Timing of INR reversal using fresh-frozen plasma in warfarin-associated intracerebral hemorrhage

  • Murtaza Akhter
  • Andrea Morotti
  • Abigail Sara Cohen
  • Yuchiao Chang
  • Alison M. Ayres
  • Kristin Schwab
  • Anand Viswanathan
  • Mahmut Edip Gurol
  • Christopher David Anderson
  • Steven Mark Greenberg
  • Jonathan Rosand
  • Joshua Norkin Goldstein
EM - ORIGINAL

Abstract

Rapid reversal of coagulopathy is recommended in warfarin-associated intracerebral hemorrhage (WAICH). However, rapid correction of the INR has not yet been proven to improve clinical outcomes, and the rate of correction with fresh-frozen plasma (FFP) can be variable. We sought to determine whether faster INR reversal with FFP is associated with decreased hematoma expansion and improved outcome. We performed a retrospective analysis of a prospectively collected cohort of consecutive patients with WAICH presenting to an urban tertiary care hospital from 2000 to 2013. Patients with baseline INR > 1.4 treated with FFP and vitamin K were included. The primary outcomes are occurrence of hematoma expansion, discharge modified Rankin Scale (mRS), and 30-day mortality. The association between timing of INR reversal, ICH expansion, and outcome was investigated with logistic regression analysis. 120 subjects met inclusion criteria (mean age 76.9, 57.5% males). Median presenting INR was 2.8 (IQR 2.3–3.4). Hematoma expansion is not associated with slower INR reversal [median time to INR reversal 9 (IQR 5–14) h vs. 10 (IQR 7–16) h, p = 0.61]. Patients with ultimately poor outcome received more rapid INR reversal than those with favorable outcome [9 (IQR 6–14) h vs. 12 (8–19) h, p = 0.064). We find no evidence of an association between faster INR reversal and either reduced hematoma expansion or better outcome.

Keywords

Intracerebral hemorrhage Warfarin Stroke Cerebral hemorrhage Anticoagulants 

Introduction

Intracerebral hemorrhage (ICH) is the most devastating form of stroke. While it accounts for only 15% of all strokes, affecting approximately 2 million people worldwide each year, fewer than 40% of survivors are functionally independent at 3 months, and at 1 year, the mortality rate is as high as 70% [1, 2].

Patients with warfarin-associated ICH (WAICH) suffer even worse outcomes, likely due to a higher risk of hematoma expansion [3, 4, 5, 6, 7]. As a result, the current guidelines recommend correcting the coagulopathy as quickly as possible [8, 9]. Studies evaluating whether rapid correction of the INR improves clinical outcomes, however, show inconsistent results. It is not clear whether correction of the INR correlates directly with clinical hemostasis [10], nor whether doing so can actually modify the course of WAICH. Observational studies of ICH have led to conflicting conclusions [11, 12, 13, 14, 15]. The largest available clinical trial of warfarin reversal for acute bleeding (including both ICH and non-ICH patients) finds that 4 factor prothrombin complex concentrate (4F-PCC) reverses the INR much more quickly than does fresh-frozen plasma (FFP), but is unable to demonstrate a statistically significant difference in clinical outcome [16]. Recent larger studies of WAICH patients suggest that more rapid use of 4F-PCCs reduces the risk of expansion, but is not per se clearly associated with outcome [17, 18].

One possibility is that these studies were underpowered to show a small but clinically relevant effect on clinical hemostasis. One randomized trial does find improved perioperative hemostasis (in mostly non-ICH patients) with 4F-PCC compared with FFP, supporting this possibility [19]. However, it still remains possible that, for many patients, rapid vs. slower INR reduction does not impact the likelihood of good outcome and that only a subset of patients will derive benefit.

The timing of INR reversal using FFP is much more variable than with 4F-PCC, and until recently was the only option available at many US centers. We, therefore, examined whether the timing of INR reversal using FFP influences hematoma expansion and outcome in WAICH.

Methods

Study design

We performed a retrospective analysis of data collected as part of an ongoing prospective cohort study of consecutive ICH patients presenting to a single tertiary care hospital [7]. Patients, or their health care proxies, signed written informed consent before enrollment, or their consent was waived by protocol-specific allowance. The study was approved by the hospital’s Institutional Review Board.

