diabetes mellitus, admission glucose, and outcomes after...

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Up to 60% of acute ischemic stroke (AIS) patients will experience hyperglycemia, depending on its definition.1,2

Poststroke hyperglycemia (PSH) is associated with poor clinical outcome and death2–4 and is commonly considered to represent an underlying impaired glucose tolerance or unrec-ognized diabetes mellitus. More often this process is the result of stress hyperglycemia,1,2 which is usually defined as a hyper-glycemia resolving spontaneously after acute illness dissipa-tion.5 Several mechanisms have been proposed to explain the observed adverse effects of PSH on clinical outcome, includ-ing increased blood–brain barrier disruption with higher hem-orrhagic risk6,7; or increased lactic acid production in ischemic tissue leading to a greater infarct size.8

In patients with AIS treated with intravenous (IV) thrombolysis (IVT), several large studies reported an association between diabetes mellitus or PSH and unfavorable outcome, hemorrhagic transformation, and death after IVT.9,10 Other series showed that PSH or diabetes mellitus were associated with lower recanalization rates in patients with stroke treated with IVT.11,12 However, a recent study found that IVT-treated patients with PSH did not have significantly worse outcomes.13 Data on PSH or diabetes mellitus in endovascular therapy–treated patients are limited.14–19 Available studies have shown conflicting results with respect to a potential detrimental effect of diabetes mellitus and PSH on clinical outcome. In opposition to the aforementioned IVT studies,

Background and Purpose—The potential detrimental effect of diabetes mellitus and admission glucose level (AGL) on outcomes after stroke thrombolysis is unclear. We evaluated outcomes of patients treated by intravenous and/or intra-arterial therapy, according to diabetes mellitus and AGL.

Methods—We analyzed data from a patient registry (n=704) and conducted a systematic review of previous observational studies. The primary study outcome was the percentage of patients who achieved a favorable outcome (modified Rankin score ≤2 at 3 months).

Results—We identified 54 previous reports that evaluated the effect of diabetes mellitus or AGL on outcomes after thrombolysis. In an unadjusted meta-analysis that included our registry data and previous available observational data, diabetes mellitus was associated with less favorable outcome (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.73–0.79) and more symptomatic intracranial hemorrhage (OR, 1.38; 95% CI, 1.21–1.56). However, in multivariable analysis, diabetes mellitus remained associated with less favorable outcome (OR, 0.77; 95% CI, 0.69–0.87) but not with symptomatic intracranial hemorrhage (OR, 1.11; 95% CI, 0.83–1.48). In unadjusted and in adjusted meta-analysis, higher AGL was associated with less favorable outcome and more symptomatic intracranial hemorrhage; the adjusted OR (95% CI) per 1 mmol/L increase in AGL was 0.92 (0.90–0.94) for favorable outcome, and 1.09 (1.04–1.14) for symptomatic intracranial hemorrhage.

Conclusions—These results confirm that AGL and history of diabetes mellitus are associated with poor clinical outcome after thrombolysis. AGL may be a surrogate marker of brain infarction severity rather than a causal factor. However, randomized controlled evidences are needed to address the significance of a tight glucose control during thrombolysis on clinical outcome. (Stroke. 2013;44:1915-1923.)

Key Words: acute stroke syndromes ■ diabetes mellitus ■ glucose ■ thrombolysis

Diabetes Mellitus, Admission Glucose, and Outcomes After Stroke Thrombolysis

A Registry and Systematic Review

Jean-Philippe Desilles, MD; Elena Meseguer, MD; Julien Labreuche, BST; Bertrand Lapergue, MD; Gaia Sirimarco, MD; Jaime Gonzalez-Valcarcel, MD; Philippa Lavallée, MD; Lucie Cabrejo, MD; Celine Guidoux, MD; Isabelle Klein, MD, PhD; Pierre Amarenco, MD; Mikael Mazighi, MD, PhD

Received January 14, 2013; accepted April 9, 2013.From the Department of Neurology and Stroke Centre, Bichat University Hospital, Paris, France (J.-P.D., E.M., B.L., G.S., J.G.V., P.L., L.C., C.G., P.A.,

M.M.); INSERM U-698 and Paris-Diderot University, Paris, France (J.-P.D., E.M., J.L., B.L., P.C.L., L.C., C.G., I.K., P.A., M.M.); and the Department of Radiology, Bichat University Hospital, Paris, France (I.K.).

The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 111.000813/-/DC1.

Correspondence to M. Mazighi, MD, PhD, Department of Neurology and Stroke Centre, Bichat University Hospital, 46, rue Henri Huchard, 75018 Paris, France. E-mail [email protected]

© 2013 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.000813

by guest on June 21, 2018http://stroke.ahajournals.org/

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http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.000813/-/DC1

http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.000813/-/DC1

mailto:[email protected]

http://stroke.ahajournals.org/


















1916 Stroke July 2013

endovascular research reported no association between successful reperfusion therapy defined as a partial or complete recanalization and diabetes mellitus or PSH.11

We therefore evaluated whether diabetes mellitus history, or admission glucose level (AGL) in patients with AIS treated by IV, intra-arterial (IA) thrombolysis (IAT) therapy may be associated with worse outcomes, by examining data from our prospective clinical registry and by conducting a systematic review of previous observational studies.

MethodsBichat Clinical RegistryStroke ProgramWe identified patients from a prospective clinical registry of patients with AIS treated between February 2002 and February 2012 at Bichat University Hospital, Paris, France. As described previously,20 before April 2007, all patients had been treated with conventional IVT, and none with an IA approach. After April 2007, patients eligible for IVT were treated with conventional IVT in case of no documented arterial occlusion and with a systematic IV–IA approach in case of documented arterial occlusion.20 Patients not eligible for IV treat-ment, with a documented arterial occlusion, were treated by the IA approach. The IA approach was performed using an IA recombinant tissue plasminogen activator dose of 0.5 mg/kg,21 followed by ad-junctive mechanical endovascular therapy if the arterial occlusion persisted. In patients with a contraindication to recombinant tissue plasminogen activator,22 a direct mechanical endovascular therapy ap-proach was considered.

Standard Protocol Approvals, Registration, and Patient ConsentsInformed consent was obtained from the patient or their representa-tive, and the research protocol was approved by the Ethics Committee from Ambroise Paré Hospital.

