Brief Report
Impact of Early Blood Pressure Variability on Stroke
Outcomes After Thrombolysis
The SAMURAI rt-PA Registry
Kaoru Endo, MD; Kazuomi Kario, MD; Masatoshi Koga, MD; Jyoji Nakagawara, MD;
Yoshiaki Shiokawa, MD; Hiroshi Yamagami, MD; Eisuke Furui, MD; Kazumi Kimura, MD;
Yasuhiro Hasegawa, MD; Yasushi Okada, MD; Satoshi Okuda, MD; Michito Namekawa, MD;
Tetsuya Miyagi, MD; Masato Osaki, MD; Kazuo Minematsu, MD; Kazunori Toyoda, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
Background and Purpose—The present study determines associations between early blood pressure (BP) variability and
stroke outcomes after intravenous thrombolysis.
Methods—In 527 stroke patients receiving intravenous alteplase (0.6 mg/kg), BP was measured 8 times within the first 25
hours. BP variability was determined as ΔBP (maximum-minimum), standard deviation (SD), coefficient of variation,
and successive variation.
Results—The systolic BP course was lower among patients with modified Rankin Scale (mRS) 0 to 1 than those without
(P<0.001). Most of systolic BP variability profiles were significantly associated with outcomes. Adjusted odds ratios
(95% confidence interval) per 10 mm Hg (or 10% for coefficient of variation) on symptomatic intracerebral hemorrhage
were as follows: ΔBP, 1.33 (1.08–1.66); SD, 2.52 (1.26–5.12); coefficient of variation, 3.15 (1.12–8.84); and successive
variation, 1.82 (1.04–3.10). The respective values were 0.88 (0.77–0.99), 0.73 (0.48–1.09), 0.77 (0.43–1.34), and 0.76
(0.56–1.03) for 3-month mRS 0 to 1; and 1.40 (1.14–1.75), 2.85 (1.47–5.65), 4.67 (1.78–12.6), and 1.99 (1.20–3.25) for
death. Initial BP values before thrombolysis were not associated with any outcomes.
Conclusions—Early systolic BP variability was positively associated with symptomatic intracerebral hemorrhage and death
after intravenous thrombolysis. (Stroke. 2013;44:XXX-XXX.)
Key Words: acute stroke
■
blood pressure variability
B
■
hypertension
■
tissue plasminogen activator
Patients and Methods
lood pressure (BP) is often elevated in patients with acute
ischemic stroke, but value of lowering BP for such patients
is controversial, particularly for those receiving intravenous
(IV) recombinant tissue plasminogen activator (rt-PA). Several
observational studies have identified a linear or U-shaped association between high systolic BP (SBP) on admission or within
the first 24 hours with symptomatic intracerebral hemorrhage
(sICH), mortality, and poor functional outcomes.1–3 BP variability is an important trigger of vascular events,4 and visit-to-visit
SBP variability is a powerful predictor of stroke, independently
of mean SBP.5 Similarly, hour-to-hour BP variability during
acute stroke also seems to predict stroke outcomes.6 The present substudy of the Stroke Acute Management with Urgent
Risk-factor Assessment and Improvement (SAMURAI) rt-PA
Registry investigates associations between early BP variability
during this period and outcomes of thrombolysis.
The SAMURAI rt-PA registry was created using a multicenter hospital-based retrospective observational design.7 Six-hundred consecutive patients with acute ischemic stroke who received IV rt-PA
(0.6 mg/kg, recommended dosage by the Japanese guidelines)8 were
registered.
Supine BP was measured just before starting IV rt-PA (initial) and at
0, 4, 8, 12, 16, 20, and 24 hours after completing the administration. Use
of antihypertensives, such as IV nicardipine, was permitted if needed
according to the guidelines.8,9 The maximum (max), minimum (min),
and average (mean) of these 8 BP values were calculated. We also
calculated the following variability profiles: the difference between
( n−1)
max and min (ΔBP), SD ( SD : (1 /(n − 1)∑
( BPi − BPmean)2 ),
( i=1)
­coefficient of variation (CV [%] : SD / BPmean × 100), and successive
variation as the square root of the average difference in BP between
each of the 8 successive measurements was calculated using the
following equation:
n−1
(1 /(n − 1)∑ i=1 ( BPi+1 − BPi )2
10
Received October 23, 2012; final revision received November 19, 2012; accepted November 26, 2012.
