Intensive Blood Pressure Reduction and Spot Sign in Intracerebral Hemorrhage: A Secondary Analysis of a Randomized Clinical Trial | Cerebrovascular Disease | JAMA Neurology | JAMA Network
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Figure.  Cohort Selection Flowchart and Trial Profile
Cohort Selection Flowchart and Trial Profile

ATACH-II indicates Antihypertensive Treatment of Acute Cerebral Hemorrhage II; CTA, computed tomographic angiography; ICH, intracerebral hemorrhage; SBP, systolic blood pressure; and SCORE-IT, Spot Sign Score in Restricting ICH Growth.

Table 1.  Baseline Characteristics
Baseline Characteristics
Table 2.  Comparison Between Different Spot Sign Definitionsa
Comparison Between Different Spot Sign Definitionsa
Table 3.  Univariate Analysis Including All CTA Within 8 Hours From Onseta
Univariate Analysis Including All CTA Within 8 Hours From Onseta
Table 4.  Effect of Intensive BP Treatment on ICH Expansion and Outcome Stratified by Spot Sign Status Using Early CTA
Effect of Intensive BP Treatment on ICH Expansion and Outcome Stratified by Spot Sign Status Using Early CTA
1.
van Asch  CJ, Luitse  MJ, Rinkel  GJ, van der Tweel  I, Algra  A, Klijn  CJ.  Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis.  Lancet Neurol. 2010;9(2):167-176.PubMedGoogle ScholarCrossref
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Demchuk  AM, Dowlatshahi  D, Rodriguez-Luna  D,  et al; PREDICT/Sunnybrook ICH CTA study group.  Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study.  Lancet Neurol. 2012;11(4):307-314.PubMedGoogle ScholarCrossref
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Del Giudice  A, D’Amico  D, Sobesky  J, Wellwood  I.  Accuracy of the spot sign on computed tomography angiography as a predictor of haematoma enlargement after acute spontaneous intracerebral haemorrhage: a systematic review.  Cerebrovasc Dis. 2014;37(4):268-276.PubMedGoogle ScholarCrossref
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Goldstein  J, Brouwers  H, Romero  J,  et al.  SCORE-IT: the spot sign score in restricting ICH growth—an ATACH-II ancillary study.  J Vasc Interv Neurol. 2012;5(suppl):20-25.PubMedGoogle Scholar
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Qureshi  AI, Palesch  YY, Barsan  WG,  et al; ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network.  Intensive blood-pressure lowering in patients with acute cerebral hemorrhage.  N Engl J Med. 2016;375(11):1033-1043.PubMedGoogle ScholarCrossref
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Qureshi  AI, Palesch  YY.  Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: design, methods, and rationale.  Neurocrit Care. 2011;15(3):559-576.PubMedGoogle ScholarCrossref
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Thompson  AL, Kosior  JC, Gladstone  DJ,  et al; PREDICTS/Sunnybrook ICH CTA Study Group.  Defining the CT angiography “spot sign” in primary intracerebral hemorrhage.  Can J Neurol Sci. 2009;36(4):456-461.PubMedGoogle ScholarCrossref
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Gazzola  S, Aviv  RI, Gladstone  DJ,  et al.  Vascular and nonvascular mimics of the CT angiography “spot sign” in patients with secondary intracerebral hemorrhage.  Stroke. 2008;39(4):1177-1183.PubMedGoogle ScholarCrossref
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Dowlatshahi  D, Brouwers  HB, Demchuk  AM,  et al.  Predicting intracerebral hemorrhage growth with the spot sign: the effect of onset-to-scan time.  Stroke. 2016;47(3):695-700.PubMedGoogle Scholar