Data Collection and DefinitionsInformation on patients’ demographic characteristics, medical histo-ry, current medications, laboratory and imaging findings, vital signs before treatment, National Institutes of Health Stroke Scale (NIHSS) scores (at admission, and at 1, 3, and 24 hours after the initiation of treatment),23 clinical outcomes were collected prospectively using a structured questionnaire. Times from symptom onset (or from when the patient was last seen in a normal condition) to initiation of treat-ments were also recorded. All patients had a computed tomography or MRI scan 24 hours after treatment onset to assess hemorrhagic com-plications. For patients receiving IA therapy, the recanalization status of the occluded artery was monitored with conventional angiography, and the time to recanalization was noted. Recanalization was mea-sured with the Thrombolysis In Myocardial Infarction (TIMI) score24 by 2 members of staff (E.M. and M.M.), and was used for all imaging modalities. Modified Rankin Scale at 3 months was assessed during face-to-face interviews or via telephone calls by a senior vascular neurologist (E.M. or M.M.), who was certified for modified Rankin Scale scoring.25

Outcome DefinitionsThe primary study outcome was the percentage of patients who achieved a favorable outcome, defined as an modified Rankin Scale score of 0 to 2 at 90 days. Secondary outcomes included excellent outcome (defined as an modified Rankin Scale score of 0–1 at 90 days), early neurological improvement (defined as an NIHSS score of 0–1 at 24 hours or a decrease of ≥4 points in NIHSS score at 24 hours), any recanalization (defined by TIMI 2–3), complete recanalization (defined by TIMI 3), 90-day mor-tality, hemorrhagic complications, and symptomatic intracerebral

hemorrhage (defined as a hemorrhage on the follow-up computed tomography/MRI scan associated with an increase of ≥4 points in NIHSS score).26

Systematic ReviewSearch Strategy and Study SelectionWe performed a computerized PubMed search of articles pub-lished between January 1996 and May 2012 to identify all obser-vational and interventional studies that investigated the effect of history of diabetes mellitus or AGL on efficacy or safety outcomes in patients with AIS treated by an IV or IA strategy. We used the search terms (thrombolysis OR fibrinolysis OR thrombolytic OR intravenous OR intra-arterial OR intra-arterial OR endovascular OR mechanical OR thrombectomy OR clot removal OR clot dis-ruption) AND stroke, without any language restriction. One author (J.L.) selected potentially relevant articles based on the title and abstract, and obtained the full text for detailed review. We also searched the reference lists of retrieved articles and published re-view articles for additional studies. Studies were selected using the following criteria: (1) if they involved subjects aged ≥18 years; (2) were retrospective or prospective (observational or interven-tional) studies with ≥100 patients with AIS treated by IV or IA approach; and (3) reported a statistical analysis on the association of outcomes (efficacy or safety) with history of diabetes mellitus or AGL. We did not select studies according to treatment strat-egy, time to treatment, or the reported outcome definitions. We screened duplicate publications based on the same data sets (ie, where data overlapped with data in other included studies). When multiple end points were reported in separate publications, or when impacts of diabetes mellitus history and AGL were reported in separate publications, duplicate publications were included. For other duplicate publications, only the report with the most com-plete data was included.

Data ExtractionTwo authors (J.L. and J.P.D.) independently extracted data using a standardized form, and any disagreement was resolved by con-sensus. We did not contact the authors of the studies to request incomplete or unpublished data. We collected the following data: report characteristics (first author’s name, journal, year of publica-tion); study design (country, study period, number of centers, AIS treatment [IV agents, IA chemical agents, IA mechanical therapy]); study sample (sample size, age, sex, admission NIHSS, time from symptom onset to treatment), incidence and definition of outcomes (functional outcome, neurological improvement, recanalization, mortality, intracranial hemorrhage), direction of association be-tween diabetes mellitus (or AGL) and each outcome, and, if avail-able, a measure of the strength of the association in univariate and multivariate analysis.

Statistical AnalysisStatistical testing was done at the 2-tailed α level of 0.05, except in tests for homogeneity in which an α level of 0.10 was used. Data were analyzed using the SAS software version 9.3 (SAS Institute, Cary, NC).

Bichat Clinical RegistryWe made univariate comparisons between patients with and without history of diabetes mellitus, using χ2 tests for categorical variables and Student t test for continuous variables (Mann–Whitney U test was used for non-Gaussian distributions). Associations between baseline characteristics and AGL were performed using linear regression analysis. We investigated the effects of diabetes mellitus history and AGL on clinical and recanalization outcomes using a logistic regression model adjusted for potential confounding factors selected on the basis of their significance with diabetes mellitus or glucose in univariate analyses (P<0.20). To check the linearity of the


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Desilles et al Diabetes Mellitus and Outcomes After Thrombolysis 1917

associations of AGL and outcomes, we categorized the AGLs into quartiles and calculated odds ratios (ORs; and their 95% confidence intervals [CIs]) for the upper 3 quartiles relative to the lowest quartiles. Because ORs increased gradually with AGL quartiles, we also computed OR per 1 SD increase in AGL. Finally, among patients

who achieved recanalization after IA therapy, we investigated the association of time to recanalization with diabetes mellitus history and AGL using Mann–Whitney U test or Spearman rank correlation analysis, respectively. Adjustment for confounding factors was done using nonparametric covariance analysis.

Table 1. Bichat Clinical Registry: Baseline Characteristics According to History of Diabetes Mellitus

History of Diabetes Mellitus

P ValueNo (n=600) Yes (n=104)

Age, y, mean (±SD) 68.3 (±17.2) 71.6 (±11.5) 0.015

Men, n (%) 326 (54.3) 69 (66.4) 0.023

Medical history

Hypertension, n (%) 299 (50.1) 73 (70.2) <0.001

Hypercholesterolemia, n (%) 165 (27.8) 49 (48.0) <0.001

Current or former smokers, n (%) 221 (38.2) 41 (42.3) 0.44

Antithrombotic medication, n (%) 233 (38.8) 48 (46.2) 0.16

Clinical measures

Platelet count, 1000/µL, mean (±SD) 230 (±71) 228 (±73) 0.82

SBP, mm Hg, mean (±SD) 151 (±22) 155 (±22) 0.12

DBP, mm Hg, mean (±SD) 81 (±13) 80 (±14) 0.82

NIHSS, median (IQR) 12 (6–18) 11 (6–17) 0.72

Documented arterial occlusion,* n (%)

None 216 (37.6) 47 (48.5) 0.22

ICA isolated or tandem with MCA 90 (15.7) 14 (14.4)

MCA isolated 244 (42.4) 32 (33.0)

Posterior circulation 25 (4.4) 4 (4.1)

AIS treatment, n (%)

IV alone 390 (65.0) 74 (71.2) 0.44

Combined IV–IA 141 (23.5) 19 (18.3)

IA alone 69 (11.5) 11 (10.6)

Mechanical clot removal, n (%) 76 (12.7) 15 (14.4) 0.62

Onset to treatment time, min, median (IQR)

158 (120–195) 166 (134–194) 0.39

AIS indicates acute ischemic stroke; DBP, diastolic blood pressure; IA, intra-arterial; ICA, internal carotid artery; IQR, interquartile range; IV, intravenous; MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; and SBP, systolic blood pressure.

