markers of increased risk of intracerebral hemorrhage...

Markers of Increased Risk of Intracerebral HemorrhageAfter Intravenous Recombinant Tissue Plasminogen

Activator Therapy for Acute Ischemic Strokein Clinical Practice

The Multicenter rt-PA Acute Stroke Survey

David Tanne, MD; Scott E. Kasner, MD; Andrew M. Demchuk, MD; Nira Koren-Morag, PhD;Sandra Hanson, MD; Martin Grond, MD; Steven R. Levine, MD;

and the Multicenter rt-PA Stroke Survey Group*

Background—Intravenous recombinant tissue plasminogen activator (rtPA) is an effective therapy for acute ischemicstroke, but it is associated with risk of intracerebral hemorrhage (ICH). Our aim was to identify, in a large cohort ofpatients, readily available baseline factors that are associated with thrombolysis-related ICH.

Methods and Results—In a multicenter retrospective and prospective investigation of individual data from 1205 patientstreated in routine clinical practice with intravenous rtPA within 3 hours of stroke symptom onset, 72 patients (6%)developed symptomatic ICH and 86 additional patients (7%) had asymptomatic ICH identified on a routine follow-upCT. In analyses based on clinical variables alone, the main attributes associated with ICH were a history of diabetesmellitus and cardiac disease, increasing stroke severity, advancing age, use of antiplatelet agents other than aspirinbefore stroke onset, and elevated pretreatment mean blood pressure. In additional analyses that incorporated baseline CTand laboratory findings (in a subset of patients), the main associations were early ischemic CT changes, in particular ifexceeding one third of middle cerebral artery territory; increasing stroke severity; diabetes mellitus or elevated serumglucose; and lower platelet counts. Final independent attributes associated with parenchymatous hematoma, defined bypurely radiologically based criteria, were similar to those of symptomatic ICH.

Conclusions—Readily available factors can identify acute ischemic stroke patients at high and low risk for rtPA-relatedICH. These factors require confirmation in a prospective cohort before clinical implementation. (Circulation. 2002;105:1679-1685.)

Key Words: hemorrhage � plasminogen activators � stroke

Intravenous recombinant tissue plasminogen activator(rtPA) administered within 3 hours of symptom onset is an

effective therapy for acute ischemic stroke.1,2 Although dataregarding the use of rtPA in clinical practice are somewhatlimited, several postmarketing studies3–9 have demonstratedoutcomes comparable to those of the pivotal National Insti-tute of Neurological Disorders and Stroke (NINDS) rtPAStroke Trial.1

At present, only a small fraction of potentially eligible strokepatients in the United States are receiving tPA therapy, and it isestimated that the rate of tPA use averages not more than 2%.10

The most critical risk of rtPA therapy, hampering widespread

endorsement by clinicians, is symptomatic intracerebral hemor-rhage (ICH). In the NINDS trial, 6.4% (20/312) patients devel-oped symptomatic ICH within 36 hours of treatment, comparedwith 0.6% in the placebo group. In the European CooperativeAcute Stroke Study (ECASS-II), treatment within 6 hours ofonset was associated with an 8.8% risk of symptomatic ICH,compared with 3.4% in the placebo arm.11

Identification of pretreatment predictors of ICH may im-prove patient selection and may be useful for individualizedcounseling of patients and families. Initial stroke severity,older age, heart disease, high blood pressure, and early CTabnormalities were reported to predict thrombolysis-related

Received November 9, 2001; revision received January 29, 2002; accepted January 29, 2002.From the Stroke Unit, Department of Neurology, Chaim Sheba Medical Center, Tel Hashomer, Israel (D.T.); Comprehensive Stroke Center, University

of Pennsylvania Medical Center, Philadelphia, Pa (S.E.K.); Foothills Hospital, Department of Clinical Neurosciences, Calgary, Canada (A.M.D.);Division of Epidemiology and Preventive Medicine, Sackler School of Medicine, Tel-Aviv, Israel (N.K-M.); Park Nicollet Neuroscience, St Louis Park,Minn (S.H.); Klinik für Neurologie der Universität zu Köln, Cologne, Germany (M.G.); and Mount Sinai School of Medicine, New York, NY (S.R.L).