Subjects

We performed a cohort study. Study subjects were patients with warfarin-related ICH (WAICH) admitted to Massachusetts General Hospital between 2000 and 2013; consecutive patients were enrolled in an ongoing prospective cohort study [11]. Additional variables for this analysis, including serial INR measurements, were then captured retrospectively. Until 2013, no agents other than Vitamin K and FFP were available at our center, and these were the only agents used in this cohort. The standard protocol at our center for WAICH during the time frame of the study was to give FFP as quickly as possible. Some of these patients were included in a prior analysis [11]. Patients were eligible for the present analysis if they were age ≥18 years, with an initial INR above 1.4, and diagnosed as having primary ICH. Exclusion criteria were suspected secondary ICH (trauma, brain tumor, and vascular malformation), hemorrhagic conversion of a cerebral infarction, bleeding disorders (hemophilia A & B, sickle cell anemia, Von Willebrand disease) primary intraventricular hemorrhage (IVH), and those who were made Comfort Measures Only within 24 h. Secondary ICH was excluded due to concern that the risk of hematoma expansion and clinical outcomes in secondary ICH can be quite different.

Clinical data

Patient demographics and past medical history were obtained for each subject by patient or family/surrogate interview or by chart review. Information included age, gender, time of symptom onset, medical history, family history, pre-ICH treatment with warfarin, use of antiplatelets, and antihypertensives. Our internal hospital protocol recommends follow-up imaging at 24 h as part of routine care. We retrospectively extracted serial INR measurements from an administrative research data registry. We also collected the time from symptom onset to normalized INR and the time from baseline to normalized INR. Rate of FFP delivery was not consistently documented in the medical records. Baseline severity of disease was measured with the ICH score, a calculation based on age, ICH volume, ICH location, initial GCS score, and presence of intraventricular blood [20]. These baseline neurologic variables were captured on arrival, prior to administration of FFP. Discharge functional outcome (modified Rankin Scale, mRS) was obtained through retrospective chart review and long-term follow-up was performed as previously described [21] to capture the mortality rate at 30 days.

Imaging

CT images were reviewed by study staff blinded to clinical data. Hemorrhage volumes were calculated using computerized planimetry with Alice (PAREXEL International Corporation) and Analyze 9.0 (Mayo Clinic, Rochester, MN, USA) software as described previously [22, 23]. Intraventricular blood was not included in ICH volume. Significant hematoma expansion was defined as relative volume increase >33% or absolute volume increase >6 mL from the initial ICH volume [24, 25, 26]. When available, CTA images were reviewed for spot sign presence, as previously described [27].

Statistical analyses

Continuous variables were summarized using mean with standard deviation, (SD) or median with interquartiles (IQR) and compared with the Student’s t test or Mann–Whitney U test, respectively. Categorical variables were expressed as count with percentage and compared between groups using the Chi-square tests. Time to INR correction was analyzed both as a continuous variable and as a binary variable with a cutpoint at 6 h from baseline INR measurement. For clarity of presentation, we operationally defined “rapid” INR reversal as INR ≤ 1.4 within 6 h [16, 28]. Patients who did not reach the goal did not have additional INR measurements after 6 h were censored at time of the last INR measurement and considered as no INR normalization within 6 h. The times to INR normalization were summarized using the Kaplan–Meier curves and compared using log-rank tests or Wilcoxon tests. Poor neurological outcome was defined as discharge Modified Rankin Scale (mRS) ≥ 4. The association between timing of INR reversal, ICH expansion, and outcome was assessed with a multivariable logistic regression model, adjusted for known predictors of ICH expansion and mortality [20]. Sensitivity analyses were conducted using different cutoffs for the definition of rapid INR reversal (1.3, 1.5, 1.7, and 2.0). All analyses were performed using SAS version 9.4 (The SAS Institute, Cary, NC, USA). Two-sided p values <0.05 were considered statistically significant.

Results

Overall, 456 patients presented to our hospital during the study period with WAICH and 120 qualified for our study (mean age 76.9, 57.5% males) (Fig. 1). The excluded patients had significantly larger hematoma volumes, lower initial GCS scores, and higher mortality, leading to disproportionately high rates of Comfort Measures Only orders and lack of follow-up imaging (not shown). The remaining demographic and clinical characteristics were similar between the included and the excluded subjects (all p values >0.1).
Fig. 1

Included and excluded patients

Table 1 shows the demographics of the study population. In the cohort overall, 100 (83.3%) patients had a poor functional outcome, and the mortality rate was 37.5% at 30 days. The median INR at baseline was 2.8 (IQR 2.3–3.4) and the median time to INR correction was 10 (IQR 6–15) h.
Table 1

