journal of stroke - association of elevated blood pressure ...with elevated acute blood pressure...
TRANSCRIPT
Copyright © 2019 Korean Stroke SocietyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
pISSN: 2287-6391 • eISSN: 2287-6405
Original Article
Journal of Stroke 2019;21(1):78-90https://doi.org/10.5853/jos.2018.02369
78 http://j-stroke.org
Background and Purpose Although arbitrary blood pressure (BP) thresholds exist for acute ischemic stroke (AIS) patients eligible for intravenous thrombolysis (IVT), current international recommendations lack clarity on the impact of mean pre- and post-IVT BP levels on clinical outcomes. Methods Eligible studies involving IVT-treated AIS patients were identified that reported the association of mean systolic BP (SBP) or diastolic BP levels before and after IVT with the following outcomes: 3-month favorable functional outcome (modified Rankin Scale [mRS] scores of 0–1) and 3-month functional independence (mRS scores of 0–2), 3-month mortality and symptomatic intracranial hemorrhage (sICH). Unadjusted analyses of standardized mean differences and adjusted analyses of studies reporting odds ratios (ORadj) per 10 mm Hg BP increment were performed using random-effects models. Results We identified 26 studies comprising 56,513 patients. Higher pre- (P=0.02) and post-treatment (P=0.006) SBP levels were observed in patients with sICH. Patients with 3-month functional independence had lower post-treatment (P<0.001) SBP whereas trended towards lower pre-treatment (P=0.06) SBP. In adjusted analyses, elevated pre- (ORadj, 1.08; 95% confidence interval [CI], 1.01 to 1.16) and post-treatment (ORadj, 1.13; 95% CI, 1.01 to 1.25) SBP levels were associated with increased likelihood of sICH. Increasing pre- (ORadj, 0.91; 95% CI, 0.84 to 0.98) and post-treatment (ORadj, 0.70; 95% CI, 0.57 to 0.87) SBP values were also related to lower odds of 3-month functional independence. Conclusions We found that elevated BP levels adversely impact AIS outcomes in patients receiving
Association of Elevated Blood Pressure Levels with Outcomes in Acute Ischemic Stroke Patients Treated with Intravenous Thrombolysis: A Systematic Review and Meta-AnalysisKonark Malhotra,a Niaz Ahmed,b Angeliki Filippatou,c Aristeidis H. Katsanos,c,d Nitin Goyal,e Konstantinos Tsioufis,f Efstathios Manios,g Maria Pikilidou,h Peter D. Schellinger,i Anne W. Alexandrov,e Andrei V. Alexandrov,e Georgios Tsivgoulisc,e
aDepartment of Neurology, West Virginia University-Charleston Division, Charleston, WV, USAbDepartment of Neurology, Karolinska University Hospital, Stockholm, SwedencSecond Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GreecedDepartment of Neurology, University of Ioannina School of Medicine, Ioannina, GreeceeDepartment of Neurology, University of Tennessee Health Science Center, Memphis, TN, USAfFirst Cardiology Clinic, Hippokration Hospital, Medical School, National and Kapodistrian University of Athens, Athens, GreecegDepartment of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, GreecehFirst Department of Internal Medicine, Hypertension Excellence Center, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, GreeceiDepartment of Neurology and Neurogeriatry, Johannes Wesling Medical Center, Ruhr University Bochum, Minden, Germany
Correspondence: Georgios TsivgoulisSecond Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, Iras 39, Gerakas Attikis, Athens 15344, Greece Tel: +30-6937178635Fax: +30-2105832471 E-mail: [email protected]
Received: August 25, 2018Revised: November 23, 2018Accepted: November 23, 2018
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 79
Introduction
Intravenous thrombolysis (IVT) is the only approved systemic re-perfusion therapy for acute ischemic stroke (AIS) patients,1 and confers a number needed to treat of eight to improve functional outcome in one additional AIS.2 The beneficial effect of tissue plasminogen activator (tPA) may be hampered in AIS patients with elevated acute blood pressure (BP) levels.3 Current American Heart Association/American Stroke Association (AHA/ASA) guide-lines recommend strict, though arbitrary, thresholds of systolic BP (SBP) >185 mm Hg and diastolic BP (DBP) >110 mm Hg before tPA-bolus, as well as during and within 24 hours after alteplase infusion (SBP >180 mm Hg and DBP >105 mm Hg).4 Observa-tional data indicate that BP protocol violations increase the risk of symptomatic intracranial hemorrhage (sICH),5,6 while elevated acute BP levels may reduce the odds of tPA-induced recanaliza-tion7 and the likelihood of functional independence.8 On the other hand, it may be argued that IVT may be delayed or even denied in AIS patients with extremely elevated BP levels due to these strin-gent BP thresholds.3 In addition, aggressive BP reduction during the first hours of acute cerebral ischemia may reduce viable pen-umbral tissue and result in expansion of the infarction and fur-ther neurological deterioration.9,10 Finally, in the absence of ran-domized data, clear consensus is lacking for the optimal BP con-trol before, during and after tPA infusion in AIS patients treated with IVT. In view of the former considerations, we conducted a systematic review and meta-analysis that sought to evaluate the impact of elevated acute BP levels before and after systemic thrombolysis on different clinical outcomes in AIS patients.
Methods
Authors declare that all supporting data are available within the article and its online supplementary files. We adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses.11 The present manuscript also adheres to the AHA Journals’ implementation of the Transparency and Openness Promotion (TOP) guidelines.12 The study design (systematic re-view and meta-analysis) was exempt for approval from the In-stitutional Review Board of our institution (Universities of Ten-nessee & West Virginia-Charleston Division).
Data sources and searchesEligible studies that reported association of mean BP levels and clinical outcomes in AIS patients treated with IVT were identi-fied by systematically searching in Ovid MEDLINE, Ovid Em-base, and Scopus databases. The combination of search strings used to query all the databases included: “blood pressure,” “systolic,” “diastolic,” “stroke,” and “cerebral ischemia”. The complete search algorithm used in MEDLINE is available in the online supplement. We restricted our search to articles in Eng-lish language, and our search spanned from database inception to February 24, 2018. Additional manual search of conference abstracts and bibliographies of articles meeting study criteria for a comprehensive literature search was conducted.
Study selection and data extractionWe identified studies that investigated the association of acute BP levels with clinical outcomes in AIS patients treated with IVT. We documented mean SBP and DBP levels reported as mean±SD during pre- and post-IVT intervals. For studies that did not report mean BP levels before tPA bolus, admission BP levels were used for descriptive analyses. During the post-thrombolysis interval, we recorded mean BP levels documented within 2 to 4 hours following tPA infusion. If this data was un-available, mean BP levels within 24 to 72 hours of IVT adminis-tration were used. Additional data on BP variability (BPV) in-cluding successive variation (SV) was collected if available from the included studies. In case of missing data, the authors of relevant studies were contacted and previously unpublished data was occasionally provided according to their discretion. We excluded studies that reported (1) outcomes not reported as per our inclusion criteria such as parenchymal hematoma or asymptomatic intracranial hemorrhage, (2) treatment with in-tra-arterial thrombolysis, mechanical thrombectomy, or sys-temic thrombolysis using agents other than alteplase, (3) de-scriptive data for BP levels reported as median values, (4) stud-ies reporting mean arterial pressure levels instead of SBP or DBP levels, and (5) case reports.
We evaluated the following clinical outcomes: 3-month fa-vorable functional outcome (defined as modified Rankin Scale [mRS] scores 0–1), 3-month functional independence (defined as mRS-scores of 0–2), 3-month mortality, sICH according to the definitions of included studies (Supplementary Table 1) and
IVT. Future randomized-controlled clinical trials will provide definitive data on the aforementioned association.Keywords Blood pressure; Stroke; Thrombolytic therapy; Intracranial hemorrhages; Outcome assessment
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236980 http://j-stroke.org
tPA-induced recanalization (in AIS patients with proximal in-tracranial occlusions) according to the definitions of included studies. Two authors (K.M. and A.F.) independently reviewed all the retrieved articles. In case of disagreements regarding the literature search results, the senior author (G.T.) was consulted to formulate a mutual consensus. The following information was extracted: name of study, first author and year of publica-tion, mean age, sex distribution, total number of study partici-pants, and clinical outcomes.
Risk of bias assessmentWe used the Newcastle-Ottawa Scale to explore sources of bias amongst the included observational studies as previously described.13 This scale uses multiple-choice questions to ad-dress the areas of selection, comparability, and exposure/out-come assessment. High quality ratings are identified with a star and studies can earn a maximum of nine star-points. A maximum of one star can be awarded for each item within the selection and exposure/outcome categories and maximum of two stars for the comparability category. The quality control and bias identification were performed independently by two reviewers (K.M. and A.F.), and disagreements if any, were re-solved by a third tie-breaking evaluator (G.T.).
Data synthesis and statistical analysisIn both unadjusted and adjusted for potential confounders analyses both pre-treatment and post-treatment SBP/DBP val-ues were handled as continuous variables, while the outcomes of interest were handled as dichotomous variables. Differences in mean pre-treatment and post-treatment BP values accord-ing to the outcomes of interest were reported in the form of standardized mean differences (SMDs) in all unadjusted analy-ses. We also conducted adjusted (for potential confounders) analyses evaluating the association of pre- and post-IVT BP levels with different clinical outcomes. The adjusted odds ratios (ORsadj) of these associations are all presented per 10 mm Hg increments in SBP or DBP levels.
SMD estimates were calculated as the mean differences divided by the corresponding pooled standard deviations, to expresses the size of the intervention effect in each study relative to the variability observed in that study.14 In all anal-yses SMDs and ORs of individual studies were pooled using the random-effects model (DerSimonian Laird).15 We used in-verse variance method to calculate SMD for continuous vari-ables. SMD were interpreted using a general rule of thumb reported by Cohen,16 in which an SMD of 0.2 represents a small effect, an SMD of 0.5 represents a medium effect, and an SMD of 0.8 or larger represents a large effect. All available
ORadj on the association of SBP and DBP increments with the respective outcomes of interest were rescaled to 10 mm Hg BP increments by raising the corresponding ORadj to the ap-propriate power,17 in studies not providing ORadj for the 10 mm Hg scale. After the overall analyses using the DerSimoni-an Laird method we performed additional sensitivity analyses for all outcomes of interest using the Hartung-Knapp-Sidik-Jonkman method.18 We also performed meta-regression anal-yses, with the use of the random-effects model, to explore heterogeneity and further evaluate the potential association between the unadjusted outcome provided by the majority of included studies and the dichotomous and normally distrib-uted patients’ baseline characteristics.
As per the Cochrane Handbook for Systematic Reviews of In-terventions,19 we assessed for heterogeneity using Cochran Q and I2 statistics. For the qualitative interpretation of heteroge-neity, I2 >50% and I2 >75% indicated substantial and consider-able heterogeneity, respectively. Publication bias across indi-vidual studies was graphically evaluated using a funnel plot,19 while funnel plot asymmetry was assessed using the Egger’s linear regression test with P<0.10 significance level. For all other outcomes of interest we performed equivalent z test for each pooled estimate, and a two-tailed P levels <0.05 was considered statistically significant. In case of funnel plot asym-metry we performed relevant adjustment for potential publica-tion bias using the Duval-Tweedie “trim and fill” approach.20
All statistical analyses were carried out with Cochrane Col-laboration’s Review Manager Software Package (RevMan 5.3), OpenMetaAnalyst21 and the Comprehensive Meta-analysis ver-sion 2 software (Biostat, Englewood, NJ, USA; https://www.meta-analysis.com).
Results
Study selection and study characteristicsSystematic search of all the databases yielded 769 articles. After removing the duplicates, the titles and abstracts from the remaining 669 studies were screened and 33 potentially eligible studies for the meta-analysis were retained. After re-trieving the full-text version of the aforementioned 33 stud-ies, seven studies were excluded due to lack of clinical out-come reporting, articles in language other than English lan-guage or use of thrombolysis other than alteplase (Supple-mentary Table 2). After careful evaluation and without dis-agreements amongst the two reviewers, 26 studies6-8,22-44 were included that met the study protocol’s inclusion criteria. The detailed flow chart of the current meta-analysis is presented in Supplementary Figure 1.
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 81
Tabl
e 1.
Stu
dy d
esig
n an
d ch
arac
teris
tics o
f inc
lude
d st
udie
s in
our m
eta-
anal
ysis
Stud
yCo
untr
ySt
udy
desig
n, re
gist
ryN
o. o
f pat
ient
sBP
mon
itorin
gsIC
H d
efin
ition
s us
edAd
just
ed v
aria
bles
Outc
omes
Ahm
ed e
t al.
(200
9)22
Mul
tinat
iona
lRe
tros
pect
ive,
SIT
S-IS
TR
(200
2–20
07)
11,0
80Ad
miss
ion:
24
hr a
fter
IVT
SITS
-MOS
TAg
e, se
x, w
eigh
t, OT
T, ba
selin
e N
IHSS
, glu
cose
, and
imag
ing,
va
scul
ar ri
sk fa
ctor
s, an
ti-H
TN a
nd a
ntip
late
let m
edic
atio
n,
func
tiona
l ind
epen
denc
e
2, 4
*
Delg
ado-
Med
eros
et
al. (
2008
)24Sp
ain
Pros
pect
ive
80Ad
miss
ion:
24
hr a
fter
IVT
-Ba
selin
e N
IHSS
, vas
cula
r risk
fact
ors,
occl
usio
n sit
e, a
nti-
HTN
trea
t-m
ent
2, 5
†
Endo
et a
l. (2
013)
24Ja
pan
Retr
ospe
ctiv
e, S
AMUR
AI
rt-P
A52
7Ad
miss
ion:
24
hr a
fter
IVT
ECAS
S 2
Age,
sex,
bas
elin
e N
IHSS
, OTT
, vas
cula
r risk
fact
ors,
anti-
HTN
trea
tmen
t pr
ior t
o IV
T, AS
PECT
S1,
3, 4
*
Hua
ng e
t al.
(201
3)25
Chin
aRe
tros
pect
ive
101
Adm
issio
n: IV
TEC
ASS
2Ba
selin
e N
IHSS
and
seru
m g
luco
se, D
M, l
euko
arai
osis
1† 1*
Idic
ula
et a
l. (2
008)
26N
orw
ayPr
ospe
ctiv
e12
7Ad
miss
ion:
24
hr a
fter
IVT
-Ag
e, se
x, b
asel
ine
NIH
SS, v
ascu
lar r
isk fa
ctor
s2*
Kelle
rt e
t al.