*Participants in the Multicenter rt-PA Stroke Survey Group are given in the Appendix.Correspondence to David Tanne, MD, Stroke Unit, Department of Neurology, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail

[email protected]© 2002 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000012747.53592.6A

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ICH after stroke, but findings have been inconsistent,12–15 andanalyses were limited by insufficient statistical power.16

In contrast to randomized clinical trials, the present dataare derived from patients treated in broad-based real-lifeclinical practice and thus may be more generalizable. Our aimwas to identify readily available factors associated withrtPA-related ICH in a large cohort of acute ischemic strokepatients treated in clinical practice.

MethodsIndividual patient data were collected from multiple data setscomprising 1205 patients with acute ischemic stroke treated inclinical practice with intravenous rtPA within 3 hours of strokeonset, following the NINDS rt-PA Stroke Trial protocol. Fifty-sixcenters/groups following the NINDS rt-PA Stroke Trial protocolwere invited to participate; 2 declined. Centers had experience withstroke thrombolysis. Some centers have previously reported theirclinical experience but could not study associations of ICH becauseof lack of statistical power. Data sources included the StandardTreatment with Alteplase to Reverse Stroke (STARS) study (296patients)6; the Minnesota Stroke Treatment in the Community(STIC) study (151)7; Cologne, Germany (132)3; 2 centers in Calgary,Canada (60)5; and 49 centers in the United States (566) (includingdata from Houston, Tex [131],8 a US multicenter survey [189],4 andthe OSF stroke network [35]9).

Investigators at each center reviewed records of consecutivepatients treated with rtPA from the time of the publication of theNINDS rt-PA Stroke Trial results until the end of 1998. A standarddata collection instrument with written instructions was used. Wecollected data on variables that, on the basis of previousthrombolysis data (in ischemic stroke or myocardial infarction)and/or biological plausibility, were potentially related to ICH oroutcome. Head CTs were read by a qualified investigator at eachcenter (except in the STIC data set, in which all CTs were readcentrally) who was aware of the clinical presentation but not ofoutcome and presence/absence of ICH. Early CT findings wereassessed and categorized as ischemic changes involving more or lessthan one third of the middle cerebral artery (MCA) territory. Timefrom stroke onset to treatment was categorized as �1 hour, 1 to 2hours, 2 to 3 hours, or �3 hours. Centers/groups were categorizedinto 5 groups (STARS, STIC, Texas, Cologne, and other centers) toassess the effect of site. Pretreatment National Institute of Healthstroke scale (NIHSS) scores,17 measuring neurological impairment,were categorized in 5-point intervals (�5, 6 to 10, 11 to 15, 16 to 20,or �20) and were extracted from the medical records unlessspecifically documented.18

ICH was categorized primarily as symptomatic versus asymptom-atic, in accord with the NINDS trial and the postmarketing prospec-tive STARS trial. Symptomatic ICH was defined as a CT-documented hemorrhage temporally related to clinical deteriorationas judged by the treating physician. Asymptomatic ICH was definedas any CT-documented hemorrhage identified on routine follow-upwithout clinical deterioration. In addition, ICH was categorized by aradiologically based approach as either parenchymatous hematoma(PH) or hemorrhagic infarction. PH was defined, according to theNINDS trial criteria, as findings of a typical homogeneous, hyper-dense lesion with a sharp border with or without edema or masseffect. This hyperdense lesion could arise at a site remote from thevascular territory of the ischemic stroke or within but not necessarilylimited to the territory of the presenting cerebral infarction. Hemor-rhage with an intraventricular extension was considered a PH.Hemorrhagic infarction was defined as findings of acute infarctionwith punctuate or variable hypodensity/hyperdensity with an indis-tinct border within the vascular territory suggested by the acuteneurological signs and symptoms. Follow-up CTs were performed atthe discretion of the treating physician and recorded when performedwithin 36 hours.

