Evidence Report/Technology Assessment 

Number 127 

Acute Stroke: Evaluation and Treatment 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0021 

Prepared by: 

University of Ottawa Evidence-based Practice Center at The University of Ottawa, Canada 

Mukul Sharma, MD, FRCPC 

Heather Clark, MD, MSc, FRCPC 

Tanya Armour, PhD 

Grant Stotts, MD, FRCPC 

Robert Coté, MD, FRCPC 

Michael D. Hill, MD, MSc, FRCPC 

Andrew M. Demchuck, MD, FRCPC 

David Moher, PhD 

Chantelle Garritty, BA, DCS 

Fatemeh Yazdi, MSc 

Kelly Lumely-Leger, MSc 

Maureen Murdock, MSc 

Margaret Sampson, MLIS 

Nick Barrowman, PhD 

Gabriela Lewin, MD 

AHRQ Publication No. 05-E023-2 

July 2005
ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Sharma M, Clark H, Armour T, Stotts G, Coté R, Hill MD, Demchuck AM, Moher D, Garritty 

C, Yazdi F, Lumely-Leger K, Murdock M, Sampson M, Barrowman N, Lewin G. Acute Stroke: 

Evaluation and Treatment. Evidence Report/Technology Assessment No. 127 (Prepared by the 

University of Ottawa Evidence-based Practice Center under Contract No. 290-02-0021). AHRQ 

Publication No. 05-E023-2. Rockville, MD: Agency for Healthcare Research and Quality. July 

2005.
iii

Preface 

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome written comments on this evidence report. They may be sent to: Director, 

Center for Outcomes and Evidence, Agency for Healthcare Research and Quality, 540 Gaither 

Road, Rockville, MD 20850 or by e-mail to epc@ahrq.gov.

Carolyn M. Clancy, M.D. 

Director 

Agency for Healthcare Research and Quality 

Jean Slutsky, P.A., M.S.P.H. 

Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Kenneth S. Fink, M.D., M.G.A., M.P.H. 

Director, EPC Program 

Agency for Healthcare Research and Quality 

Ernestine W. Murray, B.S.N., R.N., M.A.S. 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 

The authors of this report are responsible for its content. Statements in the report should not 

be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. 

Department of Health and Human Services of a particular drug, device, test, treatment, or 

other clinical service. 
iv

Acknowledgments 

Authors gratefully acknowledge the assistance of the Canadian Stroke Network (CSN) which 

was instrumental in assembling the review team. 

Dr. Isabella Steffensen provided invaluable assistance in her role as technical writer on this 

evidence report, and Linda Brown skillful and swift transcription.
v

Structured Abstract 

Context: Stroke defines an acute vascular event in the brain and is a leading cause of death and 

disability. Ischemic stroke results from decreased blood flow to a portion of the brain with 

consequent cell death. Hemorrhagic stroke, on the other hand, is a result of bleeding into the 

brain. Ischemic stroke is far more common and is potentially treatable with thrombolytic 

therapy. While effective, the wide application of this therapy has been hampered by restrictive 

selection criteria based on time since onset of symptoms. Successful treatment requires a system 

capable of rapidly identifying and evaluating prospective candidates. In this context, use of 

community education, specific ED protocols and designated treatment centers may demonstrate 

some advantages. Evidence is emerging that patient selection by time since stroke onset, 

imaging characteristics, and intra-arterial treatment may increase the probability of 

recanalization of occluded vessels. Normalization of serum glucose, acute blood pressure 

management and surgical extraction of intracerebral clot may be of benefit in some 

circumstances. 

Objectives: The purpose of this report is to systematically review the available literature in the 

field of acute stroke evaluation and treatment. The University of Ottawa Evidence-based 

Practice Center (UO-EPC) task involving the following three areas: (1) what interventions in 

acute stroke (<24 hours from onset) are effective in reducing morbidity and mortality (2) how 

safety and effectiveness of these interventions vary by timing in relation to onset of symptoms 

and (3) determine what the evidence is that specific systems of care improve outcomes of acute 

stroke. 

Data Sources: The databases searched were MEDLINE® (1966 to April Week 4 2004), Embase 

(last 6 months) and CINAHL (1982 to April Week 5 2004) using the OVID interface. Also 

searched were the Stroke Trials Directory, the Cochrane Stroke Group Registry, conference 

proceedings from the 28th International Stroke Conference 2003 (Stroke, Feb 2004) and the 

American Academy of Neurology Annual Meeting (published in Neurology). The Effective 

Practices and Organization of Care (EPOC) registry was searched by the Cochrane review group. 

Study Selection: All results of searches for evidence were provided to two reviewers for 

assessment. All studies were screened by both reviewers by reviewing the bibliographic records, 

and when meeting inclusion criteria, the subsequent full-text of the record. If the reviewers did 

not agree in finding at least one unequivocal reason for excluding the study, it was entered into 

the next phase of the review. The reasons for exclusion were noted using a modified QUOROM 

format.

Data Extraction: Two reviewers independently abstracted the contents of each included study 

using an electronic Data Abstraction form developed especially for this review. Data abstracted 

included the study and population characteristics, intervention characteristics and relevant 

outcomes of included studies. 
vi

Data Synthesis: Attempts were made to minimize, and where not possible, explain statistical 

and clinical heterogeneity. Pooled estimates were only calculated if clinically and statistically 

appropriate. In situations where it was felt to that quantitative synthesis could not be performed, 

a qualitative narrative synthesis was conducted. 

Results/ Conclusions: Currently, available data do not support a role for surgery in the 

treatment of acute intracerebral hemorrhage. Results, however, do not preclude benefit from 

surgery which involves modalities other than those studied in the acute trials (e.g., minimally 

invasive technologies) or treatment of hemispheric hematoma at very early timeframes. Further, 

the available literature did not comment on cerebellar hematoma and thus this analysis does not 

apply to infratentorial hemorrhage. 

In spite of potential importance, availability of therapy and ease of administration of 

antihypertensive agents, very little data exists to suggest that their use is of benefit (or results in 

harm) in the setting of acute ICH. A similar situation exists regarding glucose management for 

acute ischemic stroke. Further studies are required in both these areas. 

IV thrombolysis with tPA is effective and efficacious for acute ischemic stroke within 3 

hours of symptom onset. The effectiveness is strongly linked to time since onset of symptoms 

with shorter times demonstrating significantly better outcomes. Patient level meta-analysis 

suggests that treatment may be effective up to 270 minutes with treatment increasing the odds of 

death beyond 270 minutes. Further work is needed to define the risks and benefits of treatment 

outside the 3 hour window prior to advocating widespread use in these patients. Intra-arterial 

therapy remains an option for a subgroup of patients with large vessel occlusions principally in 

the middle cerebral artery distribution. The evidence for this intervention, however, remains less 

robust than for IV therapy. Limited data is available regarding patient characteristics predicting 

outcome. The system changes required to ensure prompt delivery of appropriate therapy are 

complex and operate on multiple levels. In spite of their critical role, little data exists regarding 

the efficacy of these interventions and, in particular, the relative efficacy of various components 

with regard to patient outcomes. 

Ultrasound for enhancement of thrombolysis in the setting of MCA occlusion has suggested 

efficacy in 2 studies and a definitive trial to demonstrate the benefit and risks is required. 

CT and MRI imaging for patient selection and prediction of outcome in thrombolysis has yet 

to be prospectively evaluated. The two included CT studies differ in onset to evaluation time 

with only a weak correlation between CT changes and outcome seen in the trial enrolling 

patients from 0-6 hours. Neither study quantified CT changes. The ASPECTS score is an easily 

quantifiable scoring system for early infarct changes. Retrospective evaluation of the ASPECTS 

score suggests that values below 7 correlate with poorer outcomes. As CT is widely available 

this system deserves further exploration. Additional information relevant to treatment decisions 

may be provided by CT angiography. Occlusion of proximal vessels is associated with higher 

rates of infarction and thus may influence treatment modalities. 

MRI DWI lesions correlate with the presence of infarcts in small cohorts of patients and time 

to peak measures on early scans may correlate with recanalization after IV tPA treatment. These 

findings require reproduction and further evaluation. The multiplanar abilities and potential for 

acquisition of multiple parameters are potentially attractive features of this modality and may 

assist in selecting patients with a greater ratio of benefit to harm in intravenous and intra-arterial 

treatment paradigms. 
vii

The narrow time window for thrombolysis in acute stroke as well as the relationship between 

time to treatment and outcome has led to the exploration of a number of strategies for 

optimization of outcomes. Community education programs regarding the symptoms of stroke 

have not been independently evaluated but rather studied in the context of more comprehensive 

system changes. Thus it is unclear if these programs are effective in improving patient 

outcomes. Further exploration is also required regarding the content and targeting of such 

programs. Descriptions of designated treatment centers have shown the feasibility of this 

approach but an evaluation of published criteria for and marginal effectiveness of such 

designations remains to be performed.

ix

Contents 

Evidence Report 

Chapter 1. Introduction ................................................................................................................... 3 

Overview..................................................................................................................................... 3 

Objectives ............................................................................................................................... 3 

Background............................................................................................................................. 4 

Stroke Epidemiology .............................................................................................................. 4 

Stroke Costs ............................................................................................................................ 6 

Integration of Thrombolytic Therapy into Current Practice................................................... 6 

Patient Selection for Thrombolysis......................................................................................... 7 

Community Education Programs for Stroke........................................................................... 8 

Acute Stroke Centers .............................................................................................................. 9 

Summary............................................................................................................................... 10 

Chapter 2. Methods...................................................................................................................... 11 

Overview................................................................................................................................... 11 

Key Questions Addressed in This Report................................................................................. 11 

Analytic Framework ................................................................................................................. 12 

 Study Identification................................................................................................................... 14 

Search Strategy ..................................................................................................................... 14 

Eligibility Criteria ................................................................................................................. 14 

Study Selection Process ........................................................................................................ 15 

Data Abstraction ....................................................................................................................... 16 

Summarizing the Evidence ....................................................................................................... 17 

Overview............................................................................................................................... 17 

Study Quality ........................................................................................................................ 17 

Qualitative Data Synthesis.................................................................................................... 18 

Quantitative Data Synthesis.................................................................................................. 18

Chapter 3. Results ......................................................................................................................... 19 

Results of Literature Search...................................................................................................... 19 

Report and Study Design Characteristics of Included Studies ............................................ 19 

Stroke Type.......................................................................................................................... 19 

Severity ................................................................................................................................ 19 

Quality.................................................................................................................................. 20 

Intervention A: Does Surgery Impact the Outcome in Patients with Acute Intracerebral 

Hematoma? .......................................................................................................................... 20 

Intervention B: Does Antihypertensive Treatment Reduce Stroke Related Mortality 

and Disability in Patients with Acute ICH?......................................................................... 25 

Intervention C: Does IA Thrombolysis Reduce Stroke-Related Mortality and Disability 

in Adults With Acute Ischemic Stroke?............................................................................... 27 

Intervention D: Does Treatment to Normalize Blood Glucose Levels Reduce Stroke 

Related Mortality and Disability in Adults with Acute Stroke?.......................................... 32 
x

Intervention E: Does Mechanical Thrombus Disruption Reduce Stroke-Related 

Mortality and Disability in Adults with Acute Ischemic Stroke?........................................ 34 

Intervention F: Is the Effectiveness and Safety of Thrombolytic Therapy for Adults 

with Acute Ischemic Stroke Affected by Time From Onset to Treatment? ........................ 36 

Intervention G: Do Pretreatment CT Scoring Systems Affect the Safety and Efficacy 

of Thrombolytic Therapy for Acute Ischemic Stroke?........................................................ 43 

Intervention H: Do Pretreatment MRI Scoring Systems Affect the Safety and Efficacy 

of Thrombolytic Therapy for Acute Ischemic Stroke?........................................................ 45 

Intervention I: Do CT Perfusion/Angiography Affect the Safety and Efficacy of 

Thrombolytic Therapy for Acute Ischemic Stroke? ............................................................ 48 

Intervention J: Are Community Education Programs Effective in Reducing StrokeRelated Disability and Mortality?........................................................................................ 51 

Intervention K: Are Designated Centers Effective in Reducing Stroke-Related 

Disability and Mortality? ..................................................................................................... 53 

Intervention L: Are ED Protocols for the Management of Acute Stroke Effective in 

Reducing Disability and Mortality?..................................................................................... 55 

Results of Meta-Analyses .......................................................................................................... 60 

Intervention A: Does Surgery Impact the Outcome in Patients with Acute Intracerebral 

Hematoma? .......................................................................................................................... 60 

Intervention C: Does IA Thrombolysis Reduce Stroke-Related Mortality and Disability 

in Adults with Acute Stroke?............................................................................................... 62 

Chapter 4. Discussion ................................................................................................................... 63 

Studies of Treatment of ICH...................................................................................................... 63 

Role of Thrombolysis in Stroke................................................................................................. 63 

North American Post-Marketing Experience............................................................................. 64 

Intervention A: Does Surgery Impact the Outcome in Patients with Acute Intracerebral 

Hematoma (ICH)?................................................................................................................ 65 

Intervention B: Does Antihypertensive Treatment Reduce Stroke-Related Mortality 

and Disability in Patients with Acute ICH?......................................................................... 66 

Intervention C: Does IA Thrombolysis Reduce Stroke-related Mortality and Disability 

in Adults with Acute Ischemic Stroke? ............................................................................... 66 

Intervention D: Does Treatment to Normalize Blood Glucose Levels Reduce StrokeRelated Mortality and Disability in Adults with Acute Stroke?.......................................... 67 

Intervention E: Does Mechanical Thrombus Disruption Reduce Stroke-Related 

Mortality and Disability in Adults with Acute Ischemic Stroke?........................................ 67 

Intervention F: Is the Effectiveness and Safety of Thrombolytic Therapy for Adults 

with Acute Ischemic Stroke Affected by Time from Onset to Treatment? ......................... 68 

Intervention G: Do Pretreatment CT Scoring Systems Affect the Safety and Efficacy of 

Thrombolytic Therapy for Acute Ischemic Stroke? ............................................................ 70 

Intervention H: Do Pretreatment MRI Scoring Systems Affect the Safety and Efficacy 

of Thrombolytic Therapy for Acute Ischemic Stroke?........................................................ 70 

Intervention I: Do CT Perfusion/Angiography Affect the Safety and Efficacy of 

Thrombolytic Therapy for Acute Ischemic Stroke? ............................................................ 71 

Intervention J: Are Community Education Programs Effective in Reducing StrokeRelated Disability and Mortality?........................................................................................ 71 
xi

Intervention K: Are Designated Centers Effective in Reducing Stroke-Related 

Disability and Mortality? ..................................................................................................... 73 

Intervention L: Are ED Protocols for the Management of Acute Stroke Effective in Reducing 

Disability and Mortality? ..................................................................................................... 73 

Limitations ................................................................................................................................. 74 

Research and Clinical Implications ........................................................................................... 75

ICH....................................................................................................................................... 75 

Acute Ischemic Stroke ......................................................................................................... 75 

Conclusions.......................................................................................................................... 77 

References and Included Studies .................................................................................................. 79 

List of Excluded Studies ............................................................................................................... 93 

Figures 

Figure 1. Analytic Framework for evaluation and treatment of acute stroke ...............................13 

Figure 2. Meta-analysis of the impact of surgery on death and disability in patients with acute 

intracerebral hematoma....................................................................................60 

Figure 3. Meta-analysis of the impact of surgery on death in patients with acute intracerebral 

hematoma.....................................................................................................61 

Figure 4. Meta-analysis of the impact of surgery on death in patients with acute intracerebral 

hematoma including data from the Chen RCT and STICH trial .......................................61 

Figure 5. Meta-analysis of the impact of IA thrombolysis on death and disability in patients 

with acute ischemic stroke.................................................................................62 

Figure 6. Meta-analysis of the impact of IA tPA on death in patients with acute ischemic 

stroke..........................................................................................................62 

Tables 

Table 1: Inclusion criteria ..................................................................................16 

Summary Table 1. Intervention A ................................................................................................23 

Summary Table 2. Intervention B..........................................................................27

Summary Table 3. Intervention C..........................................................................30 

Summary Table 4. Intervention D..........................................................................34 

Summary Table 5. Intervention E.................................................................................................36 

Summary Table 6. Intervention F...........................................................................41

Summary Table 7. Intervention G..........................................................................45 

Summary Table 8. Intervention H..........................................................................48 

Summary Table 9. Intervention I..................................................................................................50 

Summary Table 10. Intervention J............................................................................52

Summary Table 11. Intervention K..........................................................................55 

Summary Table 12 Intervention L..........................................................................59 
xii

Appendixes 

Appendix A. Search Strategies 

Appendix B. Correspondence to Targeted Trial Investigators 

Appendix C. Data Assessment and Data Abstraction Forms 

Appendix D. Modified QUOROM Flow Chart 

Appendix E. Evidence Tables 

Appendix F. Additional Acknowledgments 

Appendixes and Evidence Tables are provided electronically at 

http://www.ahrq.gov/clinic/tp/acstroketp.htm 
Introduction

Stroke defines an acute vascular event in the

brain and is a leading cause of death and

disability. Ischemic stroke results from decreased

blood flow to a portion of the brain with

consequent cell death. Hemorrhagic stroke, on

the other hand, is a result of bleeding into the

brain. Ischemic stroke is far more common and is

potentially treatable with thrombolytic therapy.

While effective, the wide application of this

therapy has been hampered by restrictive selection

criteria based on time since onset of symptoms.

Successful treatment requires a system capable of

rapidly identifying and evaluating prospective

candidates. In this context, use of community

education, specific ED protocols and designated

treatment centers may demonstrate some

advantages. Evidence is emerging that patient

selection by time since stroke onset, imaging

characteristics, and intra-arterial treatment may

increase the probability of recanalisation of

occluded vessels. Normalization of serum glucose,

acute blood pressure management and surgical

extraction of intracerebral clot may be of benefit

in some circumstances. 

The purpose of this report is to systematically

review the available literature in the field of acute

stroke evaluation and treatment. The task of the

University of Ottawa Evidence-based Practice

Center (UO-EPC) involved the following three

areas: (1) What interventions in acute stroke (<24

hours from onset) are effective in reducing

morbidity and mortality? (2) How do safety and

effectiveness of these interventions vary by timing

in relation to onset of symptoms? (3) What is the

evidence that specific systems of care improve

outcomes of acute stroke?

Methods 

The databases searched were MEDLINE®

(1966 to April Week 4 2004), EMBASE (last 6

months) and CINAHL® (1982 to April Week 5

2004) using the OVID interface. Also searched

were the Stroke Trials Directory, the Cochrane

Stroke Group Registry, conference proceedings

from the 28th International Stroke Conference

2003 (Stroke, February 2004) and the American

Academy of Neurology Annual Meeting

(published in Neurology). The Effective Practices

and Organization of Care (EPOC) registry was

searched by the Cochrane review group.

All results of searches for evidence were

provided to two reviewers for assessment. All

studies were screened by both reviewers by

reviewing the bibliographic records, and when

meeting inclusion criteria, the subsequent full-text

of the record. If the reviewers did not agree in

finding at least one unequivocal reason for

excluding the study, it was entered into the next

phase of the review. The reasons for exclusion

were noted using a modified QUOROM format.

Two reviewers independently abstracted the

contents of each included study using an

electronic Data Abstraction form developed

Evidence Report/Technology Assessment

Number 127

Acute Stroke: Evaluation and Treatment

Summary

Authors: Sharma M, Clark H, Armour T, Stotts G, Coté R, Hill MD, Demchuck AM, Moher D,

Garritty C, Yazdi F, Lumely-Leger K, Murdock M, Sampson M, Barrowman N, Lewin G

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

especially for this review. Data abstracted included the study

and population characteristics, intervention characteristics and

relevant outcomes of included studies.

Attempts were made to minimize and, where not possible,

explain statistical and clinical heterogeneity. Pooled estimates

were only calculated if clinically and statistically appropriate. In

situations where it was felt that quantitative synthesis could not

be performed, a qualitative narrative synthesis was conducted.

Results 

Intervention A 

Does surgery impact the outcome in patients with acute

intracerebral hematoma? Twenty-three studies were identified

by our search. Meta-analysis was conducted on four studies.

The four trials had a total of 246 subjects. The pooled estimate

favored treatment; however, the confidence interval crossed the

null (OR=0.24 [0.02, 3.03]). A meta-analysis for the outcome

of death produced similar results (OR=0.62 [0.34, 1.13]). The

meta-analysis was repeated including the study published after

the period included in the search strategy. This study had

significantly greater numbers than the other included studies;

however, the conclusion of the meta-analysis was not altered.

Once again, the odds ratio for death had a point estimate

favoring treatment; however, the confidence interval clearly

crossed the null (OR=0.81 [0.54, 1.22]). Moderate

heterogeneity was noted. 

Intervention B 

Does antihypertensive treatment reduce stroke-related

mortality and disability in patients with acute intracerebral

hemorrhage (ICH)? Six studies were identified that

investigated antihypertensive therapy for ICH. Four of these

were non comparative case series and thus were excluded from

our review. Two unique studies met eligibility criteria and were

pre- and post-designs. Neither study commented on outcomes

of death or disability. One suggested that cerebral perfusion

pressure was not altered with antihypertensive therapy.

Intervention C

Does intra-arterial (IA) thrombolysis reduce strokerelated mortality and disability in adults with acute

ischemic stroke? Of the 37 studies identified by the search

strategy, five unique publications met criteria for inclusion. Two

studies could be combined with the pooled estimates for death

and disability and death favoring treatment with a confidence

interval which crossed the null in both cases: death and

disability (OR=0.55 [0.29, 1.16]), and death (OR=0.78 [0.42,

1.47]). Thus, while the pooled estimates for these outcomes are

not statistically significant the possibility of substantial benefit

from intra-arterial therapy cannot be excluded. A pooled

estimate of the impact on disability alone could not be

obtained from the available data. A single study1 suggests an

absolute improvement in the proportion of subjects with a

mRS score < or = 2 of 15 percent. The odds ratio for this

outcome was 2.13 (1.02, 4.42).

Intervention D 

Does treatment to normalize blood glucose levels reduce

stroke-related mortality and disability in adults with acute

stroke? No studies were identified which specifically addressed

this question. Two unique publications demonstrated the

feasibility of reduction in serum glucose levels but were not

designed to measure clinical outcome.

Intervention E 

Does mechanical clot disruption reduce stroke-related

mortality and disability in adults with acute ischemic

stroke? Ten studies were identified by the search criteria and

one, which fell outside the search dates, was provided by an

expert. Of these, two unique RCTs met the criteria for

inclusion. Both evaluated the effect of ultrasound enhanced

thrombolysis in middle cerebral artery (MCA) occlusion.

Primary end points differed but the treatment effect in both

studies favored intervention.

Intervention F

Is the effectiveness and safety of thrombolytic therapy

for adults with acute ischemic stroke affected by time from

onset to treatment? No single study has attempted to

investigate the impact of timing on thrombolysis treatment

outcome. However, five unique publications examining

treatment outcomes across relevant time windows were

included.2

Studies examining enrollment of patients 3 to 5 hours after

stroke onset and 0 to 6 hours after onset did not show

treatment benefit.2,3 Reanalysis of the NINDS trial data4

suggested improved functional outcome for the 0-90 minute

stratum as compared with the 91-180 minute interval. A

patient level meta-analysis of six trials of tPA treatment for

ischemic stroke with treatment windows between 0 and 6
hours was identified which examined the relationship between

onset to treatment time and outcome.5 A clear association was

found between onset to treatment time and outcome. The odds

ratio for favorable outcome with tPA treatment in the 0 to 90

minute interval was 2.81 (95% CI 1.75-4.50). This decreased

to 1.15 (0.90-1.47) in the 271 to 360 minute interval. No

increase in mortality was noted until the 271-360 minute

interval.

Intervention G 

Do pretreatment CT scoring systems affect the safety

and efficacy of thrombolytic therapy for acute ischemic

stroke? Two unique studies were included in this analysis.6

Prospective evaluation of CT scoring systems was not available,

and both included studies are evaluations of CTs conducted

during the course of prospective trials of thrombolysis in stroke.

Analysis of CT scans from patients in the NINDS trial

demonstrates that while early infarct changes are common, they

correlate poorly with outcome.6 A weak association between

early CT changes and outcome was noted in the PROACT 2

trial.7

Intervention H 

Do pretreatment MRI scoring systems affect the safety

and efficacy of thrombolytic therapy for acute ischemic

stroke? Six studies were identified that addressed the

effectiveness of an MRI scoring system for ischemic stroke.

One multiple prospective cohort study8 and one single

prospective cohort study,9 published in 2002 and 2003, were

included in our review. Three non comparative case series

reports10-12 and one case study were excluded for level of

evidence.13 Neither of the included studies used MRI measures

prospectively to make decisions on thrombolysis. Both,

however, provided correlations with surrogate measures which

may be useful in clinical decision making. Recanalisation and

initial diffusion-weighted imaging (DWI) lesions were found to

correlate with clinical outcome and infarct volume at 60 days.

In addition, in patients treated with intravenous tPA, time to

peak was correlated with recanalisation at day 1. Thirteen of 15

patients (93 percent) whose baseline time-to-peak was less than

or equal to 36.9 milliseconds recanalized within the first day

versus 5 of 15 patients (35.7 percent) whose time-to-peak was

greater than 36.9 milliseconds.9 Suarez and colleagues8 reported

a single-center cohort in which the presence of cortical infarct

on MRI was used to select patients for IA treatment following

IV treatment. MR imaging added 17 minutes to the treatment

protocol and thus was felt to be feasible but due to the absence

of a comparison group no comment can be made about

marginal effectiveness over current treatment protocols. 

Intervention I 

Do CT perfusion/angiography affect the safety and

efficacy of thrombolytic therapy for acute ischemic stroke?

Three studies (four publications) examining CT perfusion/

angiography for ischemic stroke were identified.14-17 One

potentially relevant trial14,15 was published in abstract form and

the authors were contacted to determine if subsequent articles

were published. These were excluded following full text

screening. Study design could not be determined in two

publications and were excluded for level of evidence.18,19 One

single retrospective cohort study16 and one case-control study,17

published in 2001 and 2004, respectively, were included in our

review. 

The hyperdense MCA sign was evaluated in a small cohort

of patients treated with either IV or IA Thrombolysis.17 The

hyperdense MCA sign was associated with a greater probability

of recovery with IA than intravenous treatment (37 percent

versus 13 percent). This observational data17 suggests that this

sign may be used as a tool to triage patients between

intravenous and IA treatment. There is a higher probability that

proximal large vessel occlusion as reflected by this sign may be

associated with worse outcomes intravenously. This observation

will require testing in a prospective study. 

Kilpatrick and colleagues16 reported on a retrospective cohort

of 51 patients from a single center between 1997 and 2000. A

CT angiogram showing patent vessels was associated with a rate

of infarct of 7 percent (1/14 patients) while CT angiogram

showing occlusion had an infarct rate of 60 percent (6/10)

(p=0.008). 

Intervention J 

Are community education programs effective in

reducing stroke-related disability and mortality? One

controlled clinical trial,20 six before-after studies,21-26 and one

study for which the study design could not be determined,27

investigated the use of community education programs for

acute stroke. Subsequently, seven studies were excluded for level

of evidence.21-27 Only one study20 was included for our review.

This study was a controlled clinical trial and was published in

2003.

3
4

Morgenstern et al.20 reported on the third phase of the TLL

Temple Foundation Stroke Project. Target behaviors of lay

community (the “at-risk group”), EMS, ED physicians,

neurologists, and community primary care providers were

identified, and educational and infrastructure changes were

initiated. A portion of the multilevel intervention public service

announcements were created using local role models, volunteers

were trained to take the message to community groups, and

educational pamphlets were distributed.

Intervention K 

Are designated centers effective in reducing strokerelated disability and mortality? It has been hypothesized

that to increase utilization of thrombolytics, a dedicated stroke

center strategy should be developed.28 No studies meeting

eligibility criteria for investigating the use of designated centers

as defined by the Brain Attack Coalition were identified by our

searches.28 The studies we included were felt to most closely

resemble the model of a designated stroke center as defined by

the Brain Attack Coalition and detailed by Alberts et al.28 in

their recommendations for the establishment of primary stroke

centers. Both studies were single prospective cohort designs and

were published between 2000 and 2003.

Hill et al.29 reported on building a “brain attack” team to

administer thrombolytic therapy to patients with acute stroke

and on their initial experience with IV-administered

thrombolytics. A complex system of interventions involving all

levels of the system involved in acute stroke care was

reorganized. Over the course of the study period improvements

in certain parameters were noted. Overall, symptom onset to

treatment time was significantly decreased from a mean of

167.8 minutes to 147.4 minutes.29

Lattimore and colleagues reported on a similar process of

designation and implementation of processes to enhance

thrombolysis. An increase in the proportion of ischemic stroke

treated with tPA from 1.5 percent to 10.5 percent was noted.30

Intervention L

Are ED protocols for the management of acute stroke

effective in reducing disability and mortality? Our search

identified one case-control study,31 two single prospective

cohort studies,32,33 two single retrospective cohort studies,34,35

two non-comparative case series studies,36,37 and two studies

whose design could not be determined.38,39 The case-control and

non-comparative studies were excluded for level of evidence.

Four studies, published between 1999 and 2003, examining the

effect of ED protocols for management of acute stroke met our

eligibility criteria and were included in our final analyses.32-35

Smith et al.34 reported on the establishment of ED

procedures and training established for the purposes of

thrombolytic treatment. The program relied on ED physicians,

with neurology consultation, as primarily responsible for

treatment. Treatment times in this model compared favorably

with those in models involving comprehensive stroke team

response. A similar effort is reported by Akins.35 Similar

treatment times were achieved when ED physicians treated as

compared to consulting neurologists. The rate of protocol

violations was initially higher in the ED group (30 percent

versus 5 percent) than the neurologist group but was reduced

by staff education. Jahnke et al.33 described a comprehensive

stroke pathway implemented in the ED. Following this

intervention the stroke pathway was initiated in 97 percent of

patients as opposed to 40 percent prior. The door to needle

time decreased from a mean of 111 minutes to 77 minutes.

Discussion

Currently, available data do not support a role for surgery in

the treatment of acute intracerebral hemorrhage. Results,

however, do not preclude benefit from surgery which involves

modalities other than those studied in the acute trials (e.g.,

minimally invasive technologies) or treatment of hemispheric

hematoma at very early timeframes. Further, the available

literature did not comment on cerebellar hematoma and thus

this analysis does not apply to infratentorial hemorrhage.

In spite of potential importance, availability of therapy and

ease of administration of antihypertensive agents, very little

data exists to suggest that their use is of benefit (or results in

harm) in the setting of acute ICH. A similar situation exists

regarding glucose management for acute ischemic stroke.

Further studies are required in both these areas.

IV thrombolysis with tPA is effective and efficacious for

acute ischemic stroke within 3 hours of symptom onset. The

effectiveness is strongly linked to time since onset of symptoms

with shorter times demonstrating significantly better outcomes.

Patient level meta-analysis suggests that treatment may be

effective up to 270 minutes with treatment increasing the odds

of death beyond 270 minutes. Further work is needed to define

the risks and benefits of treatment outside the 3 hour window

prior to advocating widespread use in these patients. Intraarterial therapy remains an option for a subgroup of patients

with large vessel occlusions principally in the middle cerebral
artery distribution. The evidence for this intervention, however,

remains less robust than for IV therapy. Limited data is

available regarding patient characteristics predicting outcome.

The system changes required to ensure prompt delivery of

appropriate therapy are complex and operate on multiple levels.

In spite of their critical role, little data exists regarding the

efficacy of these interventions and, in particular, the relative

efficacy of various components with regard to patient

outcomes. 

Ultrasound for enhancement of thrombolysis in the setting

of MCA occlusion has suggested efficacy in two studies and a

definitive trial to demonstrate the benefit and risks is required.

CT and MR imaging for patient selection and prediction of

outcome in thrombolysis has yet to be prospectively evaluated.

The two included CT studies6,7 differ in onset to evaluation

time with only a weak correlation between CT changes and

outcome seen in the trial enrolling patients from 0-6 hours.

Neither study quantified CT changes. The Alberta Stroke

Program Early CT Score (ASPECTS) score is an easily

quantifiable scoring system for early infarct changes.40

Retrospective evaluation of the ASPECTS score suggests that

values below 7 correlate with poorer outcomes. As CT is widely

available, this system deserves further exploration. Additional

information relevant to treatment decisions may be provided by

CT angiography. Occlusion of proximal vessels is associated

with higher rates of infarction and thus may influence

treatment modalities. 

MRI DWI lesions correlate with the presence of infarcts in

small cohorts of patients and time to peak measures on early

scans may correlate with recanalization after IV tPA treatment.

These findings require reproduction and further evaluation.

The multiplanar abilities and potential for acquisition of

multiple parameters are potentially attractive features of this

modality and may assist in selecting patients with a greater ratio

of benefit to harm in intravenous and intra-arterial treatment

paradigms.

The narrow time window for thrombolysis in acute stroke as

well as the relationship between time to treatment and outcome

has led to the exploration of a number of strategies for

optimization of outcomes. Community education programs

regarding the symptoms of stroke have not been independently

evaluated but rather studied in the context of more

comprehensive system changes. Thus, it is unclear if these

programs are effective in improving patient outcomes. Further

exploration is also required regarding the content and targeting

of such programs. Descriptions of designated treatment centers

have shown the feasibility of this approach but an evaluation of

published criteria for and marginal effectiveness of such

designations remains to be performed. 

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by the University of Ottawa Evidence-based

Practice Center, under Contract No. 290-02-0021. It is

expected to be available in July 2005. At that time printed

copies may be obtained free of charge from the AHRQ

Clearinghouse by calling 800-358-9295. Requesters should ask

for Evidence Report/Technology Assessment No. 127, Acute

Stroke: Evaluation and Treatment. In addition, Internet users

will be able to access the report and this summary online

through AHRQ's Web site at www.ahrq.gov. 

Suggested Citation

Sharma M, Clark H, Armour T, Stotts G, Coté R, Hill MD,

Demchuck AM, Moher D, Garritty C, Yazdi F, Lumely-Leger

K, Murdock M, Sampson M, Barrowman N, Lewin G. Acute

Stroke: Evaluation and Treatment. Summary, Evidence

Report/Technology Assessment No. 127. (Prepared by the

University of Ottawa Evidence-based Practice Center under

Contract No. 290-02-0021.) AHRQ Publication No. 05-E023-

1. Rockville, MD: Agency for Healthcare Research and Quality.

July 2005.

References

1. Furlan A, Higashida R, Wechsler L et al. Intra-arterial prourokinase

for acute ischemic stroke. The PROACT II study: a randomized

controlled trial. Prolyse in Acute Cerebral Thromboembolism.[see

comment]. JAMA 1999; 282(21):2003-11.

2. Clark WM, Albers GW, Madden KP, et al. The rtPA (alteplase) 0- to

6-hour acute stroke trial, part A (A0276g) : results of a double-blind,

placebo-controlled, multicenter study. Thromblytic therapy in acute

ischemic stroke study investigators. Stroke 2000; 31(4):811-6.

3. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type

plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after

symptom onset. The ATLANTIS Study: a randomized controlled

trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in

Ischemic Stroke.[see comment]. JAMA 1999; 282(21):2019-26.

4. Marler J, Tilley BC, Lu Y, et al. Early stroke treatment associated with

better outcome: the NINDS rt-PA stroke study. Neurology 2000;

55(11):1649-55.

5
5. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with

early stroke treatment: pooled analysis of ATLANTIS, ECASS, and

NINDS rt-PA stroke trials. Lancet 2004; 363(9411):768-74.

6. Patel SC, Levine SR, Tilley BC, et al. Lack of clinical significance of

early ischemic changes on computed tomography in acute stroke.[see

comment]. JAMA 2001; 286(22):2830-8.

7. Roberts HC, Dillon WP, Furlan AJ, et al. Computed tomographic

findings in patients undergoing intra-arterial thrombolysis for acute

ischemic stroke due to middle cerebral artery occlusion: results from

the PROACT II trial.[see comment]. Stroke 2002; 33(6):1557-65.

8. Suarez JI, Zaidat OO, Sunshine JL, et al. Endovascular administration

after intravenous infusion of thrombolytic agents for the treatment of

patients with acute ischemic strokes. Neurosurgery 2002; 50(2):251-9.

9. Hermier M, Nighoghossian N, Adeleine P, et al. Early magnetic

resonance imaging prediction of arterial recanalization and late infarct

volume in acute carotid artery stroke. J Cereb Blood Flow Metab

2003; 23(2):240-8.

10. Chalela JA, Kang DW, Luby M, et al. Early magnetic resonance

imaging findings in patients receiving tissue plasminogen activator

predict outcome: Insights into the pathophysiology of acute stroke in

the thrombolysis era. Ann Neurol 2004; 55(1):105-12.

11. Neumann-Haefelin T, Du M, Fiebach DR, et al. Effect of incomplete

(spontaneous and postthrombolytic) recanalization after middle

cerebral artery occlusion: a magnetic resonance imaging study. Stroke

2004; 35(1):109-14.

12. Tong DC, Adami A, Moseley ME, et al. Prediction of hemorrhagic

transformation following acute stroke: role of diffusion- and

perfusion-weighted magnetic resonance imaging.[see comment]. Arch

Neurol 2001; 58(4):587-93.

13. O'Rourke F, Akhtar N, Emery D, et al. Use of MRI in the

identification and treatment of early ischemic stroke lesions. CMAJ

2004; 170(3):335-6.

14. Kim YB, Lee KH, Lee SJ, et al. Safety and efficacy of intravenous

thrombolysis with tissue plasminogen activator using triphasic

perfusion CT in acute ischemic stroke. Cerebrovasc Dis 2000;

10(Suppl 2):78.

15. Lee K, Lee S, Kim Y, et al. Usefulness of triphasic perfusion CT for

intravenous thrombolysis with tissue plasminogen activator in acute

ischemic stroke. Stroke 2000; 31(11):2889.

16. Kilpatrick MM, Yonas H, Goldstein S, et al. CT-based assessment of

acute stroke: CT, CT angiography, and xenon-enhanced CT cerebral

blood flow.[see comment]. Stroke 2001; 32(11):2543-9.

17. Agarwal PK. Hyperdense middle cerebral artery sign: can it be used to

select intra-arterial versus intravenous thrombolysis in acute ischemic

stroke? Cerebrovasc Dis 2004; 17(2-3):182-90.

18. Koenig M, Kraus M, Theek C, et al. Quantitative assessment of the

ischemic brain by means of perfusion-related parameters derived from

perfusion CT. Stroke 2001; 32(2):431-7.

19. Lee KH, Lee SJ, Cho SJ, et al. Usefulness of triphasic perfusion

computed tomography for intravenous thrombolysis with tissue-type

plasminogen activator in acute ischemic stroke. Arch Neurol 2000;

57(7):1000-8.

20. Morgenstern LB, Bartholomew LK, Grotta JC, et al. Sustained benefit

of a community and professional intervention to increase acute stroke

therapy. Arch Intern Med 2003; 163(18):2198-202.

21. Barsan WG, Brott TG, Broderick JP, et al. Urgent therapy for acute

stroke. Effects of a stroke trial on untreated patients. Stroke 1994;

25(11):2132-7.

22. Smith WS, Corry MD, Fazackerley J, et al. Improved paramedic

sensitivity in identifying stroke victims in the prehospital setting.

Prehosp Emerg Care 1999; 3(3):207-10.

23. Becker K, Fruin M, Gooding T, et al. Community-based education

improves stroke knowledge. Cerebrovasc Dis 2001; 11(1):34-43.

24. Morgenstern LB, King M, Staub L, et al. Community and

professional intervention to increase FDA-approved acute stroke

therapy: final main results of the TLL Temple Foundation stroke

project. Neurology 2001; 56(Suppl 3):A77.

25. Weinhardt J, Parker C. Developing a patient education video as a tool

to case manage patients who have had strokes. Nurs Case Manag

1999; 4(4):198-200.

26. Alberts MJ, Perry A, Dawson DV, et al. Effects of public and

professional education on reducing the delay in presentation and

referral of stroke patients. Stroke 1992; 23(3):352-6.

27. Williams JE, Rosamond WD, Morris DL. Stroke symptom

attribution and time to emergency department arrival: the delay in

accessing stroke healthcare study. Acad Emerg Med 2000; 7(1):93-6.

28. Alberts MJ, Hademenos G, Latchaw RE, et al. Recommendations for

the establishment of primary stroke centers. Brain Attack Coalition.

JAMA 2000; 283(23):3102-9.

29. Hill MD, Barber PA, Demchuk AM, et al. Building a "brain attack"

team to administer thrombolytic therapy for acute ischemic stroke.

CMAJ 2000; 162(11):1589-93.

30. Lattimore SU, Chalela J, Davis L, et al. Impact of establishing a

primary stroke center at a community hospital on the use of

thrombolytic therapy: the NINDS Suburban Hospital Stroke Center

experience. Stroke 2003; 34(6):e55-e57.

31. Figueira FF. Stroke study group. Preliminary results. Early intensive

care improves functional outcome. Arq Neuropsiquiatr 1994;

52(3):330-8.

32. Lin CS, Tsai J, Woo P, et al. Prehospital delay and emergency

department management of ischemic stroke patients in Taiwan,

R.O.C. Prehosp Emerg Care 1999; 3(3):194-200.

33. Jahnke HK, Zadrozny D, Garrity T, et al. Stroke teams and acute

stroke pathways: one emergency department's two-year experience. J

Emerg Nurs 2003; 29(2):133-9.

34. Smith RW, Scott PA, Grant RJ, et al. Emergency physician treatment

of acute stroke with recombinant tissue plasminogen activator: a

retrospective analysis. Acad Emerg Med 1999; 6(6):618-25.

35. Akins PT, Delemos C, Wentworth D, et al. Can emergency

department physicians safely and effectively initiate thrombolysis for

acute ischemic stroke? Neurology 2000; 55(12):1801-5.

36. Wester P, Radberg J, Lundgren B, et al. Factors associated with

delayed admission to hospital and in-hospital delays in acute stroke

and TIA: a prospective, multicenter study. Seek-Medical-Attention-inTime Study Group. Stroke 1999; 30(1):40-8.

6
37. Moulin T, Sablot D, Vidry E, et al. Impact of emergency room

neurologists on patient management and outcome. Eur Neurol 2003;

50(4):207-14.

38. Pearson BJ, Bath PM, Spence JD. Hypertension in patients presenting

with stroke. [Review]. Current Hypertension Reports 2000; 2(6):551-

7.

39. Tilley BC, Lyden PD, Brott TG, et al. Total quality improvement

method for reduction of delays between emergency department

admission and treatment of acute ischemic stroke. The National

Institute of Neurological Disorders and Stroke rt-PA Stroke Study

Group. Arch Neurol 1997; 54(12):1466-74.

40. Pexman JH, Barber PA, Hill MD, et al. Use of the Alberta Stroke

Program Early CT Score (ASPECTS) for assessing CT scans in

patients with acute stroke. AJNR Am J Neuroradiol 2001;

22(8):1534-42.

7
www.ahrq.gov

AHRQ Pub. No. 05-E023-1

July 2005

ISSN 1530-440X
 

Evidence Report

 3 

Note: Appendixes and Evidence Tables cited in this report are provided electronically at http://www.ahrq.gov/clinic/tp/acstroketp.htm 

Chapter 1. Introduction 

Overview 

Stroke defines an acute vascular event in the brain and is a leading cause of death and 

disability. The next two decades are expected to see an increase in the burden of this disease 

worldwide, due to an increase in absolute numbers and proportions of populations in older age 

groups. Ischemic stroke is the most common type of stroke and is the consequence of decreased 

blood flow to a portion of the brain; hemorrhagic stroke, on the other hand, is the result of 

bleeding into the brain. Thrombolytic therapy, most commonly with tissue plasminogen 

activator (tPA), attempts to remove the obstruction to flow. Administration of the thrombolytic 

agent results in the dissolution of blood clots and re-establishment of the supply of oxygen and 

nutrients to the affected area prior to irreversible ultra-structural changes heralding cell death. 

While it is the only available therapy for acute ischemic stroke, wide application has been 

primarily limited due to the narrow time constraints imposed by the natural history of cerebral 

ischemia, which results in irreversible changes within hours. 

Effective deployment of time dependant therapies is contingent upon symptom recognition. 

Community interventions, consisting of public education campaigns, have been promoted and 

deployed as a means to increase utilization of thrombolysis for acute ischemic stroke by 

increasing the number of patients presenting within the time window for treatment. The term 

“brain attack” has been promoted as a means to emphasize the urgency of seeking early 

treatment. Myocardial ischemia shares similar risk factors and treatment benefits linked to a 

time dependent intervention. Previous experience with community interventions of this type in 

acute myocardial infarction, which target thrombolysis to cardiac ischemia, have shown mixed 

results and the potential impact of similar campaigns on acute stroke outcomes, is unclear. Other 

system changes include designation of acute stroke centres and alterations in emergency 

department (ED) protocols. 

Evidence is emerging that patient selection by time of stroke onset, imaging characteristics, 

intraarterial (IA) treatment delivery of thrombolytic agents, and use of intercranial thrombus 

disruption, may increase the efficacy of thrombolytics. Normalization of serum glucose, acute 

blood pressure management, and surgical evacuation of intracerebral clot, may be of added 

benefit in some circumstances. At this time, a review of the impact of these interventions on 

clinical stroke outcomes is warranted in order to assist with their implementation. 

Objectives 

The purpose of this report is to systematically review the available literature in the field of 

acute stroke evaluation and treatment, in order to provide organized evidence relating to a 

number of objectives put forth by the AHRQ. The findings of the report are intended to assist 

the American Association of Health Plans (AAHP) and its member health plans in their 

development and translation of the research findings into practical information for healthcare 

providers and consumers, where applicable. The University of Ottawa Evidence-based Practice 

Center (UO-EPC) task involves the following three objectives: 
4

(1) To determine what interventions for acute stroke (delivered within the first 24 hours 

from onset of symptoms) are effective in reducing stroke-related morbidity or 

mortality. (Note: some studies that initiated interventions beyond 24 hours were also 

included if they were deemed relevant to the topic area being studied). As this 

question was very broad it was refined into 12 key questions. 

(2) To review how the safety and effectiveness of these interventions vary with the timing 

of intervention in relation to onset of symptoms. 

(3) To determine what is the evidence that specific systems of care (i.e., dedicated stroke 

programs) improve outcomes of acute stroke. 

Background 

Stroke has been defined as "rapidly developing clinical signs of focal or global disturbance of 

cerebral function with symptoms lasting 24 hours or longer or leading to death with no apparent 

cause other than of vascular origin."1

 Mechanistically, stroke may be organized into ischemic 

and hemorrhagic forms. In ischemic stroke the primary pathology is one of occlusion of arteries 

carrying blood to the brain. Hemorrhagic stroke includes intracerebral hemorrhage (ICH), which 

is the consequence of vessel rupture and cerebral damage due to pressure and toxic effects of 

blood within the closed space of the skull, and sub-arachnoid hemorrhage (SAH), which is 

bleeding into the space outside the brain but within the subarachnoid membrane. While SAH is 

often included in the definition of stroke for the purposes of surveillance and descriptive 

epidemiology, its presentation and management are sufficiently unique that it will not be 

considered for this analysis.2

 

The incidence of stroke is strongly age-linked.3

 The increasing median age of national 

populations occurring worldwide has led the World Health Organization (WHO) to target this 

disease for surveillance with the goal of reducing associated morbidity and mortality.4

 In 

developed countries such as the U.S., the burden of disease is expected to be higher due to the 

age structure of these populations and has led to the call for the development of organized 

systems of stroke care, with particular emphasis on thrombolytic therapy.5

 Public education, 

which teaches the symptoms of acute stroke and emphasizes the need to seek urgent care, has 

been seen as a means of increasing acute stroke treatment rates and, therefore, improving 

outcomes.6

 

Stroke Epidemiology 

Cerebrovascular disease is the third leading cause of death on a global basis, with rates for 

males ranging from 340.3 cases per 100,000 population in the Russian Federation to 58.7 cases 

per 100,000 in the U.S.7 An estimated 700,000 strokes occurred in the U.S. in 2002, with 

approximately 500,000 cases being first events,7,8 with mortality rates ranging from 39 cases per 

100,000 in New York State to 80.8 per 100,000 in South Carolina. The global burden of 

mortality was estimated at 4.7 million in 1995.9
5

Mortality rates due to stroke have declined for a number of populations in the twentieth 

century.10-13 In the U.S., the rate of decline was approximately 0.5% per year between 1900 and 

1920, and approximately 1.5% per year from 1950 to1970.14,15 All age groups were affected, 

suggesting that this was a period effect rather than a cohort effect. Interestingly, this decrease 

began long before effective therapies for stroke prevention treatment were available, and thus 

cannot be ascribed to medical care. This trend has not continued in the latter part of the century. 

In Rochester Minnesota, the incidence of stroke stabilized at approximately 150 per 100,000 

population and remained so from the mid-1970’s to the mid-1990’s.16,17 While the initial period 

of this stabilization coincided with the introduction of CT scanners, and thus, may be explained 

by an increased probability of diagnosis, such an effect is less likely to explain a persistent 

stabilization through the next two decades. 

While most states have shown a decrease in the mortality rate due to stroke between 1990 

and 2000, Alaska, Maryland and Oregon have shown increases over this time period. Between 

1979 and 2001, stroke discharges from short stay hospitals in the U.S. increased by 25%.7

Stroke incidence in males is 1.25 times greater than that for women. Age-adjusted stroke 

incidence rates per 100,000 population are 167 for White males, 138 for White females, 323 for 

Black males, and 260 for Black females.18 The risk for Black Americans is greater than that for 

White Americans with a risk ratio of 5 for the 35 to 44 year age group in the greater 

Cincinnati/northern Kentucky study.19,20 The risk ratio is greater than 1 for all age groups, 

although it approaches unity in the over 85 age group. It is unclear if this risk ratio reflects 

biologic or social factors or some combination thereof. In spite of the increased risks, fewer 

blacks in the U.S. are candidates for thrombolytic therapy.21 

Hispanic Americans may have an age-specific stroke incidence that differs from nonHispanic whites. Stroke surveillance in this population is challenging and the databases are 

limited. The National Longitudinal Mortality Study (NLMS) suggests that for the 45 to 59 year 

age strata, the relative risk for Hispanic men and women is 1.0 and 1.17, respectively. For the 60 

to 74 year strata, it is 0.53 to 0.76.22 These figures should be interpreted with caution due to 

small numbers. It is unclear if the reduced incidence in the older age strata reflects a true effect 

or incomplete ascertainment. 

A link between incidence, outcome, and socioeconomic status has also been documented in 

the U.K., where unskilled manual workers have a 60% higher risk of stroke than professionals, 

along with a 50% higher age-adjusted mortality rate.23 

While age-specific death rates for stroke have fallen over the last century,24-26 the number of 

such deaths is currently, and is expected to remain, greater for women than men.9

 The projected 

increase in absolute numbers in the U.S. is from approximately 700,000 in 2002 to 1,136,000 in 

2025.8

Both the pending increase in stroke mortality and the gender differences may be explained by 

the strong relationship between stroke and age. It has been over 30 years since the logarithmic 

relationship between stroke mortality and age was described by Kurtzke.27,28 Consequently, it is 

expected that the burden of disease will increase in absolute terms due to the increase in 

population median age and the alteration of the population age structure, despite stable or falling 

age-adjusted incidence rates. 
6

The risk factors for stroke overlap significantly with those for ischemic heart disease. After 

age, the most important risk factor is blood pressure. The risk of stroke increases across the 

measured pressures for both systolic and diastolic pressure.29 For each 10 mm Hg increase in 

systolic blood pressure or 5 mm Hg increase in diastolic pressure, the relative risk of stroke 

increases by a factor of 2.3.30 Anti-hypertensive treatments result in significant reductions of 

risk for first and subsequent stroke.31-33,33,33,33,34 Diabetes and smoking each increase the relative 

risk by a factor of 2.35-39 Hyper-homocysteinemia is an emerging risk factor with a relative risk 

of 5 to 7 between the highest and lowest quartiles of serum homocysteine concentration.40 Atrial 

fibrillation likewise carries a relative risk of 5 for stroke. The link to serum cholesterol is 

somewhat more complex for stroke than for coronary artery disease. Observational studies do 

not show an increased risk with elevated cholesterol levels.41 Low cholesterol may result in an 

increased risk of hemorrhagic stroke.41 In spite of this, a major therapeutic trial of lipid lowering 

therapy has demonstrated a reduction in ischemic stroke incidence without an increase in 

hemorrhagic stroke.42 However, in a sub-group within this trial, patients with prior ischemic 

stroke randomized to statin therapy did not show a reduced incidence of stroke; the benefit 

among this cohort was in reducing subsequent coronary artery disease.(HPS analysis, LANCET) 

Stroke Costs 

Stroke currently consumes significant resources through healthcare costs and disability. 

Twenty-eight percent of total stroke incidence occurs in individuals under the age of 65,43 and 

accounts for 20% of all acute care beds, and 25% of all chronic care beds.44 The acute cost per 

stroke in Ontario was estimated at C$27,500 in 1996. The absolute number of hospitalizations 

for stroke has been increasing for the past 20 years with a projected increase in hospitalizations 

of 10% to 15% between 1996 and 2016.9 Hospitalization makes up 87% of the total direct cost 

of stroke care, which was estimated by the Heart and Stroke Foundation of Canada to be 2.8 

billion dollars in 1996.9 However, this cost does not include costs related to either short- or 

long-term disability. Such costs may be considerable since, in the case of ischemic stroke, only 

25% of people make a full recovery.45 More recent costs are available for the U.S., where the 

estimated direct cost for stroke in 2004 is 33 billion dollars—41% of this is due to hospital costs 

reflecting the expense of acute care. Indirect costs due to loss of productivity are estimated at 

53.6 billion dollars.7

 

Given the trends observed in stroke over the last three decades and the associated costs, 

stroke is, and will remain for the foreseeable future, a significant problem for North American 

and other societies. 

