Abstract
Background and Objectives:
Interleukin 6 (IL-6) is a proinflammatory cytokine and an established biomarker in acute brain injury. We sought to determine whether admission IL-6 levels are associated with severity and functional outcome after spontaneous intracerebral hemorrhage (ICH).
Methods:
We performed an exploratory analysis of the recombinant activated factor VII for acute ICH (FAST) trial. Patients with admission serum IL-6 levels were included. Regression analyses were used to assess the associations between IL-6 and 90-day modified Rankin scale (mRS). In secondary analyses, we used linear regression to evaluate the association between IL-6 and baseline ICH and perihematomal edema (PHE) volumes.
Results:
Of 841 enrolled patients, we included 552 (66%) with available admission IL-6 levels (mean age 64 [SD 13], female sex 203 [37%]). IL-6 was associated with poor outcome (mRS 4–6) (per additional 1 ng/L, OR 1.30; 95% CI 1.04–1.63; p=0.02) after adjustment for known predictors of outcome after ICH and treatment group. IL-6 was associated with ICH volume after adjustment for age, sex and ICH location, and this association was modified by location (multivariable interaction p=0.002), with a stronger association seen in lobar (β 12.51, 95% CI 6.47–18.55, p<0.001) versus non-lobar (β 5.32, 95% CI 3.36–7.28, p<0.001) location. IL-6 was associated with PHE volume after adjustment for age, sex, ICH volume, and ICH location (β 1.22, 95% CI 0.15 – 2.29, p=0.03). Treatment group was not associated with IL-6 levels or outcome.
Conclusions:
In the FAST trial population, higher admission IL-6 levels were associated with worse 90-day functional outcome and larger ICH and PHE volumes.
INTRODUCTION
Spontaneous intracerebral hemorrhage (ICH) is responsible for a large proportion of all stroke-related disability.1 Therapeutic options remain limited as clinical trials targeting primary injury in ICH have failed to improve outcomes.2,3 Increasing evidence suggests that systemic inflammation contributes to both an increased risk of stroke and worse outcomes after stroke.4–7 However, serum biomarkers of systemic inflammation associated with ICH have not been extensively studied in large, multi-center cohorts.8,9
Interleukin-6 (IL-6) is a proinflammatory cytokine that has been widely studied as a biomarker of systemic inflammation in acute brain injury.10–13 Preclinical studies have shown that IL-6 is elevated after experimental ICH and may contribute to the early inflammatory response to ICH.14,15 Clinical studies have reported that serum IL-6 levels are elevated as early as 1 day after stroke16 and are higher in ICH cases compared to healthy controls.17 IL-6 may be an attractive translational target as several anti-IL-6 therapies are available clinically.18,19 Whether peripheral IL-6 levels correlate with neuroimaging markers of inflammation and functional outcome in ICH remains unknown.
We analyzed data from the Factor VII for Acute ICH (FAST) trial to determine whether IL-6 levels at admission are associated with worse functional outcomes after ICH and neuroimaging markers of ICH severity, including ICH and perihematomal edema (PHE) volumes. The FAST trial benefits from a large number of ICH patients who underwent standardized biosample collection, outcome adjudication, and neuroimaging analysis.20 We hypothesized that higher admission IL-6 levels are associated with larger ICH and PHE volumes and poor outcome after ICH.
METHODS
Data Availability
Anonymized data from the FAST trial are available by request through Novo Nordisk (https://www.novonordisk-trials.com) or the Virtual International Stroke Trials Archive (VISTA, virtualtrialsarchives.org).