Baseline characteristics (n = 120)

Age, mean ± SD, years

76.9 ± 9.4

Gender, male, n (%)

69 (58)

Hypertension, n (%)

103 (86)

Diabetes mellitus, n (%)

26 (22)

Antiplatelet agent use, n (%)

55 (46)

Baseline INR, median (IQR)

2.8 (2.3–3.4)

Baseline ICH volume, median (IQR), mL

13 (5–32)

Lobar location, n (%)

45 (38)

Time from onset to baseline NCCT, median (IQR), h

6 (3–12)

Time from onset to normalized INR, median (IQR), h

16 (9–24)

Time from baseline INR to normalized INR, median (IQR), h

10 (6–15)

FFP units, median (IQR)

4 (3–6)

CTA spot sign, n (%)

31 (26)

ICH expansion, n (%)

33/102 (32)

Discharge mRS ≥ 4

100 (83)

30-day mortality, n (%)

45 (38)

SD standard deviation, IQR interquartile range, NCCT non-contrast computed tomography, INR international normalized ratio, FFP fresh-frozen plasma, mRS modified Rankin Scale

Hematoma expansion

There was no significant association between time to INR reversal and hematoma expansion (p = 0.61). As expected, patients with hematoma expansion had significantly larger baseline ICH volumes and worse outcomes (Table 2).
Table 2

Hematoma expansion

 

No (n = 69)

Yes (n = 33)

p value

Age, (mean ± SD), years

77.0 ± 10.0

78.4 ± 6.7

0.40

Gender, male, n (%)

36 (52)

21 (64)

0.28

Hypertension, n (%)

60 (87)

28 (85)

0.35

Diabetes mellitus, n (%)

15 (22)

8 (24)

0.33

Antiplatelet use, n (%)

31 (45)

17 (52)

0.53

Admission GCS, median (IQR)

14 (9–15)

14 (9–15)

0.57

Baseline INR, median (IQR)

2.7 (2.3–3.2)

3.1 (2.5–3.5)

0.11

Baseline ICH volume, median (IQR), mL

8 (3–19)

17 (7–46)

0.01

Lobar ICH location

25 (36)

16 (48)

0.24

Hrs from onset to baseline CT, median (IQR)

7 (4–14)

6 (2–11)

0.13

Hrs from onset to normalized INR, median (IQR)

17 (11–25)

13 (9–23)

0.74

Hrs from baseline to normalized INR, median (IQR)

10 (7–16)

9 (5–14)

0.61

FFP units, median (IQR)

4 (2–6)

5 (4–6)

0.26

Discharge mRS ≥ 4, n (%)

54 (78)

29 (88)

0.19

30-day mortality, n (%)

18 (26)

17 (51)

0.01

p values < 0.05 are in bold

SD standard deviation, IQR interquartile range, NCCT non-contrast computed tomography, INR international normalized ratio, FFP fresh-frozen plasma, mRS modified Rankin Scale.

Clinical outcome

Patients with poor outcome at discharge are older, have larger ICH volumes, and lower GCS scores (Table 3). Interestingly, the time to INR correction is shorter in patients with unfavorable outcome (9.3 vs. 12.4 h, p = 0.064). Baseline INR and number of FFP units administered are similar between the two groups.
Table 3

Clinical outcome (poor outcome defined as mRS ≥ 4)

 

mRS ≥ 4 (n = 100)

mRS < 4 (n = 20)

p value

Age, (mean ± SD), years

77.8 ± 9.1

72.5 ± 9.6

0.03

Gender, male, n (%)

57 (57)

12 (60)

0.80

Hypertension, n (%)

84 (84)

19 (95)

0.43

Diabetes mellitus, n (%)

23 (23)

3 (15)

0.65

Antiplatelet use, n (%)

41 (41)

14 (70)

0.02

Admission GCS, median (IQR)

12 (7–15)

15 (15–15)

<0.001

Baseline INR, median (IQR)

2.8 (2.4–3.5)

2.9 (2.3–3.3)

0.66

Baseline ICH volume, median (IQR), mL

15 (6–39)

7 (2–13)

0.01

Lobar ICH location, n (%)

35 (35)

10 (50)

0.21

Hrs from onset to baseline NCCT, median (IQR)

6 (3–11)

8 (5–15)

0.11

Hrs from onset to normalized INR, median (IQR)

16 (9–23)

21 (15–26)

0.09

Hrs from baseline to normalized INR, median (IQR)

9 (6–14)

12 (8–19)

0.06

FFP units, median (IQR)

4 (2–6)

4 (3–5)

0.40

ICH expansion, n (%)

29/83 (35)

4/19 (21)

0.24

p values < 0.05 are in bold

SD standard deviation, IQR interquartile range, NCCT non-contrast computed tomography, INR international normalized ratio, FFP fresh-frozen plasma, mRS modified Rankin Scale.