Integration of Thrombolytic Therapy into Current Practice 

Thrombolysis for acute stroke has received widespread, though not universal, support. It is a 

complex intervention making intensive use of resources and personnel, with a narrow therapeutic 

window. Current clinical protocols limit use to a 3-hour window from symptom onset. The 

Brain Attack Coalition (BAC) in the U.S. and the Heart and Stroke Foundation of 

Canada(HSFC) advocate for multilevel system changes to increase the number of patients 
7

eligible for, and receiving, thrombolytic therapy.46,47 Such advocacy has influenced public 

policy. 

The province of Ontario, Canada is in the process of a major system change in stroke care. 

This process is unique among large jurisdictions and forms an important framework for initiating 

and evaluating such strategies. In May 1997, the HSFO of Ontario, a nonprofit group, proposed 

the creation of a coordinated system of stroke care for the province of Ontario. In 1998, a pilot 

program for regional coordination of care was launched at four sites. This was shared by the 

HSFO, and a joint stroke strategy-working group was established in partnership with the Ontario 

Ministry of Health.48 In 2000, based on the results of the initial experience, the Ministry of 

Health funded a coordinated province-wide stroke strategy. Over the next 3 years, a total of nine 

regional stroke centers were designated. The development of integrated acute stroke care was 

seen as a key role of these centers. 

The process of delivering acute stroke therapy involves a pre-hospital phase and an ED 

phase. The latter requires a rapid, intense, and at times, parallel application of clinical, 

radiological, and biochemical analysis of the potential candidate. These evaluations serve to 

interpret compliance with eligibility criteria, thereby maximizing the probability of outcomes 

that parallel results published by the National Institutes of Neurological Disorders and Stroke 

(NINDS) .49 The main determinant of eligibility is time since onset.50,51 Further, within the 

eligible group, regression analysis suggests that earlier treatment is associated with better 

outcome.51 Attention has, therefore, been focused on the pre-hospital phase. Shortening delay 

time in this phase requires recognition of symptoms, a decision to seek care, and transportation 

to a facility capable of delivering care. Multiple mass media strategies were evaluated by the 

HSFO.52 A positive effect was noted in the ability to name two or more warning signs of stroke 

after the mass media campaign and, therefore, a subsequent television campaign was launched in 

Ontario in October 2003. It is not clear, however, that such an education strategy increases the 

number of potentially treatable patients or that it improves outcomes. Furthermore, such an 

intervention runs a risk of increased number of non-stroke patients presenting to the ED. 

Evaluation and treatment of such patients might be expected to increase resource utilization and 

possibly worsen outcomes by exposing individuals to the risk of treatment who do not have any 

possibility of benefit. 

Patient Selection for Thrombolysis

Current treatment protocols for thrombolysis rely on the entry criteria used for the NINDS 

Trial.49 The NINDS trial published in 1995 was the pivotal evidence leading to regulatory 

approval of tPA in North America.49 Clinical protocols currently used for thrombolysis use trial 

criteria regarding patient selection and blood pressure management. This trial has received much 

attention and has been reanalyzed independently on at least two separate occasions.53,54

NINDS criteria require a diagnosis of acute ischemic stroke of less than 3 hours’ duration, 

absence of hemorrhage on CT scan, good blood pressure control, a NIH Stroke Scale Score of 

greater than 4 along with exclusion of those at high risk for bleeding with therapy. Reanalysis of 

the results from the original trial suggest a better outcome if treated within 0 to 90 minutes 

compared to 91 to 180 minutes.55 The stringent time constraints decrease the absolute number 
8

and percentage of individuals receiving treatment. This review will investigate the data 

regarding the relationship between onset to treatment time and outcome. 

The Cerebral Ischemic Penumbra denotes that a portion of the brain which has been rendered 

inoperative by ischemia but has not yet died.56 Time since onset forms a surrogate for tissue 

viability.57 Imaging of acute stroke holds the possibility of identifying the ischemic penumbra 

on a physiologic basis and thus increasing safety, efficacy, and through an extension of the time 

window applicability of revascularization therapy. We will review the evidence that 

pretreatment imaging improves stroke outcomes. 

Community Education Programs for Stroke 

The rates of treatment of acute stroke with the thrombolytic, tPA, are low—2% in the U.S.58

and 1.4% in Canada.59 The narrow eligibility criteria, the lack of comfort with acute neurology 

by many physicians and the perception of a high risk of adverse events contribute to the low 

treatment rates.50 The most significant limiting criterion is time since onset of symptoms. 

Englestein and colleagues retrospectively examined the records of patients admitted to a New 

York hospital with a diagnosis of stroke, for the presence of exclusion criteria for tPA.60 Of 201 

patients identified by ICD-9 codes, 94% were excluded based solely on time of presentation to 

the ED.60 Reports from other centers have documented rates of exclusion by delay time criteria 

of 44%,61 with speculation that differences arise due to variations in public awareness of 

symptoms in different communities.60 In Calgary, 1,168 patients with ischemic stroke were 

prospectively identified and evaluated for reasons for exclusion for tPA therapy. Of these, 

73.1% presented beyond 3 hours after symptom onset and thus could not be considered for 

treatment.51 This was the most common reason for exclusion from treatment. An education 

effort leading to better awareness of symptoms may, therefore, improve treatment rates. 

The Chain of Recovery Writing Group has identified a sequence of events that must take 

place in order to access time-dependent therapies in emergency situations.62 By analogy with 

processes successfully deployed for acute myocardial infarction and trauma, the chain consists 

of: identification of symptoms by patient or bystander; activation of the EMS; alerting treating 

center; and, diagnosis and treatment. 

Initiation of this entire sequence of events is contingent upon the correct identification of 

symptoms along with the appreciation of their gravity. In contrast to major trauma, the 

seriousness of stroke symptoms may not be obvious.62 

Gaps have been identified in the public knowledge of stroke symptoms. A population-based 

random-digit telephone survey was conducted in the Cincinnati region.63 While 70% of 2,173 

respondents correctly identified at least one symptom of stroke, groups at highest risk of stroke, 

including people over 75 years of age, men, and blacks, were the least knowledgeable. In a 

national U.S. phone survey of 750 adults over age 50, 42% could not identify limb numbness or 

weakness as stroke symptoms.6

 Forty percent of respondents were unaware that stroke occurs in 

the brain. Of patients with stroke, 39% were unable to identify any symptoms of stroke. This 

proportion was worst for those over the age of 65 than for those under 65 (47% vs. 28%, 

p=0.016). 
9

Williams interviewed consecutive admitted stroke patients within 72 hours of stroke onset 

regarding knowledge of, and attitude to, stroke symptoms.64 While 38% of 67 individuals 

purported to know stroke symptoms, only 25% correctly interpreted their symptoms as being due 

to stroke. Eighty-six per cent of those arriving after 3 hours felt that the symptoms were not 

serious. Interestingly, patients with prior stroke (46% vs. 16% p=0.03) were more likely to 

ascribe their symptoms to stroke but were no likelier to seek early attention (19% vs. 39% 

p=0.35). Ambulance transport was independently associated with early arrival (OR 5.55, 95% 

CI 1.37 to 22.6). Instructions to use an ambulance in the setting of acute stroke may, therefore, 

result in earlier intervention and improved outcomes. 

Wein reported on the individual activating the EMS in 429 validated admitted stroke patients, 

as part of the TLL Temple Foundation Stroke Project.65 Of these, 38% (163) of patients arrived 

by ambulance. In these cases, the person activating the system was: self, 4.3%; family member, 

60.1%; paid caregiver, 18.4%; and, coworker or other, 12.9%. It was concluded that educational 

efforts directed exclusively at patients themselves were likely to be of low yield and wider 

educational efforts were required. 

Consequently, a number of calls have been made for public education to increase knowledge 

of stroke symptoms.6,66-68 Such community interventions are expected to decrease delay time 

and consequently improve the thrombolysis treatment rates. However, several concerns about 

this approach remain. First, the experience in acute myocardial infarction raises concern about 

the effectiveness of media campaigns for public education in a similar disease state.69 Second, 

knowledge may not translate into action. Patients involved in the Asymptomatic Carotid 

Atherosclerosis Study70 received targeted education on the warning signs of stroke. In spite of 

these efforts in a group motivated enough to participate in the study, only 40% of all first events 

were reported within 3 days of occurrence.70 Participants in an advertised stroke-screening 

program were assessed before and after completion of a detailed evaluation of individual risk 

factors and counseling on risk factors and symptoms.71 After 3 months, 77% of participants 

could name warning signs, compared with 59% prior to the intervention; however, 73% reported 

no change in lifestyle in spite of an individualized written plan of action provided at the 

screening. Finally, the symptoms transmitted to the public in education campaigns are nonspecific.52 Proper identification and immediate action by the public may, therefore, result in an 

increase in the number of non-stroke patients reporting to the ED and thus have no impact on 

outcomes. 

At this stage, while community education programs appear to be attractive, it is clear that 

further review of their effectiveness is warranted. 

Acute Stroke Centers

Community education programs do not occur in isolation. It is clear that the activities carried 

out at the receiving ED may have a significant impact on treatment rates and subsequent 

outcomes. The initial experience in the Cincinnati program suggested rates of hemorrhage with 

thrombolysis as high as 16% associated with an almost 50% rate of violation of protocols.72 This 

experience was followed by a Stroke Quality Improvement Program in nine hospitals and a 

subsequent report from the same group suggested the effectiveness of this intervention, reporting 

a protocol deviation rate of 19% with symptomatic intracranial hemorrhage rate of 6.4%, a 
10

subsequent reduction over the previously reported adverse event rate.73 The Brain Attack 

Coalition has suggested criteria for the designation of stroke centers.5

 Key elements of stroke 

centers include acute stroke teams, stroke units, written care protocols and an integrated 

emergency response system. Support services felt to be important include the availability and 

interpretation of CT scans and rapid laboratory testing. The criteria for such centers were 

developed on the basis of a literature review of English language articles published between 

1966 and 2000, with recommendations issued after review by an expert panel. Establishment of 

stroke centers of this type has been promoted within North America. An estimate of their 

effectiveness would be helpful in terms of planning and justification of resource allocation in the 

wider context of healthcare. Thus, it is our objective to systematically review literature 

pertaining to the use of designated stroke centers to determine their effectiveness in the for acute 

stroke treatment. 

Summary 

Stroke is common, lethal, debilitating, and costly. Treatment in the acute phase is effective,

although available to only a small number of individuals with stroke, resource intensive, and 

potentially hazardous. Increasing the probability of treatment is beneficial on the individual 

level and is expected to also be beneficial at the societal level. The number of potential 

candidates accessing acute stroke treatment is significantly limited by the narrow time window 

between the onset of symptoms and the initiation of treatment. It is widely believed that 

strategies to increase public awareness of stroke and EMS diagnosis are likely to increase the 

number and proportion of patients who are able to receive effective but time-dependent 

interventions. Prior to advocating wide implementation of pre-hospital programs in a complex 

system, it is important to evaluate the likelihood of success of these strategies within plausible 

variations of the effects of these strategies and the risks and benefits of thrombolytic treatment of 

acute stroke. 
 11

Chapter 2. Methods 

Overview 

The UO-EPC’s evidence report on acute stroke is based on a systematic review of the 

scientific-medical literature to identify, and synthesize the results from studies addressing the 12 

questions elaborated by the Acute Stroke Review Panel. Together with content experts, UOEPC staff identified specific issues integral to the review. A Technical Expert Panel (TEP) 

provided expert guidance as to the conduct of the systematic review. Evidence tables presenting 

the key study characteristics and results from each included study were developed. Summary 

tables were derived from the synthesis tables. The methodological quality of the included 

studies was appraised, and individual study results were summarized. For some objectives, 

where meta-analysis was not appropriate, a narrative interpretation of the literature alone was 

provided. 

Key Questions Addressed in This Report 

From the UO-EPC Task three primary objectives, the following key questions were derived and 

addressed in this report. 

Intracerebral hemorrhage (ICH) 

• Does surgery for adults with acute ICH reduce stroke-related mortality and disability? 

(Intervention A)

• Does antihypertensive treatment reduce stroke-related mortality and disability? 

(Intervention B) 

Cerebral Infarction 

• Does intraarterial (IA) thrombolysis reduce stroke-related mortality and disability in 

adults with acute ischemic stroke? (Intervention C)

• Does treatment to normalize blood glucose levels reduce stroke-related mortality and 

disability in adults with acute stroke? (Intervention D)

• Does mechanical thrombus disruption reduce stroke-related mortality and disability in 

adults with acute ischemic stroke? (Intervention E)

Patient selection for thrombolysis 

• Is the effectiveness and safety of thrombolytic therapy for adults with acute ischemic 

stroke affected by time from onset to treatment? (Intervention F)

• Do pretreatment CT scoring systems affect the safety and efficacy of thrombolytic 

therapy for acute ischemic stroke? (Intervention G)

• Do pretreatment MRI scoring systems affect the safety and efficacy of thrombolytic 

therapy for acute ischemic stroke? (Intervention H)
12

• Do CT perfusion/angiography affect the safety and efficacy of thrombolytic therapy for 

acute ischemic stroke? (Intervention I)

• Do patient characteristics (i.e., age, gender, co-morbidities, functional status, 

medications) alter the safety and effectiveness of thrombolysis for acute ischemic stroke?

When available, this data was extracted from the studies and is reported under the 

individual interventions. 

Systems of care 

• Are community education programs effective in reducing stroke-related disability and 

mortality? (Intervention J)

• Are designated centers effective in reducing stroke-related disability and mortality? 

(Intervention K)

• Are ED protocols for the management of acute stroke effective in reducing disability and 

mortality? (Intervention L)

We did not systematically review the effectiveness of IV-tPA. This has been adequately assessed 

in existing reviews and has been well established for patients presenting within 3 hours. The 

seminal trial and a previously published meta-analysis is presented in the discussion section. 

Analytic Framework 

The purpose of this report was to systematically review the available literature in the field of 

acute stroke evaluation and treatment, in order to determine which interventions (delivered 

within the first 24 hours from onset of symptoms) are effective in reducing stroke-related 

morbidity or mortality. We also investigated the relationship between the safety and 

effectiveness of thrombolytic therapy and how they varied with the timing of the intervention in 

relation to the onset of symptoms. Effective acute stroke therapies require a system for rapid 

delivery of complex interventions and as such, occur within the context of an EMS capable of 

identifying and treating appropriate individuals. Each component of this system is in itself an 

intervention, which may result in harm if inappropriate candidates are submitted to treatment 

while others are missed. Thus, we have reviewed the evidence that specific systems of care (e.g., 

dedicated stroke programs) improve outcomes for patients with acute stroke. 

The analytic framework is presented in Figure 1. This framework illustrates the review’s 

context and our conceptual approach regarding relationships between symptom onset, 

interventions/decisions, and outcomes within the context of acute stroke. Within the framework, 

arrows indicate linkages (either preventive or treatment) with associated questions investigated 

by our review. For example, when an individual develops symptoms, what is the evidence for 

the effectiveness of community education programs in influencing the individual’s decision to 

seek emergency medical attention. The framework also highlights our primary outcome 

measures associated with these linkages used to define either success or failure of these 

interventions (i.e., patients are well, disabled, or dead). 
13

Surgery;

antihypertensive

therapy

ASYMPTOMATIC

DEVELOP SYMPTOMS

Dead

Disabled

Well

tPA NO tPA

Pretreatment

CT/MRI

CT/perfusion

glucose

DECISION TO SEEK ATTENTION

ER ASSESSMENT

Designated

center;

ER protocol

Dead

Disabled

Dead Well

Disabled

Well

HEMORRHAGE ISCHEMIA

Designated

center;

ER protocol;

timing of therapy

Figure 1. Analytic Framework for evaluation and treatment of acute stroke. Populations of interest in 

rectangles. Exposure in oval. Outcomes in rounded rectangles. Effect modifiers in hexagons. Solid connecting 

arrows indicate associations and effects reviewed in this report.
 14

Study Identification 

Search Strategy 

Comprehensive search strategies for each individual question were developed and tested in 

the Medline database (Search Strategy 1 in Appendix A). Initially, existing searches from the 

Cochrane Stroke Group were consulted. Indexing terms from relevant articles identified in 

Medline were used, and terms and limits were applied (such as age and trial type). These were 

repeatedly tested to ascertain recall and precision. These strategies were modified in 

consultation with the review team and then executed by two librarians, one who built the search 

and another who validated the strategies. Many of the searches were limited to adult age groups 

and randomized controlled trials (RCTs) using the Highly Sensitive Search Strategy (HSSS), 

designed by the Cochrane Collaboration to identify RCTs in Medline. All searches related to 

question 1 were limited by age and study design, as were all question 2 topics except for question 

2d, which was limited to adults but was not limited by the HSSS. Searches related to question 

three where not limited by either study design or age. Language restrictions were not imposed. 

Non-English articles were included but not used. 

The databases searched were Medline (1966 to April Week 4 2004), Embase (last 6 months) 

and CINAHL (1982 to April Week 5 2004) using the OVID interface. Also searched were the 

Stroke Trials Directory and the Cochrane Stroke Group Registry, as well as conference 

proceedings from the 28th International Stroke Conference 2003 (Stroke, Feb 2004) and the 

American Academy of Neurology Annual Meeting (published in Neurology). The Effective 

Practices and Organisation of Care (EPOC) registry was searched by the Cochrane review group 

for controlled studies, including controlled before and after (CBA) and interrupted time series 

(ITB) designs.

Records identified through electronic searching were downloaded, and duplicate records 

identified and removed using citation management software (Reference Manager®). A total of 

7,320 unique records were retrieved on the initial running of the search. An additional 163 

unique records were retrieved on the updated search run nearing the project’s completion. 

Therefore, after bibliographic records were retrieved through database searches and duplicate 

records were removed; a total of 7,483 unique items remained. The review team nominated four 

additional records. At the suggestion of the TEP, four prominent principle investigators were 

contacted regarding potential data from trials that had been prematurely terminated. Two 

investigators responded, however no unpublished data was provided. 

Eligibility Criteria 

Published and unpublished studies, reported in English,74-76 involving any research design 

(e.g., RCTs reported in English) and enrolling both male and female adult participants (age >16 

years), including members of racial/ethnic populations with acute stroke, were eligible for 

inclusion if each also met the criteria outlined in Table 1. For studies regarding systems of care 
15

for acute stroke, the intervention studied may not be applied to patients with acute stroke (i.e., 

community education programs to increase awareness of symptoms of stroke) but they must be 

applied to improve the care of patients with acute stroke. 

Table 1: Inclusion criteria 

Parameter Acute Stroke Systems of Care 

Design 

Does the article discuss an 

intervention occurring within 24 

hours of stroke? 

Does the article report an original 

intervention trial or series with 

goal to improve the care of 

patients with acute stroke? 

Intervention 

Intracerebral hemorrhage 

(ICH): surgery or 

antihypertensive treatment 

Ischemic Stroke 

Intraarterial thrombolysis, 

normalization of blood glucose, 

mechanical thrombus disruption, 

timing of intravenous (IV) 

thrombolytic therapy, utilization of 

pretreatment CT, MRI or CT 

perfusion/angiography scoring 

systems prior to IV thrombolytic 

therapy 

Community education programs, 

designated stroke centers, ED 

protocols for the management of 

acute stroke 

Outcome Reduction in related morbidity 

and mortality of stroke 

Reduction in related morbidity 

and mortality of stroke. 

Improvement in processes of 

care 

Study Selection Process 

The results of literature searches were posted to the UO-EPC’s internet-based software 

system for review. To enhance the speed and efficiency of conducting and managing the 

systematic review process, this software, which resides on a secure website, was used to enable 

the electronic capture and internal comparison (relative to explicit criteria) of multiple reviewers' 

responses to relevance screening questions, and to requests to abstract specific data (e.g., study 

quality) from bibliographic records or full reports. 

All results of searches for evidence were provided to two reviewers for assessment. A 3-step 

process was used. First, all studies were screened by both reviewers by reviewing the 

bibliographic record (i.e., title, authors, key words, abstract) and applying the inclusion/exclusion 
16

criteria. The record was retained if it appeared to contain pertinent study information according 

to the inclusion/exclusion criteria or if there was not enough information provided to determine 

eligibility at this level. If the reviewers did not agree in finding at least one unequivocal reason 

for excluding the study, it was entered into the next phase of the review. The reasons for 

exclusion were noted using a modified QUOROM format (Appendix D).77

The second step of the review required screening of the full report of the study. The full 

reports were not masked given the equivocal evidence regarding the benefits of this practice.78-80 

To be considered relevant at this second level of screening, all eligibility criteria had to be met as 

determined by both reviewers. 

There are various templates for grading the strength of evidence. Almost all of these 

approaches rate randomized controlled trials (RCTs) at the top of the ranking scheme. This is 

not surprising as RCTs have a comparator group and participants are assigned to all treatment 

groups through randomization. Randomization is unique in that it ‘controls’ for known 

confounders and, perhaps more importantly, unknown ones. Adequate randomization has been 

shown to reduce the influence of bias on the results of RCTs. Other designs, such as cohort 

studies and case control ones, also offer some control over the influence of bias. This is because 

such designs incorporate a comparator group, even though there is no randomization. 

What is less clear is the extent of bias in studies for which there is no controls (i.e., 

comparator group). Although it is feasible to provide data analytical “solutions” to such designs 

there is no adequate way to assess the influence of bias. In such circumstances it is pragmatic 

and scientifically prudent to limit systematic reviews to primary studies that have a comparator 

group.

Thus, in situations where multiple levels of evidence are available, it is generally preferable 

to focus available resources on synthesis of studies that provide higher levels of evidence (e.g. 

RCT, CCT, etc.). In addition to limiting bias, such studies focus on the contrast between groups, 

the impact of differences between studies may be much less than is often the case with studies 

lacking control groups. Thus, restricting our primary attention to higher levels of evidence, 

RCTs, CCT, cohort and case-control studies was thought to help limit one of the most 

troublesome issues in meta-analysis, namely statistical heterogeneity. 

As such, and with approval from the TEP, a third level screening was implemented beyond 

full relevance assessment where we sought to include only, whenever possible, reports of RCTs. 

For questions for which there were at least three RCT reports, designs of other reports were 

excluded. Where reports of RCTs did not exist, lower level evidence was included, such as 

reports of observational studies. 

All disagreements were resolved by consensus and, if necessary, a third party facilitated. 

Excluded studies were noted as to the reason for their ineligibility (see List of Excluded Studies 

for Level of Evidence and List of at the end of the report). 

Data Abstraction 

After training and following a calibration exercise involving two studies, two reviewers 

independently abstracted the contents of each included study using an electronic Data 
17

Abstraction form developed especially for this review (Appendix C). Once a reviewer 

completed their work, they then checked all of the data abstracted by their counterpart. Data 

abstracted included the characteristics of the: 

• Report (e.g., publication status, year of publication) 

• Study (e.g., sample size; research design; number of arms) 

• Population (e.g., baseline characteristics) 

• Intervention (e.g., IV thrombolytics according to time delivered post stroke) 

• Withdrawals and dropouts 

Summarizing the Evidence 

Overview 

Evidence tables in the Appendices offer a detailed description of the included studies (e.g., 

study design, population characteristics, intervention[s] and outcome[s]), with a study being 

represented only once. The tables are organized by research question and study design, with 

designs purporting to induce less bias coming before those designs were bias might be a more 

substantial problem (e.g., RCTs before single group pre-post studies). Question-specific 

Summary Tables embedded in the text report each study in an abbreviated fashion, highlighting 

some key characteristics, such as comparators and sample size. This allows readers to compare 

all studies addressing a given question. A study can appear in more than one Summary Table 

given that it can address more than one research question. 

Study Quality 

Evidence reports include studies of variable methodological quality. Differences in quality 

across, and within, study designs may indicate that the results of some studies are more biased 

(i.e., systematic error) than others. Systematic reviewers need to take this information into 

consideration to reduce or avoid bias whenever possible. In this report, study quality was 

assessed through examination of each individual report. No attempt was made to contact the 

authors of any report. Quality was defined as the confidence that the study’s design, conduct, 

analysis, and presentation, has minimized or avoided biases in any comparisons.81 Several 

approaches exist to assess quality including components, checklists, and scales. For this report, 

we have elected to use a combination of methods in an effort to ascertain a measure of reported 

quality across different study designs. 

For RCTs, the Jadad scale was used (Appendix C). This validated scale includes three items 

that assess the methods used to generate random assignments, double blinding, and a description 

of dropouts and withdrawals by intervention group.82 The scoring ranges from 1 to 5, with 

higher scores indicating higher quality. In addition, allocation concealment was assessed as 

adequate, inadequate or unclear (Appendix C).83 An a priori threshold scheme was used for 
18

sensitivity analysis—a Jadad total score of ≤2 indicates low quality and scores >2 indicates 

higher quality. For allocation concealment, adequate = 1, inadequate = 2, and unclear = 3. 

Cohort and case-control study reports were assessed using the Newcastle-Ottawa scale 

(NOS). The NOS is an ongoing collaboration between the Universities of Newcastle, Australia 

and Ottawa, Canada to develop an instrument providing an easy and convenient tool for quality 

assessment of nonrandomised studies to be used in a systematic review. The scale uses a “star 

system” in which a study is judged on three broad perspectives: the selection of the study groups; 

the comparability of the groups; and, the ascertainment of either the exposure for case-control 

studies, or the outcome of interest for cohort studies. The inter- and intra-rater reliability of the 

NOS have been established. The face content validity of the NOS has been reviewed based on a 

critical review of the items by several experts in the field who evaluated its clarity and 

completeness for the specific task of assessing the quality of studies to be used in a metaanalysis. Further, its criterion validity has been established with comparisons to more 

comprehensive, but cumbersome, scales. An assessment plan is being formulated for evaluating 

its construct validity with consideration of the theoretical relationship of the NOS to external 

criteria and the internal structure of the NOS components.84

We did not conduct any sensitivity analysis of quality assessments on the observational 

studies, since there is little by way of guidance to suggest what a poor quality study’s score 

would be based on for these assessment instruments. 

Qualitative Data Synthesis 

A qualitative synthesis was completed for all studies included in the Evidence Report. A 

description is provided of the progress of each citation through the review process, and includes 

information pertaining to each report, such as their sample size. The qualitative synthesis was 

performed on a question-specific basis, with studies grouped according to research design (e.g., 

RCTs, observational studies). Each synthesis includes a narrative summary of the key defining 

features of the study report, if stated, (e.g., a priori description of inclusion/exclusion criteria), 

population (e.g., diagnosis-related), intervention/exposure (e.g., use of IA thrombolysis), 

outcomes, study quality, applicability, and individual study results. A brief study-by-study 

overview typically precedes a qualitative synthesis. 

Quantitative Data Synthesis 

We performed meta-analyses of RCTs when interventions were clinically homogenous and 

two or more studies reported an outcome of interest. We focused on two dichotomous outcomes: 

(1) death, and (2) death or disability, measured as scores of 0 or 1 on the modified Rankin Scale 

(mRS). Odds ratios comparing the outcomes in the experimental and control groups were used 

as the effect measure for pooling. The chi-square test and the associated I2

 statistic85 were used 

to assess heterogeneity in odds ratios. Meta-analytic pooling was performed using the 

DerSimonian and Laird random effects method.86
 19

Chapter 3. Results 

Results of Literature Search 

A total of 9,994 bibliographic records were retrieved through database searches 

(QUOROM flow chart, Appendix D). After 2,511 duplicate records were removed, 7,483 unique 

items remained. The reviewers nominated an additional four potentially relevant studies. A total 

of 7,487 reports were evaluated against the eligibility criteria and after the initial screening for 

relevance, 6,098 records were excluded. The remaining 1389 reports were then retrieved and 

subjected to a more detailed relevance assessment. After further relevance assessment, 1,253 of 

the 1,389 reports failed to meet the inclusion criteria. An additional eligibility criterion of level 

of evidence was then applied to the 136 remaining studies. One hundred bibliographic records 

that were examined and categorized to one of the 12 specific interventions examined, were 

deemed not to provide sufficient level of evidence for their related question. The reasons for 

exclusion are listed in the QUORUM flow chart (Appendix D). In total, 36 records (reporting on 

37 studies) were deemed relevant and provided sufficient level of evidence for the systematic 

review. The Evidence Tables are presented in Appendix E and provide descriptive 

characteristics and results from the interventions. Experimental studies are presented first 

followed by observational studies in the following study design order: randomized clinical 

controlled trials; clinical controlled trials; prospective cohorts; retrospective cohorts; case-control 

studies; and before-after studies. 

Report and Study Design Characteristics of Included Studies 

The 36 studies included 6,960 individuals, ranging in age from 19 years to 95 years. 

Twenty-three studies reported on percentage of male participants, which ranged from 38.2% to 

76%.67,87-108

Stroke Type

As expected, participants with acute ischemic stroke were drawn from admitting hospitals 

and EDs in 26 of 34 studies (72.7%)55,67,92-94,97,99-102,104-118 and nine of 34 studies (27.3%) 

admitted patients with ICH.87-91,96,119-121 Two studies (6%) recruited patients with both ischemic 

and hemorrhagic stroke.95,103

Severity 

Twenty-two studies specified the baseline severity of stroke using the NIHSS. Eighteen 

studies used only the NIHSS,55,67,93,94,97,99-102,104-106,108,109,109-118 whereas, four studies used other 

scales in addition to NIHSS.92,97,107,116 Four studies included patients with all severity types 

assessed by NIHSS ,67,99,102,113 whereas, the remainder of the studies included subjects with 

moderate to severe stroke excluding mild strokes as defined by NIHSS of less than 4.55,92-
20

94,97,100,101,103,106,109-112,114-117 One study used the mRS alone,118 seven studies used other various 

scales such as the Glasgow Coma Scale (GCS),87-89,121 level of consciousness,119 New York 

Heart Association grade system,96 or clinical and neurological measures;120 five studies did not 

report on the baseline severity of stroke of the subjects recruited.90,91,95,104,105

Quality 

The quality of included RCTs (n=24) was scored using the Jadad scale (scores range from 0 

to 5). Only one RCT study reported on all Jadad items.113 Nine RCTs received only one 

point.55,87,93,95,97,115,119-121 Allocation concealment was assessed as adequate in three 

studies,92,111,113 inadequate in one,93 and unclear for the remaining 20 studies.55,67,93,94,97,99-102,104-

119 55,67,87-89,94-97,99,109,110,112,114,115,120,121 One included controlled clinical trial103 was scored using 

a modified version of the Jadad scale (range 1 to 3) and received a score of 1. Only one of the 

nine included cohort studies reported on all the NOS items,117 for a maximum of 9 points. The 

remaining reports scored between 5 and 8 points.100-102,104-106,118 One included case-control study 

received 8 points.116 Three pre-post study designs were included in our review, however, the 

quality could not be determined.90,91,105

Intervention A: Does Surgery Impact the Outcome in Patients with 

Acute Intracerebral Hematoma? 

Twenty-three studies investigating the effectiveness of surgery for ICH were identified by 

our searches. One relevant study was identified by an expert122and was published beyond our 

search dates. This study, along with five unique parallel RCTs met our eligibility criteria and 

was included in our final analyses (Summary Table 1).87-89,119-121 Studies were published 

between the years 1989 and 2003. Eighteen studies were excluded for level of evidence and 

included one non-RCT,123 three single prospective cohorts,124-126 five case-control studies,127-131

eight non-comparative case series,132-139 and one study whose design could not be determined.140

Primary intracerebral hematoma has a poor outcome, with case series approaching a 50% 

fatality rate.141 Hematoma growth is reported in 38% of patients in the first 24 hours, with 

consequent deterioration due to local pressure effects, perilesional ischemia, and toxic effects of 

thrombin and blood degradation products.142 Functional outcomes substantially impaired in 

survivors, with only 16% of patients randomized into the ISTICH Trial having either good 

recovery or moderate disability, as measured by the Glasgow Outcome Scale at 6 months.143 

Morgenstern and colleagues reported on patients with ICH from a Prospective Registry and a 

randomized trial in Houston between 1993 and 1996.87 Sequential patients were initially added 

to the registry provided that they had hematomas greater than 9 mL in size and could be operated 

on within 12 hours. The registry contained a total of 41 patients, seven of whom had surgery 

(open craniotomy) and 34 of whom were treated medically. Surgical patients were more likely 

to have shorter median time from symptom onset to arrival at the ED (2.9 hours versus 5.4 

hours). The median hematoma volumes were larger in patients receiving craniotomy (96.2 mL 

vs. 32.8 mL). In the nonrandomized group, there was a trend towards a better 6-month outcome 
21

as measured by the Barthel Index for medically treated patients (Barthel Index score of 85 versus 

65 for surgically-treated patients). This difference was not, however, significant. 

The prospectively randomized group contained 34 patients. All of the patients had a lobar or 

deep hemispheric hematoma greater than 9 mL but less than 20 mL in size. Patients with 

cerebellar and brain stem hematomas were excluded. The intervention group received 

craniotomy with hematoma extraction. The control group was admitted to a neurological 

intensive care unit with ICP monitoring. Treatment including mechanical ventilation, osmotic 

diuretics, and ventricular drainage, was carried out as needed to maintain an ICP of less than 21 

cm of water. The primary outcome measure in this randomized group was 6-month survival, 

which slightly favored the surgical group (81% versus 76%). This difference, however, was not 

significant. 

The surgical patients had somewhat poorer entry Glasgow Coma Outcome Scale (GOS) 

scores and, therefore, there was a bias against good outcome in these patients. The trial was also 

significantly hampered by low power. The limited number of subjects resulted in a 50% power 

to detect a 4-fold decrease in 6-month mortality of 25%. Of potential importance, the medically 

treated group did not have a standard regimen for blood pressure, and steroid treatment was not 

permitted. 

Teernstra et al.88 reported on a multicenter RCT carried out in the Netherlands between 1996 

and 1999 that examined the stereotactic treatment of intracerebral hematoma by means of a 

plasminogen activator (SICHPA). Seventy-one patients over the age of 45 with non-traumatic 

supratentorial hematomas with volumes of 10 mL or greater, and Glasgow eye motor scores 

between 2 and 10, were randomized to either the surgical group (n=36) or non-surgical (control) 

group (n=35). The surgical group had the intervention performed within 72 hours of onset. 

Treatment consisted of placement of a stereotactic catheter with 5000 IU of urokinase injected 

every 6 hours for eight cycles of treatment. At the end of each cycle, gentle aspiration was used 

to remove any liquefied hematoma. The control group was described as receiving “standard 

supportive care.” There was no requirement for ICP monitoring. The primary endpoint was 

death at 6 months. Mortality at this time point was 56% in the surgical group and 59% in the 

medical group with no significant difference noted in a Cox Regression Analysis. The 

stereotactic surgery group did demonstrate lower hematoma volumes. Supportive care and 

baseline characteristics were similar between the two groups, with the exception that surgical 

patients more often received low molecular weight heparin and mechanical ventilation, and 

generally had a slightly lower Glasgow Coma Score on admission. 

Auer et al.119 compared endoscopic surgery within 24 hours with conservative management. 

One hundred patients, between 30 to 80 years of age, with hematomas over 10 cm3

 and a 

neurologic deficit, were randomized. All patients had supratentorial bleeds and angiograms to 

exclude aneurysmal hemorrhage or arteriovenous malformation. Patients randomized to surgery 

had a bur hole performed through which a 6 mm neuroendoscope was inserted. The scope was 

guided by intraoperative ultrasound. Once the probe was inserted, alternating irrigation and 

suction was performed under video guidance with bleeding cauterized by means of a laser within 

the instrument. The conservatively managed group was treated with hyperosmolar agents, 

cortisone, and antifibrinolytic agents. Blood pressure was kept between 140 and 160 mmHg 

irrespective of the presenting blood pressure. Outcome was analyzed at 6 months by means of 

the mortality rate and quality of survival measured on an ad hoc 6-point scale. At 6 months, 
22

mortality was 42% in the surgical group and 70% in the medical group, which was felt to be 

significant. There was no overall difference in quality of survival. 

Batjer et al.120 studied 21 patients between 1983 and 1989 at a single center in Texas using a 

RCT design. Patients aged 30 to 75 years with putamenal hemorrhages greater than 3 cm in 

diameter by CT scanning, were included. All patients were required to be hypertensive, which 

was arbitrarily defined as a minimal recorded blood pressure within the medical record of 

160/95. Patients with minimal hemiparesis, decorticate or decerebrate posturing were excluded. 

Three arms were studied: best medical management, best medical management plus intracranial 

pressure monitoring, and surgical evacuation. Medical management was rigorously defined to 

include Decadron, antihypertensive therapy to decrease blood pressure by 25% within 24 hours, 

intermittent Lasix and Mannitol with specified criteria for intubation and mechanical ventilation. 

The second intervention was best medical management, as defined above, with intracranial 

pressure monitoring. The monitor was used to modify medical intervention such that the 

pressure was maintained at 20 mmHg. The surgical group was treated with craniotomy, with 

control of blood pressure intraoperatively, and a standardized surgical approach. The trial had a 

pre-planned sample size of 60, but was terminated after 21 patients had been randomized, since 

no difference between the three treatment groups was observed, and the outcomes were felt to be 

poor. At 6 months, 15 of 21 patients were dead or vegetative. The numbers were felt to be too 

small for meaningful statistical comparison; regardless, no differences were noted between the 

three groups. 

Juvela et al.121 reported on the experience of 52 patients with supratentorial spontaneous 

intracranial hemorrhage at a single center in Finland. Patients were enrolled between 1982 and 

1986. Patients with aneurysmal hemorrhage along with hemorrhage from arteriovenous 

malformations were excluded. Twenty-six patients were randomized to either an intervention 

group or non-intervention group. The intervention group had surgical evacuation within 48 

hours (median 14.5 hours), whereas, the non-intervention group was treated with conservative 

management. No details for perioperative care or conservative management were provided. 

Patients in the conservative group were more likely to be basal ganglion hemorrhage. Six-month 

mortality was 38% in the conservative group and 46% in the surgical group with no significant 

difference noted. There was likewise no significant difference in a dichotomized Glasgow 

Outcome Scale at 6 months. 

Zucarrello et al.89 investigated early surgical treatment for supratentorial ICH in 20 patients 

randomized over 24 months (surgical intervention n=9, medical treatment n=11). Patients were 

recruited from one university and two community hospitals. Principal eligibility criteria were 

ICH volume >10cm3

 on baseline CT scan, GOS >4, randomization within 24 hours of symptom 

onset (median 3 hours 17 minutes), and <3 hours to time of surgery (1 hour 20 minutes), with no 

evidence of ruptured aneurysm or arterovenous malformation. No significant differences were 

noted for mortality rates. The likelihood of good outcome (<3 GOS) was 56% for the surgically 

treated group and 36% in the medically treated group, which did not differ significantly. A 

nonsignificant trend for good outcome for the surgically treated group for median GOS, Barthel 

Index, and Rankin Scale was observed at 3-month follow up. A significant difference in favor of 

surgical intervention for the NIHSS score was also observed (p=0.04). 
23

Summary Table 1. Intervention A 

Study Identification 

Study 

Design Population Characteristics 

Intervention (I) 

/Comparator (C) 

Relevant 

Outcomes 

Auer, 1989 

 Austria119

RCT 

Parallel 

n=100 

Inclusion Criteria: Acute, hematoma >10 

cm3

; within 48 hr of hemorrhage with 

neurological deficits, consciousness 

impairment; age between 30-80 y; 

appropriate for surgery / angiography 

Baseline Differences: NR 

Comments: Small sample size in subgroup 

analyses; methods of randomization 

unclear; good outcome more frequent in 

alert/ somulent patientsthan in 

stuporous/comatose pts 

I: Surgery for ICH, 

(n=50) 

C: Medical tx 

(n=50) 

 Significant.y 

lower 

mortality rate 

at 6 months 

 Signficantly 

better 

outcome 

(unique 

scale) 

Batjer, 1999 

US120

RCT 

Parallel 

n=21 

Inclusion Criteria: Acute hypertensive 

putaminal ICH ≥ 3cm in diameter; moderate 

to severe hemiparesis/ uniform hemiplegia 

(grade 1-3); < 24 hr post onset 

Baseline differences: No significant 

differences between groups 

Comments: Enrolment ceased prior to 

reaching target . As Outcome of all groups 

felt to be unacceptably poor. Selection 

criteria allowed only severely disabled 

patients, with large hematomas to be 

admitted. These characteristics may have 

further heightened management morbidity 

I: Surgery for ICH 

(n=8) 

C1: Best medical 

management (n=9) 

C2: Best medical 

management + 

intracranial 

pressure monitoring 

(n=4) 

 No significant 

difference in 

mortality 

outcomes 

 No significant 

difference in 

outcome 

status 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra arterial; 

(r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed tomography; 

NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health Stroke Scale; 

mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 
24

Summary Table 1. Intervention A 

Study 

Identification 

Study 

Design Population Characteristics Intervention (I) 

/Comparator (C) 

Relevant 

Outcomes 

Juvela, 1989 

Finland121

RCT 

Parallel 

n=52 

Inclusion Criteria: Acute ICH within 24 hr 

post bleed; unconscious &/or severe 

hemiparesis or dysphasia 

Baseline differences: More combined 

thalamic & basal ganglionic hematomas & 

hematomas with intraventricular extension 

in the surgical group 

Comments: Quality of life remains poor 

although surgery improves the length of 

survival in semicomatose or stuporous pts 

 

I: Surgery for ICH 

(n=26) 

C: Conservative tx 

(n=26) 

 Significant 

difference in 

mortality rate at 

6 months 

within the GCS 

7-10 subgroup 

 No significant 

difference in 

morbidity 

Mendelow, 2005 

UK122

(reviewer 

nominated; 

published beyond 

search dates) 

RCT 

Parallel 

n=1033 

Inclusion Criteria: CT evidence of 

spontaneous supratentorial ICH, within 72 

hr; uncertainty by neurosurgeon about 

benefits of either tx; hematoma ≥ 2 cm; 

GCS≥5 

Baseline differences: NR 

Comments: Cross over from IG to CG n=31; 

from CG to IG n=140 

I: Surgery for ICH 

(n=503) 

C: Conservative tx 

(n=530) 

 No significant 

difference at 6 

mos mortality 

 No significant 

difference at 6 

mos functional 

outcomes (BI, 

mRS) 

Morgenstern, 1998 

US87

RCT 

Parallel

n=34 

Inclusion Criteria: Acute ICH <9 mL; 

diagnosed by CT within 3 hr screening, <12 

hr; GCS 5-15 

Baseline differences: Deep ICH (94% 

putaminal in surgical group vs. 59% 

putaminal in medical group) 

Comments: Small sample size; 1 pt 

randomized to medical group crossed over 

to surgical arm; 1 pt randomized to surgical 

arm excluded (surgeon refused to 

randomize) 

I: Surgery for ICH 

(n=17) 

C: Standard 

medical tx 

(n=17) 

 No difference 

in 1 or 6 month 

mortality or 6 

mo BI score 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health 

Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 
25

Summary Table 1. Intervention A 

Study Identification Study 

Design Population Characteristics Intervention (I) 

/Comparator (C) 

Relevant 

Outcomes 

Teernstra, 2003 

The Netherlands88

RCT 

Parallel 

n=71 

Inclusion Criteria: Patients with expected 

mortality of 88%; age >45 y; ICH >10 cm3

; 

within 72 hr of ictus, Glasgow eye motor 

score 2-10 

Baseline differences: More cardiovascular 

disease history in surgical group (NS) 

Comments: Small sample size; improved 

mortality rate in conservative group 

possibly due to increased supportive care 

or an specific selection bias 

I: Surgery for ICH 

(n=36) 

C: No- Surgery 

(n=35) 

 No significant 

difference (6 

months) 

mortality rate 

 No significant 

difference mRS 

(at 6 months) 

 Significant ICH 

volume 

reduction 

intervention 

group 

Zuccarello, 1999 

US89

RCT 

Parallel

n=20 

Inclusion Criteria: Acute supratentorial 

ICH >10 cm3

, diagnosed by CT, with focal 

neurological deficit; age >18y; GCS >4, 

within 24 hr of onset; surgery within 3 hr 

of randomization 

Baseline differences: No significant 

differences 

Comments: Only 10% of patients admitted 

met eligibility criteria; some patients were 

not entered because of reluctance of 

surgeon to randomize 

I: Surgery for ICH 

(n=9) 

C: Control 

(n=11) 

 No significant 

difference in 

mortality at 3 

mo 

 No significant 

difference in BI 

score at 3 mo 

 Significant 

difference for 

NIHSS at 3 mo

 Lower ICH 

volume in the 

IG 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health 

Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 

Intervention B: Does Antihypertensive Treatment Reduce Stroke 

Related Mortality and Disability in Patients with Acute ICH? 

Six studies were identified that investigated antihypertensive therapy for ICH.90,91,144-147 Four 

studies were non-comparative case series designs and were excluded from our review.144-147 

Two unique studies met eligibility criteria for investigating the effectiveness of antihypertensive 

therapy for ICH and were a pre-post design (Summary Table 3).90,91 The year of publication for 

each study was 199390 and 2000.91 Neither of these studies prospectively answers the clinical 

question posed but they were included to provide insight into relevant surrogate and safety 

measures. 
26

Kay et al.90 reported a non-randomized uncontrolled clinical trial evaluating the efficacy of 

the serotonin antagonist, ketanserin, and its antihypertensive properties to lower mean arterial 

pressure in patients with ICH without a subsequent rise in ICP.90 Ten patients, five men and five 

women aged 49 to 64 years, were recruited from the Chinese University of Hong Kong. All 

patients had a spontaneous ICH confirmed by CT scan 8 to 48 hours prior to recruitment, a 

systolic BP >180 mm Hg and/or a diastolic BP >100 mm Hg, no previous history of 

hypertension, and required ICP monitoring in the intensive care unit. The patients were sedated, 

paralyzed, endotracheally intubated and mechanically ventilated to a target PaCO2 of 30 to 34 

mm Hg. An intravenous bolus of 5 to 10 mg ketanserin was given and radial arterial pressure 

and ICP were measured continuously. BP readings were performed at multiple time points and 

compared with pre-injection pressures using analysis of variance (ANOVA) with a correction for 

multiple comparisons. 

After the intravenous bolus of ketanserin the BP decreased on average by 40/21 mm Hg 

within 5 minutes and increased gradually over the next 2 hours remaining below pre-treatment 

levels. ICP remained stable throughout the observation period and thus the calculated CPP 

decreased by a mean of 27 mm Hg after 5 minutes, and on completion of the study, steadily 

increased to be 13mmHg below the pre-treatment value. There was no evaluation of clinical 

outcomes reported in this study. 

A more recently published study by Nishiyama et al.91 explored the safety of calcium 

antagonist nicardipine and its effect on mean arterial pressure, ICP, and CPP. Twenty-two 

patients with an acute hypertensive putaminal hemorrhage requiring surgical drainage were 

recruited for a non-randomized uncontrolled clinical trial. There were 14 men and eight women 

ranging in age from 47 to 79 years. Mechanical ventilation was continued post-operatively to a 

target PaCO2 of 30 to 35 mm Hg. Post-operatively nicardipine infusion was started at 1 

μg/kg/min with rate adjustments to target systolic blood pressure between 120 to 160 mm Hg (a 

20%-30% reduction from pre-infusion levels) for 72 hours. In addition all patients received: a 

hyperosmolar solution (glycerin fructose), anti-seizure medication (phenytoin) and antibiotics. 

BP was measured directly via a radial artery catheter and ICP monitored continuously via by an 

intraventricular catheter. Middle cerebral artery blood flow velocity (Vmca) and pulsatility 

index (PI) were measured and calculated using Transcranial Doppler Ultrasound. Platelet counts 

were also monitored as an anti-platelet effect of calcium antagonists has been previously 

reported and may increase the risk of bleeding.148 Clinical outcomes included level 

consciousness using the Japan Coma Scale (included in the appendix of the article, not 

referenced elsewhere) and repeat CT imaging to evaluate extension of hemorrhage. 

Patients’ BP decreased during and up to 24 hours after the end of the Nicardipine infusion 

compared with pre-infusion. There was no difference in platelet counts. Vmca and PI were 

unchanged and ICP decreased 24 hours after the end of the infusion. CPP was decreased at 24 

and 72 hours of the infusion but was greater than 50 mm Hg at all times. Consciousness levels 

were unchanged and CT findings did not show any exacerbation of bleeding or edema. 
27

Summary Table 2. Intervention B 

Study 

Identification Study Design Population Characteristics Intervention (I) 

/Comparator (C) 

Relevant 

Outcomes 

Kay, 1993 

Hong 

Kong90

Pre-post n=10 

Inclusion Criteria: ICH confirmed by CT 8-48 

hr pre-recruitment; systolic BP >180 mm Hg, 

diastolic BP >100 mmHg 

Baseline Differences: No significant 

differences between groups 

Comments: No evaluation of clinical outcomes

I: Antihypertensive 

therapy for ICH 

(n=10) 

 Systolic arterial

pressure lower 

in IG 

 Calculated 

cerebral 

perfusion 

pressure 

decreased 

Nishiyama, 

2000 

Japan91

Pre-post n=22 

Inclusion Criteria: Acute putaminal 

hemorrhage secondary to hypertension, with 

surgical drainage of hematomas 

Baseline Differences: No significant 

differences between groups 

Comments: Weak study due to lack of control 

group & small sample size 

I: Antihypertensive 

therapy for ICH 

(n=22) 

 Significant 

decrease in 

blood pressure

 CPP 

decreased at 

24 and 72 

hours 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health 

Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index; CPP = cerebral 

perfusion pressure

Intervention C: Does IA thrombolysis reduce stroke-related mortality 

and disability in adults with acute ischemic stroke? 

A total of 37 studies investigating IA thrombolytic therapy for ischemic stroke were 

identified by our searches. Nine single prospective cohort studies,149-157 one controlled clinical 

trial,15813 non-comparative case-series,159-171 two case studies,172,173 four abstracts174-177 and three 

studies in which designs could not be determined178-180 were excluded from our final analyses. 

Five unique studies met our eligibility criteria for inclusion (Summary Table 3).92-94,109,110 All 

five studies were parallel RCTs and were published between 1999 and 2001. 

Del Zoppo and colleagues110 described the results of the PROACT I study, a North American 

multi-centre study of IA pro-urokinase compared with placebo, carried out between 1994 and 

1995. Patients aged 18 to 85 with new onset focal neurologic signs, and NIHSS scores between 

4 and 30, were randomized on a 2:1 basis to either 6 mg pro-urokinase plus heparin (100 IU/kg 

bolus plus 1000 IU/hour infusion) or saline placebo plus matching heparin. After reviewing the 
28

results on the first 16 patients, the External Safety Committee changed the infusion to 2000 IU 

bolus followed by 500 IU/hour for 4 hours. Recanalization rates in the M1 or M2 vessels at 120 

minutes, defined as TIMI 2 or 3 or better, were 57.7% in the treated group versus 14.3% in the 

control group. There was, however, no significant difference between mortality or mRS scores 

(either 0 or 1) at 90 days. 

The results of the PROACT I trial were used to design PROACT II, which was reported by 

Furlan and colleagues.92 This trial was conducted between 1996 and 1998 in North America. A 

total of 12,323 patients were screened, resulting in 474 patients subjected to angiogram, and 180 

patients randomized after meeting angiographic criteria. Eligible patients had clinical signs of 

less than 6 hours in duration in the middle cerebral artery (MCA). The NIH Stroke Scale Score 

was 4 to 30. Patients with isolated aphasia or hemianopsia were excluded. The CT scan 

excluded bleed or tumor and demonstrated early infarct signs in less than one third of the MCA 

territory. A diagnostic cerebral angiogram had to show complete occlusion or minimal perfusion 

(TIMI grade 0 or 1) in the M1 or M2 branches of the MCA. Dissection or severe carotid stenosis 

were exclusionary criteria. Randomization was on a 2:1 schedule favoring the intervention. One 

hundred and twenty-one patients received 9 mg of IA pro-urokinase over 2 hours. Heparin was 

delivered at a 2000 IU unit bolus followed by a 500 IU/hour infusion in all patients. The prourokinase was injected intra-thrombus or in the proximal face of the thrombus. Clinical 

assessments were blinded and the primary outcome was a mRS score of less than 2 at 90 days. 

This outcome was achieved by 40% of the treatment group compared with 25% of the control 

group (p=0.04). The calculated number needed-to-treat, on the basis of the absolute difference, 

was seven. Intracranial hemorrhage within 24 hours occurred in 35% of patients in the treated 

group compared with 13% in the control group. It should be noted that the control group 

contained more patients with diabetes than the treatment group (20% versus 8%). 

Kase and colleagues109 presented the subgroup analysis of PROACT II regarding bleeding. 

The group who received treatment (n=110) versus the group that received no treatment (n=64) 

was compared. Symptomatic intracranial hemorrhage occurred in 12 of the 110 patients (10.9%) 

treated with urokinase with a mean onset time of 10 hours after initiation of treatment, compared 

with two of the 64 patients (3.1%) in the control group. Mortality with symptomatic ICH was 

83%. Elevated blood glucose was associated with symptomatic intracranial hemorrhage, 

particularly if the baseline glucose was greater than 200 mg/dL (11.1 mmol/L). This resulted in 

a relative risk of bleeding of 4.2 (95% CI 1.04-11.7). 

