Acute Blood Pressure Management
in Intracerebral Hemorrhage
Equipoise Resists an Attack
Kenneth Butcher, MD, PhD, FRCP; Magdy Selim, MD, PhD
T here are 2 competing rationales for acute blood pressure
(BP) management in primary intracerebral hemorrhage
(ICH). A conservative approach is predicated on the possibility
that cerebral blood flow is passively dependent on perfusion
pressure, whereas an aggressive approach has been hypoth-
esized to improve outcomes via a reduction in early hema-
toma expansion. Although the latter is a biologically plausible
hypothesis, this relationship has not been consistently demon-
strated in retrospective or prospective studies, likely reflecting
the fact that hematoma expansion is dependent on multiple
factors, in particular the time from symptom onset to diag-
nostic scan, and baseline volume.1 The most effective way
to address this clinical equipoise is, therefore, a randomized
controlled trial of the 2 different BP management strategies.
In the ATACH-II trial (Antihypertensive Treatment of
Acute Cerebral Hemorrhage II), 1000 patients were random-
ized to a systolic BP (SBP) target of 110 to 139 mm Hg or
Downloaded from http://ahajournals.org by on September 12, 2018
140 to 179 mm Hg, after the Data Safety Monitoring Board–
recommended trial suspension on the basis of a futility
analysis.2 Despite a robust and early difference in achieved
BP between the 2 groups, the 90-day mortality and dis-
ability rate was unaffected (38.7% versus 37.7%; P=0.84).
The reasons for this lack of treatment effect are not clear.
There was no effect on the frequency of hematoma expan-
sion, although the trend was in favor of more aggressive
BP reduction (18.9% versus 24.4%; P=0.09). Conversely,
aggressive BP lowering did not result in more early neu-
rological deterioration or treatment-related serious adverse
events within 72 hours of treatment, as determined by the
investigators (1.6% versus 1.2%; P=0.59). There was, how-
ever, an increased frequency of renal adverse events within
72 hours (9.0% versus 4.0%; P=0.0002). Although the treat-
ment duration was only 24 hours, after which all patients
were treated in the same manner, this may potentially be
related to renal hypoperfusion.
How do the ATACH-II results inform practice? It does
seem that in the majority of patients, aggressive SBP reduc-
tion <140 mm Hg has no effect on 90-day functional outcome
Received September 6, 2016; final revision received September 24, 2016; accepted October 3, 2016.
From the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Canada (K.B.); and Stroke Division, Department of
Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (M.S.).
Correspondence to Magdy Selim, MD, PhD, Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Ave,
Palmer 127, Boston, MA 02460. E-mail mselim@bidmc.harvard.edu
(Stroke. 2016;47:3065-3066. DOI: 10.1161/STROKEAHA.116.015060.)
© 2016 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
3065
or mortality. This may be related in part to the fact that the
occurrence of hematoma expansion in even the conservatively
treated ATACH-II patients (24%) was lower than that seen in
the original observational studies describing hematoma expan-
sion (38%).3 This, in turn, likely reflects the fact that baseline
hematoma volumes were small in ATACH-II (median volume
≈10 mL). The ATACH-II trial results suggest that aggressive
BP reduction during the acute phase of ICH to SBP <140
mm Hg is not more effective than a reduction to SBP of 140 to
179 mm Hg and that kidney function tests should be followed
closely in patients where SBP is rapidly and aggressively low-
ered, given the observed increased frequency of renal-related
adverse events.
What are the potential harmful effects of BP reduction,
which was indeed effectively accomplished in ATACH-2?
Although it has previously been demonstrated that aggres-
sive BP reduction is not associated with a decrease in cerebral
blood flow,4 it is possible that the nicardipine-associated drop
exceeded the threshold at which perfusion is maintained in
most patients. There is also some evidence that small areas
of ischemic injury, visible only with diffusion-weighted mag-
netic resonance imaging, do develop in some ICH patients
subacutely.5 Although not conclusive, these data also sug-
gest that the diffusion-weighted magnetic resonance imag-
ing lesions may be associated with BP reduction. This raises
the possibility of a mixed benefit/harm effect in the overall
population, that is, attenuation of hematoma growth in some
patients and ischemic injury in others. The absence of diffu-
sion-weighted magnetic resonance imaging and blood flow
imaging in ATACH-II, however, makes it impossible to con-
firm or reject this hypothesis.