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Pocock  SJ, Simon  R.  Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.  Biometrics. 1975;31(1):103-115.PubMedGoogle ScholarCrossref
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Hemphill  JC  III, Bonovich  DC, Besmertis  L, Manley  GT, Johnston  SC.  The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.  Stroke. 2001;32(4):891-897.PubMedGoogle ScholarCrossref
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Anderson  CS, Heeley  E, Huang  Y,  et al; INTERACT2 Investigators.  Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage.  N Engl J Med. 2013;368(25):2355-2365.PubMedGoogle ScholarCrossref
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Delgado Almandoz  JE, Yoo  AJ, Stone  MJ,  et al.  Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion: the spot sign score.  Stroke. 2009;40(9):2994-3000.PubMedGoogle ScholarCrossref
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Waaijer  A, Prokop  M, Velthuis  BK, Bakker  CJG, de Kort  GAP, van Leeuwen  MS.  Circle of Willis at CT angiography: dose reduction and image quality—reducing tube voltage and increasing tube current settings.  Radiology. 2007;242(3):832-839.PubMedGoogle ScholarCrossref
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Chakraborty  S, Alhazzaa  M, Wasserman  JK,  et al.  Dynamic characterization of the CT angiographic “spot sign”.  PLoS One. 2014;9(3):e90431.PubMedGoogle ScholarCrossref
22.
Morotti  A, Romero  JM, Jessel  MJ,  et al.  Effect of CTA tube current on spot sign detection and accuracy for prediction of intracerebral hemorrhage expansion  [published online May 19, 2016].  AJNR Am J Neuroradiol. doi:10.3174/ajnr.A4810PubMedGoogle Scholar
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Delgado Almandoz  JE, Yoo  AJ, Stone  MJ,  et al.  The spot sign score in primary intracerebral hemorrhage identifies patients at highest risk of in-hospital mortality and poor outcome among survivors.  Stroke. 2010;41(1):54-60.PubMedGoogle ScholarCrossref
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Park  SY, Kong  MH, Kim  JH, Kang  DS, Song  KY, Huh  SK.  Role of “spot sign” on CT angiography to predict hematoma expansion in spontaneous intracerebral hemorrhage.  J Korean Neurosurg Soc. 2010;48(5):399-405.PubMedGoogle ScholarCrossref
25.
Brouwers  HB, Falcone  GJ, McNamara  KA,  et al.  CTA spot sign predicts hematoma expansion in patients with delayed presentation after intracerebral hemorrhage.  Neurocrit Care. 2012;17(3):421-428.PubMedGoogle ScholarCrossref
26.
Radmanesh  F, Falcone  GJ, Anderson  CD,  et al.  Risk factors for computed tomography angiography spot sign in deep and lobar intracerebral hemorrhage are shared.  Stroke. 2014;45(6):1833-1835.PubMedGoogle ScholarCrossref
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Boulouis  G, Morotti  A, Brouwers  HB,  et al.  Association between hypodensities detected by computed tomography and hematoma expansion in patients with intracerebral hemorrhage.  JAMA Neurol. 2016;73(8):961-968.PubMedGoogle ScholarCrossref
28.
Li  Q, Zhang  G, Huang  Y-J,  et al.  Blend sign on computed tomography: novel and reliable predictor for early hematoma growth in patients with intracerebral hemorrhage.  Stroke. 2015;46(8):2119-2123.PubMedGoogle ScholarCrossref
29.
Blacquiere  D, Demchuk  AM, Al-Hazzaa  M,  et al; PREDICT/Sunnybrook ICH CTA Study Group.  Intracerebral hematoma morphologic appearance on noncontrast computed tomography predicts significant hematoma expansion.  Stroke. 2015;46(11):3111-3116.PubMedGoogle ScholarCrossref
Original Investigation
August 2017