Since patients with the most severe clinical presentation and poor outcome are also diagnosed earlier after onset (Table 3), we repeated all the analyses using time from stroke onset to corrected INR instead of time from baseline to corrected INR and obtain the same results. In addition, to ensure that our results were not a function of the specific INR cutoff, we performed a sensitivity analysis using different INR cutoffs of 1.3, 1.5, 1.7, and 2.0, and find substantively similar results (not shown).

Timing of INR reversal

We then examined factors associated with more rapid time to INR reversal to evaluate whether clinical providers were preferentially providing more rapid reversal to more clinically severe patients (Table 4). In fact, patients who were treated successfully within 6 h had overall more severe clinical conditions, as highlighted by significantly larger ICH volume (25 vs. 10 mL, p = 0.007), lower median GCS score (10 vs. 15, p = 0.003), worse functional outcome (discharge mRS ≥ 4: 93.3 vs. 80.0%, p = 0.09), and higher 30-day mortality (56.7 vs. 31.1% p = 0.012). We observe the same significant trend when baseline ICH severity is stratified using the ICH score (Fig. 2a, b). This suggests that clinical providers are preferentially delivering FFP more quickly to those with more severe disease, leading to confounding by indication. However, when controlling for disease severity, we find no association between rapid INR reversal, ICH expansion, and outcome in a multivariable logistic regression analysis (Table 5). We also analyzed whether there is an effect of year of presentation to assess whether clinical practice changes occurred over time that impacted the analysis. We find that the year of presentation has no effect on INR reversal, hematoma expansion, mortality, or neurological outcome.
Table 4

INR reversal within 6 h

 

Time to INR normalization

<6 h (n = 30)

≥6 h (n = 90)

p value

Age, (mean ± SD), years

75.0 ± 9.8

77.6 ± 9.2

0.18

Gender, male, n (%)

11 (37)

58 (64)

0.01

Hypertension, n (%)

23 (77)

80 (89)

0.09

Diabetes mellitus, n (%)

7 (23)

19 (21)

0.21

Antiplatelet agent, n (%)

9 (30)

46 (51)

0.04

Admission GCS, median (IQR)

10 (6–14)

15 (9–15)

0.003

Baseline INR, median (IQR)

2.6 (2.3–3.4)

2.9 (2.4–3.4)

0.45

Baseline ICH volume, median (IQR), mL

25 (8–53)

10 (4–26)

0.01

Lobar ICH location

11 (37)

34 (38)

0.91

Hrs from onset to baseline NCCT, median (IQR)

3 (1–6)

7 (4–14)

<0.001

FFP units, median (IQR)

4 (2–6)

4 (3–6)

0.20

ICH expansion, n (%)

12/24 (50)

21/78 (27)

0.03

Discharge mRS ≥ 4, n (%)

28 (93)

72 (80)

0.09

30-day mortality, n (%)

17 (57)

28 (31)

0.01

p values < 0.05 are in bold

SD standard deviation, IQR interquartile range, NCCT non-contrast computed tomography, INR international normalized ratio, FFP fresh-frozen plasma, mRS modified Rankin Scale.

Fig. 2

a Association between disease severity (ICH score) and timing of INR reversal. b Kaplan–Meier curve showing timing of INR reversal by presenting ICH score

Table 5

Multivariable logistic regression of ICH expansion and outcome

 

ICH expansiona

Discharge mRS ≥ 4b

30-day mortalityc

OR (95% CI)

p

OR (95% CI)

p

OR (95% CI)

p

Onset to INR ≤ 1.4 within 6 h

2.76 (0.56–13.6)

0.21

2.14 (0.20–22.4)

0.53

1.42 (0.29–7.09)

0.67

Baseline to INR ≤ 1.4 within 6 h

2.13 (0.77–5.85)

0.14

3.28 (0.62–17.2)

