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Early clinical and radiological course, management and outcome of intracerebral hemorrhages related to new oral anticoagulantsInsights from the Registry of Acute Stroke Under New Oral Anticoagulants (RASUNOA)

Jan C Purrucker, Kirsten Haas, Timolaos Rizos, Shujah Khan, Marcel Wolf, Michael G

Hennerici, Sven Poli, Christoph Kleinschnitz, Thorsten Steiner, Peter U Heuschmann, and

Roland Veltkamp, for the RASUNOA Investigators*

*Members listed in Supplemental Content

Brief title: Intracerebral Hemorrhage on NOACs

Author names and affiliations:

Jan C. Purrucker, MD

Heidelberg University Hospital, Department of Neurology, Heidelberg, Germany

[email protected]

Kirsten Haas, MPH, PhD

Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany

[email protected]

Timolaos Rizos, MD


[email protected]

Shujah Khan


[email protected]

Marcel Wolf, MD

Heidelberg University Hospital, Department of Neuroradiology, Heidelberg, Germany

[email protected]

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Michael G. Hennerici, MD

Professor of Neurology, Universitätsmedizin Mannheim, Department of Neurology, University

of Heidelberg, Mannheim, Germany

[email protected]

Sven Poli, MD

Department of Neurology & Stroke, Tübingen University, Tübingen, Germany

[email protected]

Christoph Kleinschnitz, MD

Professor of Neurology, University Hospital Würzburg, Department of Neurology, Würzburg,

Germany

[email protected]

Thorsten Steiner, MD

Professor of Neurology, Frankfurt Hoechst Hospital, Department of Neurology, Frankfurt am

Main, Germany; Heidelberg University Hospital, Department of Neurology, Heidelberg,

Germany

[email protected]

Peter U. Heuschmann, MD, MPH

Professor of Clinical Epidemiology and Biometry, Institute of Clinical Epidemiology and

Biometry, Comprehensive Heart Failure Center, University of Würzburg; Clinical Trial Center

Würzburg, University Hospital Würzburg, Würzburg, Germany

[email protected]

Roland Veltkamp, MD

Professor of Neurology, Department of Stroke Medicine, Imperial College London, London,

United Kingdom; Heidelberg University Hospital, Department of Neurology, Heidelberg,

Germany

[email protected]

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Correspondence to:

Roland Veltkamp, M.D.

Professor of Neurology

Department of Stroke Medicine

Imperial College London

Charing Cross Campus, 3 East 6

Fulham Palace Road

London, W6 8RF

United Kingdom

Phone: 44-20-33130133

Fax: 44-20-83833309

E-mail: [email protected]

Word-Count (text only): 2796

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IMPORTANCE Intracerebral hemorrhage (ICH) is the most devastating adverse event in patients with

oral anticoagulation. So far, there is only sparse evidence regarding ICH related to non-vitamin K

antagonist oral anticoagulants (NOAC).

OBJECTIVE To evaluate the early clinical and radiological course, the acute management, and the

outcome of ICH related to NOAC.

DESIGN Prospective investigator-initiated multicenter observational study. All diagnostic and

treatment decisions including administration of hemostatic factors (e.g. prothrombin complex

concentrate, PCC) were left to the discretion of the treating physicians.

SETTING 38 stroke units across Germany (February 2012 to December 2014).

PARTICIPANTS This study included 61 consecutive patients with non-traumatic NOAC-ICH, of whom

45 (73.8%) qualified for hematoma expansion analysis.

EXPOSURES Hematoma expansion, intraventricular hemorrhage, and reversal of anticoagulation

during acute phase.

MAIN OUTCOMES AND MEASURES Frequency of substantial hematoma expansion (defined as

either relative [≥ 33%] or absolute [≥ 6ml] volume increase); any new intraventricular extension or an

increase of the modified Graeb score by ≥ 2 points; 3-months functional outcome, and factors

associated with unfavorable outcome (modified Rankin score [mRS] 3-5).

RESULTS 41% of the NOAC-ICH patients were female; mean age was 76.1 years (SD 11.6). On

admission, median NIHSS was 10 (IQR 4-18). Mean baseline hematoma volume was 23.7 ml (SD

31.3). In patients with sequential imaging for hematoma expansion analysis, substantial hematoma

expansion occurred in 37.8%. New or increased intraventricular hemorrhage was observed in 17.8%.

Overall mortality was 28.3% at 3-months, and 65.1% of survivors had an unfavorable outcome (mRS

3-5). 57.4% of the patients received PCC with no statistically significant effect on frequency of

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substantial hematoma expansion (PCC, 50% vs. no-PCC, 35.3%, p=.37) or outcome (mRS 3-5, OR

1.2 (0.37–3.9), p=.76).