(201
2)27
Germ
any
Retr
ospe
ctiv
e42
7Ad
miss
ion:
24
hr a
fter
IVT
ECAS
S 2
-3†
Kelle
rt e
t al.
(201
7)28
Mul
tinat
iona
lPr
ospe
ctiv
e, S
ITS-
ISTR
(2
002–
2013
)16
,434
Adm
issio
n: 2
4 hr
aft
er IV
TEC
ASS
2SI
TS-M
OST
Age,
sex,
bas
elin
e N
IHSS
, vas
cula
r risk
fact
ors,
SBP
1, 2
, 3, 4
*
Lind
sber
g et
al.
(200
3)29
Finl
and
Retr
ospe
ctiv
e75
Adm
issio
n: 2
4 hr
aft
er IV
T-
-2† 2*
Liu
et a
l. (2
016)
30Ch
ina
Retr
ospe
ctiv
e46
1Ad
miss
ion:
24
hr a
fter
IVT
ECAS
S 2
Age,
sex,
bas
elin
e N
IHSS
, OTT
, glu
cose
, vas
cula
r risk
fact
ors
3† 1,
3*
Mar
tins e
t al.
(201
6)31
Port
ugal
Retr
ospe
ctiv
e67
4Ad
miss
ion:
24
hr a
fter
IVT
NIN
DSAg
e, se
x, b
asel
ine
NIH
SS, E
ndov
ascu
lar t
hera
py, v
ascu
lar r
isk fa
ctor
s, SB
P3*
Men
on e
t al.
(201
2)32
Mul
tinat
iona
lPr
ospe
ctiv
e10
,242
Adm
issio
n: 2
4 hr
aft
er IV
TN
INDS
Age,
sex,
race
, bas
elin
e N
IHSS
, SBP
, glu
cose
3*
Mol
ina
et a
l. (2
004)
33M
ultin
atio
nal
Pros
pect
ive,
CLO
TBUS
T17
7Ad
miss
ion:
IVT
ECAS
S 2
-2† 2*
Mol
ina
et a
l. (2
009)
34M
ultin
atio
nal
RCT,
TUCS
ON35
Adm
issio
n: 3
6 hr
aft
er IV
TSI
TS-M
OST
Age,
sex,
OTT
, bas
elin
e N
IHSS
1, 2
, 3, 4
, 5†
1, 2
, 4*
Rusa
nen
et a
l. (2
015)
35Fi
nlan
dRe
tros
pect
ive
104
Adm
issio
n: IV
T-
Age,
sex,
bas
elin
e N
IHSS
, OTT
, vas
cula
r risk
fact
ors,
occl
usio
n sit
e2*
Saqq
ur e
t al.
(200
8)36
Mul
tinat
iona
lRe
tros
pect
ive
349
Adm
issio
n: 2
4 hr
aft
er IV
TEC
ASS
3Ag
e, se
x, b
asel
ine
NIH
SS, g
luco
se, S
BP, O
TT3† 3*
Tom
ii et
al.
(201
1)37
Japa
nPr
ospe
ctiv
e12
5Ad
miss
ion:
24
hr a
fter
IVT
-Ag
e, b
asel
ine
NIH
SS, v
ascu
lar r
isk fa
ctor
s, eG
FR2*
Toni
et a
l. (2
012)
38Ita
lyRe
tros
pect
ive,
SIT
S-IS
TR
(200
2–20
10)
3,24
6Ad
miss
ion:
24
hr a
fter
IVT
SITS
-MOS
TAg
e, se
x, b
asel
ine
NIH
SS, g
luco
se, B
P, OT
T, va
scul
ar ri
sk fa
ctor
s, fu
nc-
tiona
l ind
epen
denc
e 2,
3*
Tsiv
goul
is et
al.
(200
7)7
Mul
tinat
iona
lRe
tros
pect
ive,
CLO
TBUS
T35
1Ad
miss
ion:
2 h
r aft
er IV
TEC
ASS
3Ag
e, se
x, O
TT, b
asel
ine
NIH
SS a
nd se
rum
glu
cose
1, 2
, 3, 4
, 5†
1, 2
, 3, 4
, 5*
Tsiv
goul
is et
al.
(200
9)6
USA
Retr
ospe
ctiv
e51
0Ad
miss
ion:
IVT
ECAS
S 3
Age,
sex,
OTT
, bas
elin
e N
IHSS
, vas
cula
r risk
fact
ors a
nd m
edic
atio
ns3† 3*
Wah
lgre
n et
al.
(200
8)8
Mul
tinat
iona
lPr
ospe
ctiv
e, S
ITS-
MOS
T (2
002–
2006
)6,
483
Adm
issio
n: IV
TSI
TS-M
OST
Age,
sex,
wei
ght,
ASPE
CTS,
bas
elin
e N
IHSS
and
glu
cose
, vas
cula
r risk
fa
ctor
s and
med
icat
ions
, SBP
, fun
ctio
nal i
ndep
ende
nce
2, 3
, 4*
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236982 http://j-stroke.org
The included 26 studies comprising 56,513 patients are summarized in Table 1. Three studies were post hoc analysis of randomized-controlled clinical trials including 1,443 AIS pa-tients, while we also evaluated 23 observational studies (eight prospective and 15 retrospective) with 55,070 AIS patients. The baseline characteristics of the included patients are presented in Supplementary Table 3. Three authors of included studies responded to our request to provide previously unpublished data.7,22,34 Eight studies reported their adjusted analyses using 10-mm Hg increments in SBP or DBP;6,24,26,30,32,37,39,44 three stud-ies used 1-mm Hg increments,7,34,35 whereas the remaining studies failed to report the exact BP increments in their ad-justed analyses (Supplementary Table 4). Five studies were conducted in China, three in Finland, two in Japan, one each in Germany, Norway, Portugal, Italy, Spain, United States, whereas the remaining were multicenter, international studies.
Study quality and publication bias We assessed the risk of bias amongst the included studies using Newcastle-Ottawa scale (Supplementary Table 5). The risk of selection and comparability bias was considered low in all the studies. Outcome bias was counted as moderate as majority of the studies did not report the data on patients lost to follow-up or outcome assessment. The overall score of Newcastle-Ottawa scale was 214/234 (91.4%), which is con-sidered to represent an overall high quality.
We inspected funnel plot symmetry and Egger’s statistical test for outcomes involving ≥10 studies.19 On inspection of funnel plots, no evidence of asymmetry was observed in studies reporting pre-treatment BP parameters, either unad-justed for 3-month functional independence (Supplementary Figure 2), or adjusted 3-month functional independence (Supplementary Figure 3). Similarly, we did not observe pub-lication bias among studies reporting pre-treatment BP pa-rameters, either unadjusted for 3-month functional indepen-dence (Egger’s test P=0.70), or adjusted for 3-month favor-able functional outcome (P=0.11) and 3-month functional independence (P=0.35). However, both graphical inspection and the Egger’s test (P=0.030) uncovered the asymmetry of the funnel plot of studies reporting adjusted associations of pre-treatment SBP with 3-month favorable functional out-come (Supplementary Figure 4).
Association between BP levels and outcomesTables 2 and 3 present an overview on the overall unadjusted and adjusted analyses investigating the association of BP levels with various clinical outcomes.
Stud
yCo
untr
ySt
udy
desig
n, re
gist
ryN
o. o
f pat
ient
sBP
mon
itorin
gsIC
H d
efin
ition
s us
edAd
just
ed v
aria
bles
Outc
omes
Wal
timo
et a
l. (2
016)
39Fi
nlan
dRe
tros
pect
ive
1,86
8Ad
miss
ion:
48
hr a
fter
IVT
ECAS
S 2,
NIN
DS,
SITS
-MOS
TAg
e, S
BP, b
asel
ine
NIH
SS, g
luco
se a
nd A
SPEC
TS3*
Wu
et a
l. (2
017)
40Ch
ina
Retr
ospe
ctiv
e42
0Ad
miss
ion:
IVT
-Ag
e, se
x, B
MI,
base
line
NIH
SS, O
TT, S
BP, v
ascu
lar r
isk fa
ctor
s2† 2*
Wu
et a
l. (2
016)
41Ch
ina
Pros
pect
ive,
TIM
S-CH
INA
1,12
8Ad
miss
ion:
24
hr a
fter
IVT
NIN
DSAg
e, se
x, b
asel
ine
NIH
SS, A
SPEC
TS, O
TT, a
spiri
n us
e 1,
2, 3
*
Yan
et a
l. (2
015)
42Ch
ina
Retr
ospe
ctiv
e16
1Ad
miss
ion:
2 h
r aft
er IV
TEC
ASS
2Va
scul
ar ri
sk fa
ctor
s5†
Yong
et a
l. (2
005)
43M
ultin
atio
nal
Post
hoc
RCT
, ECA
SS61
5Ad
miss
ion:
72
hr a
fter
IVT
-Ag
e, se
x, w
eigh
t, ba
selin
e SS
S, O
TT, a
spiri
n us
e, A
SPEC
TS, v
ascu
lar r
isk
fact
ors
1†
Yong
et a
l. (2
008)
44M
ultin
atio
nal
Post
hoc
RCT
, ECA
SS 2
793
Adm
issio
n: 2
4 hr
aft
er IV
T-
Age,
sex,
bas
elin
e SS
S, O
TT, a
spiri
n us
e, A
SPEC
TS, v
ascu
lar r
isk fa
ctor
s1,
4*
(1) F
avor
able
func
tiona
l out
com
e (m
odifi
ed R
anki
n Sc
ale
[mRS
] 0–1
), (2
) fun
ctio
nal i
ndep
ende
nce
(mRS
0–2
), (3
) sIC
H, (
4) m
orta
lity,
(5) r
ecan
aliz
atio
n.BP
, blo
od p
ress
ure;
sIC
H, s
ympt
omat
ic in
trac
rani
al h
emor
rhag
e; S
ITS-
ISTR
, Saf
e Im
plem
enta
tion
of T
hrom
boly
sis in
Str
oke-
Inte
rnat
iona
l Str
oke
Thro
mbo
lysis
Reg
ister
; IVT
, int
rave
nous
thr
ombo
lysis
; SIT
S-M
OST,
Safe
Im
plem
enta
tion
of T
hrom
boly
sis in
Str
oke-
Mon
itorin
g St
udy;
OTT
, ons
et-t
o-tr
eatm
ent;
NIH
SS, N
atio
nal I
nstit
utes
of H
ealth
Str
oke
Scal
e; H
TN, h
yper
tens
ion;
SAM
URAI
rt-P
A, S
trok
e Ac
ute
Man
agem
ent w
ith U
rgen
t Ri
sk-f
acto
r Ass
essm
ent
and
Impr
ovem
ent
reco
mbi
nant
tiss
ue p
lasm
inog
en a
ctiv
ator
; ECA
SS, E
urop
ean
Coop
erat
ive
Acut
e St
roke
Stu
dy; A
SPEC
TS, A
lber
ta s
trok
e pr
ogra
m e
arly
CT
scor
e; D
M, d
iabe
tes
mel
litus
; SBP
, sy
stol
ic b
lood
pre
ssur
e; N
INDS
, Nat
iona
l Ins
titut
e of
Neu
rolo
gica
l Diso
rder
s an
d St
roke
; CLO
TBUS
T, Co
mbi
ned
Lysis
of
Thro
mbu
s in
Bra
in is
chem
ia u
sing
tran
scra
nial
Ultr
asou
nd a
nd S
yste
mic
tPA
; RCT
, ran
dom
ized
co
ntro
lled
tria
l; TU
CSON
, tra
nscr
ania
l ultr
asou
nd in
clin
ical
son
othr
ombo
lysis
; eGF
R, e
stim
ated
glo
mer
ular
filtr
atio
n ra
te; B
MI,
body
mas
s in
dex;
TIM
S-CH
INA,
thro
mbo
lysis
impl
emen
tatio
n an
d m
onito
r of a
cute
isch
-em
ic st
roke
in C
hina
; SSS
, Sca
ndin
avia
n St
roke
Sca
le.
*Adj
uste
d m
ultiv
aria
ble
data
; † Unad
just
ed d
escr
iptiv
e da
ta.
Tabl
e 1.
Con
tinue
d
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 83
Tabl
e 2.
Ove
rvie
w o
f prim
ary
and
seco
ndar
y an
alys
es o
f pre
-tre
atm
ent B
P im
pact
on
vario
us o
utco
mes
Clin
ical
out
com
eBP
leve
lUn
adju
sted
ana
lyse
sAd
just
ed a
naly
ses*
Stud
ies
SMD
(95%
CI)
PH
eter
ogen
eity
Stud
ies
OR (9
5% C
I)P
Het
erog
enei
ty
FFO
SBP
5–0
.18
(–0.
40 to
0.0
4)0.
120
I2 =76%
, P fo
r Coc
hran
Q=0
.002
80.
91 (0
.87
to 0
.95)
<0.0
01I2 =2
9%, P
for C
ochr
an Q
=0.1
9
DBP
4–0
.01
(–0.
11 to
0.1
0)0.
900
I2 =17%
, P fo
r Coc
hran
Q=0
.30
21.
00 (0
.89
to 1
.14)
0.95
0I2 =0
%, P
for C
ochr
an Q
=0.7
5
FISB
P7
–0.1
7 (–
0.34
to 0
.01)
0.06
0I2 =6
1%, P
for C
ochr
an Q
=0.0
26
0.91
(0.8
4 to
0.9
8)0.
010
I2 =47%
, P fo
r Coc
hran
Q=0
.09
DBP
60.
11 (–
0.10
to 0
.33)
0.30
0I2 =4
9%, P
for C
ochr
an Q
=0.0
83
1.36
(0.8
2 to
2.2
6)0.
230
I2 =64%
, P fo
r Coc
hran
Q=0
.06
sICH
SBP
60.
24 (0
.04
to 0
.43)
0.02
0I2 =3
7%, P
for C
ochr
an Q
=0.1
68
1.08
(1.0
1 to
1.1
6)0.
020
I2 =82%
, P fo
r Coc
hran
Q <
0.00
1
DBP
40.
11 (–
0.03
to 0
.24)
0.12
0I2 =0
%, P
for C
ochr
an Q
=0.8
31
0.99
(0.7
3 to
1.3
4)0.
950
-
Mor
talit
ySB
P3
0.17
(–0.
09 to
0.4
4)0.
200
I2=60
%, P
for C
ochr
an Q
=0.0
85
1.02
(0.9
9 to
1.0
5)0.
140
I2=0%
, P fo
r Coc
hran
Q=0
.86
DBP
2–0
.00
(–0.
