1250259 WSO International Journal of StrokeSeiffge and Anderson

Leading Opinion

International Journal of Stroke

Treatment for intracerebral

2024, Vol. 19(5) 482­–489
© 2024 World Stroke Organization
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hemorrhage: Dawn of a new era sagepub.com/journals-permissions
https://doi.org/10.1177/17474930241250259
DOI: 10.1177/17474930241250259
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David J Seiffge1 and Craig S Anderson2,3

Abstract
Intracerebral hemorrhage (ICH) is a devastating disease, causing high rates of death, disability, and suffering across
the world. For decades, its treatment has been shrouded by the lack of reliable evidence, and consequently, the
presumption that an effective treatment is unlikely to be found. Neutral results arising from several major randomized
controlled trials had established a negative spirit within and outside the stroke community. Frustration among
researchers and a sense of nihilism in clinicians has created the general perception that patients presenting with ICH
have a poor prognosis irrespective of them receiving any form of active management. All this changed in 2023 with the
positive results on the primary outcome in randomized controlled trials showing treatment benefits for a hyperacute
care bundle approach (INTERACT3), early minimal invasive hematoma evacuation (ENRICH), and use of factor
Xa-inhibitor anticoagulation reversal with andexanet alfa (ANNEXa-I). These advances have now been extended
in 2024 by confirmation that intensive blood pressure lowering initiated within the first few hours of the onset of
symptoms can substantially improve outcome in ICH (INTERACT4) and that decompressive hemicraniectomy is a
viable treatment strategy in patients with large deep ICH (SWITCH). This evidence will spearhead a change in the
perception of ICH, to revolutionize the care of these patients to ultimately improve their outcomes. We review these
and other recent developments in the hyperacute management of ICH. We summarize the results of randomized
controlled trials and discuss related original research papers published in this issue of the International Journal of
Stroke. These exciting advances demonstrate how we are now at the dawn of a new, exciting, and brighter era of ICH
management.

Keywords
Intracerebral hemorrhage, care bundle, anticoagulation reversal, blood pressure control, andexanet alfa, minimal invasive
surgery, hematoma evacuation, direct oral anticoagulants

Received: 12 April 2024; accepted: 12 April 2024

Intracerebral hemorrhage—the Treatment of ICH before 2023—

deadly sibling of ischemic stroke widespread frustration and nihilism
Intracerebral hemorrhage (ICH) is caused by the rupture For decades, treatment of ICH has been overshadowed by
of cerebral vessels which results in bleeding within limited evidence and a presumed lack of effective treatment
the brain parenchyma and/or ventricles.1 Overall,
1
ICH comprises approximately 10–15% of all strokes Department of Neurology, Inselspital University Hospital and
University of Bern, Bern, Switzerland
worldwide, but the rates are higher in low- and middle- 2
The George Institute for Global Health, Faculty of Medicine, University
income countries.2 Compared to ischemic stroke, the of New South Wales, Sydney, NSW, Australia
incidence of ICH has increased in recent years and the 3
Institute for Science and Technology for Brain-inspired Intelligence,
prognosis remains poor.3,4 Current estimates predict Fudan University, Shanghai, China
a significant increase in the incidence of ICH in
Corresponding author:
Europe related to aging and greater use of anticoagu- David Seiffge, Department of Neurology, Inselspital University Hospital
lants, with major implications for health care systems and University of Bern, Freiburgstrasse 18, CHF-3010 Bern, Switzerland.
and societies.5 Email: [email protected]

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Seiffge and Anderson 483

Figure 1. Treatment targets in intracerebral hemorrhage.

