Stroke

SPECIAL REPORT

The Story of Intracerebral Hemorrhage

From Recalcitrant to Treatable Disease
Joseph P. Broderick , MD; James C. Grotta , MD; Andrew M. Naidech, MD, MSPH; Thorsten Steiner , MME;
Nikola Sprigg , DM; Kazunori Toyoda , MD, PhD; Dar Dowlatshahi , MD, PhD; Andrew M. Demchuk , MD;
Magdy Selim , MD; J Mocco, MD; Stephan Mayer , MD

ABSTRACT: This invited special report is based on an award presentation at the World Stroke Organization/European Stroke
Organization Conference in November of 2020 outlining progress in the acute management of intracerebral hemorrhage (ICH)
over the past 35 years. ICH is the second most common and the deadliest type of stroke for which there is no scientifically proven
medical or surgical treatment. Prospective studies from the 1990s onward have demonstrated that most growth of spontaneous
ICH occurs within the first 2 to 3 hours and that growth of ICH and resulting volumes of ICH and intraventricular hemorrhage
are modifiable factors that can improve outcome. Trials focusing on early treatment of elevated blood pressure have suggested
a target systolic blood pressure of 140 mm Hg, but none of the trials were positive by their primary end point. Hemostatic agents
to decrease bleeding in spontaneous ICH have included desmopressin, tranexamic acid, and rFVIIa (recombinant factor VIIa)
without clear benefit, and platelet infusions which were associated with harm. Hemostatic agents delivered within the first several
hours have the greatest impact on growth of ICH and potentially on outcome. No large Phase III surgical ICH trial has been
positive by primary end point, but pooled analyses suggest that earlier ICH removal is more likely to be beneficial. Recent trials
emphasize maximization of clot removal and minimizing brain injury from the surgical approach. The future of ICH therapy must
focus on delivery of medical and surgical therapies as soon as possible if we are to improve outcomes.
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Key Words:  blood pressure ◼ cerebral hemorrhage ◼ hemostasis ◼ morbidity ◼ mortality

I
ntracerebral hemorrhage (ICH) accounts for >10% of
the estimated 17 million strokes worldwide each year.1,2
ICH has a mortality of >40%, and only 20% of survivors
are functionally independent at 6 months.3–5 But while we
have made tremendous strides in the treatment of acute
ischemic stroke and aneurysmal subarachnoid hemorrhage
over the past 35 years, ICH remains without a proven sci-
entific medical or surgical treatment. The neurosurgical and
interventional community has long embraced and owned
the treatment of patients with ruptured aneurysms while
the medical neurology and the neurointerventional commu-
nities have championed the acute treatment of ischemic
stroke. Thus, when the first American Heart Association
guidelines for the management of acute stroke were first
commissioned, discussed, and published in 1994, ischemic
stroke and aneurysmal subarachnoid hemorrhage each
had their own published guidelines with a great sense of
hope for new therapeutic advances.6,7 But ICH, the second
most common and the deadliest type of stroke, was not
even initially discussed as a topic for guidelines. This initial
lack of engagement by clinicians and researchers in the
early 1990s may have stemmed from the belief that ICH
occurred over minutes which provided no realistic possibil-
ity of intervention to halt the bleeding.8 In addition, patients
with an ICH subsequently had very poor outcomes, with
or without surgical removal that usually involved craniot-
omy. It was not until 1999 that American Heart Associa-
tion published the first acute treatment guidelines for this
neglected or orphan stroke subtype.9
This invited special report is based on an award pre-
sentation at the 2020 European Stroke Organization and
World Stroke Organization Meeting that told the story of
acute treatment of ICH over the past 35 years. This paper
focuses primarily on the acute treatment of ICH within

 
Correspondence to: Joseph P. Broderick, MD, Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, 260
Stetson St, Suite 2300, PO Box 670525, Cincinnati, OH. Email joseph.broderick@uc.edu
For Sources of Funding and Disclosures, see page 1912.
© 2021 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