06 to
0.0
6)0.
990
I2=0%
, P fo
r Coc
hran
Q=0
.83
20.
86 (0
.66
to 1
.13)
0.28
0I2=
0%, P
for C
ochr
an Q
=0.7
9
Reca
naliz
atio
nSB
P3
–0.2
1 (–
0.41
to –
0.01
)0.
040
I2=0%
, P fo
r Coc
hran
Q=0
.94
20.
47 (0
.12
to 1
.83)
0.28
0I2=
73%
, P fo
r Coc
hran
Q =
0.05
DBP
2–0
.30
(–0.
67 to
0.0
6)0.
110
I2=0%
, P fo
r Coc
hran
Q=0
.82
10.
90 (0
.54
to 1
.52)
0.70
0-
BP, b
lood
pre
ssur
e; S
MD,
sta
ndar
dize
d m
ean
diffe
renc
e; C
I, co
nfid
ence
inte
rval
; OR,
odd
s ra
tio; F
FO, f
avor
able
func
tiona
l out
com
e (m
odifi
ed R
anki
n Sc
ale
[mRS
] 0–1
); SB
P, sy
stol
ic b
lood
pre
ssur
e; D
BP, d
iast
olic
blo
od
pres
sure
; FI,
func
tiona
l ind
epen
denc
e (m
RS 0
–2);
sICH
, sym
ptom
atic
intr
acra
nial
hem
orrh
age.
*In th
e ad
just
ed fo
r pot
entia
l con
foun
ders
ana
lyse
s all
asso
ciat
ions
of S
BP/D
BP w
ith th
e ou
tcom
es o
f int
eres
t are
pre
sent
ed p
er 1
0 m
m H
g SB
P/DB
P in
crem
ent.
Tabl
e 3.
Ove
rvie
w o
f prim
ary
and
seco
ndar
y an
alys
es o
f pos
t-tr
eatm
ent B
P im
pact
on
vario
us o
utco
mes
Clin
ical
out
com
eBP
leve
lUn
adju
sted
ana
lyse
sAd
just
ed a
naly
ses*
Stud
ies
SMD
(95%
CI)
PH
eter
ogen
eity
Stud
ies
OR (9
5% C
I)P
Het
erog
enei
ty
FFO
SBP
2–0
.19
(–0.
26 to
–0.
13)
<0.0
01I2 =9
%, P
for C
ochr
an Q
= 0.
294
0.83
(0.7
8 to
0.8
8)<0
.001
I2 =0%
, P fo
r Coc
hran
Q=0
.43
DBP
2–0
.01
(–0.
07 to
0.0
5)0.
780
I2 =8%
, P fo
r Coc
hran
Q=0
.30
10.
97 (0
.84
to 1
.12)
0.68
0-
FISB
P4
–0.1
9 (–
0.23
to –
0.15
)<0
.001
I2 =0%
, P fo
r Coc
hran
Q=0
.64
40.
70 (0
.57
to 0
.87)
0.00
1I2 =7
9%, P
for C
ochr
an Q
<0.0
1
DBP
30.
00 (–
0.04
to 0
.04)
1.00
0I2 =0
%, P
for C
ochr
an Q
=0.7
01
0.86
(0.6
8 to
1.0
9)0.
210
-
sICH
SBP
30.
50 (0
.14
to 0
.86)
0.00
6I2 =3
3%, P
for C
ochr
an Q
=0.2
34
1.13
(1.0
1 to
1.2
5)0.
030
I2 =63%
, P fo
r Coc
hran
Q=0
.04
DBP
30.
20 (–
0.31
to 0
.71)
0.45
0I2 =5
7%, P
for C
ochr
an Q
=0.1
02
1.07
(0.9
2 to
1.2
6)0.
380
I2 =36%
, P fo
r Coc
hran
Q=0
.21
Mor
talit
ySB
P-
--
-3
1.17
(0.9
9 to
1.4
0)0.
070
I2 =47%
, P fo
r Coc
hran
Q=0
.15
DBP
--
--
11.
09 (0
.81
to 1
.47)
0.57
0-
BP, b
lood
pre
ssur
e; S
MD,
sta
ndar
dize
d m
ean
diffe
renc
e; C
I, co
nfid
ence
inte
rval
; OR,
odd
s ra
tio; F
FO, f
avor
able
func
tiona
l out
com
e (m
odifi
ed R
anki
n Sc
ale
[mRS
] 0–1
); SB
P, sy
stol
ic b
lood
pre
ssur
e; D
BP, d
iast
olic
blo
od
pres
sure
; FI,
func
tiona
l ind
epen
denc
e (m
RS 0
–2);
sICH
, sym
ptom
atic
intr
acra
nial
hem
orrh
age.
*In th
e ad
just
ed fo
r pot
entia
l con
foun
ders
ana
lyse
s all
asso
ciat
ions
of S
BP/D
BP w
ith th
e ou
tcom
es o
f int
eres
t are
pre
sent
ed p
er 1
0 m
m H
g SB
P/DB
P in
crem
ent.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236984 http://j-stroke.org
Unadjusted analysesLower post-treatment SBP levels were observed in patients with 3-month favorable functional outcome (Supplementary Figure 5A), while the two groups did not differ in terms of DBP levels (Supplementary Figure 5B). Pre-treatment SBP (Supple-mentary Figure 6A) and DBP (Supplementary Figure 6B) did not differ between patients with and without 3-month favorable functional outcome. Patients with 3-month functional inde-pendence demonstrated a lower trend towards pre-IVT SBP levels (Supplementary Figure 7A), whereas had a significantly lower SBP levels after alteplase infusion (Supplementary Figure 7B). No difference in mean pre-treatment (Supplementary Fig-ure 8A) and post-treatment (Supplementary Figure 8B) DBP levels was noted in patients with and without 3-month func-tional independence.
Higher pre-treatment (Supplementary Figure 9A) and post-treatment SBP levels (Supplementary Figure 9B) were observed in patients with sICH. No difference was documented in both pre-treatment (Supplementary Figure 10A) and post-treatment (Supplementary Figure 10B) DBP levels in patients with and without sICH. No difference in mean pre-treatment SBP (Sup-plementary Figure 11A) and DBP levels were noted in patients who were dead or alive at 3 months (Supplementary Figure 11B). No data was available to compare post-treatment BP lev-els and mortality.
Lower mean pre-treatment SBP levels were recorded in AIS patients with proximal intracranial occlusion who achieved tPA-induced recanalization (Supplementary Figure 12A), whereas no difference was observed for pre-treatment DBP levels (Supplementary Figure 12B). No data was available to evaluate the association of post-treatment BP levels with arte-rial recanalization.
We conducted additional analyses to assess the available as-sociations of BPV quantified by SV in BP levels with various clini-cal outcomes. Elevated post-treatment SV-SBP levels were ob-served in patients with sICH (two studies: SMD, 0.82; 95% con-fidence interval [CI], 0.35 to 1.30; P=0.0007; P for Cochran Q statistic=0.26; I2=20%) (Supplementary Figure 13). No additional data was available to evaluate the difference in mean pre- and post-treatment SV-BP levels with other clinical outcomes.
Adjusted analysesAfter adjusting for potential confounders, we evaluated the as-sociations of mean BP levels before and after tPA infusion with various outcomes.
Increasing mean pre-treatment SBP levels were independently associated with reduced odds of 3-month favorable functional outcome (ORadj, 0.91; 95% CI, 0.87 to 0.95) (Figure 1A) and
3-month functional independence (ORadj, 0.91; 95% CI, 0.84 to 0.98) (Figure 1B). Due to the emerging funnel plot asymmetry for the outcome of 3-month favorable functional outcome we per-formed additional analysis to account for the possibility of publi-cation bias and after imputing two missing studies with the trim and fill method (ORadj, 0.93; 95% CI, 0.84 to 1.03) (Supplemen-tary Figure 14). Also, higher pre-treatment SBP levels indepen-dently increased the likelihood of sICH (ORadj, 1.08; 95% CI, 1.01 to 1.16) (Figure 1C). No associations were noted between mean pre-treatment SBP levels and 3-month mortality (P=0.14) (Fig-ure 1D) and arterial recanalization (P=0.28) (Supplementary Fig-ure 15). Similarly, no associations were observed between mean pre-treatment DBP levels and 3-month favorable functional outcome (P=0.95) (Supplementary Figure 16), 3-month func-tional independence (P=0.23) (Supplementary Figure 17), sICH (P=0.95) (Supplementary Figure 18), 3-month mortality (P=0.28) (Supplementary Figure 19), and arterial recanalization (P=0.70) (Supplementary Figure 20).
Higher mean post-treatment SBP levels were independently associated with reduced odds of 3-month favorable functional outcome (ORadj, 0.83; 95% CI, 0.78 to 0.88) (Figure 2A) and 3-month functional independence (ORadj, 0.70; 95% CI, 0.57 to 0.87) (Figure 2B). Increasing mean post-treatment SBP were in-dependently related to higher likelihood of sICH (ORadj, 1.13; 95% CI, 1.01 to 1.25) (Figure 2C). No association was noted be-tween mean post-treatment SBP levels and 3-month mortality (P=0.07) (Figure 2D). Similarly, no associations were observed between mean post-treatment DBP levels and 3-month favor-able functional outcome (P=0.68) (Supplementary Figure 21), 3-month functional independence (P=0.21) (Supplementary Figure 22), sICH (P=0.38) (Supplementary Figure 23), and 3-month mortality (P=0.57) (Supplementary Figure 24).
Additionally, higher mean post-treatment SV-SBP levels were independently associated with reduced odds of 3-month favorable functional outcome (ORadj, 0.50; 95% CI, 0.27 to 0.91) (Supplementary Figure 25) and increased likelihood of 3-month mortality (ORadj, 1.86; 95% CI, 1.25 to 2.77) (Supple-mentary Figure 26). Increasing mean post-treatment SV-SBP levels tended to be associated with increased risk of sICH (P=0.06) (Supplementary Figure 27). Similarly, higher mean post-treatment SV-DBP levels were independently related to higher odds of 3-month mortality (P=0.003) (Supplementary Figure 28) and sICH (P=0.004) (Supplementary Figure 29). Fi-nally, no association was detected between SV-DBP and favor-able functional outcome (P=0.39) (Supplementary Figure 30).
Sensitivity and meta-regression analysesIn the sensitivity analyses using the Hartung-Knapp-Sidik-
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 85
Jonkman method we found no significant disparities with the DerSimonian Laird method for the vast majority of associa-tions, except for the unadjusted associations of post-treatment
SBP with sICH and 3-month functional independence, which were found to be marginally non-significant after introducing the Hartung-Knapp-Sidik-Jonkman method (Supplementary
A
B
Figure 1. Forest plot presenting the adjusted for potential confounders associations of pre-treatment systolic blood pressure levels with (A) favorable func-tional outcome, (B) functional independence, (C) symptomatic intracranial hemorrhage (sICH), and (D) mortality. SE, standard error; IV, intravenous; CI, confi-dence interval; mRS, modified Rankin Scale.
Endo et al, 2013Huang et al, 2013Kellert et al, 2017Liu et al, 2016Molina et al, 2009Tsivgoulis et al, 2007Wu W et al, 2016Yong et al, 2005
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=9.92, df=7 (P=0.19); I2=29%Test for overall effect: Z=4.04 (P<0.0001)
Odds ratioIV, random, 95% CI
Favours [mRS 2-6] Favours [mRS 0-1]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI -0.0408 0.0561 12.9% 0.96 [0.86, 1.07] -0.387 0.178 1.7% 0.68 [0.48, 0.96] -0.0698 0.01 43.7% 0.93 [0.91, 0.95] -0.0834 0.0519 14.4% 0.92 [0.83, 1.02] -0.408 0.217 1.2% 0.66 [0.43, 1.02] -0.08 0.062 11.1% 0.92 [0.82, 1.04] 0.202 0.105 4.6% 0.82 [0.67, 1.00] -0.1744 0.0647 10.4% 0.84 [0.74, 0.95]
100.0% 0.91 [0.87, 0.95]
WeightSE
0.5 0.7 1 1.5 2
Idicula et al, 2008Kellert et al, 2017Molina et al, 2009Rusanen et al, 2015Tomii et al, 2011Tsivgoulis et al, 2007
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=9.49, df=5 (P=0.09); I2=47%Test for overall effect: Z=2.45 (P=0.01)
Odds ratioIV, random, 95% CIlog[odds ratio]Study or subgroup
Odds ratioIV, random, 95% CI
-0.2357 0.0917 12.8% 0.79 [0.66, 0.95] -0.0466 0.0118 40.6% 0.95 [0.93, 0.98] 0 0.262 2.1% 1.00 [0.60, 1.67] -0.408 0.162 5.2% 0.66 [0.48, 0.91] -0.0408 0.0681 18.6% 0.96 [0.84, 1.10] -0.09 0.062 20.6% 0.91 [0.81, 1.03]
100.0% 0.91 [0.84, 0.98]
WeightSE
Favours [mRS 3-6] Favours [mRS 0-2]0.5 0.7 1 1.5 2
Endo et al, 2013Kellert et al, 2017Liu et al, 2016Menon et al, 2012Saqqur et al, 2008Tsivgoulis et al, 2007Tsivgoulis et al, 2009Wahlgren et al, 2008
Total (95% CI)Heterogeneity: Tau2=0.01; Chi2=38.90, df=7 (P<0.00001); I2=82%Test for overall effect: Z=2.29 (P=0.02)
Odds ratioIV, random, 95% CIlog[odds ratio]Study or subgroup
Odds ratioIV, random, 95% CI
0.077 0.1162 6.3% 1.08 [0.86, 1.36] 0.086 0.0378 16.7% 1.09 [1.01, 1.17] 0.0545 0.1297 5.4% 1.06 [0.82, 1.36] 0.1133 0.0233 18.9% 1.12 [1.07, 1.17] -0.0101 0.0104 20.3% 0.99 [0.97, 1.01] -0.03 0.098 7.9% 0.97 [0.80, 1.18] 0.1989 0.0717 11.1% 1.22 [1.06, 1.40] 0.142 0.0565 13.4% 1.15 [1.03, 1.29]
100.0% 1.08 [1.01, 1.16]
WeightSE
Favours [no sICH] Favours [sICH]0.7 0.85 1 1.2 1.5
Endo et al, 2013Kellert et al, 2017Molina et al, 2009Tsivgoulis et al, 2007Yong et al, 2008
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=1.32, df=4 (P=0.86); I2=0%Test for overall effect: Z=1.48 (P=0.14)
Odds ratioIV, random, 95% CIlog[odds ratio]Study or subgroup
Odds ratioIV, random, 95% CI
0.0296 0.1101 1.9% 1.03 [0.83, 1.28] 0.0233 0.016 90.8% 1.02 [0.99, 1.06] 0.677 0.607 0.1% 1.97 [0.60, 6.47] 0.02 0.077 3.9% 1.02 [0.88, 1.19] -0.0101 0.0838 3.3% 0.99 [0.84, 1.17]
100.0% 1.02 [0.99, 1.05]
WeightSE
Favours [no mortality] Favours [mortality]0.2 0.5 1 2 5
C
D
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236986 http://j-stroke.org
Tables 6 and 7). In the meta-regression analyses only the prevalence of dia-
betes was found to be inversely related to the likelihood of 3-month functional independence (coefficient, –0.013; 95% CI, –0.024 to –0.003; P=0.014) (Supplementary Table 8).