Intensive Blood Pressure Reduction and Spot Sign in Intracerebral Hemorrhage: A Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2J. P. Kistler Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston
  • 3Department of Neurosurgery, Brain Center Rudolf Magnus University Medical Center, Utrecht, the Netherlands
  • 4Neuroradiology Service, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 5Zeenat Qureshi Stroke Research Center, University of Minnesota, Minneapolis
  • 6Department of Public Health Sciences, Medical University of South Carolina, Charleston
  • 7Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
JAMA Neurol. 2017;74(8):950-960. doi:10.1001/jamaneurol.2017.1014
Key Points

Question  Does the computed tomographic angiography spot sign identify the patients with intracerebral hemorrhage who are most likely to benefit from intensive blood pressure reduction?

Findings  In this secondary analysis of 133 patients with intracerebral hemorrhage nested in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II randomized clinical trial, intensive blood pressure treatment did not improve outcomes in patients with a spot sign. The proportion of patients with a spot sign and a 90-day modified Rankin Scale score of 4 or greater was 20 of 27 in the intensive treatment group vs 10 of 20 in the standard treatment group.

Meaning  Our results showed no clinical benefit of intensive blood pressure reduction in patients with intracerebral hemorrhage and a spot sign.

Abstract

Importance  The computed tomographic angiography (CTA) spot sign is associated with intracerebral hemorrhage (ICH) expansion and may mark those patients most likely to benefit from intensive blood pressure (BP) reduction.

Objective  To investigate whether the spot sign is associated with ICH expansion across a wide range of centers and whether intensive BP reduction decreases hematoma expansion and improves outcome in patients with ICH and a spot sign.

Design, Setting, and Participants  SCORE-IT (Spot Sign Score in Restricting ICH Growth) is a preplanned prospective observational study nested in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) randomized clinical trial. Participants included consecutive patients with primary ICH who underwent a CTA within 8 hours from onset at 59 sites from May 15, 2011, through December 19, 2015. Data were analyzed for the present study from July 1 to August 31, 2016.

Main Outcomes and Measures  Patients in ATACH-II were randomized to intensive (systolic BP target, <140 mm Hg) vs standard (systolic BP target, <180 mm Hg) BP reduction within 4.5 hours from onset. Expansion of ICH was defined as hematoma growth of greater than 33%, and an unfavorable outcome was defined as a 90-day modified Rankin Scale score of 4 or greater (range, 0-6). The association among BP reduction, ICH expansion, and outcome was investigated with multivariable logistic regression.

Results  A total of 133 patients (83 men [62.4%] and 50 women [37.6%]; mean [SD] age, 61.9 [13.1] years) were included. Of these, 53 (39.8%) had a spot sign, and 24 of 123 without missing data (19.5%) experienced ICH expansion. The spot sign was associated with expansion with sensitivity of 0.54 (95% CI, 0.34-0.74) and specificity of 0.63 (95% CI, 0.53-0.72). After adjustment for potential confounders, intensive BP treatment was not associated with a significant reduction of ICH expansion (relative risk, 0.83; 95% CI, 0.27-2.51; P = .74) or improved outcome (relative risk of 90-day modified Rankin Scale score ≥4, 1.24; 95% CI, 0.53-2.91; P = .62) in spot sign–positive patients.

Conclusions and Relevance  The predictive performance of the spot sign for ICH expansion was lower than in prior reports from single-center studies. No evidence suggested that patients with ICH and a spot sign specifically benefit from intensive BP reduction.

Trial Registration  clinicaltrials.gov Identifier: NCT01176565

Introduction

Intracerebral hemorrhage (ICH) is still the deadliest type of stroke, with a case fatality rate at 30 days of approximately 40% and severe disability in most of the survivors.1 Baseline ICH volume is the variable most strongly associated with an unfavorable outcome,2 and as many as one-third of patients with ICH experience significant hematoma growth.3 Because of its frequency and association with poor prognosis,4 hematoma expansion is an appealing target for acute ICH treatment.5 Stratification of ICH expansion risk may help target patients with the highest likelihood to benefit from antiexpansion treatment. An association of the computed tomographic angiography (CTA) spot sign has been found with hematoma growth in a range of single-center studies6,7 and 1 multicenter study8 and may improve our ability to stratify the risk for hematoma expansion in clinical practice. However, different criteria for spot sign definition have been reported, with heterogeneity in spot sign density, dimension, morphologic features, and CTA window. To our knowledge, the diagnostic performance of different spot sign definitions has never been directly compared,9 and only 1 spot sign definition was validated in a multicenter study.8 In the present study, we investigated whether the CTA spot sign is associated with hematoma growth across a wide range of centers in a large international clinical trial and whether it identifies patients with ICH more likely to benefit from intensive BP reduction. In particular, we tested the hypothesis that intensive BP control would reduce ICH expansion and improve outcome in spot sign–positive patients, whereas those without a spot sign would not benefit from intensive BP reduction. As a secondary analysis, we compared the diagnostic performance of the 2 most commonly used spot sign definitions in the association of hematoma expansion and an unfavorable outcome.