The argument for a mixed benefit/harm effect would be more
compelling if the observed reduction in hematoma expansion was
significant or even if the point estimates of the treatment effect
size was greater. What is apparent is that hematoma expansion
can occur despite aggressive BP reduction. This disappointing
effect on hematoma expansion was seen in both ATACH-II and
the INTERACT-II trials (the Second Intensive Blood Pressure
DOI: 10.1161/STROKEAHA.116.015060
 3066  Stroke  December 2016
Reduction in Acute Cerebral Haemorrhage Trial).6 In the latter
trial, this may have been related to the fact that BP targets were
not achieved within 1 hour in 66% of the patients randomized to
the aggressive treatment target arm. This does not seem to be the
case in ATACH-II, however, where this was accomplished in 88%
of patients in the aggressive treatment arm. One possibility is that
even the effective BP reduction seen in ATACH-II was too late
to have an effect on hematoma expansion. The initial ATACH-II
design had an inclusion window of 3 hours from symptom onset,
and this was later expanded to 4.5 hours.7 The rationale for the
narrower window than that used in INTERACT-II was that the
probability of hematoma expansion decreases with time after
symptom onset. It may, therefore, be that if a significant treat-
ment effect is to be seen, BP reduction will need to begin even
earlier, potentially in the prehospital setting.
There are now 2 large randomized controlled trials of
aggressive versus conservative BP management, both of
which had negative primary end points. Nonetheless, acute
BP lowering in ICH patients remains a biologically plausible
and rational approach to the one stroke type without a proven
medical therapy, and many clinician scientists with an inter-
est in the field, ourselves included, continue to advocate for
this approach. Current American Heart Association/American
Stroke Association guidelines indicate that a target SBP of
140 mm Hg can be effective for improving functional outcome
(Class IIa; Level of Evidence B).8 We, therefore, suggest that
some equipoise persists. Additional trials where patients are
randomized to aggressive versus conservative BP targets after
ICH, possibly in the prehospital setting and ideally including
Downloaded from http://ahajournals.org by on September 12, 2018
diffusion-weighted magnetic resonance imaging for detection
of subclinical brain injury, are warranted in our opinion. Such
trials may ultimately confirm the hypothesis that earlier BP
treatment improves outcome while also determining whether
some patients are in fact harmed by this approach. Some of
these trials are either ongoing (NCT02281838) or are in plan-
ning. We anxiously await their results.
Sources of Funding
M. Selim is supported in part by grants from the NIH (U01 NS
074425) and the American Heart Association (15CSA24540001). K.
Butcher has received grant-in-aid funding from the Heart and Stroke
Foundation of Canada to complete a blood pressure–lowering trial in
intracerbral hemorrhage patients. He also has grant funding from the
Canadian Institutes for Health Research and holds a Canada Research
Chair.
Disclosures
Dr Butcher has received speaker’s fees and served on advisory boards
for Boehringer Ingelehim, Bayer, and BMS/Pfizer. The other author
reports no conflicts.
References
1. Broderick JP, Diringer MN, Hill MD, Brun NC, Mayer SA, Steiner
T, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage
Trial Investigators. Determinants of intracerebral hemorrhage growth:
an exploratory analysis. Stroke. 2007;38:1072–1075. doi: 10.1161/01.
STR.0000258078.35316.30.
2. Qureshi AI, Palesch YY, Barsan WG, Hanley DF, Hsu CY, Martin RL,
et al; ATACH-2 Trial Investigators and the Neurological Emergency
Treatment Trials Network. Intensive blood-pressure lowering in patients
with acute cerebral hemorrhage. N Engl J Med. 2016;375:1033–1043.
doi: 10.1056/NEJMoa1603460.
3. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, et
al. Early hemorrhage growth in patients with intracerebral hemorrhage.
Stroke. 1997;28:1–5.
4. Butcher KS, Jeerakathil T, Hill M, Demchuk AM, Dowlatshahi D, Coutts
SB, et al; ICH ADAPT Investigators. The intracerebral hemorrhage
acutely decreasing arterial pressure trial. Stroke. 2013;44:620–626. doi:
10.1161/STROKEAHA.111.000188.
5. Menon RS, Burgess RE, Wing JJ, Gibbons MC, Shara NM, Fernandez
S, et al. Predictors of highly prevalent brain ischemia in intracerebral
hemorrhage. Ann Neurol. 2012;71:199–205. doi: 10.1002/ana.22668.
6. Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, et al;
INTERACT2 Investigators. Rapid blood-pressure lowering in patients
with acute intracerebral hemorrhage. N Engl J Med. 2013;368:2355–
2365. doi: 10.1056/NEJMoa1214609.
7. Qureshi A, Palesch Y; ATACH II Investigators. Expansion of recruitment
time window in antihypertensive treatment of acute cerebral hemorrhage
(ATACH) II trial. J Vasc Interv Neurol. 2012;5(supp):6–9.
8. Hemphill JC 3rd, Greenberg SM, Anderson CS, Becker K, Bendok BR,
Cushman M, et al; American Heart Association Stroke Council; Council
on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology.
Guidelines for the management of spontaneous intracerebral hemor-
rhage: a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke. 2015;46:2032–2060.
doi: 10.1161/STR.0000000000000069.
Key Words: antihypertensive agents ◼ blood pressure ◼ cerebral hemorrhage
◼ hematoma ◼ retrospective studies