Discussion
To the best of our knowledge, this is the first systematic re-view and meta-analysis to evaluate the association between
acute BP levels and clinical outcomes of AIS patients treated with IVT. Among 56,513 tPA-treated AIS patients, increasing mean BP levels before and after tPA infusion reduced the likelihood of 3-month favorable functional outcome as well as 3-month functional independence. This association per-sisted in our subgroup and adjusted analyses. Although asso-ciations between increasing BP values and higher odds of functional dependence and sICH risk were documented in unadjusted and adjusted for potential confounders analyses (Tables 2 and 3), they were succinctly greater for functional
Figure 2. Forest plot presenting the adjusted for potential confounders associations of post-treatment systolic blood pressure levels with (A) favorable func-tional outcome, (B) functional independence, (C) symptomatic intracranial hemorrhage (sICH), and (D) mortality. SE, standard error; IV, intravenous; CI, confi-dence interval; mRS, modified Rankin Scale.
Endo et al, 2013Liu et al, 2016Wu W et al, 2016Yong et al, 2008
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=2.79, df=3 (P=0.43); I2=0%Test for overall effect: Z=6.65 (P<0.00001)
Odds ratioIV, random, 95% CI
Favours [mRS 2-6] Favours [mRS 0-1]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI -0.1165 0.0544 26.9% 0.89 [0.80, 0.99] -0.2458 0.0618 20.9% 0.78 [0.69, 0.88] -0.202 0.052 29.5% 0.82 [0.74, 0.90] -0.1985 0.0593 22.7% 0.82 [0.73, 0.92]
100.0% 0.83 [0.78, 0.88]
WeightSE
0.7 0.85 1 1.2 1.5
Ahmed et al, 2009Endo et al, 2013Yong et al, 2008
Total (95% CI)Heterogeneity: Tau2=0.01; Chi2=3.78, df=2 (P=0.15); I2=47%Test for overall effect: Z=1.81 (P=0.07) Favours [no mortality] Favours [mortality]
Study or subgroup 0.47 0.1912 16.5% 1.60 [1.10, 2.33] 0.0488 0.1018 36.8% 1.05 [0.86, 1.28] 0.1398 0.0764 46.7% 1.15 [0.99, 1.34]
100.0% 1.17 [0.99, 1.40]
0.5 0.7 1 1.5 2
Enod et al, 2013Liu et al, 2016Martins et al, 2016Waltimo L et al, 2016
Total (95% CI)Heterogeneity: Tau2=0.01; Chi2=8.13, df=3 (P=0.04); I2=63%Test for overall effect: Z=2.15 (P=0.03)
Favours [no sICH] Favours [sICH]
Study or subgroup 0.2151 0.1149 15.1% 1.24 [0.99, 1.55] 0.2062 0.1207 14.1% 1.23 [0.97, 1.56] 0.0315 0.009 43.5% 1.03 [1.01, 1.05] 0.157 0.065 27.3% 1.17 [1.03, 1.33]
100.0% 1.13 [0.01, 1.25]
0.5 0.7 1 1.5 2
Ahmed et al, 2009Idicula et al, 2008Tomii et al, 2011Wu L et al, 2017
Total (95% CI)Heterogeneity: Tau2=0.03; Chi2=14.07, df=3 (P=0.003); I2=79%Test for overall effect: Z=3.28 (P=0.001)
Favours [mRS 3-6] Favours [mRS 0-2]
Study or subgroup -0.6931 0.1268 22.9% 0.50 [0.39, 0.64] -0.1985 0.0881 27.5% 0.82 [0.69, 0.97] -0.4005 0.1702 18.2% 0.67 [0.48, 0.94] -0.202 0.052 31.4% 0.82 [0.74, 0.90]
100.0% 0.70 [0.57, 0.87]
0.5 0.7 1 1.5 2
Odds ratioIV, random, 95% CIlog[odds ratio]
Odds ratioIV, random, 95% CIWeightSE
Odds ratioIV, random, 95% CIlog[odds ratio]
Odds ratioIV, random, 95% CIWeightSE
Odds ratioIV, random, 95% CIlog[odds ratio]
Odds ratioIV, random, 95% CIWeightSE
A
B
C
D
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outcomes, possibly reflecting that the association of elevated BP with worse functional outcome is not solely explained by the increase in sICH risk. The association of increasing pre-treatment BP levels with lower odds of recanalization in large vessel occlusion patients treated with IVT and endovascular reperfusion therapies may represent another potential mech-anism that may account for the relationship of increasing BP levels with worse functional outcomes in AIS patients treated with systemic thrombolysis.7,45 This hypothesis is also sup-ported by the findings of the present meta-analysis, since AIS patients with tPA-induced successful recanalization had low-er pre-treatment SBP levels compared to patients with per-sisting occlusion. The inverse relationship between increased pretreatment SBP levels and vessel patency might be attrib-uted to the potential association of elevated pretreatment SBP with both increased baseline thrombus burden and im-paired endogenous capacity for fibrinolysis.7 No studies in-vestigated the relationship of post-treatment BP levels with arterial recanalization and we were unable to assess this as-sociation in the present meta-analysis. Additionally, increas-ing BPV after tPA infusion appeared to be related to higher likelihood of sICH, mortality and poor post-stroke recovery.
Our findings are in line with various individual and pooled analyses of European Cooperative Acute Stroke Study (ECASS),43 ECASS 2,44 and Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR)22 trials documenting poor outcomes in AIS patients with elevated pre- and post-IVT SBP levels. Notably, both linear22 and U-shaped22,46 associations have been reported between post-tPA SBP levels and sICH as well as 3-month mortality respectively.
Optimization of BP during AIS requires determination of var-ious hemodynamic factors including presence of ischemic pen-umbra, large vessel occlusion, collateral and recanalization status, and underlying etiopathogenic mechanisms.47 Approxi-mately three-fourths of AIS patients present with elevated SBP and/or DBP levels.48 The underlying mechanisms remain poorly understood; however, early activation of sympathetic adreno-medullary pathway and altered cerebral autoregulation within ischemic penumbra are plausible explanations.49 Wider BP fluctuations in IVT-treated patients can exacerbate reperfusion injury of blood-brain barrier and lead to hemorrhage and cere-bral edema complications. Additionally, ischemic penumbra surrounding the large infarct core is more susceptible to changes in systemic BP and reperfusion injury.50 Due to im-paired cerebral autoregulation during AIS, systemically elevated BP levels and increased BPV are associated with compromised cerebral perfusion, that likely predispose to poor functional outcomes in AIS patients treated with IVT.34,35 The positive as-
sociation that we documented between increasing BPV after tPA infusion with higher odds of mortality, poor functional outcomes and sICH lends support to the former considerations.
Our findings are in line with the recent AHA/ASA guidelines for BP control in AIS patients treated with IVT.4 However, an optimal BP level that renders a negligible risk of sICH while avoiding the impairment of cerebral perfusion remains un-known (Class I; Level of Evidence B). The recently presented randomized-controlled clinical trials51,52 attempting to evaluate the impact of BP reduction on early outcomes of AIS patients were not specifically designed to address the role of very early (within a few hours), rapid and intensive BP lowering, in AIS patients treated with tPA. The second arm of ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial may provide more definitive data on whether early inten-sive BP lowering is superior to standard guideline-recommend-ed BP management for the clinical outcome of death or dis-ability at 90 days in AIS patients treated with IVT.53
Certain limitations of the present report need to be acknowl-edged. First, substantial heterogeneity was documented in our adjusted analyses since only few studies reported associations on the increments of BP levels adjusted for different confound-ing variables. Additionally, variability was noted in the use of adjudicated definitions for sICH amongst the included studies. This likely renders a major source of bias that needs to be weighed while carefully interpreting the results of our meta-analysis. Moreover, it should be noted that adjusted analyses for the outcomes of interest were not available in a substantial proportion of included studies (Supplementary Table 4). Sec-ond, it should be acknowledged that despite the vast number of different analyses that were conducted we performed no correction for multiple comparisons. This decision was made a priori during the preparation of our manuscript protocol and after taking into account that the associations that were tested were both discrete and pre-specified. Nevertheless, it should be noted that many of the correlations were highly significant (P<0.001) and reproducible in both adjusted and unadjusted analyses (Tables 2 and 3). Thus statistical significance would have been achieved even after correcting for multiple compari-sons and using a stricter threshold for independent associa-tions on multivariable logistic regression models (e.g., P<0.005). Third, our study did not evaluate separately the association of BP variables with outcomes according to stroke subtype, in-farct size, location or vascular status of the corresponding ar-teries and perfusion status of the corresponding vascular terri-tories. It might be postulated that significant disparities could be present on the association of pre-treatment BP with out-comes between patients with hypoperfusion due to major ce-
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236988 http://j-stroke.org
rebral artery occlusion and patients with small vessel disease. Therefore, the reported associations and effect estimates by 10 mm Hg BP increments should be interpreted with caution as they represent an oversimplification of a more complex situa-tion not accounting for many other parameters, including the vascular and perfusion status. Fourth, not all the studies re-ported mean BP levels during pre- or post-IVT time intervals. Accordingly, wherever mean BP levels were unavailable, we re-corded admission BP levels, and selected BP levels following IVT that were closer to the termination of alteplase infusion. This decision was made a priori during our meta-analysis pro-tocol to avoid the possibility of reporting bias.54 Fifth, there are different indices of BPV, but we only assessed SV using limited available data from the scarce studies that assessed the rela-tionship of BPV (quantified by SV) with clinical outcomes in AIS patients treated with IVT. Sixth, it should be acknowledged that in the present meta-analysis we were unable to test the hypothesis of a U-shaped relationship between BP parameters and clinical outcomes of AIS patients treated with IVT, despite occasional reports supporting that both acute low and high BP levels may adversely affect outcomes in the settings of AIS.16,26 Last and most important, our analyses were based on observa-tional studies or post hoc analyses from randomized controlled trials that were not designed to evaluate the association of dif-ferent BP levels with outcomes in a randomized fashion. Thus, apart from inherent biases related to the design of the included studies, various disparities in the monitoring BP levels (meth-odology and frequency of serial BP measurements) and the an-tihypertensive medications used to treat excessive BP levels may have also contributed to the documented heterogeneity across included studies.
Conclusions
Our systematic review and meta-analysis indicated that elevated BP levels before and after tPA infusion are associated with re-duced likelihood of good functional outcomes and increased odds of sICH. These associations persisted even after adjustment for potential confounders, while substantial heterogeneity was documented in the majority of the reported associations. Given that the association of higher BP levels with worse clinical out-comes that we detected in the current meta-analysis cannot yield direct evidence of causality with certainty, future random-ized clinical trials are required to provide definitive data regard-ing the potential association of BP control with improved clinical outcomes of AIS patients treated with IVT and to identify the optimal BP range in this high-risk for sICH population.
Supplementary materials
Supplementary materials related to this article can be found online at https://doi.org/10.5853/jos.2018.02369.
Disclosure
Dr. Schellinger received speaker and consultant honoraria from Boehringer Ingelheim (manufacturer of rt-PA, modest), pro-vides expert testimony for German courts related to stroke pa-tients and acute treatment and served on the steering commit-tees of the CLOTBUST-ER and ECASS 4 trials.
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Supplementary Table 1. Definitions of symptomatic intracranial hemorrhage utilized by included studies
Adjudicating study Definition
NINDS1 Any ICH that had not been seen on a previous CT scan but there was subsequently either a suspicion of hemorrhage or any decline in neurologic status. To detect intracranial hemorrhage, CT scans were required at 24 hours and 7 to 10 days af-ter the onset of stroke and when clinical findings suggested hemorrhage.
ECASS 22 Any ICH with neurological deterioration (≥4 points increase on the NIHSS) from baseline or death within 22 to 36 hours. Establishment of a causal relationship between the hemorrhage and clinical deterioration or death was not a require-ment.
ECASS 3 In addition to definition of ECASS 2, the hemorrhage must have been identified as the predominant cause of the neurolog-ic deterioration.
SITS-MOST Large or remote parenchymal ICH (type 2, defined as greater than 30% of the infarct area affected by hemorrhage with mass effect or extension outside the infarct) combined with neurological deterioration (≥4 points increase on the NIHSS) from baseline or death within 22 to 36 hours.
NINDS, National Institute of Neurological Disorders and Stroke; ICH, intracranial hemorrhage; CT, computed tomography; ECASS, European Cooperative Acute Stroke Study; NIHSS, National Institutes of Health Stroke Scale; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.023692 http://j-stroke.org
Supplementary Table 2. Excluded studies with reasons for exclusion
Study Reason for exclusion
Gill et al. (2016)3 No intended outcomes compared or reported
Liu et al. (2015)4 Non-English article
Perini et al. (2010)5 No intended outcomes compared or reported
Gilligan et al. (2002)6 Patients not treated with alteplase
Nathanson et al. (2014)7 No intended outcomes compared or reported
Darger et al. (2015)8 No intended outcomes compared or reported
Bentsen et al. (2013)9 No intended outcomes compared or reported
Vol. 21 / No. 1 / January 2019
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Sup
plem
enta
ry Ta
ble
3. B
asel
ine
char
acte
ristic
s of a
cute
isch
emic
stro
ke p
atie
nts a
cros
s inc
lude
d st
udie
s
Stud
yM
ean
age
(yr)
Initi
al N
IHSS
OTT
(min
)Ba
selin
e SB
P, DB
PFe
mal
e se
x (%
)H
TN (%
)H
LD (%
)DM
(%)
AF (%
)Pr
ior A
IS/T
IA (%
)
Ahm
ed e
t al.
