T h e n e w e ng l a n d j o u r na l o f m e dic i n e
e d i t o r i a l
Blood Pressure in Intracerebral Hemorrhage  How Low
Should We Go?
Jennifer A. Frontera, M.D.
Intracerebral hemorrhage is one of the most devas- phase 3 INTERACT2 trial.7 This trial provides
tating forms of stroke. The median 1-month case the best data, to date, on acute, targeted blood-
fatality rate is 40%, and only 12 to 39% of pa- pressure control after spontaneous intracerebral
tients achieve functional independence.1 Although hemorrhage. The primary end point (a score on
previous trials of therapies for patients with this the modified Rankin scale of 3 to 6, with a score
condition have not shown a benefit with respect of 0 indicating no symptoms, a score of 5 indi-
to outcome,2,3 targeted blood-pressure manage- cating severe disability, and a score of 6 indicat-
ment after an intracerebral hemorrhage has been ing death) showed a trend toward significance
both a promising and a contentious area of re- (P = 0.06). When the end point was examined
cent study. Early elevations of blood pressure are from a different prespecified vantage point 
common after an intracerebral hemorrhage, and an ordinal analysis of the modified Rankin
many have debated whether this response is score (which has inherently better power to show
adaptive (to maintain perfusion to an ischemic effect)  a significant improvement in the out-
penumbra surrounding the hematoma) or poten- come was seen with intensive therapy. Interest-
tially deleterious (resulting in rebleeding, peri- ingly, if a score on the modified Rankin scale of
hematoma edema expansion, or both). Current 2 to 6 had been selected as the primary end
American Heart Association guidelines suggest point, as is typical in many trials involving pa-
a target mean arterial pressure of less than tients with an ischemic stroke, the results would
110 mm Hg or a blood pressure of less than have been significant with a lower point estimate
160/90 mm Hg, with some consideration given to (odds ratio, 0.83; 95% confidence interval, 0.70 to
maintaining a reasonable cerebral perfusion pres- 0.98; P = 0.03). In addition, significantly more
sure in patients with suspected elevations of in- patients in the intensive-treatment group than
tracranial pressure.4 These guidelines, however, in the standard-therapy group had active treat-
acknowledge that this blood-pressure target is ment and care withdrawn (5.4% vs. 3.3%). It is
arbitrary and not evidence-based. A lower-level possible that this discrepancy contributed to
recommendation was given for reducing blood less significant differences in outcome between
pressure to a systolic target of 140 mm Hg. This the intensive-treatment group and the standard-
recommendation was based, in part, on the therapy group.
promising pilot results of the Intensive Blood The reasons behind the trend toward improved
Pressure Reduction in Acute Cerebral Hemor- outcomes remain a mystery, however. There
rhage Trial (INTERACT), which showed a small, were no significant absolute or relative changes
but significant, attenuation in hematoma growth in hematoma growth in the intensive-treatment
over the course of 72 hours with aggressive group as compared with the standard-treatment
lowering of blood pressure (systolic pressure of group. Indeed, the volume differences between
<140 mm Hg), without an increased risk of ad- the groups was minute (adjusted mean volume,
verse events.5,6 1.4 ml). It remains a possibility that elevated
Anderson et al. now report in the Journal the blood pressure could have other systemic effects
eagerly anticipated results of the international that affect the outcome. In addition, in patients
n engl j med nejm.org
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The New England Journal of Medicine
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editorial
with disturbed autoregulation, elevated blood bral Hemorrhage (ATACH) II trial9 is the ongoing
pressure could lead to increased cerebral blood North American complement to INTERACT2.
volume and consequently elevated intracranial This study also randomly assigns patients to
pressure. a target systolic blood pressure of less than
If the results of this study with respect to the 140 mm Hg or less than 180 mm Hg but re-
primary outcome were not as robust as some quires the use of nicardipine as the sole blood-
may have hoped, practitioners should be reassured pressure lowering agent. It is hoped that this
by the safety data presented in the trial. The au- trial, which has similar primary and secondary
thors found no significant differences between end points and results due in 2016, will corrobo-
patients receiving intensive blood-pressure lower- rate the results of INTERACT2. Nonetheless, giv-
ing treatment and those receiving the standard en that INTERACT2 showed a trend toward a
treatment with respect to neurologic deteriora- reduction in the primary outcome of death or
tion, expansion of the intracerebral hemorrhage, severe disability, significant improvement in sec-
ischemic stroke, cardiovascular events, or severe ondary functional outcomes, and reassuring
symptomatic hypotension  findings that were safety data, acute blood-pressure reduction to a
consistent with the results of previous positron- target systolic blood pressure of 140 mm Hg or
emission tomographic neuroimaging studies, less appears to be a reasonable option for pa-
which failed to show an ischemic penumbra tients with spontaneous intracerebral hemorrhage.
