Blood Pressure–Lowering Treatment With Candesartan in

Patients With Acute Hemorrhagic Stroke

Mirza Jusufovic, MD; Else C. Sandset, MD, PhD; Philip M.W. Bath, FRCP, FESO;
Eivind Berge, MD, PhD;
on behalf of the Scandinavian Candesartan Acute Stroke Trial Study Group

Background and Purpose—Early and intensive blood pressure–lowering treatment seems to be beneficial in patients with
acute hemorrhagic stroke and high blood pressure. We wanted to see if similar benefits can be shown from a later and
more gradual blood pressure lowering, using data from the Scandinavian Candesartan Acute Stroke Trial (SCAST).
Methods—SCAST was a randomized- and placebo-controlled, double-masked trial of candesartan given for 7 days, in
2029 patients with acute stroke and systolic blood pressure ≥140 mm Hg. We assessed the effects of candesartan in the
274 patients with hemorrhagic stroke, using the trial’s 2 coprimary effect variables: the composite vascular end point of
vascular death, stroke or myocardial infarction, and functional outcome at 6 months, according to the modified Rankin
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Scale. We used Cox proportional hazards models and ordinal regression for analysis and adjusted for key, predefined
prognostic variables.
Results—There was no association between treatment with candesartan and risk of vascular events (17 of 144 [11.8%] versus
13 of 130 [10.0%]; hazard ratio, 1.36; 95% confidence interval, 0.65–2.83; P=0.41). For functional outcome we found
evidence of a negative effect of candesartan (common odds ratio, 1.61; 95% confidence interval, 1.03–2.50; P=0.036).
Conclusions—There was no evidence that blood pressure–lowering treatment with candesartan is beneficial during the first
week of hemorrhagic stroke. Instead, there were signs that such treatment may be harmful, but this needs to be verified
in larger studies.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120003.   (Stroke. 2014;45:3440-3442.)
Key Words: angiotensin receptor antagonists ◼ blood pressure ◼ intracranial hemorrhages ◼ monitoring, ambulatory

H emorrhagic stroke is associated with a poor prognosis, and

most trials of therapeutic interventions have shown disap-
pointing results.1 One promising target for intervention is high
blood pressure, which is common in the acute phase of hemor-
rhagic stroke.2 High blood pressure is an independent predic-
tor of poor prognosis, and recently the Intensive Blood Pressure
Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2)
gave hope that early and intensive blood pressure–lowering
treatment improves long-term functional outcome.3
The Scandinavian Candesartan Acute Stroke Trial (SCAST)
tested the effects of a later and more gradual blood pressure
lowering in patients with acute ischemic or hemorrhagic
stroke.4 The main analysis of all patients showed no evidence
of a beneficial effect of candesartan, but rather a trend toward
poorer functional outcome in the candesartan group.4 In this
prespecified analysis, we wanted to see if a different effect
was present in patients with hemorrhagic stroke.
Materials and Methods
SCAST was a randomized- and placebo-controlled trial of the an-
giotensin receptor blocker candesartan in 2029 patients presenting
<30 hours of acute ischemic or hemorrhagic stroke and systolic blood
pressure ≥140 mm Hg. The methods and main results have been
published previously.4,5 In brief, candesartan or placebo tablets were
started at ≈18 hours after stroke onset and given for 7 days, with doses
increasing from 4 to 16 mg once daily during the first 3 days, and
patients were followed for 6 months.
For the present analysis, we selected all patients with intracerebral
hemorrhage. All patients in the trial were examined with computed
tomography or MRI before inclusion, and the diagnosis of hemor-
rhagic stroke was based on the evaluation of the investigators at the
site, who were blinded to treatment assignment.
The trial had 2 coprimary effect variables: the composite vascular
end point of vascular death, stroke or myocardial infarction, and func-
tional outcome at 6 months’ follow-up, as measured by the modified
Rankin Scale.
The statistical analyses were performed according to the inten-
tion-to-treat principle and the trial’s statistical analysis plan.5 The

Received June 12, 2014; accepted August 25, 2014.