Methods
Participants

The SCORE-IT (Spot Sign Score in Restricting ICH Growth) study was a prospective preplanned analysis of patients enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) randomized clinical trial.10,11 In ATACH-II, patients with ICH were randomly assigned to intensive (systolic BP target, <140 mm Hg) vs standard (systolic BP target, <180 mm Hg) BP treatment within 4.5 hours after stroke onset. Demographic and clinical characteristics were collected at enrollment in the clinical trial, as previously described.11,12 Patients enrolled in ATACH-II were eligible for SCORE-IT if they underwent a CTA. All aspects of the study were approved by the local institutional review boards of each participating center listed at the end of the article. Written informed consent was obtained from patients or family members.

Image Acquisition and Analysis

Axial non–contrast-enhanced computed tomographic (NCCT) and CTA images were obtained at each participant’s institution by using standard local protocols. We retrospectively collected the following CTA acquisition variables: tube current level (in milliamperes) and tube voltage level (in peak kilovoltage). Baseline and follow-up hematoma volumes at 24 hours were calculated on NCCT images with semiautomated computer-assisted volumetric analysis (AnalyzeDirect medical imaging software, version 11.0; AnalyzeDirect, Inc).

First-pass CTA images were independently reviewed by trained readers (A.M. and M.J.J.) for spot sign identification according to the 2 most commonly used spot sign definitions. Disagreements in spot sign readings were adjudicated by consensus under the supervision of a neuroradiologist (J.M.R.). For the purposes of this analysis, definition 1 was validated at Massachusetts General Hospital, Boston,6 whereas definition 2 was validated in the Prediction of Hematoma Growth and Outcome in Patients With Intracerebral Hemorrhage Using the CT-Angiography Spot Sign (PREDICT) study.8,13

The diagnostic criteria used in spot sign definition 1 consisted of the presence of at least 1 focus of contrast extravasation in the hematoma, with any size or morphologic feature and density greater than 120 Hounsfield units. Definition 2 included intrahematoma contrast extravasation with a minimum diameter of 1.5 mm in any dimension, with spotlike or serpiginous shape, without any connection with vessels outside the hematoma, without corresponding hyperdensity at NCCT, and with attenuation at least double that of the background hematoma (in Hounsfield units). An illustrative comparison of both diagnostic criteria is shown in the eFigure in the Supplement.

All NCCT and CTA images were carefully reviewed to avoid the inclusion of spot sign mimics such as calcifications (visible on NCCT images) or the presence of connection between the spot sign and vessels outside the hematoma.14 The primary analysis on the effect of intensive BP control in spot sign–positive patients was performed using definition 1, as specified in the SCORE-IT study protocol.10 As a secondary analysis, CTA spot sign–positive patients according to definition 2 underwent analysis.

We had initially planned to include only CTA images obtained at those institutions that routinely perform CTA at admission in patients with ICH. However, during the trial, heterogeneity across all sites in CTA performance precluded using this inclusion criterion. The main analysis therefore included all CTA images that were obtained within 8 hours from symptom onset (operationally termed early CTA).15 As a secondary analysis, we included all CTA images irrespective of time performed.

Finally, we performed another analysis stratifying the risk for hematoma expansion with the spot sign score, a validated scoring system that accounts for the number, attenuation, and dimension of spot signs.6 The spot sign score ranges from 0 to 4 and, as the score increases, the likelihood of hematoma growth increases.

Randomization and Masking

Eligible patients were randomized at a 1:1 ratio via a centralized web-based randomization process to the intensive or standard antihypertensive treatment group. A minimization randomization scheme proposed by Pocock and Simon16 was used to control for age, baseline Glasgow Coma Scale score, presence of intraventricular hemorrhage, and clinical site. These baseline prognostic factors were identified a priori as those with imbalances that could potentially affect the primary outcome of the trial. Because of the nature of the treatment in this trial in which the infusion of nicardipine hydrochloride was titrated to target systolic BP, the treatment physicians and study personnel could not be blinded to treatment assignment. However, all sites were required to designate an individual who was blinded to treatment assignment and did not participate in the randomization or treatment of patients in the trial to be the blinded assessor of the 30- and 90-day outcomes.

Outcome Measures

The primary outcome of the present analysis was the proportion of spot sign–positive patients who experienced hematoma expansion and had a poor functional outcome at 90 days. Hematoma expansion was defined as absolute volume increase of greater than 33% from the baseline ICH volume.11 Functional outcome was measured with the modified Rankin Scale (mRS) score, and an unfavorable outcome was defined as an mRS score of 4 or greater (range, 0-6, with higher scores indicating greater disability and 6 indicating death) at 3 months.