options reflected by neutral and restrictive guideline rec- from ICH.21–23 The other key predictors of outcome are
ommendations.6,7 Several randomized controlled trials of an early time-window (i.e. <6 h of onset), high BP, base-
surgical treatment (i.e. different approaches to evacuation line hematoma volume (medium to large), intraventricu-
of parenchymal or intraventricular hematoma),8–11 blood lar extension, and prior use of oral anticoagulation
pressure (BP) control,12,13 and hemostatic therapies,14–16 therapy.24,25 Even a small initial hematoma may evolve
resulted in either borderline significant or neutral results. into a devastating large lesion (Figure 2).
The evidence was persuasive from INTERACT2,12 and Hematoma evacuation to reduce the clot burden is con-
stronger when pooled with other trials as part of an indi- ceptually simple as a pivotal treatment option to reduce
vidual patient data meta-analysis,17 for a beneficial effect of direct and indirect/secondary brain damage after ICH. Yet,
early intensive BP lowering. Although a study-level meta- a series of randomized controlled trials conducted over
analysis of hematoma evacuation also found a potential 40 years have failed to clearly show a benefit from surgery
benefit,18 there is ongoing uncertainty over which patients on the pre-defined primary outcome. Pre-defined subgroup
have the most to gain from neurosurgery along with the and secondary analysis have shown benefits of hematoma
optimal timing and technique of intervention. Collectively, evacuation in patients with altered level of consciousness
these efforts have contributed to somewhat of a negative from a lobar ICH and from external ventricular drainage in
spirit within (and outside) the stroke community, and in those with occlusive hydrocephalus.6,26 Other treatment tar-
turn degrees of frustration and nihilism regarding treatment gets include the prevention of secondary brain damage (by
approaches and the perception of a uniformly poor progno- mitigating the toxic effects of blood breakdown products),
sis for patients with ICH.19 approaches to rehabilitation as the pattern of recovery is
different in ICH to ischemic stroke, and in the secondary
prevention of recurrent ICH as well as serious ischemic
Treatment targets in ICH cardiovascular events.
Several promising treatment targets exist for ICH
(Figure 1). In the hyperacute phase, the primary aim is to
The year 2023—dawn of a new era
stop the bleeding which grows from the original site in
“domino” or “avalanche” fashion through the secondary The year 2023 will be remembered as the dawn of a new era
shearing of neighboring vessels.20 Restricting the ongoing in the treatment of ICH, with three pivotal randomized con-
bleeding cascade—usually depicted as hematoma expan- trolled trials showing clear benefits of different treatment
sion on follow-up imaging—is paramount as it is consist- approaches. First, the Early Minimally Invasive Removal
ently identified as a major predictor of poor outcome of Intracerebral Hemorrhage (ENRICH) trial showed that a

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484 International Journal of Stroke 19(5)

Figure 2. Case example of a patient with atrial fibrillation presenting with a small baseline hemorrhage early after onset with
a recent intake of a factor Xa-inhibitor, high anti-Xa activity, and elevated blood pressure resulting in devastating hematoma
expansion. ICH: denotes intracerebral hemorrhage, IVH: intraventricular hemorrhage, NIHSS: National Institute of Health stroke
severity scale, GCS: Glasgow coma scale.

Figure 3. Care bundle approach for hyperacute treatment of intracerebral hemorrhage.2,3

minimally invasive trans-sulcal parafascicular craniotomy commenced within several hours of the onset of symptoms
with endovascular clearage to remove the hematoma was resulted in improved functional outcome for a broad range
superior to usual standard of care for functional outcome.1 of patients with acute ICH.28 Finally, the Randomised Trial
First presented at the annual conference of the American of Andexanet alfa Versus Usual Care in Patients With Acute
Association of Neurological Surgeons in Los Angeles in Intracranial Haemorrhage While on an Oral Factor
April 2023, the results have only recently been published.27 Xa-Inhibitor (ANNEXa-I) found that use of intravenous
Second, the third Intensive Care Bundle with Blood andexanet alfa, a recombinant modified Factor Xa mole-
Pressure Reduction in Acute Cerebral Haemorrhage Trial cule, was superior to usual care (i.e. with 86% use of pro-
(INTERACT3) found that the implementation of a care thrombin complex concentrate) in terms of hemostatic
bundle protocol incorporating intensive BP lowering with efficacy for patients with ICH related to factor Xa-inhibitor
other management algorithms for physiological control anticoagulation therapy.29 These three positive trials pave