Statistical AnalysisInitial bivariable comparisons were performed among 3 groups:symptomatic ICH, asymptomatic ICH, and no ICH. Multivaribleanalyses were performed using logistic regression models. Pretreat-ment variables that were significant with P�0.2 in bivariableanalyses were analyzed in multivariable models and adjusted for ageand sex. Two models were performed for each end point: the firstincorporated baseline demographic and clinical variables; others alsoincorporated results of relevant laboratory and CT attributes (col-lected in a subset of the cohort). Goodness of fit was evaluated by theHosmer-Lemeshow statistic, and discriminatory ability was evalu-ated using the C statistic, or area under a receiver-operator charac-teristic curve.

The study was powered to identify as many as 10 importantvariables that were predictive of symptomatic ICH. Therefore, thesample required �50 to 100 patients with this outcome in thestudy.16 Because symptomatic ICH was expected to occur in �6% ofpatients, the requisite sample size was 800 to 1600 patients and wasachieved via recruitment of active centers and existing databases.

ResultsOf 1205 patients with acute ischemic stroke treated withintravenous rtPA, 72 patients (6%) had symptomatic ICHwithin 36 hours and 86 additional patients (7%) had asymp-tomatic ICH identified on a routine follow-up CT scan.Follow-up CT was not performed in 184 patients (15%)without evidence of neurological deterioration who wereassumed not to have ICH. Mortality rates among thesepatients without follow-up CT (7%) did not differ from thosewithout hemorrhage identified on follow-up CT (10%).

Patients with ICH more often had diabetes mellitus, atrialfibrillation, or other cardiac disease (Table 1). They moreoften used antiplatelet agents before stroke and had higherpretreatment blood pressure. Increasing age and stroke sever-ity were associated with higher risk of ICH (Figure 1). Aparticularly low rate of symptomatic ICH was noted inpatients �60 years old (2%) or with NIHSS �10 (3%). Earlyischemic changes on baseline CT were more often observedin patients with ICH. Hyperdense artery sign was noted moreoften in patients with asymptomatic but not symptomaticICH. The rate of symptomatic ICH was more than doubled inpatients with minor (�33% of MCA territory) early ischemicchanges and more than 4-fold higher in patients with major(�33%) changes compared with those without early ischemicchanges. Higher levels of serum glucose and lower plateletcounts were associated with increasing rate of ICH (Figure 2).

The associations of ICH derived from logistic regressionmodels are presented in Tables 2 and 3. In analyses basedsolely on clinical variables, significant associations of symp-tomatic ICH were older age, history of other cardiac disease,diabetes mellitus, and use of antiplatelets other than aspirinbefore stroke onset. In an analysis that also adjusted for site,categorized into 5 groups, similar associations emerged,including site as an additional independent attribute(P�0.02). Associations of all ICH were increasing strokeseverity, elevated pretreatment blood pressure, history ofdiabetes mellitus, and atrial fibrillation. The goodness-of-fitstatistic (P�0.20) indicated a good fit of this model, and theC statistic was 0.64.

In separate analyses incorporating CT and laboratory datainto the models, these variables tended to take precedenceover the clinical data. Thus, in a model evaluating associa-

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tions of symptomatic ICH, only diabetes mellitus remainedsignificant, whereas lower platelet counts and early CTabnormalities became important indicators of risk. Similarlyfor all ICH, independent associations were baseline strokeseverity, higher glucose levels, lower platelet counts, andpresence of early ischemic CT changes. Early ischemic CTchanges �33% of the MCA territory were the most robustattribute. The goodness-of-fit statistic (P�0.35) indicated agood fit of the model, and the C statistic was 0.71.

Because some variables were not collected by all groupscontributing to this study, the analyses of CT and laboratorydata were limited to a subset of patients. To determinewhether uncollected data were likely to affect the results, anadditional logistic regression model for the end point of allICH was performed that included only clinical variables

among the subset of patients for whom all CT and laboratoryvariables were present. This analysis demonstrated resultssimilar to those obtained from the complete cohort, suggest-ing that patients for whom no laboratory and CT data werecollected were comparable to the overall population.

