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830 Vol 10, August 2015, 830835 2015 World Stroke Organization
A. G. Hornslien et al. Research
Methods other), systolic blood pressure, and Scandinavian Stroke Scale
score at baseline. A pre-specified subgroup analysis was done for
Study design and participants
the primary end-point. As a sensitivity analysis, we used ordinal
SCAST was a North European, multicenter, randomized- and
logistic regression for the total number of recurrent strokes at
placebo-controlled trial of candesartan in 2,029 patients present-
three-years (categorized as no stroke, non-fatal stroke, and fatal
ing within 30 h of acute ischemic or hemorrhagic stroke and with
stroke), to see if treatment affected stroke severity (21). We used
systolic blood pressure 140 mmHg. The study design and par-
SPSS Statistics version 20 for all analyses.
ticipants have been described elsewhere (5,13). In brief, patients
were randomly allocated to treatment with candesartan or
placebo for seven-days, with doses increasing from 4 to 16 mg Results
once daily during the first three-days. After the seven-days treat-
ment period, treatment was left to the clinicians discretion, but Long-term data were available from 1,256 patients of all 1,286
candesartan was the advised antihypertensive treatment and was Scandinavian patients in the trial (98%) (Fig. 1). For the last 78
provided free of charge for six-months. The primary follow-up Swedish patients and 18 Danish patients included in the trial, we
period was six-months, and the two co-primary effect variables did not have follow-up data for the full period of three-years,
were the composite end-point of stroke, myocardial infarction, or because of delays in the updating of the Swedish National Patient
vascular death during follow-up, and functional outcome at six- Registry and the Danish Cause of Death Registry. The median
months. Written consent was sought from all patients, and the follow-up time for these 96 patients was 2 years and 45 months,
protocol was approved by the ethics committees in all countries. and they were evenly distributed between the candesartan group
and the placebo group (data not shown).
Long-term follow-up Table 1 shows the baseline characteristics of the included
We performed a prolonged follow-up for up to three-years of the patients. Demographic and clinical characteristics were well
1,286 patients from the Scandinavian countries (Norway, Sweden,
and Denmark), as pre-specified in the protocol. The patients
Table 1 Baseline characteristics
personal identification numbers were linked with the national
patient registries and cause of death registries (1419), and we Candesartan Placebo
extracted data for up till three-years after randomization, or until (n = 632) (n = 624)
death, whichever came first. The national patient registries Women 250 (40%) 275 (44%)
contain information about patients contact with all public and Age (years) 719 (112) 720 (112)
private hospitals, and for each hospitalization the registries Systolic blood pressure (mmHg) 1712 (199) 1721 (194)
include information about the date of admission and discharge, Diastolic blood pressure (mmHg) 895 (137) 892 (141)
Qualifying event
the primary diagnosis and a set of secondary diagnoses. In
Ischemic stroke 537 (85%) 531 (85%)
Norway, data linkage with the patient registry was only possible Hemorrhagic stroke 87 (14%) 85 (14%)
from 2008 onwards, so for Norwegian patients included before Other 7 (1%) 8 (1%)
2008 we used data from the Cardiovascular Disease in Norway Unknown 1 (<1%) 0
(CVDNOR) project (20). The cause of death registries include SSS score 414 (124) 411 (130)
OCSP syndrome
information about the date and cause of death. Data extraction
Total anterior 55 (9%) 57 (9%)
from all registries was performed blinded to information about Partial anterior 293 (46%) 288 (46%)
treatment allocation. Posterior 111 (18%) 91 (15%)
Lacunar 169 (27%) 182 (29%)
Effect variables Other 4 (<1%) 6 (1%)
The primary end-point was the composite end-point of stroke, Duration of symptoms (h) 181 (78) 184 (78)
myocardial infarction, or vascular death. Secondary end-points Premorbid mRS score 0 (0-0) 0 (0-0)
were recurrent stroke (non-fatal or fatal) and death of all causes. Medical history
Hypertension 362 (57%) 360 (58%)
We used the 10th version of the International Classification of
Diabetes mellitus 90 (14%) 92 (15%)
Diseases (ICD-10) to define end-points. A patient was said to have Current or previous atrial 111 (18%) 108 (17%)
had a stroke if he was hospitalized after the first 28 days of ran- fibrillation
domization with a diagnosis of I61, I63 (except I636), I64, or Previous stroke or TIA 166 (26%) 123 (20%)
G45. Myocardial infarction was defined as I21 or I22, occurring at Current use of an ACE 118 (19%) 109 (18%)
inhibitor
any time after randomization. The diagnosis of vascular death was
Thrombolytic treatment before 30 (5%) 29 (5%)
made if death occurred within 28 days of onset of stroke or randomization
myocardial infarction, or if the cause of death was G45 or R96, or
Data represent numbers (%), mean (SD), or median (IQR). Percentages
any diagnosis from chapter I.
are proportions of valid data entries, which might be lower than the
Statistical analysis number of patients in each group. SSS, Scandinavian Stroke Scale;
OCSP, Oxfordshire Community Stroke Project (both ischemic and hem-
We used the Cox proportional hazards regression model for
orrhagic strokes); mRS, modified Rankin Scale; TIA, transient ischemic
analysis of all end-points, after adjustment for the following pre- attack; ACE, angiotensin-converting enzyme.
defined prognostic variables; age, type of stroke (ischemic vs. all
2015 World Stroke Organization Vol 10, August 2015, 830835 831
Research A. G. Hornslien et al.