surrounding an intracerebral hematoma.8 Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
Some limitations of this trial bear mention-
ing. First, more than two thirds of the partici-
From the Cerebrovascular Center, Cleveland Clinic Foundation,
pants were from China. Although the incidence
Cleveland.
of intracerebral hemorrhage in Asian popula-
This article was published on May 29, 2013, at NEJM.org.
tions is more than twice the incidence in other
races, it is not clear that race or ethnicity has a
1. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A,
major effect on outcome.1 Because more pa-
Klijn CJ. Incidence, case fatality, and functional outcome of in-
tients were enrolled in Asia, the most common- tracerebral haemorrhage over time, according to age, sex, and
ethnic origin: a systematic review and meta-analysis. Lancet
ly used blood-pressure lowering drug was an
Neurol 2010;9:167-76.
intravenous alpha-adrenergic antagonist, urapi-
2. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of
dil, that is not available in the United States. recombinant activated factor VII for acute intracerebral hemor-
rhage. N Engl J Med 2008;358:2127-37.
Though a drug effect seems unlikely, it remains
3. Mendelow AD, Gregson BA, Fernandes HM, et al. Early sur-
a possibility that could limit the generalizability
gery versus initial conservative treatment in patients with spon-
of the results. Second, 72% of the patients in taneous supratentorial intracerebral haematomas in the Inter-
national Surgical Trial in Intracerebral Haemorrhage (STICH):
this study had hypertension, and 84% had pri-
a randomised trial. Lancet 2005;365:387-97.
marily deep hemorrhages that were of small vol-
4. Morgenstern LB, Hemphill JC III, Anderson C, et al. Guide-
ume (median, 11 ml). This could also limit the lines for the management of spontaneous intracerebral hemor-
rhage: a guideline for healthcare professionals from the Amer-
generalizability of the results. However, no sig-
ican Heart Association/American Stroke Association. Stroke
nificant differences in the primary outcome were
2010;41:2108-29.
seen on the basis of the region of enrollment or 5. Anderson CS, Huang Y, Arima H, et al. Effects of early inten-
sive blood pressure-lowering treatment on the growth of hema-
the volume or location of the hematoma. Third,
toma and perihematomal edema in acute intracerebral hemor-
no data on intracranial pressure or cerebral per-
rhage: the Intensive Blood Pressure Reduction in Acute Cerebral
fusion pressure were shown for either blood- Haemorrhage Trial (INTERACT). Stroke 2010;41:307-12.
6. Anderson CS, Huang Y, Wang JG, et al. Intensive Blood
pressure group. Though 62% of the patients in
Pressure Reduction in Acute Cerebral Haemorrhage Trial
each group received mannitol, suggesting that
(INTERACT): a randomised pilot trial. Lancet Neurol 2008;7:391-9.
they had increased intracranial pressure or radio- 7. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure
lowering in patients with acute intracerebral hemorrhage. N Engl
logic evidence of edema, values for intracranial
J Med 2013. DOI: 10.1056/NEJMoa1214609.
pressure were not reported. Patients with elevated
8. Zazulia AR, Diringer MN, Videen TO, et al. Hypoperfusion
intracranial pressure may require a higher mean without ischemia surrounding acute intracerebral hemorrhage.
J Cereb Blood Flow Metab 2001;21:804-10.
arterial pressure to maintain target cerebral
9. Qureshi AI, Palesch YY. Antihypertensive Treatment of Acute
perfusion pressure. In such a population, multi-
Cerebral Hemorrhage (ATACH) II: design, methods, and ration-
modality monitoring may guide individualized ale. Neurocrit Care 2011;15:559-76.
blood-pressure goals.
DOI: 10.1056/NEJMe1305047
The Antihypertensive Treatment of Acute Cere- Copyright © 2013 Massachusetts Medical Society.
n engl j med nejm.org
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The New England Journal of Medicine
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Copyright © 2013 Massachusetts Medical Society. All rights reserved.