From the National Cerebral and Cardiovascular Center, Suita, Japan (K.E., M.K., T.M., M.O., K.M., K.T.); Jichi Medical University School of Medicine,
Shimotsuke, Japan (K.K., M.N.); Nakamura Memorial Hospital, Sapporo, Japan (J.N.); Kyorin University School of Medicine, Mitaka, Japan (Y.S.); Kobe
City Medical Center General Hospital, Kobe City,Japan (H.Y.); Kohnan Hospital, Sendai, Japan (E.F.); Kawasaki Medical School, Kurashiki, Japan (K.K.);
St Marianna University School of Medicine, Kawasaki, Japan (Y.H.); NHO Kyushu Medical Center, Fukuoka, Japan (Y.O.); and NHO Nagoya Medical
Center, Nagoya, Japan (S.O.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
112.681007/-/DC1.
Correspondence to Kazunori Toyoda, MD, Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai,
Suita, Osaka 565-8565, Japan. E-mail [email protected]
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.112.681007
1
2 Stroke March 2013
Outcomes included sICH (computed tomography evidence of new
type I or type II parenchymal hemorrhage11 with ≥1-point increase from
the baseline National Institutes of Health Stroke Scale score) within the
first 36 hours and modified Rankin Scale (mRS) score of 0 to 1 and
death at 3 months. Associations between each BP profile and outcomes
were determined using binominal logistic regression models adjusted
by the known baseline characteristics (see detailed patient information
and Statistical Methods in the online-only Data Supplement).12
Results
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
Among registered patients, 65 with premorbid mRS score
2 to 5, 7 with incomplete BP values, and 1 who died within
24 hours were excluded. Thus, data from 527 patients (182
women, 70.8±11.6 years old; Online Table I shows baseline characteristics) were eligible for analysis. Twenty-three
patients (4.4%) had development sICH, 197 (37.4%) had mRS
0 to 1, and 29 (5.5%) died.
The SBP course tended to be higher among patients with
sICH than those without (P=0.083), and it was significantly
lower among patients with mRS 0 to 1 than those without
(P<0.001; Figure). BP variability profiles were larger in
patients receiving antihypertensives just before thrombolysis
than the others (online Table II).
Larger variations in all SBP variability profiles were associated with sICH and death (Table). Smaller ΔBP was significantly associated with (P=0.043) and smaller successive
variation was marginally significantly associated (P=0.081)
with mRS 0 to 1. Although larger variations in all diastolic BP
variability profiles were associated with sICH and death, no
diastolic BP profiles were associated with mRS 0 to 1 (online
Figure I and online Table III).
Discussion
The first major finding of this study was a positive association between all SBP and diastolic BP variability profiles and
sICH and death. The second major finding was that SBP levels
were lower throughout the first 25 hours after starting rt-PA
in patients who had mRS score 0 to 1 than in those who did
not. Furthermore, systolic ΔBP was inversely associated with
mRS score 0 to 1. Finally, initial BP levels, as well as most of
BP values at each time point, did not predict any outcomes.
In a substudy of the Second European-Australasian Acute
Stroke Study (ECASS-II),12 max, mean, and successive variation of 24-hour SBPs predicted hemorrhagic transformation
and 3-month outcomes after thrombolysis. In that study,
80% of the patients received thrombolytic therapy within
3 to 6 hours after onset.11 In our single-center study of IV
rt-PA, max, mean, and min of SBPs were inversely associated with 3-month mRS score 0 to 2.3 A recent single-center
study showed that successive variation of SBP higher than the
median value is associated with 3-month mRS score 0 to 2,
but not with mortality or sICH.13 Different contributions of
BP variability to outcomes among investigations including the
present study might be attributable to difference in indicators,
measures of variability, or timing of BP measurements.