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Seiffge and Anderson 485

agreement over the benefits of a care bundle approach and

Figure 4. Gabriele et al.37 report the incidence of
anticoagulation-associated intracerebral hemorrhage (OAC- that it should be implemented in all hospitals that care for
ICH) and non-anticoagulation-associated intracerebral patients with ICH.31 However, there are recognized imple-
hemorrhage (non-OAC-ICH) from a population-based study mentation challenges according to the availability of
over a period of 10 years. resources and skill mix,32 and concerns may arise over the
relative effectiveness of various components of a care bun-
dle. The most recent findings of the fourth INTEnsive
ambulance-delivered BP Reduction in hyper-ACute stroke
Trial (INTERACT4) are therefore very timely in showing
clear benefits of rapid BP control within just a few hours of
the onset of ICH.33 Furthermore, these results provide evi-
dence and underlying mechanistic support to reconfigure
systems of care for time-intensive urgency toward the man-
agement of ICH as in ischemic stroke.34

Second: direct oral anticoagulants—new

challenges for ICH treatment
the way for an entirely new, more optimistic era, of hypera- New challenges have arisen from the increased use of direct
cute treatment of ICH. We discuss these papers along with oral anticoagulants,35 which have largely replaced vitamin
several manuscripts reporting novel data on ICH in this K antagonists, for the treatment of atrial fibrillation, pulmo-
issue of the International Journal of Stroke (IJS). nary embolism, and other thromboembolic conditions.
Recent data from a study that combined two national stroke
registries found a dramatic change in the spectrum of ICH
First: care bundle approaches for with a shift from vitamin K antagonists to direct oral anti-
hyperacute treatment coagulants without a change in the profile of patients in the
last decade.36 The changing epidemiology of ICH in high
Although primary randomized controlled trials testing sin- income countries is further refined by a study of Gabriele
gle interventions (i.e. BP control, hematoma evacuation) et al.37 published in this issue of the IJS. In a population-
were neutral, these measures were implemented to different based study undertaken in the region of l’Aquila in Italy,
degrees in hyperacute treatment pathways due to positive the incidence of anticoagulation-associated ICH related to
signals from secondary analysis or non-randomized stud- direct oral anticoagulants overtook that related to vitamin K
ies. Combining different measures in a care bundle—anti- antagonists (incidence rate ratio = 4.71) from 2020 after
coagulation reversal, BP control and a care pathway for being stable over the period 2011 to 2020 (Figure 4).37
neurosurgery referral (Figure 3)—was first shown to reduce Moreover, 30-day case fatality was extremely high at 48%
30-day case fatality in a “before-and-after” quality improve- in patients with anticoagulation-associated ICH. As well as
ment project in Manchester, UK.30 The approach was sub- highlighting the importance of direct oral anticoagulant-
sequently rigorously evaluated with control of glucose and related ICH, it draws attention to the need of services to
body temperature being included in protocols without neu- better manage the condition, further emphasized in a study
rosurgery referral using an international stepped wedge that combined national stroke datasets in Norway and
cluster randomized controlled design (INTERACT3)28 Switzerland where at 3 months, overall mortality was 43%
where hospitals were centrally randomly allocated into and only 25% of patients who survived a direct oral antico-
three sequences of implementation of the care bundle agulant-related ICH were functionally independent (defined
across nine low- and middle-income and one high-income by a modified Rankin scale score of 0–2).36
countries. Overall, for the 7036 patients with ICH at 121
hospitals with available outcome data, the likelihood of a
poor functional outcome was significantly lower in the care Third: andexanet alfa—a specific reversal
bundle group (common odds ratio = 0.86, 95% confidence agent for factor Xa-inhibitor–associated
interval = 0.76–0.97; p = 0.015). INTERACT3 therefore ICH
extends knowledge of the benefits of well-organized stroke
care in showing that the implementation of a relatively sim- The results from Gabriele et al.37 and the Swiss-Norwegian
ple, time- and target-based protocol of intensive BP lower- study36 clearly identify the unmet medical need to improve
ing and other management algorithms for physiological the management of patients with factor Xa-inhibitor–
control, initiated within several hours of the onset of symp- associated ICH. A study from Hong Kong found that the
toms, improves outcome from ICH. There is increasing use of prothrombin complex concentrate, frequently rec-

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486 International Journal of Stroke 19(5)

Table 1. Overview of ongoing and completed randomized controlled trials of hematoma evacuation for patients with intracerebral
hemorrhage.