CONCLUSIONS AND RELEVANCE NOAC-ICH is associated with a high mortality and unfavorable

outcome, and hematoma expansion is frequent. Larger scale prospective studies are needed to

determine whether early administration of specific antidotes can improve the dismal prognosis of

NOAC-ICH.

TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01850797

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Intracerebral hemorrhage (ICH) is responsible for the vast majority of deaths caused by

bleeding complications during long-term anticoagulation.1,2 Because intracerebral hematoma

size and secondary hematoma enlargement are important prognostic factors in ICH,3

prevention of hematoma enlargement is a major therapeutic target of ICH management. ICH

during anticoagulation with vitamin K antagonists (VKA) accounts for 10 to 25% of all ICH.4,5

It is associated with a higher risk and a prolonged period of hematoma growth,6,7 as well as

with a higher mortality compared to ICH in non-anticoagulated patients.6,8 Compared to VKA,

all non-VKA oral anticoagulants (NOAC) carry a substantially lower risk of intracranial

hemorrhage.9,10 Nevertheless, given the rising prescription rates,11 ICH on treatment with

NOACs has become an important issue.

Three large randomized controlled trials consistently reported a mortality of NOAC-ICH of 45

to 67%, and the majority of survivors remained permanently disabled.2,12,13 Despite this

profound impact on long-term outcome, the characteristics and natural history of NOAC-ICH

in the acute phase are largely unknown. In particular, there are no prospective data on

hematoma enlargement, and the effect of hemostatic management in patients thereon. The

available evidence is limited to small retrospective studies without detailed analysis of clinical

and radiological course of NOAC-ICH, and limited information on the effectiveness of

unspecific hemostatic factors.14-24 Clinical guidelines and two recent large observational

studies regarding VKA-ICH support reversing the effect of VKA using coagulation factors to

reduce the risk of hematoma expansion.7,25-28 However, the extrapolation of treatment

concepts from VKA-ICH to NOAC-ICH has limitations because NOACs and VKAs have

dissimilar pharmacokinetics and their effects on hemostasis in the brain may differ.12,13,29-31

Moreover, although specific antidotes to reverse anticoagulation with NOAC are in clinical

testing, none of them is available in clinical routine yet.32,33 Unspecific hemostatic factors

such as prothrombin complex concentrate (PCC) are effective in preclinical models of

NOAC-ICH and healthy volunteers but their effectiveness in acute bleeding is unknown.34-37

Despite the absence of evidence in patients, current expert recommendations suggest to

antagonize the effect of NOAC by using PCC.29,30

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Here, we report the results from the ICH substudy of the Registry of Acute Stroke Under New

Oral Anticoagulants (RASUNOA), a prospective multicenter observational study designed to

describe the clinical and radiological course, management, and outcome of ICH during

therapy with NOAC in clinical routine.

Methods

Study design and sites

RASUNOA was an investigator-initiated, multicenter, prospective, observational registry

assessing the management, clinical and radiological course and outcome after acute stroke

under treatment with NOAC (NCT01850797, ClinicalTrials.gov). It was performed at 38

Departments of Neurology with a certified stroke unit in Germany. Study approval was

obtained from the ethics committee of the Medical Faculty Heidelberg, Germany, and the

ethics committees of each participating center.

Patients

Between Feb 1, 2012 and the per protocol agreed end of patient inclusion at Dec 31, 2014,

patients with acute non-traumatic intracerebral hemorrhage (ICH) fulfilling the following

eligibility criteria were included in the ICH substudy: 18 years of age or older, therapy with

NOAC (i.e. either Apixaban, Dabigatran or Rivaroxaban) at the time of the ICH, and written

informed consent by either the patient or a legal representative. ICH had to be present in

baseline neuroimaging (either CT or MRI). There were no exclusion criteria regarding

modified Rankin score (mRS) before the index ICH.

Data acquisition

All diagnostic and treatment decisions including performance of follow-up imaging, selection

of imaging modalities, and administration of hemostatic factors (e.g. PCC) were left at the

discretion of the attending physicians.

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Observational data were collected by members of staff of local centers using a paper-based

case report file to document baseline characteristics including cardiovascular risk factors,

clinical observations and laboratory findings. Double data entry was performed by two

independent staff members of the Institute of Medical Biometry and Informatics, University

Heidelberg.

Neurological status was assessed using the National Institute of Health Stroke Scale

(NIHSS) score on admission as well as 24, 48 and 72 h later. Functional outcome was

determined using the mRS, prior to stroke (pmRS), on hospital admission, at discharge and

at follow-up. The CHA2DS2VASc and HAS-BLED scores were calculated excluding the index

event.38,39 The HAS-BLED score item “labile INR” was set to zero.

