The

n e w e ng l a n d j o u r na l

of

m e dic i n e

edi t or i a l s

Blood Pressure in Intracerebral Hemorrhage How Low

Should We Go?
Jennifer A. Frontera, M.D.
Intracerebral hemorrhage is one of the most devastating forms of stroke. The median 1-month case
fatality rate is 40%, and only 12 to 39% of patients achieve functional independence.1 Although
previous trials of therapies for patients with this
condition have not shown a benefit with respect
to outcome,2,3 targeted blood-pressure management after an intracerebral hemorrhage has been
both a promising and a contentious area of recent study. Early elevations of blood pressure are
common after an intracerebral hemorrhage, and
many have debated whether this response is
adaptive (to maintain perfusion to an ischemic
penumbra surrounding the hematoma) or potentially deleterious (resulting in rebleeding, perihematoma edema expansion, or both). Current
American Heart Association guidelines suggest
a target mean arterial pressure of less than
110 mm Hg or a blood pressure of less than
160/90 mm Hg, with some consideration given to
maintaining a reasonable cerebral perfusion pressure in patients with suspected elevations of intracranial pressure.4 These guidelines, however,
acknowledge that this blood-pressure target is
arbitrary and not evidence-based. A lower-level
recommendation was given for reducing blood
pressure to a systolic target of 140 mm Hg. This
recommendation was based, in part, on the
promising pilot results of the Intensive Blood
Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT), which showed a small,
but significant, attenuation in hematoma growth
over the course of 72 hours with aggressive
lowering of blood pressure (systolic pressure of
<140 mm Hg), without an increased risk of adverse events.5,6
Anderson et al. now report in the Journal the
eagerly anticipated results of the international
2426

phase 3 INTERACT2 trial.7 This trial provides

the best data, to date, on acute, targeted bloodpressure control after spontaneous intracerebral
hemorrhage. The primary end point (a score on
the modified Rankin scale of 3 to 6, with a score
of 0 indicating no symptoms, a score of 5 indicating severe disability, and a score of 6 indicating death) showed a trend toward significance
(P=0.06). When the end point was examined
from a different prespecified vantage point
an ordinal analysis of the modified Rankin
score (which has inherently better power to show
effect) a significant improvement in the outcome was seen with intensive therapy. Interestingly, if a score on the modified Rankin scale of
2 to 6 had been selected as the primary end
point, as is typical in many trials involving patients with an ischemic stroke, the results would
have been significant with a lower point estimate
(odds ratio, 0.83; 95% confidence interval, 0.70 to
0.98; P=0.03). In addition, significantly more
patients in the intensive-treatment group than
in the standard-therapy group had active treatment and care withdrawn (5.4% vs. 3.3%). It is
possible that this discrepancy contributed to
less significant differences in outcome between
the intensive-treatment group and the standardtherapy group.
The reasons behind the trend toward improved
outcomes remain a mystery, however. There
were no significant absolute or relative changes
in hematoma growth in the intensive-treatment
group as compared with the standard-treatment
group. Indeed, the volume differences between
the groups was minute (adjusted mean volume,
1.4 ml). It remains a possibility that elevated
blood pressure could have other systemic effects
that affect the outcome. In addition, in patients

n engl j med 368;25 nejm.org june 20, 2013

The New England Journal of Medicine

Downloaded from nejm.org on March 4, 2014. For personal use only. No other uses without permission.
Copyright 2013 Massachusetts Medical Society. All rights reserved.