Additional analyses were performed to study PH (69 casesof 900 for whom data on this outcome were available). Inanalyses based on clinical variables, PH was significantlyassociated with atrial fibrillation (OR 2.28, 95% CI 1.21 to4.32), diabetes mellitus (OR 2.20, 95% CI 1.15 to 4.18),history of hypertension (OR 2.28, 95% CI 1.21 to 4.32), malesex (OR 2.29, 95% CI 1.20 to 4.35), use of antiplatelets otherthan aspirin before stroke onset (OR 5.01, 95% CI 1.49 to17.21), and NIHSS score (OR 1.35 per 1 category increase,95% CI 1.05 to 1.73). Site had borderline statistical signifi-

TABLE 1. Baseline Characteristics of Patients With Acute Ischemic Stroke With and Without ICH

Variable nSymptomatic

ICHAsymptomatic

ICH No ICH P *Symptomatic OR

(95% CI)†Asymptomatic OR

(95% CI)‡

Age, y (mean�SD) 1194 71�11 69�12 66�14 0.002 � � � � � �

Male 1201 45/72 (63) 53/86 (62) 577/1043 (55) 0.28 1.35 (0.82, 2.20) 1.30 (0.83, 2.04)

Hypertension 1198 50/71 (70) 57/86 (66) 621/1041 (60) 0.11 1.61 (0.95, 2.72) 1.33 (0.84, 2.11)

Diabetes mellitus 1195 23/71 (32) 19/86 (22) 198/1038 (19) 0.023 2.03 (1.21, 3.42) 1.20 (0.71, 2.05)

Cigarette smoking 1113 13/67 (19) 20/82 (24) 282/964 (29) 0.16 0.58 (0.31, 1.09) 0.78 (0.46, 1.14)

Prior stroke 1196 9/69 (13) 11/85 (13) 135/1042 (13) 0.99 1.01 (0.49, 2.08) 1.00 (0.52, 1.93)

Atrial fibrillation 1194 23/71 (32) 25/86 (29) 207/1037 (20) 0.009 1.92 (1.14, 3.23) 1.64 (1.01, 2.68)

Other cardiac disease 1203 36/71 (51) 32/86 (37) 356/1046 (34) 0.016 1.99 (1.23, 3.23) 1.15 (0.73, 1.81)

Aspirin therapy 1199 28/70 (40) 36/85 (42) 296/1044 (28) 0.004 1.69 (1.02, 2.77) 1.86 (1.18, 2.91)

Other antiplatelets 1179 5/70 (7) 1/82 (1) 20/1027 (2) 0.014 3.87 (1.41, 10.65) 1.61 (0.21, 12.2)

Time from onset to treatment, h 1183

�2 11/70 (16) 19/85 (22) 219/1028 (22) 1.0 1.0

2–3 53/70 (76) 62/85 (73) 708/1028 (69) 1.49 (0.77, 2.90) 1.01 (0.59, 1.72)

�3 6/70 (9) 4/85 (5) 101/1028 (9) 0.42 1.18 (0.63, 3.29) 0.46 (0.15, 1.38)

NIHSS scores 1026

�5 5/58 (9) 4/79 (5) 106/889 (12) 1.0 1.0

6–10 6/58 (10) 11/79 (14) 253/889 (29) 0.50 (0.15, 1.68) 1.15 (0.36, 3.70)

11–15 19/58 (33) 14/79 (18) 202/889 (23) 1.99 (0.72, 5.49) 1.84 (0.59, 5.72)

16–20 16/58 (28) 28/79 (35) 190/889 (21) 1.79 (0.64, 5.01) 3.91 (1.33, 11.43)

�20 12/58 (21) 22/79 (28) 138/889 (16) �0.001 1.84 (0.63, 5.39) 4.22 (1.41, 12.63)

Pretreatment, mm Hg (mean�SD)

Systolic blood pressure 1177 171�31 172�28 164�28 0.008 � � � � � �

Diastolic blood pressure 1177 90�16 91�18 87�17 0.028 � � � � � �

Mean blood pressure 1177 117�18 118�19 112�18 0.004 � � � � � �

Pulse pressure 1177 81�28 81�22 77�24 0.23 � � � � � �

CT of brain

Hyperdense artery sign 1057 6/59 (10) 19/82 (23) 120/916 (13) 0.029 0.75 (0.32, 1.79) 2.00 (1.16, 3.46)

