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Figure 1.
Death or Disability at 3 Months and Response to Treatment Assignment by Status of Cerebral Microbleeds (CMBs)
Death or Disability at 3 Months and Response to Treatment Assignment by Status of Cerebral Microbleeds (CMBs)

RR indicates relative risk.

Figure 2.
Hematoma Expansion at 24 Hours and Response to Treatment Assignment by Status of Cerebral Microbleeds (CMBs)
Hematoma Expansion at 24 Hours and Response to Treatment Assignment by Status of Cerebral Microbleeds (CMBs)

RR indicates relative risk; NA, not applicable.
aCannot be shown because of small number of events.

Table 1.  
Baseline Characteristics and Neuroimaging Findings by Status of Cerebral Microbleeds (CMBs)
Baseline Characteristics and Neuroimaging Findings by Status of Cerebral Microbleeds (CMBs)
Table 2.  
Neuroimaging Findings by Status of Cerebral Microbleeds (CMBs)
Neuroimaging Findings by Status of Cerebral Microbleeds (CMBs)
Table 3.  
Primary and Secondary Outcomes
Primary and Secondary Outcomes
1.
Greenberg  SM, Vernooij  MW, Cordonnier  C,  et al; Microbleed Study Group.  Cerebral microbleeds: a guide to detection and interpretation.  Lancet Neurol. 2009;8(2):165-174.PubMedGoogle Scholar
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Shoamanesh  A, Kwok  CS, Benavente  O.  Cerebral microbleeds: histopathological correlation of neuroimaging.  Cerebrovasc Dis. 2011;32(6):528-534.PubMedGoogle Scholar
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Boulouis  G, van Etten  ES, Charidimou  A,  et al.  Association of key magnetic resonance imaging markers of cerebral small vessel disease with hematoma volume and expansion in patients with lobar and deep intracerebral hemorrhage.  JAMA Neurol. 2016;73(12):1440-1447.PubMedGoogle Scholar
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Greenberg  SM, Nandigam  RN, Delgado  P,  et al.  Microbleeds versus macrobleeds: evidence for distinct entities.  Stroke. 2009;40(7):2382-2386.PubMedGoogle Scholar
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Altmann-Schneider  I, Trompet  S, de Craen  AJ,  et al.  Cerebral microbleeds are predictive of mortality in the elderly.  Stroke. 2011;42(3):638-644.PubMedGoogle Scholar
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Song  TJ, Kim  J, Song  D,  et al.  Association of cerebral microbleeds with mortality in stroke patients having atrial fibrillation.  Neurology. 2014;83(15):1308-1315.PubMedGoogle Scholar
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Akoudad  S, Ikram  MA, Koudstaal  PJ, Hofman  A, van der Lugt  A, Vernooij  MW.  Cerebral microbleeds and the risk of mortality in the general population.  Eur J Epidemiol. 2013;28(10):815-821.PubMedGoogle Scholar
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Romero  JR, Preis  SR, Beiser  A,  et al.  Cerebral microbleeds as predictors of mortality: the Framingham Heart Study.  Stroke. 2017;48(3):781-783.PubMedGoogle Scholar
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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 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 Scholar
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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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Menon  RS, Burgess  RE, Wing  JJ,  et al.  Predictors of highly prevalent brain ischemia in intracerebral hemorrhage.  Ann Neurol. 2012;71(2):199-205.PubMedGoogle Scholar
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16.
Shoamanesh  A, Pearce  LA, Bazan  C,  et al; SPS3 Trial Investigators.  Microbleeds in the Secondary Prevention of Small Subcortical Strokes trial: stroke, mortality, and treatment interactions.  Ann Neurol. 2017;82(2):196-207.PubMedGoogle Scholar
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Shoamanesh  A, Martinez-Ramirez  S, Oliveira-Filho  J,  et al.  Interrelationship of superficial siderosis and microbleeds in cerebral amyloid angiopathy.  Neurology. 2014;83(20):1838-1843.PubMedGoogle Scholar
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Knudsen  KA, Rosand  J, Karluk  D, Greenberg  SM.  Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria.  Neurology. 2001;56(4):537-539.PubMedGoogle Scholar
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Shoamanesh  A, Catanese  L, Romero  JR,  et al.  High prevalence of cerebral microbleeds in inner city young stroke patients.  J Stroke Cerebrovasc Dis. 2016;25(4):733-738.PubMedGoogle Scholar
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Ovbiagele  B, Wing  JJ, Menon  RS,  et al.  Association of chronic kidney disease with cerebral microbleeds in patients with primary intracerebral hemorrhage.  Stroke. 2013;44(9):2409-2413.PubMedGoogle Scholar
Original Investigation
July 2018