Statistical Analysis

Continuous variables with normal distribution were expressed as mean (SD) and with nonnormal distribution as median (range), whereas categorical variables were expressed as count (percentage). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the 2 spot sign definitions in predicting ICH expansion and poor long-term outcome are presented. The interrater reliability for the identification of any spot sign was determined using the Cohen κ statistic.

The association among BP treatment, ICH expansion, and outcome was investigated with a multivariable logistic regression analysis, stratified by spot sign status, and adjusted for known variables associated with hematoma growth and poor outcome in patients with ICH.3,17 Owing to the exploratory nature of this study, P < .05 was considered to be statistically significant, and all the analyses were performed using SAS software (version 9.4; SAS Institute Inc).

Results

The ATACH-II study was terminated early as advised by the monitoring board owing to futility. Of 1000 patients in the ATACH-II trial, 133 (13.3%) underwent a CTA within 8 hours after symptom onset (101 before and 32 after randomization) and were included in the present study (83 men [62.4%] and 50 women [37.6%]; mean [SD] age, 61.9 [13.1] years). The overall proportion of patients with at least 1 spot sign was 53 (39.8%) with definition 1 and 29 (21.8%) with definition 2. Functional outcome data at 90 days or follow-up NCCT for evaluation of ICH expansion were missing in 10 patients.

A total of 24 of 123 patients (19.5%) experienced hematoma expansion. The case-fatality rate at 90 days was 8.3% (11 patients), and 56 of 123 patients (45.5%) had a poor functional outcome at 3 months. The demographic and clinical characteristics of the study population, stratified by CTA timing, are summarized in Table 1. The Figure shows the cohort selection flowchart.

Comparison of Different Spot Sign Definitions

The interrater reliability for the identification of any spot sign was 0.75 (95% CI, 0.69-0.81) for definition 1 and 0.79 (95% CI, 0.73-0.85) for definition 2. The number of spot sign–positive CTAs was significantly higher using definition 1 (Table 2), and all the spot sign–positive scans identified with definition 2 were also spot sign positive according to definition 1. The diagnostic performance of the 2 spot sign definitions in predicting ICH expansion and unfavorable outcome is summarized in Table 2.

Effect of Intensive BP Treatment on ICH Expansion and Outcome

Table 3 shows the differences between patients positive and negative for the spot sign, stratified by BP treatment (intensive vs standard BP lowering). The proportion of patients with a spot sign and a 90-day mRS score of 4 or greater was 20 of 27 (74.1%) in the intensive treatment group vs 10 of 20 (50%) in the standard treatment group. As expected, patients with a CTA spot sign had a larger baseline hematoma volume and a higher frequency of expansion. Intensive BP reduction was not associated with a significantly lower rate of hematoma expansion in spot sign–positive patients in univariate analysis (7 of 31 [22.6%] vs 6 of 19 [31.6%]; P = .52). We found no indication of an interactive effect between spot sign status and BP treatment. The univariate analysis was repeated including only CTA obtained before randomization using both spot sign definitions (eTables 1 and 2 in the Supplement).

After adjustment for potential confounders in the multivariable regression analysis, intensive BP reduction in spot sign–positive patients was not associated with reduced ICH growth or a better outcome at 3 months (Table 4). Similar results were found using spot sign definition 2 (Table 4). We also obtained the same results when we restricted all the analyses to the subgroup of patients who underwent CTA before randomization (n = 101).

A secondary analysis including all patients with a CTA performed within 36 hours from onset (n = 166) showed the same results. Lowering of systolic BP below 140 mm Hg in patients with a spot sign did not significantly reduce the risk for hematoma expansion (relative risk, 0.68; 95% CI, 0.27-1.72; P = .41) and was not associated with improved long-term functional outcome (relative risk of mRS score, ≥4 at 90 days, 1.16; 95% CI, 0.57-2.36; P = .68).

We found no association between BP treatment and risk for hematoma growth also using a different definition of ICH expansion (relative hematoma growth >33% or absolute hematoma growth >6 mL). Finally, patients with a high spot sign score did not benefit from intensive BP reduction, as shown in eTable 3 in the Supplement.