*Thirty-two patients had no arterial examination before AIS treatment (transcranial Doppler, magnetic resonance angiography, or computed tomography angiography).

Table 2. Bichat Clinical Registry: Outcomes According to History of Diabetes Mellitus

Outcome, n (%)

History of Diabetes Mellitus

P Value* OR (95% CI)† P Value†No (n=600) Yes (n=104)

Favorable outcome (90-day mRS ≤2)

348 (58.0) 57 (54.8) 0.54 0.80 (0.47–1.34) 0.39

Excellent outcome (90-day mRS ≤1)

253 (42.2) 42 (40.4) 0.73 0.86 (0.52–1.43) 0.57

90-Day mortality 102 (17.0) 20 (19.2) 0.58 1.21 (0.65–2.22) 0.55

Early neurological improvement‡

147 (24.5) 21 (20.2) 0.34 0.73 (0.40–1.35) 0.32

Hemorrhagic complications 131 (21.8) 28 (26.9) 0.25 1.48 (0.87–2.49) 0.14

sICH§ 36 (6.0) 7 (6.7) 0.77 1.29 (0.53–3.14) 0.57

CI indicates confidence interval; mRS, modified Rankin Scale; OR, odds ratio; and sICH, symptomatic intracranial hemorrhage.*χ2 test.†Adjusted for age, sex, admission National Institutes of Health Stroke Scale (NIHSS), hypertension, hypercholesterolemia, antithrombotic therapy, and admission

systolic blood pressure (logistic regression analysis).‡Early neurological improvement defined as NIHSS score 0–1 or a decrease of ≥4 points in NIHSS score at 24 h.§Defined following the European Cooperative Acute Stroke Study (ECASS) II criteria.


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Systematic ReviewWe reported AGLs using the conventional unit (mg/dL). When neces-sary, we converted the standard unit (mmol/L) to the conventional unit by dividing by 0.0555. Using all available data, we calculated for each study, the unadjusted effect size for diabetes mellitus as ORs (and their 95% CIs) of functional outcome and symptomatic intracra-nial hemorrhage (sICH), using patients without history of diabetes mellitus as reference group. Because a majority of retrieved studies reported means (±SD) of AGL according to presence or absence of outcome, we calculated the unadjusted effect size as the standardized mean difference between patients with and without good outcome, or between patients with and without sICH. When means (±SD) were not available, we approximate the effect size using medians (interquartile range) or converting the OR associated with glucose cut-off level.27 We combined the available unadjusted effect sizes using the inverse-variance weighted random-effects model; hetero-geneity between studies was examined using the χ2 test for homoge-neity followed by the calculation of the I2 statistic. We performed a sensitivity analysis by excluding data from the Safe Implementation of Treatments in Stroke–International Stroke Thrombolysis Register (SITS-ISTR),9 because they contributed to >70% of combined data and because we cannot exclude the possibility that several studies in our meta-analysis may have participated in SITS-ISTR. Sensitivity

analyses restricted to the studies analyzed our primary study outcome (ie, favorable outcome), or those restricted to the studies where the effect size was not approximated were also reported. Finally, we ex-tracted and combined the available multivariate results; for AGL, we calculated the adjusted OR per 18 mg/dL (=1 mmol/L) increase in glucose values.

ResultsBichat Clinical RegistrySeven hundred thirty-three consecutive patients with AIS were treated with IV or IA therapy. Of these, 29 were excluded because no information on history of diabetes mellitus could be obtained (n=4), or missing AGL (n=18) or patients were lost to follow-up after discharge (n=7; Figure I in the online-only Data Supplement); finally, 709 patients were analyzed. In the study sample, 104 patients (15%) had history of dia-betes mellitus, and the mean (SD) AGL was 133 (45) mg/dL. Baseline characteristics of patients with and without history of diabetes mellitus are described in Table 1. Patients with dia-betes mellitus were older, more often men, and more often

Table 3. Bichat Clinical Registry: Outcomes According to Quartile of Admission Glucose Level

AGL, mg/dL P Value for Trend or

<103 (n=179) 103–121 (n=181) 122–148 (n=167) >148 (n=177) OR per SD

Favorable outcome (90-day mRS ≤2)

n (%) 121 (67.6) 116 (64.1) 90 (53.9) 78 (44.1) <0.0001

Unadjusted OR (95% CI) 1.00 (ref.) 0.86 (0.55–1.32) 0.56 (0.36–0.87) 0.38 (0.24–0.58) 0.70 (0.60–0.82)

Adjusted OR (95% CI)* 1.00 (ref.) 1.21 (0.71–2.06) 0.91 (0.53–1.57) 0.57 (0.33–0.97) 0.77 (0.64–0.94)

Excellent outcome (90-day mRS ≤1)

n (%) 89 (49.7) 90 (49.7) 65 (38.9) 51 (28.8) <0.0001


Adjusted OR (95% CI) * 1.00 (ref.) 1.30 (0.80–2.13) 1.01 (0.60–1.68) 0.58 (0.34–0.97) 0.80 (0.66–0.97)

90-Day mortality

n (%) 19 (10.6) 22 (12.2) 34 (20.4) 47 (26.6) <0.0001


Adjusted OR (95% CI) 1.00 (ref.) 0.74 (0.36–1.53) 1.09 (0.54–2.19) 1.62 (0.83–3.17) 1.32 (1.07–1.63)

Early neurological improvement†

n (%) 47 (26.3) 53 (29.3) 41 (24.6) 27 (15.3) 0.008



Hemorrhagic complications

n (%) 34 (19.0) 36 (19.9) 33 (19.8) 56 (31.6) 0.007



sICH‡

n (%) 5 (2.8) 7 (3.9) 12 (7.2) 19 (10.7) 0.0007



AGL indicates admission glucose level; CI, confidence interval; mRS, modified Rankin Scale; OR, odds ratio; and sICH, symptomatic intracranial hemorrhage.*Adjusted for age, sex, admission National Institutes of Health Stroke Scale (NIHSS), hypertension, hypercholesterolemia, antithrombotic therapy, and admission

systolic blood pressure.†Early neurological improvement defined as NIHSS score 0–1 or a decrease of ≥4 points in NIHSS score at 24 h.‡Defined following the ECASS II criteria.


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had treated hypertension and hypercholesterolemia than their counterparts. The same baseline characteristics were associ-ated with AGL (Table I in the online-only Data Supplement); prior use of antithrombotic medications, admission systolic blood pressure, and NIHSS score were also associated with AGL.