Composite vascular end-point 178 (28%) 203 (33%) 087 (071107)* 019*
Components of composite end-point
Stroke 107 (17%) 124 (20%)
Non-fatal 103 113
Fatal 4 10
Myocardial infarction 15 (2%) 20 (3%)
Non-fatal 11 19
Fatal 4 1
Vascular death of other causes 56 (9%) 60 (10%)
Data represent numbers (%). *Adjusted for age, cause of stroke, systolic blood pressure, and Scandinavian Stroke Scale score at baseline.
balanced between treatment groups, except that there were more ratio (HR) 087, 95% confidence interval (CI) 071107, p = 019;
patients with a history of previous stroke or TIA in the candesar- Table 2]. The figure shows that the two curves cross, which raises
tan group. As for all patients in the trial (5), blood pressure was concern over the proportional hazards assumption. We therefore
around 6/2 mmHg lower in patients allocated candesartan from performed a sensitivity analysis using logistic regression, and
day 2 onwards (p < 0001). Blood pressure was similar in the two found virtually identical results (adjusted odds ratio [OR] 081,
groups at one-, three- and six-months, and at six-months, mean 95% CI 063104, p = 011).
blood pressure was 143/80 mmHg and 142/79 mmHg in the can- Also presented in Fig. 2 is the cumulative risk of recurrent
desartan and placebo group, respectively (p = 025). stroke. There were 107/632 (169%) recurrent strokes in the can-
Figure 2 shows the cumulative risk of the composite end-point desartan group and 128/624 (205%) in the placebo group, which
of stroke, myocardial infarction or vascular death during three- was not significantly different (adjusted HR 083, 95% CI 064
years follow-up. There were 178/632 (282%) events in the can- 107, p = 015, Table 2). Additionally, we performed an ordinal
desartan group and 203/624 (325%) events in the placebo group, regression analysis to assess the effect of treatment on the severity
but the difference was not statistically significant [adjusted hazard of recurrent stroke (no stroke, non-fatal stroke, and fatal stroke),
832 Vol 10, August 2015, 830835 2015 World Stroke Organization
A. G. Hornslien et al. Research
a b
04 Candesartan 04
Placebo
Composite vascular endpoint
03 03
Recurrent stroke
02 02
01 01
00 00
Number at risk
Candesartan 632 510 461 402 632 513 467 411
Number of events
Candesartan 0 114 154 178 0 68 96 107
Fig. 2 Cumulative risk of stroke, myocardial infarction, or vascular death (a) and stroke (b) during three-years follow-up.
2015 World Stroke Organization Vol 10, August 2015, 830835 833
Research A. G. Hornslien et al.
P-value
Stroke pathology
Ischemic
0.93
Hemorrhagic
140 - 160
>200
<6
6 - 11
0.70
12 - 23
>24
History of hypertension
No
0.80
Yes
Thrombolytic treatment
No
0.71
Yes
Cardiac rhythm
Sinus rhythm
0.59
Atrial fibrillation
No
0.69
Yes
Fig. 4 Effects of treatment on the composite vascular end-point during three-years follow-up in different subgroups of patients. P-values are for the
interaction between subgroup and allocated treatment. ACE, angiotensin-converting enzyme; HR, hazard ratio.
(8) and in trials of angiotensin receptor blockers for secondary number of patients, the low risk of observation bias (due to
prevention (11,12). However, the difference was statistically non- masking of study treatment and blinded collection of long-term
significant, the ordinal analysis showed no effect of candesartan data), long follow-up, and near complete data. The complete
on the severity of recurrent stroke, and there was no effect on follow-up was possible due to the linkage with nation-wide,
all-cause death. We therefore believe that the difference in recur- automatically updated patient registries in the Scandinavian
rent stroke seen during long-term follow-up is most likely due to countries.