Early ischemic changes 1056 31/59 (53) 43/82 (52) 254/915 (28) �0.001 2.88 (1.69, 4.90) 2.87 (1.82, 4.53)

Early ischemic changes �33% 1064 9/59 (15) 8/82 (10) 39/923 (4) �0.001 4.08 (1.87, 8.89) 2.45 (1.11, 5.44)

Laboratory results

Serum glucose, mg/dL 784 158�63 150�53 136�58 0.005 � � � � � �

Platelet count, 1000/mm3 636 213�67 218�72 238�84 0.037 � � � � � �

Missing data are excluded from analysis. Categorical values are expressed as number (%), continuous variables as mean�SD.*ANOVA was conducted for continuous variables; �2 test for categorical variables.†Symptomatic ICH vs no ICH groups; ‡asymptomatic ICH vs no ICH groups.

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cance (P�0.048). Separate analyses incorporated CT andlaboratory data into the model. In a final model that used thesignificant attributes, the independent variables and oddsratios were diabetes mellitus (OR 2.69, 95% CI 1.28 to 5.68),platelet counts (OR 0.67 per 50 000 increase, 95% CI 0.50 to0.90), early CT changes �33% of MCA (OR 3.17, 95% CI1.42 to 7.04), and �33% of MCA (OR 9.38, 95% CI 3.68 to23.90).

Outcome of PatientsMortality among patients with symptomatic ICH, asymptom-atic ICH, and no ICH were 60%, 17%, and 10%, respectively;severe disability rates (modified Rankin scale 4 to 5) were32%, 29%, and 26%, respectively; and excellent outcomerates (modified Rankin scale 1 to 2) were 4%, 21%, and 34%,respectively (P�0.001).

DiscussionThe present study assists in risk prognostication for rtPA-related ICH based on clinical information, laboratory data,and head CT. Although these factors appear to influence theprobability of ICH, their presence or absence does notnecessarily reflect which patients are more or less likely to

benefit from rtPA. In this regard, secondary analysis of theNINDS rt-PA Stroke Trial failed to identify independentfactors that altered response to rtPA therapy, other than timeto treatment.19,20

This study corroborates previous findings8 suggesting anassociation between baseline serum glucose and/or diabetesmellitus with ICH after rtPA. Marked hyperglycemia anddiabetes mellitus produce damaging effects on the microvas-culature that may result in increased edema and hemorrhagictransformation after reperfusion. Early ischemic changes onCT, especially if extensive, were strongly associated withICH, and in particular PH. These ischemic changes representearly cytotoxic edema, extended hypoperfusion, and possiblythe development of irreversible injury.21 The frequency ofearly ischemic changes (31%) found in the present study iscomparable to that in clinical trials. The interrater reliabilityof identifying early CT changes and their extent is only fair.22

Therefore, although our results demonstrate the importantpredictive role of early CT changes as read by physicians inclinical practice, our findings are limited by a lack ofcentralized standard CT reading.

Borderline-low platelet counts were associated with ahigher rate of ICH. In addition, patients taking antiplatelet

Figure 1. Risk of all intracerebral hemorrhageby categories of (a) age and (b) baseline strokeseverity. Symptomatic ICH in dark gray.



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agents other than aspirin, mainly ticlopidine, were at high riskof symptomatic ICH or PH. Relatively few patients weretaking these antiplatelet agents, and thus, these finding arepreliminary and should be interpreted with caution.

Borderline-low platelet counts and/or decreased platelet func-tion may be associated with greater risk of ICH in the settingof a compromised hemostatic system after rtPA therapy.Platelets play a pivotal role in mediating the activity of theplasma fibrinolytic system, whereas thrombolytic agents havereciprocal effects on platelet function. The role of platelets

Figure 2. Risk of all intracerebral hemorrhage bycategories of (a) baseline glucose and (b) baselineplatelet counts. Symptomatic ICH in dark gray.