The EMS Bridging Trial was reported by Lewandowski and colleagues.94 This trial was a 

Phase I trial conducted between 1995 and 1996 in several centers in the United States. Patients 

with acute stroke (within 3 hours of symptom onset) and NIHSS scores greater than 5, and were 

CT-negative for hemorrhagic lesion, were enrolled. The interventional group received IV tPA 

0.6 mg/kg plus IA tPA; the latter was delivered if a thrombus was seen on angiogram. The 

control group received IV placebo plus IA tPA (1 mg) injected beyond the thrombus with 

subsequent retraction into the thrombus followed by 10 mg/hour tPA infusion. Blood pressure 

was maintained less than 180/105. The calculated sample size was 30 patients per arm; however, 

only 35 were recruited prior to the study being halted. The primary outcome was a decrease of 7 

or more points in the NIH Stroke Scale from baseline to 7 to 10 days, or a NIH Stroke Scale 

Score of 0 to 1 at 7 to 10 days. This outcome was achieved by 24% of the population in both 
29

groups. There was also no difference in the 90-day Glasgow Outcome Score, Barthel Index 

Score (95-100), or mRS Score (0 or 1). 

Keris et al.93 combined IV and IA treatment in a single-center study performed in Latvia 

between 1997 and 1998. Patients with ischemic stroke of less than a 6-hour duration in the 

internal carotid distribution were included. Edema and effacement were described as exclusion 

arms; however, explicit exclusion criteria were not given. Intervention cases received 25 mg of 

tPA IA at the proximal surface of the clot followed by 25 mg IV tPA plus 5000 IU heparin 

initially and twice a day. Analysis was performed on those who had received the intervention 

(n=12) versus those who had received no intervention (n=33). A good outcome was defined as a 

mRS score of between 0 and 3. This outcome was obtained at 12 months by 10 of the 12 

patients in the treatment arm and 11 of the 33 patients in the control arm. Fatal bleeding was 

noted in two patients, both of whom were in the combined treatment arm. Symptomatic ICH 

occurred in two patients in the combined treatment arm and 1 in the placebo/IA treatment arm. 

These rates were not significantly different between the two arms. Other systemic bleeding 

complications did not differ between the two arms. Hemorrhage was noted in two of 12 (17%) 

patients in the intervention group. The authors concluded that, in spite of baseline differences in 

the two groups, the outcome suggested a benefit for IA treatment. 
30

Summary Table 3. Intervention C 

Study 

Identification 

Study 

Design Population Characteristics Intervention (I) 

/Comparator (C) Relevant Outcomes

del Zoppo, 1998 

US & Canada110

RCT 

Parallel 

n=40 

Enrolment window: Feb 1994 - Feb 1995 

Inclusion Criteria: Acute carotid artery 

stroke; new focal neurological signs in the 

MCA within 6 hr of onset, NIHSS score ≥4; 

(except for isolated aphasia or 

hemianopsia; age 18-85y) 

Baseline differences: No significant 

differences between groups 

Comments: Small sample size; 

randomization scheme 2:1 (IG vs. CG); 

phase 2 trial Safety and dose finding 

 

I: IA Urokinase 

(n=26) 

C: Placebo 

(n=14) 

 No significant 

difference in 

mortality 

 MCA 

recanalization 

significantly 

better than IG 

 No significant 

difference in 

functional 

outcomes (mRS, 

BI, & NIHSS) 

Furlan, 1999 

US & Canada92

RCT 

Parallel 

n=180 

Enrolment window: Feb 1996 - Aug 1998 

Inclusion Criteria: Acute IS (MCA), 18-85 y; 

with new neurological symptoms < 6 hr 

post onset; NIHSS score ≥ 4 

Baseline differences: Baseline diabetes in 

CG; more ECASS CT protocol violation in 

IG 

Comments: All secondary outcomes 

favored intervention with no statistically 

significant results 

I: IA Urokinase 

(n=121) 

C: Placebo 

(n=59) 

 No significant 

mortality at 90 d 

 Significant 

improvement in 

proportion of 

patients with 

mRS ≤ 2at 90 d 

 Recanalization 

significantly 

better in IG (66% 

vs. 18%) 

 Increased 

symptomatic ICH 

in IG (10% vs. 

2%) 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health 

Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 
31

Summary Table 3. Intervention C 

Study 

Identification 

Study 

Design Population Characteristics Intervention (I) 

/Comparator (C) Relevant Outcomes

Kase, 2001 

US109 (serial 

publication of92) 

RCT 

Parallel 

n=174 

Enrolment window: NR 

 

Inclusion Criteria: Acute IS M1 or M2 

segments of MCA < 6 hr post onset; 

NIHSS score 4-30 

Baseline differences: No significant 

differences between groups 

Comments: Higher rates of 

symptomatic ICH in IG (10.9%) 

compare to that of CG (3.1%) 

I: IA Urokinase 

(n=110) 

C: Placebo 

(n=64) 

 Mortality following 

symptomatic ICH 

(83%) 

 Serum glucose 

>200 mg/dl 

increases risk of 

hemorrhage 

Keris, 2001 

Latvia93

RCT 

Parallel 

n=45 

Enrolment window: Feb 1997- Mar 

1998 

Inclusion Criteria: Acute severe 

hemiparetic IS within 6 hr post onset 

Baseline differences: Large CG 

compare to IG (n=33 vs. n=12) 

Comments: unbalanced groups due to 

randomization before consent; no 

significant benefit with tx despite 

baseline differences 

I: IV plus IA tPA 

(n=12) 

C: Conventionnel tx 

(n=33) 

 Chi2

 for mRS & 

mortality 

Lewandowski, 

1999 

US94

RCT 

Parallel 

n=35 

Enrolment window: February 1995 – 

March 1996 

 

Inclusion Criteria: Acute focal IS within 

3 hr of symptom onset (based on 

NINDA tPA stroke study) 

Baseline differences: NIHSS scores 

significantly higher in IG 

Comments: Small sample size; number 

of subjects completing all follow ups for 

each group is not specified 

I: IV+IA tPA 

(n=17) 

C: Placebo+ IA 

thrombolytic tx 

(n=18) 

 No difference in 

mortality 

 No difference in 

functional 

outcome at 3 mo 

 Arterial 

recanalization 

better in the IV+IA 

group 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health 

Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 
32

Intervention D: Does Treatment to Normalize Blood Glucose Levels 

Reduce Stroke Related Mortality and Disability in Adults with Acute 

Stroke? 

Our searches identified two unique studies investigating the effects of normalization of blood 

glucose levels in patients with ischemic stroke (Summary Table 4).95,96 Both studies were 

parallel RCTs and were published in 2004 and 1999, respectively. 

Post-stroke hyperglycemia has been identified in previous studies as being associated with 

poor stroke outcome. It is unclear to what extent this is a “normal” physiological response or 

whether it may lead to increased cerebral damage in the acute phase. The Glucose Insulin in 

Stroke Trial (GIST) has resulted in two published studies in this area. First, a Pilot study96

evaluating the feasibility of a large multicenter RCT of glucose, potassium, and insulin (GKI) in 

patients with acute stroke. Second, a small RCT that evaluated the natural history of post-stroke 

hyperglycemia and the immediate response to GKI.95

The pilot study96 was a non-blinded RCT from a single center. All patients who presented 

with an acute stroke within 24 hours of symptom onset and had a plasma glucose of 7.0 to 17.0 

mmol/L were eligible. Exclusion criteria included: New York Heart Association (NYHA) grade 

3 or 4 heart failure; renal failure (creatinine level >200 μmol/L); anemia (Hb <9 g/dL); 

radiologically documented pneumonia; coma (Glasgow Coma Scale motor subscore <4); 

previous disabling stroke (mRS Score >3); dementia; isolated posterior circulation stroke without 

physical disability; pure language disorder; previously diagnosed insulin-treated type 1 or 2 

diabetes; or, subarachnoid hemorrhage. 

Two hundred and forty-five consecutively admitted patients were screened over a 7-month 

period. Of these, 53 patients were randomized—28 to active treatment (with three patients 

withdrawn as stroke was not confirmed by post-randomization CT) and 25 to control treatment. 

Active treatment consisted of a combined infusate of 500 mL 10% dextrose, 16 U Human 

soluble insulin (Actrapid; Novo nordisk) and 20 mmol potassium chloride (KCl) administered 

through a peripheral vein at a fixed rate of 100 mL/h to a maximum volume of 2400 mL. 

Glucose testing was performed hourly by glycaemic strip aiming for a target glucose of 4 to 7 

mmol/L. Above the target range, 4 U insulin was added to the infusate. Below the target range, 

the infusate was stopped and glucose repeated in 15 minutes interval 50% dextrose was given 

intravenously if glucose ≥4 mmol/L was not achieved spontaneously in 30 minutes. When target 

range was achieved, the infusate was restarted with 4 fewer units of insulin. Control treatment 

consisted of 154 mmol/L saline at 100 mL/h to a maximum volume of 2400 mL. Glucose values 

were not treated unless they exceeded 17 mmol/L. 

Baseline blood work, BP and pulse were measured every 4 hours, and plasma glucose 

samples were measured every 8 hours during the 24 hours of infusate. All blood work was 

repeated at 48 hours. Clinical assessments of neurological impairment (European Stroke Scale 

(ESS)) and activities of daily living (Nottingham Extended Activities of Daily living for 

function) were performed at baseline, 24 hours, 48 hours, 7 days and 4 weeks by trained 

observers. Clinical assessments were not blinded to treatment allocation 
33

The average glucose level in the group as a whole at randomization was 9.1 mmol/L. The 

glucose values for the GKI group were 6.4, 6.5, and 6.9 mmol/L at 8, 16, and 24 hours, 

respectively. For the control group, the values were 7.6, 7.2and 7.6 mmol/L, respectively. These 

differences did not achieve statistical significance. In the active treatment group the insulin 

concentration had to be adjusted at least once in 23 of 25 patients. Five patients required single 

doses of 10% dextrose for low glucose values although only one patient was symptomatic. 

There was no difference in clinical outcomes between the two groups. 

The GIST-UK trial95 was a multicenter RCT. The eligibility and exclusion criteria were 

similar to the pilot study with the following exception that entry was based on plasma glucose 

levels of 6.0 to 17.0 mmol/L. Clinical outcomes were not measured in this study, as the focus 

was natural history of acute hyperglycemia in managed stroke care and efficacy, safety and 

practicability of routine intervention. 

The first 452 patients recruited had a mean age of 74.8 years and 53.3% were women. 

Overall mean admission plasma glucose was 8.37 mmol/L (SD 2.13); of note, 28.3% of the 

patients had a glucose level of between 6.0 and 6.9 mmol/L at admission. Baseline 

demographics were the same between groups. Of the recruited patients, 221 were randomized to 

receive GKI and 231 received saline solution. Plasma glucose values were significantly lower in 

the GKI group at 8, 16 and 24 hours of infusion. In both groups, the glucose values were 

significantly lower during the active or control infusion as compared to baseline. Adjustment of 

the GKI regimen was required a median of two times per patient. Twenty cases of hypoglycemia 

occurred that required treatment with 10% dextrose. Diabetic patients within the GKI group 

required significantly more insulin to reach target, as well as more changes overall compared 

with non-diabetic patients in the GKI group. 
34

Summary Table 4. Intervention D 

Study 

Identification Study Design Population Characteristics Intervention (I) 

/Comparator (C) 

Relevant 

Outcomes 

Gray, 2004 

UK95

RCT Parallel n=452 

Inclusion Criteria: Acute stroke< 24 hr post 

onset, with admission glucose level > 6 to <17 

mmol/L 

Baseline differences: No significant 

differences between groups 

Comments: Study was not reported as 

blinded; no CT in 36 patients; target capillary 

blood glucose level 4 - 7 mmol/L for the 

duration of infusion 

I: Normalization of 

blood glucose 

levels for IS 

(n=221) 

C: Control 

(n=231) 

 Significant 

difference in 

mean plasma 

glucose values 

at subsequent 

time intervals in 

24 h 

Scott, 1999 

UK96

RCT Parallel n=53 

 

Inclusion Criteria: Acute IS with neurological 

deficit lasting > 24 hr; age > 18 y; within 24 hr 

of onset 

Baseline differences: No significant 

differences between groups reported 

Comments: Small numbers with multiple 

outcome tests; no measure of severity of 

stroke at randomization; study was not 

blinded; 2 crossover from CG to IG; 3 patients 

in IG removed for protocol violations 

I: Normalization of 

blood glucose 

levels for IS 

(n=28) 

C: Control 

(n=25) 

 No Significant 

difference in 

serum glucose 

levels 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health 

Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 

Intervention E: Does Mechanical Thrombus Disruption Reduce 

Stroke-Related Mortality and Disability in Adults with Acute Ischemic 

Stroke? 

Ten studies investigating the effectiveness of mechanical thrombus disruption for ischemic 

stroke were identified by our searches. One study was identified by an expert and screened for 

inclusion.111 This study was published beyond our literature search dates. One case-control,181

five non-comparative case series,182-186 and three studies in which the design could not be 

determined,187-189were subsequently excluded from our review. Two unique parallel RCTs, 

which met our eligibility criteria, were included in our final analyses (Summary Table 5).97,111 

These studies were published in 2003 and 2004, respectively. 
35

Eggers et al. reported on a single-center, prospective RCT, of ultrasound-enhanced 

thrombolysis in MCA occlusion.97 The study was carried out between 2000 and 2002, and 

involved individuals with ischemic stroke of less than 3 hours duration in the MCA territory. All 

participants met the criteria for the NINDS Thrombolysis Protocol and had a M1 occlusion 

diagnosed by transcranial ultrasound. tPA was given as per the NINDS Protocol.49 The 

intervention group received continuous transcranial color-coded sonography. The monitoring 

was in the pulse wave Doppler mode with an instrument developing an acoustic power of 179 

mW/cm2

. The control group had patency of the vessel established by transcranial sonography at 

baseline, 20, 40 and 60 minutes. Each assessment lasted less than 2 minutes. 

Of the 1,177 candidates screened, 25 met the inclusion criteria. Of these, 11 were 

randomized to the treatment group and 14 to the control group. Exclusions were due to failure to 

meet the NINDS treatment criteria or an absence of an MI occlusion. The primary efficacy 

parameters at 90 days included the Barthel Index, mRS Score and mortality. Six of the 11 

patients in the treatment group (54.5%) and 1 of 14 patients in the control group (7.7%) met the 

pre-specified criteria of Barthel greater than or equal to 95 (p=0.037). There was, however, no 

difference between the two groups in the 90-day mRS score or in mortality. The treated group 

demonstrated a higher median peak systolic blood flow velocity at the end of 1 hour of 

treatment. However, there was no significant difference in recanalization between the two 

groups. Four patients in the treated group experienced intracranial hemorrhage or hemorrhagic 

transformation of the infarct, compared with one patient in the control group (p=0.14). 

Alexandrov and colleagues reported on the results of the CLOTBUST Study.111 This phase 

II multicenter trial was carried out in North America on patients treated with IV tPA within a 3-

hour window. One hundred and twenty-six patients were randomized to receive either placebo 

or continuous ultrasonography. Head frames were placed on all patients. The patients in the 

treatment group began ultrasonographic monitoring prior to the administration of the tPA bolus 

and for the subsequent 2 hours. Emitted power output was set at the maximal achievable level 

with selected insonation depths under the FDA allowed threshold of 750 mW. In both groups, 

follow-up measurements were taken 30, 60, 90 and 120 minutes after the tPA bolus with arterial 

recanalization defined by Doppler criteria. The groups were comparable at baseline and equal in 

number (n=63 for each arm). Symptomatic intracranial hemorrhage occurred in three patients in 

each group. The pre-specified endpoints were complete recanalization or early or dramatic 

recovery from stroke. The latter was defined as a reduction of 10 or more points in the NIHSS or 

a total NIHSS of 3 or less within 2 hours after administration of the tPA bolus. Thirty-one 

patients (49% of the treated group) and 19 patients (30% of the control group) reached the prespecified endpoints (p=0.03). Re-occlusion within 2 hours occurred in 11 patients in the treated 

group (18%) and 14 patients in the control group (22%, p=0.7). The 3-month mortality rates 

were 15% and 18% in the treated and controlled groups, respectively (p=0.4). Follow-up at 3 

months was incomplete by four patients who were excluded from the outcome analysis. mRS 

scores of 0 or 1 were present in 22 of 53 treated patients (42%) and 14 of 49 control patients 

(29%) (relative risk 1.45; 95% CI 0.84-2.51; p=0.2). 
36

Summary Table 5. Intervention E 

Study 

Identification Study Design Population Characteristics Intervention (I) 

/Comparator (C) 

Relevant 

Outcomes 

Alexandrov, 

2004 

US & 

Canada111

RCT 

Parallel 

n=126 

Inclusion Criteria: Acute IS of MCA, within 3 hr 

post onset; IG: Abnormal flow through MCA, 

with TIBI scale grade 0-3 (Thrombolysis in 

Brain Ischemia flow-grading system) before 

tPA tx 

Baseline differences: No significant differences 

between groups 

Comments: Additional IA tPA with mechanical 

manipulation n=9 (14%) in IG & n=11 (18%) in 

CG underwent additional IA tPA of thrombus 

with no effect on outcomes 

I: Mechanical 

thrombus 

disruption for IS 

(n=63) 

C: Control 

(n=63) 

 Complete 

recanalization 

or dramatic 

clinical 

recovery 

significantly 

better in IG 

Eggers, 

2003 

Germany97

RCT 

Parallel 

n=25 

Inclusion Criteria: Acute IS in MCA/ M1; 18-80 

y, within 3 hr symptom onset (according to 

NINDS criteria) 

Baseline differences: No significant differences 

between groups 

Comments: Small sample size 

I: Mechanical 

thrombus 

disruption for IS 

(n=11) 

C: Control 

(n=14) 

 Significantly 

better 

functional 

outcome in IG 

(BI at 3 mo) 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health 

Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 

Intervention F: Is the Effectiveness and Safety of Thrombolytic 

Therapy for Adults with Acute Ischemic Stroke Affected by Time From 

Onset to Treatment? 

Six parallel RCTs (in seven publications) relevant to the timing of thrombolytic therapy for 

ischemic stroke published between 1993 and 2002 met our eligibility criteria (Summary Table 

6).112 While these studies did not directly compare outcomes stratified by timing of therapy, they 

cover relevant time windows and examination of the results is instructive to the question posed. 

55,67,99,107,108,112,113 Albers et al.99 is considered to be a re-analysis of Clark et al.112 and Clark et 

al.67 Two abstracts,190,191 one multiple prospective cohort study,192 one single prospective cohort 

study,193 and one case series,194 were excluded from our synthesis for level of evidence. No one 

publication investigated the link between onset to treatment time (OTT) and outcome. The 

included studies recruited patients across relevant time windows and in concert inform decision 

making on the relationship between time and outcome. 
37

The use of tPA was well-established for the 0 to 3 hour time window by the NINDS Trial.49. 

This publication is well described elsewhere in this document. The initial trial publication did 

not describe an effect of time-to-treatment on treatment outcomes. A subsequent reanalysis55, 

along with the results of trials using tPA outside the 3-hour window, have been reported. 

Hacke and colleagues report on a trial of Intravenous tPA for acute hemispheric stroke.108 A 

total of 620 patients were randomized to receive rtPA at a dose of 1.1 mg/kg versus placebo. 

This dose of tPA is higher than in the NINDS Trial.49 Adults with hemispheric stroke syndromes 

presenting within six hours were included. Those with rapidly improving symptoms or minor 

deficits, as defined by a Scandinavian Stroke Scale Score of greater than 50, were excluded as 

were those with increased risk for bleeding. Major early infarct changes including swelling of 

the affected hemisphere or changes in greater than 33% of the MCA territory were also excluded. 

All CT scans were read in a blinded fashion independently subsequent to randomization. The 

primary endpoint was clinical outcome as defined by the Barthel Index and Modified Rankin 

Score (mRS) at 90 days. The intention to treat analysis showed no difference in either the 

Barthel Index or Modified Rankin Score at 90 days. A secondary endpoint of the combined 

Barthel Index and mRS showed a significant difference in favor of the rtPA group. One hundred 

and nine patients were identified as having major protocol violations, 66 of these being 

violations of the CT inclusion criteria. More protocol violators were in the rtPA group. Neither 

mortality nor intracranial hemorrhage differed significantly between the two groups on the 

Intention to treat analysis. 

The same group reported a second trial of 800 patients from centers in Europe, Australia and 

New Zealand randomized to receive intravenous tPA at 0.9 mg/kg or matching placebo within 

six hours of stroke onset.107 The inclusion/exclusion criteria were similar to those reported 

above. Four hundred and nine patients were randomized to the tPA group with 391 in the 

placebo group. The primary endpoint was proportion of patients with a mRS of 0 or 1 at 90 

days. Subjects were recruited between 1996 and 1998. While an absolute difference of 3.7% in 

the proportion having an mRS score of 0 or 1 was noted in favor of tPA treatment, this difference 

was not statistically significant. Thirty and 90 day mortality did not differ between these two 

groups. During the first seven days there were more deaths in the treatment group from 

intracranial hemorrhage, and the combination of cerebral edema and intracranial hemorrhage. 

Parenchymal hemorrhage within the first seven days was more common in the tPA-treated group 

than in the placebo group (11.8 versus 3.1%). Symptomatic intracranial hemorrhage also 

occurred more often in the tPA-treated group (8.8% versus 3.4%). 

Clark et al. reported the results of the rtPA 0- to 6-hour acute Thrombolytic Therapy in Acute

Ischemic Stroke Study, Part A.112 This was a multi-center North American Trial that ran from 

1991 to 1993. It included patients between the ages of 18 to 79 with acute ischemic stroke of 

less than 6 hours’ duration. A CT scan was required to exclude hemorrhage. Patients with 

minor stroke (score of less than 4 on the NIH Stroke Scale) along with rapidly improving 

symptoms were excluded. Patients with CT evidence of mass effect with midline shift were also 

excluded. This was a phase II trial with three planned safety and futility analyses at 75, 150 and 

225 patients. The trial was stopped on the basis of an interim safety analysis in October 1993 

due to safety concerns in the 5 to 6 hour window. This paper reports the results of the 142 

patients enrolled until that point. The mean time-to-treatment in this group was 4 hours 17 

minutes in the placebo arm and 4 hours 24 minutes in the tPA arm. Only 17% of the placebo 
38

group and 14% of the tPA group were treated in less than 3 hours, whereas, 34% of the placebo 

group and 31% of the tPA group were treated between 5 and 6 hours. Patients in the placebo 

group were more likely to be diabetic. A dose of tPA of 0.9 mg/kg following the dosage 

schedule of the initial NINDS trial49 was used. 

The primary planned efficacy endpoints of 30 or 90 days showed no difference in the percent 

of patients who achieved a greater than 4-point decrease on the NIH Stroke Scale at 30 days, 

though there was a significant difference at 24 hours with 40% of rtPA patients achieving this 

response versus 21% of placebo patients (p=0.02). Likewise, there was no significant difference 

in the infarct volume. Symptomatic bleeding was more likely in the tPA group by day 10 

(11.3% versus 0% in the placebo group, p=0.003). There was likewise an increased death rate in 

the treated group at 90 days (22.5% versus 7.0% placebo, p=0.009). In the 5 to 6 hour 

population, by day 10 symptomatic intracranial hemorrhage was found in 18.2% of the treated 

group versus 0% of the placebo group (p=0.03). Death by 90 days was present in 36% of the 

tPA-treated group versus 4.2% of the placebo group (p=0.01). The trial continued to enroll 

patients in the 3 to 5 hour window and results are reported in a separate publication. 

Subsequently, Clark et al.67 published data on the use of rtPA (Alteplase) for ischemic stroke 

administered within 3 to 5 hours after symptom onset. This phase 3, placebo-controlled, doubleblind RCT was conducted between December 1993 and July 1998, with 90 days of follow-up 

measurement. Patients were recruited from 40 community and university hospitals in North 

America. Six hundred and thirteen (intent-to-treat) subjects with ischemic stroke were enrolled. 

Of these, 547 subjects were treated, as assigned, within 3 to 5 hours of symptom onset. A total 

of 39 other subjects were treated within 3 hours of symptom onset, 24 were treated more than 5 

hours from symptom onset, and three subjects never received study medication. Subjects were 

administered 0.9 mg/kg of rtPA (n=272) or placebo (n=275), administered intravenously over a 

1-hour period. Neurologic (NIHSS score <1) and functional (Barthel Index, mRS, Glasgow 

Coma Scale) outcomes were assessed up to 90 days follow-up. Thirty-two percent of placebo 

patients and 34% of the rtPA patients had excellent recovery at 90 days follow-up. Within the 

first 10 days of treatment with rtPA, there was a significantly increased rate of symptomatic ICH 

(7.0% vs. 1.1% for placebo, p<0.001). Mortality at 90 days was not significant between groups 

(11.0% in the treatment group and 6.9% in the placebo group). Results in the intent-to-treat 

population were similar. 

A reanalysis of subjects (n=61) enrolled in the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study was conducted by Albers and 

colleagues in 2001.112 Patients had been randomized to receive either IV tPA or placebo within 

3 hours of symptom onset. The pre-specified primary and secondary hypotheses of the 

ATLANTIS part B trial were used to evaluate clinical outcomes in these patients. The authors 

noted that although there was a significant increase in symptomatic intracranial hemorrhage, 

patients receiving IV tPA were more likely to have favorable outcome measured by NIHSS (<1) 

at 90 day follow-up compared with placebo (p=0.01). 

Haley and colleagues reported results of a pilot RCT of tPA for acute ischemic stroke 

conducted at three centers in the U.S. between 1990 and 1991.113 This was a feasibility trial 

prior to NINDS and was stratified into the 0 to 90 minute and 90 to 180 minute windows. 

Patients with a diagnosis of ischemic stroke verified by CT scan with a measurable neurologic 

deficit on the NIH Stroke Scale were included. Patients with minor stroke consisting of only 
39

sensory loss or ataxia were excluded. TPA was delivered in a dose of 0.85 mg/kg over 60 

minutes, while a matching placebo was delivered to the control group. 

Twenty-seven patients were randomized, 20 (10 rtPA, 10 placebo) to the time stratum from 0 

to 90 minutes and 7 (4 rtPA, 3 placebo) to the time stratum of 90 to 180 minutes. While the 

median stroke scale scores in the early group were comparable, the median stroke scale score in 

the 90 to 180 minute stratum was 14 in the placebo arm and 6 in the tPA arm. No significant 

difference was found in change of NIH Stroke Scale score from baseline. No intracranial 

hemorrhage was noted in either the tPA or placebo group in the less than 90 minute time stratum. 

Small numbers in the later time stratum (i.e., 90 to 180 minutes) included one of three patients 

who died of ICH in the placebo group; none of the four patients in the tPA group died. 

Marler and colleagues reported on a reanalysis of the relationship between onset to treatment 

time and outcome at 3 months, early improvement in 24 hours, and intracranial hemorrhage 

within 36 hours.55 The initial NINDS Report49 suggested that there was no difference between 

the 0 to 90 minute and the 90 to 180 minute stratum. This subsequent reanalysis was prompted 

by the concern that other variables may have masked this association. The NINDS Study was a 

multi-center RCT that enrolled patients between 0 and 180 minutes of stroke onset to rtPA 

treatment (0.9 mg/kg delivered as a 10% bolus followed by 1-hour infusion) or to matching 

placebo. Patients with ischemic stroke scale scores greater than 4 were included. The trial was 

performed in two parts with identical protocols, with the exception that the primary outcome for 

Part A was at 24 hours, whereas, that for Part B was at 3 months. A favorable outcome was 

defined as minimal or no deaths that measured on a composite scale at six months while a 4-

point improvement in the NIH Stroke Scale Score was considered favorable at 24 hours. The 

analysis of time from onset to treatment demonstrated that within the 0 to 90 minute stratum, 

there was a tendency to cluster between 80 and 90 minutes prior to receiving treatment. There 

was a similar trend, though less marked, in the 90 to 180 minute stratum. The delay from ED 

arrival to treatment, however, was longer in the latter time window. No association was noted 

between onset to treatment time and baseline NIHSS. Suspected small vessel strokes were 

treated somewhat later than those due to large vessel occlusion; however, neither the 24 hour or 

three month outcomes varied by stroke subtype. The NIH Stroke Scale Score was a confounder 

for the relationship between onset to treatment time and outcome as the score was higher for 

tPA-treated patients in the earlier time stratum and higher for placebo patients in the later time 

stratum. After correction, an odds ratio for a good outcome at 24 hours was 1.71 in the 0 to 90 

minute stratum (95% CI 1.09-2.70) and 1.12 in the 90 to 180 minute stratum (95% CI 0.71-1.76). 

The odds ratios for good outcome at 3 months adjusted for the NIH Stroke Scale Score shows a 

similar relationship with a value of 2.11 for the 0 to 90 minute stratum (95% CI 1.33-3.35) and 

an odds ratio of 1.69 in the 90 to 180 minute time stratum (95% CI 1.09-2.62). There was, 

however, no interaction between onset to treatment time and hemorrhage at 36 hours for 

symptomatic hemorrhage or all hemorrhages. 

We did not conduct a meta-analysis of the effectiveness and safety of thorombolytic therapy 

for adults with acute ischemic stroke by time from onset to treatment since we identified a metaanalysis published in 2004 that used patient-level data from six RCTs to investigate the interval 

from onset to treatment using tPA.195 Findings of this meta-analysis indicated that the sooner the 

treatment is administered (<90 min) the more beneficial the outcome. Administration beyond 3 
40

hours was found to have some benefit, although with some associated risks. Details pertaining to 

this patient-level meta analysis are described in the discussion section. 
41

Summary Table 6. Intervention F 

Study 

Identification 

Study 

Design Population Characteristics Intervention (I) 

/Comparator (C) Relevant Outcomes

Albers, 2002 

US99

RCT 

Parallel 

n=61 

Inclusion Criteria: Acute IS within 3 hr 

symptom onset in either part A or B of 

ATLANTIS; age <79y 

Comment: Increase risk of symptomatic 

ICH similar to NINDS trial; small trend 

towards increased mortality might relate to 

small sample size and imbalances in 

baseline prognosis factors 

I: Timing of 

thorombolytic 

therapy in IS 

(n=23) 

C: Control 

(n=38) 

 No significant 

difference in 

mortality rate (at 

3 mo) 

 Significant 

increase in rate 

of ICH in IG 

 NIHSS (at 3 mo)

Clark, 2000 

North America112

RCT 

Parallel 

n=142 

Inclusion Criteria: Adult acute ischemic 

stroke, within 6 hr of onset 

Baseline differences: Significantly more 

diabetics in CG 

Comments: Trial stopped early due to 

safety concerns in the 5-6 hr group 

I: tPA 0.9 mg/kg 

(n=71) 

C: placebo 

(n=71) 

 No differences in 

primary outcome 

(proportion with 

NIHSS 

improvement of 4 

points by 90 d) 

 No difference in 

BI at 90 d 

 mRS better in 

CG in 90 d 

 Higher 

symptomatic ICH 

in IG in 10 d & 

higher mortality 

in IG in 30 d 

Clark, 1999 

US67

RCT 

Parallel 

n=547 

Inclusion Criteria: Acute IS with 

measurable focal neurological deficit of 

MCA origin; age 18-79y; within 3-5 hr post 

onset 

Comments: Negative results apply to 

patients treated > 3 hr post onset 

I: Timing of 

thorombolytic 

therapy in IS 

(n=272) 

C: Control 

(n=275) 

 No significant 

outcome in 

mortality (at 3 

mo) 

 No significant 

difference in 

functional 

outcome (BI, 

mRS, GCS at 3 

mo) 

 Increased ICH 

rates at 10 d in 

IG 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of 

Health Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 
42

Summary Table 6. Intervention F 

Study 

Identification 

Study 

Design Population Characteristics 

Intervention (I) 

/Comparator 

(C) 

Relevant Outcomes

Hacke, 1998 

Europe, Australia, 

New Zealanc107

RCT 

Parallel 

n=800 

Inclusion Criteria: Acute ischemic stroke 

within 6 hrs of onset, early infarct change 

on CT less than 33% of the MCA territory 

Baseline differences: No significant 

differences between groups 

I: rtPA 0.9 

mg/kg 

(n=409) 

C: Placebo 

(n=391) 

 No significant 

differences in 90 

d mortality 

 No significant 

differences in 

proportion with 

mRS 0 or 1 at 90 

d 

 Increased ICH in 

IG 

Hacke, 1995 

Europe 108 

RCT 

Parallel 

n=620 

Inclusion Criteria: Acute ischemic stroke, 0-

6 hrs, early infarct change on CT less than 

33% of the MCA territory 

Baseline differences: No significant 

differences between groups 

Comments: Major protocol violations in 109 

patients, 66 in the rtPA group 

I: rtPA 1.1 

mg/kg 

(n=313) 

C: Placebo 

(n=307) 

 No significant 

differences in 

mortality 

 No significant in 

outcome 

measures (BI, 

mRS at 90 d) 

Haley, 1993 

US113

RCT 

Parallel 

n=27 

Inclusion Criteria: Acute IS causing 

neurological deficit, age 18-80, within 90 

min or 91-180 min post onset 

Baseline differences: Large imbalance in 

baseline NIHSS scores in 91-180 min group

Comments: Small sample sizes; one person 

not finishing study in IG with no designation 

to < 90 m or 91-180 min; benefit to early tx 

was seen initially but not sustained at 3 

months 

I: Timing of 

thorombolytic 

therapy in IS 

(n=14) 

C: Control 

(n=13) 

 No significant 

difference in 

mortality rates 

 Significant 

improvement in 

functional 

outcome (at 24h) 

for NIHSS 

 No difference in 

hemorrhage rates

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of 

Health Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 
43

Summary Table 6 (cont’d). Intervention F 

Study 

Identification 

Study 

Design Population Characteristics Intervention (I) 

/Comparator (C) Relevant Outcomes

Marler, 2000 

US 

Part A55

RCT 

Parallel 

n=302 

Inclusion Criteria: Acute stroke 0-90 min post 

onset; NIHSS > 4 (based on NINDS tPA 

study for stroke) 

Baseline differences: NIHSS score IG > CG 

Comments: onset to tx time (OTT) 

significance at ≤10 

I: Timing of 

thrombolytic 

therapy in IS 

(n=157) 

C: Control 

(n=145) 

 No difference in 

mortality rates at 

24 hr 

 OTT interaction at 

24 hr favoring 

treatment (0-90min 

stratum vs. the 91-

180) for functional 

outcome 

(composite BI, 

mRS, NIHSS, 

GCS) 

Marler, 2000 

US 

Part B55

RCT 

Parallel 

n=320 

Inclusion Criteria: Acute stroke 91-180 min 

post onset (based on NINDS tPA study for 

stroke) 

Baseline differences: NIHSS score CG > IG; 

more delay in time to tx compare to Part A 

group 

Comments: Due to baseline differences in 

severity of stroke effect of tx may be greater 

than actual; time to tx: patients with small 

vessel strokes > patients with cardioembolic 

or large vessel strokes 

I: Timing of 

thrombolytic 

therapy in IS 

(n=153) 

C: Control 

(n=167) 

 No difference in 

mortality rates at 3 

mo; 3 mo 

functional outcome 

favoring tx (0-90 

min stratum vs. 91-

180) for functional 

outcome 

(composite BI, 

mRS, NIHSS, 

GCS) 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of 

Health Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 

Intervention G: Do Pretreatment CT Scoring Systems Affect the 

Safety and Efficacy of Thrombolytic Therapy for Acute Ischemic 

Stroke? 

Our searches for interventions examining the effectiveness of pretreatment CT scoring 

systems for ischemic stroke identified 11 studies. One case-control study,196 two single 

prospective cohort studies,197,198 and six studies whose designs could not be determined,199-204

were excluded for level of evidence. Two unique studies were included in our final analyses 

(Summary Table 7).114,115 Both studies were parallel RCTs and were published in 2001 and 

2002, respectively. 

Patel et al.114examined the frequency and significance of early infarct changes (EICs) on CT 

scans from the NINDS database. The NINDS trial described previously was a multicenter RCT 
44

carried out from 1991 to 1994 in American centers.49 The two parts of the trial (A and B) carried 

identical protocols differing only in the timing of the primary outcome collection with primary 

outcome being at 24 hours for Part A and 3 months for Part B. Patients with ischemic stroke that 

could be treated within 3 hours of onset of stroke symptoms were included. Of note, half of 

these were treated between 0 and 90 minutes of onset. Treatment consisted of tPA 0.9 mg/kg or 

matching placebo. The CT scan in this trial was used to exclude hemorrhage at the time of the 

trial. Changes other than hemorrhage were not used to exclude patients. The analysis reported 

in this paper was carried out in 1994 after conclusion and publication of primary trial results. All 

CT scans were obtained on third or fourth generation CT scanners with 10 mm thick slices. The 

coordinating center neuro-radiologist reviewed hard copies of the scans centrally. The site 

investigator supplied clinical information at the time of the initial treatment. The information 

included demographics, time since stroke onset, localization, and presumed stroke mechanism 

along with the component scores of the baseline NIHSS. The EIC’s were classified into three 

groups: 1) loss of gray-white distinction 2) hypodensity, and 3) compression of CSF spaces. 

Visual inspection was used to classify the changes as being either less than one-third of the MCA 

territory or greater than one-third of the MCA territory. Of the 624 patients randomized in the 

NINDS Trial, CT scans of 616 (99%) of the patients were available for review. Early infarct 

changes were associated with a baseline NIHSS ρ=0.23; p<0.001) and time from stroke onset ( ρ

=0.11; p=0.007). The correlation in both cases was not strong ( ρ =0.23). Of significant note, 

the EICs were not correlated with clinical outcomes after adjustment for baseline variables. This 

included the composite description of the 3-month favorable outcome along with its component 

measures of mRS Score, NIHSS, Barthel and Glasgow Outcome Score. There is likewise no 

correlation between the EICs and deterioration at 24 hours, 3-month lesion volume or death 

within 90 days. Likewise, the presence or absence of the EICs adjusted for baseline NIHSS was 

not predictive of symptomatic intracranial hemorrhage within 36 hours. These relationships held 

true whether the EICs composed less than or greater than one third of the MCA territory. 

Roberts et al.205 reported on CT findings and implications from the PROACT II Trial.115 

PROACT II92 was conducted between 1996 and 1998 and compared treatment of MCA 

occlusion within 6 hours by IA pro-urokinase coupled with IV heparin and IV heparin alone. 

The details of this study have been previously described. The current analysis was limited to the 

162 patients (108 pro-UK and 54 controlled) who received the treatment. Seventy-five percent 

of these patients had infarct changes on their baseline CT scan. A neuro-radiologist at the central 

facility reviewed all CT scans, and baseline CT volume was correlated with clinical variables 

and outcome. 

The baseline CT abnormality volume did not correlate with the baseline NIHSS. There was, 

however, a modest correlation between baseline CT volume and outcome at 90 days (r=0.17, 

p=0.05). Twenty-two of 53 (42%) patients with no CT abnormality at baseline reached a mRS 

less than or equal to 2 at 90 days. This compared to 2 of 8 (25%) of those with baseline CT 

changes having a volume of greater than 60 mL. Hemorrhagic infarction was present in 42% of 

the 108 pro-UK group and 29% of the control group at 24 hours. There was a trend toward 

increased volume of early CT changes and the presence of infarct. The mean volume in prourokinase patients with no bleeding was 11.6 ± 2.7 mL. Those with intracranial hemorrhage had 

a mean volume of 18.8 ± 3.9 mL while those with hemorrhage and clinical deterioration had a 

mean early infarct volume of 23.3 ± 8.9 mL. 
45

Summary Table 7. Intervention G 

Study 

Identification Study Design Population Characteristics Intervention (I) 

/Comparator (C) Relevant Outcomes

Patel, 2001 

US114

RCT 

Parallel 

n=624 

Inclusion Criteria: Acute IS < 3 hr (0-

90 & 91-180 min) post onset 

Baseline differences: Reports 

differences of baseline variables & EIC 

(early ischemic changes) only 

Comments: Reports outcomes as 

baseline CT scan status by tx 

associated with clinical outcomes and 

subdivided by EIC > or <1/3 EIC or no 

EIC; CTs were not used in tx decision

I: Intravenous tPA 

(n=312) 

C: Control 

(n=312) 

 Early CT changes 

not correlated 

with outcome or 

adverse events 

Roberts, 2002 

 

US115

RCT 

Parallel 

n=159 

Inclusion Criteria: Acute IS of MCA 

origin within 6 hr of onset; 

angiography: complete occlusion or 

contrast penetration with minimal 

perfusion of M1 or & M2 (based on 

PROACT (Prolyse in Acute Cerebral 

Thrombo-embolism) II trial criteria) 

Baseline differences: NR 

Comments: Article based on cohort of 

patients who received randomization & 

available CTs; no baseline/ follow up 

information for cohorts is specified 

I: IA tPA 

(n=107) 

C: Control 

(n=52) 

 Baseline CT 

volume weakly 

correlated with 

clinical outcome 

RCT = randomized clinical trial; US = United States; NR = not reported; n = number of participants; y = year; mo = 

month; d = day; hr = hour; min = minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = 

middle cerebral artery; IG = intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra 

arterial; (r)tPA = (recombinant) tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed 

tomography; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of 

Health Stroke Scale; mRS = modified Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 

Intervention H: Do Pretreatment MRI Scoring Systems Affect the 

Safety and Efficacy of Thrombolytic Therapy for Acute Ischemic 

Stroke? 

Six studies were identified that addressed the effectiveness of an MRI scoring system for 

ischemic stroke. One multiple prospective cohort study101 and one single prospective cohort 

study100 were included in our review; they were published in 2002 and 2003, respectively 

(Summary Table 8). Three non comparative case series reports206-208 and one case study were 

excluded for level of evidence.209
46

Suarez and colleagues101 reported a single-center cohort in which MRI was used to select 

patients for IA treatment following IV treatment. Patients enrolled had a diagnosis of ischemic 

stroke whose onset was less than three hours prior to the onset of treatment. The NIH Stroke 

Scale Score was greater than or equal to 4. An unenhanced CT scan had demonstrated an 

absence of hemorrhage. The blood pressure was monitored and treated if greater than 180/110. 

All patients received IV tPA at a dose of 0.6 mg/kg delivered as a 10% bolus over 1 minute with 

the remainder over 30 minutes. An emergency MRI was conducted subsequently. T1 weighted, 

T2 weighted, turbo gradient, spin echo, and echo-planar diffusion weighted axial images and 

axial time-to-peak maps were obtained. They were processed within 6 minutes and interpreted 

by the neuroradiologist. MRI changes were categorized into four groups: 1) no evidence of 

infarct 2) evidence of infarct limited to penetrating artery distributions 3) diffusion imaging 

(DWI) and perfusion-weighted imaging (PWI) mismatches suggesting infarct involving cortical 

and subcortical areas, or 4) PWI/DWI matched abnormalities suggesting acute infarction 

involving cortical and subcortical areas. Patients who had no signs of infarct on the MRI or 

infarcts involving only perforating artery distributions were not treated further. All others had 

urgent cerebral angiography. If occlusion was demonstrated on the angiography, patients were 

treated with either urokinase or tPA. This protocol initially started using urokinase, however, 

switched to tPA after FDA approval of IA tPA for acute ischemic stroke. The urokinase protocol 

involved an initial dose of 250,000 units repeated up to three times if the vessel did not 

recanalize. The tPA protocol involved 5 mg repeated until maximum dose of 0.9 mg/kg was 

achieved over the vessel recanalized. 

A total of 2,180 patients were seen at the center during this period of which 554 presented 

within 3 hours. Forty-five patients met eligibility criteria including consent for this protocol and 

were considered for angiography. Of these, 21 patients were treated solely with intravenously 

administered tPA. Seven of these had normal MRI findings while four had evidence of small 

subcortical defects and two had complete ICA occlusions. One patient exhibited complete 

improvement prior to angiography, and two patients had normal angiographic results after 

abnormal MRI results. The mean delay added by MRI imaging was 17 minutes with mean time 

to complete IA treatment of 282 ± 41 minutes in the urokinase group and 290 ± 38 in the tPA 

group. For the 24 patients who received IA tPA, the majority recanalized, 18/24. The prespecified criterion for good clinical outcome was a Barthel Score of greater than or equal to 95 at 

3 months. This was achieved by 92% of those in the IA urokinase group (12/13), 64% in the IA 

tPA group (7/11), and 66% of those in the IV treatment group (14/21). 

Hermier et al.100 reported on the use of MRI characteristics employed prospectively to 

examine the predictive value of early clinical and MR parameters on recanalization in 

thrombolytic treatment and late infarct volume. Patients were accrued between 2001 and 2002 at 

a single center in France. Patients with an ischemic stroke within the carotid territory who could 

receive MRI scanning and IV tPA within 6 hours were included. An NIHSS greater than 4 and 

an absence of bleeding on unenhanced CT were required. A baseline MRI scan including timeof-flight MR angiograpy, and DWI/PWI, was obtained. Patients with lacunar syndromes 

determined either clinically or after MRI, were excluded along with hemodynamically relevant 

stenoses of the extracranial arteries, which might affect time-to-peak analysis. A 

neuroradiologist who was unaware of the clinical data carried out interpretation of the MRI scan. 

All patients received IV tPA 0.8 mg/kg. Of 510 patients diagnosed with a stroke, 61 had stroke 

in the carotid artery and could receive the MRI within 6 hours. Of these patients, 32 met 
47

inclusion criteria and received a baseline MRI scan; three of these patients were excluded since 

their baseline scans were obscured by a motion artifact. 

The correlation between the NIH Stroke Scale Score and recanalization at day 1 was 

demonstrated with a NIH Stroke Scale Score of less than 15 correlating with canalization in the 

early time frame (p=0.046). The time-to-peak within the DWI lesion on day 0 was likewise 

correlated with early recanalization. Thirteen of 15 patients (93%) whose baseline time-to-peak 

was less than or equal to 36.9 milliseconds recanalized within the first day versus 5 of 15 patients 

(35.7%) whose time-to-peak was greater than 36.9 milliseconds. The NIH Stroke Scale Score 

and baseline time-to-peak value were the most powerful predictors of recanalization on multivariate analysis at day 0. Both the day 0 DWI lesion volume and day one recanalization 

predicted the 60-day infarct volume. Of note, the extent of day 0 DWI/PWI mismatch had nonpredictive value for early recanalization. Recanalization was correlated with a better clinical 

outcome at day 60. 
48

Summary Table 8. Intervention H 

Study 

Identification 

Study Design Population Characteristics Intervention (I) 

/Comparator (C) 

Relevant 

Outcomes 

Hermier, 

2003 

France100

Single Prospective 

Cohort 

n=28 

Population Characteristics: Acute IS, 

with pre-tx & within 6 hr MRI; NIHSS 

> 4 & no contraindication to tPA tx; 

with recanalization on MRI (IG) or 

persistent occlusion on MRI (CG) 

Comments: Small sample size; 

assessment of perfusion based on 

only seven perfusion weighted 

image (PWI) slices which might have 

caused underestimation of the 

volume of abnormality 

Observational study 

correlating outcome 

with measured 

parameters 

 Recanalization 

correlated with 

clinical 

outcome at 60 

d 

 Initial DWI 

lesion volume 

& 

recanalization 

at d 1 

predicted 60 d 

infarct volume 

Suarez, 

2002 

US101

Multiple 

Prospective 

Cohort 

n=45 

Population Characteristics: Acute IS 

< 3hr post symptom onset; no 

improvement on clinical sign; no ICH 

on CT; age 18-80; NIHSS score ≥ 4 

Comments: Study was limited with 

small sample size, lack of CG, & use 

of two different thrombolytic agents; 

tx dose of tPA lower than standard 

approved by Food & Drug 

Administration; good clinical 

outcomes (BI) was reported at 3 mo 

post tx for survivors 

I: Combined 

intravenous/intraarteri

al thrombolysis 

(n=45) 

 Symptomatic 

intracranial 

hemorrhage 

4.4% 

 Mortality 7/45 

(16%) 

US = United States; NR = not reported; n = number of participants; y = year; mo = month; d = day; hr = hour; min = 

minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = middle cerebral artery; IG = 

intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra arterial; (r)tPA = (recombinant) 

tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed tomography; NINDS = National 

Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health Stroke Scale; mRS = modified 

Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 

Intervention I: Do CT Perfusion/Angiography Affect the Safety and 

Efficacy of Thrombolytic Therapy for Acute Ischemic Stroke? 

Three studies (four publications) examining CT perfusion/angiography for ischemic stroke 

were identified.102,116,210,211 One potentially relevant trial210,211 was published in abstract form 

and the authors were contacted to determine if subsequent articles were published. These were 

excluded following full text screening. Study design could not be determined in two 

publications and were excluded for level of evidence.212,213 One single retrospective cohort 

study102 and one case-control study116 were included in our review (Summary Table 9). They 

were published in 2001 and 2004, respectively. 
49

Agarwal and colleagues reported on the significance of the hyperdense MCA sign in 

selecting patients for IA versus intravenous thrombolysis in a cohort of patients collected at a 

single American center between 1996 and 2001.116 Consecutive patients presenting at the center 

with acute ischemic stroke were considered; those patients who arrived within 3 hours of 

symptom onset and had no contraindications to tPA, were treated with 0.9 mg/kg following the 

NINDS protocol. Patients with a contraindication to intravenous tPA or presenting within 3 to 6 

hours underwent IA treatment. In these individuals, a #5 French sheath was placed in the right 

common femoral artery followed by selective catheterization of the occluded cerebral artery. 

The guidewire was used to provide mechanical disruption followed by the administration of 14 

to 20 mg of tPA by an infusion microcatheter. The total dosage was determined by the presence 

of recanalization or upon reaching the maximum dose of 20 mg. All patients received evaluation 

for MCA hyperdensity and other changes of early infarction. A hyperdense MCA was defined 

by: spontaneous visibility of the whole horizontal part of the MCA; density of the MCA higher 

than that of the surrounding brain; disappearance on bone windows; unilaterality; and, absence of 

hemorrhage. The M2 dot sign was defined as hyperdensity of an arterial structure seen as a dot 

in the sylvian fissure. Obscuration of the lentiform nucleus, loss of the insular ribbon, and 

hemispheric effacement were also assessed. A 24-hour neurologic improvement, defined as a 4-

point NIHSS Score improvement from baseline, was evaluated. 

During the course of the study, 66 patients were treated with intravenous tPA and 17 by IA 

tPA. The presence of the hyperdense MCA sign did not predict neurologic recovery in the IA 

treated patients with three of eight patients who had the sign achieving 24-hour recovery as 

defined, along with three of nine patients who did not have the sign. The hyperdense MCA sign, 

however, did predict recovery, with two of 15 patients having the hyperdense MCA sign 

achieving 24-hour recovery; conversely, 30 of 51 patients lacking the sign achieved 24-hour 

neurologic recovery (p=0.005). The M2 dot sign, loss of insular ribbon, obscuration of lenticular 

nuclei, and sulcal effacement, were not predictive of recovery with either intravenous or IA 

treatment. 

The hyperdense MCA sign was associated with a greater probability of recovery with IA than 

intravenous treatment (37% versus 13%). This observational data116 suggests that this sign may 

be used as a tool to triage patients between intravenous and IA treatment. There is a probability 

that proximal large vessel occlusion may be associated with worse outcomes intravenously. This 

observation will require testing in a prospective study. 

Kirpatrick and colleagues102 reported on a retrospective cohort of patients from a single 

center between 1997 and 2000. These were selected on the basis of an electronic record search 

seeking all patients within the period of enrollment who would have had a CT scan, CT 

angiogram and Xenon CT cerebral blood flow within 24 hours of a stroke. The clinical team 

ordered the studies at the time of the patient’s presentation. Primary intent of the study was to 

see whether abnormalities on these studies or the NIH Stroke Scale were predictive of infarct on 

the follow-up CT scan. The NIH Stroke Scale was obtained from the record or calculated from 

the neurologic examination in the record. The CT scan was reviewed by the investigators in a 

blinded fashion. The CT angiogram was coded based on the report contained within the record. 

All CT angiograms were performed on a GE Lightspeed scanner with axial helical images 

obtained from the level of C6 through the circle of Willis with 3 mm collimation. The CTA was 

defined as patent if there was no report of occluded or stenotic vessels. It was considered 
50

occluded if the ICA or MCA on the symptomatic side were reported to be occluded or heavily 

stenosed. The Xenon CT cerebral flow image was obtained at four levels and mean CBF values 

were calculated at 20 standardized cortical regions of interest. The scan level containing the 

lowest average flow in the MCA territory on the symptomatic side was used. This flow was 

categorized as normal (greater than or equal to 30 mL/100 g/minute), potentially reversible (7 to 

29 mL/100 g/minute) or irreversible (less than 7 mL/100 g/minute). The latter two categories 

were combined due to the small number of patients for statistical analysis. The groups were 

further subdivided into those examined within six hours of stroke onset and those greater than six 

hours. The latter group was too small to draw any conclusions. In the group examined prior to 

six hours (n=31), the NIH Stroke Scale Score was not predictive of infarct on the follow-up CT 

scan. Normal cerebral blood flow on the Xenon CT resulted in a rate of infarct of 8% (1/13), 

while abnormal Xenon CT blood flow resulted in a rate of infarct of 55% (6/11). This difference 

was statistically significant (p=0.023). A CT angiogram showing patent vessels was associated 

with a rate of infarct of 7% (1/14 patients) while CT angiogram showing occlusion had an infarct 

rate of 60% (6/10). This too was statistically significant (p=0.008). 

Summary Table 9. Intervention I 

Study 

Identification Study Design Population Characteristics Intervention (I) 

/Comparator (C) Relevant Outcomes

Agarwal, 

2004 

US116

Case Control n=83 

Inclusion Criteria: Acute IS, according to 

TOAST criteria; < 3 hrs post onset (IG) or 

3-6 hrs post onset & patients excluded for 

IV tPA based on NINDS criteria (CG) 

Baseline differences: NR 

Comments: Significantly shorter time to tx 

in IG 

I: Intravenous tPA 

(n=66) 

C: Intraarterial tPA 

(n=17) 

 No correlation 

with HCMAS and 

outcome for CG 

 HCMAS 

associated with 

poorer 

neurologic 

improvement at 

24h in IG 

Kilpatrick, 

2001 

US102

Single 

Retrospective 

Cohort 

n=51 

Population Characteristics: Acute 

hemispheric IS within 24 hrs post 

symptom onset, undergone CT, CT 

angiography & xenon-enhanced CT, 

cerebral blood flow; NIHSS score 1-26 

Comments: Small sample size; possible 

selection bias 

Observational 

study examining 

the prediction of 

(n=51) 

 Decreased CBF 

associated with 

higher rate of 

infarction 

 CT angiogram 

occlusion 

associated with 

higher infarction 

US = United States; NR = not reported; n = number of participants; y = year; mo = month; d = day; hr = hour; min = 

minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = middle cerebral artery; IG = 

intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra arterial; (r)tPA = (recombinant) 

tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed tomography; NINDS = National 

Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health Stroke Scale; mRS = modified 

Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 
51

Intervention J: Are Community Education Programs Effective in 

Reducing Stroke-Related Disability and Mortality? 