Contrary to the ECASS-II substudy,12 initial BP values did
not predict any outcomes in the present study. One explanation
might be that we documented BP values immediately before
starting thrombolysis and, accordingly, some very high BP
values would have been modified by antihypertensive drugs.
In addition, mental stress, bladder tonus, and other transient
stimuli also modulate BP values and, therefore, measuring
during the first few hours might not accurately reflect stroke
conditions. These findings suggest that BP values determined
during the first 24 hours of admission confer an advantage as
a predictor of prognosis.
The present study stresses the impact of variability in BP
as a predictor of stroke outcomes. These findings indicate
that the therapeutic effects of modulating acute BP variability
Table. Associations Between Systolic Blood Pressure Profiles and Outcomes
sICH
Initial
1.08
mRS 0–1
0.86–1.35
0.96
Death
0.86–1.06
1.03
0.83–1.27
0h
1.28
0.99–1.66
0.87
0.78–0.97
0.98
0.79–1.23
4h
1.24
0.99–1.57
0.89
0.80–0.99
1.05
0.86–1.30
8h
1.02
0.82–1.27
0.92
0.83–1.02
1.05
0.85–1.29
12 h
1.16
0.93–1.46
0.91
0.82–1.005
0.90
0.74–1.11
16 h
1.14
0.92–1.41
1.02
0.92–1.13
0.93
0.76–1.14
20 h
1.05
0.84–1.32
0.90
0.81–1.001
0.93
0.76–1.14
24 h
0.98
0.80–1.21
0.93
0.84–1.03
0.93
0.77–1.12
Max
1.36
1.07–1.73
0.82
0.73–0.93
1.19
0.93–1.50
Min
0.91
0.69–1.18
0.92
0.81–1.04
0.74
0.57–0.94
Mean
1.24
0.89–1.75
0.86
0.74–0.99
0.94
0.70–1.27
ΔBP
1.33
1.08–1.66
0.88
0.77–0.99
1.40
1.14–1.75
SD
2.52
1.26–5.12
0.73
0.48–1.09
2.85
1.47–5.65
CV
3.15
1.12–8.84
0.77
0.43–1.34
4.67
1.78–12.6
SV
1.82
1.04–3.10
0.76
0.56–1.03
1.99
1.20–3.25
BP indicates blood pressure; CV, coefficient of variation; Max, maximum; Min, minimum; mRS, modified Rankin Scale; SBP, systolic BP; sICH, symptomatic
intracerebral hemorrhage; SD, standard deviation; and SV, successive variation.
Odds ratio per 10 mm Hg with 95% confidence interval for each SBP profile adjusted for sex, age, baseline National Institutes of Health Stroke Scale score, onset-totreatment interval, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, intravenous antihypertensives just before recombinant tissue plasminogen activator,
and ASPECTS on first computed tomography scan. Bold indicates, P<0.05.
Endo et al Early BP Variability After IV rt-PA 3
(mmHg)
180
U+%*
U+%*
O45
O45
180
180
160
160
160
140
140
140
120
120
120
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
100
P = 0.083
P < 0.001
100
ini 0 4 8 12 16 20 24
ini 0 4 8 12 16 20 24
100
&KGF
5WTXKXGF
P = 0.762
ini 0 4 8 12 16 20 24
(h)
Figure. Comparisons of time course of systolic blood pressure according to symptomatic intracerebral hemorrhage (sICH), modified
Rankin Scale (mRS) value, and mortality at 3 months. ini indicates initial.
should be investigated. An ongoing trial of early intensive
BP-lowering in patients with thrombolysis, the Enhanced
Control of Hypertension and Thrombolysis Stroke Study
(ENCHANTED) (NCT01422616), would bring an answer for
this problem.