Study Design and Inclusion Criteria
The FAST trial was a multicenter, randomized, double-blind, placebo-controlled phase III trial of recombinant Factor VIIa (rFVIIa) for the treatment of spontaneous ICH. The trial enrolled patients with spontaneous ICH presenting within 3 hours of symptom onset at 122 sites across 22 countries from May 2005 to February 2007. Study participants were randomly assigned to receive a single dose of 80 μg of rFVIIa per kilogram, 20 μg of rFVIIa per kilogram, or placebo within four hours of stroke onset. Each patient, or their legally authorized representative, provided written informed consent for participation in the trial, and institutional review board approval was obtained at each site. The FAST study is registered with ClinicalTrials.gov (NCT00127283). We included patients with primary ICH, available serum measurements of admission IL-6, 24-hour follow-up imaging data, and 90-day modified Rankin Scale (mRS).
Standard Protocol Approvals, Registrations, and Patient Consents
This study was deemed exempt from review from our IRB because all data are de-identified and publicly available.
Serum Biomarker Collection and Neuroimaging
In the FAST trial, baseline labs and biomarkers were collected at the baseline study visit, within 4 hours of ICH symptom onset. Blood samples for cytokine analysis were centrifuged at 3000g for 5 minutes on site, frozen and stored at −80 °C, and analyzed in batches at a central core lab facility. IL-6 was measured with commercially available quantitative sandwich enzyme-linked immunosorbent assay (Quantikine®) kits obtained from R&D Systems, Inc. Laboratory determinations were performed blinded to clinical and neuroimaging findings. Computed tomography (CT) scans were collected at admission and 24 hours after initiation of study treatment. Scans were sent to a central imaging laboratory (Bio-Imaging Technologies) and analyzed in random order with the use of Analyze software (Mayo Clinic) by two neuroradiologists who were blinded to the treatment assignments. As per the FAST protocol, ICH, intraventricular hemorrhage (IVH), and PHE volumes were calculated using a semi-automated process by tracing the perimeter of appropriate high- and low-attenuation zones and calculating lesion areas for each slice multiplied by slice thickness to yield lesion volumes. PHE volumes were calculated by subtracting ICH volume from the combined ICH plus edema volume.20–22
Clinical Outcomes
The primary outcome was poor outcome at 3 months, defined as mRS of 4–6. In a secondary analysis, functional outcome was evaluated across the range of mRS scores (shift analysis). The mRS was assessed via in-person follow-up visit or by structured telephone interview.
Statistical Methods
All statistical analyses were performed using R (version 3.5.1). Data are presented as counts (percentage) for discrete variables and as median [interquartile range (IQR)] or mean [standard deviation (SD)] for continuous variables, as appropriate. The normality of variables was assessed by visually inspecting histogram plots. Non-normally distributed variables, including IL-6 levels, were natural log-transformed continuous variables to approximate normality. We also analyzed IL-6 levels in quartiles.
Regression Analyses.
Logistic regression was used to model the association between IL-6 and poor outcome and linear regression was used to test the association between IL-6 and ICH volume and PHE volume. In secondary analyses, the association between IL-6 levels and distribution of mRS scores was evaluated using ordinal logistic regression. Multivariable models were built using forward selection of covariates significant to a p-value <0.1 in univariable testing, followed by backwards elimination at a threshold of 0.1. We included the FVIIa treatment group in all outcome models to adjust for any residual confounding from the trial intervention. We tested for interaction with ICH location (lobar vs non-lobar) by adding a product term to our multivariable regression model. We then implemented the analysis after stratifying by ICH location.
RESULTS
Study Population
Of 841 patients enrolled in the FAST trial, we included 552 patients (66%) (mean age 64 years [SD 13], female sex N=202 [37%]) with admission measurements of serum IL-6 and 90-day mRS (Figure 1). Patients who were excluded due to missing admission IL-6 measurements did not differ from patients who were included in the analysis in terms of baseline characteristics or outcomes, except from age (66 years in those missing IL-6 levels versus 64 in those with IL-6 levels, p=0.05; Table 1). The median admission IL-6 level (normal range 0.5–5.0 ng/L) for included patients was 4.4ng/L (IQR 2.5–8.3 ng/L) and the quartile ranges were as follows: first quartile (Q1) 0.95–2.5, second quartile (Q2) 2.5–4.4, third quartile (Q3) 4.4–8.3, and fourth quartile (Q4) 8.3–286 ng/L. Baseline characteristics and treatment group assignment did not differ by IL-6 quartile, except patients in Q4 were older than patients in Q1 (66 years vs 61 years, p=0.05; Table 2). In all patients, the mean ICH volume was 23.4mL (SD 25.4) and the location of the ICH was non-lobar in 433 patients (81%) and lobar in 78 (15%).