Cerebral Microbleeds and the Effect of Intensive Blood Pressure Reduction on Hematoma Expansion and Functional Outcomes: A Secondary Analysis of the ATACH-2 Randomized Clinical Trial

Author Affiliations
  • 1Division of Neurology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • 2Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
  • 3J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 4Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 5Stroke Unit, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Mondino Foundation, Pavia, Italy
  • 6Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 7Zeenat Qureshi Stroke Research Center, University of Minnesota, Minneapolis
  • 8Department of Public Health Sciences, Medical University of South Carolina, Charleston
  • 9Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
JAMA Neurol. 2018;75(7):850-859. doi:10.1001/jamaneurol.2018.0454
Key Points

Question  Do patients with acute intracerebral hemorrhage with vs without cerebral microbleeds have different rates of hematoma expansion, 3-month outcomes, or response to intensive blood pressure lowering?

Findings  In this predefined subgroup analysis of a randomized clinical trial investigating optimal blood pressure lowering in 167 patients with intracerebral hemorrhage, the rates of hematoma expansion and 3-month death or disability did not differ between patients with microbleeds and those without. Patients with microbleeds responded similarly to intensive treatment.

Meaning  Patients with intracerebral hemorrhage with vs without microbleeds have similar rates of hematoma expansion and death or disability at 3 months, without apparent differential response to intensive blood pressure lowering.

Abstract

Importance  Response to intensive blood pressure (BP) lowering in acute intracerebral hemorrhage (ICH) might vary with the degree of underlying cerebral small vessel disease.

Objectives  To characterize cerebral microbleeds (CMBs) in acute ICH and to assess the potential for interaction between underlying small vessel disease (as indicated by CMB number and location) and assignment to acute intensive BP targeting for functional outcomes and hematoma expansion.

Design, Setting, and Participants  Preplanned subgroup analyses in the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial were performed. The ATACH-2 was an open-label international randomized clinical trial that investigated optimal acute BP lowering in 1000 patients with acute ICH. Analyses followed the intent-to-treat paradigm. Participants were enrolled between May 2011 and September 2015 and followed up for 3 months. Eligible participants were aged at least 18 years with ICH volumes less than 60 mL on computed tomography (CT) and a Glasgow Coma Scale score of at least 5 on initial assessment, in whom study drug could be initiated within 4.5 hours of symptom onset. Eight hundred thirty-three participants were excluded, leaving 167 who had an interpretable axial T2*-weighted gradient-recalled echo sequence on magnetic resonance imaging to assess CMBs for inclusion in these subgroup analyses.

Main Outcomes and Measures  The primary outcome of interest was death or disability (modified Ranking Scale score, 4-6) at 3 months. The secondary outcome of interest was hematoma volume expansion of at least 33% on a CT scan obtained 24 hours after randomization compared with the entry scan.

Results  A total of 167 patients were included; their mean (SD) age was 61.9 (13.2) years, and 98 (58.7%) were male. Cerebral microbleeds were present in 120 patients. Forty-six of 157 (29.3%) patients had poor outcome (modified Ranking Scale score, ≥4), and hematoma expansion was observed in 29 of 144 (20.1%) patients. Risk of poor outcome was similar for those assigned to intensive vs standard acute BP lowering among patients with CMBs (relative risk, 1.19; 95% CI, 0.61-2.33; P = .61) and those without CMBs (relative risk, 1.42; 95% CI, 0.43-4.70; P = .57), and no significant interaction was observed (interaction coefficient, 0.18; 95% CI, −1.20 to 1.55; P = .80). Risk of hematoma expansion was also similar, and no significant interaction between treatment and CMBs was observed (interaction coefficient, 0.62; 95% CI, −1.08 to 2.31; P = .48).

Conclusions and Relevance  Cerebral microbleeds are highly prevalent among patients with ICH but do not seem to influence response to acute intensive BP treatment.