the play of chance. The analysis includes only two-thirds of the patients included
There was also no evidence of benefit in any of the pre- in the trial, but this was according to plan, since data linkage with
specified subgroups. The second Intensive blood pressure Reduc- national patient registries was only possible for the Scandinavian
tion in Acute Cerebral haemorrhage Trial (INTERACT2) has patients. The patients included were broadly similar to those from
indicated that benefits can be obtained with early treatment in other countries, and is a representative sample of stroke patients
patients with hemorrhagic stroke (3) and there are some sugges- admitted to hospitals in the western world. However, with only
tions from other trials that the same is true for ischemic stroke two-thirds of the original study population, the analysis was not
(2,5). We also observed small differences in favor of treatment in adequately powered to detect a treatment effect, and this limits
patients treated very early, but the difference was far from statis- our possibilities to draw firm conclusions. The use of national
tically significant, and must not be taken as evidence of effect. patient registries may also raise some questions. First, we have
The present analysis represents the first report from a only identified patients who were hospitalized with a diagnosis of
randomized-controlled trial of the long-term effects of blood stroke or myocardial infarction, and the true incidence of these
pressure lowering treatment in the acute phase of stroke. The end-points may have been underestimated, since some patients
main strengths of this analysis is the randomization of a large may not have been hospitalized. However, the randomization of a
834 Vol 10, August 2015, 830835 2015 World Stroke Organization
A. G. Hornslien et al. Research
large number of patients will probably have ensured similar dis- 6 Qureshi AI, Palesch YY. Antihypertensive Treatment of Acute Cerebral
tribution of different severities of recurrent stroke and myocardial Hemorrhage (ATACH) II: design, methods, and rationale. Neurocrit
Care 2011; 15:55976.
infarction in the two treatment groups, and so the estimate of the
7 Anderson C. Enhanced Control of Hypertension and Thrombolysis
treatment effect will not be biased. Second, the diagnostic accu- Stroke Study (ENCHANTED). 2014. Available at https://
racy of the ICD-10 diagnostic codes relies on the quality of coding clinicaltrials.gov/show/NCT01422616. (accessed 10 March 2015).
of a large number of physicians. But, again, any misclassification 8 Schrader J, Luders S, Kulschewski A et al. The ACCESS Study: evalu-
of end-points would have been at random, and this would have ation of Acute Candesartan Cilexetil Therapy in Stroke Survivors.
Stroke 2003; 34:1699703.
diluted, rather than changed the direction of any treatment effect.
9 Sandercock P, Wardlaw JM, Lindley RI et al. The benefits and harms of
Moreover, we performed an analysis of end-points up to six- intravenous thrombolysis with recombinant tissue plasminogen acti-
months using data from the national patient registries, and com- vator within 6 h of acute ischaemic stroke (the third international
pared this with the analysis of data from the six-months visit in stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;
the trial, and found virtually identical results (data not shown). 379:235263.
10 Sigurdsson ST, Strandgaard S. Blood pressure lowering in acute
In summary, blood pressure lowering treatment with candesar-
ischaemic stroke: an update on the role of angiotensin receptor block-
tan in the acute phase of stroke had no clear beneficial effect on ers. J Hypertens 2007; 25:7435.
the risk of vascular events or death during long-term follow-up. 11 Dahlof B, Devereux RB, Kjeldsen SE et al. Cardiovascular morbidity
This result compares to the result seen during short-term and mortality in the Losartan Intervention for endpoint reduction in
follow-up in previous trials, and supports the conclusions from hypertension study (LIFE): a randomised trial against atenolol. Lancet
2002; 359:9951003.
these trials that there is no indication for routine blood pressure
12 Lithell H, Hansson L, Skoog I et al. The Study on Cognition and
lowering treatment with candesartan in the acute phase of stroke. Prognosis in the Elderly (SCOPE): principal results of a randomized
This should not, however, deter clinicians from starting blood double-blind intervention trial. J Hypertens 2003; 21:87586.
pressure lowering treatment for secondary prevention before dis- 13 Sandset EC, Murray G, Boysen G et al. Angiotensin receptor blockade
charge from hospital. in acute stroke. The Scandinavian Candesartan Acute Stroke Trial:
rationale, methods and design of a multicentre, randomised- and
placebo-controlled clinical trial (NCT00120003). Int J Stroke 2010;
Acknowledgements 5:4237.
14 Guidelines for the distribution of data from the Norwegian
Patient Register. The Norwegian Directorate of Health, 2009. Avail-
We thank Tomislav Dimoski at the Norwegian Knowledge Centre
able at https://helsedirektoratet.no/Documents/English/guidelines
for Health Services, Oslo, Norway, for his contribution by devel- .pdf. (accessed 10 March 2015).
oping software necessary for obtaining data from Norwegian hos- 15 The National Patient Register Sweden. The National Board of Health
pitals, conducting the data collection and quality assurance of and Welfare, 2015. Available at http://www.socialstyrelsen.se/register/
data in the CVDNOR project. halsodataregister/patientregistret/inenglish. (accessed 10 March
2015).
16 Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Reg-
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2015 World Stroke Organization Vol 10, August 2015, 830835 835