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 Broderick et al
Nonstandard Abbreviations and Acronyms
Special Report
ATACH Antihypertensive Treatment of Acute
Cerebral Hemorrhage
BP blood pressure
CT computed tomography
DASH Desmopressin for Reversal of
Antiplatelet Drugs in Stroke due to
Hemorrhage
FAST Recombinant Factor VIIa in Acute
Intracerebral Hemorrhage
FASTEST rFVIIa for Acute Hemorrhagic Stroke
Administered at Earliest Time
FVIII factor VIII
GTN glyceryl trinitrate
ICH intracerebral hemorrhage
INCH International Normalized Ratio Nor-
malization in Coumadin Associated
Intracerebral Hemorrhage
INTERACT Intensive Blood Pressure Reduction in
Acute Cerebral Hemorrhage Trial
IVH intraventricular hemorrhage
MISTIE Minimally Invasive Surgery Plus
Alteplase in Intracerebral Hemorrhage
Evacuation
mRS modified Rankin Scale
OR odds ratio
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PATCH Platelet Transfusion in Cerebral
Hemorrhage
rFVIIa recombinant factor VIIa
r-tPA recombinant tissue-type plasminogen
activator
SPOTLIGHT Spot Sign Selection of Intracerebral
Hemorrhage to Guide Hemostatic
Therapy
STOP-AUST Spot Sign and Tranexamic Acid on Pre-
venting ICH Growth–Australasia Trial
TICH-2 TXA for Hyperacute Primary Intrace-
rebral Hemorrhage
TXA tranexamic acid
VWF von Willebrand Factor
the first 1 to 2 days and particularly within the early hours
after onset. And as for ischemic stroke, understanding
the pathophysiology of ICH and its timing is critical for
successful therapies which still elude us. It will take a
global village of engaged investigators and clinicians to
finish the story, but the end of the first chapter is in sight.
INSIGHTS INTO THE EARLY
PATHOPHYSIOLOGY OF ICH
ICH occurs when old, damaged, or abnormal vascular struc-
tures in the brain break under pressure.10,11 Before the
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The Story of Intracerebral Hemorrhage
1980s, the completion of this bleeding was thought to occur
over minutes, but experiences with patients can change our
understanding of a disease. The seminal patient that led to
an entire new direction in research for ICH was a 58-year-
old woman who collapsed walking past the fire station in
Cincinnati in the late 1980s and was brought to a hospital
several blocks away within a short time after onset.8 At that
time, our stroke team had just started evaluating patients as
part of the first pilot study of r-tPA (recombinant tissue-type
plasminogen activator) for acute ischemic stroke, in which
patients had to be treated within 90 minutes from onset.
Because of her very early arrival, our research team saw
her within 40 minutes of symptom onset and found that
she was alert with a right hemiparesis and sensory loss.
While she initially appeared like an excellent candidate for
r-tPA, her computed tomography (CT) scan showed that
she had an 8 mL left thalamic hemorrhage (Figure 1). We
were disappointed that she was not a candidate for r-tPA,
but shortly thereafter, her nurse told us that she was getting
worse and becoming poorly responsive. We repeated the
CT of the head which showed major growth in her thalamic
hemorrhage (Figure 1). As the pilot r-tPA trial continued, we
noted many of these patients with ICH and repeated their
initial CT imaging. A substantial proportion of these patients,
imaged very soon after onset, had substantial growth of
ICH with accompanying deterioration.8
These very early clinical observations with repeated
imaging led to a subsequent prospective National Insti-
tute of Neurological Disorders and Stroke-funded study
of patients with ICH that asked the simple question: how
often does substantial growth occur in patients with spon-
taneous ICH who had their CT of the head done within
3 hours from symptom onset.12 This study demonstrated
that (1) 38% of these patients had ≥1/3 growth in the
volume of their hemorrhage from baseline on repeated
imaging, (2) the large majority of this growth occurred
within the first several hours from onset, and (3) this
growth was accompanied by neurological deterioration.
Since publication of this study, there have been a
number of prospective studies and clinical trials of ICH
that have further expanded our understanding of the fre-
quency of early substantial ICH growth. Al-Shahi Salman
et al13 published a pooled analysis of these data (Fig-
ure 2) that demonstrated the strong exponential decay
relationship between time from onset and predicted
probability of growth of ICH of >6 cc. Thus, if we are
going to change the natural history of bleeding in ICH,
we need to do this within the first hours after onset,
and our systems of care have to incorporate these time
demands as they have for ischemic stroke.
THE NATURAL HISTORY OF ICH AND ITS
THERAPEUTIC IMPLICATIONS
The baseline factors associated with ICH mortality
and functional outcome are volume of ICH, volume of
Stroke. 2021;52:1905–1914. DOI: 10.1161/STROKEAHA.121.033484
 Broderick et al
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Figure 1. Serial computed tomography (CT) scans in 58-year-old woman.
Increase in volume of intracerebral hemorrhage (ICH) of 8 cc at 50 min from onset of symptoms (upper 3 images) to 35 cc at 210 min from
onset (lower 3 images). Reprinted from Broderick et al8 with permission. Copyright ©1990, Journal of Neurosurgery.
intraventricular hemorrhage (IVH), growth of ICH dur-
ing first hours of onset, age, Glasgow Coma Scale, and
infratentorial location.5,14,15 Of these, only growth of ICH
and the resulting volumes of ICH and IVH are biologically
modifiable. Volume of ICH is the strongest determinant
of outcome with over 90% mortality in patients with ≥60
cc hemorrhage and only 1 of 71 patients with ICH vol-
ume ≥30 cm3 functioned independently at 30 days in
one study from the early 1990s.5 Half of the 44% 30-day
mortality in this study occurred within the first 2 days.
Given our improved understanding of the timing of ICH
growth and the modifiable determinants of outcome, the
potential therapeutic approaches include (1) decreasing
blood pressure (BP) pushing blood through the leak(s);
(2) plugging the hole at the site of the leak with a clot or
ideally both; (3) removing blood that causes mechanical
compression as well as inflammation and toxic effects on
surrounding brain tissue; and (4) limiting toxic effects of
blood on surrounding brain tissue by various neuropro-
tective strategies.
Stroke. 2021;52:1905–1914. DOI: 10.1161/STROKEAHA.121.033484
The Story of Intracerebral Hemorrhage
Special Report
TREATING ELEVATED BP TO LIMIT
BLEEDING AND IMPROVE OUTCOME
Sustained elevation of BP and the subsequent vascu-
lopathy is the most important modifiable risk factor for
ICH.14 Lowering BP in the first hours after onset of ICH
is a logical approach to slow bleeding through the dam-
aged vessel. A number of well-designed Phase II and
Phase III trials have tested this approach.
The Phase II INTERACT (Intensive Blood Pressure
Reduction in Acute Cerebral Hemorrhage Trial) 1 and
Phase 3 INTERACT 2 trials were global trials that tar-
geted a decrease in BP to 140 mm Hg as compared to
standard care (<180 mm Hg) using available intrave-
nous medications in participating countries in patients
randomized within 6 hours of onset.16–18 INTERACT 2
showed a nonsignificant trend toward less hemorrhage
growth in the 140 mm Hg group with earlier treatment
(3.1 cc more growth in standard group as compared to
140 mm Hg group when treated within 3 hours versus
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 Broderick et al
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Figure 2. A Illustration of the relationships between key baseline
variables and growth of intracerebral hemorrhage (ICH).
A demonstrates the strong exponential relationship between time from
onset and predicted probability of growth of ICH of >6 cc. B demonstrates
relationship between baseline ICH volume and growth. Reprinted from Al-
Shahi Salman et al13 with permission. Copyright ©2018, Elsevier.
1.2 cc in those treated at 3–6 hours). INTERACT 2 was
not positive with regards to its primary end point, a modi-
fied Rankin Scale (mRS) score of 3–6 but was positive in
its secondary end point of the distribution of the ordinal
mRS. The results of this trial are the basis for the current
Guidelines for Management of Acute ICH that target
systolic pressure of 140 mm Hg.14,19
The Phase II pilot single-arm ATACH (Antihyperten-
sive Treatment of Acute Cerebral Hemorrhage) and
Phase III randomized ATACH 2 trials focused on a more
aggressive BP target of a systolic BP of 110 to 139
mm Hg as compared to a standard control group of 140
to 179 mm Hg, using a single intravenous agent to lower
BP, nicardipine.20,21 ATACH 2 demonstrated a substan-
tial and much quicker decrease in BP as compared to
the INTERACT 2 trial but found no difference in out-
come between the 2 groups. However, in a post hoc
analysis of those participants who received nicardipine