Discussion

This prospective study of the CTA spot sign in ICH is, to our knowledge, the largest performed in terms of the number of hospitals involved and the largest study investigating the role of the CTA spot sign in selecting patients with ICH for antiexpansion treatment. We found that intensive BP lowering did not significantly reduce the rate of expansion and did not result in reduced mortality or severe disability in patients with a spot sign.

Some possible explanations for our findings include the following: (1) BP reduction does not truly influence hematoma expansion, and therefore a predictor of expansion would not help guide this therapy; (2) BP reduction reduces expansion, but the CTA spot sign is an inadequate tool to identify the patients most likely to benefit; and (3) the CTA spot sign could successfully perform this role, but we were underpowered to detect this effect in our analysis. For the first possibility, major trials have failed to convincingly demonstrate that BP lowering reduces hematoma expansion.11,18 The differences in actual BP achieved may have been inadequate to detect a true effect, but the process of ICH expansion is complex, and in most patients expansion may not be modifiable by BP reduction. For the second possibility, the suboptimal performance of the CTA spot sign in identifying patients at high risk for hematoma growth in this study may also explain our results. Compared with previous reports using the same diagnostic criteria, both definitions of spot sign showed lower sensitivity, specificity, and accuracy for prediction of ICH growth in our analysis.8,19 These discrepancies with previous studies may arise from heterogeneity and lack of standardization in the CTA acquisition protocol. The CTA acquisition variables may indeed influence the diagnostic performance of spot sign in identifying patients who will experience expansion.20-22 For the third possibility, we may have had inadequate statistical power to detect an effect of intensive BP reduction in patients at high risk for hematoma growth. All these potential explanations are not mutually exclusive, and the lack of statistical power precluded a thorough evaluation of the first 2 possibilities.

Finally, the cohort in this study showed some important differences from the general population with ICH. The patients included in our analysis were younger and had smaller hematomas, and more than half had a normal Glasgow Coma Scale score. Case fatality at 90 days was significantly lower (8.3%) compared with that of real-world studies in patients with ICH (30%-40%),1,17 leaving little room for outcome improvement with BP management (ceiling effect). In addition, the prevalence of the spot sign in this population was relatively high; using definition 1, we detected at least 1 spot sign in nearly 40% of the patients, whereas the prevalence of this imaging marker in previous studies using the same definition ranged from 17% to 23%.3,22-24 This difference may be owing to the fact that only those presenting within an early time frame (4.5 hours) were eligible for the ATACH-II trial, and the spot sign is more prevalent in early presenters15,25 despite the small baseline hematoma volume and the lack of oral anticoagulant treatment–associated ICH cases possibly having otherwise minimized spot sign detection.26 The great heterogeneity in the CTA acquisition protocol may also account for the high rate of spot sign–positive scans. The presence of poor-quality CTA images may indeed have led to the detection of false spot signs.

Our findings have important implications for future studies aimed at reducing hematoma growth in patients with ICH. First, if CTA is to be used, a protocol optimized for spot sign detection must be performed,22 which will likely help with accuracy and specificity. Second, we noted some differences in the diagnostic performance of the 2 spot sign definitions. Definition 1 had a higher sensitivity and therefore may be more suitable for selecting patients for antiexpansion treatments with minimal risk to capture as many patients as possible at high risk for hematoma growth. However, definition 2 appears to show higher specificity and may be preferred in future trials selecting patients for treatment with hemostatic therapies that may be associated with risks such as thrombotic complications. Several NCCT imaging markers have been recently reported as potentially associated with hematoma growth.27-29 Because of the low cost and wide availability, such NCCT findings may be an option for future studies to stratify the risk for ICH growth and select patients for expansion-targeted treatments.

Limitations

The main limitation of our study is the small proportion of patients who underwent CTA as part of their diagnostic workup. This analysis had an 11% power to detect a 10% difference in the risk for unfavorable outcomes between the two treatment groups at the P < .05 level. The presence of a ceiling effect owing to a mildly affected study population further reduced our power to detect a significant effect of BP treatment on ICH growth and outcome. In addition, the absolute difference in systolic BP in the 2 treatment arms was smaller compared with the expected values based on the suggested cutoffs (140 vs 180 mm Hg). The mean minimum systolic BP at 2 hours was 129 mm Hg in the intensive treatment group vs 141 mm Hg in the standard treatment arm.11 Finally, the delay between baseline NCCT and start of BP treatment and ICH expansion may have occurred in this time frame, especially in patients at high risk of ICH expansion (early presenters with a spot sign).