A structured telephone follow-up (FU) was performed by trained mRS raters of local centers

90 days after the ICH and included mRS and current antithrombotic medication. If the patient

was unable to be contacted in person, the interview was performed with a close relative, a

legal representative or a family physician familiar with the current functional and medical

status of the patient.

Data analysis

Volumetric measurements of intracerebral hematoma volume were performed on two

identical sets of CT and MRI data by two independent, experienced readers blinded for

patient characteristics. We used the open-source database and DICOM viewer OsiriX®,

Pixemo, Geneva, Switzerland. Regions of interest (ROI) around intraparenchymal

hemorrhage excluding intraventricular blood (IVH) were drawn manually on each slice.

Hematoma volume was calculated using the ROI-volume calculator. In case of volume

differences > 30%, or technical problems, images were re-assessed by both raters to seek

consensus. We used the arithmetic mean of the estimates obtained by both raters for further

analysis. The modified Graeb score, a semiquantitative scale for IVH volume measurement,

was calculated according to Hinson et al.40

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The rate of hematoma enlargement was pre-specified as a primary aim of the study.

Hematoma enlargement was determined wherever sequential brain scans were available

(see below). Substantial hematoma enlargement was defined as fulfilling at least one of the

following criteria: relative increase of hematoma volume by 33% or absolute increase

by ≥ 6 ml compared to initial imaging. Substantial intraventricular expansion was defined as

occurrence of any new intraventricular expansion of hematoma, or an increase of the

modified Graeb score of 2 points. To qualify for expansion analysis, follow-up scanning had

to be performed within 3 to 72 h after the first scan. If more than one follow-up scan was

performed within the time frame, the one closest to the 24 h time-point was chosen. Cases

with hematoma evacuation before any follow-up image within the time frame were excluded

from hematoma expansion analysis.

Statistical Analysis

Continuous variables were described by mean and standard deviation (SD) or median and

interquartile-range (IQR); for categorical variables absolute and relative frequencies were

reported. The Shapiro-Wilk test was used to ascertain distribution of data. The chi-square or

Fishers-exact test, as appropriate, were used to compare proportions in baseline

characteristics and hematoma characteristics between patients with and without follow-up

images, with or without hematoma expansion, or with or without PCC administration. To

compare continuous variables, the non-parametric Mann–Whitney U test was used due to

the skewness of the data. Bivariate correlations by the rank correlation Kendall’s tau were

used to assess the relationship between hematoma volume at baseline and patient

characteristics. Univariate logistic regression analyses were conducted for analyzing the

association of demographic and clinical characteristics with unfavorable outcome at 3 month

follow-up (defined as mRS 3-6). In case of quasi-complete separation, if there is no outcome

observation for a given category, Firth logistic regression was used and additionally the SAS-

macro %fl was applied in order to estimate odds ratios and confidence intervals with

penalized likelihood estimation methods and appendant penalized likelihood ratio tests.41-43

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Due to the limited number of patients no multivariable analyses were performed. All statistical

analyses were conducted using IBM SPSS Statistics, version 22 (IBM SPSS, Armonk, NY,

USA) and SAS 9.3 (SAS Institute Inc., Cary, NC, USA).

Results

In total, 61 patients were enrolled into the study. Of the 38 sites participating in RASUNOA,

21 sites reported at least 1 patient with a NOAC-ICH. Four of 21 centers reporting NOAC-

ICH patients enrolled 39 (64%) of the patients. Within these four centers, a proportion of 71%

of all eligible patients were included. With regard to these four centers, no statistically

significant differences between all patients treated with NOAC-ICH in the study period

(including deceased ones) and patients included in the study were found at an aggregated

level (data not shown).

Table 1 summarizes the baseline characteristics of the study cohort. Patients had a mean

age of 76.1 years (SD 11.6, range 46-97), and had a moderate to severe neurological deficit

at admission (median NIHSS 10 [IQR 4–18]). Median time since last intake of the NOAC to

first brain scan was 14.3 h (IQR 6.0–22.8; Table 2).

Baseline hematoma volumes

Median baseline hematoma volume at presentation was 10.8 ml (IQR 4–30; Table 2). Lobar

(41.0%) was slightly more frequent than deep (37.7%) location of hematoma. Neurological

status at admission was correlated with baseline hematoma volume (NIHSS, Kendall’s

tau=0.347, p<.001; eTable 1 in the Supplement). Time elapsed between symptom-onset and

initial brain scan was not significantly correlated with baseline hematoma volume. Six

patients (9.8%) were on concomitant treatment with at least one platelet inhibitor (Table 1).