within 2 hours of onset, 35 of the 192 (18.2%) of those
treated with the 110 to 139 target had growth of ICH
(>33% growth from baseline to follow-up CT scans) as
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The Story of Intracerebral Hemorrhage
compared to 42 of 162 (28.4%) of those in the 140
to 179 target, P=0.02.22 This decrease in growth was
accompanied by a greater proportion of participants
with an mRS score of 0–2 at 3 months in the 110 to
139 target group as well (41.7% versus 27.8% in the
140–179 group). In another post hoc analysis, those
with a baseline systolic BP ≥220 who were treated
with the more aggressive target of a systolic BP of
110 to 139 mm Hg had a greater rate of neurological
deterioration within 24 hours as compared to the stan-
dard group (15.5% versus 6.8%; relative risk [RR], 2.28
[95% CI, 1.03–5.07]; P=0.04).23 The rate of death and
severe disability (39.0% versus 38.4%; RR, 1.02 [95%
CI, 0.73–1.78]; P=0.92) was not significantly different
between the 2 groups. There was a significantly higher
rate of kidney adverse events in participants randomized
to intensive systolic BP reduction (13.6% versus 4.2%;
RR, 3.22 [95% CI, 1.21–8.56]; P=0.01). Among the 48
participants with a prerandomization SBP ≥220 mm Hg,
the rate of death or severe disability at 90 days was sig-
nificantly higher for individuals randomized to intensive
SBP reduction (66.7% versus 29.2%; RR, 2.29 [95% CI,
1.15–4.53]; P=0.009). The rate of hematoma expansion
(33.3% versus 26.1%; RR, 1.28 [95% CI, 0.52–3.11];
P=0.59) was similar between the 2 treatment groups.
Finally, the Phase III Rapid Intervention With Glyceryl
Trinitrate in Hypertensive Stroke Trial 2 tested the pre-
hospital initiation of antihypertensive medication (trans-
dermal glyceryl trinitrate [GTN]) within 4 hours of onset
in patients with suspected stroke that was continued for
4 days in addition to standard care of BP.24,25 The trial
found no difference in outcomes between the GTN and
sham groups, but a predefined subgroup analysis found
that patients with ICH in the GTN group had larger
hematomas (1.95 [1.07–3.58]; P=0·030) on baseline
imaging and a trend toward worse outcome. The authors
speculated that early initiation of GTN might have pre-
vented the initial vasoconstrictive response in the setting
of an arterial rupture and so led to very early hematoma
expansion. Second, venodilators, such as sodium nitro-
prusside and GTN, have been shown experimentally
and clinically to raise intracerebral pressure and reduce
cerebral blood flow, particularly if intracerebral pres-
sure is already elevated. Reduced blood flow might then
induce perihematoma ischemia. The findings of diffusion
positive changes with magnetic resonance imaging of
patients with ICH in other studies, particularly in those
with highest and the greatest decrease in BP, is sup-
portive of this speculation.26,27
Thus, while there is some evidence of benefit with
lowering BP to a target systolic BP of 140 mm Hg in
the INTERACT 2 trial and that very rapid initiation of BP
treatment may be beneficial, there is also evidence that
very aggressive lowering of the highest levels of elevated
BP may have adverse outcomes. The ideal approach
to lowering of BP in patients with ICH, including the
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 Broderick et al
targeted decrease, the speed of decrease, the effective-
ness of treatment by time from onset to treatment, and
types of agents used, requires more research.
TREATMENT TO PLUG LEAKY BLOOD
VESSEL WITH CLOT
ICH Related to Anticoagulants
Rapid hemostasis at the site of an intracranial arterio-
lar rupture is another logical way to decrease growth of
ICH and improve outcome. The randomized, open-label,
blinded-end point INCH trial (International Normalized
Ratio Normalization in Coumadin Associated Intracere-
bral Hemorrhage), a clear demonstration of the effec-
tiveness of this approach, tested prothrombin complex
concentrate versus fresh frozen plasma in 54 patients
with ICH related to the use vitamin K antagonists within
12 hours of onset.28 The trial was terminated on Febru-
ary 6, 2015, after inclusion of 50 patients, after a safety
analysis demonstrated safety concerns. Two (9%) of
23 patients in the fresh frozen plasma group versus 18
(67%) of 27 in the prothrombin complex concentrate
group reached the primary end point of international
normalized ratio ≤1.2 within 3 hours of treatment initia-
tion (adjusted odds ratio [OR] 30.6 [95% CI, 4.7–197.9];
P=0·0003). At 24 hours, the adjusted difference in
hematoma expansion was 16.4 mL less in the prothrom-
bin complex concentrate group as compared to the fresh
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frozen plasma group (95% CI, 2.9–29.9; P=0.018). Thir-
teen patients died: 8 (35%) of 23 in the fresh frozen
plasma group (5 from hematoma expansion, all occurring
within 48 hours after symptom onset) and 5 (19%) of
27 in the prothrombin complex concentrate group (none
from hematoma expansion).
Several single-arm trials of reversal agents for ICH
related to novel oral anticoagulants, idarucizumab for
dabigatran, and andexanet alpha for Factor X inhibitors,
have been published, providing additional therapeutic
options to halt bleeding in these patients.29,30
Spontaneous ICH: Platelets and Platelet
Stimulation in Setting of Antiplatelet Use
The PATCH trial (Platelet Transfusion in Cerebral Hemor-
rhage) tested the use of platelet infusions in 190 patients
with ICH who had been taking antiplatelet agents before
the ICH.31 The trial was stopped early for safety since
the odds of death or dependence at 3 months were
higher in the platelet transfusion group than in the stan-
dard care group (adjusted common OR 2.05 [95% CI,
1.18–3.56]; P=0·01), and this was associated with a
nonsignificant increase in thromboembolic events and
increased serious adverse events related to ICH in the
transfusion group. While the modest-sized trial has multi-
ple limitations, and the differences in mortality likely have
Stroke. 2021;52:1905–1914. DOI: 10.1161/STROKEAHA.121.033484
The Story of Intracerebral Hemorrhage
multiple explanations, the authors speculate that infu-
sion of platelets may have stimulated prothrombotic and
Special Report
inflammatory responses and was not sufficient to reverse
the effects of antiplatelet use on growth of hemorrhage.
Desmopressin is another medication that has been
tested in small pilot studies in patients with ICH who
have been taking antiplatelet agents.32 It stimulates the
release of VWF (von Willebrand Factor) and FVIII (fac-
tor VIII) from endothelial Weibel-Palade bodies. VWF is
responsible for platelet adhesion to collagen and may
also bind platelets through their glycoprotein IIb/IIIa
receptors, so increased levels of VWF have the poten-
tial to compensate for the platelet function defect asso-
ciated with antiplatelet drugs. A pilot trial is ongoing
(DASH [Desmopressin for Reversal of Antiplatelet Drugs
in Stroke Due to Hemorrhage] Clinical Trials.gov).
Spontaneous ICH: Antifibrinolytic Therapy
Tranexamic acid (TXA) is an antifibrinolytic agent that
has been extensively studied in patients with bleeding
of various causes, including ICH. The largest randomized
trial for spontaneous ICH was the TICH-2 trial (TXA for
Hyperacute Primary Intracerebral Hemorrhage) which
enrolled 2325 participants with ICH within 8 hours of
onset.33 Two grams of TXA (one gram over 10 minutes
followed by one gram over 8 hours) was compared with
matching placebo. TXA decreased growth of ICH sig-
nificantly by 1.4 mL. However, there was no difference
between the TXA and placebo groups who were dead
or dependent (mRS score >3), an OR 0.82 (95% CI,
0.65–1.03), P=0.08.
The STOP-AUST (Spot Sign and Tranexamic Acid on
Preventing ICH Growth–Australasia Trial) randomized
100 ICH patients with a spot sign on CT angiography
within 4 hours 30 minutes either 2 g TXA (1 g over 10
minutes followed by 1 g over 8 hours) or matching pla-
cebo.34 The primary outcome was ICH growth (>33%
relative or >6 mL absolute) at 24 hours. The median time
from onset to treatment was 150 minutes. There was
no significant difference in the primary outcome between
the 2 groups, although there was a trend towards
reduced presence of hematoma growth in the prespeci-
fied subgroup treated ≤3 hours from onset. Additional
trials of TXA focused on even earlier treatment time from
onset are ongoing.
Spontaneous ICH: Recombinant Factor VIIa
The rFVIIa (recombinant factor VIIa) is a manufactured
recombinant protein identical to FVIIa in humans that is
approved for use in patients with congenital hemophilia,
acquired hemophilia, and Glanzmann thrombasthenia.35,36
rFVIIa interacts with tissue factor at the site vessel injury
which leads to thrombin generation. In addition, rFVIIa
activates FX on the surface of activated platelets, leading
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 Broderick et al The Story of Intracerebral Hemorrhage

