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Blood Pressure-Lowering Treatment With Candesartan in Patients With Acute Hemorrhagic Stroke
Blood Pressure-Lowering Treatment With Candesartan in Patients With Acute Hemorrhagic Stroke
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
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
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Jusufovic et al Candesartan in Acute Hemorrhagic Stroke 3441
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 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
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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-
tion; A) and functional outcomes at 6 months (B).
further. Alternatively, it might imply that angiotensin recep- of spontaneous intracerebral hemorrhage: a guideline for healthcare
professionals from the American Heart Association/American Stroke
tor blockers have unwanted properties in the acute phase of
Association. Stroke. 2010;41:2108–2129.
stroke. Other trials are ongoing and will show whether agents 2. Qureshi AI, Ezzeddine MA, Nasar A, Suri MF, Kirmani JF, Hussein HM,
with other properties can produce beneficial effects when et al. Prevalence of elevated blood pressure in 563,704 adult patients
given after the first few hours of hemorrhagic stroke.11,12 with stroke presenting to the ED in the United States. Am J Emerg Med.
2007;25:32–38.
This analysis represents a subgroup of patients included in 3. Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C,
SCAST, and it is therefore at risk of false-negative conclusions, et al; INTERACT2 Investigators. Rapid blood-pressure lower-
because of the play of chance alone. Nevertheless, the analysis ing in patients with acute intracerebral hemorrhage. N Engl J Med.
2013;368:2355–2365.
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