TABLE 2. Logistic Regression Models for Prediction oftPA-Related Symptomatic ICH*

OR 95% CI

Model A: By clinical variables (n�826)

Age (per 10 years) 1.32 1.03–1.69

Other cardiac disease 1.82 1.02–3.25

Diabetes mellitus 2.23 1.21–4.13

Other antiplatelet agents 3.66 1.26–10.64

Model B: By clinical, laboratory, and CT variables(n�398)


Platelets (per 50 000 increase) 0.71 0.52–0.97

Early CT changes �33% of MCA 3.37 1.41–8.05


*Model A incorporated age, sex, hypertension, diabetes mellitus, atrialfibrillation, cigarette smoking, other cardiac disease, use of aspirin, ticlopidine/other antiplatelets, baseline NIHSS score, and mean blood pressure. Model Bincorporated all variables from model A and serum glucose, platelet counts,and early CT changes �33% and �33% of MCA.

TABLE 3. Logistic Regression Models for Prediction oftPA-Related All ICH*

OR 95% CI

Model A: By clinical variables (n�895)

NIHSS (per 1 category increase) 1.38 1.18–1.63

Mean blood pressure (per 25 mm Hg) 1.33 1.07–1.64


Atrial fibrillation 1.67 1.58–3.98

Model B: By clinical, laboratory, and CT variables(n�439)

NIHSS (per 1 category increase) 1.31 1.04–1.64

Glucose (per 50 mg/dL [2.78 mmol/L] increase) 1.36 1.11–1.67

Platelets (per 50 000/mm3 increase) 0.76 0.61–0.92



*For variables incorporated in models, see footnotes for Table 2.



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and antiplatelet agents deserves close scrutiny in futurestudies of thrombolysis for acute stroke.

Initial stroke severity assessed by the NIHSS score wasfound to be an independent marker of subsequent ICH, aspreviously shown.12 Finally, site-related variability was ob-served, and this finding suggests the importance of otherfactors possibly related to ICH risk, such as expertise,experience, protocol adherence, or other unknown elements.

LimitationsData were derived in part from pooling postmarketing studiesand are thus limited by methodological differences among thestudies. Protocol violations may have occurred, and our datareflect these potential errors as part of the reality of clinicalpractice.

Most centers had previous experience with acute stroketrials and thrombolysis and therefore may not represent allhospital types. Data included all consecutive patientstreated with rtPA, but they were obtained by voluntaryreporting without systematic auditing. Because study pro-cedures were not prospectively mandated (eg, follow-upCT), the incidence of some events such as asymptomaticICH may be underestimated. The data were therefore notused to assess absolute risk, but rather to identify associ-ations. We categorized ICH primarily as symptomatic ornot as defined in the NINDS trial. Clinical deterioration asjudged by the treating physician, however, could be part ofthe natural course of a stroke with evolving edema,independent of the coinciding hemorrhage, especially ifhemorrhagic transformation is only a minor part of a largeinfarct. Indeed, recent post hoc analysis from ECASS IIrevealed that only large PH independently impaired prog-nosis.23 Markers of subsequent PH in our analysis, how-ever, were comparable to those of symptomatic ICH.Laboratory and CT data were collected only for a subset ofpatients. Analyses showed little difference between pa-tients with and without these data, however, and also littleeffect on multivariable models. Analyses in this study wereexploratory and data-driven and should therefore be con-sidered to be primarily hypothesis-generating, requiringvalidation in future studies.

In conclusion, key clinical variables, laboratory results, andearly ischemic CT changes are associated with developmentof rtPA-related ICH in routine clinical practice. At present,the factors identified should not dissuade physicians fromtreating patients according to accepted treatment guidelines.These associations may be indicators of higher risk situationsrather than features causally related to ICH. They mayprovide clues about the pathophysiology of rtPA-related ICHthat should be evaluated prospectively in future studies of themerits of thrombolytic therapy.