to an enhanced thrombin burst at the site of injury. Throm- initial ICH volume (cumulative OR, 0.94 [95% CI, 0.91–
bin converts fibrinogen to fibrin, producing a stable clot. 0.97]; P<0.0001), Glasgow Coma Scale (cumulative OR,
Special Report

The risk of rFVIIa is related to its generation of thrombin
at the site of injured vessels or activated platelets that can
lead to myocardial infarction and ischemic stroke. rFVIIa
is easily and rapidly administered intravenously with a
rapid onset of action and a half life of several hours.
rFVIIa is the only medication to substantially decrease
bleeding in spontaneous ICH in large randomized trials of
ICH but its effectiveness is time dependent (Table 1).37–
39
After several small pilot trials, it was first tested in a
Phase IIb dose-finding trial of 399 participants in which
rFVIIa significantly decreased growth of ICH, decreased
mortality (combined 3 doses compared to placebo), and
improved outcome on the mRS score. In addition, the
effect of rFVIIa on decreasing ICH group was greatest
in the subgroup (269 patients) treated within 3 hours
of onset. The absolute increase in volume of ICH was
10.7 mL for the placebo group, as compared with 4.4 mL
for the rFVIIa-treated patients (P=0.009). Among those
treated >3 hours after onset (115 patients), the mean
increase in ICH volume was 14% for the placebo group,
as compared with 16% for the rFVIIa groups (P=0.86),
and the absolute increase was 3.1 mL, as compared
with 3.8 mL (P=0.76). Serious thromboembolic adverse
events, mainly myocardial or cerebral infarction, occurred
in 7% of rFVIIa-treated patients, as compared with 2% of
those given placebo (P=0.12).
Substantial growth (>1/3 increase of initial volume of
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1.46 [95% CI, 1.21–1.82]; P<0.0001), and age (cumula-
tive OR, 0.95 [95% CI, 0.92–0.98]; P=0.0009) predicted
outcome on the mRS.40 For each mL increase in ICH from
the baseline ICH volume and for each 10% increase in
ICH growth, patients were 6% and 16% more likely to
increase 1 full point on the mRS.40
The subsequent Phase III FAST (Recombinant Fac-
tor VIIa in Acute Intracerebral Hemorrhage Trial) of 841
participants also demonstrated decreased growth of
ICH as compared to placebo, which was the greatest
when administered within 2 hours of onset, but no dif-
ference was seen in functional outcome between the
2 groups at 90 days.39 The overall frequency of throm-
boembolic serious adverse events was similar in the 3
groups; however, arterial events were more frequent in
the group receiving 80 μg/kg of rFVIIa than in the pla-
cebo group (9% versus 4%, P=0.04).
Some of the differences in outcome between the
Phase IIb and Phase III trials relate to imbalances
between the placebo group and rFVIIa groups in the pro-
portion of patients with IVH, a known factor associated
with mortality and outcome (higher in placebo patients
in the Phase IIb trial and higher in rFVIIa groups in the
Phase III trial). However, a subsequent post hoc analy-
sis focusing on ICH patients with hemorrhages <60 cc
and smaller IVHs, demonstrated the strong effect of time
from onset to treatment, and to a lesser extent age, upon