From the Departments of Neurology (M.J., E.C.S.) and Internal Medicine (E.B.), Oslo University Hospital, Oslo, Norway; and Stroke Trials Unit,
Division of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom (P.M.W.B.).
Guest Editor for this article was Stephen M. Davis, MD, FRACP.
Presented in part at the European Stroke Conference, Nice, France, May 6–9, 2014.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
114.006433/-/DC1.
Correspondence to Eivind Berge, MD, PhD, Oslo University Hospital, Department of Internal Medicine, Kirkeveien 166, NO-0407 Oslo, Norway.
E-mail eivind.berge@medisin.uio.no
© 2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.006433

3440
 Jusufovic et al   Candesartan in Acute Hemorrhagic Stroke    3441

composite vascular end point was analyzed by time to first event,

using Cox proportional hazard models, and functional outcome was
analyzed by ordinal regression, after checking that the parallel lines
assumption was met. All analyses were adjusted for predefined prog-
nostic variables: age, Scandinavian Stroke Scale score, and systolic
blood pressure. In the subgroup analyses, heterogeneity of the treat-
ment effect was assessed by adding an interaction term in the unad-
justed model. The effects on the secondary end points were shown
with unadjusted risk ratios. All analyses were performed with the
SPSS software (version 18.0; SPSS Statistics, Chicago, IL).

Results
In total, 274 patients with hemorrhagic stroke were included in
the trial. Baseline characteristics were well balanced between
the 2 treatment groups, except that there were more patients
with atrial fibrillation and diabetes mellitus in the candesartan
group (Table), and follow-up data were 99% complete. Figure 1. Effects of treatment on mean systolic (SBP) and dia-
Mean systolic blood pressure started at 174 mm Hg in both stolic blood pressure (DBP) during the treatment period.
groups and fell in both groups during the treatment period, but
was lower in patients treated with candesartan already from
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poorer functional outcome (adjusted common odds ratio,

day 2, and the mean systolic difference from day 4 onward 1.61; 95% confidence interval, 1.03–2.50; P=0.036). A for-
was ≈5 mm Hg (Figure 1). mal goodness-to-fit test gave no evidence that the proportional
The cumulative risk of the composite end point of vascular odds assumption was violated (P=0.32).
death, stroke, or myocardial infarction is shown in Figure 2. There were no statistically significant differences in the
The composite vascular end point occurred in 17 of 144 risks of the secondary end points (Table in the online-only
patients (11.8%) treated with candesartan and in 13 of 130 Data Supplement), and there was no indication of a ben-
controls (10.0%; adjusted hazard ratio, 1.36; 95% confidence eficial effect of candesartan in any of the subgroups, includ-
interval, 0.65–2.83; P=0.41; panel A). ing patients treated early after stroke onset (<6 hours) or in
Figure 2 also shows the distribution of modified Rankin patients with very high systolic blood pressure at baseline
Scale scores in the 2 groups at 6 months (panel B). Treatment (Figure in the online-only Data Supplement).
with candesartan was associated with an increased risk of a
Discussion
Table.  Baseline Characteristics for Patients With
INTERACT2 indicated that early and intensive blood pres-
Hemorrhagic Stroke sure–lowering treatment is beneficial in patients with intra-
cerebral hemorrhage,3 but no beneficial effects could be seen
Candesartan (n=144) Placebo (n=130) in our trial. Instead, we found that treatment with candesartan
Age, y 67.2 (12.3) 68.0 (11.9) was associated with a worsening in functional outcome, as in
Sex (female) 49 (34) 39 (30) the main analysis of all patients in the trial.4 These diverging
Premorbid mRS 0 0 findings can possibly be explained by the fundamental differ-
Medical history
ences between the 2 trials. In INTERACT2, treatment was
started at ≈3.7 hours and a systolic blood pressure difference
 Hypertension 95 (68) 73 (61)
of 10 mm Hg was achieved <30 minutes.3 In SCAST, treat-
 Previous stroke or TIA 26 (18) 16 (13) ment was started at ≈18 hours, and the maximal difference in
 Atrial fibrillation 20 (14) 7 (6) systolic blood pressure of 5 mm Hg was achieved on day 4.4
 Diabetes mellitus 21 (15) 8 (6) Clearly, the 2 interventions affect very different pathophysi-
 Baseline SBP, mm  Hg 173.6 (18.3) 175.4 (20.7) ological mechanisms. Although INTERACT2 was designed
 Baseline DBP, mm  Hg 95.9 (14.1) 94.8 (14.6) to reduce hematoma growth,6 SCAST aimed to protect against
 SSS score 37 (24–46) 37.5 (27–46) the effects of high blood pressure and activation of the renin–
angiotensin system during the aftermath of the hemorrhage.
 Duration of symptoms, h 15.8 (8.3) 15.9 (8.2)
SCAST was based on the findings from observational stud-
OCSP syndrome
ies that high blood pressure is detrimental in the acute phase
 Total anterior 16 (11) 13 (10) of stroke,2,7 possibly because of the negative effects of high
 Partial anterior 70 (49) 55 (43) blood pressure on microcirculation, edema, and hematoma
 Posterior 27 (19) 21 (16) growth.6,8,9 The study was also based on findings from experi-
 Lacunar 31 (22) 40 (31) mental studies and 1 clinical study indicating that candesar-
 Current use of an ACE inhibitor 39 (27) 22 (18) tan has beneficial effects in the acute phase of stroke.10 The
Data are n (%), mean±SD, or median (interquartile range). ACE indicates
absence of any sign of beneficial effects in SCAST might
angiotensin-converting enzyme; DBP, diastolic blood pressure; mRS, modified imply that treatment was started too late to limit brain injury,
Rankin Scale; OCSP, Oxfordshire Community Stroke Project; SBP, systolic blood and that blood pressure reduction after the first few hours can
pressure; SSS, Scandinavian Stroke Scale; and TIA, transient ischemic attack. only reduce cerebral perfusion and increase brain injury even
 3442  Stroke  November 2014
Figure 2. Cumulative risk of the composite vascular end point during 6 months’ follow-up (vascular death, stroke, or myocardial infarc-
Downloaded from http://stroke.ahajournals.org/ by guest on August 16, 2017
tion; A) and functional outcomes at 6 months (B).
further. Alternatively, it might imply that angiotensin recep-
tor blockers have unwanted properties in the acute phase of
stroke. Other trials are ongoing and will show whether agents
with other properties can produce beneficial effects when
given after the first few hours of hemorrhagic stroke.11,12
This analysis represents a subgroup of patients included in
SCAST, and it is therefore at risk of false-negative conclusions,
because of the play of chance alone. Nevertheless, the analysis
was prespecified and represents a group of patients random-
ized to blood pressure–lowering treatment, with blinded out-
come assessments and complete follow-up. Furthermore, the
results are consistent with the result from the main analysis
of all effect variables and in all the prespecified subgroups.4
In summary, we found no beneficial effect of later and more
gradual blood pressure–lowering treatment with candesartan
given after the first few hours of hemorrhagic stroke. Instead,
we found signs of a negative effect on functional outcome.
This might imply that treatment was started too late or that
angiotensin receptor blockers have unwanted properties in
the acute phase of stroke. Further studies are needed to help
clarify the effects of blood pressure–lowering drugs after the
first few hours of hemorrhagic stroke.
Sources of Funding
The trial was funded by grants from the South Eastern Norway
Regional Health Authority and Oslo University Hospital. AstraZeneca
supplied the study drugs, and AstraZeneca and Takeda supported the
trial with limited, unrestricted grants.
Disclosures
P.M.W. Bath received travel support from AstraZeneca to attend
meetings in the trial steering committee. Dr Berge received payment
for lectures given at meetings arranged by AstraZeneca. The other
authors report no conflicts.
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 Blood Pressure−Lowering Treatment With Candesartan in Patients With Acute
Hemorrhagic Stroke
Mirza Jusufovic, Else C. Sandset, Philip M.W. Bath and Eivind Berge
on behalf of the Scandinavian Candesartan Acute Stroke Trial Study Group
Downloaded from http://stroke.ahajournals.org/ by guest on August 16, 2017