AppendixThe following data sets, institutions, and investigators contributed tothis survey (number of patients treated in parentheses, in decreasingorder): STARS data set: S.A. Hamilton (296); STIC data set (23hospitals): S.K. Hanson (151); Klinik für Neurologie der Universitätzu Köln, Cologne, Germany: M. Grond (132); Hermann, St Luke’sEpiscopal, Southwest Memorial, and Northwest Memorial Hospitals,Houston, Tex: J.C. Grotta, L. Morgenstern, D. Krieger, S.E. Kasner,

C. Villar, D. Chiu, T. Wein, S. Hickenbottom, R. Felberg, A.M.Demchuk (131); Foothills Medical Center, Calgary, Canada: A.M.Buchan, A.M. Demchuk, P. Barber, N. Newcommon (60); DentNeurological Institute, Buffalo, NY: V.E. Bates, K. Vereczkey-Porter (50); University of Pennsylvania Medical Center, Philadel-phia, Pa: S.E. Kasner, J.C. Chalela, M.L. McGarvey (35); OSFStroke Network, St Francis Medical Center, Peoria, Ill: D.Z. Wang(35); UPMC Stroke Institute, Pittsburgh, Pa: J. DeCampo, L.R.Wechsler (30); Medical College of Wisconsin, Milwaukee, Wis: J.R.Binder, D. Book (27); Henry Ford Hospital, Detroit, Mich: D. Tanne,S. Daley, M.J. Gorman, P. Mitsias, C.A. Lewandowski, S.R. Levine(26); Barrow Neurological Institute, Phoenix, Ariz: J.L. Frey, H.Jahnke (26); University of South Alabama, Mobile: R. Zweifler, N.Koscicki (26); Souers Stroke Institute, St Louis, Mo: S. Cruz-Flores(23); Seton-Hall University, East Orange, NJ: P. Verro (20); StrokeTreatment and Research Center, Medical College of Ohio, Toledo:G. Tiejen (18); Washington University School of Medicine, St Louis,Mo: J.M. Lee, T. Lowenkopf (16); University of Virginia HealthSciences Center, Charlottseville: B.B. Worrall, K.C. Johnston (14);Yale University School of Medicine, New Haven, Conn: P. Fayad, J.Boiser (14); St John Hospital, Detroit, Mich: T. Giancarlo, A.Schuster (11); Harborview Medical Center, Seattle, Wash: K.J.Becker (10); Marshfield Clinic, Marshfield, Wis: P.N. Karanjia (10);University of Alberta Hospital, Edmonton, Canada: A. Shuaib, P.Kochanski (8); University of Michigan Medical Center, Ann Arbor,Mich: P. Scott (8); Sparrow Hospital, Lansing, Mich: S. Wehner (6);Thomas Jefferson University Hospital, Philadelphia, Pa: J.M. Dayno,R. Bell (5); University of Rochester, Rochester, NY: C. Benesch (5);Wayne State University, Detroit, Mich: W.M. Coplin, S. Chaturvedi(5); University of Wisconsin, Madison, Wis: D. Dulli (4); UCLASchool of Medicine, Los Angeles, Calif: M.A. Kalafut, C.S. Kidwell,J.L. Saver (3). Coordinated at Henry Ford Hospital and HealthScience Center: D. Tanne, S. Daley, L. Salowich-Palm, L.R. Schultz,L. D’Olhaberriague, S.R. Levine.

AcknowledgmentsThis study was supported by National Institutes of Health (NIH)grant K23-NS02147 (Dr Kasner), NIH training grant T32-NS07412 to the University of Texas–Houston Medical School,the Canadian Institutes of Health, the Alberta Heritage Founda-tion for Medical Research (Dr Demchuk), an American HeartAssociation Grant-in-Aid (Dr Hanson), and NIH grant R01-NS30896 (Dr Levine).

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Martin Grond, Steven R. Levine and the Multicenter rt-PA Stroke Survey GroupDavid Tanne, Scott E. Kasner, Andrew M. Demchuk, Nira Koren-Morag, Sandra Hanson,

Multicenter rt-PA Acute Stroke SurveyTheTissue Plasminogen Activator Therapy for Acute Ischemic Stroke in Clinical Practice:

Markers of Increased Risk of Intracerebral Hemorrhage After Intravenous Recombinant

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