Sources of Funding
This study was supported in part by grants-in-aid from the Ministry of
Health, Labor, and Welfare of Japan.
Disclosures
M. Koga receives research support from the Japan Cardiovascular
Research Foundation. K. Minematsu receives honoraria from
Mitsubishi-Tanabe Pharma and Kyowa Hakko Kirin Pharma.
K. Toyoda receives research support from Mitsubishi-Tanabe Pharma.
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Impact of Early Blood Pressure Variability on Stroke Outcomes After Thrombolysis: The
SAMURAI rt-PA Registry
Kaoru Endo, Kazuomi Kario, Masatoshi Koga, Jyoji Nakagawara, Yoshiaki Shiokawa, Hiroshi
Yamagami, Eisuke Furui, Kazumi Kimura, Yasuhiro Hasegawa, Yasushi Okada, Satoshi Okuda,
Michito Namekawa, Tetsuya Miyagi, Masato Osaki, Kazuo Minematsu and Kazunori Toyoda
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
Stroke. published online January 17, 2013;
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/early/2013/01/17/STROKEAHA.112.681007
Data Supplement (unedited) at:
http://stroke.ahajournals.org/content/suppl/2013/02/19/STROKEAHA.112.681007.DC1
http://stroke.ahajournals.org/content/suppl/2013/10/02/STROKEAHA.112.681007.DC2
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ONLINE SUPPLEMENT
Impact of Early Blood Pressure Variability on Stroke Outcomes after
Thrombolysis: the SAMURAI rt-PA Registry
Supplemental explanation for the SAMURAI rt-PA Registry
The Stroke Acute Management with Urgent Risk-factor Assessment and
Improvement (SAMURAI) rt-PA Registry was created using a multicenter
hospital-based retrospective observational design. Six hundred consecutive patients with
acute ischemic stroke who received intravenous rt-PA were registered between October
2005 (when intravenous alteplase therapy was approved in Japan) through July 2008 at
10 stroke centers in Japan. Patient eligibility and alteplase dosage were determined
based on the Japanese guidelines for intravenous rt-PA therapy. Each patient received a
single alteplase dose of 0.6 mg/kg intravenously with 10% given as a bolus within three
hours of stroke onset followed by a continuous intravenous infusion of the remainder
over a period of 1 hour. The ethics committee at each participating institution approved
the study protocol.
Baseline data collected from all patients comprised sex, age, comorbidities
(hypertension, diabetes, and dyslipidemia), time from onset to treatment, neurological
deficits assessed as National Institutes of Health Stroke Scale (NIHSS) scores, and
stroke subtype according to the Trial of ORG 10172 in Acute Stroke Treatment
(TOAST) categories. All patients underwent brain CT scans according to a standard
protocol before rt-PA administration and early ischemic change was assessed using the
Alberta Stroke Program Early CT Score (ASPECTS).
According to the guidelines, antihypertensive agents were administrated to
reduce BP levels to <185/110 mmHg just before rt-PA administration and to maintain
the levels at <180/105 mmHg during the first 24 hours thereafter.
Supplemental Methods for Statistical analysis
Data were statistically analyzed using JMP Pro 9.0.2 statistical software (SAS Institute
Inc.). The time courses of BP between patients with and without each outcome were
compared using a two-way repeated measures analysis of variance. Associations
between each BP profile and stroke outcomes were determined using binominal logistic
regression models adjusted by the known baseline characteristics. Results were
presented as odds ratios (OR: per 10% for CV and per 10 mmHg for others) with 95%
confidential intervals (CI) for each BP profile. A probability value < 0.05 was
considered significant.