One controlled clinical trial,103 six before-after studies,214-219 and one study for which study 

design could not be determined,220 investigated the use of community education programs for 

acute stroke. Subsequently, seven studies were excluded for level of evidence.214-220 Only one 

study103 was included for our review (Summary Table 10). This study was a controlled clinical 

trial and was published in 2003. The before-after studies did not address relevant clinical 

outcomes and thus we were unable to extract data from these studies. We did however 

summarize the studies, including population characteristics and limitations in the Appendix. 

(Appendix E) 

Prior to FDA approval of thrombolytic treatment, acute stroke was not perceived as an 

emergent reason to present to a healthcare facility. Educational programs for the community and 

healthcare professionals involved in care of patients with acute stroke were deemed essential, as 

thrombolytic therapy must be urgently administered in order to be beneficial. 

The TLL Temple Foundation Stroke Project was established after approval of thrombolytic 

therapy by the FDA, with the goal to increase utilization of this therapy in a non-urban 

community in East Texas. Results of the first and second phases of the study have been 

published221—phase 1 reported on baseline data in the intervention community and the control 

community and the development of the intervention; phase 2 included an evaluation of the 

intervention. 

Morgenstern et al. reported on the third phase of the TLL Temple Foundation Stroke 

Project—a quasi-experimental comparison between two communities to determine if the 

beneficial effect of the Community and Professional Intervention would be sustained after the 

active intervention had been completed.103 In this report, comparisons are made with the other 

phases of the project in a before-after design. The financial sponsors of this project mandated 

that a specific community receive the intervention, and that another, comparable community be 

chosen by the project investigator. The intervention and its development were published in a 

companion publication.221 In summary, the intervention was developed based on the process of 

Intervention Mapping to create a multi-level program that delivered a community 

communication campaign combined with professional development and organisation change to 

increase access to stroke therapy in rural east Texas. Target behaviors of lay community (the 

“at-risk group”), EMS, ED physicians, neurologists, and community primary care providers were 

identified, and educational and infrastructure changes were given. For example, to target 

community members, public service announcements were created using local role models, 

volunteers were trained to take the message to community groups, and educational pamphlets 

were distributed. Changes made to EMS included assigning a higher priority for the transport of 

acute stroke patients, development of protocols, and reinforcement and use of mock stroke codes 

were performed. To target physicians, changes included providing continuing medical education 

provided, the use of mock stroke codes, and the distribution of newsletters. 

Active surveillance by fellowship stroke-trained neurologists, was used to capture all 

hospitalized stroke cases in the 10 hospitals (five from each community) using a method 

developed by WHO in the Monica Study.222 
52

In this third phase of the study, 2,184 patients were screened, and 238 validated cases were 

documented. Baseline demographics of patients from the two communities were different. 

Patients from the control community had a higher prevalence of co-morbid illnesses compared 

with the intervention group community: hypertension (87.5% vs. 75.4%); diabetes (48.2% vs. 

27.1%); CAD (56.9% vs. 31.5%); AF (68.4% vs. 10.9%); and, previous stroke (65.2% vs. 

44.1%). More patients in the control community had a neurological consultation compared with 

the intervention community (59.1% vs. 45.0%). 

The primary outcome was the proportion of patients treated with IV alteplase. This included, 

nine out of 13 eligible patients (69.2%) in the intervention community, compared with only one 

of 5 eligible patients (20%) in the control community. The secondary outcome was the 

proportion of patients who presented to the hospital within 2 hours of symptom onset. There was 

no significant difference between the two communities—i.e., 28.6% of patients from the 

intervention community and 22.6% of patients in the control community. 

A comparison in both communities over the three phases of this project was reported for 

internal hospital delay and physician reluctance to utilize tPA in acute stroke. In the intervention 

community, there was a significant reduction in the proportion of patients who experienced 

internal hospital delay and a significant reduction in physician reluctance to utilize tPA in acute 

stroke. In the control community, there was a similar reduction in hospital delay but no change 

in physician reluctance to utilize tPA over the three phases of this project. 

Summary Table 10. Intervention J 

Study 

Identification Study Design Population Characteristics Intervention (I) 

/Comparator (C) Relevant Outcomes

Morgenstern, 

2003 

US103

Controlled 

Clinical Trial

n=1427 (for all 3 phases); phase 3 only: 

n=238 

Inclusion Criteria: County residents 

experience of cerebrovascular event; IV 

tPA inclusion according to NINDS 

criteria 

Comments: Study demonstrates a 

sustained benefit from educational 

intervention, with possibility of physician 

professional intervention being the most 

or only successful part of the 

intervention 

I: Community 

education program 

for acute stroke 

(n=748/ phase 3: 

n=130) 

C: Control 

(n=679/ phase 3: 

n=108) 

 11.2% of 

ischemic stroke 

treated with tPA 

vs. 2.2% 

 Improvement in 

frequency of IV 

tPA tx in eligible 

candidates 

US = United States; NR = not reported; n = number of participants; y = year; mo = month; d = day; hr = hour; min = 

minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = middle cerebral artery; IG = 

intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra arterial; (r)tPA = (recombinant) 

tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed tomography; NINDS = National 

Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health Stroke Scale; mRS = modified 

Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 
53

Intervention K: Are Designated Centers Effective in Reducing StrokeRelated Disability and Mortality? 

Initially, no studies meeting eligibility criteria for investigating the use of designated centers 

as defined by the Brain Attack Coalition were identified by our searches. However, two 

studies104,105 were included since they provided valuable end points (numbers treated and time to 

treatment). Both studies were single prospective cohort designs and were published between 

2000 and 2003 (Summary Table 11). 

It has been hypothesized that to increase utilization of thrombolytics, a dedicated stroke 

center strategy should be developed.5

 The studies we included were felt to most closely 

resemble the model of a designated stroke center as defined by the Brain Attack Coalition and 

detailed by Alberts et al. (2000) in their recommendations for the establishment of primary 

stroke centers.5

Hill et al.104 reported on building a “brain attack” team to administer thrombolytic therapy to 

patients with acute stroke and on their initial experience with IV-administered thrombolytics. 

Although thrombolytic therapy was approved for use in Canada in 1999 (the FDA approved its 

use in the U.S. in 1996), the Calgary Regional Stroke Program received special permission from 

the local health authority and began a program of open-label thrombolytic therapy for stroke in 

1996 following FDA approval for its use in the U.S. The project was initially approved as a pilot 

study; after 20 patients, an audit was performed to assess safety and complication concerns. The 

model of care was organized around five essential elements of acute stroke care (all beginning 

with the letter “R”): Recognition, Reaction, Response, Reveal, and Reperfusion. The major 

changes that were instituted to achieve success of this program was the funding of a “blocked 

bed” on the stroke unit i.e., a bed that was always available for a patient to receive thrombolytic 

therapy enabling rapid removal of patients with acute stroke from the ED. In addition, a 

campaign was launched to educate the public to increase awareness and “recognition” of stroke 

symptoms. EMS were asked to change their dispatch protocols to decrease “response” times by 

elevating acute stroke to a priority one transfer where all patients with stroke-onset symptoms 

less than 3 hours were preferentially transferred to the stroke center, bypassing other hospitals. 

The stroke center was contacted by EMS, and the stroke team contacted on patient’s arrival to 

ED thus decreasing the “reveal” time. The ED staff treated stroke as a life-threatening situation, 

performed a preliminary assessment, and urgently arranged for CT scanning to decrease the time 

to “reperfusion”. 

The initial audit of 20 patients revealed no safety concerns.104 From the inception of the 

stroke program through to Jan 31, 1999, 69 patients were treated with IV-administered 

thrombolytics. A 1-year audit demonstrated that 6% of all patients admitted with acute stroke 

were treated with thrombolytics. Outcome data, reported in a separate publication,223 compared 

favorably with data reported in published RCTs, with the exception that when patients were 

treated beyond the 3-hour window, 25% had a symptomatic hemorrhage with 83% of these 

patients having died by the 90-day follow-up. 

Hill et al.104 reported that EMS had treatment times equal to or less than target times 

recommended by the NINDS stroke study group,224 with a mean time from symptom onset to ED 

arrival of 55.8 minutes (range 15-125 minutes). Once the patient arrived at the ED, a mean time 
54

of 46.1 minutes (range 5-130 minutes) was required to obtain a CT scan and a further mean time 

of 55.6 minutes (range 20-315 minutes) was required for initiation of thrombolytic treatment. 

Treatment times improved significantly over the study period—mean treatment time for the first 

half of the study period was 63.3 minutes compared with 48.6 minutes for the second half of the 

study. ED to CT and ED to treatment times did not significantly change. Overall symptom 

onset to treatment time was significantly decreased from a mean of 167.8 minutes to 147.4 

minutes.104

Hill et al.104 concluded that if the public can be taught to recognize the symptoms of stroke 

and react by calling EMS, EMS will promptly get the patient to the hospital. The authors were 

sobered by the fact that the improvement in time gain overall, was due primarily to getting 

patients to the hospital faster. 

A 4-month pilot study was started at Suburban Hospital in Bethesda MD to establish a stroke 

center for the region.105 A stroke critical care pathway was developed which incorporated EMS 

policies, immediate notification of the stroke team, initiation of urgent diagnostic tests, and 

medical management for thrombolytics. Community education (i.e., lectures emphasizing the 

symptoms of stroke and need for rapid response by activation of EMS and risk assessment 

screenings) targeting local community centers, particularly those with senior citizen populations, 

was provided by the stroke team. Stroke education was provided to ED personnel, hospital 

personnel, diagnostic imaging, and laboratory staff as well as regional EMS and the local 

community. 

On January 3, 2000, around-the-clock coverage was instituted for acute stroke.105 The 

stroke-care critical care pathway mandated contacting the stroke team for any patient presenting 

with a suspected new stroke and persistent deficit <6 hours in duration. Data was collected 

prospectively until December 31, 2001 for all patients assessed by the stroke team including 

demographic data, presentation times, treatment times, reasons for non-treatment, radiological 

times and findings, stroke scale results (NIHSS, mRS), and disposition. Measured time intervals 

to action (in minutes) were computed as a running 2-month average.105 Results were compared 

with benchmarks from the Standard Treatment with Alteplase to Reverse Stroke Study 

(STARS).225

A total of 511 patients were admitted to the hospital with a diagnosis of suspected ischemic 

stroke; 420 patients had the diagnosis confirmed and 271 arrived within 3 hours of symptom 

onset.105 Over the 2-year period the following times decreased: time from patient arrival to 

paging of the stroke team (median of 24 min to 10 min); time from receiving the stroke-team 

page to arrival of the stroke team (median of 28 min to 6 min); and, time of triage to time of CT 

(median of 52 min to 42 minutes). The overall median time to treatment from onset was 134 

minutes, and the median door-to-needle time was 88 minutes.105

During the 4-month pilot study, four of 117 patients with ischemic stroke were treated with 

thrombolytics (3.4%).105 Of the 420 patients diagnosed with suspected ischemic stroke over the 

2-year study period, there were 44 patients treated with thrombolytics—10.5% of the total and 

16.2% of those arriving to hospital within 3 hours of the onset of symptoms.105 Clinical 

outcomes and time to treatment were similar to that reported by STARS.225
55

This study demonstrated that a coordinated stroke strategy and development of a stroke 

center led to a decrease in treatment and investigation times over the investigation phase in 

addition to increasing the proportion of patients who received thrombolytics.105

Lattimore and colleagues reported the experience of establishing an acute stroke program at a 

Maryland hospital.105 The community education program associated with this effort consisted of 

multiple onsite programs with screening efforts, lectures and engagement of local media that 

were coupled with an intense reorganisation of ED protocols and designation of an acute stroke 

response time. Delay time prior to the intervention was not reported but an increase in the 

treated proportion, from 1.5% prior to the intervention to 10.5% during the subsequent 2 years, 

was noted. No comment was made regarding the relative contributions of the elements of the 

intervention to the observed outcome. Thus, the relative contribution of the educational effort 

cannot be separated from the overall effect. 

Summary Table 11. Intervention K 

Study 

Identification Study Design Population Characteristics Intervention (I) 

/Comparator (C) 

Relevant 

Outcomes 

Hill, 2000 

Canada104

Single 

Prospective 

Cohort 

Inclusion criteria: Acute IS, treated 

within 3 hrs of symptom onset 

Observational study 

describing 

development of 

designated centers for 

acute stroke 

 6% of IS 

treated within 

the 1st y of 

program 

inception (n = 

69) 

Lattimore, 

2003 

US105

Pre-Post Inclusion criteria: Acute IS with 

persistent neurological deficits, all 

inclusion criteria based on NINDS & 

guidelines from a Special Writing Group 

of the American Heart Association 

I: Use of designated 

centers for acute 

stroke 

 Establishment 

of stroke 

center 

correlated 

with S 

increase in 

proportion of 

IS treated 

(1.5% to 

10.5%) 

US = United States; NR = not reported; n = number of participants; y = year; mo = month; d = day; hr = hour; min = 

minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = middle cerebral artery; IG = 

intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra arterial; (r)tPA = (recombinant) 

tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed tomography; NINDS = National 

Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health Stroke Scale; mRS = modified 

Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 

Intervention L: Are ED Protocols for the Management of Acute Stroke 

Effective in Reducing Disability and Mortality? 

After the publication of NINDS,49 proponents have widely advocated for the implementation 

of “stroke teams” to increase the proportion of patients who are eligible to receive thrombolytic 

therapy and increase utilization of thrombolytic therapy in this population.49 
56

From our search we identified one case-control study,226 two single prospective cohort 

studies,118 two single retrospective cohort studies,106,117 two non-comparative case series 

studies,227,228 and two studies whose design could not be determined.229,230 The case-control and 

non-comparative studies were excluded for level of evidence. Four studies106,117,118 examining 

the effect of ED protocols for management of acute stroke met our eligibility criteria and were 

included in our final analyses (Summary Table 12). These studies were published between 1999 

and 2003. 

Smith et al.106 proposed an ED model for two main reasons. First, EDs were already staffed 

for rapid assessment, and second, an ED model was already used for administering thrombolytics 

for acute myocardial infarction in many centers. Smith and colleagues’ ED model included 

guidelines and checklists to evaluate exclusion and inclusion criteria for treatment with 

thrombolytics, an informed consent package, treatment guidelines including dosing charts, and 

post-treatment ICU order sets. Prior to implementation, educational efforts using lectures, small 

group sessions, and written material were directed at the ED physicians, nursing and ancillary 

staff and other services including Radiology, Neurology, and the ICU. All ED physicians had 

access to their local neurologist, and at the same time a regional stroke team was also in 

development. 

They performed a retrospective analysis of patients included in their ED model in four 

teaching hospitals in Michigan. Pharmacy records were used to identify patients treated with 

thrombolytics and the information was cross-referenced with medical record searches using 

diagnosis-related group codes used to identify all patients with acute stroke and thrombolytic 

use. A study physician reviewed each identified record to abstract patient demographics, 

medical and social history, physical exam findings, complications, length of stay, and stroke 

severity using the NIHSS. The physician reviewer estimated within 5-point ranges the NIHSS 

based on documented physical examination in the medical record prior to treatment if the NIHSS 

was not documented in the medical record. The primary outcome was length of hospital stay, as 

well as whether the patient was ICH symptomatic or not, pre-hospital time to ED presentation, 

and ED time data. 

Over the study period, 37 patients received thrombolytic therapy. The average time from 

onset of symptoms to ED arrival was 64 minutes for patients arriving by EMS and 84 minutes 

for those arriving by car. This data was given for only two of the hospitals that provided care for 

24 of the patients. Times for care in the ED were available for 34 of the 37 patients. 

Thrombolytic therapy began an average of 97 minutes after arrival in the ED and 166 minutes 

after stroke onset. Neurology consultation was provided for 23 of the 37 patients (nine in person 

and 14 by telephone). Treatment protocol violations were identified in seven patients, all 

relating to administration of thrombolytic therapy after the 180-minute time window. Four of the 

37 patients developed a symptomatic hemorrhage within 36 hours after treatment but none of 

these patients were treated outside the 180-minute time window. Neurological outcomes in the 

35 survivors at the time of discharge were normal for four patients, improved for 16 patients, 

unchanged for 10 patients, and worse for five patients. Fifteen patients were discharged home 

and 15 to a rehabilitation facility. 

Time intervals used in the ED model compared favorably to times reported in publications of 

dedicated stroke teams.231 ED physicians consulted a neurologist in the majority of cases but 
57

often only a telephone discussion was required to support facilitating the timeliness of 

administering treatment. 

Akins et al. reported on a study that also evaluated an ED-based protocol for delivering 

thrombolytic therapy with transfer of patient care to a neurological service when feasible.117 

This group established a prospective stroke registry of patients treated with thrombolytics at five 

community hospitals within the Mercy Healthcare system of Sacramento. Forty-six consecutive 

patients who received thrombolytic therapy are reported in this study. The local ED physicians 

developed their own approach to thrombolytic therapy in collaboration with neurologists and 

radiologists. Clinical information was abstracted from patient records using a standardized form, 

and clinical outcomes included the mRS score obtained by telephone contact with the patient or 

family 3-months after treatment. Complete data was obtained on only 43 patients. The 

dependent variable for analysis was treatment initiation by an ED physician (n=23 patients) or a 

neurologist (n=20 patients). 

There were no differences between the two groups in terms of age, baseline stroke severity 

(NIHSS), ED presentation to thrombolytic therapy, recovery to normal function, mortality, or 

symptomatic hemorrhage rates. A trend was detected for a shorter time interval from CT scan to 

treatment by a neurologist. This was felt to be secondary to the ability of the neurologist to 

interpret the CT scans. 

Initially, during the first year of the protocol, there were more protocol deviations. Thus, a 

local education program was given to ED staff and local neurologists. As well, nurse strokespecialist support was implemented in all five hospitals. Seven protocol deviations occurred 

before the education endeavor compared with only one after the education program was 

provided. It was not explicitly reported who made the protocol deviations but it is stated in the 

discussion that it was not surprising that ED physicians would make errors in the dosing of 

thrombolytics, as it was a markedly different dose than they were conditioned to use for patients 

with acute myocardial infarction. Details regarding the education program and data collection 

were not well presented; hence, an independent assessment of the effectiveness of the program 

was not feasible. 

Jahnke et al. reported on their experience with ED stroke teams and acute stroke pathways, 

over a 2-year period.118 This group recognized a problem in achieving target times for 

thrombolytic treatment after a retrospective review that determined that the majority of potential 

candidates for treatment arrived in the ED more than 2 hours from symptom onset. They 

developed a stroke team and implemented a written stroke pathway. Prior to implementation, the 

emergency personnel were educated using group sessions and posters displayed in the ED. The 

pathway included a standardized set of orders and instructions for the management of acute 

ischemic stroke. Listed on the pathway were universal stroke symptoms to help staff recognize 

eligible patients. The pathway gave consideration to the time of stroke onset to determine 

potential eligibility of the patient for thrombolytic therapy, and urgent activation of the stroke 

team would occur for patients who presented less than 6 hours from onset of symptoms or nonurgent calls for patients with transient ischemic stroke or symptom with onset >6 hours. The ED 

physician assessed all patients, and a member of the stroke team would assess and calculate the 

NIHSS. Documentation of times was performed to allow rating of performance of the stroke 

team. 
58

Implementation of the pathway identified a number of strategic changes that needed to 

perform to ensure success. This included identification of two levels of stroke team referral, 

urgent and non-urgent patients. Also, a major delay identified was time to obtain a CT scan; the 

CT scanner was geographically distant from the ED and this led to placement of a CT scan in the 

ED. Another delay identified was time to obtain laboratory test results. Again the laboratory 

was geographically distant and point of service laboratory equipment was obtained for the ED. 

Over the 2-year period, 71 patients were eligible for thrombolytic therapy; 65 patients 

received treatment and six patients declined. Of the patients who received treatment, one patient 

died, two required nursing home level of care, 25 were transferred to rehabilitation and 37 were 

discharged home. Comparing the first year to the second year, there were significant decreases 

in the following time intervals. First, time from presentation in the ED to ED physician 

assessment decreased from an average of 33 minutes to 7 minutes. Second, time from 

presentation to CT scan order decreased from an average of 38 minutes to 7 minutes. Lastly, 

time from presentation in the ED to completion of the CT scan decreased from an average of 88 

minutes to 44 minutes. Compliance for initiating the stroke pathway increased from 40% to 97% 

of eligible patients, and “door-to-needle” time for the administration of thrombolytic therapy 

decreased from an average of 111 minutes to 77 minutes. This group still hopes to achieve the 

NINDS 60 minute goal. 
59

Summary Table 12: Intervention L 

Study 

Identification Study Design Population Characteristics Intervention (I) 

/Comparator (C) Relevant Outcomes

Akins, 2000 

US232 

Single 

Retrospective 

Cohort 

Inclusion criteria: Consecutive 

acute IS treated with IV tPA 

according to NINDS protocol 

treated by emergency room 

physician or neurologist 

Observational study 

examining ED 

physician’s ability to 

initiate thrombolysis 

 Protocol 

deviations higher 

for ED physicians 

compared to 

neurologists 

 Number of 

patients treated 

n=43 

Jahnke, 2003 

US118

Single 

Prospective 

Cohort 

Inclusion criteria: Acute stroke with 

mild to severe neurological deficits

Observational 

study examining 

ED protocol 

 Number of 

patients treated 

n=65 

 Door-to-needle 

time decreased 

following 

implementation of 

the protocol 

Smith, 1999 

US106

Single 

Retrospective 

Cohort 

Inclusion criteria: Acute IS treated 

with tPA, presented to ED 64 (29) 

min post onset 

Observational 

study examining 

the ability of ED 

physicians to treat 

thrombolysis 

 Of 37 patients 

treated, door-toneedle time was 

97± 35 min 

US = United States; NR = not reported; n = number of participants; y = year; mo = month; d = day; hr = hour; min = 

minutes; s = second; IS = ischemic stroke; ICH = intracranial hemorrhage; MCA = middle cerebral artery; IG = 

intervention group; CG = control group; tx = treatment; IV = intravenous; IA = intra arterial; (r)tPA = (recombinant) 

tissue plasminogen activator; MRI = magnetic resonance imaging; CT = computed tomography; NINDS = National 

Institute of Neurological Disorders and Stroke; NIHSS = National Institutes of Health Stroke Scale; mRS = modified 

Rankin Scale; GCS = Glasgow Coma Scale; BI = Barthel Index 
60

Results of Meta-Analyses 

Meta-analyses could only be performed on two of the interventions examined (Intervention A 

and Intervention C). 

Intervention A: Does Surgery Impact the Outcome in Patients with 

Acute Intracerebral Hematoma? 

Death and Disability: The meta-analysis for the mRS included four eligible studies (Figure 

2).88,89,119,120 Two studies87,121 were excluded from our disability analysis (mRS score 0 to 1) 

because data could not be extracted. Juvela et al.121 reported morbidity of survivors at 6 months 

after hemorrhage for both groups using an independently derived scale which describes patients 

as either independent (minimally or moderately disabled) or dependant (severely disabled or 

vegetative). Morgenstern et al.87 reported median values (Barthel <61) at 6 months that 

identified patients with either poor outcome or death. The four trials had a total of 246 subjects 

(range, n=20 to n=100). Note that the Batjer study120 made no contribution to the pooled 

estimate since in both groups all patients experienced death or severe disability. 

Review : Stroke

Comparison: 03 mRS >1 (death and disability) Intervention A 

Outcome: 01 mRS >1 (death and disability) Intervention A 

Study Treatment Control OR (random) Weight OR (random)

or sub-category n/N n/N 95% CI % 95% CI

 Auer 41/50 50/50 35.74 0.04 [0.00, 0.77] 

 Batjer 8/8 13/13 Not estimable 

 Teernstra 36/36 34/35 31.81 3.17 [0.13, 80.58] 

 Zuccarello 7/9 11/11 32.45 0.13 [0.01, 3.11] 

Total (95% CI) 103 109 100.00 0.24 [0.02, 3.03]

Total events: 92 (Treatment), 108 (Control)

Test for heterogeneity: Chi2 = 4.01, df = 2 (P = 0.13), I2 = 50.1%

Test for overall effect: Z = 1.10 (P = 0.27)

 0.01 0.1 1 10 100

 Favours treatment Favours control

Figure 2. Meta-analysis of the impact of surgery on death and disability in patients with acute 

intracerebral hematoma. 

Note that of the three studies that contributed to the above meta-analysis, there was 

substantial heterogeneity, therefore, the random effects pooled estimate (and associated 

confidence interval) should be interpreted with caution. 

Death: The meta-analysis for death outcomes included six eligible studies (Figure 3).87-

89,120,121,121 Summary Table 1 includes a description of eligible trials. All studies examined the 

effectiveness of surgical intervention compared with standard or usual care. The six studies had 

a total of 298 participants (range, n=20 to n=100). Follow-up interval for studies was 90 days for 

all studies. 

Two reports examining surgical intervention for surgical intervention for intracerebral 

hemorrhage (a meta-analysis published in 2002233 and randomized trial published in 2005122
61

were also identified. The meta-analysis included two studies which were not captured by our 

searches. One by McKissock et al. was published prior to our search date of 1964. The second, 

by Chen (1992) was a non-English language citation, and hence, was excluded by our search 

strategy. The Surgical Trial in Intracerebral Haemorrhage (STICH)122 was published beyond our 

search date, but was identified by a reviewer. With regards to the Chen 1992 trial, we were able 

to extract enough mortality data from this meta-analysis233 to use as a sensitivity check in our 

current meta-analysis, as well as from the STICH trial.122 (Figure 4). We could not extract data 

from the STICH trial for death and disability outcomes (mRS) because they used a prognosisbased modified Rankin index which did not permit us to recover the modified Rankin index. 

Review : Stroke

Comparison: 01 Intervention A - Surgery 

Outcome: 01 Death 

Study Treatment Control OR (random) Weight OR (random)

or sub-category n/N n/N 95% CI % 95% CI

 Auer 21/50 35/50 28.90 0.31 [0.14, 0.71] 

 Batjer 4/8 11/13 7.62 0.18 [0.02, 1.41] 

 Juvela 12/26 10/26 20.24 1.37 [0.45, 4.14] 

 Morgenstern 3/17 4/17 10.73 0.70 [0.13, 3.72] 

 Teernstra 20/36 20/35 24.95 0.94 [0.37, 2.40] 

 Zuccarello 2/9 3/11 7.56 0.76 [0.10, 5.96] 

Total (95% CI) 146 152 100.00 0.62 [0.34, 1.13]

Total events: 62 (Treatment), 83 (Control)

Test for heterogeneity: Chi2 = 6.86, df = 5 (P = 0.23), I2 = 27.1%

Test for overall effect: Z = 1.56 (P = 0.12)

 0.1 0.2 0.5 1 2 5 10

 Favours treatment Favours control

Figure 3. Meta-analysis of the impact of surgery on death in patients with acute intracerebral hematoma. 

Review : Stroke

Comparison: 01 Intervention A - Surgery 

Outcome: 04 Death (including STITCH) 

Study Surgery Conservative Trx OR (random) Weight OR (random)

or sub-category n/N n/N 95% CI % 95% CI

 Auer 21/50 35/50 15.25 0.31 [0.14, 0.71] 

 Batjer 4/8 11/13 3.60 0.18 [0.02, 1.41] 

 Chen 15/64 11/63 14.25 1.45 [0.61, 3.46] 

 Juvela 12/26 10/26 10.20 1.37 [0.45, 4.14] 

 Morgenstern 3/17 4/17 5.15 0.70 [0.13, 3.72] 

 Teernstra 20/36 20/35 12.89 0.94 [0.37, 2.40] 

 Zuccarello 2/9 3/11 3.57 0.76 [0.10, 5.96] 

 Mendelow , D 173/468 189/497 35.08 0.96 [0.74, 1.24] 

Total (95% CI) 678 712 100.00 0.81 [0.54, 1.22]

Total events: 250 (Surgery), 283 (Conservative Trx)

Test for heterogeneity: Chi2 = 10.76, df = 7 (P = 0.15), I2 = 35.0%

Test for overall effect: Z = 1.00 (P = 0.32)

 0.1 0.2 0.5 1 2 5 10

 Favours treatment Favours control

Figure 4. Meta-analysis of the impact of surgery on death in patients with acute intracerebral hematoma 

including data from the Chen RCT (data extracted from a meta-analysis published in 2002)51 and STICH122

trial. 

Regardless of whether the Chen study is included, the pooled estimate is not statistically 

significant. There was, however, a moderate degree of heterogeneity in study outcomes. Note 

that only the study by Auer119 showed a statistically significant benefit from surgery. 
62

Intervention C: Does IA Thrombolysis Reduce Stroke-Related 

Mortality and Disability in Adults with Acute Stroke? 

Death and disability. Two studies examining the use of IA tPA for acute ischemic stroke were 

included in our meta-analysis (Figure 5).92,110 The two trials included 220 subjects. Note that in 

this case, there is no detectable statistical heterogeneity, and the random effects model provides 

identical results to a fixed effects model. 

Review : Stroke

Comparison: 02 Intervention C 

Outcome: 02 mRS >1 (death and disability) Intervention C 

Study Treatment Control OR (random) Weight OR (random)

or sub-category n/N n/N 95% CI % 95% CI

 Furlan 89/121 49/59 78.78 0.57 [0.26, 1.25] 

 del Zoppo 18/26 11/14 21.22 0.61 [0.13, 2.82] 

Total (95% CI) 147 73 100.00 0.58 [0.29, 1.16]

Total events: 107 (Treatment), 60 (Control)

Test for heterogeneity: Chi2 = 0.01, df = 1 (P = 0.93), I2 = 0%

Test for overall effect: Z = 1.53 (P = 0.12)

 0.1 0.2 0.5 1 2 5 10

 Favours treatment Favours control

Figure 5. Meta-analysis of the impact of IA thrombolysis on death and disability in patients with acute 

ischemic stroke. 

Death: The meta-analysis for death outcomes associated with the use of IA tPA for acute 

ischemic stroke included two studies (Figure 6).92,110 The two trials included 220 subjects. Note 

that in this case, there is no detectable statistical heterogeneity, and the random effects model 

provides identical results to a fixed effects model.

Review : Stroke

Comparison: 02 Intervention C 

Outcome: 01 Death Intervention C 

Study Treatment Control OR (random) Weight OR (random)

or sub-category n/N n/N 95% CI % 95% CI

 Furlan 30/121 16/59 78.93 0.89 [0.44, 1.80] 

 del Zoppo 7/26 6/14 21.07 0.49 [0.13, 1.93] 

Total (95% CI) 147 73 100.00 0.78 [0.42, 1.47]

Total events: 37 (Treatment), 22 (Control)

Test for heterogeneity: Chi2 = 0.56, df = 1 (P = 0.45), I2 = 0%

Test for overall effect: Z = 0.77 (P = 0.44)

 0.1 0.2 0.5 1 2 5 10

 Favours treatment Favours control

Figure 6. Meta-analysis of the impact of IA tPA on death in patients with acute ischemic stroke.

Statistical significance of pooled results. Neither of the pooled estimates was statistically 

significant. Note, however, that the wide confidence intervals of the pooled estimates do not 

rule-out the possibility of substantial benefit from IA thrombolytic therapy.
63

Chapter 4. Discussion 

Studies of Treatment of ICH 

The meta-analysis performed for the surgical trials, for both death, and death and disability, 

showed heterogeneity within the trials. This may be the consequence of different surgical 

techniques used in the trials. The confidence interval associated with a pooled effect estimate for 

both endpoints is large and does not preclude a clinically significant treatment effect from 

surgical intervention particularly in certain subgroups of patients. Current clinical opinion holds 

that surgery be considered for patients with cerebellar hemorrhage, particularly if the diameter 

exceeds 3 cm, and for young patients with significant hemispheric hemorrhage experiencing 

clinical deterioration.234

In spite of the potential wide applicability of anti-hypertensive therapy following ICH very 

little data is available regarding this intervention. Both studies included had very small numbers 

and were significantly hampered by lack of measurement of clinical effect. The study examining 

intravenous ketanserin on arterial and intracranial pressures in a small group of patients raises the 

possibility that cerebral perfusion pressure might be affected by anti-hypertensive therapy.90 

Role of Thrombolysis in Stroke 

Stroke due to vascular occlusion (ischemic stroke) comprises 80% of all stroke.235 The 

mechanisms of occlusion are varied but have in common the deposition of platelets and fibrin. 

Fibrin is a protein that is deposited in strands enmeshing red blood cells and platelets alike. 

Plasminogen is released from the vascular endothelium and converted to plasmin by 

plasminogen activator and plays a role in regulating the duration and propagation of clots within 

the body. The human gene can be spliced into bacteria to allow for large-scale production of tPA 

and harvested in commercially viable quantities. Genentech received FDA approval for its use 

in the coronary circulation in 1987 with subsequent use in acute occlusions of the coronary 

arteries. 

Prior to the publication of the NINDS Trial of IV rtPA delivered within 3 hours of stroke 

onset,236 no acute therapy had been shown to modify the outcome of ischemic stroke in human 

trials. Two potential interventions for acute ischemic stroke therapy were: 1) re-establishing 

blood flow prior to cell death, and 2) limiting irreversible damage in ischemic brain. Efforts had 

been mainly directed at reducing neuronal metabolism49,237 neuroprotection,238 and 

antioxidation.239 While the sequence of molecular events which led from energy failure through 

membrane depolarization, cytotoxin release, calcium influx with subsequent activation of 

destructive enzymes had been well worked out;239 attempts to influence the process in humans 

had been ineffective.240,241 Preclinical work on rodent models of these interventions had been 

highly successful, suggesting a profound disconnection between animal models of stroke and the 

human syndrome studied in clinical trials. Several reasons have been suggested for this failure to 

translate laboratory results into clinical outcomes. 
64

Animal models have focused on short time periods of drug administration and outcome 

evaluation with a focus on anatomic measurements (volume of infarct) rather than functional 

goals.241 While consideration of such trials has not stopped,241,242 the results suggest a need for a 

renewal of efforts on reversing vascular occlusion prior to the development of irreversible 

cellular damage. 

Thrombolysis enjoys a prominence in acute stroke due to this critical role of reestablishing 

perfusion in the face of repeated failure of other strategies. It is the only medical treatment 

approved for acute ischemic stroke in the U.S. and Canada. The stroke community in North 

America has embraced this treatment for acute stroke.66,243-245 However, the evidence supporting 

this treatment rests on substantially fewer trials and numbers of patients than that accumulated 

for cardiac ischemia. 

Subsequent guidelines suggested that tPA should be used within 3 hours of stroke onset.53 

Similar recommendations followed in Canada from the Canadian Stroke Consortium246 with the 

recommendation that use be limited to sites with personnel with experience in acute stroke care. 

Post-marketing surveillance mandated by HPB and maintained by the CASES database247

demonstrated a treatment rate in Canada of 6% of all stroke.59 Variability was noted in treatment 

rates between sites. There are currently nine designated stroke centers in the Province of Ontario 

with rates of thrombolysis ranging from 2.9% to 20.6% for the period July to December, 2002.248

Our search for references examining the effectiveness of thrombolytic therapy for acute 

stroke identified 343 reviews. Of these, the majority did not consider intravenous tPA, acute 

stroke or were narrative reviews. One195 analyzed the relationship between onset to treatment 

time and outcome and is further discussed under Intervention F. This left two reviews for 

inclusion.249,250 

Wardlaw and colleagues249 reviewed 18 trials including 5727 patients. Sixteen were double 

blind and while a variety of thrombolytic agents were used, 50% of the patients in trials included 

utilized intravenous tPA. Overall, thrombolytic therapy administered in the 0 to 6 hour window 

decreased the proportion of patients who are dependent at three to six months (odds ratio 0.84, 

95% CI, 0.75-0.95). Patients treated within this time frame also had greater odds of death at the 

end of 3 to 6 month follow-up (odds ratio 1.33, 95% CI, 1.15-1.53). For patients treated within 

the 0 to 3-hour window, death or dependency was reduced further (OR 0.66, 95% CI 0.53-0.83) 

with no increase in the risk of death (OR 1.13, 95% CI, 0.86-1.48). Some heterogeneity of effect 

was noted. Data on ethnicity was not available. The reviewers did comment that there was 

limited data on patients over the age of 80. Graham and colleagues250 conducted a meta-analysis 

regarding the safety of tPA for acute ischemic stroke. Fifteen published open-label studies 

including 2,639 treated patients were included. In spite of an overall rate of protocol violation of 

19.8%, the symptomatic intracranial hemorrhage rate was 5.2% (95% CI, 4.3-6.0). This 

compared favorably with the NINDS Trial rate of 6.4%. Of significance, however, was the cross 

study correlation of mortality rate with protocol violation rate (r=0.67, p=0.018). 

North American Post-Marketing Experience 

The largest published post-marketing cohort was the Standard Treatment with Alteplase to 

Reverse Stroke (STARS) study.225 This group of 389 had baseline characteristics similar to 
65

NINDS with comparable outcomes. The symptomatic intracranial hemorrhage rate was 3.3% 

with 35% of treated patients having minimal or no disability at one month. 

A report from Cleveland was initially worrisome in showing high rates of complications. In 

particular, the symptomatic ICH rate was 20%—more than double that seen in the NINDS trial 

and far higher than the NINDS placebo hemorrhage rate of 0.6%.72 The authors noted a protocol 

violation rate (most frequently time criteria) of greater than 50% and subsequently instituted a 

quality improvement program in participating institutions, following which the experience was 

reevaluated.73 Significant improvement was noted with a symptomatic ICH rate of 6.4% in the 

face of a protocol deviation rate of 19.1%. 

tPA received provisional approval in Canada on February 16, 1999.247 As a condition of 

approval, a prospective cohort of patients treated with tPA was mandated (Canadian Activase for 

Stroke Effectiveness Study [CASES]).59 The resulting dataset assembled from 25 academic and 

35 community sites contained 1,135 patients and is the largest such group yet assembled. This 

prospective cohort was collected between February 17, 1999 and June 30, 2001. Outcome data 

was assessed at 90 days with central reading of the initial and 24-hour scan to ensure an unbiased 

estimate of the hemorrhage rate. Eighty-four percent of all cases treated in the country were 

included, based on a comprehensive survey of all Canadian hospitals with CT scanners and an on 

site audit of four randomly selected centers. Neither the rate of excellent functional recovery 

defined by mRS 0, 1, 2, (38.6%) or the rate of intracranial hemorrhage (4.5%) differed 

significantly from that observed in the NINDS trial .59 A protocol violation rate of 13.8% was 

noted with the majority being time violations (treatment over 3 hours). The distribution of 

outcomes for those with protocol violations did not differ significantly from the group as a 

whole. Such outcomes have been reflected in several other observational studies.59

Intervention A: Does Surgery Impact the Outcome in 

Patients with Acute Intracerebral Hematoma (ICH)? 

ICH represents approximately 9% of the 700,000 strokes which occur in the U.S. every year.7

 

Significant morbidity and mortality is associated with this condition. 

Older studies on surgical treatment of ICH are hampered by the low sample sizes. Only the 

study by Morgenstern87 and Batjer120 provided power calculations. Sample size was limited by 

poor accrual in the SICHPA trial88 and by a perception of futility in the Batjer trial.120 In 

addition to poor power, the low sample size increases the possibility of baseline imbalances. 

With the notable exception of Batjer,120 the management, particularly in the control or medical 

arm, was poorly specified. Potentially important covariates such as intracranial pressure, 

hypertension, glucose control, and the institution of mechanical ventilation, were either not 

specified or unreported. None of the included studies specified blinded outcome assessment. In 

addition, all studies included patients with supratentorial hemorrhage and no studies included 

patients with infratentorial hemorrhage. 

The STICH trial,122 which accrued 1,033 patients, overcame a number of the issues which 

limited the early trials. The time window for surgical treatment was rather large at 24 hours. 

Further, the method of clot evacuation was not pre-specified. The mean time between ictus and 

randomization was long, at 22 hours. Thus, the possibility that early treatment with minimally-
66

invasive surgical modalities improves outcomes. Finally the primary endpoint was measured in a 

blinded fashion. 

Our meta-analysis does not preclude a benefit for treatment. The point estimate favors 

surgery, with the confidence interval crossing the null (Figure 2). Given the issues identified 

above, a well-designed, appropriately powered prospective evaluation is required. 

Intervention B: Does Antihypertensive Treatment Reduce 

Stroke-Related Mortality and Disability in Patients with Acute 

ICH? 

Brain injury in ICH is due to direct mechanical injury related to expanding clot, increased 

intracerebral pressure (ICP), herniation secondary to mass effect and the toxic effects of 

extravascular blood. Patients who have an ICH often have an acute rise in systemic arterial 

pressure (BP) and this may be beneficial to maintain cerebral perfusion pressure (CPP). CPP is 

the difference between mean arterial pressure and ICP. This elevation in BP may also put the 

patient at increased risk of extension of the hemorrhage. 

Nishiyama et al.91 was a small study, which did demonstrate a decrease in CPP. In this study 

this reduction did not lead to any adverse clinical outcomes suggesting some concern regarding 

safety; albeit with a very limited population. Current American Heart Association writing group 

guidelines suggest that the management of elevated blood pressure in patients with ICH be 

individualized based on the patient’s age, history of hypertension, presumed cause of 

hemorrhage and interval since onset.251 For patients with a history of hypertension it is 

recommended that the mean arterial pressure be maintained at less than 130 mmHg by this 

writing group. 

In spite of wide applicability and potential simplicity of antihypertensive treatment after 

intracerebral hemorrhage, the data available to informed clinical decision making is extremely 

poor. Choice of agent, modality of treatment and timing all remain open questions. A new large 

trial which addresses some aspects of the clinical questions is required. 

Intervention C: Does IA Thrombolysis Reduce Stroke-related 

Mortality and Disability in Adults with Acute Ischemic 

Stroke? 

The study by Keris93 used sequential randomization, suggesting that allocation concealment 

was incomplete. Further assessment was not blinded and the analysis was not performed on an 

intention-to-treat basis. These methodology issues raise questions about the conclusions of this 

trial. PROACT I and II demonstrate the possibility of using IA therapy to establish reperfusion. 

Further, PROACT II suggests that recanalization of vessels achieved within the six-hour window 

can result in a significant clinical improvement. Enlarging the time window for acute 

thrombolysis would potentially increase the number of patients treated. Of concern are the very 

large number of patients who need to be screened and subjected to angiography to achieve this 
67

result. Interventional therapy is thus a very resource-intensive course to follow in acute stroke. 

More accessible forms of acute imaging to establish vessel occlusion such as CT or MR 

angiography may be helpful in improving on the odds of receiving treatment after screening. 

Such noninvasive methods might decrease procedure related complications and enhance safety 

by eliminating individuals without vessel occlusion from potentially hazardous treatment albeit 

at a cost of adding time to treatment. 

The EMS Bridging Trial94 is a Phase I trial demonstrating the feasibility of combined 

treatment, combining IV and IA treatment as the possible advantage of reducing the time to 

canalization. This study demonstrates feasibility and results of a larger trial currently underway 

is awaited. 

A new trial of intra-arterial treatment would be helpful in patient selection. In particular the 

timing since symptom onset, thrombus location and criteria for combining with IV therapy 

remain to be elucidated. 

Intervention D: Does Treatment to Normalize Blood Glucose 

Levels Reduce Stroke-Related Mortality and Disability in 

Adults with Acute Stroke? 

Weir and colleagues analyzed the outcomes of 750 non-diabetic patients in an attempt to 

correlate plasma glucose with clinical outcomes.252 Of some 750 patients included in the model, 

86% had ischemic stroke while the remainder were cerebral hemorrhages. Hyperglycemia with 

serum glucose greater than 8 mmol/L predicted a poor chance of survival and independence. 

This effect was persistent after adjusting for age, stroke type and severity. This observation 

suggests that elevated serum glucose is more than a marker for severe vascular event. As 

hypoglycemia can be a significant detrimental influence on neurologic outcome, randomized trial 

evidence should be obtained prior to advocating specific treatment protocols particularly in the 

setting of modest elevations of plasma glucose. 

Neither of the included studies95,96 addressed our question on whether treatment to normalize 

blood glucose levels would reduce stroke related mortality and disability in adults with acute 

stroke. The study of Gray et al.95 did demonstrate that without specific intervention, plasma 

glucose values do decrease 24 hours after stroke but we still do not know whether treatment will 

lead to improved outcomes. 

Current consensus guidelines in the absence of evidence recommend lowering glucose levels 

above 16.63 mmol/L.253 Glucose values decreased 24 hours after stroke; however, it is unknown 

whether treatment will lead to improved outcomes. Further trials examining this issue are 

required. 

Intervention E: Does Mechanical Thrombus Disruption 

Reduce Stroke-Related Mortality and Disability in Adults with 

Acute Ischemic Stroke? 
68

Both included studies compared continuous ultrasound monitoring during acute thrombolysis 

with no such monitoring.97,111 The observation of early recanalization is consistent across both 

of these studies. Eggers et al. reports a benefit in the small group studied (n=25) for treatment 

only in the Barthel Index, with no significant benefit in mortality or mRS score.97 Alexandrov111

demonstrated superior efficacy for early recanalization and the prespecified endpoint of early 

dramatic recovery (decrease in the NIH Stroke Scale Score of 10 points on a NIH Stroke Scale 

Score of less than or equal to 3), but no significant differences between the two groups at 3 

months. While these results are encouraging, a larger trial to ensure both the safety and efficacy 

of this treatment modality is required. Particularly critical is establishing an enduring benefit by 

reducing mortality, disability or both at 3 months. Alexandrov111 points out that the results may 

not be generalizable as use of the modality requires skill and experience. Other mechanical 

modalities including balloons, suction devices, and mechanical clot extraction modalities have 

yet to report randomized results. 

A phase I study of the MERCI mechanical embolus retrieval device was published 

recently.254 Twenty eight patients were studied with a mean time from onset to treatment of just 

over 6 hours. Successful recanalization was achieved in 43% patients using embolectomy alone. 

This increase of 64% when intra-arterial tPA was added. This early publication is of interest and 

further study of these devices is warranted. In the small number of papers published, patient 

selection and interaction with other modalities such as intra-arterial tPA remains unclear. 

Future well-designed studies investigating mechanical thrombus disruption to reduce strokerelated mortality and disability are needed. 

Intervention F: Is the Effectiveness and Safety of 

Thrombolytic Therapy for Adults with Acute Ischemic Stroke 

Affected by Time from Onset to Treatment? 

Hacke and colleagues, writing for the ATLANTIS, ECASS, and NINDS tPA study group 

investigators, provided a patient-level meta-analysis of the relation between onset to treatment 

time and outcome for thrombolysis.195 Data from six trials that had treatment windows between 

0 and 6 hours were obtained—NINDS Parts 1 and 2, ECASS 1 and 2, and ATLANTIS Parts A 

and B.195 These included trials encompass 99% of patient data available from RCTs of tPA. The 

trials varied in the time inclusion criteria. Both NINDS trials were restricted to patients treated 

between 0 and 3 hours. The ECASS trials included patients treated between 0 and 6 hours. 

ATLANTIS A enrolled from 0 to 360 minutes while ATLANTIS B initially recruited from 0 to 

300 minutes, and subsequent to the publication and acceptance of the NINDS data was narrowed 

to 180 from 300 minutes. Inclusion and exclusion criteria in the trials were similar. A diagnosis 

of acute ischemic stroke with CT evidence refuting hemorrhage was required. Patients at high 

risk of bleeding with thrombolytic therapy, including those who had had trauma or recent 

surgery, were excluded. Both the ECASS trials and ATLANTIS B excluded patients with early 

infarct signs on the baseline CT scan. This was not a requirement in the NINDS trials. 

Favorable outcome for the purposes of this analysis was defined as scores on the Rankin Scale of 

0 or 1, Barthel Index of 95 to 100, and a NIHSS score of 0 or 1. These ranges represent minimal 

or no disability. A logistic regression model was constructed to assess the relationship between 
69

onset to treatment time and favorable outcome at 90 days. A multivariable logistic regression 

model was constructed including possible confounding variables. 

The final results were presented as an intention-to-treat analysis including patients on whom 

data was incomplete (n=2,775). The median age of this group was 68 years; 84.6% were White 

(non-Hispanic), 9.1% Black, 2% Hispanic, 0.9% Asian, with the remainder being from other 

ethnic backgrounds or unreported. The median baseline NIH Stroke Scale Score was 11 with a 

median onset to treatment time of 243 minutes. Of note, 67% of patients were treated beyond 

the 3-hour window. The final model included treatment, onset to treatment time, age, blood 

glucose, admission NIHSS, baseline diastolic pressure, interaction between age and NIHSS, and 

interaction between onset-to-treatment time, and treatment. An association was found between 

onset-to-treatment time and outcome. The odds ratio for favorable outcome with tPA treatment 

in the 0 to 90 minute interval was 2.81 (95% CI 1.75-4.50). This decreased to 1.15 (0.90-1.47) 

in the 271 to 360 minute interval. The 95% confidence interval of the adjusted odds ratio for 

favorable treatment remained above 1, indicating benefit for treatment until 270 minutes (4.5 

hours) after onset of symptoms. Likewise, the adjusted odds ratio for death exceeded 1 only in 

the interval between 271 and 360 minutes. Interestingly, there was not a strong association 

between 3-month favorable outcome and baseline NIHSS in any time stratum. This also 

confirms a strong association between stroke outcome and time to treatment. Of significance, 

the relationship holds throughout the currently used therapeutic window of 0 to 3 hours. 

Parenchial hematoma were seen in 5.3% of patients compared to 1.1% of placebo patients in 

multivariate modeling for hemorrhage, which included onset to treatment time (OTT), age, and 

NIHSS scores. The OTT and treatment interaction was not significant. Use of tPA and age 

increased the probability of hemorrhage but OTT and baseline NIHSS scores did not. 

The prospective studies identified in this review did not prospectively validate treatment 

beyond the 3-hour window.102,116 The study characteristics did not allow for a useful 

combination of results. Thus, this patient-level meta-analysis provides the best current summary 

of the evidence for a relationship between time to intervention and clinical outcomes. 

Thus, it is imperative that systems be designed to provide treatment as soon as possible after 

onset of symptoms rather than aiming for treatment within 3-hours of onset. In addition, there is 

suggestion of benefit beyond the 3-hour window. This benefit is smaller than that in earlier time 

frames consistent with the overall results of the analysis. It is entirely possible that significant 

benefit accrues to a subgroup of patients treated beyond 3 hours. The suggestion of benefit in 

later time windows will require validation from prospective studies that may also provide the 

defining characteristics of the group most likely to benefit or conversely be harmed. Since a 

treatment effect in these later time windows is smaller than that observed earlier, larger groups of 

patients will need to be randomized.195

In Canada, tPA for stroke was commissioned in 1999 . The approving body required a 

prospective registry for safety in the context of routine care. Over 2.5 years, 1,135 patients were 

enrolled in 61 centers in Canada. For all patients 90 day outcome and hemorrhage rates were 

determine, along with baseline and 24 hour CT scans which were viewed centrally. 

The median NIHSS scores were identical to that seen in the NINDS trial. Thirty six percent 

of the patients made a complete functional recovery and returned to the baseline state at 90 days. 

This result was not significantly different than the NINDS trial (p=0.15). The rate of 

symptomatic intracranial hemorraghe was 4.6% compared to the NINDS rate of 6.4%.255
70

Intervention G: Do Pretreatment CT Scoring Systems Affect 

the Safety and Efficacy of Thrombolytic Therapy for Acute 

Ischemic Stroke? 

Prospective evaluation of CT scoring systems was not available, and both included studies 

are evaluations of CT’s conducted during the course of prospective trials of thrombolysis in 

stroke. Barber and colleagues256 evaluated 203 consecutive patients treated with thrombolytic 

therapy within 3-hours of prospective scoring of their CT scans according to a 10-point scale 

based on an unenhanced axial CT scan. The value was calculated from two cuts within the MCA 

territory. A normal scan obtained a score of 10 points with one point subtracted for each area of 

early ischemic change. The ASPECTS Score correlated with baseline NIH Stroke Scale Score in 

an inverse manner (Spearman’s rho = -0.56, p < 0.001). An ASPECTS Score of less than 7 had 

strong predictive value for death or dependence. With dependence defined as a Rankin Score of 

3 to 5, the odds ratio for good functional outcome was 82 (95% CI 23-290). Similarly, an 

ASPECTS Score of less than or equal to 7 was predictive of the presence of symptomatic 

hemorrhage (odds ratio 14, 95% CI 1.8-117). Good correlation was noted between the 

ASPECTS Scores of pairs of stroke neurologist/radiology trainees and the neuroradiologists 

(kappa = 0.85, 0.71, 0.89 respectively). 

Retrospective application of the ASPECTS score to CT scans used in the PROACT II Trial 

suggests that those with an ASPECTS Score greater than seven were three times (OR 3.2, 95% 

CI 1.2-9.1) more likely to have an independent functional outcome when compared with 

controls, whereas, those with a score less than or equal to seven were much less likely to do so. 

The wide availability of CT scanners along with the ease of use of the ASPECTS Score 

suggests this may become an important tool in treatment decisions. 

Intervention H: Do Pretreatment MRI Scoring Systems Affect 

the Safety and Efficacy of Thrombolytic Therapy for Acute 

Ischemic Stroke? 