Figure 1.
Flowchart summarizing the selection of study patients from the FAST trial based on the availability of outcome data and baseline IL-6 measurements. A total of 552 patients were included in the study. Abbreviations: FAST = Factor VII for acute ICH trial, IL-6 = interleukin 6.
Table 1.
Baseline characteristics of included and excluded patients
| Covariate | Missing IL-6 Level (n = 267) | With IL-6 Level (n = 552) | p |
|---|---|---|---|
| Age, year, mean [SD] | 66 [13] | 64 [13] | 0.05 |
| Female, No. (%) | 106 (40) | 202 (37) | 0.39 |
| Hypertension, No. (%) | 219 (93) | 467 (93) | 0.91 |
| Hyperlipidemia, No. (%) | 72 (31) | 153 (31) | 0.89 |
| Diabetes, No. (%) | 31 (13) | 60 (12) | 0.74 |
| Atrial Fibrillation, No. (%) | 10 (4) | 19 (4) | 0.87 |
| Coronary Artery Disease, No. (%) | 14 (6) | 28 (6) | 0.91 |
| COPD, No. (%) | 4 (2) | 16 (3) | 0.44 |
| ICH Location, No. (%) | 0.92 | ||
| Non-lobar | 202 (81) | 433 (81) | |
| Lobar | 35 (14) | 78 (15) | |
| ICH Volume, mL, mean [SD] | 22 [25] | 23 [26] | 0.65 |
| PHE Volume, mL, mean [SD] | 16 [18] | 18 [22] | 0.18 |
| Presence of IVH, n (%) | 97 (36) | 205 (37) | 0.86 |
| Treatment Group, No. (%) | 0.74 | ||
| 20 ug | 90 (34) | 172 (31) | |
| 80 ug | 81 (30) | 183 (33) | |
| Placebo | 96 (36) | 197 (36) | |
| Poor Outcome (mRS 4–6), No. (%) | 128 (48) | 262 (48) | 0.91 |
Abbreviations: SD = standard deviation, COPD = chronic obstructive pulmonary disease, ICH = intracerebral hemorrhage, PHE = perihematomal edema, IVH = intraventricular hemorrhage, mRS = modified Rankin Scale
Table 2.
Baseline clinical and neuroimaging characteristics of included patients by IL-6 quartile
| All | Q1 | Q2 | Q3 | Q4 | p | |
|---|---|---|---|---|---|---|
| n | 552 | 142 | 136 | 136 | 138 | |
| Age, year, mean [SD] | 64 [13] | 61 [13] | 64 [13] | 64 [13] | 66 [13] | 0.05 |
| Female, No. (%) | 202 (37) | 56 (39) | 41 (30) | 51 (37) | 55 (40) | 0.31 |
| Hypertension, No. (%) | 467 (93) | 115 (94) | 117 (91) | 125 (95) | 115 (91) | 0.49 |
| Hyperlipidemia, No. (%) | 153 (31) | 40 (33) | 41 (32) | 39 (30) | 34 (27) | 0.83 |
| Diabetes, No. (%) | 60 (12) | 7 (6) | 17 (13) | 18 (14) | 18 (14) | 0.12 |
| Atrial Fibrillation, No. (%) | 19 (4) | 5 (4) | 4 (3) | 5 (4) | 5 (4) | 0.87 |
| Coronary Artery Disease, No. (%) | 28 (6) | 3 (3) | 12 (9) | 8 (6) | 5 (4) | 0.09 |
| COPD, No. (%) | 16 (3) | 3 (3) | 5 (4) | 3 (2) | 5 (4) | 0.78 |
| Systolic BP (mmHg) | 179 (30) | 177 (30) | 177 (27) | 181 (30) | 181 (30) | 0.47 |
| Leukocytes (ug/l) | 9 (3) | 8 (3) | 8 (3) | 9 (3) | 12 (4) | <0.001 |
| Thrombocytes (ug/l) | 240 (60) | 243 (64) | 235 (58) | 241 (73) | 240 (72) | 0.81 |
| Glucose (mg/dl) | 135 (50) | 120 (37) | 133 (46) | 132 (51) | 153 (56) | <0.001 |