Supplemental Tables and Figures
Table S1. Baseline Characteristics
n=527
Female
182 (34.5%)
Age, y
70.8±11.6
Hypertension
319 (60.5%)
Diabetes Mellitus
95 (18.0%)
Dyslipidemia
112 (21.3%)
Atrial Fibrillation
215 (40.8%)
Baseline NIHSS score
12 (7-18)
Alberta Stroke Program Early CT Score
9 (8-10)
Onset-to-treatment time, min
141 (121-165)
Intravenous antihypertensives just before rt-PA
151 (28.7%)
Stroke subtype
Cardioembolism
326 (61.9%)
Atherothrombotic stroke
84 (15.9%)
Lacune
27 (5.1%)
Other
90 (17.1%)
Data are no. of patients (%), mean±SD for continuous variables, and median (IQR) for
discontinuous variables.
Table S2. Blood pressure variability in patients with and without intravenous
antihypertensives just before thrombolysis
SBP
Antihypertensives (+)
Antihypertensives (-)
p value
ΔBP (mmHg)
48.3 ± 18.4
39.9 ± 16.1
<0.001
SD (mmHg)
15.2 ± 5.65
12.7 ± 4.91
<0.001
CV (%)
10.1 ± 3.88
9.10 ± 3.55
0.003
SV (mmHg)
20.0 ± 7.62
16.1 ± 6.63
<0.001
ΔBP (mmHg)
33.2 ± 15.4
29.8 ± 12.7
0.008
SD (mmHg)
10.4 ± 4.51
9.48 ± 3.80
0.014
CV (%)
13.3 ± 5.72
12.8 ± 5.39
0.353
SV (mmHg)
14.1 ± 6.69
12.2 ± 5.51
0.001
DBP
Student’s t test was used.
Table S3. Associations between DBP Profiles and Outcomes
sICH
mRS0-1
Death
Initial
0.99
0.73-1.33
1.00
0.88-1.14
0.87
0.66-1.14
0h
1.32
0.99-1.74
0.98
0.86-1.12
1.03
0.78-1.34
4h
1.27
0.92-1.74
0.97
0.84-1.11
1.09
0.81-1.46
8h
0.92
0.67-1.25
0.91
0.79-1.04
0.99
0.74-1.33
12h
0.86
0.62-1.17
0.99
0.86-1.14
0.83
0.61-1.12
16h
1.06
0.78-1.41
0.99
0.86-1.14
0.90
0.66-1.20
20h
0.90
0.65-1.23
1.01
0.87-1.17
1.02
0.77-1.35
24h
0.89
0.64-1.22
0.99
0.86-1.15
0.74
0.54-1.35
Max
1.41
1.05-1.88
0.91
0.78-1.05
1.23
0.92-1.62
Min
0.68
0.45-1.01
1.00
0.84-1.19
0.67
0.46-0.97
Mean
1.04
0.67-1.61
0.96
0.79-1.17
0.87
0.57-1.30
ΔBP
1.54
1.21-1.98
0.91
0.78-1.06
1.44
1.13-1.84
SD
5.66
2.33-14.3
0.71
0.42-1.17
3.46
1.43-8.14
CV
3.71
1.91-7.25
0.80
0.55-1.15
2.71
1.40-5.13
SV
2.40
1.32-4.26
0.86
0.61-1.22
2.37
1.35-4.11
OR (/10% for CV; /10 mmHg for others) with 95%CI for each DBP profile adjusted for
sex, age, baseline NIHSS score, onset-to-treatment interval, hypertension, diabetes
mellitus, dyslipidemia, atrial fibrillation, intravenous antihypertensives just before rt-PA,
and ASPECTS on first CT scan. Bold type, p <0.05.
mRS 0-1
mRS 2-6
sICH(+)
sICH(-)
(mmHg)
Died
Survived
120
120
120
100
100
100
80
80
80
60
60
60
P = 0.539
P = 0.807
40
40
40
ini 0
4
8 12 16 20 24
P = 0.167
ini 0
4
8 12 16 20 24
ini 0
4
8 12 16 20 24
(h)
Figure S1.
Comparisons of time course of DBP according to sICH, mRS value
and mortality at three months.