The time frames used in patient selection for thrombolysis represent surrogate measures of 

viable tissue. Perfusion and diffusion weighted MRI scanning raise the possibility of patient 

selection on the basis of the demonstration of viable tissue with impaired perfusion. Perfusion 

weighted imaging (PWI) allows visualization of altered areas of blood flow.257 Energy failure 

with the resulting inability to maintain water and ionic gradients results in decreased diffusion of 

water in the brain.258 

Butcher and colleagues259 have suggested that quantitative PWI mapping may be useful in 

predicting the fate of tissue. Thirty-five patients with acute stroke, 17 of whom were treated with 

tPA, were imaged within 6 hours of onset. The mean transit time was found to be prolonged in 

infarcted areas relative to salvaged areas (p=0.001) with an approximately 10% reduction in 

regional cerebral blood flow (p=0.01). From this study, the mean transit time appeared to be the 
71

perfusion measure most predictive of outcome though delineation of absolute perfusion 

thresholds resulting in infarction could not be accomplished. This may, in part, be due to the 

dependence not only on absolute perfusion but also the duration of hypoperfusion. The 

interaction between these two measures is difficult to arrive at through the use of a single image 

during the course of an infarction. 

Nevertheless, MRI definition of salvageable tissue versus tissue irreversibly committed to 

infarction when applied prospectively has the potential to enhance both the safety and efficacy of 

thrombolysis. 

Intervention I: Do CT Perfusion/Angiography Affect the 

Safety and Efficacy of Thrombolytic Therapy for Acute 

Ischemic Stroke? 

Prospective use of CT perfusion and angiography techniques in patient selection for 

thrombolysis was not identified. The two studies included demonstrate correlation of outcome 

with findings on CT angiography or CT perfusion techniques including Xenon CT. CT 

angiography permits the identification of large vessel occlusion without the risk of invasive 

techniques and thus has potential applicability in identifying patients who may benefit from 

invasive forms of revascularization (IA thrombolysis or thrombus retrieval). As noted above for 

Intervention H, the availability of physiologically-based criteria to select individuals with 

salvageable tissue presents the opportunity for significant benefit. In this regard, a CT is cheaper 

and more widely available than MRI scanning. Further MRI scanning has the potential to add 

increased time prior to treatment and decrease numbers available for treatment due to MR 

exclusion criteria, which include ferromagnetic foreign substances, claustrophobia and the 

requirement to closely monitor unstable patients. 

The impact of the study by Kilpatrick102 is limited by the small number of patients and biases 

inherent in selecting this particular group of patients for study. Nevertheless, the hypothesis that 

low cerebral blood flow as demonstrated on Xenon CT or major vascular occlusion is associated 

with infarct, and presumably worse clinical outcome, deserves more detailed prospective study 

as this may aid in singling out patients who may benefit from more aggressive therapy and 

furthermore those in which the risks of more aggressive therapy are warranted. 

Intervention J: Are Community Education Programs 

Effective in Reducing Stroke-Related Disability and 

Mortality? 

Both included studies demonstrate that multi-faceted educational and system changes for the 

provision of acute stroke care increased utilization of tPA. Given the complexity of this 

intervention we are unable to determine what components of this intervention led to the 

increased utilization. It remains unclear if community education programs are effective in 
72

improving outcome in acute stroke. A number of similarities exist with the care of acute cardiac 

ischemia and it is instructive to examine the parallel and data in this field for relevance to stroke. 

Ischemic heart disease is the leading cause of death in Canada and other industrialized 

countries.260 Myocardial death under ischemic conditions is a time dependent phenomenon 

requiring a series of biochemical events and is not simultaneous with the onset of ischemia.261 

As is the case in stroke, this time dependence provides an opportunity for therapeutic 

intervention and early treatment of myocardial infarction has been shown to decrease infarct size 

and reduce mortality.262,263 Rapid access to emergency treatment requires prompt identification 

of symptoms by patients or bystanders and presentation to an appropriate facility. Reperfusion 

of ischemic tissue can then be achieved through thrombolysis or angioplasty with the 

effectiveness of therapy being contingent on speed of delivery.262-264 Patient delay in seeking 

care in North America is several hours and is felt to contribute to lower than expected outcomes 

from the application of available procedures.264 Prompt and appropriate application of such 

resource intensive procedures might be expected to improve outcomes. Increased awareness of 

symptoms and need for urgency amongst patients might result in reduced delay and increase 

rates of thrombolytic treatment. 

As acute myocardial infarction is the presenting symptom of ischemic heart disease in a 

substantial percentage of patients, a campaign aimed at unselected members of the community 

would be expected to reach the greatest members of people expected to benefit. Previous 

experience with community interventions in this area spans two decades, far longer than the 

experience in acute stroke. The REACT trial, reported by Luepker, was a RCT of the efficacy of 

community intervention on delay time employing cluster randomization of twenty U.S. cities 

into matched control and intervention pairs.69 The design of the intervention was complex and 

involved expects in health behavior and epidemiology. The process of intervention design and 

its theoretical framework is extensively described in a companion publication.265 ED staff in 

study hospitals were trained in standardized questioning of patients regarding the nature and 

onset of acute symptoms. Matched pairs of cities were comparable in age distribution, education 

level, ethnic distribution, median income and baseline median delay time from symptom onset to 

presentation. Delay times were log transformed to obtain a more normal distribution. The trend 

of delay time was calculated by linear regression of log delay against calendar time adjusted for 

the patient level covariates: age, sex and past history of coronary artery disease. The trends were 

then compared pair wise with the matched communities. Delay times were available for 73% of 

the population of interest. A baseline period of four months was compared to the intervention 

period of eighteen months. The study had an 80% power to detect an end of trial difference of 

30 minutes between intervention and control groups. During the study period mean delay time 

dropped by about 10 minutes in both the reference and intervention groups. The primary 

outcome response, which was the slope difference (%/yr) between intervention and reference 

groups, was 2.3% (95% CI -5.5 to 10.8). The intervention was consequently felt to be 

ineffective. 

This result in a methodologically superior design to those carried out in the field of acute 

stroke is of concern. Application of ineffective strategies, at a minimum, diverts resources away 

other applications. Further, there is the possibility that a campaign which increases the number 

of patients presenting with potential stroke increases the probability of false positive diagnoses 

and, thereby, worsen outcomes. 
73

Intervention K: Are Designated Centers Effective in 

Reducing Stroke-Related Disability and Mortality? 

Studies evaluating the brain attack coalition definition of a stroke center were not identified. 

Thus, each study reviewed in this section had a different approach in development of a stroke 

center. Each study did demonstrate decreased time intervals in the treatment continuum from 

presentation through the hospital stay. The percentage of patients treated is a significant 

surrogate measure of outcomes and, assuming the treatment meets the NINDS protocol, one 

might infer that improving the percent of patients treated would result in improved outcomes. 

None of these studies demonstrated adequately that their strategy led to decreased stroke 

morbidity and mortality. At present, the potential effect of the establishment of a stroke center 

according to the pre-specified definition is not known and waits empiric validation. The 

magnitude of the effect may depend on the pre-existing infrastructure, geography and 

demographics of the area served. While the need for such a validation may not be readily 

apparent it impacts significantly on resource allocation in a competitive economic environment 

and has broader implications for public health. 

One possible alternative with Stroke Centres strategy is dispersing the expertise through the 

use of Telemedicine. Technology currently exists which permits the visualization and 

examination of both the patient and the scan at a location remote from the examining physician. 

While this would transfer physician expertise in the treating center (i.e. nursing, radiology, 

technology, and/or laboratory support). Comparisons of each approach would be helpful in 

further stroke system planning. 

Intervention L: Are ED Protocols for the Management of 

Acute Stroke Effective in Reducing Disability and Mortality? 

At this time, we were unable to identify any studies that addressed our research question of 

whether ED protocols for the management of acute stroke are effective in reducing disability and 

mortality. The studies by Smith et al.106 and Jahnke et al.118 evaluated ED protocols and 

document the time to treatment with thrombolytics. Smith et al.106 compared the times to 

treatment in patients in their study with historical data and conclude that their ED protocol yields 

similar times to treatment than previously published in the original trials231 Jahnke et al.118

compared the time to thrombolytic treatment between those who received treatment in the first 

year of the protocol and the second year. They document an improvement in time to treatment in 

the second year of the protocol though outcomes are not reported. The last study by Akins et 

al.117 compared patients who had their treatment initiated by the ED physician versus the 

neurologist. The patients had similar presentations and baseline risks and there were no 

differences in outcomes between these two small groups. Initially they identified more protocol 

violations by the ED physicians as well as a shorter time interval to treatment by the neurologist. 

This study did not demonstrate any difference in outcome between the ED physician treatment 

and neurologist treatment but the study size was very small and with the increased protocol 

violations and increased length to treatment there is the possibility that in a larger study worse 

outcomes would be found with this model. 
74

The studies available were limited in methodology and outcomes assessed. In particular, the 

clinically significant outcomes of mortality and morbidity were not examined. 

Limitations 

Our literature searches were restricted to English language publications. Although, this 

limited our review it is unlikely that it biased the results in any meaningful way.74,75

Our levels of evidence “guiding principle” was to limit our review to include reports of 

RCTs, whenever possible. There is debate within the literature as to the merits of excluding 

reports of high quality observational studies from addressing questions within a systematic 

review.266-269 There is little empirical data as to whether the inclusion of such studies introduced 

bias into the results. We elected to take the more conservative scientific position of providing 

‘bias free’ estimates of effectiveness whenever possible. Quality assessing observational studies, 

and designs is problematic. There is no published validated scheme available. We used the NOS 

for assessing quality, and while we believe it has some appropriate psychometric properties, the 

index itself is unpublished. There is some data which suggests that assessments using 

unpublished systems as a grading system might introduce bias.270 

In spite of the clear indication that early time to treatment improves outcomes and the 

complexity of the multilevel interventions required to accomplish these targets, a limited number 

of studies were available for review in all areas examined in our report. This may reflect a bias, 

which does not equate system interventions with medical therapies. With the significant 

exception of thrombolytic therapy for acute ischemic stroke, methodologic inadequacies were 

apparent in all topic areas. Further detailed information on the influence of patient 

characteristics (e.g., race) on outcome was either unavailable or unreported. 

We identified a meta-analysis examining surgical intervention for ICH that was published in 

2002,233 which presented data from two trials that were not identified by our search strategy. 

Our search did not capture these references, since the study by McKissock et al. was published in 

1961, prior to our search date of 1964. The study by Chen (1992) is a non-English language 

citation and hence, was not captured since our search was limited to English language citations. 

Chen et al. was a large RCT investigating surgical intervention for ICH. We were able to extract 

enough data from the meta-analysis pertaining to mortality outcomes to include this data in our 

meta-analysis as a sensitivity check (Figure 4). We were less inclined to extract data from the 

McKissock et al. results since it was determined that the surgical methodology for ICH had 

substantially advanced since the time that this report was published and hence, would have been 

heterogeneous with other studies included in our review. 

Five studies examined IA thrombolytic therapy for ischemic stroke. Due to heterogeneity of 

interventions and comparisons, we obtained pooled estimates based on only two studies.92,110 

We excluded Keris et al.93 because they did not provide 90-day follow-up assessment data and 

there were concerns regarding methodology of the trial. Lewandowski et al.94 randomized 

patients to IV tPA and IA tPA or to IV placebo and IA tPA. So the contrast between the two 

groups is IV tPA versus IV placebo. Conceptually, this study was not combinable with the other 

studies. 
75

The effect measure selected for pooling the outcomes of death and death and disability was 

the odds ratio. Other effect measures suitable for dichotomous outcomes including the relative 

risk and absolute risk reduction could also be considered, and might show different results. 

However, the odds ratio has several statistical advantages, one being it has been shown to 

frequently exhibit less heterogeneity than other effect measures.271 In addition, the odds ratio 

was used in a previous meta-analysis, which could facilitate comparison. 

For surgical interventions for ICH, there was evidence of some statistical heterogeneity, 

although not statistically significant. It should be noted, however, that tests of heterogeneity in 

meta-analysis are recognized to have limited power, particularly when the number of studies is 

small.272 We used random effects methods to adjust for statistical heterogeneity, which results in 

wider confidence intervals for the pooled estimate. Furthermore, random effects pooled 

estimates should be interpreted with some caution. 

Research and Clinical Implications 

ICH

In spite of the significant morbidity and mortality associated with ICH, and the potential 

negative effects of pressure and blood products within the brain, surgical evacuation of the 

hematoma remains unproven. Randomized trials did not include cerebellar hematomas, and 

thus, these findings cannot be implied to hematomas in the posterior fossa. In spite of the 

negative data, our results do not preclude the possibility of a benefit from surgery. There was 

some heterogeneity within trials and the pooled point estimate favored surgery, albeit with a 

large confidence interval. Further trials in this may be helpful. Such trials should likely be 

conducted in a multi-center format, since single-center trials suffer from low patient accrual. 

Both the non-surgical interventions and outcome collection will need to be standardized. In 

particular, principles of withdrawal of care should be established for such trials as part of the 

protocol, and monitored subsequently. The perception of futility amongst caregivers and 

families may influence behavior and invalidate trial results. Areas specifically requiring further 

delineation include timing and type of surgery. Minimally invasive surgery has increased in 

utility in many areas and thus data from older trials may not be sufficient to exclude new 

technologies. 

Antihypertensive therapy has not been well studied in patients with ICH. Hypertension 

remains a significant risk factor for hemorrhage, and thus, may well impact on clinical outcomes 

including the rate of hematoma expansion and recurrent hemorrhage in the setting of acute ICH. 

Antihypertensive therapy has potential wide application in this group of patients. Until such 

time as further data is available, guidelines provide a reasonable basis for the clinical 

management of ischemic stroke.251 

Timing, modalities of treatment, and treatment target remain open issues for further research. 
76

Acute Ischemic Stroke

IV thrombolysis with tPA remains the sole approved intervention for acute ischemic stroke. 

Data from primary trials and meta-analyses suggests a significant benefit of treatment in the 

window from 0 to 3 hours after stroke onset. Individual patient-level meta-analysis suggests that 

earlier treatment significantly improves outcomes and systems should be designed so as to 

provide treatment to eligible patients as soon as possible after stroke onset. 

A paucity of data is available regarding the outcomes of specific subgroups of patients. In 

particular, further data should be sought regarding outcomes in specific ethnic groups, the elderly 

(over the age of 80), and specific stroke subtypes. At present, there is no data to suggest any 

group identified on the basis of these characteristics should be excluded from treatment. 

Regression analysis of the relationship between onset to treatment time and outcome, 

suggests that there may be benefit for thrombolytic therapy up to 41⁄2 hours after onset. It is 

clear, however, that the odds ratio for good improvement drops significantly for the 3 to 41⁄2 hour 

time frame compared with earlier time frames. Prospective trial data for benefit beyond 3 hours 

is lacking, and the selection of patients most likely to benefit from therapy within this time 

window remains a challenge. It is likely that development of imaging techniques in this group 

will identify the minority of patients capable of benefiting in this time frame. Further data 

should be specifically sought with regard to the subgroup of patients who may benefit beyond 

the three-hour window. Likewise, information on the relative risk of hemorrhage in the current 

treatment window would be helpful. 

IA therapy has prospective evidence to suggest a benefit up to 6 hours after onset. However, 

the pooled effect estimates, suggest that the benefit is not robust. Centers capable of delivering 

this treatment, however, may use it in those patients outside the traditional IV-treatment window 

who are not candidates for IV tPA. There may be further benefit in combining this treatment 

with IV therapy; this is the subject of upcoming combination trials. Intra-arterial therapy 

requires a significant investment of resources. In addition, as compared to intravenous therapy, 

the time to treatment is likely to be increased due to the invasive and specialized nature of the 

therapy. 

Time since onset of symptoms remains a surrogate for the pathophysiologic state of affected 

tissue. Ideally, the goal of pre-treatment diagnostic analysis should be the identification of viable 

tissue in which infarction can be prevented by reestablishing blood flow. Both CT and MRI 

techniques hold promise in this regard. MRI, through multi-modality and multi-planar 

techniques, may be the examination of choice in the future. Limitations due to expense, 

additional time, and MR exclusions remain to be overcome, however. Simple CT scoring 

systems, such as ASPECTS and CT perfusion/angiography, provide similar data in a shorter time 

frame. As CT scanners are more widely distributed, these techniques remain a viable option. 

The literature to date, however, has not employed these techniques prospectively to make 

treatment decisions. Thus, the information from imaging techniques must be taken in the clinical 

context including onset to treatment time and current approved treatment protocols and balancing 

probable efficacy with risk. Further work is expected to define subgroups in whom these 

techniques are likely to be of most benefit; for instance, those in whom the onset time is not 

known or those who fall outside traditional treatment windows. In addition, reliable 
77

identification of patients without probability of benefit will enhance treatment efficacy by 

eliminating them from further therapy. 

Acute stroke therapy exists within a system framework capable of timely identification of 

acute stroke, triage, and delivery of effective therapy. These systems include a pre-hospital and 

in-hospital phase. Given the strong link between outcome and onset to treatment time, an 

effective means to alter behavior of the public to permit rapid identification of acute stroke and 

the engagement of EMS, is helpful. The data in this regard, however, suggests that the 

traditional approaches using advertising strategies, have limited evidence for a benefit in stroke 

and evidence for a lack of benefit in cardiac ischemia. Further work regarding effective means 

of altering behavior in the context of acute stroke is required. As noted above, compelling 

evidence exists to suggest that outcomes are strongly related to the time required to deliver 

therapy. Systems of care including EMS, designation of treatment sites, and in-hospital 

protocols remain the only means to achieve this outcome. In spite of the critical importance of 

these systems, little empiric evidence exists as to their efficacy and, further, the relative efficacy 

of various components of the system. Until such time as this evidence is forthcoming, each 

aspect of the system will require efforts at validation. 

Conclusions 

Currently, available data do not support a role for surgery in the treatment of acute 

intracerebral hemorrhage. Results, however, do not preclude benefit from surgery which 

involves modalities other than those studied in the acute trials (e.g. Minimally invasive 

technologies) or treatment of hemispheric hematoma at very early timeframes. In spite of 

potential importance, available therapies and ease of administration of antihypertensive agents, 

very little data exists to suggest that their use is of benefit in the setting of acute ICH. Further 

studies are required in this area. 

IV thrombolysis with tPA is effective and efficacious for acute ischemic stroke. The 

effectiveness is strongly linked to time since onset of symptoms with shorter times 

demonstrating significantly better outcomes. Intraarterial therapy remains an option for a 

subgroup of patients with large vessel occlusions principally in the middle cerebral artery 

distribution who are not candidates for IV tPA. The evidence for this intervention, however, 

remains less robust than for IV therapy. Limited data is available regarding patient 

characteristics predicting outcome. The system changes required to ensure prompt delivery of 

appropriate therapy are complex and operate on multiple levels. In spite of their critical role, 

little data exists regarding the efficacy of these interventions and, in particular, the relative 

efficacy of various components with regard to patient outcomes. 
78
79

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2237. No original empirical evidence presented. 

Albers GW. Rationale for early intervention in acute 

stroke. [Review] [32 refs]. Am J Cardiol 

1997;80(4C):4D-10D. No original empirical evidence 

presented. 
99

Albers GW. Prevention and management issues in 

stroke. Consultant 2003;43(2):243-251. No original 

empirical evidence presented. 

Alberts MJ. Emergency brain resuscitation. [Review] 

[48 refs]. Compr Ther 1997;23(6):391-399. No 

original empirical evidence presented. 

Alberts MJ. TPA in stroke. Neurology 1993;43233No 

original empirical evidence presented. 

Alberts MJ, Bennett CA, Rutledge VR. Hospital 

charges for stroke patients. Stroke 1996;27(10):1825-

1828. No intervention of interest studied. 

Alberts MJ, Easton JD. Stroke Best Practices: A Team 

Approach to Evidence-Based Care. J Natl Med Assoc 

2004;96(4 SUPPL.):5S-20S. No original empirical 

evidence presented. 

Alexander KP, Peterson ED. Evidence-based care for 

all patients. Am J Med 2003;114(4):333-335. No 

original empirical evidence presented. 

Alexandrov AV, Burgin WS, Demchuk AM et al. 

Speed of intracranial clot lysis with intravenous tissue 

plasminogen activator therapy: sonographic 

classification and short-term improvement. Circulation 

2001;103(24):2897-2902. No intervention of interest 

studied. 

Alexandrov AV, Demchuk AM, Felberg RA et al. 

High rate of complete recanalization and dramatic 

clinical recovery during tPA infusion when 

continuously monitored with 2-MHz transcranial 

doppler monitoring.[see comment]. Stroke 

2000;31(3):610-614. No intervention of interest 

studied. 

Alexandrov AV, Demchuk AM, Felberg RA et al. 

Intracranial clot dissolution is associated with embolic 

signals on transcranial Doppler. J Neuroimaging 

2000;10(1):27-32. No intervention of interest studied. 

Alexandrov AV, Grotta JC. Arterial reocclusion in 

stroke patients treated with intravenous tissue 

plasminogen activator. Neurology 2002;59(6):862-

867. No intervention of interest studied. 

Alexandrov AV, Hall CE, Labiche LA et al. Ischemic 

Stunning of the Brain: Early Recanalization Without 

Immediate Clinical Improvement in Acute Ischemic 

Stroke. Stroke 2004;35(2):449-452. No intervention of 

interest studied. 

Alexandrov AV, Masdeu JC, Devous MD S et al. 

Brain single-photon emission CT with HMPAO and 

safety of thrombolytic therapy in acute ischemic 

stroke. Proceedings of the meeting of the SPECT Safe 

Thrombolysis Study Collaborators and the members of 

the Brain Imaging Council of the Society of Nuclear 

Medicine. [Review] [32 refs]. Stroke 

1997;28(9):1830-1834. No original empirical evidence 

presented. 

Alexandrov AV, Pullicino PM, Meslin EM et al. 

Agreement on disease-specific criteria for do-notresuscitate orders in acute stroke. Members of the 

Canadian and Western New York Stroke Consortiums. 

Stroke 1996;27(2):232-237. No original empirical 

evidence presented. 

Algra A. Atenolol (50mg a day) in patients after a TIA 

or minor stroke. Cerebrovasc Dis 1992;2236Study did 

not involve relevant population [defined as adult (>16) 

with acute stroke]. 

Allen GS. Role of calcium antagonists in cerebral 

arterial spasm. Am J Cardiol 1985;55(3):149B-153B. 

No human participants. 

Allen KR, Hazelett S, Jarjoura D et al. Effectiveness 

of a postdischarge care management model for stroke 

and transient ischemic attack: a randomized trial. 

Journal of Stroke & Cerebrovascular Diseases 

2002;11(2):88-98. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Allen KR, Hazelett SE, Palmer RR et al. Developing a 

stroke unit using the acute care for elders intervention 

and model of care. [Review] [30 refs]. J Am Geriatr 

Soc 2003;51(11):1660-1667. No original empirical 

evidence presented. 

Alteplase for thrombolysis in acute ischemic stroke. 

Medical Letter on Drugs & Therapeutics 

1996;38(987):99-100. No original empirical evidence 

presented. 

Alter M, Lai SM, Friday G et al. Stroke recurrence in 

diabetics. Does control of blood glucose reduce risk? 

Stroke 1997;28(6):1153-1157. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Alvarez-Sabin J, Molina C, Montaner J et al. [Clinical 

benefit following the implementation of a specialized 

urgent stroke care system].[see comment]. [Spanish]. 

Med Clin (Barc) 4-17-2004;122( 14):528-531. Unable 

to obtain by final date for inclusion. 

Amery A, Birkenhager W, Brixko P et al. Mortality 

and morbidity results from the European Working 

Party on High Blood Pressure in the Elderly trial. 

Lancet 1985;1(8442):1349-1354. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Andrews PJ. Critical care management of acute 

ischemic stroke. Curr Opin Crit Care 2004;10(2):110-

115. No original empirical evidence presented. 
100

Anzola GP, Zavarize P, Morandi E et al. Transcranial 

Doppler and risk of recurrence in patients with stroke 

and patent foramen ovale. Eur J Neurol 

2003;10(2):129-135. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Arai T, Sekizawa K, Yoshimi N et al. Cabergoline and 

silent aspiration in elderly patients with stroke [2]. J 

Am Geriatr Soc 2003;51(12):1815-1816. No original 

empirical evidence presented. 

Arai T, Yasuda Y, Takaya T et al. Angiotensin II 

receptor antagonists cannot prevent symptomless 

dysphagia in hypertensive bedridden older patients 

with stroke. J Am Geriatr Soc 2000;48(12):1741-1742. 

No original empirical evidence presented. 

Arai T, Yoshimi N, Fujiwara H et al. Serum substance 

P concentrations and silent aspiration in elderly 

patients with stroke. Neurology 2003;61(11):1625-

1626. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Ardern-Holmes SL, Raman R, Anderson NE et al. 

Opinion of New Zealand physicians on management 

of acute ischaemic stroke: results of a national survey. 

Australian & New Zealand Journal of Medicine 

1999;29(3):324-330. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Arjona A, Serrano-Castro. [Malignant middle cerebral 

artery infarction: medical or surgical treatment?]. Rev 

Neurol 1-16-2004;38(2):145-150. Non-English 

publication. 

Arterburn D, Noel PH. Extracts from "Clinical 

Evidence". Obesity. BMJ 2001;322(7299):1406-1409. 

No original empirical evidence presented. 

Aschenbrenner D S. HRT Reconsidered: What should 

you tell patients about it now? [Review] [13 refs]. 

AJN, American Journal of Nursing 2004;104( 6):51-

53. Unable to obtain by final date for inclusion. 

Asia Pacific Consensus Forum on Stroke 

Management. [Review] [0 refs]. Stroke 

1998;29(8):1730-1736. No original empirical evidence 

presented. 

Asimos A W, Norton H J, Price M F et al. Therapeutic 

yield and outcomes of a community teaching hospital 

code stroke protocol. Acad Emerg Med 2004;11( 

4):361-370. Unable to obtain by final date for 

inclusion. 

Aslanyan S, Fazekas F, Weir CJ et al. Effect of blood 

pressure during the acute period of ischemic stroke on 

stroke outcome: a tertiary analysis of the GAIN 

International Trial. Stroke 2003;34(10):2420-2425. No 

intervention of interest studied. 

Aspirin and cardiovascular disease. S Afr Med J 

2003;93(12 I):892No original empirical evidence 

presented. 

Asplund K, Hagg E, Helmers C et al. The natural 

history of stroke in diabetic patients. Acta Med Scand 

1980;207(5):417-424. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Avery J K. Loss prevention case of the month. Was 

there real deviation in this case? Tenn Med 2003;96( 

12):548-549. Unable to obtain by final date for 

inclusion. 

Awad IA, Fayad P, Abdulrauf SI. Protocols and 

critical pathways for stroke care. [Review] [26 refs]. 

Clin Neurosurg 1999;4586-100. No original empirical 

evidence presented. 

Ayala C, Croft JB, Keenan NL et al. Increasing trends 

in pre-transport stroke deaths--United States, 1990-

1998. Ethn Dis 2003;13(2 Suppl 2):S131-S137. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Aylward P. Can we improve on front-loaded alteplase 

(r-TPA)? Australian & New Zealand Journal of 

Medicine 1998;28(4):511-513. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Aylward PE, Wilcox RG, Horgan JH et al. Relation of 

increased arterial blood pressure to mortality and 

stroke in the context of contemporary thrombolytic 

therapy for acute myocardial infarction. A randomized 

trial. GUSTO-I Investigators. Ann Intern Med 

1996;125(11):891-900. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Azcona A, Lataste X. Isradipine in patients with acute 

ischaemic cerebral infarction. An overview of the 

ASCLEPIOS Programme. Drugs 1990;40 Suppl 252-

57. No intervention of interest studied. 

Baardman T, Hermens WT, Lenderink T et al. 

Differential effects of tissue plasminogen activator and 

streptokinase on infarct size and on rate of enzyme 

release: influence of early infarct related artery 

patency. The GUSTO Enzyme Substudy.[comment]. 

Eur Heart J 1996;17(2):237-246. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Background. Health Technol Assess 2004;8(1):No 

original empirical evidence presented. 

Badrinath P. Preventing stroke with ramipril. Results 

should have been presented in ways that help 

practising clinicians.[see comment][comment]. BMJ 

2002;325(7361):439No original empirical evidence 

presented. 
101

Baird AE, Donnan GA, Austin MC et al. Reperfusion 

after thrombolytic therapy in ischemic stroke 

measured by single-photon emission computed 

tomography. Stroke 1994;25(1):79-85. No original 

empirical evidence presented. 

Baird TA, Parsons MW, Phanh T et al. Persistent 

poststroke hyperglycemia is independently associated 

with infarct expansion and worse clinical outcome. 

Stroke 2003;34(9):2208-2214. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Barber AC. Changes in stroke care at Auckland 

Hospital between 1996 and 2001. N Z Med J 

2004;117(1190):U797No intervention of interest 

studied. 

Barber M, Langhorne P, Stott DJ. Barriers to delivery 

of thrombolysis for acute stroke. Age & Ageing 

2004;33(2):94-95. No original empirical evidence 

presented. 

Barber PA, Demchuk AM, Zhang J et al. Computed 

tomographic parameters predicting fatal outcome in 

large middle cerebral artery infarction. Cerebrovasc 

Dis 2003;16(3):230-235. No intervention of interest 

studied. 

Barber PA, Hill MD, Demchuk AM et al. Doubts, 

fears and misconceptions. What is the future of 

thrombolysis in acute stroke? [Review] [33 refs]. Can 

J Neurol Sci 2000;27(4):283-287. No original 

empirical evidence presented. 

Barber A, Charleston A, Anderson N et al. Changes in 

stroke care at Auckland Hospital between 1996 and 

2001.[see comment]. N Z Med J 3-12-2004;117( 

1190):U797Unable to obtain by final date for 

inclusion. 

Barber P A, Parsons M W, Desmond P M et al. The 

use of PWI and DWI measures in the design of 

"proof-of-concept" stroke trials. J Neuroimaging 

2004;14( 2):123-132. Unable to obtain by final date 

for inclusion. 

Barch C, Spilker J, Bratina P et al. Nursing 

management of acute complications following rt-PA 

in acute ischemic stroke. The NINDS rt-PA Stroke 

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1997;29(6):367-372. No original empirical evidence 

presented. 

Barinaga M. Finding new drugs to treat stroke. 

Science 1996;272(5262):664-666. No original 

empirical evidence presented. 

Barnes MP. Community Rehabilitation after Stroke. 

Critical Reviews in Physical & Rehabilitation 

Medicine 2003;15(3-4):223-234. No original 

empirical evidence presented. 

Barr JD, Connors JJ, Sacks D et al. Quality 

improvement guidelines for the performance of 

cervical carotid angioplasty and stent placement: 

Developed by a collaborative panel of the American 

Society of Interventional and Therapeutic 

Neuroradiology, the American Society of 

Neuroradiology, and the Society of Interventional 

Radiology. Journal of Vascular & Interventional 

Radiology 2003;14(9 I):1079-1093. No human 

participants. 

Barrowman NJ. Missing the point (estimate)? 

Confidence intervals for the number needed to 

treat.[comment]. CMAJ Canadian Medical 

Association Journal 2002;166(13):1676-1677. No 

human participants. 

Barsan WG, Brott TG, Broderick JP et al. Time of 

hospital presentation in patients with acute stroke. 

Arch Intern Med 1993;153(22):2558-2561. No 

intervention of interest studied. 

Barsan WG, Brott TG, Olinger CP et al. Identification 

and entry of the patient with acute cerebral infarction. 

[Review] [35 refs]. Ann Emerg Med 

1988;17(11):1192-1195. No original empirical 

evidence presented. 

Barton J, Levene J, Kladakis B et al. Stroke: a group 

learning approach. Nurs Times 2002;98(7):34-35. No 

original empirical evidence presented. 

Bath P. Alteplase not yet proven for acute ischaemic 

stroke.[see comment][comment]. Lancet 

1998;352(9136):1238-1239. No original empirical 

evidence presented. 

Bath P, Bath F, Rashid P et al. Acute ischaemic stroke. 

Large trial of effect of reducing blood pressure in 

acute stroke is being set up.[comment]. BMJ 

2000;321(7256):300. No original empirical evidence 

presented. 

Bauer RB, Tellez H. Dexamethasone as treatment in 

cerebrovascular disease. 2. A controlled study in acute 

cerebral infarction. Stroke 1973;4(4):547-555. No 

intervention of interest studied. 

Baumgartner RW, Studer A, Arnold M et al. 

Recanalisation of cerebral venous thrombosis. Journal 

of Neurology, Neurosurgery & Psychiatry 

2003;74(4):459-461. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Bazta JJ, Hornillos M, Rodriguez M et al. More on 

PROSPER [10] (multiple letters). Lancet 

2003;361(9363):1135-1136. No original empirical 

evidence presented. 
102

Becker KJ. Thrombolysis for acute ischemic stroke. 

[Review] [52 refs]. Physical Medicine & 

Rehabilitation Clinics of North America 

1999;10(4):773-785. No original empirical evidence 

presented. 

Becker KJ, Baxter AB, Bybee HM et al. Extravasation 

of radiographic contrast is an independent predictor of 

death in primary intracerebral hemorrhage. Stroke 

1999;30(10):2025-2032. No intervention of interest 

studied. 

Becker KJ, Tirschwell DL. Ensuring patient safety in 

clinical trials for treatment of acute stroke.[see 

comment][comment]. JAMA 2001;286(21):2718-

2719. No original empirical evidence presented. 

Bednar MM, Gross CE. Antiplatelet therapy in acute 

cerebral ischemia.[see comment]. [Review] [96 refs]. 

Stroke 1999;30(4):887-893. No original empirical 

evidence presented. 

Behrens S, Daffertshofer M, Interthal C et al. 

Improvement in stroke quality management by an 

educational programme. Cerebrovasc Dis 

2002;13(4):262-266. No intervention of interest 

studied. 

Belardi P, Lucertini G, Ermirio D. Stump pressure and 

transcranial Doppler for predicting shunting in carotid 

endarterectomy. European Journal of Vascular & 

Endovascular Surgery 2003;25(2):164-167. Study did 

not involve relevant population [defined as adult (>16) 

with acute stroke]. 

Ben Hur T, Cohen J E. Case 5-2004: a man with 

slurred speech and left hemiparesis.[comment]. N 

Engl J Med 5-20-2004;350( 21):2213-2214. Unable to 

obtain by final date for inclusion. 

Benavente O, Hart RG. Stroke: part II. Management 

of acute ischemic stroke. [Review] [21 refs]. Am Fam 

Physician 1999;59(10):2828-2834. No original 

empirical evidence presented. 

Bendixen BH, Ocava L. Evaluation and management 

of acute ischemic stroke. [Review] [54 refs]. Curr 

Cardiol Rep 2002;4(2):149-157. No original empirical 

evidence presented. 

Benesch C. Antithrombotic and thrombolytic therapy 

for ischemic stroke. Curr Atheroscler Rep 

2003;5(4):267-275. No original empirical evidence 

presented. 

Bennett J, Glasziou P. Ins and outs of the 

pharmaceutical benefits scheme. Med Today 

2003;4(3):105-110. Unable to obtain by final date for 

inclusion. 

Bentur N, Resnizky S. Care of acute stroke patients in 

general hospitals in Israel. Israel Medical Association 

Journal: Imaj 2003;5(5):343-345. No intervention of 

interest studied. 

Berger C, Fiorelli M, Steiner T et al. Hemorrhagic 

transformation of ischemic brain tissue: asymptomatic 

or symptomatic?[see comment]. Stroke 

2001;32(6):1330-1335. No intervention of interest 

studied. 

Berglund G, Sannerstedt R, Andersson O et al. 

Coronary heart-disease after treatment of 

hypertension. Lancet 1978;1(8054):1-5. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Berlis A, Lutsep H, Barnwell S et al. Mechanical 

thrombolysis in acute ischemic stroke with 

endovascular photoacoustic recanalization. Stroke 

2004;35( 5):1112-1116. Unable to obtain by final date 

for inclusion. 

Berrouschot J, Barthel H, Hesse S et al. Reperfusion 

and metabolic recovery of brain tissue and clinical 

outcome after ischemic stroke and thrombolytic 

therapy. Stroke 2000;31(7):1545-1551. No 

intervention of interest studied. 

Bes A, Orgogozo JM, Poncet M et al. A 24-month, 

double-blind, placebo-controlled multicentre pilot 

study of the efficacy and safety of nicergoline 60 mg 

per day in elderly hypertensive patients with 

leukoaraiosis. Eur J Neurol 1999;6(3):313-322. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Bhalla A, Wolfe CD, Rudd AG. Management of acute 

physiological parameters after stroke. [Review] [79 

refs]. QJM 2001;94(3):167-172. No original empirical 

evidence presented. 

Birkmeyer JD. Invited commentary: Is it a mistake to 

focus on errors? Surgery 2003;133(6):622-623. No 

human participants. 

Bis JC, Smith NL, Psaty BM et al. Angiotensinogen 

Met235Thr polymorphism, angiotensin-converting 

enzyme inhibitor therapy, and the risk of nonfatal 

stroke or myocardial infarction in hypertensive 

patients. Am J Hypertens 2003;16(12):1011-1017. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Bisset AF, Chesson R. Qualitative study on patients 

with stroke. Leaves questions unanswered.[comment]. 

BMJ 1995;311(7010):949-950. No original empirical 

evidence presented. 

Black A. Innocence revisited - 38. Med Today 

2003;4(8):99Unable to obtain by final date for 

inclusion. 
103

Blackman DJ, Ferguson JD, Sprigings DC et al. 

Revascularisation for acute coronary syndromes in 

older people. Age & Ageing 2003;32(2):129-135. No 

original empirical evidence presented. 

Blake K. Evaluation of stroke family support services. 

National Research Register 2001;(1):Unable to obtain 

by final date for inclusion. 

Blard J M, Finiels P J, Combalbert A et al. 

[Symptomatic aneurysms of the postero-inferior 

cerebellar artery. A multicenter retrospective study of 

29 cases]. [Review] [53 refs] [French]. Rev Neurol 

(Paris) 1997;155(1):41-50. Non-English publication. 

Blood pressure, in Acute, Stroke Collaboration et al. 

Interventions for deliberately altering blood pressure 

in acute stroke.[update of Cochrane Database Syst 

Rev. 2000;(2):CD000039; PMID: 10796286]. 

[Review] [50 refs]. Cochrane Database Syst Rev 

2001;(3):CD000039No original empirical evidence 

presented. 

Blood pressure, in Acute, Stroke Collaboration et al. 

Vasoactive drugs for acute stroke. [Review] [168 

refs]. Cochrane Database Syst Rev 

2000;(4):CD002839No original empirical evidence 

presented. 

Blood pressure lowering for the secondary prevention 

of stroke: rationale and design for PROGRESS. 

PROGRESS Management Committee. Perindopril 

Protection Against Recurrent Stroke Study. [Review] 

[20 refs]. Journal of Hypertension - Supplement 

1996;14(2):S41-S45. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Boatright. New urgency for rapid transport of patients 

with stroke to appropriate hospitals. [Review] [2 refs]. 

J Emerg Nurs 2003;29(4):344-346. No original 

empirical evidence presented. 

Boger R H. [Asymmetrical methylarginine (ADMA) 

as a cardiovascular risk factor: epidemiological and 

prospective data]. [Review] [31 refs] [German]. Dtsch 

Med Wochenschr 4-8-2004;129( 15):820-824. Unable 

to obtain by final date for inclusion. 

Bogousslavsky J, Aarli J, Kimura J. Stroke and 

neurology: A plea from the WFN. Lancet Neurology 

2003;2(4):212-213. No human participants. 

Bogousslavsky J, Aarli J, Kimura J. Stroke: Time for a 

global campaign? Cerebrovasc Dis 2003;16(2):111-

113. No human participants. 

Bogousslavsky J, Paciaroni M, Gallai V. Acute stroke 

treatment: thrombolysis. [Review] [27 refs]. 

Cerebrovasc Dis 2000;10 Suppl 414-16. No original 

empirical evidence presented. 

Boissel JP, Gueyffier F, Boutitie F. Risk reduction for 

stroke and coronary events.[comment]. Lancet 

2002;359(9313):1249-1. No original empirical 

evidence presented. 

Bokemark L, Blomstrand C, Fagerberg B. 

[Considerable differences in the management of 

stroke. A study of structured vs. conventional care (see 

comments)] TO:Stora skillnader i slaganfallsvarden. 

Studie av strukturerad vard kontra konventionell. 

Unable to obtain by final date for inclusion. 

Bonnono C, Criddle LM. Acute ischemic stroke 

Emergi-path. J Emerg Nurs 2000;26(4):340-342. No 

original empirical evidence presented. 

Bonnono C, Criddle LM, Lutsep H et al. Emergi-paths 

and stroke teams: an emergency department approach 

to acute ischemic stroke. J Neurosci Nurs 

2000;32(6):298-305. No original empirical evidence 

presented. 

Booth B. The knowledge nurses need to educate 

patients about stroke. Nurs Times 1994;90(15):32-34. 

No original empirical evidence presented. 

Borhani NO. Clinical trials on the efficacy of 

pharmacologic intervention reducing mortality from 

cardiovascular diseases. Cardiology 1985;72(5-6):366-

375. No human participants. 

Bousser MG. Cerebral venous thrombosis: nothing, 

heparin, or local thrombolysis?[see 

comment][comment]. Stroke 1999;30(3):481-483. No 

original empirical evidence presented. 

Bowler JV. Vascular cognitive impairment. Stroke 

2004;35(2):386-388. No original empirical evidence 

presented. 

Boysen G, Engell HC, Henriksen H. The effect of 

induced hypertension on internal carotid artery 

pressure and regional cerebral blood flow during 

temporary carotid clamping for endarterectomy. 

Neurology 1972;22(11):1133-1144. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Bozik M. He who pays the piper calls the tune: The 

role of the industry sponsor in acute stroke trials. Eur 

Neurol 2003;49(2):128-130. No human participants. 

Bozzao A, Floris R, Fasoli F et al. Cerebrospinal fluid 

changes after intravenous injection of gadolinium 

chelate: Assessment by FLAIR MR imaging. Eur 

Radiol 2003;13(3):592-597. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 
104

Bozzao A, Floris R, Villani A et al. [An evaluation of 

the carotid bifurcation and of the intracranial circle by 

angio-spiral computed tomography]. [Italian]. Radiol 

Med (Torino) 1998;95(6):577-582. Non-English 

publication. 

Bradley RN. Educating the public about stroke: Role 

in improving outcomes. Disease Management & 

Health Outcomes 2003;11(5):321-325. No original 

empirical evidence presented. 

Brainin M, Olsen TS, Chamorro A et al. Organization 

of stroke care: education, referral, emergency 

management and imaging, stroke units and 

rehabilitation. European Stroke Initiative. Cerebrovasc 

Dis 2004;17 Suppl 21-14. No human participants. 

Braithwaite V, McGown A. Caregivers'' emotional 

well-being and their capacity to learn about stroke. J 

Adv Nurs. 1993;18(2):195-202. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Bratina P, Greenberg L, Pasteur W et al. Current 

emergency department management of stroke in 

Houston, Texas. Stroke 1995;26(3):409-414. No 

intervention of interest studied. 

Brauer DJ, Schmidt BJ, Pearson V. A framework for 

care during the stroke experience. Rehabil Nurs 

2001;26(3):88-93. No original empirical evidence 

presented. 

Braus D F, Strobel J, Myers A et al. [Stereotactic 

evacuation and early rehabilitation in space-occupying 

cerebral hemorrhage]. [German]. Wien Med 

Wochenschr 1991;141(7):136-140. Non-English 

publication. 

Bravata DM, Kim N, Concato J et al. Hyperglycaemia 

in patients with acute ischaemic stroke: How often do 

we screen for undiagnosed diabetes? Qjm: Monthly 

Journal of the Association of Physicians 

2003;96(7):491-497. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Bravata DM, Kim N, Concato J et al. Thrombolysis 

for acute stroke in routine clinical practice.[see 

comment]. Arch Intern Med 2002;162(17):1994-2001. 

No intervention of interest studied. 

Brett B, Peak EJ, Nair A et al. Do not resuscitate 

decisions. More consumer education and involvement 

are needed.[comment]. BMJ 2001;322(7278):103-104. 

No original empirical evidence presented. 

Brice JH, Griswell JK, Delbridge TR et al. Stroke: 

from recognition by the public to management by 

emergency medical services. [Review] [32 refs]. 

Prehosp Emerg Care 2002;6(1):99-106. No original 

empirical evidence presented. 

Brockington CD, Lyden PD. Criteria for selection of 

older patients for thrombolytic therapy. [Review] [38 

refs]. Clin Geriatr Med 1999;15(4):721-739. No 

original empirical evidence presented. 

Broderick JP. William M. Feinberg Lecture: stroke 

therapy in the year 2025: burden, breakthroughs, and 

barriers to progress. Stroke 2004;35(1):205-211. No 

original empirical evidence presented. 

Broderick JP. Recanalization therapies for acute 

ischemic stroke. [Review] [59 refs]. Semin Neurol 

1998;18(4):471-484. No original empirical evidence 

presented. 

Broderick JP. Practical considerations in the early 

treatment of ischemic stroke. [Review] [17 refs]. Am 

Fam Physician 1998;57(1):73-80. No original 

empirical evidence presented. 

Broderick JP, Hacke W. Treatment of acute ischemic 

stroke: Part II: neuroprotection and medical 

management. [Review] [45 refs]. Circulation 

2002;106(13):1736-1740. No original empirical 

evidence presented. 

Broderick JP, Hacke W. Treatment of acute ischemic 

stroke: Part I: recanalization strategies. [Review] [63 

refs]. Circulation 2002;106(12):1563-1569. No 

original empirical evidence presented. 

Broderick JP, Lu M, Kothari R et al. Finding the most 

powerful measures of the effectiveness of tissue 

plasminogen activator in the NINDS tPA stroke trial. 

Stroke 2000;31(10):2335-2341. No intervention of 

interest studied. 

Brott T. Thrombolysis for stroke. Arch Neurol 

1996;53(12):1305-1306. No original empirical 

evidence presented. 

Brott T. Thrombolytic therapy for stroke. [Review] 

[172 refs]. Cerebrovascular & Brain Metabolism 

Reviews 1991;3(2):91-113. No original empirical 

evidence presented. 

Brott T, Broderick J, Kothari R. Thrombolytic therapy 

for stroke. [Review] [50 refs]. Curr Opin Neurol 

1994;7(1):25-35. No original empirical evidence 

presented. 

Brott T, Haley EC, Levy DE et al. The investigational 

use of tPA for stroke. Ann Emerg Med 

1988;17(11):1202-1205. No original empirical 

evidence presented. 

Brott T, Lu M, Kothari R et al. Hypertension and its 

treatment in the NINDS rt-PA stroke trial. Stroke 

1998;29(8):1504-1509. No intervention of interest 

studied. 
105

Brown DL. Deaths associated with platelet 

glycoprotein IIb/IIIa inhibitor treatment. Heart 

2003;89(5):535-537. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Brown DL, Haley EC. Post-emergency department 

management of stroke. Emerg Med Clin North Am 

2002;20(3):687-702. No original empirical evidence 

presented. 

Brown MM. Brain attack: a new approach to stroke. 

[Review] [20 refs]. Clin Med (Northfield Il) 

2002;2(1):60-65. No original empirical evidence 

presented. 

Brown MM, Humphrey PR. Carotid endarterectomy: 

recommendations for management of transient 

ischaemic attack and ischaemic stroke. Association of 

British Neurologists.[see comment]. BMJ 

1992;305(6861):1071-1074. No human participants. 

Brozman M, Gobo T, Raisova M et al. Intravenous rtPA thrombolytic therapy in fifty-six ischemic stroke 

patients - A prospective follow-up study. Acta Clinica 

Croatica 2003;42(4):289-297. No intervention of 

interest studied. 

Brucker AB, Vollert-Rogenhofer H, Wagner M et al. 

Heparin treatment in acute cerebral sinus venous 

thrombosis: a retrospective clinical and MR analysis 

of 42 cases. Cerebrovasc Dis 1998;8(6):331-337. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Bruno A. Tissue-plasminogen activator for acute 

ischaemic stroke.[comment]. Lancet 

1997;349(9050):503-504. No original empirical 

evidence presented. 

Bruno A, Biller J, Adams HP J et al. Acute blood 

glucose level and outcome from ischemic stroke. Trial 

of ORG 10172 in Acute Stroke Treatment (TOAST) 

Investigators. Neurology 1999;52(2):280-284. No 

intervention of interest studied. 

Bruno A, Biller J, Adams HP et al. Acute blood 

glucose level and outcome from ischemic stroke. 

Neurology 1999;52280-284. No intervention of 

interest studied. 

Bruno A, Levine SR, Frankel MR et al. Admission 

glucose level and clinical outcomes in the NINDS rtPA Stroke Trial. Neurology 2002;59(5):669-674. No 

intervention of interest studied. 

Bruno A, Saha C, Williams L S et al. IV insulin during 

acute cerebral infarction in diabetic patients. 

Neurology 4-27-2004;62( 8):1441-1442. Unable to 

obtain by final date for inclusion. 

Brunyee P. Stroke services. The right register. Health 

Serv J 1999;109(5668):31No human participants. 

Bryan RN. Diffusion-weighted imaging: to treat or not 

to treat? That is the question.[comment]. Ajnr: 

American Journal of Neuroradiology 1998;19(2):396-

397. No human participants. 

Bukachi F, Clague Waldenstrom A, Kazzam E et al. 

Clinical outcome of coronary angioplasty in patients 

with ischaemic cardiomyopathy. Int J Cardiol 

2003;88(2-3):167-174. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Burgin WS, Staub L, Chan W et al. Acute stroke care 

in non-urban emergency departments. Neurology 

2001;57(11):2006-2012. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Burkart DJ, Borsa JJ, Anthony JP et al. Thrombolysis 

of acute peripheral arterial and venous occlusions with 

tenecteplase and eptifibatide: A pilot study. Journal of 

Vascular & Interventional Radiology 2003;14(6):729-

733. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Butcher K, Parsons M, Baird T et al. Perfusion 

thresholds in acute stroke thrombolysis. Stroke 

2003;34(9):2159-2164. No intervention of interest 

studied. 

Butterworth RJ, Cluckie A, Jackson SH et al. 

Pathophysiological assessment of nitric oxide (given 

as sodium nitroprusside) in acute ischaemic stroke. 

Cerebrovasc Dis 1998;8(3):158-165. No intervention 

of interest studied. 

Cabral NL, Moro C, Silva GR et al. Study comparing 

the stroke unit outcome and conventional ward 

treatment: a randomized study in Joinville, Brazil. Arq 

Neuropsiquiatr 2003;61(2A):188-193. No intervention 

of interest studied. 

Cakmak S, Derex L, Berruyer M et al. Cerebral 

venous thrombosis: clinical outcome and systematic 

screening of prothrombotic factors. Neurology 

2003;60(7):1175-1178. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Calcium-channel therapy similar but not equivalent to 

diuretic and beta-blocker treatment in reducing 

cardiovascular disease. Hosp Formul 

2003;38(6):345Unable to obtain by final date for 

inclusion. 

Candelise L, Roncaglioni C, Aritzu E et al. 

Thrombolytic therapy. From myocardial to cerebral 

infarction. The MAST-I Group. Multicentre Acute 

Stroke Trial. [Review] [134 refs]. Ital J Neurol Sci 

1996;17(1):5-21. No original empirical evidence 

presented. 
106

Cao P, Zannetti S, Giordano G et al. Cerebral 

tomographic findings in patients undergoing carotid 

endarterectomy for asymptomatic carotid stenosis: 

short-term and long-term implications. Eur J Vasc 

Surg 1999;29(6):995-1005. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Caplan LR. Now is an exciting time to care for stroke 

patients. South Med J 2003;96(4):329-330. No human 

participants. 

Carrageta MO, Negrao L, de Padua F. Communitybased stroke prevention: a Portuguese challenge.[see 

comment]. [Review] [21 refs]. Health Rep 

1994;6(1):189-195. No human participants. 

Carroll C, Hobart J, Fox C et al. Stroke in Devon: 

knowledge was good, but action was poor. Journal of 

Neurology, Neurosurgery & Psychiatry 

2004;75(4):567-571. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Carrozzella J, Jauch EC. Emergency stroke 

management: a new era. [Review] [27 refs]. Crit Care 

Nurs Clin North Am 2002;37(1):35-57. No human 

participants. 

Carson JL, Armas-Loughran B. Blood transfusion: 

Less is more? Crit Care Med 2003;31(9):2409-2410. 

No original empirical evidence presented. 

Carter AB. Hypotensive therapy in stroke survivors. 

Lancet 1970;1(7645):485-489. No intervention of 

interest studied. 

Caso V, Hacke W. The very acute stroke treatment: 

fibrinolysis and after. [Review] [37 refs]. Clinical & 

Experimental Hypertension (New York) 2002;24(7-

8):595-602. No original empirical evidence presented. 

Castaldo JE, Nelson JJ, Reed JF et al. The delay in 

reporting symptoms of carotid artery stenosis in an atrisk population. The Asymptomatic Carotid 

Atherosclerosis Study experience: a statement of 

concern regarding watchful waiting. Arch Neurol 

1997;54(10):1267-1271. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Castellan L, Causin F, Danieli D et al. Carotid stenting 

with filter protection. Correlation of ACT values with 

angiographic and histopathologic findings. AJNR Am 

J Neuroradiol 2003;30(2):103-108. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Catford J. The health of the nation. Coronary heart 

disease and stroke. Br J Hosp Med 1993;49(1):11-14. 

No original empirical evidence presented. 

Cavallini A, Micieli G, Marcheselli S et al. Role of 

monitoring in management of acute ischemic stroke 

patients. Stroke 2003;34(11):2599-2603. No 

intervention of interest studied. 