| Body Temperature (°C) | 36 (0.6) | 36 (0.6) | 36 (0.6) | 36 (0.6) | 36 (0.7) | 0.57 |
| ICH Location, No. (%) | <0.001 | |||||
| Deep | 433 (81) | 119 (86) | 112 (84) | 115 (85) | 91 (68) | |
| Lobar | 78 (15) | 16 (12) | 12 (9) | 17 (13) | 33 (25) | |
| ICH Volume, mL, mean [SD] | 23.5 [25.7] | 15.6 [16.1] | 17.3 [17.3] | 25.6 [25.4] | 35.6 [34.7] | <0.001 |
| PHE Volume, mL, mean [SD] | 5.4 [3.0] | 4.5 [2.0] | 4.8 [2.3] | 5.2 [3.1] | 6.9 [3.4] | <0.001 |
| IVH present, No (%) | 205 (37) | 47 (34) | 38 (28) | 59 (43) | 61 (44) | 0.01 |
| Treatment Group, No. (%) | 0.84 | |||||
| 20 ug | 172 (31) | 45 (32) | 45 (33) | 40 (29) | 43 (31) | |
| 80 ug | 183 (33) | 42 (30) | 48 (35) | 51 (37) | 46 (33) | |
| Placebo | 197 (35) | 55 (39) | 45 (33) | 47 (34) | 50 (36) |
Abbreviations: ICH = intracerebral hemorrhage, SD = standard deviation, PHE = perihematomal edema
Association Between Admission IL-6 and Functional Outcome
Patients with a poor outcome had a higher median admission IL-6 level than those with a favorable outcome (5.6 ng/L [IQR 3.1–12.3] versus 3.6 ng/L [IQR 2.0–5.7], unadjusted p<0.001). In multivariable analysis, a 1 ng/L increase in IL-6 level was associated with a 30% increase in the odds of a poor functional outcome (OR 1.30, 95% CI 1.04–1.63, p=0.02) after adjustment for age, sex, ICH volume, GCS, IVH, hematoma expansion > 33%, ICH location, and rFVIIa treatment (Table 3). These results were consistent in sensitivity analyses stratified by treatment group (IL-6*treatment group multivariable interaction p = 0.98) and in sensitivity analyses adjusting for lymphocyte count and body temperature. IL-6 was also associated with worse functional outcome when evaluating the entire range of mRS scores in ordinal analysis (adjusted OR 1.43, 95% CI 1.21 – 1.68, Table 3). When evaluated in quartiles, the highest quartile of IL-6 was associated with a 4.5-fold increase (95% CI 2.7–7.4) in the odds of a poor outcome compared to the lowest quartile in unadjusted analyses, and a 2.0-fold increase (95% CI 1.2–4.5) in adjusted analyses (Figure 2).
Table 3.
Association of admission IL-6 level with functional outcome
| Model | Poor Outcome (mRS 4–6) | Across mRS Scale (mRS 0–6) | ||
|---|---|---|---|---|
| OR (95% CI) | p | OR (95% CI) | p | |
| IL-6, unadjusted | 1.65 (1.39 – 1.98) | <0.001 | 1.79 (1.54 – 2.09) | <0.001 |
| IL-6, adjusted* | 1.30 (1.04 – 1.63) | 0.02 | 1.43 (1.21 – 1.68) | <0.001 |
Abbreviations: OR = odds ratio, CI = confidence interval
Adjusted for age, sex, baseline ICH volume (natural log), GCS, presence of IVH, hematoma expansion >33%, hemorrhage location, and rFVIIa treatment
Figure 2.