Diabetes Mellitus and OutcomesIn univariate analysis as well as multivariate analysis, we found no significant differences for all study clinical outcomes regarding diabetes mellitus history (Table 2). In addition, among the 240 patients who received IA therapy, there was no significant difference in recanalization rates between the diabetes mellitus subgroups. Rate of any recanalization (TIMI 2–3) was 66.7% in patients with history of diabetes mellitus and 74.3% in the group without (P=0.38); complete recanali-zation rates were, respectively, 40.0% and 49.5% (P=0.33). In multivariate analysis, the OR associated with diabetes mellitus

was 0.89 (95% CI, 0.37–2.12; P=0.79) for any recanalization and 0.97 (95% CI, 0.42–2.22; P=0.94) for complete recana-lization. In the subset of patients who achieved any recana-lization (n=176), the median time from symptom onset to recanalization was 285 minutes (interquartile range, 255–311 minutes) in patients with history of diabetes mellitus and 245 minutes (interquartile range, 212–333 minutes) in the group without (unadjusted/adjusted P=0.080/0.052).

Admission Blood Glucose Levels and OutcomesWhatever the clinical outcomes, higher AGLs were associated with a decreased rate of good outcomes (Table 3). Conversely, higher AGLs were associated with an increased rate of adverse outcomes (90-day mortality and hemorrhagic compli-cations). In multivariate analysis, AGL remained significantly associated with all outcomes, except with early neurologi-cal improvement (adjusted OR per 1 SD increase, 0.83; 95% CI, 0.66–1.04; P=0.10). In patients who received IA therapy,

Figure 1. Forest plots of unadjusted odds ratios (ORs) for (A) good outcome and (B) symptomatic intracranial hemorrhage associated with diabetes mellitus history. Ellipses denote not available. CI indicates confidence interval. References to the studies listed are provided in the online-only Data Supplement.


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AGL were not significantly associated with recanalization. The adjusted OR per 1 SD increase in glucose level was 1.08 (95% CI, 0.78–1.50; P=0.63) for any recanalization and 1.20 (95% CI, 0.89–1.61; P=0.23) for complete recanalization. In the subset of patients who achieved any recanalization, AGL tended to be correlated with higher time to recanalization (unadjusted/adjusted P=0.054/0.095)

Systematic ReviewThe literature search identified 15 735 citations, of which 218 full articles were read and 55 were judged eligible for inclu-sion in the systematic review (Figure II in the online-only Data Supplement). The main baseline characteristics, treatment strategies, and outcomes (definitions and incidences), with a brief description of direction of association between diabetes mellitus and outcomes or between AGL and outcomes are summarized in Table II in the online-only Data Supplement.

Diabetes Mellitus and OutcomesThe available unadjusted estimates of the effect of diabetes mellitus on functional outcome and sICH in individual

and combined studies (including our results) are shown in the Figure 1. Combining the available unadjusted results for functional outcome (19 studies, n=21 368), the incidence of good outcome was significantly lower in patients with history of diabetes mellitus than in those without (Figure 1A). A similar result was found in sensitivity analysis excluding SITS-ISTR (combined OR, 0.65; 95% CI, 0.56–0.76), or restricted to studies that analyzed favorable outcome (combined OR, 0.77; 95% CI, 0.73–0.80) or combining the available multivariate ORs (6 studies; n=19 364; Table 4). When combining the available unadjusted results for sICH outcome (13 studies; n=21 564), we found a significant increase in sICH risk for patients with history of diabetes mellitus (Figure 1B). A similar result was found when the National Institute of Neurological Disorders and Stroke (NINDS) definition was used in SITS-ISTR (combined OR, 1.38; 95% CI, 1.21–1.56) or when this study was excluded (combined OR, 1.57; 95% CI, 1.19–2.07). However, when we combined the available multivariable results (5 studies, n=18 478), the association between diabetes mellitus and sICH was no longer significant (Table 4).

Table 4. Individual and Combined ORs for Good Outcome and sICH Associated With Diabetes Mellitus History and Admission Glucose Levels in Multivariable Analysis

First Author’s Name

Good Outcome* sICH*

OR (95% CI) P Value OR (95% CI) P Value

Impact of diabetes mellitus

Desilles (2013)36 0.80 (0.47–1.34) 0.39 1.29 (0.53–3.14) 0.57

Sobesky J 0.46 (0.25–0.84) 0.01 … …

Uyttenboogaart (2007)37 … … 0.37 (0.05–2.75) 0.33

Galimanis (2012)14 0.39 (0.21–0.71) 0.002 … …

Meurer (2010)13 … … 0.33 (0.07–1.50) 0.15

Ahmed (2010)9 0.83 (0.73–0.94) 0.005 0.94 (0.65–1.35) 0.72

Elkind MSV 0.72 (0.33–1.58) 0.41 ... ...

Demchuk (1999)34/Tanne 0.50 (0.27–0.91) 0.02 2.23 (1.21–4.13) 0.01

Combined 0.77 (0.69–0.87) <0.001 1.11 (0.83–1.48) 0.48

Combined without Ahmed (2010)9 0.55 (0.42–0.73) <0.001 1.45 (0.91–2.32) 0.12

Impact of glucose†

Desilles (2013)36 0.87 (0.81–0.93) 0.009 1.13 (1.01–1.26) 0.04

Kohrmann M 0.88 (0.78–0.99) 0.03 … …

Makihara N 0.91 (0.83–1.00) 0.07 … …

Uyttenboogaart (2007)37 0.91 (0.75–1.09) 0.32 1.41 (0.96–1.92) 0.06

Engelter ST 0.77 (0.64–0.94) 0.002 … …

Hallevi H 0.82 (0.68–0.98) 0.03 … …

Meurer (2010)13 … … 1.03 (0.86–1.23) 0.70

Ahmed (2010)9 0.93 (0.91–0.95) <0.001 1.07 (1.02–1.13) 0.008

Cucchiara B 0.95 (0.89–1.00) 0.07 ... ...

Kase (2001) 19 … ... 1.25 (1.04–1.50) 0.018

Demchuk (1999)34 0.91 (0.83–0.99) 0.03 ... ...

Combined 0.92 (0.90–0.94) <0.001 1.09 (1.04–1.14) <0.001

Combined without Ahmed (2010)9 0.90 (0.87–0.93) <0.001 1.14 (1.05–1.24) 0.002

CI indicates confidence interval; OR, odds ratio; and sICH, symptomatic intracranial hemorrhage.*Please see Table II in the online-only Data Supplement for the outcome definition and references.†ORs calculated per 18 mg/dL (=1 mmol/L) increase in admission glucose level.


