Taiwan (36): Jiann-Shing Jeng, MD, PhD (principal investigator); Sung-Chun Tang, MD, PhD; Li-Kai Tsai, MD, PhD, and Shin-Joe Yeh, MD (co-principal investigators); and Yu-Ting Wang (primary coordinator). Columbia University Medical Center, New York, New York (27): Sachin Agarwal, MD, MPH (principal investigator); Stephan A. Mayer, MD (principal investigator), and M. Cristina Falo, PhD, and Angela Velazquez, MD (primary coordinators). St Cloud Hospital, St Cloud, Minnesota (26): M Fareed K Suri, MD (principal investigator) and Melissa A. Freese, BSN, RN, CNRN (primary coordinator). Abington Memorial Hospital, Abington, Pennsylvania (23): Qaisar A. Shah, MD (principal investigator); Karin Jonczak, CRNP; and Patricia Businger, CRNP (primary coordinators). Baylor College of Medicine, Houston, Texas (20): Jose I. Suarez, MD, and Paulina B. Sergot, MD (principal investigators) and Eusebia Calvillo, RN, and Kelly Rogers Keene, BSN, RN (primary coordinators). Stroke & Neurovascular Center, JFK Medical Center, Edison, New Jersey (18): Jawad F. Kirmani, MD (principal investigator); Spozhmy Panezai, MD (co-principal investigator); Charles Porbeni, MD; and Nnamdi Uhegwu, MD, and Briana DeCarvalho, MSN, RN (primary coordinators). Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (18): Ching-Huang Lin, MD and Yuk-Keung Lo, MD (principal investigators) and Yi-Ting Hsu (primary coordinator). Guilford Neurologic Associates, Greensboro, North Carolina (16): Pramod Sethi, MD (principal investigator) and Rizwan Sabir and Wesley Harbison, RN, MHA (primary coordinators). Kyorin University, Tokyo, Japan (16): Yoshiaki Shiokawa, MD, PhD (principal investigator) and Masataka Torii MD, PhD (primary coordinator). St. Marianna University Hospital, Kawasaki, Kanagawa, Japan (16): Yasuhiro Hasegawa, MD, PhD (principal investigator) and Yuki Ohta, PhD, and Sachiko Takenoshita, PhD (primary coordinators). China Medical University Hospital, Taichung, Taiwan (16): Chun-Lin Liu, MD (principal investigator) and Li-Te Tseng (primary coordinator). Hennepin County Medical Center, Minneapolis, Minnesota (14): Thomas A. Bergman, MD (principal investigator); Gustavo J. Rodriguez, MD (principal investigator, former); Kathryn France, BA, RN, PHN, CCRC, CCRA (primary coordinator); and Kathleen Miller, BSN CCRC (primary coordinator, former). Gifu University Hospital, Gifu, Japan (14): Toru Iwama, MD, PhD (principal investigator); Shin-ichi Yoshimura, MD, PhD (principal investigator); Yusuke Egashira, MD, PhD; and Toshinori Takagi, MD, PhD (primary coordinators). University Hospital Heidelberg, Heidelberg, Germany (14): Julian Bösel, MD (principal investigator) and Perdita Beck (primary coordinator). Department of Neurosurgery, Nakamura Memorial Hospital, Sapporo, Hokkaido, Japan (13): Kenji Kamiyama, MD (principal investigator) and Ryo Fujii and Megumi Chiba (primary coordinators). Grady Memorial Hospital, Atlanta, Georgia (12): Gustavo Pradilla, MD (principal investigator); Alex J. Hall, MS, RN (primary coordinator); and Michael P. Lunney, MPH, NRP (primary coordinator, former). Kansas University Medical Center, Kansas City (12): Katherine Palmieri, MD (principal investigator); Abhijit Lele, MD (principal investigator, former); Rachel Henning, RN, BSN, CCRP (primary coordinator); and Stephanie Thomas-Dodson and Angie Ballew (primary coordinators, former). Stanford University, Stanford, California (12): Chitra Venkatasubramanian, MBBS, MD, MSc (principal investigator); Christine Wijman, MD (principal investigator, former, deceased); Rosita Thiessen, BA, CCRP (primary coordinator); and Madelleine Garcia and Ami Okada, PhD (primary coordinators, former). Tokyo Saiseikai Central Hospital, Tokyo, Japan (12): Haruhiko Hoshino, MD (principal investigator) and Chiaki Arakawa (primary coordinator). Wuhan Brain Hospital, Wuhan, China (12): Yuhua Chen, MD (principal investigator) and Jin Li, MD (primary coordinator). Memorial Hermann–Texas Medical Center, Houston (11): Tiffany R. Chang, MD (principal investigator) and Misty Ottman (primary coordinator). Valley Baptist Medical Center, Harlingen, Texas (11): Ameer E. Hassan, DO (principal investigator) and Olive Sanchez, MSN, RN, BC (primary coordinator). Kohnan Hospital, Sendai, Miyagi, Japan (11): Eisuke Furui, MD (principal investigator) and Aki Osanai (primary coordinator). Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (11): Li-Ming Lien, MD, PhD (principal investigator); Hsu-Ling Yeh, MD (investigator); and I-Yu Lee (primary coordinator). Seoul National University Hospital, Seoul, South Korea (11): Byung-Woo Yoon, MD, PhD (principal investigator); Yeo-Jung Chae; and Jae-Young Jo, RN (primary coordinators). UAB Comprehensive Stroke Center, Birmingham, Alabama (10): Angela N. Hays, MD (principal investigator); Andrei V. Alexandrov, MD (principal investigator, former); April Sisson, BSN, RN (primary coordinator); and Lynn Merritt, RN (primary coordinator, former). Massachusetts General Hospital, Boston (10): Joshua N. Goldstein, MD, PhD (principal investigator); Gregory Tirrell, MS (primary coordinator); Abigail Cohen, Kristen McNamara, and Lauren Barton (primary coordinators, former). St Marianna University Tokyo Hospital, Kawasaki, Kanagawa, Japan (10): Toshihiro Ueda, MD (principal investigator) and Yoko Kaji (primary coordinator). National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (10): Yasushi Okada, MD, PhD (principal investigator); Asako Nakamura, MD, PhD; and Kouichirou Maeda (primary coordinators). Datong Third People's Hospital, Datong, Shanxi Province, China (10): Xudong Ren, MD (principal investigator) and Kang Ye (primary coordinator). University of Bonn, Bonn, Germany (10): Hartmut Vatter, MD (principal investigator); Erdem Güresir, MD (investigator); and Azize Boströem, MD (investigator, primary coordinator). Ochsner Clinic Foundation, New Orleans, Louisiana (9): Ifeanyi Iwuchukwu, MD (principal investigator); Arash Afshinnik, MD; and Kenneth Gaines, MD (principal investigators, former) and William Itoua Nganongo (primary coordinator). Temple University Hospital, Philadelphia, Pennsylvania (9): Nina T. Gentile, MD (principal investigator); Vernon S. Kalugdan, BSN, RN; and Brent Freeman (primary coordinators). Novant Health Research Institute–Novant Health Forsyth Medical Center, Winston-Salem, North Carolina (9): Benjamin Anyanwu, MD (principal investigator); Chere Chase-Gregory, MD, MHS (principal investigator, former); and Kevin Colston, LPN, CRC (primary coordinator). Henry Ford Hospital, Detroit, Michigan (9): Christopher Lewandowski, MD (principal investigator); Joseph B. Miller, MD, MS (investigator); Shannen Berry-Hymon, RN (primary coordinator); Kathleen Mays-Wilson, MS, BSN, RN, CCRP; and Anne Marie Lundell, BSN, RN (primary coordinators, former). University of Pennsylvania, Philadelphia (8): Steven Messe, MD (principal investigator) and Nichole Gallatti, MSEd (primary coordinator). National Hospital Organization Nagoya Medical Center, Nagoya City, Aichi, Japan (8): Satoshi Okuda, MD (principal investigator) and Kazumi Nakamura (primary coordinator). University Hospitals Case Medical Center, Cleveland, Ohio (7): Nicholas Bambakidis, MD (principal investigator) and Valerie Cwiklinski (primary coordinator). Lehigh Valley Hospital, Allentown, Pennsylvania (7): Hermann Christian Schumacher, MD (principal investigator, former) and Kathy Knapp, Susan Nabhan, and Leighanne Hartman (primary coordinators). Keio University Hospital, Tokyo, Japan (7): Yoshiaki Itoh, MD, PhD, Takato Abe, MD, PhD, and Shinichi Takahashi, MD, PhD (principal investigators) and Mao Okamoto (primary coordinator). National Cheng Kung University Hospital, Tainan, Taiwan (7): Chih-Hung Chen, MD (principal investigator) and Ya-Fang Hsueh (primary coordinator). Advocate Christ Medical Center, Oak Lawn, Illinois (6): Erik Kulstad, MD (principal investigator); Michael T. Stanek, MD (co-principal investigator); and Kathleen Hesse, RN, CCRC (primary coordinator). King's County Medical Center, New York, New York (6): Susan W. Law, DO (principal investigator); Helen Valsamis, MD (principal investigator, former); Steven R. Levine, MD (investigator); Bryce Petty, CCRC (primary coordinator); and Sarah Z. Weingast, Saroj D. Kunnakkat, Bruhati Shah, and Vanessa Arnedo (primary coordinators, former). Baotou Central Hospital, Baotou, China (6): Yuechun Li, MD (principal investigator) and Qiang Chen (primary coordinator). Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea (6): Hee-Joon Bae, MD, PhD (principal investigator); Joungsim Kim (primary coordinator); and Juri Park, RN (coordinator). Regions Hospital, St. Paul, Minnesota (5): Michael D. Zwank, MD (principal investigator); Tenbit Emiru, MD, PhD (principal investigator, former); Emily Mischel, MA (primary coordinator); and Sandi Wewerka, MPH (primary coordinator, former). University of California San Diego, San Diego (5): Dawn Meyer, FNP-C, PhD (principal investigator); Karen Rapp, BSN, RN, CCRC (primary coordinator); and Nancy Kelly, Ronelyn Chavez, and Teresa Rzesiewicz (primary coordinators, former). Palmetto Health Richland and University of South Carolina, Columbia (5): Souvik Sen, MD (principal investigator); Evelyn Kennedy, MSN, RN, CCRP (primary coordinator); and Krista Vaughan, RNC, and Selena Lollar, RN (primary coordinators, former). St Joseph's Regional Medical Center, Paterson, New Jersey (5): Dorothea Altschul, MD (principal investigator); Avery Katz, MD (principal investigator, former); Bogdana Dikovytska, CCRC (primary coordinator); and Milicent Titus, CCRP (primary coordinator, former). Martin-Luther University Hospital Halle-Wittenberg, Halle (Saale), Germany (5): Katja E. Wartenberg, MD, PhD (principal investigator); Doreen Herale (primary coordinator); and Sandra Seidl (primary coordinator, former). University of Tübingen, Tübingen, Germany (5): Sven Poli, MD (principal investigator); Ulf Ziemann, Florian Härtig, Martin Ribitsch, Hardy Richter, Matthias Ebner, and Alexandra Gaenslen (investigators); and Julia Zeller (primary coordinator). Tulane Medical Center, New Orleans, Louisiana (4): Ramy El Khoury, MD (principal investigator); Elizabeth Jones (principal investigator, NETT hub, and site former); Sheryl Martin-Schild, MD, PhD (investigator); and Annie Stell and Cheryl Carmody (primary coordinators, former). Sinai-Grace Hospital, Detroit, Michigan (4): Gregory M. Norris, MD (principal investigator) and Valerie Mika (primary coordinator). Yale –New Haven Hospital, New Haven, Connecticut (4): David M. Greer, MD, MA (principal investigator); Kimberly Kunze, MSN, RN (primary coordinator); and Janet R. Halliday, BS, RN (primary coordinator, former). Mayo Clinic Florida, Jacksonville, FL, USA (4): W. David Freeman, MD (principal investigator); Emily Edwards, MS, CCRP (primary coordinator); and Dale Gamble, MHSc, CCRP; and Sothear Luke, MPH, CCRP (primary coordinators, former). Tampa General Hospital/University of South Florida School of Medicine, Tampa, FL, USA (4): David Z. Rose, MD (principal investigator) and Tara McTigue, RN, CCRC (primary coordinator). University of Louisville, Department of Neurology, Louisville, KY, USA (4): Jignesh J. Shah, MD (principal investigator); Kerri S. Remmel, MD, PhD (principal investigator, former); and Ann Jerde (primary coordinator). Medical College of Wisconsin, Milwaukee (4): Ann Helms, MD (principal investigator); Ling Zhong, PhD (primary coordinator); and Emon Das (primary coordinator, former). Colorado Neurological Institute, Englewood (4): Ira Chang, MD (principal investigator); Alicia Novak, PhD and Laura Greeley (primary coordinators); and Paula Fisk, BS, CCRP, Ashley Bittner, BS, CCRP, and Lenden Neeper, BS, CCRP (primary coordinators, former). Fairview Southdale Hospital, Edina, Minnesota (4): Alexander Y. Zubkov, MD, PhD (principal investigator); Abbey Staugaitis, MSN (primary coordinator); Kathryn France, BA, RN, PHN, CCRC, CCRA; and Kathleen Miller, BSN, CCRC (primary coordinators, former). Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania (4): J. Christopher Zacko, MD (principal investigator) and Deborah Hoffman, BSN (primary coordinator). Eastern Idaho Regional Medical Center, Idaho Falls (4): Kenneth E. Krell, MD (principal investigator); Erich Garland, MD and Douglas N. Whatmore, MD (investigators); and Amy Thornley, ACNP-BC (primary coordinator). Research Medical Center, Kansas City, Missouri (4): Iftekhar Ahmed, MD (principal investigator); Sarah Dunalewicz (coordinator); and Jennifer W. Feeback, Amy Akins, Pamela McCann (primary coordinators, former). Tri-Service General Hospital and the National Defense Medical Center, Taipei, Taiwan (4): Hsin-I Ma, MD, PhD (principal investigator) and Pei-Min Hsiao (primary coordinator). University Medical Center Brackenridge, Austin, Texas (3): Jefferson T. Miley, MD (principal investigator) and Laura Lachance, MA, CCRP (primary coordinator). Rhode Island Hospital, Providence (3): Lisa H. Merck, MD, MPH (principal investigator); Bradford B. Thompson, MD (co–principal investigator); and Jena Lerch (primary coordinator). UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (3): Bradley J. Molyneaux, MD, PhD, Clifton W. Callaway, MD, PhD, and Jon C. Rittenberger, MD (principal investigators); Sara DiFiore, Pamela Fazio, RN, CNC, and Kara Armbuster, BSN, RN (primary coordinators). Detroit Receiving Hospital, Detroit, Michigan (3): Greg M. Norris, MD (principal investigator); Wazim Mohamed, MD, and Mohammad S Ibrahim, MD (investigators); Valerie H. Mika, MS and Amy Spencer (primary coordinators); and Cathey Boyer (primary coordinator, former). SUNY Downstate Medical Center/University Hospital of Brooklyn, Brooklyn, New York (3): Steven R. Levine, MD (principal investigator); Bryce Petty (primary coordinator); and Sarah Z. Weingast, Saroj D. Kunnakkat, Bruhati Shah, Marijayne Bushey, and Vanessa Arnedo (primary coordinators, former). Maine Medical Center, Portland (3): David B. Seder, MD (principal investigator); Richard R. Riker, MD (investigator); and Barbara F. McCrum, RN, BSN (primary coordinator). Sutter Roseville Medical Center, Roseville, California (3): Asim Mahmood, MD (principal investigator); Michele Guillen (primary coordinator); and Teresa Carter (primary coordinator, former). University of New Mexico, Albuquerque (3): Huy Tran, MD (principal investigator); Marc Malkoff, MD (principal investigator, former); and Theresa Wussow, BSSN, RN, and Alice Brown, CNP (primary coordinators). Providence Brain and Spine Institute, Portland, Oregon (3): Ted Lowenkopf, MD (principal investigator) and Monica Rodriguez (primary coordinator). University Hospital Mannheim, Mannheim, Germany (3): Marc Fatar, MD (principal investigator) and Kathrin Knoll (primary coordinator). Texas Tech University Health Sciences Center of El Paso, El Paso (2): Gustavo J. Rodriguez, MD (principal investigator); Alberto Maud, MD (co-principal investigator); and Elizabeth Ledger (primary coordinator). University of California San Francisco Medical Center, San Francisco, (2): Wade Smith, MD, PhD (principal investigator) and Michelle Meeker, BSN, RN (primary coordinator). University of Kentucky, Lexington, (2): Luther Creed Pettigrew, MD (principal investigator) and Linda Dechtenberg and Joann Short, RN, BSN (primary coordinators). Banner University Medical Center–Tucson Campus, Tuscon, Arizona, USA (5): Kurt Denninghoff, MD (principal investigator); Chelsea S. Kidwell, MD (principal investigator); and Andrew Laine (primary coordinator). Parkview Hospital, Fort Wayne, Indiana (2): Rakesh Khatri, MD (principal investigator) and Jeanne Carroll, RN BA CCRC (primary coordinator). University of Mississippi Medical Center, Jackson, MS, USA (2): Hartmut Uschmann, MD (principal investigator); As’ad Ehtisham, MD (principal investigator, former); and Marcia Bankston (primary coordinator, former). The Ohio State University, Wexner Medical Center, Columbus (2): Michel Torbey, MD, MPH (principal investigator); Chad Miller, MD (principal investigator, former); Réza Behrouz, DO (principal investigator, former); Nirav Patel, MBBS, MPH; (primary coordinator); and Leonard Basobas (primary coordinator, former). Brigham and Women’s Hospital, Boston, MA, USA (2): Galen Henderson, MD (principal investigator); Sherry Chou, MD (principal investigator); Sarah Clark and Simone Renault (primary coordinators); and Gabriela Santos, Sarah Suh, Kristina Lieu, and Ross Merkin (primary coordinators, former). Boston Medical Center, Boston, Massachusetts (2): Joseph D. Burns, MD (principal investigator) and Helena Lau, MSPH, RN (primary coordinator). St Louis University, St Louis, Missouri (2): Salavador Cruz-Floes, MD (principal investigator); Eve M. Holzemer, DNP, ANP-BC; Susan Eller, MA, RN, CCRC; Susan Brown, RN, CCRC (primary coordinators); and JoAnn Filla-Taylor, BSN, RN, CCRC (primary coordinator, former). Hoag Memorial Hospital Presbyterian, Newport Beach, California (2): David Brown, MD (principal investigator) and Laura Whitaker (primary coordinator). Changhua Christian Hospital, Changhua, Taiwan (2): Mu-Chien Sun, MD (principal investigator) and Pi-Ju Hsiao (primary coordinator). University Hospital Leipzig, Leipzig, Germany (2): Dominik Michalski, MD (principal investigator); Carsten Hobohm, MD (principal investigator); and Daniela Urban (primary coordinator). University of California Davis Medical Center, Sacramento (1): Daniel K. Nishijima, MD (principal investigator); Glen C. Jickling, MD (co-principal investigator); Laura Beth Jones (primary coordinator); and Tirath Sanghera, CCRC (primary coordinator, former). University of Florida, Gainesville (1): Anna Khanna, MD (principal investigator); Vishnumurthy Shushrutha Hedna, MD (principal investigator, former); and Rosie Kizza, RN (primary study coordinator). Aurora St. Luke’s Medical Center, Milwaukee, WI, USA (1): Elizabeth Marriott, MD (principal investigator) and Linda Yanny, RN, BSN, CCRC (primary coordinator). Seton Medical Center Austin, Austin, Texas (1): Jefferson T. Miley, MD (principal investigator); Laura LaChance, MA, CCRP (primary coordinator); and Alison M. von Eberstein, PhD, RN, BSN (primary coordinator, former). UPMC Mercy Hospital, Pittsburgh, Pennsylvania (1): Bradley J. Molyneaux, MD, PhD; Clifton W. Callaway, MD, PhD; and Jon C. Rittenberger, MD (principal investigators); and Sara Difiore (primary coordinator). Emory University Hospital, Atlanta, Georgia (1): Gustavo Pradilla, MD (principal investigator); Alex J. Hall, MS, RN (primary coordinator); and Michael P. Lunney, MPH, NRP (primary coordinator, former). Santa Clara Valley Medical Center, San Jose, California (1): Marco Lee, MD, PhD (principal investigator) and Anita Visweswaran (primary coordinator). William Beaumont Hospital-Royal Oak, Royal Oak, Michigan (1): Robert Swor, DO (principal investigator) and Mara Branoff, RN, BSN (primary coordinator/research nurse clinician). Akron General Hospital, Akron, Ohio (1): James M. Gebel, MD (principal investigator) and Debra Hudock, MSN (primary coordinator). St Luke’s Marion Bloch Neuroscience Institute, Kansas City, Kansas (1): Darren Lovick, MD (principal investigator) and Bridget Brion (primary coordinator). United Health Services Hospitals, Inc–Wilson Medical Center, Johnson City, New York (1): Yahia M. Lodi, MD (principal investigator); Varun Reddy, MD (investigator); and Terri Peters (primary coordinator). Vanderbilt Stroke Center, Nashville, Tennessee (1): Michael T. Froehler, MD, PhD (principal investigator); Howard S. Kirshner, MD (investigator); and Matthew M. Warrick (primary coordinator). Oklahoma University Health Sciences