n engl j med nejm.org

1

e d i t o r i a l

T h e

ne w e ngl a nd jou r na l

o f

m e dicine

Blood Pressure in Intracerebral Hemorrhage — How Low

Should We Go?

Jennifer A. Frontera, M.D.

Intracerebral hemorrhage is one of the most devas-

tating forms of stroke. The median 1-month case

fatality rate is 40%, and only 12 to 39% of pa-

tients 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 manage-

ment after an intracerebral hemorrhage has been

both a promising and a contentious area of re-

cent 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 poten-

tially deleterious (resulting in rebleeding, peri-

hematoma 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 pres-

sure in patients with suspected elevations of in-

tracranial 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 Hemor-

rhage 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 ad-

verse events.

5,6

Anderson et al. now report in the Journal the

eagerly anticipated results of the international

phase 3 INTERACT2 trial.

7

This trial provides

the best data, to date, on acute, targeted blood-

pressure 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 indi-

cating severe disability, and a score of 6 indicat-

ing 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 out-

come was seen with intensive therapy. Interest-

ingly, 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 pa-

tients 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 treat-

ment 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 standard-

therapy 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

The New England Journal of Medicine

Downloaded from nejm.org by Wlodzimierz Kmiotczyk on June 4, 2013. For personal use only. No other uses without permission.

Copyright © 2013 Massachusetts Medical Society. All rights reserved.

editorial

n engl j med nejm.org

2

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 au-

thors found no significant differences between

patients receiving intensive blood-pressure–lower-

ing treatment and those receiving the standard

treatment with respect to neurologic deteriora-

tion, expansion of the intracerebral hemorrhage,

ischemic stroke, cardiovascular events, or severe

symptomatic hypotension — findings that were

consistent with the results of previous positron-

emission tomographic neuroimaging studies,

which failed to show an ischemic penumbra

surrounding an intracerebral hematoma.

8

Some limitations of this trial bear mention-

ing. First, more than two thirds of the partici-

pants were from China. Although the incidence

of intracerebral hemorrhage in Asian popula-

tions 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 pa-

tients were enrolled in Asia, the most common-

ly used blood-pressure–lowering drug was an

intravenous alpha-adrenergic antagonist, urapi-

dil, 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 pri-

marily deep hemorrhages that were of small vol-

ume (median, 11 ml). This could also limit the

generalizability of the results. However, no sig-

nificant 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 per-

fusion pressure were shown for either blood-

pressure group. Though 62% of the patients in

each group received mannitol, suggesting that

they had increased intracranial pressure or radio-

logic 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, multi-

modality monitoring may guide individualized

blood-pressure goals.

The Antihypertensive Treatment of Acute Cere-

bral Hemorrhage (ATACH) II trial

9

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 re-

quires the use of nicardipine as the sole blood-

pressure–lowering agent. It is hoped that this

trial, which has similar primary and secondary

end points and results due in 2016, will corrobo-

rate the results of INTERACT2. Nonetheless, giv-

en that INTERACT2 showed a trend toward a

reduction in the primary outcome of death or

severe disability, significant improvement in sec-

ondary 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 pa-

tients 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 in-

tracerebral 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 hemor-

rhage. N Engl J Med 2008;358:2127-37.

3.

Mendelow AD, Gregson BA, Fernandes HM, et al. Early sur-

gery versus initial conservative treatment in patients with spon-

taneous supratentorial intracerebral haematomas in the Inter-

national Surgical Trial in Intracerebral Haemorrhage (STICH):

a randomised trial. Lancet 2005;365:387-97.

4.

Morgenstern LB, Hemphill JC III, Anderson C, et al. Guide-

lines for the management of spontaneous intracerebral hemor-

rhage: a guideline for healthcare professionals from the Amer-

ican Heart Association/American Stroke Association. Stroke

2010;41:2108-29.

5.

Anderson CS, Huang Y, Arima H, et al. Effects of early inten-

sive blood pressure-lowering treatment on the growth of hema-

toma and perihematomal edema in acute intracerebral hemor-

rhage: 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. DOI: 10.1056/NEJMoa1214609.

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 ration-

ale. Neurocrit Care 2011;15:559-76.

DOI: 10.1056/NEJMe1305047

Copyright © 2013 Massachusetts Medical Society.

The New England Journal of Medicine

Downloaded from nejm.org by Wlodzimierz Kmiotczyk on June 4, 2013. For personal use only. No other uses without permission.

Copyright © 2013 Massachusetts Medical Society. All rights reserved.