Conclusions

We report 2 major findings in this study. For the first time, to our knowledge, we have prospectively validated that a CTA spot sign is associated with hematoma expansion, but the diagnostic accuracy of this marker was lower compared with findings in previous single-center studies. Second, even in patients with a CTA spot sign (and thus a higher risk for expansion), we found no evidence that intensive BP reduction lowers the risk for expansion or improves outcome.

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Article Information

Corresponding Author: Andrea Morotti, MD, J. P. Kistler Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, 175 Cambridge St, Ste 300, Boston, MA 02114 (andrea.morotti85@gmail.com).

Accepted for Publication: March 28, 2017.

Published Online: June 19, 2017. doi:10.1001/jamaneurol.2017.1014

Author Contributions: Dr Goldstein 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.

Study concept and design: Morotti, Brouwers, Qureshi, Rosand, Goldstein.

Acquisition, analysis, or interpretation of data: Morotti, Brouwers, Romero, Jessel, Vashkevich, Schwab, Afzal, Cassarly, Greenberg, Martin, Rosand, Goldstein.

Drafting of the manuscript: Morotti, Goldstein.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Cassarly, Martin.

Obtained funding: Rosand, Goldstein.

Administrative, technical, or material support: Morotti, Jessel, Schwab, Greenberg, Qureshi.

Study supervision: Martin, Rosand, Goldstein.

Conflict of Interest Disclosures: Dr Rosand reports research funding from the National Institutes of Health (NIH). Dr Goldstein reports research funding from the NIH, Boehringer Ingelheim, Pfizer, and Portola and consulting for Bristol Myers Squibb. No other disclosures were reported.

Funding/Support: The present study was supported by award 5R01NS073344 from the National Institute of Neurological and Communicative Disorders and Stroke.

Role of the Funder/Sponsor: The funding source had no role in 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.