editorials

with disturbed autoregulation, elevated blood

pressure could lead to increased cerebral blood
volume and consequently elevated intracranial
pressure.
If the results of this study with respect to the
primary outcome were not as robust as some
may have hoped, practitioners should be reassured
by the safety data presented in the trial. The authors found no significant differences between
patients receiving intensive blood-pressurelowering treatment and those receiving the standard
treatment with respect to neurologic deterioration, expansion of the intracerebral hemorrhage,
ischemic stroke, cardiovascular events, or severe
symptomatic hypotension findings that were
consistent with the results of previous positronemission tomographic neuroimaging studies,
which failed to show an ischemic penumbra
surrounding an intracerebral hematoma.8
Some limitations of this trial bear mentioning. First, more than two thirds of the participants were from China. Although the incidence
of intracerebral hemorrhage in Asian populations is more than twice the incidence in other
races, it is not clear that race or ethnicity has a
major effect on outcome.1 Because more patients were enrolled in Asia, the most commonly used blood-pressurelowering drug was an
intravenous alpha-adrenergic antagonist, urapidil, that is not available in the United States.
Though a drug effect seems unlikely, it remains
a possibility that could limit the generalizability
of the results. Second, 72% of the patients in
this study had hypertension, and 84% had primarily deep hemorrhages that were of small volume (median, 11 ml). This could also limit the
generalizability of the results. However, no significant differences in the primary outcome were
seen on the basis of the region of enrollment or
the volume or location of the hematoma. Third,
no data on intracranial pressure or cerebral perfusion pressure were shown for either bloodpressure group. Though 62% of the patients in
each group received mannitol, suggesting that
they had increased intracranial pressure or radiologic evidence of edema, values for intracranial
pressure were not reported. Patients with elevated
intracranial pressure may require a higher mean
arterial pressure to maintain target cerebral
perfusion pressure. In such a population, multimodality monitoring may guide individualized
blood-pressure goals.
The Antihypertensive Treatment of Acute Cere-

bral Hemorrhage (ATACH) II trial9 is the ongoing

North American complement to INTERACT2.
This study also randomly assigns patients to
a target systolic blood pressure of less than
140 mm Hg or less than 180 mm Hg but requires the use of nicardipine as the sole bloodpressurelowering agent. It is hoped that this
trial, which has similar primary and secondary
end points and results due in 2016, will corroborate the results of INTERACT2. Nonetheless, given that INTERACT2 showed a trend toward a
reduction in the primary outcome of death or
severe disability, significant improvement in secondary functional outcomes, and reassuring
safety data, acute blood-pressure reduction to a
target systolic blood pressure of 140 mm Hg or
less appears to be a reasonable option for patients with spontaneous intracerebral hemorrhage.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Cerebrovascular Center, Cleveland Clinic Foundation,
Cleveland.
This article was published on May 29, 2013, at NEJM.org.
1. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A,

Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and
ethnic origin: a systematic review and meta-analysis. Lancet
Neurol 2010;9:167-76.
2. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of
recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008;358:2127-37.
3. Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH):
a randomised trial. Lancet 2005;365:387-97.
4. Morgenstern LB, Hemphill JC III, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke
2010;41:2108-29.
5. Anderson CS, Huang Y, Arima H, et al. Effects of early intensive blood pressure-lowering treatment on the growth of hematoma and perihematomal edema in acute intracerebral hemorrhage: the Intensive Blood Pressure Reduction in Acute Cerebral
Haemorrhage Trial (INTERACT). Stroke 2010;41:307-12.
6. Anderson CS, Huang Y, Wang JG, et al. Intensive Blood
Pressure Reduction in Acute Cerebral Haemorrhage Trial
(INTERACT): a randomised pilot trial. Lancet Neurol 2008;7:391-9.
7. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure
lowering in patients with acute intracerebral hemorrhage. N Engl
J Med 2013;368:2355-65.
8. Zazulia AR, Diringer MN, Videen TO, et al. Hypoperfusion
without ischemia surrounding acute intracerebral hemorrhage.
J Cereb Blood Flow Metab 2001;21:804-10.
9. Qureshi AI, Palesch YY. Antihypertensive Treatment of Acute
Cerebral Hemorrhage (ATACH) II: design, methods, and rationale. Neurocrit Care 2011;15:559-76.
DOI: 10.1056/NEJMe1305047
Copyright 2013 Massachusetts Medical Society.

n engl j med 368;25 nejm.org june 20, 2013

The New England Journal of Medicine

Downloaded from nejm.org on March 4, 2014. For personal use only. No other uses without permission.
Copyright 2013 Massachusetts Medical Society. All rights reserved.

2427