Centers for, Disease Control, Prevention (CDC). 

Awareness of stroke warning signs--17 states and the 

U.S. Virgin Islands, 2001. MMWR Morb Mortal 

Wkly Rep 5-7-2004;Morbidity & Mortality Weekly 

Report. 53( 17):359-362. Unable to obtain by final 

date for inclusion. 

Chalela JA, Kang DW, Warach S. Multiple cerebral 

microbleeds: MRI marker of a diffuse hemorrhageprone state. J Neuroimaging 2004;14(1):54-57. No 

human participants. 

Chalmers J. Volhard Lecture. Brain, blood pressure 

and stroke. [Review] [73 refs]. J Hypertens 

1998;16(12 Pt 2):1849-1858. No original empirical 

evidence presented. 

Chamorro A, Obach V. Anticoagulant therapy. 

Cerebrovasc Dis 2003;15(SUPPL. 2):49-55. No 

original empirical evidence presented. 

Chan LL, Khoo JB, Thng CH et al. Diffusion 

weighted MR imaging in acute stroke: the SGH 

experience. Singapore Med J 2002;43(3):118-123. No 

intervention of interest studied. 

Chang GY, Lackey NR, Gates MF. An ischemic 

stroke during intravenous recombinant tissue 

plasminogen activator infusion for evolving 

myocardial infarction. Eur J Neurol 2001;8(3):267-

268. No intervention of interest studied. 

Chappel D, Bailey J, Stacy R et al. Implementation 

and evaluation of local-level priority setting for stroke. 

Public Health 2001;115(1):21-29. No human 

participants. 

Chasis H. Appraisal of antihypertensive drug therapy. 

Circulation 1974;50(1):4-8. No original empirical 

evidence presented. 

Chaturvedi S. Should the multicenter carotid 

endarterectomy trials be repeated? Arch Neurol 

2003;60(5):774-775. No original empirical evidence 

presented. 

Cheanvechai V, Harthun NL, Graham LM et al. 

Incidence of peripheral vascular disease in women: Is 

it different from that in men? Journal of Thoracic & 

Cardiovascular Surgery 2004;127(2):314-317. No 

original empirical evidence presented. 

Check mental status or risk missing problems. Hosp 

Case Manag 2003;11(5):72-74. No original empirical 

evidence presented. 
107

Cheung RT. Hong Kong patients'' knowledge of stroke 

does not influence time-to-hospital presentation. J Clin 

Neurosci 2001;8(4):311-314. No intervention of 

interest studied. 

Chilton R. Web alert. Curr Atheroscler Rep 

2001;3(4):271-272. No human participants. 

Ciccone A, Sterzi R, Crespi V et al. Thrombolysis for 

acute ischemic stroke: the patient''s point of view. 

Cerebrovasc Dis 2001;12(4):335-340. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Circulation Respiratory, health. CIHR Institute. 

Unable to obtain by final date for inclusion. 

Claesson L, Gosman-Hedstrom G, Fagerberg B et al. 

Hospital re-admissions in relation to acute stroke unit 

care versus conventional care in elderly patients the 

first year after stroke: the Goteborg 70+ Stroke study. 

Age & Ageing 2003;32(1):109-113. No intervention 

of interest studied. 

Clark D, Forbes C. Patient empowerment stroke--a 

strategy for Scotland. Scott Med J 2001;46(3):71-72. 

No human participants. 

Clark MS, Rubenach S, Winsor A. A randomized 

controlled trial of an education and counselling 

intervention for families after stroke. Clin Rehabil 

2003;17(7):703-712. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Coca A. Actual blood pressure control: are we doing 

things right? [Review] [43 refs]. Journal of 

Hypertension - Supplement 1998;16(1):S45-S51. No 

human participants. 

Coe M. Understanding the CVA patient. The damage 

is much more than physical. Nurs Care 1974;7(5):16-

18. No human participants. 

Cohen DL, Grant FM. The effect of randomisation 

without CT on treatment in one large international 

stroke trial centre. Age & Ageing 1997;26(suppl 

1):42No intervention of interest studied. 

Collaborative systematic review of the randomised 

trials of organised inpatient (stroke unit) care after 

stroke. Stroke Unit Trialists'' Collaboration.[see 

comment]. BMJ 1997;314(7088):1151-1159. No 

original empirical evidence presented. 

Collice MD. Surgery for intracerebral hemorrhage. 

Neurol Sci 2004;25 Suppl 1S10-S11. No original 

empirical evidence presented. 

Collins DR, McCormack PM, O''Neill D. General 

perception of stroke. Poor knowledge of stroke can be 

improved by simple measures.[comment]. BMJ 

2002;325(7360):392No original empirical evidence 

presented. 

Connors JJ. Pharmacologic Agents in Stroke 

Prevention, Acute Stroke Therapy, and Interventional 

Procedures. Journal of Vascular & Interventional 

Radiology 2004;15(1 II):S87-S101. No original 

empirical evidence presented. 

Cornu C, Amsallem E, Serradj-Jaillard AA. 

Thrombolytic therapy for acute ischemic stroke. 

[Review] [45 refs]. American Journal of 

Cardiovascular Drugs 2001;1(4):281-292. No original 

empirical evidence presented. 

Coull BM, Brockschmidt JK, Howard G et al. 

Community hospital-based stroke programs in North 

Carolina, Oregon, and New York. IV. Stroke 

diagnosis and its relation to demographics, risk 

factors, and clinical status after stroke. Stroke 

1990;21(6):867-873. No intervention of interest 

studied. 

Counsell C. Meta-analysis. Practical Neurology 

2003;3(5):300-305. No human participants. 

Coutts S, Frayne R, Sevick R et al. Microbleeding on 

MRI as a marker for hemorrhage after stroke 

thrombolysis.[comment]. Stroke 2002;33(6):1457-

1458. No original empirical evidence presented. 

Coutts SB, Simon JE, Tomanek AI et al. Reliability of 

assessing percentage of diffusion-perfusion 

mismatch.[see comment]. Stroke 2003;34(7):1681-

1683. No intervention of interest studied. 

Crawley F, Clifton A, Buckenham T et al. Comparison 

of hemodynamic cerebral ischemia and microembolic 

signals detected during carotid endarterectomy and 

carotid angioplasty. Stroke 1997;28(12):2460-2464. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Crisostomo RA, Garcia MM, Tong DC. Detection of 

diffusion-weighted MRI abnormalities in patients with 

transient ischemic attack: correlation with clinical 

characteristics. Stroke 2003;34(4):932-937. No 

intervention of interest studied. 

CRITICAL PATH NETWORK. Study says EDs don’t 

meet time targets for stroke: patients not given 

diagnostic tests in recommended time frames. Hosp 

Case Manag 2003;11(8):119-122. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Crocco T, Gullett T, Davis SM et al. Feasibility of 

neuroprotective agent administration by prehospital 

personnel in an urban setting. Stroke 2003;34(8):1918-

1922. No intervention of interest studied. 

Crocco TJ, Kothari RU, Sayre MR et al. A nationwide 

prehospital stroke survey. Prehosp Emerg Care 

1999;3(3):201-206. No intervention of interest 

studied. 
108

Crocco TJ, Moreno R, Jauch EC et al. Teaching ACLS 

stroke objectives to prehospital providers: a casebased approach. Prehosp Emerg Care 2003;7(2):229-

234. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

CVA (cerebrovascular accident) pathway cuts across 

seven hospital units. Hosp Case Manag 1998;6(2):33-

34. No original empirical evidence presented. 

D''Afflitti JG, Weitz GW. Rehabilitating the stroke 

patient through patient-family groups. Int J Group 

Psychother 1974;24(3):323-332. No human 

participants. 

Daffertshofer M, Hennerici M. Ultrasound in the 

treatment of ischaemic stroke. [Review] [60 refs]. 

Lancet 2003;2(5):283-290. No original empirical 

evidence presented. 

Daley S, Braimah J, Sailor S et al. Education to 

improve stroke awareness and emergent response. The 

NINDS rt-PA Stroke Study Group. [Review] [12 refs]. 

J Neurosci Nurs 1997;29(6):393-396. No original 

empirical evidence presented. 

Dancer S. Redesigning care for the nonhemorrhagic 

stroke patient. J Neurosci Nurs 1996;28(3):183-189. 

No original empirical evidence presented. 

Daugherty SA, Berman R, Entwisle G et al. 

Cerebrovascular events in the Hypertension Detection 

and Follow-up Program. Prog Cardiovasc Dis 

1986;29(3 Suppl 1):63-72. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Davalos A. Fibrinolytic therapy for acute stroke: the 

Spanish experience. ECASS-II Spanish Group. 

Cerebrovasc Dis 1999;9(Suppl 3):9-15. No 

intervention of interest studied. 

Davalos A, Cendra E, Gonzalez B et al. Double blind 

randomized clinical trial of nicardipine vs placebo in 

acute ischemic stroke: clinical, radiological and 

biochemical evaluation of the ischemic area. 

Preliminary results. Neurol India 

1989;37(Suppl):Unable to obtain by final date for 

inclusion. 

Davalos A, Fernandez-Real JM, Ricart W et al. Ironrelated damage in acute ischemic stroke.[erratum 

appears in Stroke 1994 Nov;25(11):2300]. Stroke 

1994;25(8):1543-1546. No intervention of interest 

studied. 

Davalos A, Toni D, Iweins F et al. Neurological 

deterioration in acute ischemic stroke: potential 

predictors and associated factors in the European 

cooperative acute stroke study (ECASS) I. Stroke 

1999;30(12):2631-2636. No intervention of interest 

studied. 

Davalos A, De C E, Genis D et al. Double blind 

clinical trial of nicardipine versus placebo in the 

treatment of the acute phase of stroke. Neurology 

1992;7(6):157Unable to obtain by final date for 

inclusion. 

Davenport J, Hanson SK, Altafullah IM et al. tPA: a 

rural network experience.[comment]. Stroke 

2000;31(6):1457-1458. No original empirical evidence 

presented. 

Davenport R, Dennis M. Neurological emergencies: 

acute stroke.[see comment]. [Review] [99 refs]. 

Journal of Neurology, Neurosurgery & Psychiatry 

2000;68(3):277-288. No original empirical evidence 

presented. 

Davenport RJ. Treating hypertension after 

stroke.[comment]. BMJ 1994;309(6955):669No 

original empirical evidence presented. 

Davis PH, Clarke WR, Bendixen BH et al. Silent 

cerebral infarction in patients enrolled in the TOAST 

Study. Neurology 1996;46(4):942-948. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Davis S, Tress B, Barber PA et al. Echoplanar 

magnetic resonance imaging in acute stroke. [Review] 

[45 refs]. J Clin Neurosci 2000;7(1):3-8. No original 

empirical evidence presented. 

Davis SM, Donnan GA. Thrombolysis for stroke: 

defining the time window.[comment]. Stroke 

2002;33(2):495-496. No original empirical evidence 

presented. 

Davis SM, Donnan GA. Stroke unit design: high tech 

versus low tech.[comment]. Stroke 

2004;35(4):1021No original empirical evidence 

presented. 

Davis TME, Colagiuri S. The continuing legacy of the 

United Kingdom prospective diabetes study. Med J 

Aust 2004;180(3):104-105. No original empirical 

evidence presented. 

Dawson K, Gordon BJ, Guend A. Progress in reducing 

stroke mortality in Wisconsin, 1984-1998. WMJ 

1998;101(3):32-36. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

de Bray, JM Missoum A, Dubas F et al. Detection of 

vertebrobasilar intracranial stenoses: transcranial 

Doppler sonography versus angiography. J Ultrasound 

Med 1997;16(3):213-218. No intervention of interest 

studied. 
109

De Deyn, PP Reuck, JD Deberdt W et al. Treatment of 

acute ischemic stroke with piracetam. Members of the 

Piracetam in Acute Stroke Study (PASS) Group. 

Stroke 1997;28(12):2347-2352. No intervention of 

interest studied. 

De Keyser J. Thrombolysis and hemorrhagic 

transformation.[comment]. Stroke 2002;33(3):724No 

original empirical evidence presented. 

De Keyser J, Sulter G, Langedijk M et al. 

Management of acute ischaemic stroke. [Review] [25 

refs]. Acta Clin Belg 1999;54(5):302-305. No original 

empirical evidence presented. 

De Keyser J, Van dV V, Schellens RL et al. Safety 

and pharmacokinetics of the neuroprotective drug 

lubeluzole in patients with ischemic stroke. Clin Ther 

1997;19(6):1340-1351. No intervention of interest 

studied. 

Debrun GM, Aletich VA, Kehrli P et al. Aneurysm 

geometry: an important criterion in selecting patients 

for Guglielmi detachable coiling. [Review] [139 refs]. 

Neurol Med Chir (Tokyo) 1998;38 Suppl1-20. No 

original empirical evidence presented. 

del Zoppo, GJ. Thrombolysis: from the experimental 

findings to the clinical practice. [Review] [78 refs]. 

Cerebrovasc Dis 2004;17 Suppl 1144-152. No original 

empirical evidence presented. 

del Zoppo, GJ. Thrombolysis in acute stroke. 

[Review] [105 refs]. Actas Luso Esp Neurol Psiquiatr 

Cienc Afines 1995;10 Suppl 237-47. No original 

empirical evidence presented. 

del Zoppo, GJ. An open, multicenter trial of 

recombinant tissue plasminogen activator in acute 

stroke. A progress report. The rt-PA Acute Stroke 

Study Group. Stroke 1990;21(12 Suppl):IV174-IV175. 

No intervention of interest studied. 

del Zoppo, GJ Poeck K, Pessin MS et al. Recombinant 

tissue plasminogen activator in acute thrombotic and 

embolic stroke. Ann Neurol 1992;32(1):78-86. No 

intervention of interest studied. 

DeLemos CD, Atkinson RP, Croopnick SL et al. How 

effective are "community" stroke screening programs 

at improving stroke knowledge and prevention 

practices? Results of a 3-month follow-up study. 

Stroke 2003;34(12):e247-e249. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Demaerschalk BM. Evidence-Based Clinical Practice 

Education in Cerebrovascular Disease. Stroke 

2004;35(2):392-396. No original empirical evidence 

presented. 

Demchuk AM, Burgin WS, Christou I et al. 

Thrombolysis in brain ischemia (TIBI) transcranial 

Doppler flow grades predict clinical severity, early 

recovery, and mortality in patients treated with 

intravenous tissue plasminogen activator.[see 

comment]. Stroke 2001;32(1):89-93. No intervention 

of interest studied. 

Denby F, Harvey RL. An educational intervention for 

stroke rehabilitation patients and their families: 

Healthy living after stroke. Top Stroke Rehabil 

2003;9(4):34-45. No original empirical evidence 

presented. 

Dennis M. Stroke services: the good, the bad and the... 

J R Coll Physicians Lond 2000;34(1):92-96. No 

human participants. 

Dennis M, Langhorne P. So stroke units save lives: 

where do we go from here?[see comment]. [Review] 

[25 refs]. BMJ 1994;309(6964):1273-1277. No 

original empirical evidence presented. 

Dennis M, O''Rourke S, Slattery J et al. Evaluation of 

a stroke family care worker: results of a randomised 

controlled trial.[see comment]. BMJ 

1997;314(7087):1071-1076. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Dennis MS. Stroke unit versus neurology ward--a 

short commentary. J Neurol 2003;250(11):1370-1371. 

No human participants. 

Derex L, Nighoghossian N, Hermier M et al. Early 

detection of cerebral arterial occlusion on magnetic 

resonance angiography: predictive value of the 

baseline NIHSS score and impact on neurological 

outcome. Cerebrovasc Dis 2002;13(4):225-229. No 

intervention of interest studied. 

Derex L, Tomsick TA, Brott TG et al. Outcome of 

stroke patients without angiographically revealed 

arterial occlusion within four hours of symptom onset. 

Ajnr: American Journal of Neuroradiology 

2001;22(4):685-690. No intervention of interest 

studied. 

Derex LN. Thrombolysis for ischemic stroke in 

patients with old microbleeds on pretreatment MRI. 

Cerebrovasc Dis 2004;17(2-3):238-241. No 

intervention of interest studied. 

Dezsi L. Fibrinolytic actions of ACE inhibitors: a 

significant plus beyond antihypertensive therapeutic 

effects.[comment]. Cardiovasc Res 2000;47(4):642-

644. No original empirical evidence presented. 

Diuretics prevail as initial therapy in largest 

hypertension trial ever. Hosp Formul 

2003;38(1):17+23No original empirical evidence 

presented. 
110

Di Carlo A, Lamassa M, Baldereschi M et al. Sex 

differences in the clinical presentation, resource use, 

and 3-month outcome of acute stroke in Europe: data 

from a multicenter multinational hospital-based 

registry. Stroke 2003;34(5):1114-1119. No 

intervention of interest studied. 

Di Napoli M, Papa F. Angiotensin-converting enzyme 

inhibitor use is associated with reduced plasma 

concentration of C-reactive protein in patients with 

first-ever ischemic stroke. Stroke 2003;34(12):2922-

2929. No intervention of interest studied. 

Diamantopoulos EJ, Andreadis EA, Vassilopoulos CV 

et al. Adherence to an intensive antihypertensive 

follow-up programme. J Hum Hypertens 

2003;17(6):437-439. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Diaz FG, Ausman JI, Mehta B et al. Acute cerebral 

revascularization. J Neurosurg 1985;63(2):200-209. 

No intervention of interest studied. 

Dibler CB. Management of the stroke patient. 1994 

Ishmael Essay Award. [Review] [15 refs]. J Okla Dent 

Assoc 1994;85(1):22-24. No original empirical 

evidence presented. 

Dion JE. Management of Ischemic Stroke in the Next 

Decade: Stroke Centers of Excellence. Journal of 

Vascular & Interventional Radiology 2004;15(1 

II):S133-S141. No original empirical evidence 

presented. 

Dippel DW, Du Ry, van Beest et al. The validity and 

reliability of signs of early infarction on CT in acute 

ischaemic stroke. Neuroradiology 2000;42(9):629-

633. No intervention of interest studied. 

DM approach to post-stroke care shows early promise. 

Senior Care Management 2003;6(3):33-37. No 

original empirical evidence presented. 

Doggrell SA. Alteplase: descendancy in myocardial 

infarction, ascendancy in stroke. [Review] [91 refs]. 

Expert Opin Investig Drugs 2001;10(11):2013-2029. 

No original empirical evidence presented. 

Doggrell S A, SCOPE (Study, of Cognition et al. 

Candesartan for the prevention and treatment of stroke 

- results of the SCOPE and ACCESS trials. [Review] 

[10 refs]. Expert Opin Pharmacother 2004;5( 3):687-

690. Unable to obtain by final date for inclusion. 

Dollet JM, Champigneulle B, Evangelista M et al. 

Sclerotherapy versus propranolol after first variceal 

haemorrhage in alcoholic cirrhosis. Lancet 

1985;2(8446):97No original empirical evidence 

presented. 

Donnan GA. Stroke: prediction, prevention, and 

outcome. [Review] [5 refs]. Lancet 2004;3(1):9No 

original empirical evidence presented. 

Donnan GA. Therapy in cerebrovascular disease: 

current status and future directions. [Review] [144 

refs]. Med J Aust 1991;155(8):563-571. No original 

empirical evidence presented. 

Donnan GA, Davis SM. Controversy: the essence of 

medical debate. Stroke 2003;34(2):372-373. No 

human participants. 

Donnelly M, Power M, Russell M et al. Randomized 

controlled trial of an early discharge rehabilitation 

service: the Belfast Community Stroke Trial. Stroke 

2004;35(1):127-133. No intervention of interest 

studied. 

Dorman P, Sandercock P. TPA within 3 hours of acute 

ischaemic stroke?[see comment]. Lancet 

1996;348(9042):1600-1601. No original empirical 

evidence presented. 

Dorman T, Thompson DA, Breslow MJ et al. 

Nicardipine versus nitroprusside for breakthrough 

hypertension following carotid endarterectomy. J Clin 

Anesth 2001;13(1):16-19. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Drake WE J, Dietrich BJ, Hunt G et al. Community 

action in stroke management. Am J Public Health 

1972;62(4):522-529. No original empirical evidence 

presented. 

Drake W E, Hamilton M J, Carlsson M et al. Acute 

stroke management and patient outcome: the value of 

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studied. 

Dressman LA, Hunter J. Stroke awareness and 

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involve relevant population [defined as adult (>16) 

with acute stroke]. 

Drummond A E. The effects of a stroke unit on 

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22. Study did not involve relevant population [defined 

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Ducharme J, Currie T, Ovens H et al. Acute stroke 

management.[comment]. Can Fam Physician 

2001;472458No human participants. 

Dulli DA, Dempsey RJ, Levine RL. Attitudes and 

approaches to acute ischemic stroke in Wisconsin 

hospitals. WMJ 2001;100(5):44-49. No intervention of 

interest studied. 
111

Dumo P, Fagan SC, Carhuapoma J. Thrombolysis in 

acute ischemic stroke. [Review] [9 refs]. Am J Health 

Syst Pharm 1997;54(19):2213-2217. No original 

empirical evidence presented. 

Dundas R, Morgan M, Redfern J et al. Ethnic 

differences in behavioural risk factors for stroke: 

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population [defined as adult (>16) with acute stroke]. 

Dunn SA, Nelson CD, Peterson PM. An education 

program about stroke. Rehabil Nurs 1984;9(5):27-29. 

No original empirical evidence presented. 

Dustan HP, Roccella EJ, Garrison HH. Controlling 

hypertension. A research success story. [Review] [67 

refs]. Arch Intern Med 1996;156(17):1926-1935. No 

original empirical evidence presented. 

Eames S, McKenna K, Worrall L et al. The suitability 

of written education materials for stroke survivors and 

their carers. Top Stroke Rehabil 2003;10(3):70-83. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Easton KL, Zemen DM, Kwiatkowski S. Developing 

and implementing a stroke education series for 

patients and families. Rehabil Nurs 1994;19(6):348-

351. Study did not involve relevant population 

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Eaves YD. ''What happened to me'': rural African 

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Nurs 2000;32(1):37-48. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Ebersole P. The horse & buggy syndrome or was good 

enough for grandpa good enough for me? Geriatr Nurs 

(Minneap) 1999;20(2):62-63. No original empirical 

evidence presented. 

Ebrahim S, Smith GD. Exporting failure? Coronary 

heart disease and stroke in developing countries. Int J 

Epidemiol 2001;30(2):201-205. No human 

participants. 

Eckert B, Koch C, Thomalla G et al. Acute basilar 

artery occlusion treated with combined intravenous 

Abciximab and intra-arterial tissue plasminogen 

activator: report of 3 cases. Stroke 2002;33(5):1424-

1427. No intervention of interest studied. 

Eckstein HH, Schumacher H, Dorfler A et al. Carotid 

endarterectomy and intracranial thrombolysis: 

simultaneous and staged procedures in ischemic 

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involve relevant population [defined as adult (>16) 

with acute stroke]. 

Edmans J A. Comparison of stroke unit and nonstroke unit. Unable to obtain by final date for 

inclusion. 

Edwards G. Good practice for keeping stroke patients 

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evidence presented. 

Effect of angiotensin-converting enzyme inhibition 

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Curr Hypertens Rep 1999;1(6):466-467. No original 

empirical evidence presented. 

Effect of antihypertensive treatment on stroke 

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involve relevant population [defined as adult (>16) 

with acute stroke]. 

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sonographic patterns of tandem internal carotid 

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2002;33(1):99-102. No intervention of interest 

studied. 

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endarterectomy does not affect long-term blood 

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Cerebrovasc Dis 1998;8(1):20-24. Study did not 

involve relevant population [defined as adult (>16) 

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Mt Sinai J Med 2003;70(1):27-37. No original 

empirical evidence presented. 

Elliott BM, Collins GJ J, Youkey Donohue et al. 

Intraoperative local anesthetic injection of the carotid 

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relevant population [defined as adult (>16) with acute 

stroke]. 

Ellis SJ. Tissue-plasminogen activator for acute 

ischaemic stroke.[comment]. Lancet 

1997;349(9050):504. No original empirical evidence 

presented. 

Enevoldsen EM, Norby J, Rohr N et al. Outcome for 

patients with carotid stenosis undergoing carotid 

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Neurol Scand 1999;99(6):340-348. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 
112

Engelstein E, Margulies J, Jeret JS. Lack of t-PA use 

for acute ischemic stroke in a community hospital: 

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Am J Emerg Med 2000;18(3):257-260. No 

intervention of interest studied. 

Englert J, Davis K M, Koch K E. Using clinical 

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Eo E-K, Ryu J-Y, Cheon Y-J et al. Effects of Training 

Paramedics on Prehospital Stroke Management. 

Neurology Psychiatry & Brain Research 

2003;10(4):165-172. Unable to obtain by final date for 

inclusion. 

Eriksson S, Olofsson B-O, Wester P-O. Test study. A 

Swedish multicentre trial of long term atenolol 

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population [defined as adult (>16) with acute stroke]. 

Evans DM. Stroke education: the development of a 

documentation system and resource guide. Axone 

1998;20(1):19-22. No original empirical evidence 

presented. 

Evans MF. Do intensive blood pressure lowering and 

low-dose ASA help our hypertensive patients? Can 

Fam Physician 1998;442655-2657. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Evans SN, Ahmed U, Fotherby MD. Effect of 

antihypertensive therapy on blood pressure after 

stroke. Cerebrovasc Dis 1998;8(Suppl 4):No 

intervention of interest studied. 

Exall K, Johnston H. Caring for carers coping with 

stroke. Nurs Times 1999;95(11):50-51. No original 

empirical evidence presented. 

Ezura M, Takahashi A, Shimizu H et al. Diffusionweighted MRI and selection of patients for fibrinolytic 

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2000;42(5):379-383. No intervention of interest 

studied. 

Fagan SC, Morgenstern LB, Petitta A et al. Costeffectiveness of tissue plasminogen activator for acute 

ischemic stroke. NINDS rt-PA Stroke Study 

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890. No intervention of interest studied. 

Fagan SC, Zarowitz BJ, Robert S. "Brain attack": an 

indication for thrombolysis? [Review] [70 refs]. Ann 

Pharmacother 1992;26(1):73-80. No original empirical 

evidence presented. 

Falconer JA, Roth EJ, Sutin JA et al. The critical path 

method in stroke rehabilitation: lessons from an 

experiment in cost containment and outcome 

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1993;19(1):8-16. No original empirical evidence 

presented. 

Farquhar JW, Fortmann SP, Maccoby N et al. The 

Stanford Five-City Project: design and methods. Am J 

Epidemiol 1985;122(2):323-334. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Fassbender K, Dempfle CE, Mielke O et al. Changes 

in coagulation and fibrinolysis markers in acute 

ischemic stroke treated with recombinant tissue 

plasminogen activator. Stroke 1999;30(10):2101-

2104. No intervention of interest studied. 

Favrole P, Guichard J-P, Crassard I et al. DiffusionWeighted Imaging of Intravascular Clots in Cerebral 

Venous Thrombosis. Stroke 2004;35(1):99-103. No 

intervention of interest studied. 

Feigenson JS, McDowell F. Stroke rehabilitation; 

Alternatives for health-care delivery. N Y State J Med 

1980;80(5):752-756. No human participants. 

Felberg RA. Case study: Brain attack. Ochsner Journal 

2003;5(1):44-46. No original empirical evidence 

presented. 

Felberg RA. From the editor''s desk. Ochsner Journal 

2003;5(1):Unable to obtain by final date for inclusion. 

Felberg RA, Naidech A. The five Ps of acute ischemic 

stroke treatment: Parenchyma, pipes, perfusion, 

penumbra, and prevention of complications. Ochsner 

Journal 2003;5(1):5-11. No original empirical 

evidence presented. 

Ferguson JJ. New treatments for acute ischemic 

stroke. Circulation 1996;93(9):1604. No original 

empirical evidence presented. 

Fessler AJ, Alberts MJ. Stroke treatment with tissue 

plasminogen activator in the setting of aortic 

dissection. Neurology 2000;54(4):1010. No original 

empirical evidence presented. 

Fiebach JB, Schellinger PD, Jansen O et al. CT and 

diffusion-weighted MR imaging in randomized order: 

diffusion-weighted imaging results in higher accuracy 

and lower interrater variability in the diagnosis of 

hyperacute ischemic stroke.[see comment]. Stroke 

2002;33(9):2206-2210. No original empirical evidence 

presented. 

Fiehler J, von Bezold M, Kucinski T et al. Cerebral 

blood flow predicts lesion growth in acute stroke 

patients. Stroke 2002;33(10):2421-2425. No 

intervention of interest studied. 

Fieschi C, Argentino C, Lenzi GL et al. Clinical and 

instrumental evaluation of patients with ischemic 
113

stroke within the first six hours. J Neurol Sci 

1989;91(3):311-321. No intervention of interest 

studied. 

Fieschi C, Sette G, Toni D. Assessment of brain tissue 

viability under clinical circumstances. [Review] [62 

refs]. Acta Neurochirurgica - Supplementum 

1999;7373-80. No original empirical evidence 

presented. 

Fink JN, Caplan LR. Cerebrovascular cases. [Review] 

[67 refs]. Med Clin North Am 2003;87(4):755-770. 

No intervention of interest studied. 

Fiorelli M, Bastianello S, von Kummer R et al. 

Hemorrhagic transformation within 36 hours of a 

cerebral infarct: relationships with early clinical 

deterioration and 3-month outcome in the European 

Cooperative Acute Stroke Study I (ECASS I) 

cohort.[see comment]. Stroke 1999;30(11):2280-2284. 

No intervention of interest studied. 

Fischer J. TPA for acute ischemic stroke. S D J Med 

1997;50(2):69-70. No original empirical evidence 

presented. 

Fisher M, Bozik ME. 90-day outcome of patients 

receiving i.v. tPA in the POST trials. Stroke 

2003;34(1):283. No intervention of interest studied. 

Fisher M, Brott TG. Emerging therapies for acute 

ischemic stroke: new therapies on trial. [Review] [32 

refs]. Stroke 2003;34(2):359-361. No human 

participants. 

Fisher M, Davalos A. Emerging therapies for 

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2004;35(2):367-369. No original empirical evidence 

presented. 

Fisher TR. Education is key to stroke-prevention 

program. Pa Med 1997;100(3):43-44. No original 

empirical evidence presented. 

Fisher WS, Jordan WD. Carotid angioplasty. Surg 

Neurol 1998;50(4):295-298. No original empirical 

evidence presented. 

Fitzmaurice DA, Raftery JP, Bryan S. Policy 

dilemmas for oral anticoagulation management. Br J 

Gen Pract 2000;50(459):779-780. No original 

empirical evidence presented. 

Fjaertoft H, Ekeberg G, Loge AD et al. Extended 

stroke unit care with early supported discharge coordinated by a stroke team improves outcome for 

stroke patients. Eur J Neurol 1999;6(5):A8-A9. No 

intervention of interest studied. 

Fjaertoft H, Indredavik B, Lydersen S. Stroke unit 

care combined with early supported discharge: longterm follow-up of a randomized controlled trial.[see 

comment]. Stroke 2003;34(11):2687-2691. No 

intervention of interest studied. 

Fleck LM, Hayes OW. Ethics and consent to treat 

issues in acute stroke therapy. Emerg Med Clin North 

Am 2002;20(3):703-715. No original empirical 

evidence presented. 

Fleishaker JC, Peters GR. Pharmacokinetics of 

tirilazad and U-89678 in ischemic stroke patients 

receiving a loading regimen and maintenance regimen 

of 10 mg/kg/day of tirilazad. J Clin Pharmacol 

1996;36(9):809-813. No intervention of interest 

studied. 

Fleming T, Borer J, Armstrong PW et al. Food and 

Drug Administration: Cardiovascular and Renal Drugs 

Advisory Committee, 98th meeting, January 6th-7th, 

2003. Circulation 2003;107(2):e9002-e9003. No 

original empirical evidence presented. 

Fletcher BJ, King K. Stroke Nursing Committee: 

addressing a special need of the Council of 

Cardiovascular Nursing. Stroke 2001;32(5):1238No 

human participants. 

Flint J. The expert patient: Good thinking or a cross to 

bear? British Journal of Cardiology 2003;10(1):11+13. 

No original empirical evidence presented. 

Foell RB, Silver B, Merino JG et al. Effects of 

thrombolysis for acute stroke in patients with preexisting disability. CMAJ Canadian Medical 

Association Journal 2003;169(3):193-197. No 

intervention of interest studied. 

Foerch C, Du Mesnil, DR Singer O et al. S100B as a 

surrogate marker for successful clot lysis hyperacute 

middle cerebral artery occlusion. Journal of 

Neurology, Neurosurgery & Psychiatry 

2003;74(3):322-325. No intervention of interest 

studied. 

Fogari R, Pasotti C, Zoppi A et al. Effect of 

perindopril and atenolol on plasm PAI-1 in 

hypertensive patients with acute ischemic stroke. 

Stroke 2003;34(1):309. No intervention of interest 

studied. 

Fogelholm R, Murros K, Rissanen A et al. Factors 

delaying hospital admission after acute stroke. Stroke 

1996;27(3):398-400. No intervention of interest 

studied. 

Folden SL. Effect of a supportive-educative nursing 

intervention on older adults'' perceptions of self-care 

after a stroke. Rehabil Nurs 1993;18(3):162-167. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Ford G, Freemantle N. ECASS-II: Intravenous 

alteplase in acute ischaemic stroke. Lancet 
114

1999;35365-68. No original empirical evidence 

presented. 

Forster A, Smith J, Young J et al. Information 

provision for stroke patients and their caregivers. 

[Review] [54 refs]. Cochrane Database Syst Rev 

2001;(3):CD001919No original empirical evidence 

presented. 

Fotherby MD. Stroke, blood pressure and 

antihypertensive therapy. J Hum Hypertens 

1997;11625-627. No original empirical evidence 

presented. 

Fotherby MD, Panayiotou B. Antihypertensive 

therapy in the prevention of stroke: what, when and 

for whom? [Review] [72 refs]. Drugs 1999;58(4):663-

674. No original empirical evidence presented. 

Fournier A, Mazouz H, Achard JM. STOPPING at the 

CAPPP of good HOPE.[comment]. Nephrology 

Dialysis Transplantation 2001;16(1):185-187. No 

original empirical evidence presented. 

Fournier A, Oprisiu R, Andrejak M et al. Reducing the 

Risk of Stroke [2] (multiple letters). J Am Med Assoc 

2003;289(15):1927-1929. No human participants. 

Fragoso YD, Baroncelli C, Gibbons AP et al. Does 

effective secondary prevention of ischemic events start 

at hospitalization? Medgenmed [Computer File]: 

Medscape General Medicine 2000;2(1):E23. No 

original empirical evidence presented. 

Frankel MR. Update: The Paul Coverdell Georgia 

stroke registry pilot prototype. Ethn Dis 2003;13(3 

SUPPL. 3). No human participants. 

Frankel MR, Morgenstern LB, Kwiatkowski T et al. 

Predicting prognosis after stroke: a placebo group 

analysis from the National Institute of Neurological 

Disorders and Stroke rt-PA Stroke Trial. Neurology 

2000;55(7):952-959. No intervention of interest 

studied. 

Frazier JM, Kane KY. ACE inhibitors are better than 

diuretics for treatment of hypertension in the elderly. J 

Fam Pract 2003;52(6):436-438. No original empirical 

evidence presented. 

Frijling BD, Lobo CM, Keus IM et al. Perceptions of 

cardiovascular risk among patients with hypertension 

or diabetes. Patient Education & Counseling 

2004;52(1):47-53. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Fuentes B, Tejedor ED. Re: Randomized controlled 

study of stroke unit versus stroke team care in 

different stroke subtypes.[comment]. Stroke 

2002;33(7):1740-1741. No original empirical evidence 

presented. 

Fujioka K. Clinical trials and anti-obesity agents: 

Expect the unexpected. Curr Opin Investig Drugs 

2003;4(10):1164-1165. No human participants. 

Furlan AJ. Acute stroke therapy: beyond i.v. tPA. 

[Review] [10 refs]. Cleve Clin J Med 2002;69(9):730-

734. No original empirical evidence presented. 

Furlan AJ, Abou-Chebi A. The role of recombinant 

pro-urokinase (r-pro-UK) and intra-arterial 

thrombolysis in acute ischaemic stroke: the PROACT 

trials. Prolyse in Acute Cerebral Thromboembolism. 

Current Medical Research & Opinion 2002;18 Suppl 

2s44-s47. No original empirical evidence presented. 

Futrell N, Millikan CH. Stroke is an emergency. 

[Review] [198 refs]. Dis Mon 1996;42(4):199-264. No 

original empirical evidence presented. 

Gabis LV, Yangala R, Lenn NJ. Time lag to diagnosis 

of stroke in children. Pediatrics 2002;110(5):924-928. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Gagliardi R, Benvenuti L, Guizzardi G. Acute 

operation in cases of middle cerebral artery occlusion. 

Neurosurgery 1983;12(6):636-639. No original 

empirical evidence presented. 

Gagnon RL, Marsh ML, Smith RW et al. Intracranial 

hypertension caused by nitroglycerin. Anesthesiology 

1979;51(1):86-87. No original empirical evidence 

presented. 

Gambhir IS, Gupta SS, Singh DS. Sublingual 

nifedipine in hypertensive emergencies with special 

reference to cerebrovascular accident. J Indian Med 

Assoc 1991;89(8):231-234. No intervention of interest 

studied. 

Garraway WM, Akhtar AJ, Prescott RJ et al. 

Management of acute stroke in the elderly: 

preliminary results of a controlled trial. BMJ 

1980;280(6220):1040-1043. No intervention of 

interest studied. 

Gaumann DM, Tassonyi E, Rivest RW et al. 

Cardiovascular and endocrine effects of clonidine 

premedication in neurosurgical patients.[see 

comment]. Can J Anaesth 1991;38(7):837-843. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Gavestinel produces no benefit for stroke patients, 

study finds. Clin Resour.Manag 2001;2(11):173-175. 

No original empirical evidence presented. 

Gebel JM, Sila CA, Sloan MA et al. Thrombolysisrelated intracranial hemorrhage: a radiographic 

analysis of 244 cases from the GUSTO-1 trial with 

clinical correlation. Global Utilization of 

Streptokinase and Tissue Plasminogen Activator for 
115

Occluded Coronary Arteries. Stroke 1998;29(3):563-

569. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Generalized efficacy of t-PA for acute stroke. 

Subgroup analysis of the NINDS t-PA Stroke Trial. 

Stroke 1997;28(11):2119-2125. No intervention of 

interest studied. 

Gerber CS. Stroke: historical perspectives. Crit Care 

Nurs Q 2003;26(4):268-275. No original empirical 

evidence presented. 

Geroldi C, Galluzzi S, Testa C et al. Validation study 

of a CT-based weighted rating scale for subcortical 

ischemic vascular disease in patients with mild 

cognitive deterioration. Eur Neurol 2003;49(4):193-

209. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Gerriets T, Postert T, Goertler M et al. DIAS I: 

duplex-sonographic assessment of the cerebrovascular 

status in acute stroke. A useful tool for future stroke 

trials. Stroke 2000;31(10):2342-2345. No intervention 

of interest studied. 

Ghosh S, Aronow WS. Utilization of lipid-lowering 

drugs in elderly persons with increased serum lowdensity lipoprotein cholesterol associated with 

coronary artery disease, symptomatic peripheral 

arterial disease, prior stroke, or diabetes mellitus 

before and after an educational program on 

dyslipidemia treatment. Journals of Gerontology 

Series A-Biological Sciences & Medical Sciences 

2003;58(5):432-435. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Gibbon B. Stroke care and rehabilitation. Nurs Stand 

Spec Suppl 1995;9(43):31-35. No original empirical 

evidence presented. 

Giese M, Lackland DT, Egan BM. The hypertension 

initiative of South Carolina. Promoting cardiovascular 

health through better blood pressure control. Journal - 

South Carolina Medical Association 2001;97(2):57-

62. No original empirical evidence presented. 

Gifford RW J. Long-term clinical trials in 

hypertension. [Review] [23 refs]. Journal of 

Hypertension - Supplement 1990;8(2):S17-S22. No 

original empirical evidence presented. 

Gil Nunez, AC Vivancos, MJ. Organization of 

medical care in acute stroke: importance of a good 

network. [Review] [131 refs]. Cerebrovasc Dis 

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Gitlin LN, Luborsky MR, Schemm RL. Emerging 

concerns of older stroke patients about assistive device 

use. Clin Gerontol 1998;38(2):169-180. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Glader EL, Stegmayr B, Norrving B et al. Sex 

differences in management and outcome after stroke: a 

Swedish national perspective. Stroke 

2003;34(8):1970-1975. No intervention of interest 

studied. 

Gladman J, Barer D, Langhorne P. Specialist 

rehabilitation after stroke.[comment]. BMJ 

1996;312(7047):1623-1624. No human participants. 

Gladman J, Whynes D, Lincoln N. Cost comparison of 

domiciliary and hospital-based stroke rehabilitation. 

DOMINO Study Group. Age & Ageing 

1994;23(3):241-245. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Glasziou P, Guyatt GH, Dans AL et al. Applying the 

results of trials and systematic reviews to individual 

patients.[see comment]. ACP J Club 

1998;129(3):A15-A16. No original empirical evidence 

presented. 

Goh KY, Poon WS. Recombinant tissue plasminogen 

activator for the treatment of spontaneous adult 

intraventricular hemorrhage. Surg Neurol 

1998;50(6):526-531. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Goldberg RJ, Mooradd M, Gurwitz JH et al. Impact of 

time to treatment with tissue plasminogen activator on 

morbidity and mortality following acute myocardial 

infarction (The second National Registry of 

Myocardial Infarction). Am J Cardiol 1998;82(3):259-

264. Study did not involve relevant population 

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Goldstein LB. Editorial comment--Advertising 

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population [defined as adult (>16) with acute stroke]. 

Goldstein LB. Prevention and health services delivery. 

[Review] [20 refs]. Stroke 2003;34(2):367-369. No 

human participants. 

Goldstein LB. Effects of amphetamines and small 

related molecules on recovery after stroke in animals 

and man. [Review] [117 refs]. Neuropharmacology 

2000;39(5):852-859. No original empirical evidence 

presented. 

Goldstein LB. Common drugs may influence motor 

recovery after stroke. The Sygen In Acute Stroke 

Study Investigators.[see comment]. Neurology 

1995;45(5):865-871. No intervention of interest 

studied. 
116

Goldstein LB. Blood Pressure Management in Patients 

with Acute Ischemic Stroke. Hypertension 2004;43(2 

I):137-141. No original empirical evidence presented. 

Goldstein LB, Albers GW. Patient safety in trials of 

therapy for acute ischemic stroke.[comment]. JAMA 

2002;287(8):987No original empirical evidence 

presented. 

Goldstein LB, Amarenco P. Prevention and health 

services delivery. Stroke 2004;35(2):401-403. No 

original empirical evidence presented. 

Goldstein LB, SASS I. Antihypertensives and stroke 

recovery. Stroke 1998;29317Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Goldstein LB, Edwards MG, Wood DP. Delay 

between stroke onset and emergency department 

evaluation. Neuroepidemiology 2001;20(3):196-200. 

No intervention of interest studied. 

Goldstein LB, Hey LA, Laney R. North Carolina 

stroke prevention and treatment facilities survey: rtPA 

therapy for acute stroke. Stroke 1998;29(10):2069-

2072. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Goldstein LB, Hey LA, Laney R. North Carolina 

stroke prevention and treatment facilities survey. 

Statewide availability of programs and services. 

Stroke 2000;31(1):66-70. No human participants. 

Goldstein LB, Matchar DB, Hoff-Lindquist J et al. VA 

Stroke Study: Neurologist care is associated with 

increased testing but improved outcomes. Neurology 

2003;61(6):792-796. No intervention of interest 

studied. 

Gompertz P, Pound P, Briffa J et al. How useful are 

non-random comparisons of outcomes and quality of 

care in purchasing hospital stroke services? Age & 

Ageing 1995;24(2):137-141. No intervention of 

interest studied. 

Gompertz P, Slack A, Vogel M et al. Education in 

stroke: strategies to improve stroke patient care. 

[Review] [14 refs]. Hospital Medicine (London) 

2002;63(7):408-411. No original empirical evidence 

presented. 

Gonzaga-Camfield R. Developing an emergency 

department team for treatment of stroke with 

recombinant tissue plasminogen activator. Crit Care 

Nurs Clin North Am 1999;11(2):261-268. No original 

empirical evidence presented. 

Gordon DL. The Mississippi Stroke Education 

Consortium: a state-based template to promote stroke 

awareness, prevention and emergency treatment. 

Neuroepidemiology 2000;19(1):1-12. No human 

participants. 

Gorelick PB. Stroke prevention: windows of 

opportunity and failed expectations? A discussion of 

modifiable cardiovascular risk factors and a 

prevention proposal. Neuroepidemiology 

1997;16(4):163-173. No original empirical evidence 

presented. 

Gorman MJ. Acute thrombolytic therapy in stroke: 

focus on the 3- to 6-hour time window. [Review] [20 

refs]. Ethn Dis 2002;12(1):S1-S7. No original 

empirical evidence presented. 

Gosman-Hedstrom G, Claesson L, Blomstrand C et al. 

Use and cost of assistive technology the first year after 

stroke. A randomized controlled trial. Int J Technol 

Assess Health Care 2002;18(3):520-527. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Grade C, Redford B, Chrostowski J et al. 

Methylphenidate in early poststroke recovery: a 

double-blind, placebo-controlled study. Archives of 

Physical Medicine & Rehabilitation 1998;79(9):1047-

1050. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Gradison M. Decreasing the morbidity, mortality, and 

cost of stroke through awareness and 

prevention.[comment]. Am Fam Physician 

2003;68(12):2335-2340. No original empirical 

evidence presented. 

Graf J, Skutta B, Kuhn FP et al. Computed 

tomographic angiography findings in 103 patients 

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potential and clinical relevance. J Neurol 

2000;247(10):760-766. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Graham CA. Transient cerebral ischemia demands 

urgent evaluation. Stroke 2003;34(10):2451-2452. No 

original empirical evidence presented. 

Graham GD. Tissue plasminogen activator for acute 

ischemic stroke in clinical practice: a meta-analysis of 

safety data. Stroke 2003;34(12):2847-2850. No 

original empirical evidence presented. 

Gray CS, Scott JF, French JM et al. Prevalence and 

prediction of unrecognised diabetes mellitus and 

impaired glucose tolerance following acute stroke. 

Age & Ageing 2004;33(1):71-77. No original 

empirical evidence presented. 

Green D. Thrombosis and Stroke: Foreword. Top 

Stroke Rehabil 2003;10(3):v-vi. No human 

participants. 
117

Greenberg RK. Endovascular therapy or conventional 

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Med 2003;70(12):1038-1054. No original empirical 

evidence presented. 

Griffith DN, James IM, Newbury PA et al. The effect 

of beta-adrenergic receptor blocking drugs on cerebral 

blood flow. Br J Clin Pharmacol 1979;7(5):491-494. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Grotta J. Lubeluzole treatment of acute ischemic 

stroke. The US and Canadian Lubeluzole Ischemic 

Stroke Study Group.[see comment]. Stroke 

1997;28(12):2338-2346. No intervention of interest 

studied. 

Grotta J, Bratina P. Subjective experiences of 24 

patients dramatically recovering from stroke. Stroke 

1995;26(7):1285-1288. No intervention of interest 

studied. 

Grotta JC. Adding to the effectiveness of intravenous 

tissue plasminogen activator for treating acute 

stroke.[comment]. Circulation 2003;107(22):2769-

2770. No original empirical evidence presented. 

Grotta JC, Alexandrov AV. tPA-associated 

reperfusion after acute stroke demonstrated by 

SPECT.[comment]. Stroke 1998;29(2):429-432. No 

intervention of interest studied. 

Grotta JC, Chiu D, Lu M et al. Agreement and 

variability in the interpretation of early CT changes in 

stroke patients qualifying for intravenous rtPA 

therapy.[comment]. Stroke 1999;30(8):1528-1533. No 

intervention of interest studied. 

Grotta JC, Welch KM, Fagan SC et al. Clinical 

deterioration following improvement in the NINDS rtPA Stroke Trial. Stroke 2001;32(3):661-668. No 

intervention of interest studied. 

Gruber A, Ungersbock K, Reinprecht A et al. 

Evaluation of cerebral vasospasm after early surgical 

and endovascular treatment of ruptured intracranial 

aneurysms.[see comment]. Neurosurgery 

1998;42(2):258-267. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Guadagno JV, Calautti C, Baron J-C. Progress in 

imaging stroke: Emerging clinical applications. Br 

Med Bull 2003;65(pp 145-157):-157. No original 

empirical evidence presented. 

Gueyffier F. Secondary Prevention of Stroke: Beyond 

Meta-Analyses. Stroke 2003;34(11):2748-2749. No 

original empirical evidence presented. 

Gueyffier F, Boissel JP, Boutitie F et al. Effect of 

antihypertensive treatment in patients having already 

suffered from stroke. Gathering the evidence. The 

INDANA (INdividual Data ANalysis of 

Antihypertensive intervention trials) Project 

Collaborators. Stroke 1997;28(12):2557-2562. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Guo Y, Jiang X, Zhou Z et al. Relationship between 

levels of serum C-reactive protein, leucocyte count 

and carotid plaque in patients with ischemic stroke. J 

Huazhong Univ Sci Technolog Med Sci 

2003;23(3):263-265. No intervention of interest 

studied. 

Gupta A, Thomas P. General perception of stroke. 

Knowledge of stroke is lacking.[comment]. BMJ 

2002;325(7360):392No original empirical evidence 

presented. 

Gupta R, Schumacher HC, Mangla S et al. Urgent 

endovascular revascularization for symptomatic 

intracranial atherosclerotic stenosis.[see comment]. 

Neurology 2003;61(12):1729-1735. No intervention of 

interest studied. 

Gurwitz JH, Gore JM, Goldberg RJ et al. Risk for 

intracranial hemorrhage after tissue plasminogen 

activator treatment for acute myocardial infarction. 

Participants in the National Registry of Myocardial 

Infarction 2.[see comment]. Ann Intern Med 

1998;129(8):597-604. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Gusev E I, Martynov M I, Boiko A N et al. 

[Antihypertensive treatment with eprosartan mesilate 

of patients in acute and late periods of ischemic 

stroke]. [Russian]. Zh Nevrol Psikhiatr Im S S 

Korsakova 2003;S. Korsakova. 103( 11):15-20. 

Unable to obtain by final date for inclusion. 

Hachinski V. Awareness: the first step to 

action.[comment]. Stroke 2002;33(5):1173No original 

empirical evidence presented. 

Hachinski V. Our Readers Speak. Stroke 

2004;35(1):No original empirical evidence presented. 

Hack W, Kaste M, Bogousslavsky J et al. European 

Stroke Initiative Recommendations for Stroke 

Management-update 2003. Cerebrovasc Dis 

2003;16(4):311-337. No original empirical evidence 

presented. 

Hacke W, Bluhmki E, Steiner T et al. Dichotomized 

efficacy end points and global end-point analysis 

applied to the ECASS intention-to-treat data set: post 

hoc analysis of ECASS I. Stroke 1998;29(10):2073-

2075. No intervention of interest studied. 

Hacke W, Brott T, Caplan L et al. Thrombolysis in 

acute ischemic stroke: controlled trials and clinical 

experience. [Review] [12 refs]. Neurology 1999;53(7 
118

Suppl 4):S3-14. No original empirical evidence 

presented. 

Hacke W, Donnan G, Fieschi C et al. Association of 

outcome with early stroke treatment: pooled analysis 

of ATLANTIS, ECASS, and NINDS rt-PA stroke 

trials. Lancet 2004;363(9411):768-774. No original 

empirical evidence presented. 

Hacke W, Kaste M, Olsen TS et al. European Stroke 

Initiative: recommendations for stroke management. 

Organisation of stroke care. J Neurol 

2000;247(9):732-748. No original empirical evidence 

presented. 

Hacke W, Marler J. TPA in acute stroke. Eur Heart J 

1997;181360. No original empirical evidence 

presented. 

Hacke W, Ringleb P, Stingele R. Update in 

thrombolytic therapy. [Review] [15 refs]. Rev Neurol 

(Paris) 1999;155(9):662-665. No original empirical 

evidence presented. 

Hademenos G. Metro Stroke Task Force: first-year 

experience. Stroke 1999;30(11):2512. No original 

empirical evidence presented. 

Haley EC J, Levy DE, Brott TG et al. Urgent therapy 

for stroke. Part II. Pilot study of tissue plasminogen 

activator administered 91-180 minutes from onset. 

Stroke 1992;23(5):641-645. No intervention of interest 

studied. 

Haley EC J, Lewandowski C, Tilley BC. Myths 

regarding the NINDS rt-PA Stroke Trial: setting the 

record straight.[see comment]. Ann Emerg Med 

1997;30(5):676-682. No original empirical evidence 

presented. 

Haley EC, TPA Bridging, Study Group. Pilot 

randomised trial of tissue plasminogen activator in 

acute ischemic stroke. Neurology 1992;42(Suppl 3). 

No intervention of interest studied. 

Hammett DC, MacFadyen JC. Don''t keep that ACE 

(inhibitor) up your sleeve! Is ramipril effective for 

secondary prevention of cardiovascular disease and 

stroke? Can Fam Physician 2000;46(4):821-823. No 

original empirical evidence presented. 

Hampton. Mega-trials and equivalence trials: 

Experience from the INJECT study. Eur Heart J 

1996;17(SUPPL. E):28-34. No original empirical 

evidence presented. 

Hanger HC, Fogarty B, Wilkinson TJ et al. Stroke 

patients'' views on stroke outcomes: death versus 

disability. Clin Rehabil 2000;14(4):417-424. Study did 

not involve relevant population [defined as adult (>16) 

with acute stroke]. 