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AGLs and OutcomesCombining the available unadjusted effect sizes (calculated as the standardized mean differences; 21 studies, n=22 042), patients with good outcome had a significantly lower AGL than patients without good outcome (Figure 2A). A simi-lar result was found in sensitivity analysis excluding SITS-ISTR (pooled effect size, −0.26; 95% CI, −0.18 to −0.33), or restricted to studies that analyzed favorable outcome (pooled effect size, −0.26; 95% CI, −0.17 to −0.36), or excluding the approximate effect sizes (pooled effect size, −0.28; 95% CI, −0.20 to −0.36). Regarding sICH outcome, patients with sICH had a significantly higher AGL than patients without sICH (Figure 2B). A similar difference was found when the NINDS definition was used in SITS-ISTR (pooled effect size, 0.30; 95% CI, 0.19–0.40) or when this study was excluded (pooled effect size, 0.28; 95% CI, 0.14–0.42), or when the approxi-mate effect sizes were excluded (pooled effect size, 0.33; 95%

CI, 0.18–0.47). When combining the available multivariable results (calculated as ORs per 18 mg/dL of glucose), AGL remained associated with poor outcome and sICH (Table 4).

DiscussionIn the present meta-analysis, history of diabetes mellitus and AGL were associated with lower rate of good outcome after thrombolysis. In addition, AGL was significantly associ-ated with increased risk of sICH, which was not observed in patients with history of diabetes mellitus. In patients eligible for IA thrombolysis in our clinical registry, there was no docu-mented effect of AGL on recanalization rates.

Arterial recanalization grade and speed has been reported to be one of the strongest predictors of favorable outcome after thrombolysis.20 In 2 previous IVT studies, AGL11 or diabetes mellitus 12 were associated with lower recanalization rates, suggesting an impaired fibrinolytic response in the setting

Figure 2. Forest plots of unadjusted standardized mean difference (SMD) In admission glucose level between patients with and without good outcome (A) and between patients with and without symptomatic intracranial hemorrhage (sICH; B). aApproximate using median and interquartile range. bApproximate using the odds ratio of outcome associated with a cut-off of glucose level. Ellipses denote not avail-able. CI indicates confidence interval.


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of elevated blood glucose concentration. Evidence supports the contribution of both chronic and acute hyperglycemia to coagulation activation,28,29 whereas hyperinsulinemia decreases fibrinolytic activity by increasing the production of plasminogen activator inhibitor.30,31 In contrast with these data, we did not find any association between recanalization and AGL or diabetes mellitus in IAT-treated patients. These results are in accordance with other previous IAT studies.14–19 The antifibrinolytic effect of hyperglycemia may be overcome by direct IAT and mechanical endovascular techniques explaining the difference between the IVT and IAT studies.32 The poorer clinical prognosis associated with AGL in case of IAT would therefore not be related to a recanalization rate difference, suggesting other underlying mechanisms.

Hyperglycemia and diabetes mellitus are strongly linked to increased risk of sICH after thrombolytic treatment.33,34 Experimental studies showed that diabetes mellitus and hyperglycemia are associated with blood–brain barrier and microvasculature impairments, as well as increased hemorrhagic infarct conversion after reperfusion.35 Recently, blood–brain barrier disruption after IAT was associated with AGL36 suggesting that the detelerious effect on clinical outcome of hyperglycemia may be secondary to a blood–brain barrier disruption and subsequent sICH. Hyperglycemia is also independently associated with reduced salvage of perfusion–diffusion lesion mismatch tissue, larger final infarct volume, and poor clinical outcome.4 This effect on the penumbra might also explain why hyperglycemia is not associated with worse outcome in lacunar stroke because a penumbra is usually not present in this subtype of stroke.37 Hyperglycemia can cause a worse clinical outcome despite recanalization with a markedly larger increase of the infarction volume.38 Although restoration of the blood flow to the ischemic tissue is essential for penumbral salvage, reperfusion itself can also induce injury; and hyperglycemia is associated with increased reperfusion injury.8,39 Despite all these supporting data, and pending the results of ongoing randomized trials, such as stroke Hyperglycemia Insulin Network Effort (SHINE) trial,40 to date, no clinical trial shows that glucose-lowering treatment improves clinical outcome in patients with AIS.41,42 Hyperglycemia could therefore be only a surrogate marker of larger infarct volume, explaining why interventional studies on hyperglycemia were all inconclusive.

The major limitations of our analysis were the use of obser-vational data, including: the lack of available adjusted results or adequate data to estimate the adjusted effect sizes in a sig-nificant number of studies (which was explained by the dif-ference in objectives between the present systematic review and previous studies); the absence of data on glucose levels time course, HbA1C values, diabetes mellitus’ duration, and type of diabetes mellitus treatment; and the intrinsic biases in baseline characteristics of nonrandomized studies. In patients treated by the endovascular approach, other unavailable data may influence clinical prognosis, such as infarct volumes or collateral flow. Due to multiple comparisons (particularly done in our registry analysis), we cannot exclude the pos-sibility of false-positive association. Finally, the presence of microbleeds or leukoaraiosis, conditions related to hemor-rhagic risk,43 were not documented in our registry or in the

retrieved studies, which is a potential source of heterogeneity in our findings.

In summary, AGL and history of diabetes mellitus are asso-ciated with poor clinical outcome in AIS patients treated by IV or IA thrombolysis. However, the causal relationship between AGL and worse prognosis remains undetermined and needs randomized controlled evidences, such as the ongoing SHINE trial. In fact, only data brought by a large multicenter trial may indicate the role of therapeutic intervention on glycemia in the setting of acute stroke, if any.

Sources of FundingFunding for this study was provided in part by SOS-ATTAQUE CEREBRALE and supported by the Département Hospitalo-Universitaire FIRE (Fibrosis Inflammation Remodeling) of Université Paris-Diderot, France.

DisclosuresNone.

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Pierre Amarenco and Mikael MazighiJaime Gonzalez-Valcarcel, Philippa Lavallée, Lucie Cabrejo, Celine Guidoux, Isabelle Klein,

Jean-Philippe Desilles, Elena Meseguer, Julien Labreuche, Bertrand Lapergue, Gaia Sirimarco,Registry and Systematic Review

Diabetes Mellitus, Admission Glucose, and Outcomes After Stroke Thrombolysis: A

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2013 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/STROKEAHA.111.000813

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SUPPLEMENTAL MATERIAL

Supplemental Tables :

Table e-1. Bichat clinical registry: baseline characteristics according to the quartile of blood glucose level at admission.