These patients were older and had significantly higher baseline hematoma volumes

compared to patients without (median 30 ml [IQR 26–39] vs. 9 ml [3–19], p=.03).

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Hematoma expansion

Hematoma expansion (HE) could be analyzed in 45 patients with sequential cranial imaging

within 3 to 72 h (median time between scans: 21.1 h [13.2-27.5]). Baseline characteristics of

the expansion analysis group did not differ significantly from the entire study cohort (Table

1). Substantial hematoma expansion occurred in 37.8% of cases (Table 2). In 6.7%,

intraventricular extension developed since the initial scan, and in an additional 11.1% a

relevant increase of intraventricular bleeding was observed (Table 2).

Reversal of anticoagulation

Thirty-five of the 61 patients (57.4%) received 4-factor PCC (mean dose 2390 IU [SD 980]).

Patients receiving PCC had a worse clinical status, and tended to more frequently have

suffered a deep hemorrhage (eTable 2 and 3 in the Supplement). Larger baseline hematoma

volumes were found in the subgroup of PCC patients receiving follow-up imaging (p=.04).

Moreover, the time interval between last NOAC intake and initial brain image tended to be

shorter in patients receiving PCC. Administration of PCC showed no statistically significant

effect on early hematoma expansion and functional outcome at 3 month, respectively

(Tables 3 and 4).

Clinical outcomes

Overall mortality rate was 16.4% during the acute inpatient stay, and 28.3% (n=1 data

missing) at 3-months (Figure 1). There was a strong association between clinical deficit at

admission and death and dependency at 3 months (Table 4). Larger hematoma volume and

intraventricular extension at baseline were associated with an unfavorable outcome including

death at 3 months (mRS 3-6) (OR 2.4, 95% CI 1.0-5.5, p=.046, OR 8.1, 95% CI 1.6–40.3,

p=.01, respectively). In contrast, no statistically significant association with unfavorable

outcome was found for substantial hematoma expansion. The 43 survivors at 90 days after

the hemorrhagic event had a median mRS of 4 (IQR 2–5). Five of the 61 enrolled patients

(8.2%) underwent surgical hematoma evacuation of whom four were still alive at 3 months.

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A sensitivity analysis restricted to the most frequently used NOAC among the study

population showed no major differences in demographic and clinical characteristics as well

as main outcomes compared to the whole NOAC-ICH group (eTable 4 and 5 in the

Supplement).

Resumption of oral anticoagulation

In terms of subsequent stroke prevention, no patient was anticoagulated at the time of

discharge from the acute hospital. In 10 of the 43 survivors (23.3%), oral anticoagulation had

been resumed by day 90 after the hemorrhagic event.

Discussion

Our prospective observational study provides major new insights into the clinical and

radiological course, management, and outcome of NOAC-ICH. Characteristics of NOAC-ICH

at baseline including hematoma volume and location are similar as previously reported for

VKA-ICH.6,7 Subsequent substantial hematoma expansion occurred in more than one-third of

NOAC-ICH patients. Although recommended in current expert guidance,29,30 only little more

than half of the patients received PCC for anticoagulation reversal, but no statistical

significant association with outcome was observed.

Mean hematoma volume in NOAC-ICH (24 ml [SD 31]) was at the upper end of the range

previously reported for ICH in non-anticoagulated patients (13 to 26),3,4,44,45 but within the

ranges reported for VKA-ICH (14 to 48 ml) (eTable 6).4,45,46 Moreover, we observed

intraventricular hematoma extension with a similar frequency reported for VKA-ICH with

INR < 3.0.3,4,6,7,28,44,47 Thus, our prospective data do not support a previous retrospective

report showing smaller ICH volumes in NOAC-ICH compared to VKA-ICH.48 The hematomas

were frequently found in lobar location, possibly reflecting the increasing contribution of

cerebral amyloid angiopathy to the risk of intracerebral bleeding in the elderly.5,49 Compared

to studies on VKA-ICH, the proportion of patients with previous stroke including prior ICH

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was higher. This finding might reflect the fact, that given the reduced risk of ICH, NOACs are

considered first line for patients at high risk for ICH.10

Our definition of substantial hematoma expansion included thresholds for absolute (≥ 6 ml) or

relative (≥ 33%) hematoma increase. Substantial hematoma enlargement was found in

37.8% of our NOAC-ICH patients. This proportion is within the range reported for VKA-

associated ICH (36 to 56%),6,7,50 and higher compared to ICH in non-anticoagulated patients

