Comment
Blood pressure lowering in acute ischaemic stroke
thrombolysis
Whether raised blood pressure in patients with
acute ischaemic stroke should be lowered or not is
an unresolved issue in acute stroke management.
Data from observational studies show that high
blood pressure after stroke is associated with poor
outcome.1 Especially in the setting of intravenous
thrombolysis, high blood pressure increases the risk
of treatment-related intracerebral haemorrhage; thus,
patients with very high and treatment-resistant blood
pressure are often excluded from treatment, even
though current recommendations on blood pressure
management in stroke thrombolysis are not based
on evidence from randomised trials.2 Optimal blood
pressure management in the setting of reperfusion
therapies for acute ischaemic stroke is also unknown:
with intensive blood pressure management, there
are concerns that the harm associated with reduced
blood flow from collateral vessels to the ischaemic
penumbra could offset the potential benefit of
reduced risk of thrombolysis-related intracranial
haemorrhage.
In The Lancet, Craig Anderson and colleagues3
report the findings of the blood pressure control
arm of the ENCHANTED trial: an international,
randomised, open-label, blinded-endpoint trial of
2227 alteplase-eligible patients with acute ischaemic
stroke (38·0% female, 73·7% Asian ethnicity, mean
age 66·9 years [SD 12·2], with mild-to-moderate
stroke severity [National Institutes of Health Stroke
Scale score 7]). Patients were randomly allocated
within 6 h of stroke onset to receive intensive (target
systolic blood pressure 130–140 mm Hg within 1 h) or
guideline-recommended (target <180 mm Hg) blood
pressure lowering therapy over 72 h. The primary
efficacy endpoint was functional status at 90 days,
measured by a shift of modified Rankin Scale (mRS)
scores. The key safety endpoint was any intracranial
haemorrhage. Mean systolic blood pressure over
24 h was 144·3 mm Hg (SD 10·2) in the intensive
group and 149·8 mm Hg (12·0) in the guideline group
(p<0·0001), not reaching the planned 15 mm Hg
difference.3 No significant shift in mRS scores between
groups was observed (odds ratio [OR] 1·01, 95% CI
www.thelancet.com Published online February 7, 2019 http://dx.doi.org/10.1016/S0140-6736(19)30196-5 1
0·87–1·17); however, fewer intracranial haemorrhages
were recorded in the intensive group (160 [14·8%] of
1081 patients) than in the guideline group (209 [18·7%]
Burger/Phanie/Science Photo Library
of 1115; OR 0·75, 0·60–0·94, p=0·0137).3
ENCHANTED is the first, to our knowledge, large
randomised trial to investigate blood pressure
management in the setting of intravenous thrombolysis
for acute ischaemic stroke, and adds important evidence.
Notably, intensive blood pressure management reduced Published Online
February 7, 2019
the risk of intracranial haemorrhage but did not improve http://dx.doi.org/10.1016/
functional outcome.3 This finding might be related to S0140-6736(19)30196-5
the smaller than envisaged difference in blood pressure See Online/Articles
http://dx.doi.org/10.1016/
between the groups, or the inclusion of mainly patients S0140-6736(19)30038-8
with mild-to-moderate stroke, who are less likely to
develop symptomatic intracerebral haemorrhage.
However, this new evidence is somewhat disenchanting.
Like other large trials,4,5 ENCHANTED showed a neutral
effect of blood pressure lowering on functional outcome
in acute stroke.
This neutral effect, despite high blood pressure being
associated with poor outcomes in acute ischaemic
stroke,1 might be explained in several ways. First, the
pathophysiological mechanism of the transient rise
in blood pressure during and after an acute ischaemic
stroke is poorly understood. Population-based data
show that patients with spontaneous intracerebral
haemorrhage have substantially raised blood pressure
in the acute phase compared with premorbid levels,
whereas patients with acute ischaemic stroke have
blood pressure closer to premorbid levels.6 Thus, acute
and post-stroke hypertension is probably mainly related
to premorbid hypertension rather than to a stroke-
specific response.6 Second, because of the rightward
shift in autoregulatory curve seen in patients with long-
standing hypertension, rapid blood pressure lowering
might compromise cerebral perfusion. In ENCHANTED,3
the blood pressure target was reduced from
140–150 mm Hg to 130–140 mm Hg during the trial in
an effort to accentuate the blood pressure difference
between groups. However, this target might have
been too low, causing hypoperfusion in the intensive
treatment group and neutralising favourable outcomes
resulting from reduced intracranial haemorrhage.
 Comment
Third, the pragmatic design of ENCHANTED with
broad inclusion criteria could have contributed to the
neutral results. Patient selection for stroke treatment
is becoming increasingly important; several trials that
have used a one-size-fits-all concept have not shown
benefits of treatment.5,7 Advanced imaging in patient
selection has been key to the major improvements
seen in the treatment of acute stroke, exemplified by
the endovascular treatment trials, and trials of wake-up
stroke.8–11
Further trials on blood pressure lowering treatment
approaches in patients with acute stroke are
warranted. Such trials should select patients on the
basis of pathophysiological considerations (ie, vessel
imaging and perfusion studies), and test whether
blood pressure should be lowered after rather
than before recanalisation therapy in patients with
large vessel occlusion. As clinicians, we are treating
individuals: thus, more evidence for individualised
treatment approaches is needed. The use of advanced
imaging—the most relevant biomarker in acute stroke
management—should be implemented in future
randomised controlled trials of blood pressure lowering
in these patients to better understand the underlying
mechanisms of benefit or harm related to treatments
under investigation.
*Else Charlotte Sandset, Urs Fischer
Department of Neurology, Oslo University Hospital, 0424 Oslo,
Norway (ECS); Department of Research and Development,
The Norwegian Air Ambulance Foundation, Oslo, Norway (ECS);
and Department of Neurology, University Hospital Bern and
University of Bern, Bern, Switzerland (UF)
else@sandset.net
2 www.thelancet.com Published online February 7, 2019 http://dx.doi.org/10.1016/S0140-6736(19)30196-5
ECS was a visiting fellow at the George Institute for Global Health in Sydney, NSW,
Australia, under the mentorship of Article author Craig Anderson in 2016, and a
visiting fellow at the Stroke Trials Unit in Nottingham, UK, under the mentorship of
Article author Philip Bath in 2014. ECS was the trial manager of the Scandinavian
Candesartan Acute Stroke Trial; is on the international advisory board of the Rapid
Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial-2, and the Blood
pressure in Acute Stroke Collaboration steering committee (which will include
ENCHANTED data); and has received speaker’s fees from Bayer and Novartis
unrelated to this work. UF receives consulting fees from Medtronic, Stryker, and
CSL Behring, and receives research grants from the Swiss National Science
Foundation, the Swiss Heart Foundation, and Medtronic.
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2 Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 guidelines for the early
management of patients with acute ischemic stroke: a guideline for
healthcare professionals from the American Heart Association/American
Stroke Association. Stroke 2018; 49: e46–110.
3 Anderson C, Huang Y, Lindley RI, et al. Intensive blood pressure reduction
with intravenous thrombolysis therapy for acute ischaemic stroke
(ENCHANTED): an international, randomised, open-label,
blinded-endpoint, phase 3 trial. Lancet 2019; published online Feb 7.
http://dx.doi.org/10.1016/S0140-6736(19)30038-8.
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