Trial Registration  ClinicalTrials.gov Identifier: NCT01176565

Introduction

Cerebral microbleeds (CMBs) are remnants of prior cerebral microhemorrhages at the level of arterioles and capillaries visualized on blood-sensitive magnetic resonance imaging (MRI) sequences.1 Among patients with intracerebral hemorrhage (ICH), CMBs are highly prevalent and have evolved as radiological markers of underlying cerebral small vessel disease (CSVD), representing most notably hypertensive arteriopathy (arteriolosclerosis) (deep CMBs) or cerebral amyloid angiopathy (CAA) (strictly lobar CMBs).2 In both CSVD subtypes, advanced disease (marked by increasing CMB counts) is characterized histopathologically by thickened vessel walls.

While many analyses have examined whether CSVD subtypes influence risk of developing incident ICH (or recurrent ICH), one intriguing possibility is that their presence can be used clinically during acute ICH to mark those at highest risk of ongoing bleeding and hematoma expansion. Observational data characterizing the association between CMBs and hematoma expansion have been conflicting.3-5 On the one hand, it might be thought that more severe CSVD marks more fragile vessels with higher risk of continued bleeding after ICH.4,5 On the other hand, the thickened vessel walls associated with high CMB counts6 may be more resistant to secondary vessel rupture from perihematomal mechanical shear stress during hematoma expansion, limiting hematoma growth.3,6 Finally, CMBs may have additional important clinical implications as predictors of stroke-related outcome and mortality.7-10

The results of the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial offer a powerful opportunity to examine the association of CMBs, blood pressure (BP) management, hematoma expansion, and outcome in ICH. To explore the role of CSVD in ICH, we performed a preplanned secondary analysis of MRI images obtained during the ATACH-2 trial of intensive BP reduction in ICH. We hypothesized that the likelihood of hematoma expansion, clinical deterioration, and response to intensive BP lowering might vary with the underlying CSVD state, as inferred by CMB number and location.

Methods
Study Design

The rationale, design, and main results of the ATACH-2 international randomized clinical trial have been reported elsewhere.11,12 Spot Sign Score in Restricting ICH Growth (SCORE-IT) is a prospective observational study nested within the ATACH-2 trial with preplanned subgroup analysis of CMBs in trial participants who underwent a clinical brain MRI during their initial hospitalization.13

Standard Protocol Approvals, Registrations, and Patient Consents

The ATACH-2 trial protocol and consent forms were approved by the institutional review board or equivalent ethics committee at each participating site (eAppendix in the Supplement). All participants or their legally authorized representative provided written informed consent.

Study Participants

In brief, ATACH-2 was an open-label international randomized clinical trial that investigated optimal acute BP target in 1000 patients with acute ICH (eFigure in the Supplement). Eligible participants were patients aged at least 18 years with ICH volumes less than 60 mL on computed tomography (CT) and a Glasgow Coma Scale (GCS) score of at least 5 on initial assessment, in whom study drug could be initiated within 4.5 hours of symptom onset. At least one systolic BP reading exceeding 179 mm Hg from the time of symptom onset was required for eligibility.

The ATACH-2 trial participants were eligible for the present subgroup analyses if they had a clinical brain MRI as part of their initial hospitalization. The MRI had to have an interpretable axial T2*-weighted gradient-recalled echo (GRE) sequence allowing for CMB detection.

Intervention

Eligible participants were randomly assigned (1:1) to a systolic BP target of 110 to 139 mm Hg (intensive treatment) vs a target of 140 to 179 mm Hg (standard treatment) with the use of intravenous nicardipine hydrochloride. The infusion was started within 4.5 hours of symptom onset.

Data Collection

Demographic information and vascular risk factors were prospectively recorded at the time of study enrollment. This has been described previously for the ATACH-2 trial.11,12

Imaging Acquisition and Analysis

Computed tomography and MRI images were reviewed centrally by the ATACH-2 and SCORE-IT teams. Intracerebral hemorrhage topography, volume, and associated intraventricular hemorrhage (IVH) were rated on CTs obtained at entry. Intrahematomal contrast extravasation (or spot sign) was rated on CT angiography as previously described.13

In addition to CMBs, MRI markers of interest included diffusion-weighted imaging hyperintense lesions (DWIHLs), defined as regions of intraparenchymal hyperintensity on diffusion-weighted imaging, with associated hypointensity or isointensity on apparent diffusion coefficients that is distinct from the primary ICH and perihematomal edema.14,15 White matter hyperintensity (WMH) was evaluated visually on fluid-attenuated inversion recovery images using the Fazekas scale.15

Cerebral microbleeds were rated according to criteria proposed by the Microbleed Study Group.1 The CMB count severity was coded a priori as absent (0 CMBs), mild (1-2 CMBs), moderate (3-10 CMBs), or severe (>10 CMBs),16 and CMB topography was coded as strictly lobar (with or without concurrent cerebellar CMBs), strictly deep (deep and/or cerebellar CMBs), or mixed (concurrent lobar and deep CMBs).