Blood glucose level at admission <103

(n=179) 103-121 (n=181)

122-148 (n=167)

>148 (n=177)

Pa

Age, years, mean (±SD) 61 (±18) 69 (±16) 72 (±15) 73 (±14) <0.001Men, n (%) 115 (64.3) 103 (57.0) 84 (50.3) 93 (52.5) 0.065 Hypertension, n (%) 60 (33.5) 92 (50.8) 96 (58.2) 124 (70.5) <0.001Hypercholesterolemia, n (%) 50 (28.1) 49 (27.5) 52 (31.1) 63 (36.4) 0.046 Current or former smokers, n (%) 79 (45.7) 72 (40.7) 49 (31.2) 62 (36.7) 0.10 Antithrombotic, n (%) 65 (36.3) 64 (35.4) 67 (40.1) 85 (48.0) 0.007 Platelet count, 1,000/µl, mean (±SD) 221 (±66) 235 (±71) 233 (±77) 231 (±70) 0.67 SBP, mmHg, mean (±SD) 147 (±21) 151 (±22) 152 (±22) 156 (22) 0.002 DBP, mmHg, mean (±SD) 82 (13) 80 (15) 80 (14) 81 (13) 0.46 NIHSS, median (IQR) 10 (5-16) 11 (5-18) 13 (6-19) 14 (8-18) 0.007 Documented arterial occlusion, n (%)

None 70 (40.5) 69 (40.0) 57 (35.6) 67 (40.6) 0.54 ICA isolated or tandem with MCA 28 (16.2) 28 (16.1) 25 (15.6) 23 (13.9) MCA isolated 70 (40.5) 68 (39.1) 69 (43.1) 69 (41.8) Posterior circulation 5 (2.9) 9 (5.2) 9 (5.6) 6 (3.6)

AIS treatment, n (%) IV alone 118 (65.9) 118 (65.2) 112 (67.1) 116 (65.5) 0.92 Combined IV–IA 46 (25.7) 39 (21.6) 35 (21.0) 40 (22.6) IA alone 15 (8.4) 24 (13.3) 20 (12.0) 21 (11.9)

Mechanical clot removal, n (%) 24 (13.4) 25 (13.8) 19 (11.4) 23 (13.0) 0.96 OTT, min, median (IQR) 150 (118-188) 157 (125-205) 154 (120-185) 166 (130-199) 0.81

a P-values were calculated using blood glucose level as continuous variable (linear regression analysis) Abbreviations: AIS= acute ischemic stroke; DBP= diastolic blood pressure; IA= intra-arterial; ICA= internal carotid artery; IQR= interquartile range; IV = intravenous; MCA = middle cerebral artery; MRA= magnetic resonance angiography; NIHSS= National Institutes of Health Stroke Scale; OTT= onset to treatment time; SBP= systolic blood pressure; SD= standard deviation.

Table e-2. Summary of Retrieved Studies Assessing Impact of diabetes and/or admission Glucose on Acute Ischemic Stroke Outcomes after Reperfusion Therapy

Region/ Country

Center Study period

N Age (men)

NIHSS

Treatment, [Time]

Diabetes n(%)

Glucose mg/dl

Outcome Definitions

n(%)

Direction of association (crude/adjusted) Diabetes Glucose

Australia Royal Melbourne hospital, 2003-2009 1

161 71 (52%)

14 IV rtPA [156 min]

35(22) 140 NI (≥50% decrease in 24h NIHSS) 44 (27) 0 / 0 - / -

Austria Wagner-Jauregg hospital, 2003-2006 2

111 69 (49%)

14a IV rtPA [157 min

a]

22 (20) 118a Favorable outcome 90-day mortality

52 (47) 14 (13)

0 / - 0 / 0

0 / 0 0 / 0

Belgium Leuven hospital 2000-2005 3

100 73 (58%)


a]

12 (12) 123 Modified Favorable outcome

34 (34) 0 / … 0 / …

Canada CASES registry 1999-2001 4-5

1098 70 (55%)

14a IV rtPA [153 min]

166 (15) >140 (27%)

Excellent Outcome 90-day mortality Any ICH sICH (ICH with any clinical worsening)

396 (36) 237 (22) 318 (29) 49 (4)

… / … … / … 0 / ...

… / …

- / - + / + + / … + / 0

London Health Science center, 1999-2003 6

216 72 (51%)


50 (23) 140 NI (≥ 8-points decrease in 24h NIHSS or 24h

NIHSS=0-1) 61 (28) - / 0 - / -

Czech Republic

Palacky/Ostrava hospitals, 2005-2010 7

146 67 (54%)


29 (20) >100 (82%)

Recanalisation (TIBI 3-5 / TICI 2-3 at 2h

after infusion) 58 (40) 0 / … 0 / …

France Lille hospital 2003-2009 8

252 68 (52%)


a]

39 (15) 120a 90-day mortality 40 (16) … / … … / 0

Lyon hospital 1994-2000 9

157 64 (59%)

... IV rtPA [236 min]

29 (18) 140 Any ICH 42 (27) 0 / … 0 / …

Nice hospital 2003-2007 10

142 66 (58%)


17 (12) >120 (49%)

Favorable outcome 71 (50) 0 / 0 - / -

Tenon hospital 2002-2007 11

120 65 (64%)


22 (18) 137 NI (≥5-points decrease in 1h NIHSS) Excellent outcome

22 (18) 44 (37)

0 / … … / …

0 / … 0 / …

Germany Cologne hospitals 1996-2005 12

450 66 (62%)

11a

IV rtPA [135 min

a]

78 (17) … Favorable outcome

239 (53)

- / -

… / …

German stroke 1658 65 .... IV rtPA 395 (24) … In-hospital mortality 166 (10) + / 0 … / …

registers study group 2000-2002 13

(58%) [<3h, 91%]

Heidelberg hospital 1998-2005 14

382 71 (59%)

13 IV rtPA [140 min

a]

… 120a Excellent outcome Favorable outcome 90-day mortality sICHNINDS

142 (37) 191 (50) 65 (17) 24 (6)

… / … … / … … / … … / …

0 / 0 - / - + / 0 0 / …

Heidelberg hospital 2007-2009 15

427 73 (48%)


101 (24) 135 Any ICH sICHECASS-II

51 (12) 10 (2)

0 / … 0 / …

0 / … 0 / …

Italy Verona hospital 2004-2010 16

178 … (58%)

<16 (80%)

IV rtPA [<3h, 66%]

33 (19) 129 Favorable outcome NI (≥4-points decrease in 24-72h NIHSS) sICHECASS-II

116 (65) 20 (11) 10 (6)

0 / … 0 / … 0 / …

0 / ... 0 / ... 0 / ...

Japan J-ACT trial 2002-2003 17

103 71 (62%)


19 (18) 141 Excellent outcome 90-day mortality sICHECASS-II

38 (37) 10 (10) 6 (6)

0 / … 0 / … 0 / …

0 / ... 0 / … 0 / …

SAMURAI registry, 2005-2008 18-19

600 72 (63%)

13a

IV rtPA [145 min]

110 (18) 137 Excellent outcome 90-day mortality ICH sICH (…)

199 (33) 43 (7) 119 (20) 23 (4)

… / 0 … / 0 … / … … / …

- / 0 … / + 0 / + 0 / 0

South Korea Yonsei hospital 2000-2005 20

127 66 (55%)

17 IV rtPA ± IA UK [160 min

a]

32 (25) 160 NI (≥20% decrease in 24h NIHSS) Favorable outcome

64 (52) 66 (52)

0 / … 0 / …

0 / … 0 / …

Netherlands Groningen hospital 2002-2005 21

176 67 (55%)

13a

IV rtPA [<3h, 57%]

20 (11) 116 Favorable outcome 80 (45) 0 / … 0 / 0

Groningen hospital 2002-2006 22

252 68 (54%)

12a

IV rtPA [174 min

a]

29 (12) 115 sICH (ICH and >3-points increase in 48h

NIHSS) 13 (5) 0 / 0 0 / 0

Norway Bergen hospital 1998-200623

127 63 (65%)

13a IV rtPA [...]