(200
9)10
70 (6
0–76
)13
(8–1
8)14
5 (1
15–1
70)
151
(138
–168
), 82
(74–
90)
41.5
NA
34.7
17.4
2612
.5
Delg
ado-
Med
eros
et
al. (
2008
)1169
.1±1
3.6
15 (1
0–19
)19
4.3±
64.7
149±
28, 8
2±16
42.5
53.8
33.8
21.3
NA
NA
Endo
et a
l. (2
013)
1270
.8±1
1.6
12 (7
–18)
141
(121
–165
)N
A34
.560
.521
.318
40.8
NA
Hua
ng e
t al.
(201
3)13
62.8
2±14
.25
(mRS
0–
1); 6
8.81
±9.8
5 (m
RS 2
–6)
12.0
2±5.
26
(mRS
0–1
); 15
.78±
4.98
(m
RS 2
–6)
142.
8±72
.6 (m
RS 0
–1);
154.
2±61
.8 (m
RS 2
–6)
135.
45±1
9.36
(mRS
0–1
); 14
8.78
±19.
39 (m
RS
2–6)
84.2
5±11
.13
(mRS
0–1
); 88
.3±1
2.09
(mRS
2–6
)
54.5
(mRS
0–1
); 47
.8 (m
RS 2
–6)
65.4
5 (m
RS
0–1)
; 71.
74
(mRS
2–6
)
30.9
1 (m
RS
0–1)
; 23.
91
(mRS
2–6
)
9.09
(mRS
0–
1); 2
8.26
(m
RS 2
–6)
27.2
7 (m
RS
0–1)
; 39.
13
(mRS
2–6
)
7.27
(mRS
0–1
); 8.
7 (m
RS 2
–6)
Idic
ula
et a
l. (2
008)
1463
.7±1
413
(med
ian)
NA
156±
23, 8
5±17
34.6
51.2
30.4
6.3
25.4
23.2
Kelle
rt e
t al.
(201
2)15
74.9
±14.
6 (s
ICH
); 72
.7±1
2.8
(no
sICH
)
15.5
±12
(sIC
H);
10.5
±9 (n
o sIC
H)
NA
NA
80 (s
ICH)
; 51.
8 (n
o sIC
H)
100
(sIC
H);
80.6
(n
o sIC
H)
30 (s
ICH
); 24
.5 (n
o sIC
H)
30 (s
ICH
); 24
.2 (n
o sIC
H)
50 (s
ICH
); 32
.7 (n
o sIC
H)
NA
Kelle
rt e
t al.
(201
7)16
71 (6
3–77
)11
(7–1
6)14
5 (1
20–1
70)
155
(140
–168
), N
A40
.369
.734
.711
24.2
13.1
Lind
sber
g et
al.
(200
3)17
63.6
30.3
±10.
0 (S
SS)
NA
NA
46.6
64N
A13
2321
Liu
et a
l. (2
016)
1867
.4±1
3.03
10 (5
–16)
232.
9±93
.85
153.
5±22
.56,
85.
6±14
.66
35.8
67.9
40
.120
.839
.917
.6
Mar
tins e
t al.
(201
6)19
73.2
8±11
.50
15.2
9±7.
0115
0.25
±55.
27N
A46
.180
.452
.724
.648
.9N
A
Men
on e
t al.
(201
2)20
69.9
±14.
711
(7–1
8)13
5 (1
10–1
60)
NA
49.1
672
.238
.524
.220
.623
.8
Mol
ina
et a
l. (2
004)
2167
.9±1
3.6
16 (1
3–20
)13
4.1±
46.7
NA
52.5
49.6
NA
23.5
26.5
NA
Mol
ina
et a
l. (2
009)
2263
±15
(Coh
ort 1
); 68
±15
(Coh
ort
2); 6
5±14
(Co-
hort
3)
10 (4
–14)
(Co-
hort
1);
16 (9
–21
) (Co
hort
2);
12 (7
–14)
(Co-
hort
3)
139±
33 (C
ohor
t 1);
130±
32 (C
ohor
t 2);
126±
46 (C
ohor
t 3)
150±
22 (C
ohor
t 1);
153±
32 (C
ohor
t 2);
157±
19 (C
ohor
t 3)
79±1
2 (C
ohor
t 1);
74±1
8 (C
ohor
t 2);
79±1
8 (C
o-ho
rt 3
)
34.6
NA
NA
NA
NA
NA
Rusa
nen
et a
l. (2
015)
23 6
8.7±
13.4
14 (1
0)13
0±38
NA
4265
NA
1638
NA
Saqq
ur e
t al.
(200
8)24
69±1
316
(12–
20)
134±
3215
7±22
, NA
47N
AN
AN
AN
AN
A
Tom
ii et
al.
(201
1)25
72.7
±913
(7–1
8)N
A15
8.4±
33, 8
8.1±
19.4
2671
4020
4920
Toni
et a
l. (2
012)
26*
45 (1
8–50
)11
.3±5
.814
5 (1
17–1
72)
140
(125
–153
), 81
(73–
90)
41.7
27.1
20.6
5.8
4.6
7.1
Tsiv
goul
is et
al.
(200
7)27
69±1
4 (re
cana
-liz
ed);
68±1
3 (n
on-r
ecan
aliz
ed)
17 (6
) (re
cana
-liz
ed);
15 (6
) (n
on-r
ecan
a-liz
ed)
142
(43)
(rec
anal
ized
); 14
5 (4
8) (n
on-r
ecan
a-liz
ed)
160±
22 (r
ecan
aliz
ed);
152±
23 (n
on-r
ecan
a-liz
ed)
NA
47 (r
ecan
aliz
ed);
46 (n
on-r
ecan
a-liz
ed)
67 (r
ecan
aliz
ed);
60 (n
on-r
e-ca
naliz
ed)
NA
37 (r
ecan
a-liz
ed);
20
(non
-rec
an-
aliz
ed)
35 (r
ecan
a-liz
ed);
27
(non
-re-
cana
lized
)
NA
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.023694 http://j-stroke.org
Stud
yM
ean
age
(yr)
Initi
al N
IHSS
OTT
(min
)Ba
selin
e SB
P, DB
PFe
mal
e se
x (%
)H
TN (%
)H
LD (%
)DM
(%)
AF (%
)Pr
ior A
IS/T
IA (%
)
Tsiv
goul
is et
al.
(200
9)28
71±1
1 (s
ICH
); 66
±15
(no
sICH
)12
(10)
(sIC
H);
8 (7
) (no
sICH
)14
0 (8
0) (s
ICH
); 12
5 (6
5)
(no
sICH
)16
9±29
(sIC
H);
156±
24
(no
sICH
)85
±21
(sIC
H);
82±1
6 (n
o sIC
H)
45 (s
ICH
); 44
(no
sICH
)68
(sIC
H);
55 (n
o sIC
H)
NA
19 (s
ICH
); 13
(n
o sIC
H)
23 (s
ICH
); 11
(n
o sIC
H)
NA
Wah
lgre
n et
al.
(200
8)29
†73
(sIC
H);
68 (n
o sIC
H)
13 (s
ICH
); 12
(no
sICH
)14
0 (s
ICH
); 14
0 (n
o sIC
H)
160
(sIC
H);
150
(no
sICH
)85
(sIC
H);
81 (n
o sIC
H)
42 (s
ICH
); 40
(no
sICH
)76
(sIC
H);
58 (n
o sIC
H)
42 (s
ICH
); 35
(n
o sIC
H)
23 (s
ICH
); 16
(n
o sIC
H)
36 (s
ICH
); 24
(n
o sIC
H)
19 (s
ICH
); 10
(no
sICH
)
Wal
timo
et a
l. (2
016)
3070
(63–
78) (
sICH
); 69
(59–
76) (
no
sICH
)
15 (1
0–21
) (s
ICH
); 9
(5–
15) (
no sI
CH)
135
(105
–230
) (sIC
H);
120
(89–
166)
(no
sICH
)15
7 (1
35–1
71) (
sICH
); 15
5 (1
40–1
71) (
no sI
CH)
41.3
(sIC
H);
43.5
(n
o sIC
H)
64.2
(sIC
H);
58.0
(n
o sIC
H)
39.4
(sIC
H);
38.9
(no
sICH
)
19.3
(sIC
H);
13.9
(no
sICH
)
30.3
(sIC
H);
26.6
(no
sICH
)
11.0
(sIC
H);
13.2
(n
o sIC
H)
Wu
et a
l. (2
017)
3160
.04±
11.0
8 (m
RS
0–2)
; 62
.71±1
2.31
(m
RS 3
–6)
4 (2
–7) (
mRS
0–
2); 1
0 (4
–13
) (m
RS 3
–6)
200
(136
–257
.5) (
mRS
0–
2); 2
07 (1
57.5
–26
7.25
) (m
RS 3
–6)
147.
31±2
1.72
(mRS
0–2
); 14
9.85
±22.
61 (m
RS
3–6)
NA
24.11
(mRS
0–2
); 31
.54
(mRS
3–
6)
64.8
2 (m
RS
0–2)
; 73.
08
(mRS
3–6
)
40.71
(mRS
0–
2); 3
1.54
(m
RS 3
–6)
32.8
1 (m
RS
0–2)
; 36.
92
(mRS
3–6
)
12.6
5 (m
RS
0–2)
; 14.
62
(mRS
3–6
)
22.9
2 (m
RS 0
-2);
24.6
2 (m
RS
3-6)
Wu
et a
l. (2
016)
3263
.48±
11.3
411
(7–1
6)16
9.2±
4814
8.03
±20.
95, N
A39
.01
59.1
36.
4717
.38
17.9
118
.44
Yan
et a
l. (2
015)
3368
.81±
11.4
912
.51±
6.62
(re-
cana
lized
); 12
.96±
5.39
(n
on-r
ecan
a-liz
ed)
238.
14±9
6.88
(rec
ana-
lized
); 22
5.30
±92.
39
(non
-rec
anal
ized
)
147.
98±2
0.21
, 83
.01±
15.0
732
.366
.7 (r
ecan
a-liz
ed);
67.6
(n
on-r
ecan
a-liz
ed)
NA
14.9
(rec
ana-
lized
); 18
.9
(non
-rec
an-
aliz
ed)
56.3
(rec
ana-
lized
); 47
.3
(non
-re-
cana
lized
)
NA
Yong
et a
l. (2
005)
34‡
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Yong
et a
l. (2
008)
35§
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Valu
es a
re p
rese
nted
as m
edia
n (in
terq
uart
ile ra
nge)
, mea
n±st
anda
rd d
evia
tion,
or n
umbe
r (%
).N
IHSS
, Nat
iona
l Ins
titut
es o
f Hea
lth S
trok
e Sc
ale;
OTT
, ons
et-t
o-tr
eatm
ent;
SBP,
syst
olic
blo
od p
ress
ure;
DBP
, dia
stol
ic b
lood
pre
ssur
e; H
TN, h
yper
tens
ion;
HLD
, hyp
erlip
idem
ia; D
M, d
iabe
tes
mel
litus
; AF,
atria
l fib
rilla
-tio
n; A
IS, a
cute
isch
emic
stro
ke; T
IA, t
rans
ient
isch
emic
att
ack;
NA,
not
ava
ilabl
e; m
RS, m
odifi
ed R
anki
n Sc
ale;
sICH
, sym
ptom
atic
intr
acra
nial
hem
orrh
age;
SSS
, Sca
ndin
avia
n St
roke
Sca
le.
*Res
ults
repo
rted
for p
atie
nts 1
8 to
50
year
s old
; † Dem
ogra
phic
var
iabl
es fo
r sIC
H/S
afe
Impl
emen
tatio
n of
Thr
ombo
lysis
in S
trok
e-M
onito
ring
Stud
y (S
ITS-
MOS
T) is
pre
sent
ed; ‡ 50
.4%
of c
ohor
t was
trea
ted
with
intr
a-ve
nous
thro
mbo
lysis
(IVT
). Sp
ecifi
c de
mog
raph
ic d
etai
ls fo
r IVT
coh
ort w
ere
not a
vaila
ble;
§ 51.3
% o
f coh
ort w
as tr
eate
d w
ith IV
T. Sp
ecifi
c de
mog
raph
ic d
etai
ls fo
r IVT
coh
ort w
ere
not a
vaila
ble.
Sup
plem
enta
ry Ta
ble
3. C
ontin
ued
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 5
Supp
lem
enta
ry Ta
ble
4. S
tudi
es w
ith a
djus
ted
anal
yses
bas
ed o
n 1
mm
Hg
or 1
0 m
m H
g BP
incr
emen
ts
BP in
crem
ents
Stud
yPr
e-IV
TPo
st-I
VT
FFO
FI
sICH
Mor
talit
yRe
cana
lizat
ion
FFO
FIsIC
HM
orta
lity
Per 1
0 m
m H
g En
do e
t al.
(201
3)12
SBP
0.96
(0.8
6–1.
06)
-1.
08 (0
.86–
1.35
)1.
03 (0
.83–
1.27
)-
0.89
(0.8
0–0.
99)
-1.
24 (0
.99–
1.57
)1.
05 (0
.86–
1.30
)
DBP
1.0
(0.8
8–1.
14)
-0.
99 (0
.73–
1.33
)0.
87 (0
.66–
1.14
)-
0.97
(0.8
4–1.
11)
-1.
27 (0
.92–
1.74
)1.
09 (0
.81–
1.46
)
Idic
ula
et a
l. (2
008)
14SB
P-
0.79
(0.6
6–0.
97)
--
--
0.82
(0.6
9–1.
00)
--
DBP
-0.
97 (0
.74–
1.03
)-
--
-0.
86 (0
.68–
1.01
)-
-
Liu
et a
l. (2
016)
18SB
P0.
920
(0.8
31–
1.01
8)-
1.05
6 (0
.819
–1.
363)
--
0.78
(0.6
91–0
.879
)-
1.22
9 (0
.970
–1.5
58)
-
Mar
tins e
t al.
(201
6)19
SBP
--
--
--
-1.
03 (1
.01–
1.05
)-
Men
on e
t al.
(201
2)20
SBP
--
1.12
(1.0
7–1.
17)
--
--
--
Tom
ii et
al.
(201
1)25
SBP
-0.
96 (0
.84–
1.08
)-
--
-0.
67 (0
.48–
0.91
)-
-
Tsiv
goul
is et
al.
(200
9)28
SBP
--
1.22
(1.0
6–1.
41)
--
--
--
Wal
timo
et a
l. (2
016)
30SB
P-
--
--
--
1.17
(1.0
3–1.
33)
-
Yong
et a
l. (2
008)
35SB
P0.
84 (0
.74–
0.94
)-
-0.