(12 to 26%).4,51,52 When limiting the analysis to the relative increase of ICH volume only, the

rate of hematoma expansion was at the upper end of a range reported for ICH in non-

anticoagulated patients,2, 3, 28, 29 nearly identical to a large recent study on VKA-OAC patients,7

and also resembled that of other VKA-ICH studies.3 We did not find an association of

substantial hematoma enlargement with dichotomized 3-month functional outcome, since

initial hematoma size largely determined unfavorable outcome. Initial IVH was associated

with unfavorable 3-months outcome. Secondary IVH extension and IVH expansion occurred

in 17.8% of our patients in accordance with data reported for VKA-ICH (6 to 18%).53,54

No specific NOAC antidote has been approved for reversal of anticoagulation in severe

hemorrhage in clinical routine yet. Studies in experimental ICH and healthy volunteers,

respectively, suggested efficacy of PCC for reversal of NOAC.34-37 Consequently, current

expert guidance suggests administering 30-50 IU/kg of PCC in severe acute hemorrhage.18, 19

However, we failed to observe any association of PCC on hematoma expansion and

outcome in our observational study. This might be caused by the fact, that patients receiving

PCC showed different baseline characteristics (appendix) including more frequent deep

hematoma location and more severe initial neurological deficit being associated with bad

outcome. In addition, in contrast to preclinical NOAC-ICH studies and the optimal efficacy in

VKA-ICH,7,28,34,35, PCC were often not administered in the first 5 hours after symptom-onset.

Our study design, the limited sample size and the potential for confounding by indication do

not allow drawing any conclusions regarding a potential association between PCC treatment

and outcome. Although Idarucizumab, an antibody fragment binding to dabigatran, showed

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effective reversal of anticoagulation with dabigatran,33 and other antidotes are under

development,32 their effectiveness in NOAC-ICH remains to be shown.

Limitations

Our study had some limitations. Comparison to VKA-ICH and ICH in non-anticoagulated

patients was performed referring to previously published, mostly retrospective observational

studies. Validation of results in future prospective studies using matched control groups is

therefore necessary, and current comparisons should be interpreted with caution.

Recruitment was not complete in the majority of participating centers. However, we

performed a sensitivity analysis including aggregated baseline characteristics of eligible

cases at the four top-recruting centers, which revealed no statistically significant differences

to the patients actually included in our analysis. Some patients may have died before

informed consent could be collected and data of these could not be included as mandated by

the ethics committee. However, although this may have led to underestimation of mortality,

the observed case fatality in our dataset is consistent with previous data.55 Additionally,

primary neurosurgical patients were not enrolled at all centers, so patients with worse clinical

status might be underrepresented, although short-term mortality in our cohort is consistent

with data from a recent retrospective neurosurgical case series.23 Our study was not intended

to detect potential differences of ICH related features among different agents, among classes

of agents (i.e. direct thrombin inhibitors vs. Factor Xa inhibitors) or among different doses of

a specific NOAC. In addition, the small sample size hampers more detailed statistical

analyses. However, we are currently planning a larger prospective cohort (RASUNOA-Prime,

clinicaltrials.gov identifier NCT02533960). Finally, as only a limited number of patients

underwent very early imaging and sequential imaging for hematoma expansion analysis was

only available in 74% of our patients, the actual rate of hematoma enlargement may be

estimated inadequately. It remains to be shown that successful reversal of anticoagulation

translates into improvement of clinical outcome via prevention of hematoma enlargement.

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Despite these limitations, the present study represents the largest, most detailed and only

prospective analysis of NOAC-ICH to date.

Conclusions

NOAC-ICH is associated with a high mortality and unfavorable outcome, and hematoma

expansion is frequent. Larger scale prospective studies are needed to determine whether

early administration of specific antidotes can improve the dismal prognosis of NOAC-ICH.

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Author Contributions:

Drs. Purrucker and Veltkamp 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: Veltkamp, Purrucker, Rizos.

Drafting of the manuscript: Purrucker, Veltkamp, Heuschmann, Haas.

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

Analysis, and interpretation of data: Purrucker, Haas, Heuschmann, Veltkamp, Wolf

Statistical analysis: Haas, Heuschmann.

Acquisition of data: Purrucker, Khan, Rizos, Hennerici, Poli, Kleinschnitz, Steiner, Veltkamp, and all

authors listed in the Supplemental as local principal investigators.