Primary
Surgical technique Control Sample size ICH volume Timing outcome Status

ENRICH Brain path Usual care 300 30–80 mL <24 h uw-mRS published
NCT02880878 6mo

NESICH Endoscopy guided Usual care 560 ⩾25 mL <24 h mRS recruiting
NCT05539859 Deep ICH 6mo

MIND Artemis Usual care 500 20-80 mL <72 h mRS 6mo recruiting
NCT03342664 Death

EVACUATE Surgiscope, mini- Usual care 240 ⩾20 mL <8 h mRS 0–3 recruiting
NCT04434807 craniotomy 6mo

DIST Endoscopy guided Usual care 600 ⩾10 mL <8 h mRS 6mo recruiting
NCT05460793

EMINENT-ICH Endoscopy guided Usual care 200 20-100 mL <24 h mRS 6mo recruiting
NCT05681988

ommended in guidelines,38 was not associated with After conditional approval by the US Food and Drug
any benefit in patients with direct oral anticoagulant- Administration (FDA), ANNEXa-I was initiated to com-
associated ICH,39 further amplifying the need for better pare andexanet alfa with usual care in patients with intrac-
treatment options. Andexanet alfa, a recombinant modi- ranial hemorrhage.29 The study enrolled patients with factor
fied factor Xa molecule that acts as a decoy and sequesters Xa-inhibitor associated ICH within 15 h of last intake and
factor Xa-inhibitors, was first tested in a single arm 6 h of the onset of symptoms. A total of 900 patients were
unblinded study (ANNEXa-4) without any control planned to be enrolled, but the trial was stopped after the
group.40 To overcome these limitations, Siepen et al.41 first prespecified interim analysis for efficacy was under-
performed an individual patient data analysis of taken in 450 patients in May 2023, and the results in a final
ANNEXa-4 and TICH-NOAC (NCT02866838) published sample of 530 participants were presented at the World
in this issue of the IJS.41 Outcomes for patients who Stroke Congress in October. In both data sets (450 and 530
received andexanet alfa (from ANNEXa-4) were com- patients, respectively), andexanet alfa was superior for
pared with patients who received usual care (i.e. no treat- hemostatic efficacy compared to usual care, with absolute
ment or prothrombin complex concentrate) in a small differences of 13% and 11%, respectively. However, andex-
randomized controlled trial conducted in Switzerland, anet alfa increased the incidence of serious thromboem-
where patients received add-on therapy with tranexamic bolic complications, with an absolute between-group
acid or placebo on top of usual care.41 Both trials were difference of 4.6%. However, the trial was not powered to
ideally suited to be combined as the baseline characteris- show a difference in mortality or functional outcome, and
tics (i.e. age, time since last intake, etc) of participants only assessed at 30 days.
were comparable, important confounders (i.e. anti-Xa These data indicate that andexanet alfa is superior for
activity, treatment metrics) were prospectively collected, hemostatic efficacy in patients with factor Xa-inhibitor–
and all the outcomes (i.e. hematoma expansion, func- associated ICH, with findings of the individual patient data
tional outcome, and thromboembolic events) were sys- analysis of Siepen et al.42 confirm the results of ANNEXa-I.
tematically captured and adjudicated by central blinded However, given the current cost of andexanet alfa and its
reviewers. Siepen et al. found that andexanet alfa was associated potential complications further data are required
independently associated with lower odds of hematoma to guide its application in routine practice.
expansion compared to usual care without any associa-
tion with thromboembolic complications or differences Fourth: future challenges—factor
in functional outcome or mortality. The results provide
support for andexanet alfa being superior to usual care
XI inhibitors
through the provision of hemostatic efficacy in patients Novel factor XI inhibitors are promising treatment options
with factor Xa-inhibitor–associated ICH, a finding for stroke prevention in patients with arteriosclerosis-
which requires confirmation in randomized controlled related ischemic stroke or atrial fibrillation as they inhibit
trials. thrombosis without compromising hemostasis.43 Cerebral