Odds ratio plot on a logarithmic scale demonstrating the risk for poor outcome (mRS 4–6) in patients in each quartile of IL-6 level. The lowest IL-6 quartile is the reference level. Multivariable models include age, sex, baseline ICH volume (natural log), GCS, presence of IVH, hematoma expansion >33%, hemorrhage location, and rFVIIa treatment. Error bars show 95% confidence intervals.
Association between IL-6 and Neuroimaging Markers of Severity and Secondary Injury
Baseline neuroimaging characteristics by IL-6 quartile are shown in Table 2. Higher levels of IL-6 were associated with increased baseline ICH volume (β 5.32, 95% CI 3.22–7.43, p<0.001), PHE volume (β 6.58, 95% CI 4.89–8.27, p<0.001), and presence of IVH (OR 1.32, 95% CI 1.08 – 1.63, p=0.008) in univariable analyses. In multivariable models that accounted for age, sex, and ICH location, IL-6 was independently associated with baseline ICH volume (β 5.40, 95% CI 3.28–7.51, p<0.001). Additionally, IL-6 level remained a significant predictor of baseline PHE volume (β 1.22, 95% CI 0.15–2.29, p=0.03) after adjusting for age, sex, ICH location, and baseline ICH volume (Table 4). IL-6 was not associated with presence of IVH after adjustment for ICH volume and location. In secondary analyses, IL-6 was not associated with hematoma expansion (defined as >6 cc or >33% increase) at 24 hours in univariable (OR 1.08, 95% CI 0.91–1.30, p=0.38) or multivariable (OR 0.95, 95% CI 0.78–1.16, p=0.60) analyses.
Table 4.
Linear regression analyses of log-transformed IL-6 level and baseline neuroimaging metrics
| Model | Univariable | Multivariable | ||
|---|---|---|---|---|
| β (95% CI) | p | β (95% CI) | p | |
| ICH Volume | ||||
| All ICH | 5.32 (3.22 – 7.43) | <0.001 | 5.40 (3.28 – 7.51)* | <0.001 |
| Lobar | 12.51 (6.47 – 18.55) | <0.001 | 12.06 (6.02 – 18.10)* | <0.001 |
| Non-lobar | 5.32 (3.36 – 7.28 | <0.001 | 5.43 (3.46 – 7.40)* | <0.001 |
| PHE Volume | ||||
| All ICH | 6.58 (4.89 – 8.27) | <0.001 | 1.22 (0.15 – 2.29)** | 0.03 |
| IVH Presence | OR (95% CI) | p | OR (95% CI) | p |
| All ICH | 1.32 (1.08 – 1.63) | 0.008 | 1.22 (0.97 – 1.55)** | 0.09 |
Abbreviations: ICH=intracerebral hemorrhage, PHE = perihematomal edema, IL-6 = interleukin 6, CI = confidence interval
Adjusted for age and sex
Adjusted for age, sex, baseline ICH volume, and hemorrhage location
Lobar Location Modifies the Association Between IL-6 and ICH Volume
Median IL-6 levels were higher in lobar versus non-lobar ICH (7.4 ng/l [IQR 10.2] vs 4.0 ng/l [IQR 5.1], unadjusted p=0.004). There was a significant interaction between ICH location and IL-6 level when predicting ICH volume (multivariable β 7.18, 95% CI 2.57–11.80, p=0.002). In location-stratified analyses, there was a stronger association between admission IL-6 levels and ICH volume in lobar hemorrhages (unadjusted: β 12.51, 95% CI 6.47–18.55, p<0.001; adjusted for age and sex: β 12.06, 95% CI 6.02–18.10, p<0.001) than in non-lobar hemorrhages (unadjusted: β 5.32, 95% CI 3.36–7.28, p<0.001; adjusted for age and sex: β 5.43, 95% CI 3.46–7.40, p<0.001) (Table 4).