Stroke. 2014;45:3440-3442; originally published online September 25, 2014;

doi: 10.1161/STROKEAHA.114.006433
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2014 American Heart Association, Inc. All rights reserved.
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Online supplement

Title: Blood pressure lowering treatment with candesartan in patients with

acute hemorrhagic stroke

Supplemental Table I. Adverse events during 6 months’ follow-up

Candesartan Placebo Risk ratio P-value

(n=144) (n=130) (95% CI)
Death from any cause 18 (13) 11 (8) 1.48 (0.73-3.01) 0.28
Vascular death 15 (10) 8 (6) 1.69 (0.74-3.86) 0.21
Ischemic stroke 2 (1) 6 (5) 0.30 (0.06-1.46) 0.14
Hemorrhagic stroke 3 (2) 3 (2) 0.90 (0.19-4.39) 1.00
Recurrent stroke 5 (3) 9 (7) 0.50 (0.17-1.46) 0.21
Myocardial infraction 2 (1) 1 (1) 1.81 (0.17-19.7) 1.00
Stroke progression 5 (3) 7 (5) 0.64 (0.21-1.98) 0.44
Symptomatic hypotension 0 (0) 0 (0) NA NA
Renal failure 1 (1) 3 (2) 0.30 (0.03-2.86) 0.35
Venous thromboembolism 0 (0) 1 (1) NA NA
Data are n (%). NA denotes not applicable.

Supplemental Figure I. Effect of treatment in the pre-specified subgroups: Composite

vascular end-point and functional outcome