All MRI images were independently rated by one primary rater (A.S.) and by one secondary rater (A.M., J.O.-F., or F.S.). The primary rater (A.S.) has previously demonstrated excellent intrarater reliability (n = 55, κ = 0.82, 91% agreement)16 and interrater reliability (A.S. and J.O.-F.) (n = 40; intraclass correlation coefficient, 0.99)17 for CMB detection in separate cohorts. The raters were masked to baseline features and outcomes. Any disagreement between the primary rater and secondary rater was reviewed and resolved according to consensus between the primary rater and whichever secondary rater had rated the particular image in question.

Outcomes

The primary outcome of interest in the ATACH-2 trial was death or disability (defined as a modified Ranking Scale score of 4-6) at 3 months. The secondary outcome of interest was hematoma volume expansion of at least 33% on a CT scan obtained 24 hours after randomization compared with the entry scan.

Statistical Analysis

Patient demographic and clinical characteristics were compared between groups in cross-sectional analyses using a χ2 test or Fisher exact test for categorical variables and a t test or Kruskal-Wallis test for continuous variables. The association between CMBs and death or disability was investigated with a multivariable logistic regression analysis and adjusted for assigned treatment group, age, baseline GCS score, the presence or absence of IVH at baseline, and other covariates. The association between CMBs and hematoma expansion was investigated with multivariable logistic regression analysis and adjusted for assigned treatment group, age, WMH score (Fazekas scale total score), and time from onset to baseline CT. These covariates were selected a priori based on the known predictors of these outcomes. Treatment interaction was assessed. Analyses followed the intent-to-treat paradigm, and participants were followed up for 90 days. All tests were 2 sided, and statistical significance was accepted at the .05 level. Analyses were performed with statistical software (SAS, version 9.4; SAS Institute).

A priori power calculations were performed. Assuming that the overall frequency of ICH expansion would be 40%, we projected that 30% of those with CMBs and 50% of those without CMBs will develop expansion. If 500 patients had GRE MRI available, we would have had 91% power to detect this. If 200 patients had these imaging data available, there would need to be a 27% difference in expansion rates to have 80% power to detect this. For the primary outcome of death or disability, if 200 patients had GRE MRI available, we would have 87% power to detect a 40% difference in outcome due to the intervention, and if 500 patients had GRE MRI available, there would need to be a 20% difference in outcome to have 94% power to detect this.

Results

Overall, 167 of 1000 (16.7%) enrolled participants between May 2011 and September 2015 had images available to assess CMBs and were included in these analyses. Of 833 participants who were excluded, 763 (91.6%) did not undergo MRI, 41 (4.9%) did not have an axial GRE sequence available, 15 (1.8%) were enrolled at centers where the institutional review board did not approve central review of MRIs, 12 (1.4%) had uninterpretable (ie, motion degraded) GRE MRI, and 2 (0.2%) were excluded because the MRI suggested that the symptomatic hemorrhage was hemorrhagic infarction rather than the primary ICH. Patients included in this analysis had lower ICH severity as measured by the GCS score and the National Institutes of Health Stroke Scale score compared with the remainder of the ATACH-2 trial participants, manifested higher white blood cell counts, and were less likely to have a history of hypertension, but they did not otherwise differ significantly (eTable in the Supplement). Included participants had a mean (SD) age of 61.9 (13.2) years, and 98 (58.7%) were male. Histories of hypertension (125 of 165 [75.8%]), smoking (71 of 154 [46.1%]), and hyperlipidemia (45 of 162 [27.8%]) were prevalent. Magnetic resonance imaging was performed a median of 1.3 days (interquartile range [IQR], 0.2-5 days) after randomization.