DISCUSSION
We report a pre-specified exploratory analysis of the FAST trial testing the association of admission levels of serum IL-6 with poor functional outcome and neuroimaging markers of secondary injury after spontaneous, non-traumatic ICH. We found that higher levels of IL-6 were associated with poor functional outcome at 90 days as well as increased baseline ICH and PHE volumes. Furthermore, we found that ICH location modified the association between admission IL-6 level and ICH volume, with a larger magnitude of effect seen in lobar versus other locations.
Our findings are the first from a large multi-center study to show an association between IL-6 and functional outcome after ICH. Our results confirm a small single-center study that reported an association between IL-6 levels and 30-day mortality after ICH23 and add that IL-6 levels at admission are a marker of poor functional outcome at 90 days. Several mechanisms could explain the association between IL-6 and outcome. First, our results suggest that this finding could be mediated through larger ICH and PHE volumes at baseline, both of which are strong predictors of outcome.24,25 While a small, single-center study previously showed that baseline IL-6 levels are associated with a higher risk of hematoma expansion at 24 hours in patients with ICH,26 our study did not confirm this association. Second, elevated levels of early inflammatory markers could suggest a higher burden of baseline comorbidities and a predisposition to worse outcomes.27 In our cohort, patients in the highest quartile of IL-6 levels were older and had significantly higher glucose levels than those in the lowest quartile, which has been associated with poor outcomes after ICH in prior studies.28 The mechanism underlying this association with hyperglycemia is unknown but may be related to microvascular hypoperfusion in the perihematomal tissue surrounding larger hematomas.29 In this study, glucose was not significantly associated with outcome in multivariable analysis and was backwards eliminated from the final model. Other baseline characteristics and comorbidities also did not differ by IL-6 quartile. Finally, elevated IL-6 levels could also indicate a more robust inflammatory response to the ICH that incites secondary injury cascades leading to impaired healing and recovery.30 A previous study has reported an association between the development of systemic inflammatory response syndrome (SIRS) and worse outcome after ICH.4 Although our data suggest a dose-response relationship between higher IL-6 levels and worse functional outcomes, randomized data are needed to determine whether IL-6 is causally related to worse outcomes.
We also found an association between IL-6 levels and ICH volume. Larger ICH volumes may trigger a greater systemic inflammatory response both in the central nervous system and in the periphery, resulting in higher IL-6 levels early after ICH. In location-stratified analyses, we also found a stronger association between IL-6 and ICH volume in lobar versus deep hemorrhages. Patients with lobar ICH are older, often have a greater burden of comorbidities, and have larger hemorrhage volumes. These factors may contribute to the greater inflammatory response seen in lobar ICH. Further research is needed determine the source of early IL-6 after ICH and determine whether the association between ICH volume and IL-6 levels is causal.27,31
We also report an association between higher IL-6 levels and larger admission PHE volumes. PHE, seen on CT scans as the hypodense rim surrounding the ICH, is a neuroimaging marker of secondary injury after ICH and has been associated with poor outcomes.32–34 An early systemic inflammatory response to ICH may be both a contributor of and a response to PHE volume. Early PHE formation is thought to be driven by both osmotic fluid shifts and early activation of immune cells in the perihematomal area by oxidative stress and the coagulation cascade.33,35,36 These immune cells both produce and respond to cytokines, including IL-6, to regulate the inflammatory response to ICH.37 In this study, both ICH volume and IL-6 levels were independently associated with PHE volume, suggesting a role of both in PHE formation. Further research is needed to determine whether IL-6 is associated with PHE outside of the acute period.