99 (0
.84–
1.18
)-
0.82
(0.7
3–0.
91)
--
1.15
(0.9
9–1.
34)
Per 1
mm
Hg
Mol
ina
et a
l. (2
009)
22SB
P0.
96 (0
.92–
1.02
)1.
00 (0
.95–
1.06
)-
1.07
(0.9
5–1.
21)
0.98
(0.9
4–1.
02)
--
--
DBP
1.01
(0.9
5–1.
07)
1.05
(0.9
7–1.
13)
-0.
97 (0
.86–
1.09
)0.
99 (0
.94–
1.04
)-
--
-
Rusa
nen
et a
l. (2
015)
23SB
P-
0.96
(0.9
3–1.
00)
--
--
--
-
Tsiv
goul
is et
al.
(200
7)27
SBP
0.99
2 (0
.980
–1.
004)
0.99
1 (0
.979
–1.
004)
0.99
7 (0
.978
–1.
016)
1.00
2 (0
.987
–1.
016)
0.85
(0.7
4–0.
98)
--
--
Hua
ng e
t al.
(201
3)13
SBP
-0.
96 (0
.93–
1.00
)-
--
--
--
Wu
et a
l. (2
016)
32SB
P0.
98 (0
.96–
1.00
)-
--
--
--
-
Wu
et a
l. (2
017)
31SB
P-
--
--
0.98
(0.9
7–0.
99)
--
-
Lind
sber
g et
al.
(200
3)17
DBP
-1.
07 (1
.01–
1.14
)-
--
--
--
Per 2
0.5
mm
H
gW
ahlg
ren
et a
l. (2
008)
29SB
P-
-1.
33 (1
.06–
1.65
)-
--
--
-
Per 2
5 m
m H
gKe
llert
et a
l. (2
017)
16SB
P0.
84 (0
.80–
0.88
)0.
89 (0
.84–
0.94
)1.
24 (1
.03–
1.49
)1.
06 (0
.98–
1.15
)-
--
--
Valu
es a
re p
rese
nted
as a
djus
ted
odds
ratio
(95%
con
fiden
ce in
terv
al).
BP, b
lood
pre
ssur
e; IV
T, in
trav
enou
s tr
eatm
ent;
FFO,
favo
rabl
e fu
nctio
nal o
utco
me
(mod
ified
Ran
kin
Scal
e [m
RS] 0
–1);
FI, f
unct
iona
l ind
epen
denc
e (m
RS 0
–2);
sICH
, sym
ptom
atic
intr
acra
nial
hem
orrh
age;
SBP
, sys
tolic
bl
ood
pres
sure
; DBP
, dia
stol
ic b
lood
pre
ssur
e.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.023696 http://j-stroke.org
Supplementary Table 5. Quality assessment of included studies with the Newcastle-Ottawa Scale
Study Selection Comparability Outcome Overall score
Ahmed et al. (2009)10 4* 2* 2* 8/9
Delgado-Mederos et al. (2008)11 4* 2* 2* 8/9
Endo et al. (2013)12 4* 2* 2* 8/9
Huang et al. (2013)13 4* 2* 2* 8/9
Idicula et al. (2008)14 4* 2* 2* 8/9
Kellert et al. (2012)15 4* 2* 2* 8/9
Kellert et al. (2017)16 4* 2* 2* 8/9
Lindsberg et al. (2003)17 4* 2* 3* 9/9
Liu et al. (2016)18 4* 2* 2* 8/9
Martins et al. (2016)19 4* 2* 2* 8/9
Menon et al. (2012)20 4* 2* 2* 8/9
Molina et al. (2004)21 4* 2* 3* 9/9
Molina et al. (2009)22 4* 2* 3* 9/9
Rusanen et al. (2015)23 4* 2* 2* 8/9
Saqqur et al. (2008)24 4* 2* 3* 9/9
Tomii et al. (2011)25 4* 2* 2* 8/9
Toni et al. (2012)26 4* 2* 2* 8/9
Tsivgoulis et al. (2007)27 4* 2* 3* 9/9
Tsivgoulis et al. (2009)28 4* 2* 2* 8/9
Wahlgren et al. (2008)29 4* 2* 2* 8/9
Waltimo et al. (2016)30 4* 2* 3* 9/9
Wu et al. (2017)31 4* 2* 2* 8/9
Wu et al. (2016)32 4* 2* 2* 8/9
Yan et al. (2015)33 4* 2* 2* 8/9
Yong et al. (2005)34 4* 2* 2* 8/9
Yong et al. (2008)35 4* 2* 2* 8/9
Overall score 104/104 52/52 58/78 214/234
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 7
Supp
lem
enta
ry Ta
ble
6. S
ensit
ivity
ana
lyse
s on
the
prim
ary
and
seco
ndar
y an
alys
es o
f pre
-tre
atm
ent B
P im
pact
on
vario
us o
utco
mes
Clin
ical
out
com
eBP
leve
lUn
adju
sted
ana
lyse
sAd
just
ed a
naly
ses*
Stud
ies
SMD
(95%
CI)
PH
eter
ogen
eity
Stud
ies
OR (9
5% C
I)P
Het
erog
enei
ty
FFO
SBP
5–0
.23
(–0.
56 to
0.0
9)0.
16I2 =8
8%, P
for C
ochr
an Q
<0.
018
0.89
(0.8
1 to
0.9
6)<0
.01
I2 =76%
, P fo
r Coc
hran
Q=0
.19
DBP
4–0
.02
(–0.
23 to
0.1
8)0.
82I2 =6
1%, P
for C
ochr
an Q
=0.3
02
1.00
(0.8
9 to
1.1
4)0.
95I2 =7
5%, P
for C
ochr
an Q
=0.4
6
FISB
P7
–0.1
8 (–
0.38
to 0
.02)
0.08
I2 =76%
, P fo
r Coc
hran
Q=0
.01
60.
89 (0
.79
to 0
.99)
0.04
I2 =75%
, P fo
r Coc
hran
Q=0
.09
DBP
60.
13 (–
0.18
to 0
.43)
0.41
I2 =74%
, P fo
r Coc
hran
Q=0
.08
31.
33 (0
.85
to 2
.09)
0.20
I2 =55%
, P fo
r Coc
hran
Q=0
.06
sICH
SBP
60.
23 (0
.01
to 0
.46)
0.04
I2 =51%
, P fo
r Coc
hran
Q=0
.16
81.
08 (1
.02
to 1
.14)
<0.0
1I2 =7
1%, P
for C
ochr
an Q
<0.
01
DBP
40.
11 (–
0.04
to 0
.26)
0.14
I2 =5%
, P fo
r Coc
hran
Q=0
.83
10.
99 (0
.73
to 1
.34)
0.95
-
Mor
talit
ySB
P3
0.26
(–0.
23 to
0.7
6)0.
29I2 =8
7%, P
for C
ochr
an Q
=0.0
85
1.03
(0.8
8 to
1.1
8)0.
73I2 =7
6%, P
for C
ochr
an Q
=0.8
6
DBP
2–0
.00
(–0.
06 to
0.0
6)0.
99I2 =0
%, P
for C
ochr
an Q
=0.8
32
0.86
(0.6
6 to
1.1
3)0.
29I2 =0
%, P
for C
ochr
an Q
=0.7
9
Reca
naliz
atio
nSB
P3
–0.2
1 (–
0.41
to –
0.01
)0.
04I2 =0
%, P
for C
ochr
an Q
=0.9
42
0.47
(0.1
3 to
1.7
5)0.
26I2 =7
1%, P
for C
ochr
an Q
=0.0
5
DBP
2–0
.30
(–0.
67 to
0.0
6)0.
11I2 =1
2%, P
for C
ochr
an Q
=0.8
21
0.90
(0.5
4 to
1.5
2)0.
70-
BP, b
lood
pre
ssur
e; S
MD,
sta
ndar
dize
d m
ean
diffe
renc
e; C
I, co
nfid
ence
inte
rval
; OR,
odd
s ra
tio; F
FO, f
avor
able
func
tiona
l out
com
e (m
odifi
ed R
anki
n Sc
ale
[mRS
] 0–1
); SB
P, sy
stol
ic b
lood
pre
ssur
e; D
BP, d
iast
olic
blo
od
pres
sure
; FI,
func
tiona
l ind
epen
denc
e (m
RS 0
–2);
sICH
, sym
ptom
atic
intr
acra
nial
hem
orrh
age.
*In th
e ad
just
ed fo
r pot
entia
l con
foun
ders
ana
lyse
s all
asso
ciat
ions
of S
BP/D
BP w
ith th
e ou
tcom
es o
f int
eres
t are
pre
sent
ed p
er 1
0 m
m H
g SB
P/DB
P in
crem
ent.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.023698 http://j-stroke.org
Supp
lem
enta
ry Ta
ble
7. S
ensit
ivity
ana
lyse
s on
the
prim
ary
and
seco
ndar
y an
alys
es o
f pos
t-tr
eatm
ent B
P im
pact
on
vario
us o
utco
mes
Clin
ical
out
com
eBP
leve
lUn
adju
sted
ana
lyse
sAd
just
ed a
naly
ses*
Stud
ies
SMD
(95%
CI)
PH
eter
ogen
eity
Stud
ies
OR (9
5% C
I)P
Het
erog
enei
ty
FFO
SBP
2–0
.21
(–0.
31 to
–0.
10)
<0.0
1I2 =2
8%, P
for C
ochr
an Q
=0.2
94
0.83
(0.7
8 to
0.8
9)<0
.01
I2 =28%
, P fo
r Coc
hran
Q=0
.43
DBP
2–0
.02
(–0.
12 to
0.0
8)0.
70I2 =2
8%, P
for C
ochr
an Q
=0.3
01
0.97
(0.8
4 to
1.1
2)0.
68-
FISB
P4
–0.2
1 (–
0.31
to –
0.11
)<0
.01
I2 =16%
, P fo
r Coc
hran
Q=0
.64
40.
70 (0
.56
to 0
.87)
<0.0
1I2 =8
2%, P
for C
ochr
an Q
<0.
01
DBP
30.
00 (–
0.17
to 0
.17)
0.99
I2 =12%
, P fo
r Coc
hran
Q=0
.70
10.
86 (0
.68
to 1
.09)
0.21
-
sICH
SBP
30.
52 (–
0.04
to 1
.08)
0.07
I2 =63%
, P fo
r Coc
hran
Q=0
.22
41.
11 (1
.02
to 1
.22)
0.02
I2 =52%
, P fo
r Coc
hran
Q=0
.04
DBP
30.
22 (–
0.45
to 0
.88)
0.52
I2 =73%
, P fo
r Coc
hran
Q=0
.10
21.
08 (0
.90
to 1
.28)
0.39
I2 =41%
, P fo
r Coc
hran
Q=0
.21
Mor
talit
ySB
P-
--
-3
1.19
(0.9
5 to
1.5
1-)
0.13
I2 =69%
, P fo
r Coc
hran
Q=0
.15
DBP
--
--
11.
09 (0
.81
to 1
.47)
0.57
-
BP, b
lood
pre
ssur
e; S
MD,
sta
ndar
dize
d m
ean
diffe
renc
e; C
I, co
nfid
ence
inte
rval
; OR,
odd
s ra
tio; F
FO, f
avor
able
func
tiona
l out
com
e (m
odifi
ed R
anki
n Sc
ale
[mRS
] 0–1
); SB
P, sy
stol
ic b
lood
pre
ssur
e; D
BP, d
iast
olic
blo
od
pres
sure
; FI,
func
tiona
l ind
epen
denc
e (m
RS 0
–2);
sICH
, sym
ptom
atic
intr
acra
nial
hem
orrh
age.
*In th
e ad
just
ed fo
r pot
entia
l con
foun
ders
ana
lyse
s all
asso
ciat
ions
of S
BP/D
BP w
ith th
e ou
tcom
es o
f int
eres
t are
pre
sent
ed p
er 1
0 m
m H
g SB
P/DB
P in
crem
ent.
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 9
Supplementary Table 8. Meta-regression analyses on the association of baseline characteristics with the likelihood of functional independence at 3 months
Variable No. of studies Coefficient (95% CI) P
Female sex 7 –0.003 (–0.024 to 0.018) 0.764
Hypertension 5 0.005 (–0.034 to 0.045) 0.794
Dyslipidemia 4 –0.018 (–0.077 to 0.042) 0.559
Diabetes mellitus 6 –0.013 (–0.024 to –0.003) 0.014
Atrial fibrillation 4 –0.012 (–0.037 to 0.012) 0.321
Prior stroke or transient ischemic attack 3 –0.002 (–0.018 to 0.013) 0.759
CI, confidence interval.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236910 http://j-stroke.org
Supplementary Figure 1. Flow-chart diagram presenting the selection of eligible studies.
Records identi�ed through: 256 Scopus, 504 Embase/MEDLINE
636 Records excluded
Full text articles excluded:5 No reported outcomes, 1 not treated with alteplase, 1 non-English article
9 Additional bibliographic
search
Iden
ti�ca
tion
Incl
uded
Scre
enin
gEl
igib
ility
669 Records after duplicate removal
33 Full-text articles assessed for eligibility
26 Studies included in qualitative synthesis
26 Studies included in quantitative synthesis (meta-analysis)
669 Records screened
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 11
Supplementary Figure 2. Funnel plot of the included studies evaluating the unadjusted associations of pre-treatment blood pressure variables with functional independence. SE, standard error; SMD, standardized mean dif-ference; SBP, systolic blood pressure; DBP, diastolic blood pressure.
0
0.1
0.2
0.3
0.4
0.5
SE (SMD)
SMD-0.5 -0.25 0 0.25 0.5
SubgroupsSBP DBP
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236912 http://j-stroke.org
Supplementary Figure 3. Funnel plot of the included studies evaluating the adjusted association of pre-treatment blood pressure variables with functional independence. SE, standard error; OR, odds ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure.
0
0.05
0.1
0.15
0.2
SE (log[OR])
OR
-0.85 -0.9 1 1.1 1.2SubgroupsSBP DBP
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 13
Supplementary Figure 4. Funnel plot of the included studies evaluating the adjusted association of pre-treatment blood pressure variables with fa-vorable functional outcome. SE, standard error; OR, odds ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure.
0
0.02
0.04
0.06
0.08
0.1
SE (log[OR])
OR-0.85 -0.9 1 1.1 1.2
SubgroupsSBP DBP
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236914 http://j-stroke.org
Supplementary Figure 5. Forest plots evaluating the associations of post-treatment (A) systolic blood pressure levels and (B) diastolic blood pressure levels with favorable functional outcome. mRS, modified Rankin Scale; SMD, standardized mean difference; SD, standard deviation; IV, intravenous; CI, confidence interval.