Antihypertensive Treatment of Acute Cerebral Hemorrhage II and Neurological Emergencies Treatment Trials Investigators:Trial Coordination Center: Zeenat Qureshi Stroke Research Center, University of Minnesota, Minneapolis: Adnan I. Qureshi, MD (Principal Investigator); 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, Charleston: Yuko Y. Palesch, PhD (Principal Investigator); Renee Martin, PhD, and Wenle Zhao, PhD (Coinvestigators); Lydia Foster, MS, and Jaime Speiser, MS (Biostatisticial Programmers); 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, Baltimore, Maryland: Daniel F. Hanley, MD (Chair); Carlos S. Kase, MD, and J. Ricardo Carhuapoma, MD (Committee Members); and Nichol McBee, MPH, CCRP (Independent Oversight Committee Coordinator). National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (Bethesda, Maryland), Representatives: Claudia Moy, PhD (Project Scientist), and Scott Janis, PhD (Program Official). NINDS-Appointed Data and Safety Monitoring Board: J. Claude Hemphill III, MD, MAS (Chair), and Brian L. Hoh, MD, FACS, FAHA, Mario Zucharello, MD, and Michael K. Parides, PhD (Board Members). Regional/National Clinical Coordinating Centers: United States: The Neurological Emergency Treatment Trials (NETT) Network, University of Michigan, Ann Arbor: William Barsan, MD (NETT Network Principal Investigator); Robert Silbergleit, MD (NETT Network Coinvestigator); 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); 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, Austin); 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); and Ana Maria Gomez Ramirez (The Ohio State University, Columbus). Neurocritical Care Research Network: Jose I. Suarez (Principal Investigator). Japan: National Cerebral and Cardiovascular Center and Japan Cardiovascular Research Foundation, Osaka: 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, Taichung: 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). Clinical Sites and Site Investigators (by number of patients enrolled at each center):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 (Coprincipal 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, former; currently Director, Institute for Critical Care Medicine–Icahn School of Medicine at Mount Sinai), 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), and 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 and Neurovascular Center, JFK Medical Center, Edison, New Jersey (18): Jawad F. Kirmani, MD (Principal Investigator); Spozhmy Panezai, MD (Coprincipal Investigator); and Charles Porbeni, MD; 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; currently Texas Tech University Health Sciences Center of El Paso, Texas); 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); and 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, initial, in memory of); 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), 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), and Yeo-Jung Chae and Jae-Young Jo, RN (Primary Coordinators). UAB Comprehensive Stroke Center, Birmingham, AL, USA (10): Angela N. Hays, MD (Principal Investigator); Andrei V. Alexandrov, MD (Principal Investigator, former; currently Semmes Murphy Professor and Chair, Department of Neurology, University of Tennessee Health Science Center); 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); and Abigail Cohen, Kristen McNamara, and Lauren Barton (Primary Coordinators, former). St. Marianna University Tokoyo 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), and 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, Louisianna (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), and 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); and 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; currently Capital Health, New Jersey); 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 (Coprincipal 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; currently Hennepin County Medical Center, Minneapolis, Minnesota); Emily Mischel, MA (Primary Coordinator); and Sandi Wewerka, MPH (Primary Coordinator, former). University of California 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, Alexandra Gaenslen (Investigators); and Julia Zeller (Primary Coordinator). Tulane Medical Center, New Orleans, Louisianna (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 (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 (4): David Z. Rose, MD (Principal Investigator), and Tara McTigue, RN, CCRC (Primary Coordinator). University of Louisville, Department of Neurology, Louisville, Kentucky (4): Jignesh J. Shah, MD (Principal Investigator); Kerri S. Remmel, MD, PhD (Principal Investigator, former, currently Professor and Chair, Department of Neurology, University of Louisville, Kentucky); 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, and 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); and 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). State University of New York 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 (Coprincipal Investigator); and Elizabeth Ledger (Primary Coordinator). University of Califonia, San Francisco Medical Center (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 (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 (2): Hartmut Uschmann, MD (Principal Investigator); As’ad Ehtisham, MD (Principal Investigator, former; currently Ehtisham Neurovascular Institute, Wichita, Kansas); 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; currently Associate Professor, University of Texas Health Science Center–San Antonio); Nirav Patel, MBBS, MPH (Primary Coordinator); and Leonard Basobas (Primary Coordinator, former). Brigham and Women’s Hospital, Boston, Massachusetts (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). Saint Louis University, Saint Louis, Missouri (2): Salavador Cruz-Floes, MD (Principal Investigator); Eve M. Holzemer, DNP, ANP-BC, Susan Eller, MA, RN, CCRC, and 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, affiliation Department of Neurology, University of Leipzig); 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 (Coprincipal 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, currenlty University of New Mexico, Albuquerque); and Rosie Kizza, RN (Primary Study Coordinator). Aurora St. Luke’s Medical Center, Milwaukee, Wisconsin (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; currently Florida State University School of Information, Tallahassee). Universiy of Pittsburgh Medical Center Mercy Hospital, Pittsburgh, Pennsylvania (1): Bradley J. Molyneaux, MD, PhD, CliftonW. 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, Department of Neurosurgery, Stanford University, Stanford, California), 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). Saint 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; currently Nippon Medical School, Tokyo, Japan), 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, 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 (Investigators, Department of Internal Medicine, Frankfurt University Hospital); and Sabrina J. Ritter (Primary Coordinator). Charite Universitätsmedizin Berlin, Berlin, Germany (1): Heinrich J. Audebert, MD (Principal Investigator), and Mrs. Jadranka Denes (Primary Coordinator). 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), State University of New York Downstate Medical Center (Brooklyn), Temple University (Philadelphia, Pennsylvania), The Ohio State University (Columbus), University of Arizona (Tucson), University of California San Francisco, University of Cincinnati (Ohio), University of Kentucky (Lexington), University of Minnesota (Minneapolis), University of Pennsylvania (Philadelphia), University of Pittsburgh (Pennsylvania), University of Texas–Houston, Virginia Commonwealth University (Richmond), Wayne State University (Detroit, Michigan). A directory listing of US network hubs, hub principal investigators, site principal investigators, and study coordinators affiliated with the NETT Network is available online (http://nett.umich.edu/directory).

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