Study supervision: Veltkamp

Conflicts of interest

JP received travel and congress participation support from Pfizer, outside the submitted work. TR

received consulting honoraria, speakers’ honoraria, travel support or research support from

Boehringer Ingelheim, Bayer HealthCare, BMS Pfizer and Portola. SP received personal fees from

Boehringer Ingelheim and Bayer. TS received speaker fees and consultant honoraria from Boehringer

Ingelheim, BMS Pfizer, Bayer, and Daiichy Sanyo. PUH reports grants from BMBF, EU, Charité, Berlin

Chamber of Physicians, German Parkinson Society, University Hospital Würzburg, Robert-Koch-

Institute, Charité–Universitätsmedizin Berlin (within MonDAFIS for biometry; member scientific board;

MonDAFIS is supported by an unrestricted research grant to the Charité from Bayer), University

Göttingen (within FIND-AFrandomized for stroke adjudication; member stroke adjucation committee;

FIND-AFrandomized is supported by an unrestricted research grant to the University Göttingen from

Boehringer-Ingelheim), and University Hospital Heidelberg (within RASUNOA-prime for biometry and

data management; member steering committee; RASUNOA-prime is supported by an unrestricted

research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim), outside

submitted work. RV has received speaker fees, consulting honoraria and research support from Bayer,

Boehringer Ingelheim, BMS, Pfizer, Daiichi Sankyo, CSL Behring. All other authors declare that they

have no conflicts of interest.

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Funding/Support: This study was an academic, investigator-initiated study without commercial

funding.

Role of the Sponsor: The academic sponsor (Heidelberg University Hospital) had no role in the

design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the

preparation, review, or approval of the manuscript; and decision to submit the manuscript for

publication. The authors had full access to all of the data, and had final responsibility for the decision

to submit for publication.

Acknowledgments

We thank all RASUNOA collaborators, including participating centers local physicians, radiologists and

study nurses for their support during the study.

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Figure 1: Functional Outcome for all NOAC related Intracerebral Hemorrhage Patients. Modified Rankin score (mRS) was recorded before the intracerebral hemorrhage and 90 days after the stroke, with 0=no symptoms, and 6=death.

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Table 1. Patient CharacteristicsAll Patients

(n = 61)Expansion

Analysis Group (n = 45)

No Follow-up Image

(n = 16)

P Value

Age, mean (SD), years 76.1 (11.6) 76.6 (11.3) 74.7 (12.5) .58Women, No. (%) 25 (41.0) 17 (37.8) 8 (50.0) .56Indication for oral anticoagulation, No. (%)

>.99

Atrial fibrillation 59 (96.7) 43 (95.6) 16 (100)Venous thromboembolism 2 (3.3) 2 (4.4) 0

Non vitamin-K antagonist oral anticoagulant, No. (%)

.75

Apixaban 5 (8.2) 3 (6.7) 2 (12.5)Dabigatran 7 (11.5) 5 (11.1) 2 (12.5)Rivaroxaban 49 (80.3) 37 (82.2) 12 (75.0)

Concomitant platelet inhibition, No. (%) 6 (9.8) 6 (13.3) 0Aspirin 4 (6.6) 4 (8.9) 0Clopidogrel 1 (1.6) 1 (2.2) 0Aspirin + Clopidogrel 1 (1.6) 1 (2.2) 0

CHA2DS2VASc score, median (IQR)a 5 (3.5–6) 5 (4–6) 4 (3–5) .06HAS-BLED score, median (IQR)b 2 (2–3) 3 (2–3) 2 (2–3) .05Coexisting condition, No. (%)

Previous ischemic stroke/ TIA 24 (39.3) 18 (40.0) 6 (37.5) >.99Previous intracranial hemorrhage 5 (8.2) 5 (11.1) 0 .31Hypertension 53 (86.9) 41 (91.1) 12 (75.0) .19Hyperlipidemia 20 (32.8) 17 (37.8) 3 (18.8) .22Diabetes mellitus 18 (29.5) 15 (33.3) 4 (25.0) .76Heart failure 13 (21.3) 10 (22.2) 3 (18.8) >.99Peripheral vascular disease 6 (9.8) 6 (13.3) 0 .33

Renal function at admission >.99GFR ≥ 60 ml/min, No. (%) 40 (71.4) 29 (70.7) 11 (73.3)GFR < 60 ml/min, No. (%) 16 (28.6) 12 (29.3) 4 (26.7)Creatinin level, median (IQR),

mg/dl0.95 (0.70–1.20) 0.97 (0.73–1.22) 0.89 (0.70–1.15) .71

Modified Rankin scale score, median (IQR)c

Before strokee 2 (0–3) 2 (1–3) 1.5 (0–3) .75At admission 5 (4–5) 5 (3.5–5) 5 (4–5) .41