Center, Oklahoma City (1): Evgeny Sidorov, MD, PhD (principal investigator); Akram Shhadeh, MD (principal investigator, former); and Bradley Hightower (primary coordinator). Kawasaki Medical School, Okayama, Japan (1): Kazumi Kimura, MD, PhD (principal investigator, former) and Kensaku Shibazaki (primary coordinator). Taipei Veterans Hospital, Taipei, Taiwan (1): Chang-Ming Chern, MD (principal investigator) and Chia-Hui Lin and Chia-Wei Lin Hsu (primary coordinators). Department of Neurology at Klinikum Frankfurt Hoechst, Frankfurt, Germany (1): Thorsten Steiner, MD, MME (principal investigator); Corina Epple, MD, Mari-Carmen Lichti, MD, Johannes Trabert, and Anna Katharina Flügel, MD, Department of Internal Medicine, Frankfurt University Hospital (investigators); and Sabrina J. Ritter (primary coordinator). Charite Universitätsmedizin Berlin, Berlin, Germany (1): Heinrich J. Audebert, MD (principal investigator) and Jadranka Denes (primary coordinator). Coordination Centers: Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 Trial Coordination Center: Zeenat Qureshi Stroke Research Center, University of Minnesota: principal investigator: Adnan I. Qureshi, MD; Haitham Hussein, MD (consent and case report forms development); Jill M. Novitzke, MPA, BSN, CCM, CLNC (monitoring oversight); Cathie Witzel, BA (administrative assistance, editing); Bo Connelly, JD (project manager); Saqib A. Chaudhry, MD (education development); Emily I. Abbott, JD, CPA (grants and contracts, international liaison); Erik T. Maland, BAN, RN, PHN (clinical research associate and monitor); Kathryn A. France, BA, RN, PHN, CCRC, CCRA (clinical research associate, clinical trial nurse-coordinator, domestic affairs and protocol liaison, monitor); Basit Rahim, MD (clinical tools design); Zachariah Miller, MA (communications coordinator); Alfredo J. Caceres, MD (central imaging reader); Logan J. Brau, BS (imaging technician); Mushtaq H. Qureshi, MD (central imaging analyst); Jessy K. Thomas, MS, CCRP (project manager); Mohammad R. Afzal, MD (assistant to central imaging analyst); and Norrita Rech, BS, MA, CCRP (grants and contracts). Statistical and Data Coordination Center: Data Coordination Unit, Department of Public Health Sciences, Medical University of South Carolina: principal investigator: Yuko Y. Palesch, PhD, Renee Martin, PhD, and Wenle Zhao, PhD (co-investigators); Lydia Foster, MS, and Jaime Speiser, MS (biostatistical programmers)l Catherine Dillon, BS (trials operations manager); Jaemyung Kim, MBA (senior IS developer); Cassidy Conner, MS, Adam Henry, MPH, and Kristina Hill, MPH, MIS (data managers); Kristen Clasen, MEd (regulatory documents manager); and Christy Cassarly (graduate research assistant). Independent Oversight Committee: Johns Hopkins University, Division of Brain Injury Outcomes: Daniel F. Hanley, MD (chair); Carlos S. Kase, MD, and J. Ricardo Carhuapoma, MD (committee members); and Nichol McBee, MPH, CCRP (IOC coordinator). National Institute of Neurological Disorders and Stroke of the National Institutes of Health representatives: Claudia Moy, PhD (project scientist) and Scott Janis, PhD (program official). National Institute of Neurological Disorders and Stroke–-Appointed Data and Safety Monitoring Board: J. Claude Hemphill III, MD, MAS (chair) and Brian L. Hoh, MD, Mario Zucharello, MD, and Michael K. Parides, PhD (board members). Regional/National Clinical Coordinating Centers: US: The Neurological Emergency Treatment Trials (NETT) Network, University of Michigan: William Barsan, MD (NETT Network principal investigator); Robert Silbergleit, MD (NETT Network co-investigator); Joshua N. Goldstein, MD, PhD (investigator); Valerie Stevenson, BAS, LRT, CCRP (administrative director); Erin Bengelink, MS (site manager); Joy Black, BSN, MS (education coordinator); Mickie Speers, BSN, Donna Harsh, MS, Carol Van Huysen, BS, Angela Caveney, PhD, and Andrace Deyampert, MSHS (monitors); and Beth Grundman and Allison DuRoss (research assistants). Additional NETT hub participants: Jan Claassen, MD (Columbia University, New York, New York); Michelle Biros, MD (University of Minnesota, Minneapolis); David Wright, MD (Emory University, Atlanta, Georgia); James Quinn, MD and Rosen Mann (Stanford University, Stanford, California); Jill Baren, MD (University of Pennsylvania, Philadelphia); Robert Welch, MD (Wayne State University, Detroit, Michigan); Tom Aufderheide, MD, Melissa Mena, and Erica Chopskie (Medical College of Wisconsin, Milwaukee); Roger Humphries, MD (University of Kentucky, Lexington); Monica Mendoza-Moore (University of Texas); Katherine Lamond (University of Pennsylvania, Philadelphia); Ryan Callahan and Melissa Howell, (Massachusetts General Hospital, Boston); Patricia M. McNelis and Hannah Reimer (Temple University, Philadelphia, Pennsylvania); Ginny Stasinski and Bruce Barnhart (University of Arizona, Tucson); Ryan McCormick (University of California, San Francisco, San Francisco); and Ana Maria Gomez Ramirez (Ohio State University, Columbus). Neurocritical Care Research Network (NCRN): Jose I. Suarez (principal investigator). Japan: National Cerebral and Cardiovascular Center and Japan Cardiovascular Research Foundation: Kazunori Toyoda, MD, PhD (lead national principal investigator); Haruko Yamamoto, MD PhD (lead project manager); Masatoshi Koga, MD PhD, Shoichiro Sato, MD, PhD, and Sohei Yoshimura, MD, PhD (coordination for Japanese sites); Mayumi Fukuda-Doi, MD, MPH (regulatory manager); Kanae Hirase RN, CCRC (lead monitor); Shuhei Okazaki, MD, PhD (monitor); and Hiromi Ohara, RN, CCRC (coordinator). China: Beijing Tiantan Hospital Clinical Coordinating Center: Yongjun Wang, MD, PhD (lead national principal investigator); Zeyu Ding, MD, PhD (lead coordinator); Dandan Wang, MD (regulatory specialist); and Nannan Xu (clinical research associate). Taiwan: China Medical University Hospital Clinical Trial Center of Excellence: Chung Y. Hsu, MD, PhD (lead national principal investigator); Dana Lin (lead coordinator); Mamiko Suzuki (lead monitor); and Chin-Ting Hsu, Jou-Ping Hsu, and Emma Ho, MS, BSN (monitors). Germany: Coordinating Center for Clinical Trials, University Hospital Heidelberg: Thorsten Steiner, MD (lead national principal investigator); Andrea Seidel-Glätzer, MA, RN (project manager); Claudia Simonis, PhD (clinical research associate), and Ulrike Berlet, Pharmacist (clinical research associate). South Korea: Seoul National University Hospital Clinical Coordinating Center: Byung-Woo Yoon, MD, PhD (lead national principal investigator); Dongjin Yoo, MD (lead project manager); Youngrang Lee, MS (project manager); Jae Young Jo, RN (coordinator); Juri Park, RN (coordinator); and EunHye Hu (monitor). US: NETT Network Participating Hubs, listed alphabetically: Columbia University Medical Center, New York, New York; Emory University, Atlanta, Georgia; Henry Ford Health System, Detroit, Michigan; Massachusetts General Hospital, Boston; Medical College of Wisconsin, Milwaukee; Oregon Health & Science University, Portland; Stanford University, Stanford, California; SUNY Downstate Medical Center, Brooklyn, New York; Temple University, Philadelphia, Pennsylvania; The Ohio State University, Columbus; University of Arizona, Tucson; University of California, San Francisco, San Francisco; University of Cincinnati, Cincinnati, Ohio; University of Kentucky, Lexington; University of Minnesota, Minneapolis; University of Pennsylvania, Philadelphia; University of Pittsburgh, Pittsburgh, Pennsylvania; University of Texas, Houston; Virginia Commonwealth University, Richmond; and Wayne State University, Detroit, Michigan. A directory listing US network hubs, hub PIs, site principal investigators and study coordinators affiliated with the Neurological Emergency: Treatment Trials Network is available at https://nett.umich.edu/directory.