Abstract
29
Abstract
血栓溶解後早期の血圧変動が脳卒中転帰に及ぼす影響
SAMURAI rt-PA Registry
Impact of Early Blood Pressure Variability on Stroke Outcomes After Thrombolysis
The SAMURAI rt-PA Registry
Kaoru Endo, MD1; Kazuomi Kario, MD2; Masatoshi Koga, MD1; Jyoji Nakagawara, MD3; Yoshiaki Shiokawa,
MD4; Hiroshi Yamagami, MD5; Eisuke Furui, MD6; Kazumi Kimura, MD7; Yasuhiro Hasegawa, MD8; Yasushi
Okada, MD9; Satoshi Okuda, MD10; Michito Namekawa, MD2; Tetsuya Miyagi, MD1; Masato Osaki, MD1;
Kazuo Minematsu, MD1; Kazunori Toyoda, MD1
1
National Cerebral and Cardiovascular Center, Suita, Japan; 2 Jichi Medical University School of Medicine, Shimotsuke, Japan; 3 Nakamura
Memorial Hospital, Sapporo, Japan; 4 Kyorin University School of Medicine, Mitaka, Japan; 5 Kobe City Medical Center General Hospital,
Kobe City, Japan 6 Kohnan Hospital, Sendai, Japan; 7 Kawasaki Medical School, Kurashiki, Japan; 8 St Marianna University School of Medicine,
Kawasaki, Japan; 9 NHO Kyushu Medical Center, Fukuoka, Japan; and 10 NHO Nagoya Medical Center, Nagoya, Japan
背景および目的：本研究では，静脈内血栓溶解療法後早期
，
オッズ比（ 95％信頼区間）は，Δ BP：1.33（ 1.08 〜 1.66 ）
の血圧（ BP ）変動と脳卒中転帰の関連を確認する。
SD：2.52（ 1.26 〜 5.12 ）
，変動係数：3.15（ 1.12 〜 8.84 ）
，
方法：アルテプラーゼ（ 0.6 mg/kg ）の静脈内投与を受けて
および逐次変動：1.82（ 1.04 〜 3.10 ）
であった。一方，3 カ
いる脳卒中患者 527 例の BP を発症から 25 時間以内に 8
月間修正 Rankin スコア（ mRS ）
が 0 〜 1 の場合は，それぞ
回測定した。BP 変動は，Δ BP（ 最高値－最低値 ）
れ 0.88（ 0.77 〜 0.99 ）
，0.73（ 0.48 〜 1.09 ）
，0.77（ 0.43 〜
，標準偏
1.34 ）
，および 0.76（ 0.56 〜 1.03 ）
で，死亡の場合は，1.40
差（ SD ），変動係数，および逐次変動で確認した。
，2.85（ 1.47 〜 5.65 ）
，4.67（ 1.78 〜 12.6 ）
，
結果：収縮期 BP の推移は，修正 Rankin スコア（ mRS ） （ 1.14 〜 1.75 ）
および 1.99（ 1.20 〜 3.25 ）
であった。血栓溶解療法前の最
が 0 〜 1 の患者の方が 2 〜 6 の患者よりも小さかった
初の BP はどの転帰とも無関係であった。
（p ＜ 0.001 ）
。収縮期 BP 変動プロファイルのほとんどが
結論：静脈内血栓溶解療法後早期の収縮期 BP の変動は，
転帰と有意に関連していた。症候性脳内出血（ sICH ）に対
症候性脳内出血および死亡と正の相関を示した。
する 10 mmHg（あるいは変動係数の 10％）あたりの調整
Stroke 2013; 44: 816-818
（mmHg）
180
sICH
（＋）
sICH
（−）
180
mRS 0 ∼ 1
mRS 2 ∼ 6
180
160
160
160
140
140
140
120
120
120
100
= 0.083
100
初回 0 4 8 12 16 20 24
< 0.001
初回 0 4 8 12 16 20 24
100
死亡
生存
= 0.762
初回 0 4 8 12 16 20 24
（時間）
図
症候性脳内出血（sICH），修正 Rankin スコア（ mRS ），および 3 カ月時点の死亡率別に見た収縮期血圧の経時的変化の比較。