NIHSS at admission, median (IQR)d 10 (4–18) 9 (4–17) 16 (5–20) .23Death during acute stay, No. (%) 10 (16.4) 5 (11.1) 5 (31.3) .11Death until follow-upe, No. (%) 17 (28.3) 11 (25.0) 6 (37.5) .35Death within 5 days, No. (%) 6 (9.8) 2 (4.4) 4 (25.0) .04Length of stay (days), median (IQR) 10 (5–15.5) 10 (5.5–16) 8.5 (2–13) .19Abbreviations: TIA, transient ischemic attack; GFR, glomerular filtration rate (electronic GFR as reported by the centers); NIHSS, National Institutes of Health Stroke Scale. a CHA2DS2VASc score, range 0-9, from low to high risk of ischemic stroke in atrial fibrillation.b HAS-BLED score, range 0-9, from low to high risk of hemorrhage under oral anticoagulation.c Modified Rankin scale score, from 0 (no symptoms) to 6 (death).d NIHSS, stroke related neurological deficits, from 0 (no symptoms) to 42.e Before intracerebral hemorrhage functional status missing in two patients. Outcome at day 90 missing in one patient.

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Table 2. Hematoma CharacteristicsAll Patients

(n = 61)Expansion

Analysis Group (n = 45)

No Follow-up Image (n = 16)

P Value

Onset to baseline CT/MRI, median (IQR), hours

Including cases with unknown onseta

5.25 (2.0–11.75) 4.5 (2.0–10.4) 6.2 (1.7–13.7) .66

Exact onset (n = 43) 2.8 (1.4–6.5) 2.6 (1.5–6.1) 2.9 (1.1–24.4) .98Last intake NOAC, median (IQR), hours (only cases with exact time window, n = 29)

14.3 (6.0–22.8) 14.5 (6.0–25.1) 14.0 (5.5–16.6) .49

Hematoma characteristics at baselineHematoma volum, ml

Median (IQR) 10.8 (4.0–30.0) 8.9 (4.0–17.9) 28.7 (4.1–85.7) .06Mean (SD) 23.7 (31.3) 15.9 (19.2) 45.4 (46.5)

Intraventricular extension, No. (%) 27 (44.3) 20 (44.4) 7 (43.8) >.99Modified Graeb score, median (IQR)b

9 (4 – 14) 6 (3 – 14) 14 (8 -15) .13

Location of hemorrhage, No. (%)Supratentorial 47 (77.0) 37 (82.2) 10 (62.5) .16Infratentorial 14 (23.0) 8 (17.8) 6 (37.5)Deep 23 (37.7) 21 (46.7) 2 (12.5) .11Lobar 25 (41.0) 16 (35.6) 9 (56.3)Cerebellar 10 (16.4) 6 (13.3) 4 (25.0)Brainstem 3 (4.9) 2 (4.4) 1 (6.3)

PCC administration, No. (%) 35 (57.4) 28 (62.2) 7 (43.8) .25Hematoma characteristics at follow-up-imagingTime since baseline CT/MRI, median (IQR), hours

21.1 (13.2–27.5)

Hematoma volume, mlMedian (IQR) 9.9 (5.1–22.6)Mean (SD) 19.7 (24.1)

Absolute and relative differencesMedian (IQR) 0.5 (-1.6–4.8)Mean (SD) 3.8 (11.4)Range -7.8 – 54.1% volume change, median (IQR) 10.6 (-6.7–89.8)Volume increase ≥ 33%, No. (%) 15 (33.3)Volume increase ≥ 6 ml, No. (%) 7 (15.6)Substantial hematoma expansion, No. (%)c

17 (37.8)

Intraventricular extensionNew intraventricular hemorrhage, No. (%)

3 (6.7)

Modified Graeb score (change from baseline) (n=20)

Absolute change of score, median (IQR)

0 (-1–2)

Increase ≥ 2 pts, No. (%) 5 (11.1)Abbreviations: CT, computer tomography; MRI, magnetic resonance imaging; NOAC, non vitamin-K antagonist oral anticoagulant; PCC, prothrombin complex concentrate.a In case of unknown exact onset, last seen well was taken as onset.b Modified Graeb score, from 0 (no intraventricular blood) to 32 (all compartments are filled with blood and expanded) c Substantial hematoma expansion defined as volume increase ≥ 33% and/or 6 ml

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Table 3. Factors Associated With Substantial Hematoma Expansion in Patients With Follow-up Neuroimaging (Expansion Analysis Subgroup)

Substantial Hematoma Expansion

(n = 17)

No expansion(n = 28)

P Value

Age, mean (SD), years 70.6 (14.8) 80.2 (6.6) .02Women, No. (%) 6 (35.3) 11 (39.3) >.99Coexisting condition, No. (%)

Previous ischemic stroke/ TIA 4 (23.5) 14 (50.0) .12Previous intracranial hemorrhage 2 (11.8) 3 (10.7) >.99Hypertension 15 (88.2) 26 (92.9) .63Hyperlipidemia 6 (35.3) 11 (39.3) >.99Diabetes mellitus 7 (41.2) 8 (28.6) .52Heart failure 1 (5.9) 9 (32.1) .06Peripheral vascular disease 2 (11.8) 4 (14.3) >.99