8 (6) 120 Favorable outcome … / … … / … … / 0

Spain Germans Trias I Pujol hospital, 2003-2007 24

125 68 (60%)

16a

IV rtPA [140 min]

30 (24) 113a Recanalisation (TIBI 4-5 at 24h after

infusion)

72 (58)

- / ... - / …

Germans Trias I Pujol hospital, 2003-2008 25

234 68 (63%)

14a

IV rtPA [146 min]

57 (24) 135 PHECASS-II 33 (14) 0 / … 0 / …

De la Santa Creu I

Sant Pau hospital, 2000-2008 26

182 68 (54%)

14a IV rtPA [mean 143 min]

40 (22) 130 NI(≥4-points decrease in 24h NIHSS Favourable outcome PHECASS-II

99 (54) 106 (58) 15 (8)

… / … … / … … / …

0 / … 0 / … + / 0

Vall d’Hebron hospital, 2007-2008 27

139 74 (47%)


31 (22) 139 NI(≥4-points decrease in discharge NIHSS) 82 (59) 0 / … 0 / 0


221 70 (51%)


48 (22) >140 (37%)

Recanalisation (Any .at 2h after infusion) 141 (64) 0 / … - / -


138 69 (55%)


28 (20) 156 Favorable outcome sICHECASS-II

67 (49) 8 (6)

0 / … … / …

- / - 0 / …

Villarroel Clinical Hospital, 2002-2010 30

317 72 (56%)

11a

IV ± IA [135 min

a]

78 (25) 128a Excellent outcome 101 (32) - / … 0 / …

4 University hospitals (excluding Vall d’Hebron) 31

254 67 (58%)

15a

IV rtPA [150 min]

57 (22) 140 Favorable outcome 142 (56) 0 / … 0 / …

7 University hospitals (excluding Vall d’Hebron) 1999-2004 32

605 68 (58%)

15a

IV rtPA [151 min]

130 (21) 135 sICHECASS-II 26 (4) + / 0 + / 0

Switzerland Bern hospital 1992-2010 33

623 64 (54%)

15a

IA UK ± MET [268 min

a]

95 (15) … Favorable outcome 90-day mortality Recanalisation (TIMI 2-3 post treatment)

Asymptomatic ICH sICHECASS-II

300 (49) 120 (19) 437 (70) 110 (18) 34 (5)

… / - … / 0 … / 0 … / 0 … / 0

… / … … / … … / … … / … … / …

5 university and 4 community hospitals, 1998-2003 34

325 65 (64%)

14 IV rtPA [158 min

a]

50 (15) 138 Excellent outcome 118 (36) 0 / … - / -

Thailand Thammasat hospital 2007-2010 35

197 64 (60%)


50 (25) 137 Excellent outcome 90-day mortality

93 (47) 23 (12)

0 / 0 + / 0

- / 0 + / +

USA Barrow neurological institute, Phoenix, 1996-2005 36

510 65 (55%)

8a

IV rtPA [126 min

a] 68 (13) 118a sICHNINDS 31 (6) 0 / 0 0 / 0

Cleveland university hospital, 1993-2006 37

488 66 (56%)

13 IV and/or IA [195 min]

105 (22) 142 Recanalisation (TIMI 2-3 at 6h from onset)

Asymptomatic ICH sICHNINDS

207 (76) 86 (11) 52 (18)

0 / … … / 0 0 / …

… / 0 … / 0 + / +

Massachusetts general hospital, 2003-2007 38

352 74 (53%)

14a IV and/or IA […]

69 (20) 119a sICHNINDS 20 (6) 0 / … … / …

Ohio State University College of Medicine, 1995-2007 39

104 68 (54%)

16a

IA [285 min

a]

20 (19) ... Any ICH sICHNINDS

26 (25) 7 (7)

… / + … / 0

… / … … / …

UCLA stroke center, 2002-2006 40

104 71 (49%)

17 IV and/or IA [...]

17 (16) 129 sICH (ICH with any clinical worsening) 17 (16) 0 / 0 + / 0

University of Pittsburgh, 1999-2006 41

185 65 (…)

17 IA ± IV rtPA [333 min]

42 (23) ... ICH 69 (37) 0 / ... ... / ...

University of Pittsburgh, 1999-2005 42

168 64 (…)

17 IA ± IV rtPA [337 min]

34 (20) ... Recanalisation (TIMI 2-3 post-treatment) Recanalisation (TIMI 3 post-treatment)

106 (63) 47 (28)

0 / ... 0 / ...

... / ...

... / ...

UTH stroke center, 1998-2007 43

190 62 (…)

19a

IA ± IV rtPA [277 min]

42 (22) 144 Good outcome (90-day mRs 0-3) 64 (34) 0 / 0 - / -

4 emergency department in Michigan, 1996-2005 44

268 … …. IV rtPA […]

… 131 Discharge disability (mRs>2) In-hospital mortality Any ICH sICHECASS-II

... (...) 35 (13) 27 (10) 18 (7)

… / 0 … / 0 … / 0 … / 0

… / 0 … / 0 … / 0 … / 0

7 endovascular centers, 2005-2009 45

614 67 (47%)

16 IA ± MET […]

166 (27) 140 Favorable outcome 90-day mortality

239 (39) 189 (31)

- / 0 0 / 0

- / - + / +

13 endovascular centers, 46

1122 67 (48%)

17 IA and/or MET [298 min]

265 (24) … Recanalisation (TIMI 2-3 post-treatment) 767 (68) 0 / … … / …

NINDS trial 1991-1994 47

285 … … IV rtPA […]

… (…) … NI (≥ 8-points decrease in 24h NIHSS or 24h

NIHSS=0) 89 (31)

… / 0

… / 0

NINDS trial

1991-1994 48

312 68 (57)

14a

IV rtPA [90 min

a]

… (22) 149 ICH sICHNINDS

34 (11) 20 (6)

0 / … 0 / …

0 / 0 0 / 0

Australia/ Europe

SITS-ISTR, 2002-2007 49

16 049 69 (59%)

12a

IV rtPA [145 min

a] 2735 (17) 117a Favorable outcome

90-day mortality sICHNINDS

sICHSITS-MOST

7222 (53) 2038 (15) 1193 (8) 263 (2)

- / - + / + + / 0 + / 0

- / - + / + + / + + / +

North America (USA/Canada)