SMDIV, random, 95% CI
Favours [mRS 2-6] Favours [mRS 0-1]
mRS 2-6mRS 0-1
Ahmed et al., 2009Yong et al., 2005
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=1.10, df=1 (P=0.29); I2=9%Test for overall effect: Z=5.80 (P<0.00001)
-0.18 [-0.23, -0.14]-0.31 [-0.55, -0.08]
-0.19 [-0.26, -0.13]
144174.6
2124.5
3,269111
3,380
148182.6
2226.1
5,609192
5,801
92.6%7.4%
100.0%
-0.2 -0.1 0 0.1 0.2
MeanStudy or subgroup SD Total Mean SD Total WeightSMD
IV, random, 95% CI
SMDIV, random, 95% CI
Favours [mRS 0-1] Favours [mRS 2-6]-0.2 -0.1 0 0.1 0.2
mRS 2-6mRS 0-1
Ahmed et al., 2009Yong et al., 2005
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=1.09, df=1 (P=0.30); I2=8%Test for overall effect: Z=0.28 (P=0.78)
-0.00 [-0.04, 0.04]-0.13 [-0.36, 0.11]
-0.01 [-0.07, 0.05]
79100.8
1313.4
3,267111
3,378
79102.5
1413.4
5,602192
5,794
93.0%7.0%
100.0%
MeanStudy or subgroup SD Total Mean SD Total WeightSMD
IV, random, 95% CI
A
B
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 15
Supplementary Figure 6. Forest plots evaluating the association of pre-treatment (A) systolic blood pressure levels and (B) diastolic blood pressure levels with favorable functional outcome. mRS, modified Rankin Scale; SMD, standardized mean difference; SD, standard deviation; IV, intravenous; CI, confidence interval.
Ahmed et al., 2009Huang et al., 2013Molina et al., 2009Tsivgoulis et al., 2007Yong et al., 2005
Total (95% CI)Heterogeneity: Tau2=0.04; Chi2=16.91, df=4 (P=0.002); I2=76%Test for overall effect: Z=1.57 (P=0.12)
SMDIV, random, 95% CI
Favours [mRS 2-6] Favours [mRS 0-1]
mRS 2-6mRS 0-1
-0.5 -0.25 0 0.25 0.5
MeanStudy or subgroup SD Total Mean SD Total WeightSMD
IV, random, 95% CI 151 21 3,412 152 21 5,943 31.0% -0.05 [-0.09, -0.01] 135.45 19.3 55 148.78 19.39 46 15.5% -0.68 [-1.09, -0.28] 147 22 18 165 27 15 7.5% -0.72 [-1.43, -0.01] 155 22 95 159 23 197 22.7% -0.18 [-0.42, 0.07] 157.7 24.9 111 154 22.7 192 23.3% 0.16 [-0.08, 0.39] 3,691 6,393 100.0% -0.18 [-0.40, 0.04]
Ahmed et al., 2009Huang et al., 2013Molina et al., 2009Yong et al., 2005
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=3.63, df=3 (P=0.30); I2=17%Test for overall effect: Z=1.12 (P=0.90)
SMDIV, random, 95% CI
Favours [mRS 2-6] Favours [mRS 0-1]
mRS 2-6mRS 0-1MeanStudy or subgroup SD Total Mean SD Total Weight
SMDIV, random, 95% CI
83 13 3,410 83 14 5,931 75.8% 0.00 [-0.04, 0.04] 84.25 11.13 55 88.3 12.09 46 6.3% -0.35 [-0.74, 0.05] 80 15 18 77 16 15 2.2% -0.19 [-0.50, 0.88] 87.8 13 111 86.9 12.2 192 15.7% -0.07 [-0.16, 0.31] 3,594 6,184 100.0% -0.01 [-0.11, 0.10]
-0.5 -0.25 0 0.25 0.5
A
B
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236916 http://j-stroke.org
Supplementary Figure 7. Forest plots evaluating the association of (A) pre-treatment and (B) post-treatment systolic blood pressure levels with functional independence. mRS, modified Rankin Scale; SMD, standardized mean difference; SD, standard deviation; IV, intravenous; CI, confidence interval.
-0.5 -0.25 0 0.25 0.5
Ahmed et al., 2009Delgado-Mederos et al., 2008 (non-recanalized)Delgado-Mederos et al., 2008 (recanalized)Lindsberg et al., 2003Molina et al., 2009Tsivgoulis et al., 2007Wu L et al., 2017
Total (95% CI)Heterogeneity: Tau2=0.02; Chi2=15.27, df=6 (P=0.02); I2=61%Test for overall effect: Z=1.88 (P=0.06)
SMDIV, random, 95% CI
Favours [mRS 3-6] Favours [mRS 0-2]
mRS 3-6mRS 0-2Study or subgroup Mean SD TotalMean SD Total Weight
SMDIV, random, 95% CI
151 21 4,830 152 22 4,525 31.7% -0.05 [-0.09, -0.01] 145.1 26.4 14 155.5 35 22 5.5% -0.32 [-0.99, 0.36] 145.7 23.3 32 150.5 27.9 12 5.7% -0.19 [-0.86, 0.47] 160 21 43 155 28 32 10.0% -0.20 [-0.25, 0.66] 151 23 22 164 17 11 4.7% -0.60 [-1.34, 0.14] 150.4 20.7 137 160.6 24.5 155 20.5% -0.45 [-0.68, -0.21] 147.31 21.72 253 149.85 22.61 130 21.9% -0.12 [-0.33, 0.10] 5,331 4,887 100.0% -0.17 [-0.34, 0.01]
-0.5 -0.25 0 0.25 0.5
Ahmed et al., 2009Delgado-Mederos et al., 2008 (non-recanalized)Delgado-Mederos et al., 2008 (recanalized)Wu L et al., 2017
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=1.67, df=3 (P=0.64); I2=0%Test for overall effect: Z=9.00 (P<0.00001)
SMDIV, random, 95% CI
Favours [mRS 3-6] Favours [mRS 0-2]
mRS 3-6mRS 0-2Study or subgroup Mean SD TotalMean SD Total Weight
SMDIV, random, 95% CI
145 21 4,621 149 23 4,257 95.5% -0.18 [-0.22, -0.14] 140.3 18.1 14 150.4 23.1 36 0.4% -0.45 [-1.08, 0.17] 137.5 19.2 32 143.8 19.9 12 0.4% -0.32 [-0.99, 0.35] 142.98 18.93 253 148.6 21.78 130 3.7% -0.28 [-0.49, -0.07] 4,920 4,435 100.0% -0.19 [-0.23, 0.15]
A
B
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 17
Supplementary Figure 8. Forest plots evaluating the association of (A) pre-treatment and (B) post-treatment diastolic blood pressure levels with functional independence. mRS, modified Rankin Scale; SMD, standardized mean difference; SD, standard deviation; IV, intravenous; CI, confidence interval.
-0.5 -0.25 0 0.25 0.5
Ahmed et al., 2009Delgado-Mederos et al., 2008 (non-recanalized)Delgado-Mederos et al., 2008 (recanalized)Lindsberg et al., 2003Molina et al., 2004Molina et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.03; Chi2=9.83, df=5 (P=0.08); I2=49%Test for overall effect: Z=1.04 (P=0.30)
SMDIV, random, 95% CI
Favours [mRS 3-6] Favours [mRS 0-2]
mRS 3-6mRS 0-2Study or subgroup Mean SD TotalMean SD Total Weight
SMDIV, random, 95% CI
83 13 4,827 82 14 4,514 40.3% 0.07 [0.03, 0.11] 79.9 16.3 14 88.2 20 22 7.9% -0.43 [-1.11, 0.24] 79.8 12 32 78.7 13.2 12 8.2% 0.09 [-0.58, 0.75] 92 12 43 84 12 32 13.7% 0.66 [0.19, 1.13] 81.1 12 87 81.9 19 90 22.9% -0.05 [-0.34, 0.24] 81 15 22 74 15 11 7.0% 0.46 [-0.28, 1.19] 5,025 4,681 100.0% -0.11 [-0.10, 0.33]
-0.2 -0.1 0 0.1 0.2
Ahmed et al., 2009Delgado-Mederos et al., 2008 (non-recanalized)Delgado-Mederos et al., 2008 (recanalized)
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=0.72, df=2 (P=0.70); I2=0%Test for overall effect: Z=0.00 (P=1.00)
SMDIV, random, 95% CI
Favours [mRS 3-6] Favours [mRS 0-2]
mRS 3-6mRS 0-2Study or subgroup Mean SD TotalMean SD Total Weight
SMDIV, random, 95% CI
79 13 4,616 79 15 4,253 99.2% 0.00 [-0.04, 0.04] 76.6 7.9 14 78.6 11.3 22 0.4% -0.19 [-0.86, 0.48] 73 8 32 71.2 8.8 12 0.4% 0.22 [-0.45, 0.88] 4,662 4,287 100.0% 0.00 [-0.04, 0.04]
A
B
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236918 http://j-stroke.org
Supplementary Figure 9. Forest plot evaluating the associations of (A) pre-treatment and (B) post-treatment systolic blood pressure levels with symptomatic intracranial hemorrhage (sICH). SMD, standardized mean difference; SD, standard deviation; IV, intravenous; CI, confidence interval.
Ahmed et al., 2009Liu et al., 2016Molina et al., 2009Saqqur et al., 2008Tsivgoulis et al., 2007Tsivgoulis et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.02; Chi2=7.97, df=5 (P=0.16); I2=37%Test for overall effect: Z=2.40 (P=0.02)
SMDIV, random, 95% CI
Favours [no sICH] Favours [sICH]
No sICHsICHMeanStudy or subgroup SD Total Mean SD Total Weight
SMDIV, random, 95% CI
158 18 179 151 21 10,477 37.8% 0.33 [0.19, 0.48] 157.4 19.9 12 153.4 22.6 449 9.3% 0.18 [-0.40, 0.75] 166 24 3 152 24 32 2.5% 0.57 [-0.62, 1.76] 156 27 26 157 22 323 15.9% -0.04 [-0.44, 0.36] 157 27 28 158 22 323 16.6% -0.04 [-0.43, 0.34] 159 29 31 156 24 479 17.9% 0.53 [0.17, 0.90] 279 12,083 100.0% 0.24 [0.40, 0.43]
Ahmed et al., 2009Kellert et al., 2017Molina et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.04; Chi2=2.98, df=2 (P=0.23); I2=33%Test for overall effect: Z=2.75 (P=0.006)
SMDIV, random, 95% CI
Favours [no sICH] Favours [sICH]
No sICHsICHMeanStudy or subgroup SD Total Mean SD Total Weight
SMDIV, random, 95% CI
158 23 169 146 22 9,951 69.2% 0.54 [0.39, 0.70] 182.68 20.87 10 179.97 21.99 376 23.1% 0.12 [-0.50, 0.75] 176 20 3 148 22 32 7.7% 1.25 [0.03, 2.47] 182 10,359 100.0% 0.50 [0.14, 0.86]
-0.5 -0.25 0 0.25 0.5
-1 -0.5 0 0.5 1
A
B
Vol. 21 / No. 1 / January 2019
https://doi.org/10.5853/jos.2018.02369 http://j-stroke.org 19
Supplementary Figure 10. Forest Plots evaluating the association of (A) pre-treatment and (B) post-treatment diastolic blood pressure levels with symptom-atic intracranial hemorrhage (sICH). SMD, standardized mean difference; SD, standard deviation; IV, intravenous; CI, confidence interval.
Ahmed et al., 2009Liu et al., 2016Molina et al., 2009Tsivgoulis et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=0.90, df=3 (P=0.83); I2=0%Test for overall effect: Z=1.57 (P=0.12)
SMDIV, random, 95% CI
Favours [sICH] Favours [no sICH]
No sICHsICHMeanStudy or subgroup SD Total Mean SD Total Weight
SMDIV, random, 95% CI
84 13 178 83 13 10,463 80.1% 0.08 [-0.07, 0.23] 90 13 12 85.5 14.7 449 5.3% 0.31 [-0.27, 0.88] 82 29 3 77 15 32 1.3% 0.30 [-0.88, 1.49] 85 21 31 82 16 479 13.3% 0.18 [-0.18, 0.55] 224 11,423 100.0% 0.11 [-0.03, 0.24]
Ahmed et al., 2009Kellert et al., 2017Molina et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.11; Chi2=4.68, df=2 (P=0.10); I2=57%Test for overall effect: Z=0.76 (P=0.45)
SMDIV, random, 95% CI
Favours [no sICH] Favours [sICH]
No sICHsICHMeanStudy or subgroup SD Total Mean SD Total Weight
SMDIV, random, 95% CI
83 15 169 79 14 9,943 55.6% 0.29 [0.13, 0.44] 94.9 12.45 10 99.39 14.5 376 30.9% -0.31 [-0.94, 0.32] 92 9 3 79 13 32 13.6% 0.99 [-0.22, 2.20] 182 10,351 100.0% 0.20 [-0.31, 0.71]
-0.2 -0.1 0 0.1 0.2
-1 -0.5 0 0.5 1
A
B
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
https://doi.org/10.5853/jos.2018.0236920 http://j-stroke.org
Supplementary Figure 11. Forest plots evaluating the association of pre-treatment (A) systolic blood pressure levels and (B) diastolic blood pressure levels with mortality. SMD, standardized mean difference; SD, standard deviation; IV, intravenous; CI, confidence interval.
Ahmed et al., 2009Molina et al., 2009Tsivgoulis et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.03; Chi2=4.94, df=2 (P=0.08); I2=60%Test for overall effect: Z=1.27 (P=0.20)
SMDIV, random, 95% CI
Favours [no mortality] Favours [mortality]
No mortalityMortalityMeanStudy or subgroup SD Total Mean SD Total Weight
SMDIV, random, 95% CI
152 22 1,379 151 21 8,096 59.4% 0.05 [-0.01, 0.10] 176 19 3 153 21 32 4.5% 1.08 [-0.14, 2.29] 162 27 61 156 21 231 36.2% 0.27 [-0.02, 0.55] 1,443 8,359 100.0% 0.17 [-0.09, 0.44]
Ahmed et al., 2009Molina et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=0.05, df=1 (P=0.83); I2=0%Test for overall effect: Z=0.01 (P=0.99)
SMDIV, random, 95% CI
Favours [no mortality] Favours [mortality]
No mortalityMortalityMeanStudy or subgroup SD Total Mean SD Total Weight
SMDIV, random, 95% CI
83 15 1,375 83 13 8,086 99.8% 0.00 [-0.06, 0.06] 77 25 3 79 14 32 0.2% -0.13 [-1.32, 1.05] 1,378 8,118 100.0% -0.00 [-0.06, 0.06]
-1 -0.5 0 0.5 1
-1 -0.5 0 0.5 1
A
B
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Supplementary Figure 12. Forest plots evaluating the association of pre-treatment (A) systolic blood pressure levels and (B) diastolic blood pressure levels with recanalization. SMD, standardized mean difference; SD, standard deviation; IV, intravenous; CI, confidence interval.