While this is the first large, multi-center study of IL-6 in ICH with standardized biosample collection, neuroimaging, and outcome ascertainment, our study has some important limitations to consider. First, due to limited datasets with available IL-6 measurements, we were not able to replicate our findings. While other small studies have shown associations of IL-6 levels with mortality after ICH,23,38 another single-center study of 126 patients with ICH did not find an association between IL-6 levels within 24 hours of admission and 3-month outcome as measured by the Canadian Stroke Severity scale.39 These results may be explained by small sample size to detect differences in IL-6 levels, collection of IL-6 at non-standardized time points outside of the hyper-acute window (as in this study), or differences hospital course or outcome measures. Therefore, our results need replication in independent multi-center cohorts and in patients that have undergone different medial or surgical interventions. Second, the FAST trial collected IL-6 measurements at admission, precluding observations regarding the temporal profile of IL-6 levels throughout recovery. However, the collection of IL-6 levels within 4 hours of ICH symptom onset in this study suggests that IL-6 levels could be used as an early prognostic factor. Third, we lacked data on long-term outcomes and imaging to evaluate the association between IL-6 and ICH recovery. Fourth, other markers and downstream mediators of IL-6 signaling, including soluble IL-6 receptor and c-reactive protein, were not available to confirm our findings. Fifth, because the FAST trial excluded patients on oral anticoagulation, the association between IL-6 and functional outcome after anticoagulant-related ICH was not addressed in this study. Lastly, as an observational study, we are unable to draw any conclusions regarding causality. Further studies are needed to determine whether a causal relationship exists between IL-6 and clinical outcomes and whether anti-therapies IL-6 therapies can improve outcome after ICH.
CONCLUSIONS
In conclusion, we found that levels of IL-6 at admission are associated with worse functional outcome after ICH. We also found that higher levels of IL-6 are associated with larger ICH and PHE volumes. Further studies are needed to evaluate the role of IL-6 as a potential interventional target in ICH.
Acknowledgments
Sources of Funding
This study was supported by the American Heart Association Medical Student Research Fellowship. The funding entities 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; or decision to submit the manuscript for publication
Author Disclosures
Ms. Leasure is supported by the American Heart Association Medical Student Fellowship.
Ms. Kuohn reports no disclosures.
Mr. Vanent reports no disclosures.
Dr. Bevers is supported by the National Institute of Neurological Disorders and Stroke (K23NS112474), the American Academy of Neurology (AI18–0000000062), the Andrew David Heitman Neurovascular Foundation, and reports grants and personal fees from Biogen outside the submitted work.
Dr. Kimberly reports grants and personal fees from NControl Therapeutics and grants and personal fees from Biogen outside the submitted work; in addition, Dr. Kimberly has a patent to PCT/US2018/018537 issued and licensed.
Dr. Mayer reports no disclosures.
Dr. Steiner reports no disclosures.
Dr. Matouk reports no disclosures.
Dr. Sansing is supported by the NIH (R01NS095993, R01NS097728, U01NS113445).
Dr. Falcone is supported by the National Institute on Aging (K76AG59992), the National Institute of Neurological Disorders and Stroke (R03NS112859), the American Heart Association (18IDDG34280056), a Yale Pepper Scholar Award (P30AG021342), and the Neurocritical Care Society Research Fellowship.
Dr. Sheth is supported by the NIH (U24NS107136, U24NS107215, R01NR018335, R01NS107215, U01NS106513, R03NS112859) and the American Heart Association (18TPA34170180, 17CSA33550004). Dr. Sheth also reports grants from Bard, Hyperfine, Biogen, Novartis; personal fees from Zoll, Ceribell, NControl; and other from Alva outside the submitted work
Non-standard Abbreviations and Acronyms
- ICH
Intracerebral Hemorrhage
- PHE
Perihematomal Edema
- IL-6
Interleukin 6
- FAST
Factor VII for Acute ICH Trial
- mRS
modified Rankin Scale
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Anonymized data from the FAST trial are available by request through Novo Nordisk (https://www.novonordisk-trials.com) or the Virtual International Stroke Trials Archive (VISTA, virtualtrialsarchives.org).