Hanger HC, Mulley GP. Questions people ask about 

stroke. Stroke 1993;24(4):536-538. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Hankey GJ. Clomethiazole: an unsuccessful bachelor, 

but perhaps a prosperous married man?[comment]. 

Stroke 2002;33(1):128-129. No intervention of interest 

studied. 

Hankey GJ. Stroke: how large a public health 

problem, and how can the neurologist help? [Review] 

[36 refs]. Arch Neurol 1999;56(6):748-754. No 

original empirical evidence presented. 

Hankey GJ. Thrombolytic therapy in acute ischaemic 

stroke: the jury needs more evidence. [Review] [27 

refs]. Med J Aust 1997;166(8):419-422. No original 

empirical evidence presented. 

Hankey GJ, Deleo D, Stewart-Wynne EG. Stroke 

units: an Australian perspective. Australian & New 

Zealand Journal of Medicine 1997;27(4):437-438. No 

intervention of interest studied. 

Hankey GJ, Heart Outcomes, PE Perindopril et al. 

Angiotensin-converting enzyme inhibitors for stroke 

prevention: is there HOPE for PROGRESS After 

LIFE? [Review] [19 refs]. Stroke 2003;34(2):354-356. 

No original empirical evidence presented. 

Hankey G J, Deleo D, Stewart Wynne E G. Acute 

hospital care for stroke patients; a randomised 

controlled trial. Cerebrovasc Dis 1995;5. No 

intervention of interest studied. 

Hanley DF. Review of critical care and emergency 

approaches to stroke. [Review] [21 refs]. Stroke 

2003;34(2):362-364. No original empirical evidence 

presented. 

Hanley DF, Hacke W. Critical Care and Emergency 

Medicine Neurology. Stroke 2004;35(2):365-366. No 

original empirical evidence presented. 

Hansson L, Himmelmann A. Carvedilol in the 

treatment of hypertension--a review of the clinical 

data base. [Review] [178 refs]. Scandinavian 

Cardiovascular Journal Supplement 1998;4767-80. No 

original empirical evidence presented. 

Hansson L, Lithell H, Skoog I et al. Study on 

COgnition and Prognosis in the Elderly (SCOPE). 

Blood Press 1999;8(3):177-183. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Hantson L, Gheuens J, Tritsmans L et al. Hospital 

referral of stroke patients: a survey of attitudes in 

general practice, and consideration of entry times for 

clinical trials. Clinical Neurology & Neurosurgery 

1994;96(1):32-37. No intervention of interest studied. 
119

Harbison J, Hossain O, Jenkinson D et al. Diagnostic 

accuracy of stroke referrals from primary care, 

emergency room physicians, and ambulance staff 

using the face arm speech test. Stroke 2003;34(1):71-

76. No intervention of interest studied. 

Harmon RL, Woolley SM, Horn LJ. Use of clonidine 

for spasticity arising from stroke and brain injury: a 

pilot placebo-controlled trial. Archives of Physical 

Medicine & Rehabilitation 1996;77934. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Hart E. Evaluating a pilot community stroke service 

using insights from medical anthropology. J Adv 

Nurs. 1998;27(6):1177-1183. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Hart RG, Benavente O. Stroke: part I. A clinical 

update on prevention. [Review] [27 refs]. Am Fam 

Physician 1999;59(9):2475-2482. No original 

empirical evidence presented. 

Hashimoto Y, Terasaki T, Yonehara T et al. Critical 

pathway and hospital-hospital cooperation in acute 

stroke: Reduction of the length of hospital stay. 

Interventional Neuroradiology.6(SUPPL.1):251-5, 

2000. 2000;6(1 Suppl):251-255. No intervention of 

interest studied. 

Hedner T, Himmelmann A, Kjeldsen SE. Contrasting 

messages but not contradicting results from ALLHAT 

and ANBP2. Blood Press 2003;12(2):68-69. No 

original empirical evidence presented. 

Heinsius T, Bogousslavsky J, van Melle G. Large 

infarcts in the middle cerebral artery territory. 

Etiology and outcome patterns.[see comment][erratum 

appears in Neurology 1998 Jun;50(6):1940-3]. 

Neurology 1998;50(2):341-350. No intervention of 

interest studied. 

Heiss WD, Graf R, Grond M et al. Quantitative 

neuroimaging for the evaluation of the effect of stroke 

treatment. [Review] [29 refs]. Cerebrovasc Dis 1998;8 

Suppl 223-29. No original empirical evidence 

presented. 

Heiss WD, Grond M, Thiel A et al. Ischaemic brain 

tissue salvaged from infarction with alteplase. Lancet 

1997;349(9065):1599-1600. No intervention of 

interest studied. 

Heiss WD, Grond M, Thiel A et al. Tissue at risk of 

infarction rescued by early reperfusion: a positron 

emission tomography study in systemic recombinant 

tissue plasminogen activator thrombolysis of acute 

stroke. Journal of Cerebral Blood Flow & Metabolism 

1998;18(12):1298-1307. No intervention of interest 

studied. 

Heiss WD, Kracht L, Grond M et al. Early 

[(11)C]Flumazenil/H(2)O positron emission 

tomography predicts irreversible ischemic cortical 

damage in stroke patients receiving acute thrombolytic 

therapy. Stroke 2000;31(2):366-369. No intervention 

of interest studied. 

Heiss WD, Kracht LW, Thiel A et al. Penumbral 

probability thresholds of cortical flumazenil binding 

and blood flow predicting tissue outcome in patients 

with cerebral ischaemia.[see comment]. Brain Dev 

2001;124(Pt 1):20-29. No intervention of interest 

studied. 

Helgeland A. Treatment of mild hypertension: a five 

year controlled drug trial. The Oslo study. Am J Med 

1980;69(5):725-732. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Hemphill JC. New treatments for stroke. [Review] [22 

refs]. Prog Cardiovasc Nurs 1998;13(1):4-15. No 

human participants. 

Henkel J. New success against stroke. Prevention, 

improved therapies help fight this devastating 

condition. FDA Consum 1998;32(2):12-16. No 

original empirical evidence presented. 

Hennekens CH. Role of aspirin with thrombolytic 

therapy in acute myocardial infarction. Chest 

1990;97(4 Suppl):151S-155S. No original empirical 

evidence presented. 

Henriques IL, Bogousslavsky J. Value of stroke data 

banks for the analysis of clinical syndromes. [Review] 

[13 refs]. Neuroepidemiology 1994;13(6):296-300. No 

intervention of interest studied. 

Herd AM. Current management of acute ischemic 

stroke. Part 2: Antithrombotics, neuroprotectives, and 

stroke units.[see comment]. Can Fam Physician 

2001;471795-1800. No human participants. 

Herd AM. Current management of acute ischemic 

stroke. Part 1: Thrombolytics and the 3-hour 

window.[see comment]. Can Fam Physician 

2001;471787-1793. No original empirical evidence 

presented. 

Hermier M, Nighoghossian N, Derex L et al. 

Hypointense transcerebral veins at T2*-weighted 

MRI: a marker of hemorrhagic transformation risk in 

patients treated with intravenous tissue plasminogen 

activator. Journal of Cerebral Blood Flow & 

Metabolism 2003;23(11):1362-1370. No intervention 

of interest studied. 

Heros RC, Camarata PJ, Latchaw RE. Brain attack. 

Introduction. [Review] [114 refs]. Neurosurg Clin N 

Am 1997;8(2):135-144. No original empirical 

evidence presented. 
120

Hess DC, Wheby MS. Ischemic stroke. Medical 

Crossfire 2003;5(7):17-19. No human participants. 

Heuschmann PU, Berger K, Misselwitz B et al. 

Frequency of thrombolytic therapy in patients with 

acute ischemic stroke and the risk of in-hospital 

mortality: the German Stroke Registers Study 

Group.[see comment]. Stroke 2003;34(5):1106-1113. 

No intervention of interest studied. 

Heyman A, Fields WS, Keating RD. Joint study of 

extracranial arterial occlusion. VI. Racial differences 

in hospitalized patients with ischemic stroke. JAMA 

1972;222(3):285-289. No intervention of interest 

studied. 

Hickenbottom SL, Morgenstern LB. Educating North 

America: lessons learned. Journal of Stroke & 

Cerebrovascular Diseases 2002;11(3/4):174-182. No 

original empirical evidence presented. 

Higashida RT, Furlan AJ, Roberts H et al. Trial design 

and reporting standards for intra-arterial cerebral 

thrombolysis for acute ischemic stroke.[see 

comment][erratum appears in Stroke. 2003 

Nov;34(11):2774]. Stroke 2003;34(8):e109-e137. No 

original empirical evidence presented. 

Hilker R, Poetter C, Findeisen N et al. Nosocomial 

pneumonia after acute stroke: implications for 

neurological intensive care medicine.[see comment]. 

Stroke 2003;34(4):975-981. No intervention of interest 

studied. 

Hill MD, Buchan AM. Methodology for the Canadian 

Activase for Stroke Effectiveness Study (CASES). 

CASES Investigators.[erratum appears in Can J 

Neurol Sci 2002 Feb;29(1):103]. Can J Neurol Sci 

2001;28(3):232-238. No intervention of interest 

studied. 

Hill MN. Comprehensive hypertension care in young 

urban black men: an example of a program of nursing 

research that integrates genetic science, clinical 

interventions, and patient outcomes. Crit Care Nurs 

Clin North Am 2000;35(3):773-793. No original 

empirical evidence presented. 

Hillis AE, Barker PB, Beauchamp NJ et al. MR 

perfusion imaging reveals regions of hypoperfusion 

associated with aphasia and neglect. Neurology 

2000;55(6):782-788. No intervention of interest 

studied. 

Hillis AE, Ulatowski JA, Barker PB et al. A pilot 

randomized trial of induced blood pressure elevation: 

Effects on function and focal perfusion in acute and 

subacute stroke. Cerebrovasc Dis 2003;16(3):236-246. 

No intervention of interest studied. 

Hinchey JA, Benesch C. Thrombolytic therapy in 

patients with acute ischemic stroke. [Review] [28 

refs]. Arch Neurol 2000;57(10):1430-1436. No 

original empirical evidence presented. 

Hinckley JJ, Packard ME. Family education seminars 

and social functioning of adults with chronic aphasia. 

J Commun Disord 2001;34(3):241-254. No original 

empirical evidence presented. 

Hinton RC, Mohr JP, Ackerman RH et al. 

Symptomatic middle cerebral artery stenosis. Ann 

Neurol 1979;5(2):152-157. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Ho SS, Metreweli C, Yu CH. Color velocity imaging 

quantification in the detection of intracranial collateral 

flow. Stroke 2002;33(7):1795-1798. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Hoang KD, Rosen P. The efficacy and safety of tissue 

plasminogen activator in acute ischemic strokes. 

[Review] [59 refs]. Am J Emerg Med 1992;10(3):345-

352. No original empirical evidence presented. 

Hoballah JJ, Nazzal MM, Jacobovicz C et al. Entering 

the ninth decade is not a contraindication for carotid 

endarterectomy. Angiology 1998;49(4):275-278. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Hock N. Neuroprotective and thrombolytic agents: 

advances in stroke treatment. [Review] [51 refs]. J 

Neurosci Nurs 1998;30(3):175-184. No original 

empirical evidence presented. 

Holloway RG, Vickrey BG, Benesch C et al. 

Development of performance measures for acute 

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2001;32(9):2058-2074. No intervention of interest 

studied. 

Horowitz N, Kapeliovich M, Beyar R et al. Stenting in 

acute myocardial infarction: In hospital and long-term 

follow-up. Israel Medical Association Journal: Imaj 

2003;5(2):107-111. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Horstmann S, Kalb P, Koziol J et al. Profiles of matrix 

metalloproteinases, their inhibitors, and laminin in 

stroke patients: influence of different therapies.[see 

comment]. Stroke 2003;34(9):2165-2170. No 

intervention of interest studied. 

Hospital focus. Teach patients to recognize warning 

signs of stroke. Article adapted from one that appeared 

in sister company American Health Consultants' 

newsletter ED Nursing. RN 2002;65(10):Suppl. No 

original empirical evidence presented. 
121

Hou M-C, Lin H-C, Liu T-T et al. Antibiotic 

Prophylaxis after Endoscopic Therapy Prevents 

Rebleeding in Acute Variceal Hemorrhage: A 

Randomized Trial. J Gastroenterol Hepatol 

2004;39(3):746-753. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

How do stroke units improve patient outcomes? A 

collaborative systematic review of the randomized 

trials. Stroke Unit Trialists Collaboration. [Review] 

[30 refs]. Stroke 1997;28(11):2139-2144. No original 

empirical evidence presented. 

Hu KK. Fighting for a peaceful death: a personal 

essay. J Palliat Med 2001;4(2):209-213. No original 

empirical evidence presented. 

Hui E, Lum CM, Woo J et al. Outcomes of elderly 

stroke patients. Day hospital versus conventional 

medical management. Stroke 1995;26(9):1616-1619. 

No intervention of interest studied. 

Hund E, Grau A, Hacke W. Neurocritical care for 

acute ischemic stroke. [Review] [87 refs]. Neurosurg 

Clin N Am 1997;8(2):271-282. No human 

participants. 

Hurst RW, Haskal ZJ, Zager E et al. Endovascular 

stent treatment of cervical internal carotid artery 

aneurysms with parent vessel preservation. Surg 

Neurol 1998;50(4):313-317. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Hurtubise A. Organized stroke care is emerging in 

Ontario.[comment]. Can Fam Physician 2002;4831-

32. No human participants. 

Hussein Z, Fraser IJ, Lees KR et al. Pharmacokinetics 

of 619C89, a novel neuronal sodium channel inhibitor, 

in acute stroke patients after loading and discrete 

maintenance infusions. Br J Clin Pharmacol 

1996;41(6):505-511. No intervention of interest 

studied. 

Hux K, Rogers T, Mongar K. Common perceptions 

about strokes. J Community Health 2000;25(1):47-65. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Hyde SL, Dowell MS. Acute stroke management: the 

importance of vital signs. Nurse 2 Nurse 

2002;2(12):10. Unable to obtain by final date for 

inclusion. 

Iacopino DG, Conti A, Battaglia C et al. Transcranial 

Doppler ultrasound study of the effects of nitrous 

oxide on cerebral autoregulation during neurosurgical 

anesthesia: A randomized controlled trial. J Neurosurg 

2003;99(1):58-64. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Iadecola C, Gorelick PB. Hypertension, Angiotensin, 

and Stroke: Beyond Blood Pressure. Stroke 

2004;35(2):348-350. No original empirical evidence 

presented. 

Iino K, Abe K, Kariya S et al. A controlled, doubleblind study of dl-alpha-tocopheryl nicotinate (JuvelaNicotinate) for treatment of symptoms in hypertension 

and cerebral arteriosclerosis. Jpn Heart J 

1977;18(3):277-283. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Indredavik B. Stroke units - the Norwegian 

experience. Cerebrovasc Dis 2003;15 Suppl 119-20. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Indredavik B, Bakke F, Slordahl SA et al. Stroke unit 

treatment. 10-year follow-up. Stroke 1999;30(8):1524-

1527. No intervention of interest studied. 

Indredavik B, Bakke F, Slordahl SA et al. Treatment 

in a combined acute and rehabilitation stroke unit: 

which aspects are most important? Stroke 

1999;30(5):917-923. No intervention of interest 

studied. 

Indredavik B, Bakke F, Solberg R et al. Benefit of a 

stroke unit: a randomized controlled trial. Stroke 

1991;22(8):1026-1031. No intervention of interest 

studied. 

Indredavik B, Fjaertoft H, Ekeberg G et al. The benefit 

of an extended stroke unit service. A randomised 

controlled trial. Stroke 2000;31(11):2832. No 

intervention of interest studied. 

Indredavik B, Fjaertoft H, Ekeberg G et al. Benefit of 

an extended stroke unit service with early supported 

discharge: A randomized, controlled trial.[see 

comment]. Stroke 2000;31(12):2989-2994. No 

intervention of interest studied. 

Indredavik B, Slordahl SA, Bakke F et al. Stroke unit 

treatment. Long-term effects.[see comment]. Stroke 

1997;28(10):1861-1866. No intervention of interest 

studied. 

Indredavik B, et al. Treatment in a combined acute 

and rehabilitation stroke unit. Stroke 2000;30(5):917-

923. No intervention of interest studied. 

Innes K, Stroke Nurse, Collaborative Group. 

Thrombolysis for acute ischaemic stroke: core nursing 

requirements. [Review] [30 refs]. Br J Nurs 

2003;12(7):416-424. No original empirical evidence 

presented. 

Ischemic stroke pathway relies on ED order sheets. 

Hosp Case Manag 1977;7(4):67-68. No human 

participants. 
122

Ischemic stroke pathway relies on ED order sheets. 

RN 1999;62(10):24ac7-24ac8. No human participants. 

Iso H, Shimamoto T, Naito Y et al. Effects of a longterm hypertension control program on stroke incidence 

and prevalence in a rural community in northeastern 

Japan. Stroke 1998;29(8):1510-1518. No original 

empirical evidence presented. 

Iwase M, Yamamoto M, Yoshinari M et al. Stroke 

topography in diabetic and nondiabetic patients by 

magnetic resonance imaging. Diabetes Research & 

Clinical Practice 1998;42(2):109-116. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Jaeger M, Schuhmann MU, Samii M et al. 

Neurosurgical emergencies and missing neurosurgical 

intensive care unit capacity: is "operate-and-return" a 

sound policy?[see comment]. Eur J Emerg Med 

2002;9(4):334-338. No intervention of interest 

studied. 

Jaffary F, Khan T, Kamali F et al. The effect of 

stability of oral anticoagulant therapy upon patientperceived health status and quality of life. J Am 

Geriatr Soc 2003;51(6):885-887. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Jaillard A, Cornu C, Durieux A et al. Hemorrhagic 

transformation in acute ischemic stroke. The MAST-E 

study. MAST-E Group. Stroke 1999;30(7):1326-1332. 

No intervention of interest studied. 

Jauch E, Yealy DM, Adams JG. Society for Academic 

Emergency Medicine (SAEM) Neurologic 

Emergencies Interest Group Response to the SAEM 

Board Position on Optimizing Care of the Stroke 

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2004;11(1):116-118. No original empirical evidence 

presented. 

Jauss M, Krieger D, Hornig C et al. Surgical and 

medical management of patients with massive 

cerebellar infarctions: results of the German-Austrian 

Cerebellar Infarction Study.[erratum appears in J 

Neurol 1999 Jul;246(7):628]. J Neurol 

1999;246(4):257-264. No intervention of interest 

studied. 

Jeffery J. Setting up a stroke club. Health Visit 

1990;63(2):56-58. No original empirical evidence 

presented. 

Jensen K, Bunemann L, Riisager S et al. Cerebral 

blood flow during anaesthesia: influence of 

pretreatment with metoprolol or captopril. Br J 

Anaesth 1989;62(3):321-323. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Jensen ME, Kallmes DF. The current status of 

endovascular stroke therapy. [Review] [14 refs]. Va 

Med Q 1998;125(2):133-137. No original empirical 

evidence presented. 

Jichici D, Frank JI. Thrombolytic therapy in 

neurointensive care. [Review] [126 refs]. Crit Care 

Clin 1997;13(1):201-227. No original empirical 

evidence presented. 

Jin L, Jin H, Zhang G et al. Changes in coagulation 

and tissue plasminogen activator after the treatment of 

cerebral infarction with lumbrokinase. Clinical 

Hemorheology & Microcirculation 2000;23(2-4):213-

218. No intervention of interest studied. 

Johansson L, Jansson JH, Boman K et al. Tissue 

plasminogen activator, plasminogen activator 

inhibitor-1, and tissue plasminogen 

activator/plasminogen activator inhibitor-1 complex as 

risk factors for the development of a first stroke. 

Stroke 2000;31(1):26-32. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Johnson S, Snelling. Comparison of out-of-hospital 

diagnosis of stroke with emergency department 

diagnosis of stroke. Acad Emerg Med 2001;8(5):489. 

No intervention of interest studied. 

Johnston KC, Connors AF J, Wagner DP et al. Risk 

adjustment effect on stroke clinical trials. Stroke 

2004;35(2):e43-e45. No intervention of interest 

studied. 

Johnston KC, Connors AF J, Wagner DP et al. 

Predicting outcome in ischemic stroke: external 

validation of predictive risk models. Stroke 

2003;34(1):200-202. No intervention of interest 

studied. 

Johnston KC, Connors AF, Wagner DP et al. A 

predictive risk model for outcomes of ischemic stroke. 

Stroke 2000;31(2):448-455. No intervention of interest 

studied. 

Johnston KC, Wagner DP, Connors AF et al. Risk 

adjustment uncovers greater treatment effects of 

NINDS tPA trial. Stroke 2003;34(1):256. No 

intervention of interest studied. 

Johnston KC, Wagner DP, Haley EC et al. Combined 

clinical and imaging information as an early stroke 

outcome measure. Stroke 2002;33(2):466-472. No 

intervention of interest studied. 

Johnston SC, Easton JD. Are patients with acutely 

recovered cerebral ischemia more unstable?[see 

comment]. Stroke 2003;34(10):2446-2450. No 

intervention of interest studied. 
123

Johnston SC, Fung LH, Gillum LA et al. Utilization of 

intravenous tissue-type plasminogen activator for 

ischemic stroke at academic medical centers: the 

influence of ethnicity.[see comment]. Stroke 

2001;32(5):1061-1068. No intervention of interest 

studied. 

Johnston SC, Leira EC, Hansen MD et al. Early 

recovery after cerebral ischemia risk of subsequent 

neurological deterioration. Ann Neurol 

2003;54(4):439-444. No intervention of interest 

studied. 

Jonas S, Tran AQ, Eisenberg E et al. Does effect of a 

neuroprotective agent on volume of experimental 

animal cerebral infarct predict effect of the agent on 

clinical outcome in human stroke? [Review] [34 refs]. 

Ann N Y Acad Sci 1997;825281-287. No original 

empirical evidence presented. 

Jordan WD J, Voellinger DC, Doblar DD et al. 

Microemboli detected by transcranial Doppler 

monitoring in patients during carotid angioplasty 

versus carotid endarterectomy. Semin Thorac 

Cardiovasc Surg 1999;7(1):33-38. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Jordan WD J, Voellinger DC, Fisher WS et al. A 

comparison of carotid angioplasty with stenting versus 

endarterectomy with regional anesthesia.[see 

comment]. Eur J Vasc Surg 1998;28(3):397-402. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Jorgensen H, Nakayama H, Raaschou HO et al. Stroke 

in patients with diabetes. The Copenhagen Stroke 

Study. Stroke 1994;25(10):1977-1984. No 

intervention of interest studied. 

Jorgensen HS, Kammersgaard LP, Nakayama H et al. 

Treatment and rehabilitation on a stroke unit improves 

5-year survival. A community-based study. Stroke 

1999;30(5):930-933. No intervention of interest 

studied. 

Jorgensen HS, Nakayama H, Raaschou HO et al. 

Acute stroke: prognosis and a prediction of the effect 

of medical treatment on outcome and health care 

utilization. The Copenhagen Stroke Study. Neurology 

1997;49(5):1335-1342. No intervention of interest 

studied. 

Jorgensen HS, Nakayama H, Reith J et al. Factors 

delaying hospital admission in acute stroke: the 

Copenhagen Stroke Study. Neurology 

1996;47(2):383-387. No intervention of interest 

studied. 

Jorgensen HS, Reith J, Nakayama H et al. Potentially 

reversible factors during the very acute phase of stroke 

and their impact on the prognosis: is there a large 

therapeutic potential to be explored? Cerebrovasc Dis 

2001;11(3):207-211. No intervention of interest 

studied. 

Kain K, Catto AJ, Carter AM et al. Decreased 

fibrinolytic potential in South Asian women with 

ischaemic cerebrovascular disease. Br J Haematol 

2001;114(1):155-161. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Kallmes DF, Kallmes MH. Cost-effectiveness of 

angiography performed during surgery for ruptured 

intracranial aneurysms. AJNR Am J Neuroradiol. 

1997;18(8):1453-1462. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Kalra L. Scoring systems for the differential diagnosis 

of ischaemic and haemorrhagic stroke. Natl Med J 

India 2003;16(1):1-3. No original empirical evidence 

presented. 

Kalra L, Evans A, Perez I et al. A randomised 

comparison of processes of care between stroke unit 

and stroke team management. Cerebrovasc Dis 

2001;11(Suppl 4):Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Kane R L, Chen Q, Finch M et al. Functional 

outcomes of posthospital care for stroke and hip 

fracture patients under medicare. J Am Geriatr Soc 

1998;46(12):1525-1533. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Kaposzta Z, Clifton A, Molloy J et al. Snitrosoglutathione reduces asymptomatic embolization 

after carotid angioplasty. Circulation 

2002;106(24):3057-3062. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Karanjia PN, Nelson JJ, Lefkowitz DS et al. 

Validation of the ACAS TIA/stroke algorithm. 

Neurology 1997;48(2):346-351. No intervention of 

interest studied. 

Kase CS, Pessin MS, Zivin JA et al. Intracranial 

hemorrhage after coronary thrombolysis with tissue 

plasminogen activator. Am J Med 1992;92(4):384-

390. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Kasner SE. Editorial comment--More than one way to 

lyse a clot.[comment]. Stroke 2004;35(4):911-912. No 

original empirical evidence presented. 

Kasner SE, Grotta JC. Emergency identification and 

treatment of acute ischemic stroke.[see comment]. 

[Review] [53 refs]. Ann Emerg Med 1997;30(5):642-

653. No original empirical evidence presented. 
124

Kasner SE, Grotta JC. Ischemic stroke. [Review] [73 

refs]. Neurol Clin 1998;16(2):355-372. No original 

empirical evidence presented. 

Kaste M. Thrombolysis in ischaemic stroke -- present 

and future: role of combined therapy. [Review] [33 

refs]. Cerebrovasc Dis 2001;11 Suppl 155-59. No 

original empirical evidence presented. 

Kaste M, Overgaard K, del Zoppo G et al. Who 

benefits and who suffers from iv recombinant tissue 

plasminogen activator (rt-PA) in ischemic hemispheric 

stroke. Subgroup analyses of ECASS. Stroke 

1996;27(1):164. No intervention of interest studied. 

Katz SG, Kohl RD. Does the choice of material 

influence early morbidity in patients undergoing 

carotid patch angioplasty? Surgery 1996;119(3):297-

301. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Katzan IL, Hammer MD, Furlan AJ et al. Quality 

improvement and tissue-type plasminogen activator 

for acute ischemic stroke: a Cleveland update. Stroke 

2003;34(3):799-800. No intervention of interest 

studied. 

Katzan I L, Graber T M, Furlan A J et al. Cuyahoga 

County Operation Stroke speed of emergency 

department evaluation and compliance with National 

Institutes of Neurological Disorders and Stroke time 

targets. Stroke 2003;34(4):994-998. No intervention of 

interest studied. 

Katzman R, Clasen R, Klatzo I et al. Report of Joint 

Committee for Stroke Resources. IV. Brain edema in 

stroke. [Review] [290 refs]. Stroke 1977;8(4):512-540. 

No human participants. 

Kawiak W, Fidor A, Grabarz B. The influence of 

glucose loading on the content of free fatty acids in 

blood of patients with cerebral infarction and with 

acute transient circulatory cerebral insufficiency. 

Annales Universitatis Mariae Curie-Sklodowska - 

Sectio d - Medicina 1992;47147-151. No intervention 

of interest studied. 

Kawiak W, Pilarczyk M, Chmielewska B et al. The 

effect of piracetam on the content of glucose in the 

blood of patients with cerebral infarction at the very 

early stage of the illness. Annales Universitatis Mariae 

Curie-Sklodowska - Sectio d - Medicina 1992;47153-

156. No intervention of interest studied. 

Kelley RE. Thrombolytic therapy for acute ischemic 

stroke. [Review] [17 refs]. J La State Med Soc 

2000;152(5):253-258. No human participants. 

Kendall MJ. Hypertension in the elderly. Basic Res 

Cardiol 1998;93 Suppl 243-46. No original empirical 

evidence presented. 

Kennedy J, Buchan AM. Acute Neurovascular 

Syndromes: Hurry Up, Please, It''s Time. Stroke 

2004;35(2):360-362. No original empirical evidence 

presented. 

Kennedy J, Buchan AM, Barnett HJ. Thrombolysis 

must be considered after stroke.[comment]. BMJ 

2001;323(7318):937. No original empirical evidence 

presented. 

Kennedy J, Ma C, Buchan AM. Organization of 

regional and local stroke resources: methods to 

expedite acute management of stroke. [Review] [65 

refs]. Current Neurology & Neuroscience Reports 

2004;4(1):13-18. No original empirical evidence 

presented. 

Kennedy M S, Ferri R S, Sofer D. tPA after stroke: the 

sooner the better: clinical benefit is gone by six hours. 

AJN, American Journal of Nursing 2004;104(6):18. 

Unable to obtain by final date for inclusion. 

Kent DM, Ruthazer R, Selker HP. Are some patients 

likely to benefit from recombinant tissue-type 

plasminogen activator for acute ischemic stroke even 

beyond 3 hours from symptom onset? Stroke 

2003;34(2):464-467. No original empirical evidence 

presented. 

Kent DMH. In acute ischemic stroke, are 

asymptomatic intracranial hemorrhages clinically 

innocuous? Stroke 2004;35(5):1141-1146. No original 

empirical evidence presented. 

Kent TA, Soukup VM, Fabian RH. Heterogeneity 

affecting outcome from acute stroke therapy: making 

reperfusion worse. [Review] [169 refs]. Stroke 

2001;32(10):2318-2327. No original empirical 

evidence presented. 

Kernan WN. Re: Evaluation of acute candesartan 

cilexetil therapy in stroke survivors.[comment]. Stroke 

2003;34(12):e237-e238. No original empirical 

evidence presented. 

Kida Y, Kobayashi T, Mori Y. Radiosurgery of 

angiographically occult vascular malformations. 

[Review] [25 refs]. Neurosurg Clin N Am 

1999;10(2):291-303. No original empirical evidence 

presented. 

Kidwell CS, Saver JL, Mattiello J et al. Thrombolytic 

reversal of acute human cerebral ischemic injury 

shown by diffusion/perfusion magnetic resonance 

imaging. Ann Neurol 2000;47(4):462-469. No 

intervention of interest studied. 

Kidwell CS, Saver JL, Mattiello J et al. Diffusionperfusion MRI characterization of post-recanalization 

hyperperfusion in humans. Neurology 

2001;57(11):2015-2021. No intervention of interest 

studied. 
125

Kidwell CS, Saver JL, Schubert GB et al. Design and 

retrospective analysis of the Los Angeles Prehospital 

Stroke Screen (LAPSS). Prehosp.Emerg Care 

1998;2(4):267-273. No intervention of interest 

studied. 

Kidwell CS, Shephard T, Tonn S et al. Establishment 

of primary stroke centers: a survey of physician 

attitudes and hospital resources. Neurology 

2003;60(9):1452-1456. No human participants. 

Kikuchi H, Yamaguchi T, Hiroshi ABE et al. 

Thrombolytic Therapy of SM-9527 (Duteplase; rt-PA) 

in Hyperacute Embolic Stroke. The clinical efficacy 

and safety of thrombolytic agent in a randomized 

double-blind study. Rinsho Hyoka (Clinical 

Evaluation) 1994;22(1):105-139. No intervention of 

interest studied. 

Kilbride C. Stroke treatment for everyone: the team 

approach. International Journal of Therapy & 

Rehabilitation 2003;10(6):246. No original empirical 

evidence presented. 

Kim S. [Scope]. [Review] [4 refs] [Japanese]. Nippon 

Rinsho - Japanese Journal of Clinical Medicine 

2004;62 Suppl 3644-647. Unable to obtain by final 

date for inclusion. 

King DF, Trouth AJ, Adams AO. Factors preventing 

African Americans from seeking early intervention in 

the treatment of ischemic strokes. J Natl Med Assoc 

2001;93(2):43-46. No intervention of interest studied. 

Kinoshita T, Okudera T, Tamura H et al. Assessment 

of lacunar hemorrhage associated with hypertensive 

stroke by echo-planar gradient-echo T2*-weighted 

MRI. Stroke 2000;31(7):1646-1650. No intervention 

of interest studied. 

Kirby RL. Rehabilitation and stroke. CMAJ Canadian 

Medical Association Journal 1999;160(6):784-785. No 

human participants. 

Kisly CA. Striking back at stroke. Hospitals 

1973;47(22):64-72. No original empirical evidence 

presented. 

Kissela B, Broderick J, Woo D et al. Greater 

Cincinnati/Northern Kentucky Stroke Study: volume 

of first-ever ischemic stroke among blacks in a 

population-based study. Stroke 2001;32(6):1285-1290. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Kjeldsen SE, Fossum E, Reims HM et al. 

Hypertension treatment and stroke prevention. Blood 

Press 2003;12(5-6):264-268. No original empirical 

evidence presented. 

Kleiman CS. Assisting the stroke patient. Dent Assist 

J 1981;50(3):22-23. No human participants. 

Klijn CJ, Hankey GJ, American Stroke et al. 

Management of acute ischaemic stroke: new 

guidelines from the American Stroke Association and 

European Stroke Initiative. [Review] [6 refs]. Lancet 

2003;2(11):698-701. No original empirical evidence 

presented. 

Knapp P, Young J, House A et al. Non-drug strategies 

to resolve psycho-social difficulties after stroke. 

[Review] [26 refs]. Age & Ageing 2000;29(1):23-30. 

No original empirical evidence presented. 

Kobayashi S, Okada K, Koide H et al. Subcortical 

silent brain infarction as a risk factor for clinical 

stroke. Stroke 1997;28(10):1932-1939. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Koennecke HC, Nohr R, Leistner S et al. Intravenous 

tPA for ischemic stroke team performance over time, 

safety, and efficacy in a single-center, 2-year 

experience. Stroke 2001;32(5):1074-1078. No 

intervention of interest studied. 

Kohara K, Igase M, Yinong J et al. Asymptomatic 

cerebrovascular damages in essential hypertension in 

the elderly. Am J Hypertens 1997;10(8):829-835. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Koller RL, Anderson DC. Intravenous thrombolytic 

therapy for acute ischemic stroke. Weighing the risks 

and benefits of tissue plasminogen activator. [Review] 

[10 refs]. Postgrad Med 1998;103(4):221-224. No 

original empirical evidence presented. 

Koops L, Lindley RI. Thrombolysis for acute 

ischaemic stroke: consumer involvement in design of 

new randomised controlled trial.[see comment]. BMJ 

2002;325(7361):415. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Koudstaal PJ, van Gijn J, Frenken CW et al. TIA, 

RIND, minor stroke: a continuum, or different 

subgroups? Dutch TIA Study Group. Journal of 

Neurology, Neurosurgery & Psychiatry 

1992;55(2):95-97. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Koutlas E, Rudolf J, Grivas G et al. Factors 

influencing the pre- and in-hospital management of 

acute stroke - Data from a Greek tertiary care hospital. 

Eur Neurol 2004;51(1):35-37. No intervention of 

interest studied. 

Krespi Y, Gurol ME, Coban O et al. Stroke unit versus 

neurology ward--a before and after study. J Neurol 

2003;250(11):1363-1369. No intervention of interest 

studied. 
126

Krieger DW, De Georgia, MA Abou-Chebl A et al. 

Cooling for acute ischemic brain damage (cool aid): 

an open pilot study of induced hypothermia in acute 

ischemic stroke. Stroke 2001;32(8):1847-1854. No 

intervention of interest studied. 

Krieger DW, Demchuk AM, Kasner SE et al. Early 

clinical and radiological predictors of fatal brain 

swelling in ischemic stroke. Stroke 1999;30(2):287-

292. No intervention of interest studied. 

Kristensen B O, Lindsten H, Malm J et al. 

[Hemicraniectomy in malignant mid-cerebral 

infarction. Further trials needed before its acceptance 

in clinical practice]. [Swedish]. Lakartidningen 3-11-

1998;95(11):1145-1148. Non-English publication. 

Krogsgaard AR, McNair A, Hilden T et al. 

Reversibility of cerebral symptoms in severe 

hypertension in relation to acute antihypertensive 

therapy. Danish Multicenter Study. Acta Med Scand 

1986;220(1):25-31. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Krueger K, Kugel H, Grond M et al. Late resolution of 

diffusion-weighted MRI changes in a patient with 

prolonged reversible ischemic neurological deficit 

after thrombolytic therapy. Stroke 2000;31(11):2715-

2718. No intervention of interest studied. 

Kunnel B, Heller M. Thrombolytics and stroke: what 

do emergency medicine residents perceive? Acad 

Emerg Med 1999;6(11):1174-1176. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Kupersmith MJ, Vargas ME, Yashar A et al. Occipital 

arteriovenous malformations: visual disturbances and 

presentation.[see comment]. Neurology 

1996;46(4):953-957. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Kuramoto K, Matsushita S, Kuwajima I. The 

pathogenetic role and treatment of elderly 

hypertension. Jpn Circ J 1981;45(7):833-843. No 

original empirical evidence presented. 

Kwan J, Hand P, Sandercock P. A systematic review 

of barries to delivery of thrombolysis for acute stroke. 

Age & Ageing 2004;33(2):116-121. No original 

empirical evidence presented. 

Kwan J, Sandercock P. In-hospital care pathways for 

stroke: A cochrane systematic review. Stroke 

2003;34(2):587-588. No original empirical evidence 

presented. 

Kwan J, Hand P, Sandercock P. Improving the 

efficiency of delivery of thrombolysis for acute stroke: 

a systematic review. [Review] [39 refs]. QJM 

2004;97( 5):273-279. Unable to obtain by final date 

for inclusion. 

Kwiatkowski TG, Libman RB, Frankel M et al. 

Effects of tissue plasminogen activator for acute 

ischemic stroke at one year. National Institute of 

Neurological Disorders and Stroke Recombinant 

Tissue Plasminogen Activator Stroke Study 

Group.[see comment]. N Engl J Med 

1999;340(23):1781-1787. No intervention of interest 

studied. 

Labiche LA, Al Senani F, Wojner AW et al. Is the 

benefit of early recanalization sustained at 3 months? 

A prospective cohort study. Stroke 2003;34(3):695-

698. No intervention of interest studied. 

LaCombe DM, Gordon DL, Issenberg SB et al. Stroke 

on the mend.[see comment]. J Emerg Med Serv JEMS 

2000;25(10):32-41. No original empirical evidence 

presented. 

Laloux P. [Medical treatment for cerebral 

atherothrombosis]. [Review] [27 refs] [French]. J 

Pharm Belg 2004;59( 1):35-37. Unable to obtain by 

final date for inclusion. 

LaMonte MP, Bahouth MN, Hu P et al. Telemedicine 

for acute stroke: triumphs and pitfalls. Stroke 

2003;34(3):725-728. No intervention of interest 

studied. 

Landahl S, Lernfelt B. Cardiac function and cerebral 

blood flow in elderly hypertensive patients. Nephron 

1990;55 Suppl 198. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Lang W, Domanovits H, Gorzer H et al. Thrombolysis 

in acute ischemic stroke. Acta Anaesthesiol Scand 

1997;Supplementum. 11134-37. No original empirical 

evidence presented. 

Langhorne P. Editorial comment--Early supported 

discharge: an idea whose time has come?[comment]. 

Stroke 2003;34(11):2691-2692. No original empirical 

evidence presented. 

Langhorne P. Developing comprehensive stroke 

services: an evidence-based approach. Postgrad Med J 

1995;71(842):733-737. No human participants. 

Langhorne P, Cadilhac D, Feigin V et al. How should 

stroke services be organised? [Review] [45 refs]. 

Lancet 2002;1(1):62-68. No original empirical 

evidence presented. 

Langhorne P, Dennis MS. Stroke units: the next 10 

years. Lancet 2004;363(9412):834-835. No original 

empirical evidence presented. 

Langhorne P, Pollock A. What are the components of 

effective stroke unit care? Age & Ageing 

2002;31(5):365-371. No original empirical evidence 

presented. 
127

Langhorne P, Tong BL, Stott DJ. Association between 

physiological homeostasis and early recovery after 

stroke. Stroke 2000;31(10):2518-2519. No original 

empirical evidence presented. 

Langhorne P, Williams BO, Gilchrist W et al. A 

formal overview of stroke unit trials. Rev Neurol 

1995;23(120):394-398. No original empirical evidence 

presented. 

Langhorne P, Williams BO, Gilchrist W et al. Do 

stroke units save lives?[see comment]. Lancet 

1993;342(8868):395-398. No original empirical 

evidence presented. 

Lansberg MG, Tong DC, Norbash AM et al. Intraarterial rtPA treatment of stroke assessed by diffusionand perfusion-weighted MRI. Stroke 1999;30(3):678-

680. No intervention of interest studied. 

Lapchak PA. Development of thrombolytic therapy 

for stroke: a perspective. [Review] [72 refs]. Expert 

Opin Investig Drugs 2002;11(11):1623-1632. No 

original empirical evidence presented. 

Lapchak PA, Araujo DM. Development of the nitronebased spin trap agent NXY-059 to treat acute ischemic 

stroke. [Review] [59 refs]. CNS Drug Rev 

2003;9(3):253-262. No human participants. 

Larkin M. Heart association urges passage of US 

stroke legislation. Lancet Neurology 2004;3( 5):260. 

Unable to obtain by final date for inclusion. 

Larrue V, von Kummer R, del Zoppo G et al. 

Hemorrhagic transformation in acute ischemic stroke. 

Potential contributing factors in the European 

Cooperative Acute Stroke Study. Stroke 

1997;28(5):957-960. No original empirical evidence 

presented. 

Launois R, Giroud M, Megnigbeto AC et al. 

Estimating the cost-effectiveness of stroke units in 

France compared with conventional care. Stroke 

2004;35(3):770-775. No intervention of interest 

studied. 

Lavine SD, Masri LS, Levy ML et al. Temporary 

occlusion of the middle cerebral artery in intracranial 

aneurysm surgery: time limitation and advantage of 

brain protection. J Neurosurg 1997;87(6):817-824. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Le Roux, PD Newell, DW Lam et al. Cerebral 

arteriovenous oxygen difference: a predictor of 

cerebral infarction and outcome in patients with severe 

head injury.[see comment]. J Neurosurg 1997;87(1):1-

8. Study did not involve relevant population [defined 

as adult (>16) with acute stroke]. 

Leary MC, Saver JL, Gobin YP et al. Beyond tissue 

plasminogen activator: mechanical intervention in 

acute stroke. [Review] [32 refs]. Ann Emerg Med 

2003;41(6):838-846. No original empirical evidence 

presented. 

Lee K. Aneurysm precautions: a physiologic basis for 

minimizing rebleeding. Heart & Lung: Journal of 

Acute & Critical Care 1980;9(2):336-343. No human 

participants. 

Lee KH, Cho SJ, Byun HS et al. Triphasic perfusion 

computed tomography in acute middle cerebral artery 

stroke: a correlation with angiographic findings. Arch 

Neurol 2000;57(7):990-999. No intervention of 

interest studied. 

Lee SH, Bae HJ, Yoon BW et al. Low concentration 

of serum total cholesterol is associated with multifocal 

signal loss lesions on gradient-echo magnetic 

resonance imaging: analysis of risk factors for 

multifocal signal loss lesions. Stroke 

2002;33(12):2845-2849. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Lee TM, Ho DS, Chan CC. Preliminary 

neuropsychological outcomes of angioplasty and 

stenting of extracranial cerebral arteries. Perceptual & 

Motor Skills 1999;88(1):267-270. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Leeman M, Naeije R, Degaute JP et al. Acute central 

and renal haemodynamic responses to tertatolol and 

propranolol in patients with arterial hypertension 

following head injury. J Hypertens 1986;4(5):581-587. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Lees KR. Therapeutic interventions in acute stroke. 

[Review] [92 refs]. Br J Clin Pharmacol 

1992;34(6):486-493. No original empirical evidence 

presented. 

Lees KR, Dyker AG. Blood pressure control after 

acute stroke. [Review] [22 refs]. Journal of 

Hypertension - Supplement 1996;14(6):S35-S38. No 

original empirical evidence presented. 

Lees KR, Dyker AG, Dykes AG. Diagnosis and 

therapeutic aspects of stroke.[erratum appears in Neth 

J Med 1996 Mar;48(3):123 Note: Dykes AG[corrected 

to Dyker AG]]. [Review] [22 refs]. Neth J Med 

1995;47(4):195-198. No original empirical evidence 

presented. 

Lehmann A, Van Gelder, NM. Introducing Professor 

Anders C. Hamberger: A man of all seasons. 

Neurochem Res 2003;28(2):171-172. No human 

participants. 
128

Lemieux-Charles L, McGuire W, Blidner I. Building 

interorganizational knowledge for evidence-based 

health system change.[see comment]. Health Care 

Manage Rev 2002;27(3):48-59. No human 

participants. 

Lenzer J. Controversial stroke trial is under review 

following BMJ report.[comment]. BMJ 

2002;325(7373):1131. No original empirical evidence 

presented. 

Lenzer J. Alteplase for stroke: money and optimistic 

claims buttress the "brain attack" campaign.[see 

comment]. [Review] [54 refs]. BMJ 

2002;324(7339):723-729. No original empirical 

evidence presented. 

Lenzi GL, Argentino C. SPREADing the stroke units? 

PROSIT!. Shinkei Kenkyu No Shimpo 2004;25(1). No 

original empirical evidence presented. 

Leonard AD, Brey RL. Patient page. Blood pressure 

control and stroke: an ounce of prevention is worth a 

pound of cure.[original report in Neurology. 2002 Jul 

9;59(1):23-5; PMID: 12105296]. Neurology 

2002;59(1):E1-E2. No human participants. 

Lepore MR J, Sternbergh WC, Salartash K et al. 

Influence of NASCET/ACAS trial eligibility on 

outcome after carotid endarterectomy. Eur J Vasc Surg 

2001;34(4):581-586. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Levi C R, Australasian Stroke, Unit Network et al. 

Tissue plasminogen activator (tPA) in acute ischaemic 

stroke: time for collegiate communication and 

consensus. Med J Aust 6-21-2004;180( 12):634-636. 

Unable to obtain by final date for inclusion. 

Levine SR, Brott TG. Thrombolytic therapy in 

cerebrovascular disorders. [Review] [231 refs]. Prog 

Cardiovasc Dis 1992;34(4):235-262. No original 

empirical evidence presented. 

Levine SR, Gorman M. "Telestroke" : the application 

of telemedicine for stroke. [Review] [74 refs]. Stroke 

1999;30(2):464-469. No original empirical evidence 

presented. 

Levy DE, Brott TG, Haley EC J et al. Factors related 

to intracranial hematoma formation in patients 

receiving tissue-type plasminogen activator for acute 

ischemic stroke. Stroke 1994;25(2):291-297. No 

intervention of interest studied. 

Lewin A, Blaufox MD, Castle H et al. Apparent 

prevalence of curable hypertension in the 

Hypertension Detection and Follow-up Program. Arch 

Intern Med 1985;145(3):424-427. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Leys D, Kwiecinski H, Bogousslavsky J et al. 

Prevention. European Stroke Initiative. Cerebrovasc 

Dis 2004;17 Suppl 215-29. No original empirical 

evidence presented. 

Liapis CD, Kakisis JD, Kostakis AG. Carotid stenosis: 

factors affecting symptomatology.[see comment]. 

Stroke 2001;32(12):2782-2786. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Libman RB, Wirkowski E, Alvir J et al. Conditions 

that mimic stroke in the emergency department. 

Implications for acute stroke trials.[see comment]. 

Arch Neurol 1995;52(11):1119-1122. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Liebson P R. VISP and INVEST. Prev Cardiol 

2004;7( 2):93-96. Unable to obtain by final date for 

inclusion. 

Lin TCC. Impact of the high-risk and mass strategies 

on hypertension control and stroke mortality in 

primary health care. J Hum Hypertens 2004;18(2):97-

105. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Lin CS, Tsai J, Woo P et al. Prehospital delay and 

emergency department management of ischemic 

stroke patients in Taiwan, R.O.C. Prehosp Emerg Care 

1999; 3(3):194-200. 

Lindley RI. Further randomized controlled trials of 

tissue plasminogen activator within 3 hours are 

required. Stroke 2001;32(11):2708-2709. No original 

empirical evidence presented. 

Lindley RI. Drug therapy for acute ischaemic stroke: 

risks versus benefits. [Review] [40 refs]. Drug Saf 

1998;19(5):373-382. No original empirical evidence 

presented. 

Lindsberg PJ, Kaste M. Thrombolysis for acute stroke. 

[Review] [41 refs]. Curr Opin Neurol 2003;16(1):73-

80. No original empirical evidence presented. 

Lindsberg PJ, Soinne L, Roine RO et al. Communitybased thrombolytic therapy of acute ischemic stroke in 

Helsinki. Stroke 2003;34(6):1443-1449. No 

intervention of interest studied. 

Linfante I, Hirsch JA, Selim M et al. Safety of LatestGeneration Self-expanding Stents in Patients with 

NASCET-Ineligible Severe Symptomatic Extracranial 

Internal Carotid Artery Stenosis. Arch Neurol 

2004;61(1):39-43. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 
129

Linfante I, Llinas RH, Selim M et al. Clinical and 

vascular outcome in internal carotid artery versus 

middle cerebral artery occlusions after intravenous 

tissue plasminogen activator. Stroke 2002;33(8):2066-

2071. No intervention of interest studied. 

Link J, Manke C, Rosin L et al. [Carotid 

endarterectomy and carotid stenting. A pilot study of a 

prospective, randomized and controlled comparison]. 

[German]. Radiologe 2000;40(9):813-820. NonEnglish publication. 

Lip GY, Beevers DG. ACE inhibitors in vascular 

disease: some PROGRESS, more HOPE. [Review] 

[10 refs]. J Hum Hypertens 2001;15(12):833-835. No 

original empirical evidence presented. 

Lisboa RC, Jovanovic BD, Alberts MJ. Analysis of 

the safety and efficacy of intra-arterial thrombolytic 

therapy in ischemic stroke. Stroke 2002;33(12):2866-

2871. No original empirical evidence presented. 

Lisk DR, Grotta JC, Lamki LM et al. Should 

hypertension be treated after acute stroke? A 

randomized controlled trial using single photon 

emission computed tomography. Arch Neurol 

1993;50(8):855-862. No intervention of interest 

studied. 

Liu L, Gong L, Guang WJ et al. Blood pressure 

lowering in patients with cerebrovascular disease: 

results of the randomized Post-stroke 

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Cardiol 1998;31(Suppl 2A):211AStudy did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Liu L, Wang JG, Celis H et al. Implications of the 

Systolic Hypertension in China trial. [Review] [10 

refs]. Clinical & Experimental Hypertension (New 

York) 1999;21(5-6):499-505. No original empirical 

evidence presented. 

Liu M, Wardlaw J. Thrombolysis (different doses, 

routes of administration and agents) for acute 

ischaemic stroke. [Review] [11 refs]. Cochrane 

Database Syst Rev 2000;(2):CD000514. No original 

empirical evidence presented. 

Liu B Y, Li X Q, Chen C H. [Effects of nao-yi-an on 

tumor necrosis factor alpha and insulin resistance of 

acute intracerebral hemorrhagic patients]. [Chinese]. 

Hunan Yi Ke Da Xue Xue Bao 2-28-2002;27(1):41-

42. Non-English publication. 

Livingston S. NSF for older people: (4) Stroke. Can 

Pharm J 2003;270(7256):19-21. No original empirical 

evidence presented. 

Livingston S. NSF for older people: (1) What does the 

NSF for older people mean for pharmacy practice? 

Can Pharm J 2003;270(7253):830-832. No original 

empirical evidence presented. 

Longstreth WT, Tirschwell DL. The next 30 years of 

stroke for patients, providers, planners, and politicians. 

Stroke 2003;34(9):2113No human participants. 

Lorencowicz R, Zderkiewicz E. [Problems of patient 

care after surgical treatment for intracranial aneurysm 

with regard to independent living at home]. [Polish]. 

Pol Merkuriusz Lek 1997;2(10):247-249. Non-English 

publication. 

Losito A, Gaburri M, Errico R et al. Survival of 

patients with renovascular disease and ACE inhibition. 

Clin Nephrol 1999;52(6):339-343. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Loulidi J, Sztajzel R. [Cerebrovascular accident: a 

medical emergency]. [Review] [26 refs] [French]. Rev 

Med Suisse Romande 2003;123( 1):5-9. Unable to 

obtain by final date for inclusion. 

Lu S R, Liao Y C, Fuh J L et al. Nimodipine for 

treatment of primary thunderclap headache. Neurology 

4-27-2004;62( 8):1414-1416. Unable to obtain by final 

date for inclusion. 

Luders S, Effenberger K, Venneklaas U et al. 

ACCESS-study: acute candesartan cilexetil evaluation 

in stroke survivors. Dtsch Med Wochenschr 

1999;124(Suppl 3):S119. No intervention of interest 

studied. 

Luepker RV, Rastam L, Hannan PJ et al. Community 

education for cardiovascular disease prevention. 

Morbidity and mortality results from the Minnesota 

Heart Health Program. Am J Epidemiol 

1996;144(4):351-362. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Luisi A, Hume AL. Thrombolysis in acute ischemic 

stroke.[see comment]. [Review] [20 refs]. J Am Board 

Fam Pract 1998;11(2):145-151. No original empirical 

evidence presented. 

Lyden P. Lingual angioedema, ACE inhibitors, and 

tPA: Commentary. Neurology 2003;60(9):1403Unable 

to obtain by final date for inclusion. 

Lyden P. Pilot study of tenecteplase (TNK) in acute 

ischaemic stroke: preliminary report. Stroke 

2003;34(1):246. No intervention of interest studied. 

Lyden P, the CLASS, IHT Investigators. Combined 

clomethiazole and tPA for acute stroke in TACS 

patients - CLASS-T functional outcome results. Stroke 

2000;31(11):2864No intervention of interest studied. 