Renal function at admission .15GFR ≥ 60 ml/min, No. (%) 13 (86.7) 16 (61.5)GFR < 60 ml/min, No. (%) 2 (13.3) 10 (38.5)Creatinin level, median (IQR), mg/dl 0.90 (0.69–1.05) 1.00 (0.81–1.29) .24

CHA2DS2VASc score, No. (%)a 4 (3–5) 5.5 (5–7) .001HAS-BLED score, No. (%)b 2 (2–2.5) 3 (2–3) .002Modified Rankin scale score, median (IQR)c

Before stroke 1 (0–2.5) 2 (1–4) .11At admission 4 (3.5–5) 5 (3–5) .65

NIHSS at admission, median (IQR)d 10 (5–22) 9 (2–17) .35Onset to baseline CT/MRI, median (IQR), hours

Including cases with unknown onset 2.8 (1.7–6.7) 5.45 (2.2–19.1) .16Exact onset (n = 31) 2.45 (1.4–5.9) 3.3 (1.5–6.5) .39

Last intake NOAC (hours) (only cases with exact time window, n = 29), median (IQR)

13.7 (4.2–31.8) 14.5 (6.7–22.7) .75

Baseline hematoma volume, median (IQR), ml

5.9 (1.6–17.3) 11.6 (6.5–18.0) .10

Location, No. (%)Supratentorial 14 (82.4) 23 (82.1) >.99Infratentorial 3 (17.6) 5 (17.9)Deep 9 (52.9) 12 (42.9) .18Lobar 5 (29.4) 11 (39.3)Cerebellar 1 (5.9) 5 (17.9)Brainstem 2 (11.8) 0

PCC administration, No. (%) 12 (70.6) 16 (57.1) .53Abbreviations: TIA, transient ischemic attack; GFR, glomerular filtration rate (electronic GFR as reported by the centers); NIHSS, National Institutes of Health Stroke Scale; NOAC, non vitamin-K antagonist oral anticoagulant.a CHA2DS2VASc score, range 0-9, from low to high risk of ischemic stroke in atrial fibrillation.b HAS-BLED score, range 0-9, from low to high risk of hemorrhage under oral anticoagulation.c Modified Rankin scale score, from 0 (no symptoms) to 6 (death).d NIHSS, stroke related neurological deficits, from 0 (no symptoms) to 42.

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Table 4. Factors Associated With Unfavorable Outcome (mRS 3-6) at 3-Months Follow Up (Univariate Analysis)

OR (95% CI) P ValueAge ≥ 76 years 2.25 (0.68–7.42) .18Gender: female 1.46 (0.43–4.98) .54Coexisting condition

Previous ischemic stroke/ TIA 3.50 (0.87–14.11) .08Previous intracranial hemorrhage 4.21 (0.43-564.92) .26Hypertension 1.00 (0.18–5.58) >.99Hyperlipidemia 0.46 (0.14–1.54) .21Diabetes mellitus 0.61 (0.18–2.06) .43Heart failure 2.10 (0.11–10.80) .37Peripheral vascular disease 1.76 (0.19 - 16.30) .62

Renal function: GFR < 60 ml 0.49 (0.14–1.78) .28CHA2DS2VASc scorea 1.35 (0.93–1.95) .11HAS-BLED scoreb 3.32 (1.30–8.45) .01Modified Rankin scale score before strokec

1.79 (1.16–2.91) .02

Modified Rankin scale score at admissionc

2.91 (1.61–5.25) <.001

NIHSS at admissiond 1.23 (1.07–1.42) .004Baseline hematoma volumee 2.37 (1.02–5.53) .05Location: Supratentorial 0.48 (0.09–2.44) .37Location: Deep 1.33 (0.39–4.55) .65Substantial hematoma expansion 0.74 (0.17–3.25) .69PCC administration 1.20 (0.37–3.87) .76Intraventricular extension (baseline) 8.13 (1.64–40.27) .01Abbreviations: TIA, transient ischemic attack; GFR, glomerular filtration rate (electronic GFR as reported by the centers); NIHSS, National Institutes of Health Stroke Scale. a CHA2DS2VASc score, range 0-9, from low to high risk of ischemic stroke in atrial fibrillation; per increment.b HAS-BLED score, range 0-9, from low to high risk of hemorrhage under oral anticoagulation; per increment.c Modified Rankin scale score, from 0 (no symptoms) to 6 (death); per increment.d NIHSS, stroke related neurological deficits, from 0 (no symptoms) to 42; per increment.e Per log-transformed increment (ml)

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