Seventy-two percent (n = 120) of 167 patients had at least one CMB (Table 1). Worse renal function was overrepresented in patients with CMBs compared with those without CMBs. Black and Asian race/ethnicity seemed to be overrepresented in patients with CMBs. Table 2 lists detailed neuroimaging findings in the patients with CMBs. Their median CMB count was 4 (IQR, 1-12). Among patients with at least one CMB, CMBs were strictly lobar in 30 patients (25.0%), strictly deep in 34 patients (28.3%), and mixed in 56 patients (46.7%). Patients with CMBs had greater degrees of WMH on MRI but not DWIHLs. There were no appreciable differences in regard to ICH volume or topography, the presence of IVH, or computed tomographic angiography (CTA) spot sign between patients with and without CMBs.

During a mean (SD) follow-up of 92.3 (8.3) days, 46 of 157 (29.3%) patients had poor outcome of death or disability (modified Ranking Scale score, ≥4), including 12 of 41 (29.3%) patients without CMBs and 34 of 116 (29.3%) patients with CMBs (Table 3). Participants with CMBs were not at increased risk of death or disability (adjusted relative risk [aRR], 0.83; 95% CI, 0.40-1.71; P = .61). Hematoma expansion was observed in 29 of 144 (20.1%) patients, including 8 of 40 (20.0%) patients without CMBs and 21 of 104 (20.2%) patients with CMBs. In multivariable analysis, patients with CMBs were not at reduced risk of hematoma expansion (relative risk [RR], 1.00; 95% CI, 0.42-2.39; P = .99). The lack of association between CMBs and the outcomes of interest was consistent across the prespecified CMB severity and topography categories. In post hoc exploratory analyses of 13 of 167 (7.8%) participants fulfilling clinicoradiographic criteria for probable CAA (lobar ICH with strictly lobar CMBs18), we detected a difference in the rates of hematoma expansion at 24 hours between patients with probable CAA (5 of 9 [55.6%]) and patients without CMBs (8 of 40 [20.0%]) (crude RR, 2.78; 95% CI, 1.19-6.51; P = .04). However, this association did not withstand adjusted analyses (aRR, 1.79; 95% CI, 0.44-7.31; P = .42). The lack of association with death or disability was consistent in patients with probable CAA.

Risk of poor outcome was similar for those assigned to intensive vs standard acute BP lowering among patients with CMBs (crude RR, 1.19; 95% CI, 0.61-2.33; P = .61) and those without CMBs (crude RR, 1.42; 95% CI, 0.43-4.70; P = .57), and no significant interaction was observed (interaction coefficient, 0.18; 95% CI, −1.20 to 1.55; P = .80) (Figure 1). The rates of hematoma expansion at 24 hours were similar with intensive acute BP lowering in patients with CMBs (crude RR, 0.54; 95% CI, 0.22-1.34; P = .18) compared with those without CMBs (crude RR, 1.00; 95% CI, 0.24-4.18; P = 1.00), and no significant interaction between treatment and CMBs was observed (interaction coefficient, 0.62; 95% CI, −1.08 to 2.31; P = .48) (Figure 2). There was no effect modification observed with the prespecified CMB severity and topography categories for either outcome or in exploratory post hoc analyses of patients with probable CAA.

Discussion

In this well-characterized cohort of patients with ICH of mild to moderate severity who had an acute hypertensive response (SBP, >179 mm Hg), CMBs were highly frequent and disproportionately associated with renal dysfunction. In addition, CMBs were associated with the presence of WMH. We did not observe greater death or disability at 3 months in patients with CMBs, and the rates of hematoma expansion were similar in patients with CMBs compared with those without CMBs. Moreover, there was no interaction observed between the degree of BP lowering and CMBs for the outcomes of death or disability at 3 months or hematoma expansion at 24 hours.