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Seiffge and Anderson 487

microbleeds are hemorrhagic imaging markers of bleeding- best medical treatment of spontaneous supratentorial intrac-
prone cerebral small vessel disease, a major cause underly- erebral hemorrhage (SWITCH) (NCT02258919) trial.50
ing ICH in elderly adults.44 It is hypothesized that cerebral The results were presented at the European Stroke
microbleeds may either directly convert into symptomatic Organisation Conference in Basel, Switzerland in 15–17
macrohemorrhage and/or predict ICH through the overall May 2024. Decompressive surgery is now a possible option
small vessel disease burden in patients on anticoagulants.45 in patients with space-occupying large deep ICH (Beck
In this issue of the journal, Balali et al.46 report reassuring et al 2024).51
data from secondary analysis of PACIFIC-STROKE
(NCT04304508),47 a randomized controlled phase-II trial
assessing the factor XI inhibitor asundexian. They found Summary and outlook
that patients receiving asundexian were not at increased There is now renewed vigor in the management of patients
risk of developing new cerebral microbleeds on follow-up with ICH in the community, driven by several abovemen-
magnetic resonance imaging (MRI), hemorrhagic transfor- tioned positive trials of hyperacute treatment: benefits of a
mation of baseline ischemic stroke, or intracranial bleeding care bundle approach driving by early intensive BP lower-
compared to patients receiving placebo. Taken together, ing, and the use of early endoscopic surgical hematoma
asundexian appears safe in patients with non-cardioembolic evacuation and reversal of factor Xa-inhibitor activity
ischemic stroke and hemorrhage-prone cerebral small ves- using andexanet alfa in appropriately selected patients. For
sel disease marked by cerebral microbleeds on MRI. the first time in history, there is now convincing evidence
that ICH is a treatable disease. We therefore need to aban-
don nihilism and inertia. While ongoing trials will add fur-
Fifth: hematoma evacuation: one positive ther evidence to this landscape, the time has come to shift
trial and unanswered questions in systems of care toward urgent, active management of
In theory, early evacuation of the blood clot from the brain patients with ICH. The year 2023 was the starting point;
should translate into significant benefits for patients with responsibility for the new era of ICH management is now
ICH, likely comparable to the benefits seen with mechani- upon us all.
cal thrombectomy for large vessel occlusion ischemic
stroke.48 Unfortunately, several pivotal trials of different Declaration of conflicting interests
interventional approaches9–11 have been neutral, although a The author(s) declared the following potential conflicts of interest
systematic review and meta-analysis identified a treatment with respect to the research, authorship, and/or publication of this
benefit.18 ENRICH included 300 patients to show a benefit article: D.J.S. received funding from the Swiss National Science
of early minimal invasive surgery compared to usual care in Foundation, the Swiss Heart Foundation, the Bangerter-Rhyner
ICH.27 After a preplanned interim efficacy analysis, enroll- foundation, and AstraZeneca. D.J.S. received fees (paid to his
institution) for speaker bureau and consultancy from AstraZeneca,
ment of patients with deep anterior hematomas was stopped
VamX, Bioxodes, Javelin, and Pfizer. C.S.A. reports receiving
so that the final study population comprised approximately research grants from the National Health and Medical Research
70% of patients with lobar ICH. Overall, minimal invasive Council of Australia, the Medical Research Council and Medical
hematoma evacuation was shown superior to usual care on Research Foundation of the UK, and Penumbra and Takeda, paid
the utility weighted modified Rankin scale score approach to his institution.
assessing functional outcome. This is a major step forward
to support surgery for ICH, but several questions remain Funding
over the optimal timing, technique, patient selection, and
The author(s) received no financial support for the research,
use of ancillary treatments. A number of ongoing trials will
authorship, and/or publication of this article.
assess different approaches for haematoma evacation
(Table 1). In this issue of IJS, Wang et al.49 report their pro-
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International Journal of Stroke, 19(5)