ICH) occurred in 35% to 40% of ICH subjects in the the potential effectiveness of rFVIIa.38 The importance
rFVIIa Phase IIb trial, although nearly three-fourths of of time to treatment is also demonstrated by the SPOT-
patients had some growth in bleeding between the base- LIGHT trial (Spot Sign Selection of Intracerebral Hemor-
line and 24-hour scan. In this trial, percentage growth rhage to Guide Hemostatic Therapy).41 This trial tested
(cumulative OR, 0.84 [95% CI, 0.75–0.92]; P<0.0001), rFVIIa versus placebo in participants with a spot sign
on CT angiogram, a marker of ongoing bleeding. Unfor-
Table 1.  Decrease in ICH Growth Between Baseline and tunately, the time from onset to treatment with study
Follow-Up Imaging in Published Trials medication was longer due to the additional imaging
and interpretation. As a result, almost all of the growth
Time interval to Decrease in ICH
Treatment start of treatment growth, cc in ICH in both the rFVIIa and placebo groups occurred
Lowering BP (INTERACT 2) 3–4 h 30 min 1.3
between the baseline CT and follow-up CT done at the
start of study medication (Table 2—written communica-
Lowering BP (INTERACT 2) 0–3 h 3.1
tion, Andrew Demchuk, 2019). In other words, rFVIIa was
Lowering BP (ATACH 2) 0–2 h 2.0
given at a time point when most bleeding had stopped.
Tranexamic acid (TICH-2) 0–8 h 1.4
Additional analyses of the rFVIIa Phase 3 and Phase 2b
Tranexamic acid (STOP-AUST) 0–4 h 30 min 1.8 trials, using the FASTEST (rFVIIa for Acute Hemorrhagic
(SPOT sign)
Stroke Administered at Earliest Time) inclusion crite-
Tranexamic acid (STOP-AUST) 0–3 h (SPOT sign) 4.9
ria, demonstrate the importance of time to treatment in
rFVIIa 20 µg/kg (FAST trial) 0–4 h 2.8 future trials of rFVIIa (Table 3).
rFVIIa 80 µg/kg (FAST trial) 0–4 h 3.8
rFVIIa 80 µg/kg (FAST trial) 0–2 h 5.6
rFVIIa 160 µg/kg (Phase IIb trial) 0–4 h 6
SURGICAL REMOVAL OF ICH
ATACH indicates Antihypertensive Treatment of Acute Cerebral Hemorrhage;
No large, well-designed Phase III randomized controlled
BP, blood pressure; FAST, Recombinant Factor VIIa in Acute Intracerebral Hem- surgical trial of ICH, whether using craniotomy alone, min-
orrhage; ICH, intracerebral hemorrhage; INTERACT, Intensive Blood Pressure imally invasive stereotactic removal of ICH, or both, has
Reduction in Acute Cerebral Hemorrhage Trial; rFVIIa, recombinant factor VIIa;
STOP-AUST, Spot Sign and Tranexamic Acid on Preventing ICH Growth–Austral-
been positive per its primary end point. This lack of ben-
asia Trial; and TICH-2, TXA for Hyperacute Primary Intracerebral Hemorrhage. efit is reflected in the guidelines for acute management