0.16

2.14 (0.74–6.14)

0.16

aAdjusted for baseline ICH volume, baseline INR, time from onset to baseline NCCT

bAdjusted for age and baseline ICH volume

cAdjusted for age, admission GCS, and baseline ICH volume

Finally, we analyzed the subset of patients for whom a CTA spot sign (a neuroimaging predictor of subsequent hematoma expansion [27]) was present (n = 31, 25.8% of patients), hypothesizing that these patients at the highest risk for expansion might specifically benefit from more rapid INR reversal. However, hematoma expansion is again not associated with slower INR reversal (median 8 vs. 10 h, p = 0.26), functional outcome at discharge (mRS ≥ 4: 9 vs. 10 h, p = 0.99), or mortality at 30 days (7 vs. 10 h, p = 0.80) (not shown).

Discussion

Overall, we find no independent association between timing of INR reversal, hematoma expansion, and outcome in this cohort of patients with WAICH. In univariate analysis, patients treated more rapidly experience the worst outcomes. This counterintuitive result appears to arise from confounding by indication. As the procurement and delivery of FFP require multiple steps, this process is likely highly subject to variability on the part of providers. Multivariate analysis, however, shows no effect of rapid INR reversal on hematoma expansion or clinical outcome.

Other studies have previously examined whether there is an association between more rapid INR reversal and clinical outcome. Two groups show no improved clinical outcomes from faster INR reversal [11, 12]. Many show that PCC more rapidly and completely reverses anticoagulation based on laboratory values [13, 28, 29, 30, 31, 32, 33]. Sarode et al. find that 4-factor PCC reverses the INR much more quickly than does FFP, but no statistically significant association with outcome is demonstrated. Other studies observe a reduced incidence of hematoma expansion with more rapid INR reversal with PCC, but again with no link to clinical outcome [13, 34]. Kuwashiro et al. show that while PCC does not seem to improve outcomes compared to FFP, analyzing just the subset of patients with initial INR > 2.0 does show a statistical difference [33]. Parry-Jones et al. in contrast find that FFP plus PCC may be better than either alone, but the biological basis for this is not clear [35]. Kuramatsu et al. did find that among those receiving PCC, those reversed to an INR < 1.3 within 4 h—combined with a blood pressure reduction <160 mmHg—show decreased in-hospital mortality and less hematoma expansion [17]. This finding suggests that there may be a time window for any effect of WAICH reversal and that such an effect may be blood pressure dependent. The strongest evidence in favor of PCC for coagulopathy reversal in WAICH comes from the INCH trial [18]. This prospective, randomized clinical trial shows superiority of PCC over FFP in preventing ICH expansion. No association with improved clinical outcome is detected, which may have been due to small sample size, as two other groups have detected a significant association between PCC use and outcomes [36, 37].

Like PCC, Recombinant Factor VIIa (rFVIIa) has been studied in its role as an INR reversal agent. Studies suggest faster INR correction with rFVIIa [14, 38] and even reduced hematoma expansion [39, 40], but show no clear association with outcome.

It is surprising that any effect of rapid INR reversal on outcome has been so difficult to consistently demonstrate. There are multiple possibilities for this. First, INR may be an inadequate marker of effective hemostasis. It may be that even when the INR is normalized, clinical hemostasis is not yet achieved. Support from this hypothesis comes from the fact that recombinant Factor VIIa can immediately normalize the INR, without normalizing clinical hemostasis [10]. In addition, many of the studies using PCCs come from different countries, using different products, some of which contain minimal Factor VII [41]. As a result, studies of rapid INR reversal may be limited by its inability to accurately capture when true clinical hemostasis has been achieved.

Second, there may be a therapeutic time window for reversal, and many patients in the studies performed thus far (including ours) may have received reversal too far outside this window to detect an effect. Indeed, studies of INR reversal with FFP show times to reversal of 7, 8.5, 29, and 32 h, highlighting how surprisingly long this process takes in actual clinical practice [11, 12, 42, 43, 44]. The study by Kuramatsu does suggest that if PCC is used, doing so within 4 h is best [17].