MERCI, Multi-MERCI, 2001-2005 50

305 72 (48%)

19a MET (+-IV,IAT) [258 min

a]

… (….) … Recanalisation (TIMI 2-3 post-treatment)

Favorable outcome 90-day mortality

197 (65) 94 (32) 114 (38)

0 / 0 - / 0

0 / …

0 / 0 - / 0

0 / …

Worldwide

SAINT I, SAINT II trials, 2003-2006 51

965 68 (57%)


193 (20) 133 Favorable outcome Any ICH Asymptomatic ICH sICHNINDS

… (46) 221 (23) 167 (17) 54 (6)

… / 0 0 / 0 0 / 0 0 / 0

… / 0 + / 0 + / 0 0 / 0

North America GAIN trial, 1998-1999 52

333 68 (55%)

14 IV rtPA […]

74 (22) … Excellent outcome 90-day mortality

91 (28) … (19)

… / 0 …. / 0

… / … … / …

North America PROACT II trial, 1996-1998 53

110 65 (61%)

17 IA proUK [309 min]

16 (14) 134 sICHNINDS 12 (11) 0 / … + / +

North America, Europe

Multicenter rt-PA Stroke Survey, 1994-1998 54-55

1205 67 (56%)

≤16 60%

IV rtPA [<3h, 91%]

240 (20) 138 Excellent outcome Any ICH sICHNINDS

… (33) 158 (13) 72 (6)

- / - + / + + / +

- / - + / + + / 0

Abbreviation : CASES=canadian alteplase for stroke effectiveness study; ECASS=european cooperative acute stroke study; GAIN=glycine antagonist in neuroprotection; J-ACT=japan alteplase clinical trial; IA=intraarterial; ICH=intracranial hemorrhage; IV=intravenous; MERCI=mechanical embolus removal in cerebral ischemia; MET=mechanical endovascular therapy; mRS=modified Rankin Scale; NI=neurological improvement; NIHSS=national institutes of health stroke scale; NINDS=national institute of neurological disorders and stroke; PH=parenchymal hematoma; PROACT=Prolyse in acute cerebral thrombolysis; TIBI=thrombolysis in brain ischemia; TICI=thrombolysis in cerebral infarction; TIMI=thrombolysis in myocardial infarction; rTPA=recombinant tissue plasminogen activator; SAINT=stroke acute ischemic NXY treatment; SAMURAI=stroke acute management with urgent risk-factor assessment and improvement; sICH=symptomatic intracranial hemorrhage; SITS-ISTR=safe implementation of treatments in stroke-international stroke thrombolysis register; UCLA=university of california los angeles; UK=urokinase; UTH=university of texas at Houston. Data are presented as mean (a or median) unless otherwise indicated. … indicates not done. Favorable outcome defined as a 90-day mRS ≤2 and excellent outcome as a 90-day mRS ≤1. Brief summary of systematic review of association between diabetes and outcomes : Of the seven independent studies (n=1226 patients) that evaluated the effect of diabetes on neurological improvement (with various definitions), one reported a detrimental effect of diabetes in univariate analysis but not in multivariate analysis.6 Of the 23 independent studies (n=23710) that evaluated the effect of diabetes on

functional outcome (favorable in 13 studies, excellent in 7 studies and other definition in 3 studies), six (n=18755)2,33,49,54 reported a detrimental effect of diabetes, with the statistical analysis including the highest number of covariables. Of the eleven studies (n=20861) that analyzed mortality outcome (nine at 90-day and two at hospital discharge), only the largest study (n=16049)49 reported an increased risk of death among diabetics in univariate as well as in multivariate analysis. Regarding sICH, 14 studies (n=4796) reported similar risks in the diabetic and non-diabetic groups, two (n=16654) reported an increased risk associated with diabetes in univariate analysis only,32,49 and one (n=1205)55 reported an increased risk in both univariate and multivariable analyses. When any or asymptomatic ICH was studied (12 studies, n=6066), two reported an increased risk associated with diabetes in multivariable analyses.39,55 Finally, among the eight studies (n=3198) that analyzed recanalization, one reported an unadjusted detrimental effect of diabetes in recanalization assessed at 24h after IV rtPA treatment24; all of the 4 studies restricted to IA therapy did not report significant association. Brief summary of systematic review of association between glucose and outcomes : Of the eight studies (n=1408) that evaluated the effect of AGL on neurological improvement, two reported an inverse association in univariate and multivariate analysis;1,6 all other reported no association. Of the 25 independent studies that evaluated the effect of AGL on favorable outcome, 13 reported no association (n=3028), three (n=1102) reported an inverse association in univariate analysis only18,35,50 and 9 (n=20143) reported an inverse association in univariate and multivariate analysis.4,10,14,29,35,43,,45,49,54 Of them, one reported a positive association with favorable outcome but not with excellent outcome.14 Regarding mortality (11 studies, n=19979), an increase risk of death associated with higher AGL was reported in 6 studies (n=18940)4,10,14, 24,35,45,49 which remained significant after adjustment in 5 studies. Regarding sICH (18 studies, n=23794), an increase risk associated with higher AGL was reported in 7 studies (n=19659)5,32,37,40,49,53,55 which was significant in multivariate analysis for 3 studies (n=16647).6,37,53 When any or asymptomatic ICH was analyzed (11 studies, n=5936), two studies (n=1805) reported a positive association in multivariable analyses19,55 and 3 (n=2245) reported a positive association in univariate analysis only.5,26,51 Finally, among the 5 studies (n=1285) that analyzed recanalization, two reported an inverse association between AGL and recanalization rate (one in univariate analysis).24,28

Supplemental figures :

Figure e-1. Flow chart of study sample for Bichat Registry.

29 patients with missing data on diabetes, pre-treatment glucose level, or 90-day follow-up. (mean age=64 years; men=69%)

733 patients with AIS treated by IV and/or IA therapy between February 2002 and February 2012.

704 patients included in analysis : - 464 treated by IV approach - 160 treated by IV/A approach (adjunctive MET, n=53) - 80 treated by IA approach (direct MET, n=30; adjunctive MET, n=8)

600 patients with no history of diabetes mean±SD glucose level : 124 ± 35 mg/dl

104 patients with history of diabetes mean±SD glucose level : 187 ± 57 mg/dl

Abbreviations : AIS=acute ischemic stroke; IA=intraarterial; IV=intravenous; MET=mechanical

endovascular therapy; SD=standard deviation

Figure e-2. Flow diagram of the systematic review screening process

15 735 citations identified by computerized search

15 517 excluded by title and abstract review

218 reports retrieved for more detailed evaluation

- no data on subgroup treated by reperfusion therapy (n=5)

55 reports included

- data overlap (n=49)

- number of cases <100 (n=10)

163 excluded by full text review : - no information on impact of diabetes/admission glucose level (n=99)

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