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 Broderick et al The Story of Intracerebral Hemorrhage

Table 2.  SPOTLIGHT Trial: Volume of ICH+IVH at 3 Time Points in Both Treatment Groups

rFVIIa (N=19), ICH+IVH Placebo (N=25), ICH+IVH

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Timing of scan Stroke onset to CT, h volume, mL, median (IQR) volume, mL, median (IQR)
Baseline CT 1.4 (1.2–2.6) 24.1 (16.0–41.4) 23.1 (11.5–53.0)
Immediate postdose CT 3.0 (2.5–4.3) 35.9 (20.8–63.0) 30.4 (21.4–63.1)
24-h CT 26.6 (26.1–27.8) 31.3 (17.4–64.8) 33.3 (18.5–59.6)

CT indicates computed tomography; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; rFVIIa, recombinant fac-
tor VIIa; and SPOTLIGHT, Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy.

of ICH.14,19 Pooled and meta-analysis of present trial to
date have suggested that patients with earlier removal,
mid-range volumes of ICH, minimally invasive removal,
and younger age may be more likely to benefit with sur-
gical removal.42,43 In addition, the MISTIE (Minimally Inva-
sive Surgery Plus Alteplase in Intracerebral Hemorrhage
Evacuation) 3 trial of minimally invasive removal of ICH
using r-tPA after stabilization of ICH volume by repeated
imaging, indicated that more complete removal of ICH,
and standardization of surgical techniques were associ-
ated with better outcomes.44,45 Trials of minimally invasive
mechanical removal of ICH without r-tPA are ongoing.46
Much of the rationale for removal of ICH has been
based upon preclinical work highlighting the toxicity of
blood products on surrounding brain which likely do have
a longer time course.47–49 Randomized trials of medical
therapies of neuroprotection to decrease the toxicity
of ICH on surrounding brain tissue have been neutral
thus far but remain an area of future study.50,51 However,
Downloaded from http://ahajournals.org by on July 23, 2022
of ICH over medical therapies, if done very quickly, is that
it could be done in patients with larger volumes of ICH
in whom outcomes are uniformly very poor with medical
therapies designed to slow or halt bleeding. Hyperacute
removal is likely to involve minimally invasive techniques
that monitor and treat ongoing bleeding.55,56 Pilot trials of
ultra-early surgery are ongoing or are in planning stages.
Effective hemostatic treatments that limit ongoing bleed-
ing could also lead to improved hemostasis during ultra-
early removal of ICH.
WHERE WE ARE NOW AND THE PATH
FORWARD
The large majority of bleeding in ICH occurs within the
first 2 to 3 hours after onset and if we are going to change
the natural history, as we have for ischemic stroke, we
will have to replicate and surpass the time restrictions of