Third, there may be a powerful influence of confounding by indication and our results support this hypothesis. In particular with FFP, there are multiple steps required for obtaining this product (including ordering from the blood bank, type-specific matching, thawing, and delivery, as well as variability in infusion rate). Therefore, providers may act more rapidly in the most severe patients (those destined for the worst outcomes irrespective of therapy) and more slowly in the less severe patients (those destined for the best outcomes and perhaps the greatest opportunity to benefit). Our data bear this out, suggesting that the fastest INR reversal occurs with the most severely injured patients. We did attempt to control for disease severity with multivariable analysis, but it may be that additional unmeasured factors caused confounding that we cannot control for. Future studies investigating the relationship between timing of INR reversal, ICH expansion, and outcome should account for confounding by indication to the extent possible. With the now widespread availability of 4F-PCC in the United States, which can be delivered more rapidly, much of the variability in timing of WAICH reversal may be minimized.

Fourth, it may be that if INR reversal improves outcome, it does so only in concert with other interventions. Kuramatsu et al. find that only when rapid reversal is combined with blood pressure reduction is there an association with improved outcomes [17]. Future studies should evaluate a “bundle” of care for patients with WAICH, including multiple processes of care as well as faster INR reversal. Furthermore, there may be alternate measures that are more appropriate for measurement of coagulopathy. For example, thromboelastography (TEG) or thromboelastometry (ROTEM) may more accurately determine if a WAICH patient is effectively being reversed, although data on the effectiveness of these measures are sparse [45].

Our study has some strengths and some limitations. One strength is the fact that all patients received FFP for warfarin reversal. As a result, our study likely captures true clinical practice, and the fact that there is much greater variability in time to reversal using FFP than there is using other agents (such as PCC) creates, in theory, a greater opportunity to detect an effect of time to reversal. Unfortunately, this proved to be a limitation as well, as this variability also introduced a confounding effect. We accounted for this by multivariate analysis. Other limitations include the possibility of a survival bias in the hematoma expansion analysis. Patients with large hematomas are more likely to experience hematoma growth and to die before follow-up NCCT. Finally, patients included in the present study were enrolled over a long time period, with potential other changes in clinical care during this time.

In conclusion, we find no independent association between rapid INR reversal with FFP, ICH expansion, and clinical outcome.

Notes

Author contribution

MA: Study concept and design; analysis and interpretation of the data, drafting of the manuscript, critical revision of the manuscript for important intellectual content; statistical expertise; study supervision; and final approval of version being published. AM: Analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; statistical expertise; and final approval of version being published. ASC: Analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; administrative, technical, or material support; and final approval of version being published. YC: Study concept and design; analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; statistical expertise; and final approval of version being published. AMA: Acquisition of the data; critical revision of the manuscript for important intellectual content; administrative, technical, or material support; and final approval of version being published. KS: Acquisition of the data; critical revision of the manuscript for important intellectual content; administrative, technical, or material support; and final approval of version being published. AV: Acquisition of the data; analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; statistical expertise; and final approval of version being published. MEG: Acquisition of the data; analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; statistical expertise; and final approval of version being published. CDA: Acquisition of the data; analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; statistical expertise; obtained funding; and final approval of version being published. SMG: Acquisition of the data; analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; statistical expertise; and final approval of version being published. JR: Study concept and design; acquisition of the data; analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; obtained funding; and final approval of version being published. JNG: Study concept and design; acquisition of the data; analysis and interpretation of the data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical expertise; obtained funding; study supervision; and final approval of version being published.

Compliance with ethical standards

Funding

This study was funded by support from NIH NINDS K23NS086873, NIH NINDS K23AG02872605, NIH NINDS 5R01NS073344, and NIH NINDS R01NS059727.

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Data

The data sets during or analyzed during the current study are available from the corresponding author on reasonable request.

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Copyright information

© SIMI 2017

Authors and Affiliations

  • Murtaza Akhter
    • 1
    • 3
  • Andrea Morotti
    • 2
  • Abigail Sara Cohen
    • 2
  • Yuchiao Chang
    • 3
  • Alison M. Ayres
    • 2
  • Kristin Schwab
    • 2
  • Anand Viswanathan
    • 2
  • Mahmut Edip Gurol
    • 2
  • Christopher David Anderson
    • 2
  • Steven Mark Greenberg
    • 2
  • Jonathan Rosand
    • 2
  • Joshua Norkin Goldstein
    • 3
  1. 1.Department of Emergency MedicineUniversity of Arizona College of Medicine–Phoenix and Maricopa Integrated Health SystemPhoenixUSA
  2. 2.Department of Neurology, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  3. 3.Department of Emergency Medicine, Massachusetts General HospitalHarvard Medical SchoolBostonUSA

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