The observed 71.9% (120 of 167) prevalence of CMBs in our ICH cohort is higher than that previously reported in Western populations19 and likely reflects the large proportion of Asian participants in the present study. This may also be explained by the fact that the trial’s eligibility criteria mandated an acute hypertensive response with SBP exceeding 179 mm Hg, which would have selected patients having ICH with more advanced CSVD. The association between CMBs and poor renal function is consistent with the premise that both renal dysfunction and CMBs can serve as markers of hypertensive end-organ damage.16,20,21

Contrary to our hypothesis, CMBs were not a predictor of death or disability at 3 months. Accordingly, underlying vascular disease and particularly CSVD may have confounded the previously reported associations with mortality in broader populations.9,10 Fittingly, CMBs were not reported to be a predictor of mortality in patients with lacunar stroke enrolled in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.16 The lack of an association between CMBs and hematoma expansion or CTA spot sign was unexpected. Prior studies4,5 have demonstrated associations between CMBs and hematoma expansion or CTA spot sign in the setting of CAA-related ICH. Therefore, it is possible that patients with CAA-related ICH, who may typically be seen with lower levels of acute hypertensive response, were underrepresented in the ATACH-2 trial. Indeed, only 7.8% (13 of 167) of participants included in our analyses fulfilled criteria for probable CAA.

Strengths and Limitations

To our knowledge, these reported findings are the first assessing effect modification between CMBs and randomized hyperacute stroke therapies. We did not detect a treatment interaction between treatment assignment and CMBs for the outcomes of death or disability at 3 months or hematoma expansion at 24 hours, although our sample size was lower than expected and may have lacked sufficient power to detect an effect of even moderate size. There was a suggestion for change in the direction of the point effect estimate favoring intensive BP lowering in patients with CMBs for the outcome of hematoma expansion. However, because the treatment interaction was statistically insignificant and our analysis had limited power to confidently detect such an effect, these observations require further exploration in larger samples. Moreover, our results were limited by the unavailability of MRI sequences to allow for CMB assessment in all ATACH-2 trial participants and by the trial’s eligibility criteria, which limit the generalizability of our findings to all ICH. Selection bias was indeed evident, with patients undergoing MRI who were included in our analysis having less neurological deficit than the other ATACH-2 trial participants. The nonstandardization of GRE sequence acquisition parameters and the unavailability of data on these parameters, which were never captured, is a major limitation that may have resulted in heterogeneous CMB detection rates across the various recruitment centers and confounded our results. A final limitation is that our sample was underpowered to appropriately assess risk by CMB burden and topography.

Conclusions

Subgroup analysis of the first randomized clinical trial to date assessing treatment interactions with CMBs in patients with acute ICH demonstrated that CMBs are highly frequent in patients with ICH of mild to moderate severity who are seen with an acute hypertensive response (SBP, >179 mm Hg). We did not find that CMBs influence ICH-related death or disability at 3 months or hematoma expansion at 24 hours. Response to intensive acute BP treatment did not differ in patients having ICH with vs without CMBs.

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Article Information

Accepted for Publication: January 11, 2018.

Corresponding Author: Ashkan Shoamanesh, MD, Division of Neurology, Department of Medicine, McMaster University, Room C4-118, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton St E, Hamilton, ON L9G 1J8, Canada (ashkan.shoamanesh@phri.ca).

Published Online: April 16, 2018. doi:10.1001/jamaneurol.2018.0454

Author Contributions: Drs Shoamanesh and Cassarly had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Shoamanesh, Qureshi, Greenberg, Rosand, Goldstein.

Acquisition, analysis, or interpretation of data: Shoamanesh, Morotti, Romero, Oliveira-Filho, Schlunk, Jessel, Ayres, Vashkevich, Schwab, Afzal, Cassarly, Martin, Rosand, Goldstein.

Drafting of the manuscript: Shoamanesh.

Critical revision of the manuscript for important intellectual content: Morotti, Romero, Oliveira-Filho, Schlunk, Jessel, Ayres, Vashkevich, Schwab, Afzal, Cassarly, Martin, Qureshi, Greenberg, Rosand, Goldstein.

Statistical analysis: Cassarly, Martin.

Obtained funding: Qureshi, Rosand, Goldstein.

Administrative, technical, or material support: Shoamanesh, Morotti, Romero, Vashkevich, Schwab, Afzal.

Study supervision: Martin, Qureshi, Rosand, Goldstein.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grant U01-NS062091 (Dr Qureshi) from the National Institute of Neurological Disorders and Stroke and by grant NIH-NINDS R01NS073344 (Dr Rosand) from the National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Role of the Funder/Sponsor: The funding sources 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.

Group Information: 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 (Biostatistical 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, 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), 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, 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 (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 California, 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, Tucson, 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): Salvador Cruz-Flores, 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, currently 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). University of Pittsburgh Medical Center 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, 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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