much of the damage associated with ICH is mechanical
whose time course is likely much shorter based upon the
limited preclinical animal data exploring this issue.52–54 If
mechanical damage is time dependent, the future suc-
cess of surgical removal of ICH will depend upon very
early removal, stabilization of ongoing bleeding during
surgery, removal of sufficient blood to limit mechanical
damage and toxicity, and minimization of brain injury dur-
ing access to the ICH. One advantage of surgical removal
the initial tPA trials. rFVIIa has the best data thus far for
decreasing ICH growth, although data from TXA and BP
trials also indicate the importance of rapid treatment. All
medical approaches must strive to limit adverse events
that can limit the impact of slowing the growth of ICH.
We need to exclude patients in the medical trials who
have an extremely poor prognosis even if we can slow
the growth of ICH (eg, patients with an ICH volume ≥60
cc or those with large volumes of IVH). Surgical trials

Table 3.  Subgroup Analyses From FAST and Phase IIb rFVIIa Trials Which Include FASTEST Imaging
Criteria: Baseline ICH Volume of ≥2 and <60 cc, and No or a Small Volume of IVH, That Is, IVH Score ≤7

FAST trial: minutes from onset to Absolute % in mRS score

treatment in patients age ≤80 mRS score 0–2 FVIIa mRS score 0–2 placebo 0–2 in favor of rFVIIa at 90 d
  ≤150 42% 42% 0%
  ≤140 46% 41% 5%
  ≤130 49% 41% 8%
  ≤120* 52% 38% 14%
Phase IIB trial: minutes from onset mRS score 0–2 FVIIa mRS score 0–2 placebo Absolute % in mRS score
to treatment in patients age ≤80 0–2 in favor of rFVIIa at 90 d
  ≤150 42% 32% 10%
  ≤140 47% 30% 17%
  ≤130 50% 25% 25%
  ≤120 50% 20% 30%

FAST indicates Recombinant Factor VIIa in Acute Intracerebral Hemorrhage; FASTEST, rFVIIa for Acute Hemorrhagic Stroke Admin-
istered at Earliest Time; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; mRS, modified Rankin Scale; and rFVIIa,
recombinant factor VIIa.
*N=25 in FVIIA and 32 in placebo group.