Delgado-Mederos et al., 2008Molina et al., 2009Tsivgoulis et al., 2007
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=0.13, df=2 (P=0.94); I2=0%Test for overall effect: Z=2.07 (P=0.04)
SMDIV, random, 95% CI
Favours no recanalization Favours recanalization
No recanalizationRecanalizationStudy or subgroup Mean SD TotalMean SD Total Weight
SMDIV, random, 95% CI
146.9 24.3 44 151.1 31.9 36 20.4% -0.15 [-0.59, 0.29] 150 27 17 157 21 18 8.9% -0.28 [-0.95, 0.38] 152 27 94 157 21 257 70.7% -0.22 [-0.46, 0.02] 155 311 100.0% -0.21 [-0.41, -0.01]
Delgado-Mederos et al., 2008Molina et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=0.05, df=1 (P=0.82); I2=0%Test for overall effect: Z=1.62 (P=0.11)
SMDIV, random, 95% CI
Favours no recanalization Favours recanalization
No recanalizationRecanalizationStudy or subgroup Weight
SMDIV, random, 95% CI
79.5 12.2 44 84.8 19.3 36 69.2% -0.33 [-0.78, 0.11] 76 14 17 80 18 18 30.8% -0.24 [-0.91, 0.42] 61 54 100.0% -0.30 [-0.67, 0.06]
Mean SD TotalMean SD Total
-1 -0.5 0 0.5 1
-0.5 -0.25 0 0.25 0.5
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Supplementary Figure 13. Forest plot evaluating the association of post-treatment successive variation of systolic blood pressure levels and symptomatic intracranial hemorrhage (sICH). SMD, standardized mean difference; SD, standard deviation; IV, intravenous; CI, confidence interval.
Kellert et al., 2007Liu et al., 2016
Total (95% CI)Heterogeneity: Tau2=0.02; Chi2=1.25, df=1 (P=0.26); I2=20%Test for overall effect: Z=3.38 (P=0.0007)
SMDIV, random, 95% CI
Favours [no sICH] Favours [sICH]
No sICHsICHMeanStudy or subgroup SD Total Mean SD Total Weight
SMDIV, random, 95% CI
16.14 7.94 10 13.47 4.63 376 46.6% 0.56 [-0.07, 1.19] 19.4 4.84 12 14.9 4.26 449 53.4% 1.05 [0.47, 1.63] 22 825 100.0% 0.82 [0.35, 1.30]
-1 -0.5 0 0.5 1
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Supplementary Figure 14. Funnel plot of the included (blue circles) and imputed (red circles) by the Duval and Tweedie’s trim and fill method stud-ies evaluating the adjusted association of pre-treatment blood pressure variables with favorable functional outcome.
Stan
dard
err
or
Funnel plot of standard error by point (log)
Point (log)
0.0
0.1
0.2
0.3
0.4
-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0
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Supplementary Figure 15. Forest plot evaluating the adjusted association of pre-treatment systolic blood pressure levels and recanalization. SE, standard er-ror; IV, intravenous; CI, confidence interval.
Molina et al., 2009Tsivgoulis et al., 2007
Total (95% CI)Heterogeneity: Tau2=0.74; Chi2=3.71, df=1 (P=0.05); I2=73%Test for overall effect: Z=1.09 (P=0.28)
Odds ratioIV, random, 95% CI
Favours no recanalization Favours recanalization
log[odds ratio]Study or subgroup SE WeightOdds ratio
IV, random, 95% CI -0.202 0.213 61.2% 0.82 [0.54, 1.24] -1.625 0.707 38.8% 0.20 [0.05, 0.79] 100.0% 0.47 [0.12, 1.83]
-0.05 -0.2 0 5 20
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SE WeightEndo et al., 2013Molina et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=0.10, df=1 (P=0.75); I2=0%Test for overall effect: Z=0.07 (P=0.95)
Odds ratioIV, random, 95% CI
Favours [mRS 2-6] Favours [mRS 0-1]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI 0 0.0652 95.8% 1.00 [0.88, 1.14] 0.1 0.312 4.2% 1.11 [0.60, 2.04] 100.0% 1.00 [0.89, 1.14]
0.05 0.7 1 1.5 2
Supplementary Figure 16. Forest plot evaluating the adjusted association of pre-treatment diastolic blood pressure levels and favorable functional outcome. SE, standard error; IV, intravenous; CI, confidence interval; mRS, modified Rankin Scale.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
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SE WeightIdicula et al., 2008Lindsberg et al., 2003Molina et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.13; Chi2=5.60, df=2 (P=0.06); I2=64%Test for overall effect: Z=1.20 (P=0.23)
Odds ratioIV, random, 95% CI
Favours [mRS 3-6] Favours [mRS 0-2]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI -0.0305 0.1381 45.8% 0.97 [0.74, 1.27] 0.677 0.294 31.3% 1.97 [1.11, 3.50] 0.488 0.404 23.0% 1.63 [0.74, 3.60] 100.0% 1.36 [0.82, 2.26]
0.5 0.7 1 1.5 2
Supplementary Figure 17. Forest plot evaluating the adjusted association of pre-treatment diastolic blood pressure levels and functional independence. SE, standard error; IV, intravenous; CI, confidence interval; mRS, modified Rankin Scale.
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SE WeightEndo et al., 2013
Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z=0.06 (P=0.95)
Odds ratioIV, random, 95% CI
Favours [sICH] Favours [no sICH]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI -0.0101 0.1554 100.0% 0.99 [0.73, 1.34] 100.0% 0.99 [0.73, 1.34]
0.5 0.7 1 1.5 2
Supplementary Figure 18. Forest plot evaluating the adjusted association of pre-treatment diastolic blood pressure levels and symptomatic intracranial hemorrhage (sICH). SE, standard error; IV, intravenous; CI, confidence interval.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
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Supplementary Figure 19. Forest plot evaluating the adjusted association of pre-treatment diastolic blood pressure levels and mortality. SE, standard error; IV, intravenous; CI, confidence interval.
SE WeightEndo et al., 2013Molina et al., 2009
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=0.07, df=1 (P=0.79); I2=0%Test for overall effect: Z=1.07 (P=0.28)
Odds ratioIV, random, 95% CI
Favours [no mortality] Favours [mortality]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI -0.1393 0.1409 95.0% 0.87 [0.66, 1.15] -0.305 0.614 5.0% 0.74 [0.22, 2.46] 100.0% 0.86 [0.66, 1.13]
0.2 0.5 1 2 5
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SE WeightMolina et al., 2009
Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z=0.38 (P=0.70)
Odds ratioIV, random, 95% CI
Favours no recanalization Favours recanalization
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI -0.101 0.264 100.0% 0.90 [0.54, 1.52] 100.0% 0.90 [0.54, 1.52]
0.5 0.7 1 1.5 2
Supplementary Figure 20. Forest plot evaluating the adjusted association of pre-treatment diastolic blood pressure levels and recanalization. SE, standard error; IV, intravenous; CI, confidence interval.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
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SE WeightEndo et al., 2013
Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z=0.42 (P=0.68)
Odds ratioIV, random, 95% CI
Favours [mRS 2-6] Favours [mRS 0-1]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI -0.0305 0.0734 100.0% 0.97 [0.84, 1.12] 100.0% 0.97 [0.84, 1.12]
0.5 0.7 1 1.5 2
Supplementary Figure 21. Forest plot evaluating the adjusted association of post-treatment diastolic blood pressure levels and favorable functional out-come. SE, standard error; IV, intravenous; CI, confidence interval; mRS, modified Rankin Scale.
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SE WeightIdicula et al., 2008
Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z=1.26 (P=0.21)
Odds ratioIV, random, 95% CI
Favours [mRS 3-6] Favours [mRS 0-2]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI -0.1508 0.1198 100.0% 0.86 [0.68, 1.09] 100.0% 0.86 [0.68, 1.09]
0.2 0.5 1 2 5
Supplementary Figure 22. Forest plot evaluating the adjusted association of post-treatment diastolic blood pressure levels and functional independence. SE, standard error; IV, intravenous; CI, confidence interval; mRS, modified Rankin Scale.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
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Supplementary Figure 23. Forest plot evaluating the adjusted association of post-treatment diastolic blood pressure levels and symptomatic intracranial hemorrhage (sICH). SE, standard error; IV, intravenous; CI, confidence interval.
SE WeightEndo et al., 2013Martins et al., 2016
Total (95% CI)Heterogeneity: Tau2=0.01; Chi2=1.57, df=1 (P=0.21); I2=36%Test for overall effect: Z=0.88 (P=0.38)
Odds ratioIV, random, 95% CI
Favours [no sICH] Favours [sICH]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI 0.239 0.1645 18.5% 1.27 [0.92, 1.75] 0.0325 0.0135 81.5% 1.03 [1.01, 1.06] 100.0% 1.07 [0.92, 1.26]
0.5 0.7 1 1.5 2
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Odds ratioIV, random, 95% CISE Weight
Endo et al., 2013
Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z=0.57 (P=0.57)
Odds ratioIV, random, 95% CI
Favours [no mortality] Favours [mortality]
log[odds ratio]Study or subgroup 0.0862 0.1515 100.0% 1.09 [0.81, 1.47] 100.0% 1.09 [0.81, 1.47]
0.50.20.1 1 52 10
Supplementary Figure 24. Forest plot evaluating the adjusted association of post-treatment diastolic blood pressure levels and mortality. SE, standard error; IV, intravenous; CI, confidence interval.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
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Odds ratioIV, random, 95% CISE Weight
Endo et al., 2013Liu et al., 2016Yong et al., 2008
Total (95% CI)Heterogeneity: Tau2=0.23; Chi2=10.84, df=2 (P=0.004); I2=82%Test for overall effect: Z=2.25 (P=0.02)
Odds ratioIV, random, 95% CI
Favours [mRS 2-6] Favours [mRS 0-1]
log[odds ratio]Study or subgroup -0.2744 0.1558 37.5% 0.76 [0.56, 1.03] -1.3984 0.3045 29.7% 0.25 [0.14, 0.45] -0.5621 0.2488 32.8% 0.57 [0.35, 0.93] 100.0% 0.50 [0.27, 0.91]
0.20.05 1 5 10
Supplementary Figure 25. Forest plot evaluating the adjusted associations of post-treatment successive variation of systolic blood pressure levels and favor-able functional outcome. SE, standard error; IV, intravenous; CI, confidence interval; mRS, modified Rankin Scale.
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SE WeightEndo et al., 2013Yong et al., 2008
Total (95% CI)Heterogeneity: Tau2=0.00; Chi2=0.18, df=1 (P=0.67); I2=0%Test for overall effect: Z=3.06 (P=0.002)
Odds ratioIV, random, 95% CI
Favours [no mortality] Favours [mortality]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI 0.6881 0.2581 61.6% 1.99 [1.20, 3.30] 0.5128 0.3269 38.4% 1.67 [0.88, 3.17] 100.0% 1.86 [1.25, 2.77]
0.05 0.2 1 5 20
Supplementary Figure 26. Forest plot evaluating the adjusted associations of post-treatment successive variation of systolic blood pressure levels and mor-tality. SE, standard error; IV, intravenous; CI, confidence interval.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
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Supplementary Figure 27. Forest plot evaluating the adjusted associations of post-treatment successive variation of systolic blood pressure levels and symp-tomatic intracranial hemorrhage (sICH). SE, standard error; IV, intravenous; CI, confidence interval.
SE WeightEndo et al., 2013Liu et al., 2016
Total (95% CI)Heterogeneity: Tau2=0.53; Chi2=3.61, df=1 (P=0.06); I2=72%Test for overall effect: Z=1.85 (P=0.06)
Odds ratioIV, random, 95% CI
Favours [no sICH] Favours [sICH]
log[odds ratio]Study or subgroupOdds ratio
IV, random, 95% CI 0.5988 0.2855 58.3% 1.82 [1.04, 3.18] 1.8111 0.5704 41.7% 6.12 [2.00, 18.71] 100.0% 3.02 [0.94, 9.74]
0.05 0.2 1 5 20
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Odds ratioIV, random, 95% CISE Weight
Endo et al., 2013
Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z=3.01 (P=0.003)
Odds ratioIV, random, 95% CI
Favours [no mortality] Favours [mortality]
log[odds ratio]Study or subgroup 0.8629 0.2871 100.0% 2.37 [1.35, 4.16] 100.0% 2.37 [1.35, 4.16]
0.10.01 1 10 100
Supplementary Figure 28. Forest plot evaluating the adjusted associations of post-treatment successive variation of diastolic blood pressure levels and mor-tality. SE, standard error; IV, intravenous; CI, confidence interval.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
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Odds ratioIV, random, 95% CISE Weight
Endo et al., 2013
Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z=2.87 (P=0.004)
Odds ratioIV, random, 95% CI
Favours [no sICH] Favours [sICH]
log[odds ratio]Study or subgroup 0.8755 0.305 100.0% 2.40 [1.32, 4.36] 100.0% 2.40 [1.32, 4.36]
0.10.01 1 10 100
Supplementary Figure 29. Forest plot evaluating the adjusted associations of post-treatment successive variation of diastolic blood pressure levels and symptomatic intracranial hemorrhage (sICH). SE, standard error; IV, intravenous; CI, confidence interval.
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Odds ratioIV, random, 95% CISE Weight
Endo et al., 2013
Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z=0.86 (P=0.39)
Odds ratioIV, random, 95% CI
Favours [no sICH] Favours [sICH]
log[odds ratio]Study or subgroup -0.1508 0.1752 100.0% 0.86 [0.61, 1.21] 100.0% 0.86 [0.61, 1.21]
0.20.05 1 5 20
Supplementary Figure 30. Forest plot evaluating the adjusted associations of post-treatment successive variation of diastolic blood pressure levels and fa-vorable functional outcome. SE, standard error; IV, intravenous; CI, confidence interval; sICH, symptomatic intracranial hemorrhage.
Malhotra et al. BP and Outcomes in IVT-Treated Strokes
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