Stroke. 2021;52:1905–1914. DOI: 10.1161/STROKEAHA.121.033484 May 2021   1911

 Broderick et al
have to address the early pathophysiology of mechanical
damage due to ICH while limiting brain injury from clot
Special Report
removal. New trials focusing on very early treatment are
in the planning stages.
The National Institute of Neurological Disorders and
Stroke has funded a trial of medical therapy for ICH that
attempts to address the previously discussed issues. The
objective of the FASTEST trial is to establish the first treat-
ment for acute ICH within a time window and subgroup
of patients who are most likely to benefit.57 FASTEST is a
randomized, double-blind controlled efficacy trial of rFVIIa
plus best standard therapy versus placebo plus best stan-
dard therapy (including INTERACT 2 goal of target BP
of 140 mm Hg). The trial includes subjects with a base-
line volume of ICH <60 cc, no or a small volume of IVH
(IVH score ≤758), age ≤80 years, and most importantly,
treatment begun within 2 hours. To enroll subjects within
2 hours, and as many as possible within 1 hour, we are
using mobile stroke units,59–61 exception from informed
consent, and improved acute stroke treatment processes
as for ischemic stroke including automatic calculation of
volume of ICH, decreased door to needle, etc.
We will randomly assign patients in a 1:1 ratio to
intravenous rFVIIa or placebo at a dose of 80 µg/kg
(maximum 10 000 µg or 10 mg) and administered intra-
venously over 2 minutes. All investigators and patients
will be blinded throughout the course of the study. To
limit time to completion and interpretation of imaging, we
require only baseline noncontrast CT but will collect CT
Downloaded from http://ahajournals.org by on July 23, 2022
angiography if it is done as standard of care. The trial
plans for a maximum of 860 participants at 100+ hos-
pitals and 15+ mobile stroke units in the United States,
Canada, Japan, Germany, Spain, and the United King-
dom. The primary outcome measure is the distribution
of the ordinal mRS score at 180 days (specifically, mRS
score 0–2, 3, 4–6 per discussions with the Food and
Drug Administration).
Improving outcome after acute ICH is likely to require
a multipronged approach of decreasing bleeding in the
first hours, rapid removal of blood with minimization of
brain injury, therapies that limit toxicity of blood within the
brain, and innovative approaches to neurorecovery which
for ICH is still in its infancy. Our successes in changing
the outcomes of ischemic stroke make us hopeful that
the next chapters in the story of ICH treatment will also
lead to improved outcomes for our patients.
ARTICLE INFORMATION
Presented in part at the European Stroke Organisation-World Stroke Organiza-
tion 2020 Virtual Conference, November 7–9, 2020.
Affiliations
University of Cincinnati Gardner Neuroscience Institute, OH (J.P.B.). Memorial
Hermann Hospital-Texas Medical Center, Houston, TX (J.C.G.). Department of
Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL
(A.M.N.). Department of Neurology, Klinikum Frankfurt Höchst, Frankfurt, Ger-
many (T.S.). Department of Neurology, Heidelberg University Hospital, Germany
1912   May 2021
The Story of Intracerebral Hemorrhage
(T.S.). Stroke Trials Unit, Division of Clinical Neuroscience, University of Not-
tingham, City Hospital Campus, England (N.S.). Department of Cerebrovascular
Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
(K.T.). Ottawa Hospital Research Institute, University of Ottawa, Canada (D.D.).
Calgary Stroke Program, Departments of Clinical Neurosciences and Radiology,
Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Al-
berta, Canada (A.M.D.). Beth Israel Deaconess Medical Center, Boston, MA (M.S.).
Harvard Medical School, Boston, MA (M.S.). Department of Neurosurgery, Icahn
School of Medicine at Mount Sinai, New York City, NY (J.M.). Westchester Medical
Center Health Network, Departments of Neurology and Neurosurgery, New York
Medical College, Valhalla, NY (S.M.).
Acknowledgments
Dr Broderick drafted the article and the remaining authors reviewed and added
critical revisions to the article.
Sources of Funding
The National Institute of Neurological Disorders and Stroke (NINDS) grants:
U01NS086872, U01NS110772; Japan Agency for Medical Research and De-
velopment (AMED): 20lk0201094h0002.
Disclosures
Dr Broderick is the principal investigator (PI) of the National Institutes of Health
(NIH)–funded FASTEST trial (FVIIa for Acute Hemorrhagic Stroke Administered at
Earliest Time) that receives in-kind study medication from Novo Nordisk and mon-
ies to Department of Neurology and Rehabilitation Medicine from Genentech for
his role on Steering Committee of TIMELESS trial (Tenecteplase in Stroke Patients
Between 4.5 and 24 Hours) and from Ono Pharmaceuticals for role as consultant.
Dr Grotta is a PI for the NIH-funded FASTEST trial and has grant support from CSL
Behring. Dr Naidech is a PI for the NIH-funded FASTEST trial and is supported by
R01 NS110779. T. Steiner is the German PI for the FASTEST Trial and has speaker
honoraria and consultancy fees from Boehringer, Bayer, BMS-Pfizer, Daiichy Sanyo,
and Portola. Dr Dowlatshahi is the PI for the FASTEST trial in Canada and re-
ceives salary support from the Heart & Stroke Foundation of Canada and holds
patent no. PAT 80049P-2 US for Computerized Automatic Detection of Leakage
(CARL): method and system for identifying bleeding. Dr Demchuk is a member of
organizing committee of FASTEST trial. He holds a patent and is a shareholder for
the company Circle NVI for stroke imaging software. The SPOTLIGHT trial (Spot
Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy) was
funded by a grant from the Canadian Institutes for Health Research. He reports
grants from CIHR during the conduct of the study; personal fees from ANNEXA-I
outside the submitted work; in addition, Dr Demchuk has a patent to Circle NVI is-
sue. N. Sprigg is the PI for the FASTEST trial in the United Kingdom and received
NIHR HTA funding for TICH-2 study (TXA for Hyperacute Primary Intracerebral
Hemorrhage; NIHR HTA project code 11_129_109). Dr Toyoda is the PI for the
FASTEST Trial in Japan and receives speaker honoraria from Daiichi-Sankyo, Bayer
Yakuhin, Bristol-Myers-Squibb, Takeda, and Nippon Boehringer-Ingelheim. Dr Selim
receives support from the National Institute of Neurological Disorders and Stroke
(NINDS; 1U01NS102289) and serves on the Advisory Board of MedRhythms Inc.
Dr Mocco serves as the Food and Drug Administration IDE holder and National
PI for the INVEST trial (A Single Arm, Feasibility Study of Minimally Invasive En-
doscopic Surgical Treatment With Apollo for Supratentorial Intracerebral Hemor-
rhage), evaluating the use of the Apollo and Artemis Devices for ICH evacuation,
which is an Independent Investigator run trial that is funded by Penumbra. Dr Mocco
has previously served as a consultant and investor in Rebound Therapeutics, which
was acquired by Integra. Dr Mocco also reports other from Imperative Care, other
from Cerebrotech, other from Viseon, other from Endostream, other from Vastrax,
other from RIST, other from Synchron, other from Viz.ai, other from Perflow, other
from CVAid, other from Cardinal Consulting, other from Blink TBI, other from Seren-
ity, other from Truvic, grants from Stryker Neurovascular, grants from Microvention,
and grants from Penumbra outside the submitted work. Dr Mayer is the safety
monitor for the FASTEST trial, is on the data and safety monitoring committee
for the CHARM trial (Study to Evaluate the Efficacy and Safety of Intravenous
BIIB093 [Glibenclamide] for Severe Cerebral Edema Following Large Hemispheric
Infarction), is PI of the ICHOR-S trial (The Intracranial Hemorrhage -Slice), is on
the steering committee of the PhINEST study (Pharyngeal ICU Novel Electrical
Stimulation Therapy), has received consultancy fees from Bayer, Biogen, Ceribell,
Idorsia, MaxQ AI, and Phagenesis, and has stock options in NeurOptics
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