Lyden P, the CLASS, IHT Investigators. Effect of 

combined clomethiazole and tPA for acute stroke on 

CT outcomes: edema, hemorrhage and hematoma 
130

volume in CLASS-T. Stroke 2000;31(11):2886-2887. 

No intervention of interest studied. 

Lyden P, Lu M, Jackson C et al. Underlying structure 

of the National Institutes of Health Stroke Scale: 

results of a factor analysis. NINDS tPA Stroke Trial 

Investigators. Stroke 1999;30(11):2347-2354. No 

intervention of interest studied. 

Lyden P, Lu M, Kwiatkowski T et al. Thrombolysis in 

patients with transient neurologic deficits. Neurology 

2001;57(11):2125-2128. No intervention of interest 

studied. 

Lyden P, Shuaib A, Ng K et al. Clomethiazole Acute 

Stroke Study in ischemic stroke (CLASS-I): final 

results.[see comment]. Stroke 2002;33(1):122-128. No 

intervention of interest studied. 

Lyden PD. Further randomized controlled trials of tPA 

within 3 hours are required-not!. Stroke 

2001;32(11):2709-2710. No original empirical 

evidence presented. 

Lyden PD, the CLASS, IHT Investigators. Safety and 

efficacy of combined clomethiazole and tPA for acute 

stroke - CLASS-T: a pilot study. Neurology 

2000;54(Suppl 3). No intervention of interest studied. 

Mackenzie AF, Colvin Kenny, GN Bisset et al. Closed 

loop control of arterial hypertension following 

intracranial surgery using sodium nitroprusside. A 

comparison of intra-operative halothane or isoflurane. 

Anaesthesia 1993;48(3):202-204. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Macko RF, Kittner SJ, Ivey FM et al. Effects of 

vitamin therapy on plasma total homocysteine, 

endothelial injury markers, and fibrinolysis in stroke 

patients. Journal of Stroke & Cerebrovascular 

Diseases 2002;11(1):1-8. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

MacMahon S. Will ACE inhibitor therapy reduce 

secondary stroke? Cardiovascular Journal of Southern 

Africa 2000;12(1):53-54. No original empirical 

evidence presented. 

Madden K. Optimal timing of thrombolytic therapy in 

acute ischaemic stroke.[see comment]. [Review] [26 

refs]. CNS Drugs 2002;16(4):213-218. No original 

empirical evidence presented. 

Madhavan R, Chaturvedi S. Transient ischaemic 

attacks : new approaches to management. [Review] 

[54 refs]. CNS Drugs 2003;17(5):293-305. No original 

empirical evidence presented. 

Madhavan R, Jacobs BS, Levine SR. Stroke trials: 

what have we learned? [Review] [24 refs]. Neurol Res 

2002;24 Suppl 1S27-S32. No original empirical 

evidence presented. 

Mahaffey KW, Harrington RA, Simoons ML et al. 

Stroke in patients with acute coronary syndromes: 

incidence and outcomes in the platelet glycoprotein 

IIb/IIIa in unstable angina. Receptor suppression using 

integrilin therapy (PURSUIT) trial. The PURSUIT 

Investigators. Circulation 1999;99(18):2371-2377. No 

intervention of interest studied. 

Mahla K, Rizk T, Fischer C et al. [Intracranial 

cavernoma. Surgical results of 47 cases]. [French]. 

Neurochirurgie 1999;45(4):286-292. Non-English 

publication. 

Mahon BR, Nesbit GM, Barnwell SL et al. North 

American clinical experience with the EKOS 

MicroLysUS infusion catheter for the treatment of 

embolic stroke. AJNR Am J Neuroradiol 

2003;24(3):534-538. No original empirical evidence 

presented. 

Mancia G, Brown M, Castaigne A et al. Outcomes 

with nifedipine GITS or Co-amilozide in hypertensive 

diabetics and nondiabetics in Intervention as a Goal in 

Hypertension (INSIGHT).[see comment]. 

Hypertension 2003;41(3):431-436. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Manelfe C, Larrue V, von Kummer R et al. 

Association of hyperdense middle cerebral artery sign 

with clinical outcome in patients treated with tissue 

plasminogen activator. Stroke 1999;30(4):769-772. No 

intervention of interest studied. 

Mann H. Thrombolysis for acute ischaemic stroke. 

Trial participants need to be informed of uncertainty 

principle.[comment]. BMJ 2002;325(7376):1363. No 

original empirical evidence presented. 

Mann J. Truths about the NINDS study: setting the 

record straight. West J Med 2002;176(3):192-194. No 

original empirical evidence presented. 

Manor DE, Richardson LD, Shen. Assessing urban 

community knowledge of acute stroke: results with a 

culturally sensitive instrument. Acad Emerg Med 

2003;10(5):490-491. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Mant J, Carter J, Wade DT et al. The impact of an 

information pack on patients with stroke and their 

carers: a randomized controlled trial. Clin Rehabil 

1998;12(6):465-476. No intervention of interest 

studied. 

Manzella SM, Galante K. Establishment of stroke 

treatment plans: one hospital''s experience. J Neurosci 

Nurs 2000;32(6):306-310. No original empirical 

evidence presented. 
131

Marder VJ, Stewart D. Towards safer thrombolytic 

therapy. [Review] [106 refs]. Semin Hematol 

2002;39(3):206-216. No original empirical evidence 

presented. 

Mariak Z A. [In Process Citation]. Neurol Neurochir 

Pol 2004;38(1):51-54. Non-English publication. 

Marks MP, Holmgren EB, Fox AJ et al. Evaluation of 

early computed tomographic findings in acute 

ischemic stroke. Stroke 1999;30(2):389-392. No 

intervention of interest studied. 

Marks MP, Tong DC, Beaulieu C et al. Evaluation of 

early reperfusion and i.v. tPA therapy using diffusionand perfusion-weighted MRI.[see comment]. 

Neurology 1999;52(9):1792-1798. No intervention of 

interest studied. 

Markus HS, Clifton A, Buckenham T et al. 

Improvement in cerebral hemodynamics after carotid 

angioplasty. Stroke 1996;27(4):612-616. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Marler Brott T, Haley EC, Levy D. Evaluation of 

tissue plasminogen activator early in the course of 

acute ischemic stroke. Thrombolytic Therapy in Acute 

Ischemic Stroke Berlin : Springer-Verlag 1991;1st ed. 

152-160p. No intervention of interest studied. 

Marler Goldstein, LB. Medicine. Stroke--tPA and the 

clinic. Science 2003;301(5640):1677. No original 

empirical evidence presented. 

Marshall RS, Rundek T, Sproule DM et al. Monitoring 

of cerebral vasodilatory capacity with transcranial 

Doppler carbon dioxide inhalation in patients with 

severe carotid artery disease. Stroke 2003;34(4):945-

949. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Martin BJ, Yip B, Hearty M et al. Outcome, functional 

recovery and unmet needs following acute stroke. 

Experience of patient follow up at 6 to 9 months in a 

newly established stroke service. Scott Med J 

2002;47(6):136-137. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Martin JB, Pache JC, Treggiari-Venzi M et al. Role of 

the distal balloon protection technique in the 

prevention of cerebral embolic events during carotid 

stent placement. Stroke 2001;32(2):479-484. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Martin JF, Hamdy N, Nicholl J et al. Double-blind 

controlled trial of prostacyclin in cerebral infarction. 

Stroke 1985;16(3):386-390. No intervention of interest 

studied. 

Masten Y, Gary A. Is anyone listening? Does anyone 

care? Menopausal and postmenopausal health risks, 

outcomes, and care. [Review] [20 refs]. Nurse Pract 

Forum 1999;10(4):195-200. No human participants. 

Matias-Guiu J, Molto JM, Galiano L et al. Pilot double 

blind placebo controlled trial of nicardipine versus 

placebo for cognitive impairment in minor stroke 

patients. J Neurol 1992;239(Suppl 2):39. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Matsumoto M. [Cerebrovascular disease: Impact of 

INDANA meta-analysis and PROGRESS trial]. 

[Review] [18 refs] [Japanese]. Nippon Rinsho - 

Japanese Journal of Clinical Medicine 2004;62 Suppl 

3605-611. Unable to obtain by final date for inclusion. 

Matthews PM. Finding Landmarks for Understanding 

White Matter Stroke. Stroke 2004;35(1):92-93. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Maxwell MH, Ford CE. Cardiovascular morbidity and 

mortality in HDFP patients 50-69 years old at entry. J 

Cardiovasc Pharmacol 1985;7 Suppl 2S5-S9. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Maze L M, Bakas T. Factors associated with hospital 

arrival time for stroke patients. J Neurosci Nurs 6-20-

0155;36( 3):136-141. Unable to obtain by final date 

for inclusion. 

Mazouz H, Makdassi R, Tribouilloy C et al. Risk 

reduction for stroke and coronary events.[comment]. 

Lancet 2002;359(9313):1249-1250. No original 

empirical evidence presented. 

Mc GR, Rudd A. Management of stroke. [Review] [58 

refs]. Postgrad Med J 2003;79(928):87-92. No original 

empirical evidence presented. 

McAlister FA. Primary prevention of heart disease and 

stroke.[comment]. CMAJ Canadian Medical 

Association Journal 1998;158(1):24-25. No human 

participants. 

McAlister FA, Zarnke KB, Campbell NR et al. The 

2001 Canadian recommendations for the management 

of hypertension: Part two--Therapy. Can J Cardiol 

2002;18(6):625-641. No original empirical evidence 

presented. 

McCormack J, Rangno R, Wright JM. Thiazides firstline treatment for hypertension. Can Fam Physician 

2003;49(JULY):879No original empirical evidence 

presented. 
132

McDonald PS, Mayer P, Dunn L. Adult/elderly care 

nursing. National Service Framework for Older 

People: stroke coordinators. Br J Nurs 

2002;11(19):1259-1261. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

McKernan MG. One-stop shopping: A CT protocol for 

imaging of acute stroke. Appl Radiol 2003;32(6 

SUPPL.):18-23. No original empirical evidence 

presented. 

McNair A, Krogsgaard AR, Hilden T et al. Severe 

hypertension with cerebral symptoms treated with 

furosemide, fractionated diazoxide or dihydralazine. 

Danish Multicenter Study. Acta Med Scand 

1986;220(1):15-23. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

McNair A, Krogsgaard AR, Hilden T et al. 

Reversibility of cerebral symptoms in severe 

hypertension in relation to acute antihypertensive 

therapy. Danish Multicenter study. Acta Medica 

Scandinavica - Supplementum 1985;693107-110. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

McNaughton H, McPherson K, Taylor W et al. 

Relationship between process and outcome in stroke 

care. Stroke 2003;34(3):713-717. No intervention of 

interest studied. 

McPherson K M, Kersten P. Knowledge and action in 

stroke--are either good enough? Qual Saf Health Care 

2004;13( 3):166-167. Unable to obtain by final date 

for inclusion. 

Medicare initiates public education re stroke (MAPS). 

J Med Assoc Ga 1997;86(3):171. No original 

empirical evidence presented. 

Mehler PS, Coll Estacio R, Esler A et al. Intensive 

blood pressure control reduces the risk of 

cardiovascular events in patients with peripheral 

arterial disease and type 2 diabetes. Circulation 

2003;107(5):753-756. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Menapace RH, Lana RE. Physical rehabilitation and 

attitudes of CVA and pulmonary patients. Psychol Rep 

1971;28(3):763-768. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Mendelow AD, Investigators the, Steering Committee. 

The International Surgical Trial in Intracerebral 

Haemorrhage (ISTICH). Acta Neurochir Suppl 

2003;86441-443. No intervention of interest studied. 

Mendelow AD, Teasdale GM, Barer D et al. Outcome 

assignment in the International Surgical Trial of 

Intracerebral Haemorrhage. [Review] [10 refs]. Acta 

Neurochir (Wien) 2003;145(8):679-681. No human 

participants. 

Mendis S. Workshop on secondary prevention of 

myocardial infarction and stroke and management of 

cardiovascular risk. Anadolu Kardiyol Derg 

2003;3(4):366-367. No original empirical evidence 

presented. 

Meredith P. Do pharmacologic differences among 

antihypertensive agents point to clinical benefits? 

[Review] [22 refs]. Am J Cardiol 1999;84(10A):22S27S. No original empirical evidence presented. 

Merino JG, Silver B, Wong E et al. Physician 

knowledge of the benefits, risks, and contraindications 

of tissue plasminogen activator for acute ischemic 

stroke. Stroke 2001;32(9):2208-2209. No original 

empirical evidence presented. 

Merino JG, Silver B, Wong E et al. Extending tissue 

plasminogen activator use to community and rural 

stroke patients. Stroke 2002;33(1):141-146. No 

intervention of interest studied. 

Meschia JF, Brott TG. New insights on thrombolytic 

treatment of acute ischemic stroke. [Review] [36 refs]. 

Current Neurology & Neuroscience Reports 

2001;1(1):19-25. No original empirical evidence 

presented. 

Mesotten D, Van den, BG. Clinical potential of insulin 

therapy in critically ill patients. [Review] [86 refs]. 

Drugs 2003;63(7):625-636. No human participants. 

Messe SR, Tanne D, Demchuk AM et al. Dosing 

Errors May Impact the Risk of rt-PA for Stroke: The 

Multicenter rt-PA Acute Stroke Survey. Journal of 

Stroke & Cerebrovascular Diseases 2004;13(1):35-40. 

No intervention of interest studied. 

Messerli FH. The LIFE study: the straw that should 

break the camel’s back. Eur Heart J 2003;24(6):487-

489. No original empirical evidence presented. 

Messerli FH, Jacoby DS, Rader DJ. Vascular 

Protection of ACE Inhibitors [6] (multiple letters). 

Arch Intern Med 2003;163(22):2791-2793. No 

original empirical evidence presented. 

Meyer JS, Eadie GA, Ericsson AD et al. A pilot study 

of antihypertensive therapy in cerebrovascular disease. 

J Am Geriatr Soc 1967;15(4):313-321. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Meyer JS, Rauch GM. Why emergency XeCT-CBF 

should become routine in acute ischemic stroke before 

thrombolytic therapy. Keio J Med 2000;49 Suppl 

1A25-A28. No original empirical evidence presented. 
133

Mickey RM, Goodwin GD. The magnitude and 

variability of design effects for community 

intervention studies. Am J Epidemiol 1993;137(1):9-

18. Study did not involve relevant population [defined 

as adult (>16) with acute stroke]. 

Miller JE. Knowledge of stroke risk factors, 

symptoms, and treatment among New Jersey adults. N 

J Med 2001;98(7):47-53. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Miller PR, Fabian TC, Croce MA et al. Prospective 

screening for blunt cerebrovascular injuries: analysis 

of diagnostic modalities and outcomes. Ann Surg 

2002;236(3):386-393. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Miller RM, Woo D. Stroke: current concepts of care. 

[Review] [8 refs]. Geriatr Nurs (Minneap) 

1999;20(2):66-69. No original empirical evidence 

presented. 

Minchin A, Wensley M. The medical nurse 

practitioner''s role in early stroke recognition. Nurs 

Times 2003;99(7):33-35. No original empirical 

evidence presented. 

Miranda LS, Turkel RA, Ahmed O et al. 

Anticoagulation for stroke prevention in a Medicare 

population with atrial fibrillation. J Fla Med Assoc 

1997;84(4):227-231. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Mitchell. Does aspirin prevent stroke? Br J Gen Pract 

1979;223(1337):668-672. No original empirical 

evidence presented. 

Mitka M. Efforts needed to foster participation of 

blacks in stroke studies. JAMA 2004;291(11):1311-

1312. No original empirical evidence presented. 

Mitka M. Tensions Remain over tPA for Stroke. J Am 

Med Assoc 2003;289(11):1363-1364. No human 

participants. 

Miyazawa N, Toyama K, Arbab AS et al. Evaluation 

of crossed cerebellar diaschisis in 30 patients with 

major cerebral artery occlusion by means of 

quantitative I-123 IMP SPECT. Ann Nucl Med 

2001;15(6):513-519. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Mohr JP. Thrombolytic therapy for ischemic stroke: 

from clinical trials to clinical practice.[comment]. 

JAMA 2000;283(9):1189-1191. No original empirical 

evidence presented. 

Molina CA, Alexandrov AV, Demchuk AM et al. 

Improving the predictive accuracy of recanalization on 

stroke outcome in patients treated with tissue 

plasminogen activator.[see comment]. Stroke 

2004;35(1):151-156. No intervention of interest 

studied. 

Molina CA, Alvarez-Sabin J, Montaner J et al. 

Thrombolysis-related hemorrhagic infarction: a 

marker of early reperfusion, reduced infarct size, and 

improved outcome in patients with proximal middle 

cerebral artery occlusion.[see comment]. Stroke 

2002;33(6):1551-1556. No intervention of interest 

studied. 

Molina CA, Montaner J, Abilleira S et al. Time course 

of tissue plasminogen activator-induced recanalization 

in acute cardioembolic stroke: a case-control study. 

Stroke 2001;32(12):2821-2827. No intervention of 

interest studied. 

Molina CA, Montaner J, Arenillas JF et al. 

Differential pattern of tissue plasminogen activatorinduced proximal middle cerebral artery recanalization 

among stroke subtypes. Stroke 2004;35(2):486-490. 

No intervention of interest studied. 

Moloney A, Critchlow B, Jones K. A multidisciplinary care pathway in stroke - does it improve 

care? (abstract). Age & Ageing 1999;28(Suppl 1):42. 

No intervention of interest studied. 

Monitoring your blood pressure. Postgrad Med 

1999;105(5):209-210. No original empirical evidence 

presented. 

Monger C, Carr JH, Fowler V. Evaluation of a homebased exercise and training programme to improve sitto-stand in patients with chronic stroke. Clin Rehabil 

2002;16(4):361-367. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Montaner J, Fernandez-Cadenas I, Molina CA et al. 

Safety profile of tissue plasminogen activator 

treatment among stroke patients carrying a common 

polymorphism (C-1562T) in the promoter region of 

the matrix metalloproteinase-9 gene. Stroke 

2003;34(12):2851-2855. No intervention of interest 

studied. 

Montaner J, Molina CA, Monasterio J et al. Matrix 

metalloproteinase-9 pretreatment level predicts 

intracranial hemorrhagic complications after 

thrombolysis in human stroke. Circulation 

2003;107(4):598-603. No intervention of interest 

studied. 

Montaner J, Vidal C, Molina C et al. Selecting the 

target and the message for a stroke public education 

campaign: a local survey conducted by neurologists. 

Eur J Epidemiol 2001;17(6):581-586. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 
134

Moonis M. Imaging in acute ischemic stroke : 

relevance to management. Neurol India 2002;50 

SupplS30-S36. No original empirical evidence 

presented. 

Moore LW, Maiocco G, Schmidt SM et al. Research 

for practice. Perspectives of caregivers of stroke 

survivors: implications for nursing. Medsurg Nurs 

2002;11(6):289-295. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Mori E, Lajolla CA, Yoneda Y et al. Double-blind, 

placebo-controlled trial of recombinant tissue 

plasminogen activator (rt-PA) in acute stroke. 

Neurology 1991;41(Suppl.1):347. No intervention of 

interest studied. 

Mori E, Yoneda Y, Tabuchi M et al. Intravenous 

recombinant tissue plasminogen activator in acute 

carotid artery territory stroke.[see comment]. 

Neurology 1992;42(5):976-982. No intervention of 

interest studied. 

Morris DC, Silver B, Mitsias P et al. Treatment of 

acute stroke with recombinant tissue plasminogen 

activator and abciximab. Acad Emerg Med 

2003;10(12):1396-1399. No intervention of interest 

studied. 

Morris DL, Rosamond W, Madden K et al. Prehospital 

and emergency department delays after acute stroke: 

the Genentech Stroke Presentation Survey. Stroke 

2000;31(11):2585-2590. No intervention of interest 

studied. 

Morris DL, Shah SM, Huff JS. Future trends. 

[Review] [38 refs]. Emerg Med Clin North Am 

2002;20(3):717-729. No original empirical evidence 

presented. 

Morrison VL, Johnston M, MacWalter RS et al. 

Improving emotional outcomes following acute 

stroke: a preliminary evaluation of work-book based 

intervention. Scott Med J 1998;43(2):52-53. No 

intervention of interest studied. 

Mosca L. Cardiology patient page. Heart disease 

prevention in women. American Heart Association. 

Circulation 3-16-2004;109( 10):e158-e160. Unable to 

obtain by final date for inclusion. 

Moser M. No surprises in blood pressure awareness 

study findings: We can do a better job. Arch Intern 

Med 2003;163(6):654-656. No original empirical 

evidence presented. 

Mountz JM, Liu HG, Deutsch G. Neuroimaging in 

cerebrovascular disorders: measurement of cerebral 

physiology after stroke and assessment of stroke 

recovery. [Review] [46 refs]. Semin Nucl Med 

2003;33(1):56-76. No original empirical evidence 

presented. 

MRC trial of treatment of mild hypertension: principal 

results. Medical Research Council Working Party.[see 

comment]. British Medical Journal Clinical Research 

Ed 1985;291(6488):97-104. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Muir KW, Lees KR. Initial experience with 

remacemide hydrochloride in patients with acute 

ischemic stroke. Ann N Y Acad Sci 1995;765322-323. 

No intervention of interest studied. 

Muir KW, Lees KR, Ford I et al. Magnesium for acute 

stroke (Intravenous Magnesium Efficacy in Stroke 

trial): randomised controlled trial.[see comment]. 

Lancet Neurol 2004;363(9407):439-445. No 

intervention of interest studied. 

Murphy J. Pharmacological treatment of acute 

ischemic stroke. [Review] [33 refs]. Crit Care Nurs Q 

2003;26(4):276-282. No original empirical evidence 

presented. 

Murphy N, Kazek MP, Van Vleymen B et al. 

Economic evaluation of Nootropil in the treatment of 

acute stroke in France. Pharmacol Res 

1997;36(5):373-380. No intervention of interest 

studied. 

Murray K. Put a stop to stroke. Nurs Stand Spec Suppl 

2002;16(36):13-28. No original empirical evidence 

presented. 

Myco F. Stroke patients. A new way of living. Nurs 

Times 1986;82(14):24-27. No original empirical 

evidence presented. 

Nabavi DG, Droste DW, Kemeny V et al. Potential 

and limitations of echocontrast-enhanced 

ultrasonography in acute stroke patients: a pilot 

study.[see comment]. Stroke 1998;29(5):949-954. No 

intervention of interest studied. 

Nabavi DG, Kloska SP, Nam EM et al. MOSAIC: 

Multimodal Stroke Assessment Using Computed 

Tomography: novel diagnostic approach for the 

prediction of infarction size and clinical outcome. 

Stroke 2002;33(12):2819-2826. No intervention of 

interest studied. 

Nagai M, Onaka U, Abe I et al. Comparison of the 

efficacy of nilvadipine and terazosin in elderly 

hypertensive patients with stroke. J Hypertens 

1994;12(Suppl 3):87. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Naidech A, Khasani S, Lafaye K et al. Chart review 

and pilot study of blood pressure control in acute 

ischemic stroke. J La State Med Soc 2003;155(2):99-

102. No intervention of interest studied. 
135

Naish J. One pill fits all. Nurs Stand Spec Suppl 

2002;17(50):17-Sep. No original empirical evidence 

presented. 

Nakano S, Iseda T, Kawano H et al. Parenchymal 

hyperdensity on computed tomography after intraarterial reperfusion therapy for acute middle cerebral 

artery occlusion: incidence and clinical significance. 

Stroke 2001;32(9):2042-2048. No intervention of 

interest studied. 

Naylor AR, Bolia A, Abbott RJ et al. Randomized 

study of carotid angioplasty and stenting versus 

carotid endarterectomy: a stopped trial.[see comment]. 

Eur J Vasc Surg 1998;28(2):326-334. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Naylor AR, Sandercock PA, Sellar RJ et al. Patterns of 

vascular pathology in acute, first-ever cerebral 

infarction. Scott Med J 1993;38(2):41-44. No 

intervention of interest studied. 

Nazarian SM, Sanders PL, Thomas SL. Stroke 

education by utility bill inserts. J Ark Med Soc 

2001;98(5):150-152. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Nazir FS, Overell Bolster. The effect of losartan on 

global and focal cerebral perfusion and on renal 

function in hypertensives in mild early ischaemic 

stroke. J Hypertens 2004;22(5):989-995. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Nazir FS, Overell Hilditch, TE Less et al. The effect 

of losartan on global and focal cerebral perfusion and 

renal function in hypertensives in early ischaemic 

stroke. Cerebrovasc Dis 2003;16(suppl 4):31. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Neal B, Anderson C, Chalmers J et al. Blood pressure 

lowering in patients with cerebrovascular disease: 

results of the PROGRESS (Perindopril Protection 

Against Recurrent Stroke Study) pilot phase. Clinical 

& Experimental Pharmacology & Physiology 

1996;23(5):444-446. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Neal B, MacMahon S. An overview of 37 randomised 

trials of blood pressure lowering agents among 

270,000 individuals. World Health OrganizationInternational Society of Hypertension Blood Pressure 

Lowering Treatment Trialists'' Collaboration. Clinical 

& Experimental Hypertension (New York) 1999;21(5-

6):517-529. No original empirical evidence presented. 

Neal B, MacMahon S. PROGRESS (perindopril 

protection against recurrent stroke study): rationale 

and design. PROGRESS Management Committee 

[corrected][erratum appears in J Hypertens 1996 

Apr;14(4):535]. J Hypertens 1995;13(12 Pt 2):1869-

1873. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Nedeltchev K, Arnold M, Brekenfeld C et al. Pre- and 

in-hospital delays from stroke onset to intra-arterial 

thrombolysis. Stroke 2003;34(5):1230-1234. No 

intervention of interest studied. 

Nedeltchev K, Mattle HP. Diabetes and stroke. 

Cerebrovasc Dis 2003;15(SUPPL. 2):25-30. No 

original empirical evidence presented. 

Neilson GH, Seldon WA. Propranolol in angina 

pectoris. Med J Aust 1969;1(17):856-857. Study did 

not involve relevant population [defined as adult (>16) 

with acute stroke]. 

Nesbit GM, Clark WM, O''Neill OR et al. Intracranial 

intraarterial thrombolysis facilitated by microcatheter 

navigation through an occluded cervical internal 

carotid artery. J Neurosurg 1996;84(3):387-392. No 

original empirical evidence presented. 

Newcommon N. TPA in acute ischemic stroke. A 

Calgary experience. Axone 2000;21(4):73-75. No 

human participants. 

Newell SD J, Englert J, Box-Taylor A et al. Clinical 

efficiency tools improve stroke management in a rural 

southern health system. Stroke 1998;29(6):1092-1098. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Ng PP, Higashida RT, Cullen SP et al. Intraarterial 

thrombolysis trials in acute ischemic stroke. Journal of 

Vascular & Interventional Radiology 2004;15(1 Pt 

2):S77-S85. No original empirical evidence presented. 

Nicol MF. Barriers to effective stroke care out of 

hours need to be broached.[comment]. BMJ 

2002;325(7364):596No human participants. 

Nighoghossian N, Berthezene Y, Meyer R et al. 

Assessment of cerebrovascular reactivity by dynamic 

susceptibility contrast-enhanced MR imaging. J 

Neurol Sci 1997;149(2):171-176. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Nighoghossian N, Hermier M, Adeleine P et al. 

Baseline magnetic resonance imaging parameters and 

stroke outcome in patients treated by intravenous 

tissue plasminogen activator. Stroke 2003;34(2):458-

463. No intervention of interest studied. 

Nighoghossian N, Hermier M, Berthezene Y et al. 

Early diagnosis of hemorrhagic transformation: 

diffusion/perfusion-weighted MRI versus CT scan. 

Cerebrovasc Dis 2001;11(3):151-156. No intervention 

of interest studied. 
136

Nolan S, Naylor G, Burns M. Code Gray -- an 

organized approach to inpatient stroke. Crit Care Nurs 

Q 2003;26(4):296-302. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Nomura H, Morita C, Kuwano S et al. Efficacy of 

combination antiplatelet therapy and nicardipine for 

chronic cerebral infarction. Clin Ther 1996;18(3):483-

490. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Norris JS, Valiante TA, Wallace MC et al. A simple 

relationship between radiological arteriovenous 

malformation hemodynamics and clinical 

presentation: a prospective, blinded analysis of 31 

cases. J Neurosurg 1999;90(4):673-679. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Norris JW, Buchan A, Cote R et al. Canadian 

guidelines for intravenous thrombolytic treatment in 

acute stroke. A consensus statement of the Canadian 

Stroke Consortium. Can J Neurol Sci 1998;25(3):257-

259. No original empirical evidence presented. 

No stroke center? Give tPA in ER. Senior Care 

Management 2003;6(3):37-40. No original empirical 

evidence presented. 

not found, in reference. [Therapy of hypertension. 

Lasting organ protection moves into the foreground]. 

[German]. MMW Fortschr Med 11-20-2003;145( 

47):62Unable to obtain by final date for inclusion. 

not found, in reference. Sentara’s neuroscience 

network. Health Care Strateg Manage 2004;22( 

6):18Unable to obtain by final date for inclusion. 

Nowak G, Schwachenwald D, Schwachenwald R et al. 

Intracerebral hematomas caused by aneurysm rupture. 

Experience with 67 cases. Neurosurg Rev 

1998;21(1):5-9. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

O'Connell JE, Gray CS. Treatment of post-stroke 

hypertension. A practical guide. [Review] [50 refs]. 

Drugs Aging 1996;8(6):408-415. No original 

empirical evidence presented. 

O'Farrell B, Evans D. The continuum of care: the 

process and development of a nursing model for stroke 

education. Axone 1998;20(1):16-18. No original 

empirical evidence presented. 

O'Mahony PG, Rodgers H, Thomson RG et al. 

Satisfaction with information and advice received by 

stroke patients. Clin Rehabil 1997;11(1):68-72. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

O'Neal TB, Landry B, Chehardy P et al. Update on 

American Heart Association education and 

information initiatives. J La State Med Soc 

1997;149(5):172-174. No original empirical evidence 

presented. 

O'Rourke M. Accurate measurement of arterial 

pressure. J Hum Hypertens 2003;17(7):445-447. No 

human participants. 

O'Very DI. Stroke=brain attack. Ochsner Journal 

2003;5(1):58. No original empirical evidence 

presented. 

Ogasawara K, Noda A, Yasuda S et al. Effect of 

calcium antagonist on cerebral blood flow and oxygen 

metabolism in patients with hypertension and chronic 

major cerebral artery occlusion: a positron emission 

tomography study. Nucl Med Commun 

2003;24(1):71-76. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Ogasawara K, Ogawa A, Doi M et al. Prediction of 

acute embolic stroke outcome after local intraarterial 

thrombolysis: value of pretreatment and posttreatment 

99mTc-ethyl cysteinate dimer single photon emission 

computed tomography. Journal of Cerebral Blood 

Flow & Metabolism 2000;20(11):1579-1586. No 

intervention of interest studied. 

Ogasawara K, Ogawa A, Konno H et al. Combination 

of early and delayed SPET imaging using technetium99m ethyl cysteinate dimer immediately after local 

intra-arterial thrombolysis. Eur J Nucl Med 

2001;28(4):498-505. No intervention of interest 

studied. 

Ogilvy CS, Stieg PE, Awad I et al. AHA Scientific 

Statement: Recommendations for the management of 

intracranial arteriovenous malformations: a statement 

for healthcare professionals from a special writing 

group of the Stroke Council, American Stroke 

Association. Stroke 2001;32(6):1458-1471. No 

original empirical evidence presented. 

Ogungbo B. Stroke website and world stroke mailing 

list. QJM 2003;96(1):81-82. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Ohta H, Nakano S, Yokogami K et al. Appearance of 

early venous filling during intra-arterial reperfusion 

therapy for acute middle cerebral artery occlusion: a 

predictive sign for hemorrhagic complications. Stroke 

2004;35(4):893-898. No intervention of interest 

studied. 

Ohtani R, Kazui S, Tomimoto H et al. Clinical and 

radiographic features of lobar cerebral hemorrhage: 

hypertensive versus non-hypertensive cases. Adv 

Intern Med 2003;42(7):576-580. No intervention of 

interest studied. 
137

Okwumabua JO, Martin B, Clayton-Davis J et al. 

Stroke Belt initiative: the Tennessee experience. 

Journal of Health Care for the Poor & Underserved 

1997;8(3):292-299. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Oliver MF. Sounding board. Risks of correcting the 

risks of coronary disease and stroke with drugs. N 

Engl J Med 1982;306(5):297-298. No human 

participants. 

Oosterga M, Voors AA, Pinto YM et al. Effects of 

quinapril on clinical outcome after coronary artery 

bypass grafting (The QUO VADIS Study). QUinapril 

on Vascular Ace and Determinants of Ischemia. Am J 

Cardiol 2001;87(5):542-546. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Opinion and evidence in neurology and psychiatry. 

CNS Drugs 2003;17(4):285-291. No original 

empirical evidence presented. 

Optimal criteria for care of patients with stroke. 

JAMA 1973;226(2):164-168. No original empirical 

evidence presented. 

Oradei DM, Waite NS. Group psychotherapy with 

stroke patients during the immediate recovery phase. 

Am J Orthopsychiatry 1974;44(3):386-395. Study did 

not involve relevant population [defined as adult (>16) 

with acute stroke]. 

Organised inpatient (stroke unit) care for stroke. 

Stroke Unit Trialists'' Collaboration.[update in 

Cochrane Database Syst Rev. 2002;(1):CD000197; 

PMID: 11869570]. [Review] [33 refs]. Cochrane 

Database Syst Rev 2000;(2):CD000197. No original 

empirical evidence presented. 

Osaki Y, Matsubayashi K, Yamasaki M et al. Poststroke hypertension correlates with neurologic 

recovery in patients with acute ischemic stroke. 

Hypertension Research - Clinical & Experimental 

1998;21(3):169-173. No intervention of interest 

studied. 

Ozeren A, Acarturk E, Koc F et al. Silent cerebral 

lesions on magnetic resonance imaging in subjects 

with coronary artery disease. Jpn Heart J 

1998;39(5):611-618. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Padma MV, Gaikwad S, Jain S et al. Distribution of 

vascular lesions in ischaemic stroke: a magnetic 

resonance angiographic study. Natl Med J India 

1997;10(5):217-220. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Page for patients. Hormone replacement therapy. Prev 

Med 2001;32(4):311-312. No human participants. 

Pancioli AM, Broderick J, Kothari R et al. Public 

perception of stroke warning signs and knowledge of 

potential risk factors.[see comment]. JAMA 

1998;279(16):1288-1292. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Panella M, Marchisio S, Di Stanislao F. Reducing 

clinical variations with clinical pathways: Do 

pathways work? Int J Qual Health Care 

2003;15(6):509-521. No intervention of interest 

studied. 

Paoni NF, Steinmetz HG, Gillett N et al. An 

experimental model of intracranial hemorrhage during 

thrombolytic therapy with t-PA. Thrombosis & 

Haemostasis 1996;75(5):820-826. No human 

participants. 

Parahoo K, Thompson K, Cooper M et al. Stroke: 

awareness of the signs, symptoms and risk factors--a 

population-based survey. Cerebrovasc Dis 

2003;16(2):134-140. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Parmar MS. Preventing stroke with ramipril. 

Presentation of data is misleading.[comment]. BMJ 

2002;325(7361):439. No original empirical evidence 

presented. 

Parsons MW, Barber PA, Chalk J et al. Diffusion- and 

perfusion-weighted MRI response to thrombolysis in 

stroke.[see comment]. Ann Neurol 2002;51(1):28-37. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Parsons MW, Barber PA, Desmond PM et al. Acute 

hyperglycemia adversely affects stroke outcome: a 

magnetic resonance imaging and spectroscopy 

study.[see comment]. Ann Neurol 2002;52(1):20-28. 

No intervention of interest studied. 

Parving HH. Diabetic hypertensive patients. Is this a 

group in need of particular care and attention? 

[Review] [27 refs]. Diabetes Care 1999;22 Suppl 

2B76-B79. No original empirical evidence presented. 

Pasquarello MA. Measuring the impact of an acute 

stroke program on patient outcomes. J Neurosci Nurs 

1990;22(2):76-82. No intervention of interest studied. 

Pasquarello MA. Developing, implementing, and 

evaluating a stroke recovery group. Rehabil Nurs 

1990;15(1):26-29. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Passero S, Filosomi G. Posterior circulation infarcts in 

patients with vertebrobasilar dolichoectasia. Stroke 

1998;29(3):653-659. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 
138

Pearson RM, Griffith DN, Woollard M et al. 

Comparison of effects on cerebral blood flow of rapid 

reduction in systemic arterial pressure by diazoxide 

and labetalol in hypertensive patients: preliminary 

findings. Br J Clin Pharmacol 1979;8(Suppl 2):195S198S. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Pelz DM. Advances in interventional neuroradiology. 

Stroke 2003;34(2):357-358. No original empirical 

evidence presented. 

Penney JB, Hahn JL. Stroke and heart attack 

prevention education. Medsurg Nurs 1994;3(6):459-

464. No intervention of interest studied. 

Pepe PE, Zachariah BS, Sayre MR et al. Ensuring the 

chain of recovery for stroke in your community. Chain 

of Recovery Writing Group. [Review] [19 refs]. 

Prehosp Emerg Care 1998;2(2):89-95. No original 

empirical evidence presented. 

Pepe PE, Zachariah BS, Sayre MR et al. Ensuring the 

chain of recovery for stroke in your community. Acad 

Emerg Med 1998;5(4):352-358. No original empirical 

evidence presented. 

Pereira AC, Martin PJ, Warburton EA. Thrombolysis 

in acute ischaemic stroke. [Review] [62 refs]. Postgrad 

Med J 2001;77(905):166-171. No original empirical 

evidence presented. 

Perkin GD. New approach to treatment of recent 

stroke? BMJ 1979;1(6173):1283. No original 

empirical evidence presented. 

Perren F, Bogousslavsky J. Hypertension and lowering 

blood pressure. Cerebrovasc Dis 2003;15(SUPPL. 

2):19-23. No original empirical evidence presented. 

Perry HM J, Davis BR, Price TR et al. Effect of 

treating isolated systolic hypertension on the risk of 

developing various types and subtypes of stroke: the 

Systolic Hypertension in the Elderly Program (SHEP). 

JAMA 2000;284(4):465-471. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Pessina AC, Pigato R, Palu CD. Clinical experiences 

with methyldopa. Clinical & Experimental 

Pharmacology & Physiology - Supplement 1978;451-

54. Study did not involve relevant population [defined 

as adult (>16) with acute stroke]. 

Pettersen J A, Hudon M E, Hill M D. Intra-arterial 

thrombolysis in acute ischemic stroke: a review of 

pharmacologic approaches. [Review] [107 refs]. 

Expert Review of Cardiovascular Therapy 2004;2( 

2):285-299. Unable to obtain by final date for 

inclusion. 

Phatouros CC, Sasaki TY, Higashida RT et al. Stentsupported coil embolization: the treatment of fusiform 

and wide-neck aneurysms and pseudoaneurysms. 

Neurosurgery 2000;47(1):107-113. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Phelps MA, Rodriguez RM, Passanante M et al. EMS 

activation in a cohort of critically ill patients. Am J 

Emerg Med 2002;22(2):127-131. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Phillips SJ, Eskes GA, Gubitz GJ et al. Description 

and evaluation of an acute stroke unit.[see comment]. 

CMAJ Canadian Medical Association Journal 

2002;167(6):655-660. No original empirical evidence 

presented. 

Piepgras A, Roth H, Schurer L et al. Rapid active 

internal core cooling for induction of moderate 

hypothermia in head injury by use of an extracorporeal 

heat exchanger. Neurosurgery 1998;42(2):311-317. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Pierce LL, Gordon M, Steiner V. Families dealing 

with stroke desire information about self-care needs. 

Rehabil Nurs 2004;29(1):14-17. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Pikus HJ, Heros RC. Stroke: indications for emergent 

surgical intervention. [Review] [122 refs]. Clin 

Neurosurg 1999;45113-127. No original empirical 

evidence presented. 

Pillekamp F, Grune M, Brinker G et al. Magnetic 

resonance prediction of outcome after thrombolytic 

treatment. Magn Reson Imaging 2001;19(2):143-152. 

No human participants. 

Pittock SJ, Meldrum D, Hardiman O et al. Patient and 

hospital delays in acute ischaemic stroke in a Dublin 

teaching hospital.[see comment]. Ir Med J 

2003;96(6):167-168. No intervention of interest 

studied. 

Pittock SJ, Meldrum D, Hardiman O et al. The 

Oxfordshire Community Stroke Project Classification: 

Correlation with imaging, associated complications, 

and prediction of outcome in acute ischemic stroke. 

Journal of Stroke & Cerebrovascular Diseases 

2003;12(1):1-7. No intervention of interest studied. 

Pollman PJ. A 29-year-old soldier with heat stroke. J 

Emerg Nurs 2001;27(2):119-123. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 
139

Popa C, Lugoji G, Popescu A et al. Calcium blockers 

in ischemic stroke. Romanian Journal of Neurology & 

Psychiatry 1992;30(3):189-196. No intervention of 

interest studied. 

Popa G, Voiculescu V, Popa C et al. Stroke and 

hypertension. Antihypertensive therapy withdrawal. 

Romanian Journal of Neurology & Psychiatry 

1995;33(1):29-35. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Porteous GH, Corry MD, Smith WS. Emergency 

medical services dispatcher identification of stroke 

and transient ischemic attack. Prehosp Emerg Care 

1999;3(3):211-216. No intervention of interest 

studied. 

Post-stroke antihypertensive treatment study. A 

preliminary result. PATS Collaborating Group. Chin 

Med J 1995;108(9):710-717. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Poulias GE, Skoutas B, Doundoulakis N et al. Kinking 

and coiling of internal carotid artery with and without 

associated stenosis. Surgical considerations and longterm follow-up. Panminerva Med 1996;38(1):22-27. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Pound P, Sabin C, Ebrahim S. Observing the process 

of care: a stroke unit, elderly care unit and general 

medical ward compared. Age & Ageing 

1999;28(5):433-440. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Powers WJ. 10 Most commonly asked questions about 

carotid artery occlusion. Proc Aust Assoc Neurol 

2003;9(3):167-169. No original empirical evidence 

presented. 

Prabhakar S, Das CP. Ischaemic stroke: new frontiers. 

[Review] [59 refs]. Neurol India 1999;47(3):168-177. 

No original empirical evidence presented. 

Pranesh MB, Dinesh NS, Mathew V et al. 

Hemicraniectomy for large middle cerebral artery 

territory infarction: outcome in 19 patients.[see 

comment]. J Neurol Neurosurg Psychiatry 

2003;74(6):800-802. No intervention of interest 

studied. 

Prevention, education programs head off high cost of 

stroke. Healthc Demand Dis Manag 1998;4(6):85-91. 

No original empirical evidence presented. 

Prinsley DM. Effects of industrial action by the 

ambulance service on day hospital patients. BMJ 

1971;3(767):170-171. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Progress and stroke--it''s time to translate evidence 

into action. Cardiovascular Journal of Southern Africa 

2002;13(5):267-Oct. No original empirical evidence 

presented. 

PROGRESS - Perindopril Protection Against 

Recurrent Stroke Study: characteristics of the study 

population at baseline. Progress Management 

Committee. J Hypertens 1999;17(11):1647-1655. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Protocol for prospective collaborative overviews of 

major randomized trials of blood-pressure-lowering 

treatments. World Health Organization-International 

Society of Hypertension Blood Pressure Lowering 

Treatment Trialists'' Collaboration.[see comment]. J 

Hypertens 1998;16(2):127-137. No original empirical 

evidence presented. 

Psaty BM, Lumley T, Furberg CD et al. Health 

outcomes associated with various antihypertensive 

therapies used as first-line agents: a network metaanalysis.[see comment]. JAMA 2003;289(19):2534-

2544. No original empirical evidence presented. 

Puca A. Thrombolysis in cerebral ischemia. A review 

of clinical and experimental data. [Review] [65 refs]. J 

Neurosurg Sci 1993;37(2):63-70. No original 

empirical evidence presented. 

Puranen J, Laakso M, Riekkinen PJ S et al. Efficacy of 

antiplatelet treatment in hypertensive patients with 

TIA or stroke. J Cardiovasc Pharmacol 

1998;32(2):291-294. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Qiu Y, Lin Y, Tian X et al. Hypertensive intracranial 

hematomas: Endoscopic-assisted keyhole evacuation 

and application of patent viewing dissector. Chin Med 

J 2003;116(2):195-199. Unable to obtain by final date 

for inclusion. 

Quaglini S, Caffi E, Cavallini A et al. Simulation of a 

stroke unit careflow. Medinfo 2001;10(Pt 2):1190-

1191. No intervention of interest studied. 

Qureshi AI, Bliwise DL, Bliwise NG et al. Rate of 24-

hour blood pressure decline and mortality after 

spontaneous intracerebral hemorrhage: a retrospective 

analysis with a random effects regression model.[see 

comment]. Crit Care Med 1999;27(3):480-485. No 

intervention of interest studied. 

Qureshi AI, Siddiqui AM, Kim SH et al. Reocclusion 

of recanalized arteries during intra-arterial 

thrombolysis for acute ischemic stroke. Ajnr: 

American Journal of Neuroradiology 2004;25(2):322-

328. No intervention of interest studied. 
140

Rabinov J, Schwamm L, Putman C et al. Imageguided vascular recanalization in acute stroke. 

[Review] [47 refs]. Semin Roentgenol 

2002;37(3):237-248. No original empirical evidence 

presented. 

Ramrakha S, Giles A. Take a letter ... an audit of GP 

referrals in south west Sydney. Aust Fam Physician 

2001;30(4):395-398. No intervention of interest 

studied. 

Rapp K, Bratina P, Barch C et al. Code Stroke: rapid 

transport, triage and treatment using rt-PA therapy. 

The NINDS rt-PA Stroke Study Group. [Review] [10 

refs]. J Neurosci Nurs 1997;29(6):361-366. No 

original empirical evidence presented. 

Rasool AHG, Rahman ARA, Choudhury SR et al. 

Blood pressure in acute intracerebral haemorrhage. J 

Hum Hypertens 2004;18(3):187-192. No original 

empirical evidence presented. 

Rasool A H, Rahman A R, Choudhury S R et al. 

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192. Unable to obtain by final date for inclusion. 

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Drugs Aging 2003;20(4):241-251. No original 

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with acute stroke]. 

Redman AR, Ryan GJ. Aggrenox versus other 

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Rees J, Wilcox Cuddihy, RA. Psychology in 

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Br J Clin Pharmacol 1993;35(4):341-342. No original 

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Reker DM, Hoenig H, Zolkewitz MA et al. The 

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Reports from the American College of Cardiology 

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evidence presented. 

Report of the Joint Committee for Stroke Facilities. II. 

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original empirical evidence presented. 

Report of the joint committee for stroke facilities. IX. 

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presented. 

Report of The Joint Committee For Stroke Facilities. 

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Archives of Gerontology & Geriatrics 1998;27(Suppl 

6):17-22. Study did not involve relevant population 

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Richardson BK. Overview of geriatric emergencies. 

Mt Sinai J Med 2003;70(2):75-84. No original 

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not involve relevant population [defined as adult (>16) 

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Richardson-Nassif K, Swartz R, Reardon M. 

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involve relevant population [defined as adult (>16) 

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Richter RW, Bengen B, Bruun B et al. The Harlem 

regional stroke program: an overview. Archives of 

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141

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not involve relevant population [defined as adult (>16) 

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Riggs JE. Tissue-type plasminogen activator should 

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presented. 

Riggs JE. Tissue-type plasminogen activator should 

not be used in acute ischemic stroke. Arch Neurol 

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for inclusion. 

Riggs JE. Cost-effectiveness of tissue plasminogen 

activator for acute ischemic stroke. Neurology 

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presented. 

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population [defined as adult (>16) with acute stroke]. 

Rincon FMS. Novel therapies for intracerebral 

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No original empirical evidence presented. 

Ringel SP, Hughes RL. Evidence-based medicine, 

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empirical evidence presented. 

Robins M, Weinfeld FD. The National Survey of 

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presented. 

Robinson L. Ischemic strokes arriving too late for tPA 

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presented. 

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Robinson T G, Potter J F. Blood pressure in acute 

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1):6-12. Unable to obtain by final date for inclusion. 

Rocca WA, Dorsey FC, Grigoletto F et al. Design and 

baseline results of the monosialoganglioside early 

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1992;23(4):519-526. No intervention of interest 

studied. 

Roccella EJ. Meeting the 1990 hypertension 

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Health Rep 1985;100(6):652-656. No original 

empirical evidence presented. 

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pressure and risk of stroke in patients with 

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Transient Ischaemic Attack Collaborative Group. BMJ 

1996;313(7050):147Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Rodgers H, Atkinson C, Bond S et al. Randomized 

controlled trial of a comprehensive stroke education 

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studied. 

Rodgers H, Bond S, Curless R. Inadequacies in the 

provision of information to stroke patients and their 

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evidence presented. 

Rodgers H, Dennis M, Cohen D et al. British 

Association of Stroke Physicians: benchmarking 

survey of stroke services. Age & Ageing 

2003;32(2):211-217. No human participants. 

Rohde V, Rohde I, Thiex R et al. Fibrinolysis therapy 

achieved with tissue plasminogen activator and 

aspiration of the liquefied clot after experimental 

intracerebral hemorrhage: rapid reduction in 

hematoma volume but intensification of delayed 

edema formation. J Neurosurg 2002;97(4):954-962. 

No human participants. 

Rohde V, Schaller C, Hassler WE. Intraventricular 

recombinant tissue plasminogen activator for lysis of 

intraventricular haemorrhage. Journal of Neurology, 

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Study did not involve relevant population [defined as 

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142

Ronning OM, Guldvog B. Stroke unit versus general 

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Stroke 1998;29(3):586-590. No intervention of interest 

studied. 

Ronning OM, Guldvog B. Stroke units versus general 

medical wards, I: twelve- and eighteen-month 

survival: a randomized, controlled trial. Stroke 

1998;29(1):58-62. No intervention of interest studied. 

Ronning OM, Guldvog B, Stavem K. The benefit of 

an acute stroke unit in patients with intracranial 

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Rook AR. Acetylcholine-induced cardiac arrest during 

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involve relevant population [defined as adult (>16) 

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Roquer J, Lorenzo JL, Pou A. The anterior inferior 

cerebellar artery infarcts: a clinical-magnetic 

resonance imaging study. Acta Neurol Scand 

1998;97(4):225-230. No intervention of interest 

studied. 

Rosa G, Pinto G, Orsi P et al. Control of post 

anaesthetic shivering with nefopam hydrochloride in 

mildly hypothermic patients after neurosurgery. Acta 

Anaesthesiol Scand 1995;39(1):90-95. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Rosenbaum D, Zabramski J, Frey J et al. Early 

treatment of ischemic stroke with a calcium 

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intervention of interest studied. 

Rosenthal SG, Pituch MJ, Greninger LO et al. 

Perceived needs of wives of stroke patients. Rehabil 

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relevant population [defined as adult (>16) with acute 

stroke]. 

Rosenwasser RH. Re: Safety of intraventricular 

sodium nitroprusside and thiosulfate for the treatment 

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original empirical evidence presented. 

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serious adverse events in hypertensive patients 

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empirical evidence presented. 

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Thromb Res 2001;103 Suppl 1S125-S133. No original 

empirical evidence presented. 

Rother J. Imaging-guided extension of the time 

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empirical evidence presented. 

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intravenous thrombolysis on MRI parameters and 

functional outcome in acute stroke <6 hours. Stroke 

2002;33(10):2438-2445. No intervention of interest 

studied. 

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stroke and TIA: the need for high-quality, large-scale 

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original empirical evidence presented. 

Rothwell PM, Howard SC, Spence JD et al. 

Relationship between blood pressure and stroke risk in 

patients with symptomatic carotid occlusive 

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Rowe AK, Frankel MR, Sanders KA. Stroke 

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population [defined as adult (>16) with acute stroke]. 

Ruland S, Gorelick PB, Schneck M et al. Acute stroke 

care in Illinois: a statewide assessment of diagnostic 

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2002;33(5):1334-1339. No intervention of interest 

studied. 

Ruland S, Raman R, Chaturvedi S et al. Awareness, 

treatment, and control of vascular risk factors in 

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Ryan M, Rhoney DH, Luer MS et al. New and 

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presented. 

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Expanded modes of tissue plasminogen activator 

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Rx for stroke: aspirin, within 48 hours. Heart Advis 

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143

Sacco RL. Preventing Stroke among Blacks: The 

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Ann Neurol 1989;25(4):382-390. No intervention of 

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Sacco S, Marini C, Carolei A. Medical treatment of 

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Sae-Sia W. Chinese elderly patients'' perceptions of 

their rehabilitation needs following a 

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original empirical evidence presented. 

Saito Y. Angiographic findings of vertebral basilar 

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76. Study did not involve relevant population [defined 

as adult (>16) with acute stroke]. 

Salazar J, Vaquero J, Martinez P et al. Clinical and CT 

scan assessment of benign versus fatal spontaneous 

cerebellar haematomas. Acta Neurochir (Wien) 

1986;79(2-4):80-86. No human participants. 

Samama M. Haemorrhagic aspects of thrombolytic 

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Samuelsson O, Wilhelmsen L, Elmfeldt D et al. 

Predictors of cardiovascular morbidity in treated 

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Sandercock P. Managing stroke: the way forward.[see 

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original empirical evidence presented. 

Sanders KA, Frankel MR. Stroke care and prevention 

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Ga 2001;90(1):29-31. No original empirical evidence 

presented. 

Sansing LH, Kaznatcheeva EA, Perkins CJ et al. 

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interest studied. 

Sareen D. Current concepts in the management of 

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Saunders FW, Marshall WJ. Diltiazem: dose it affect 

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did not involve relevant population [defined as adult 

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Saver JL. Coping with an embarrassment of riches. 

How stroke centers may participate in multiple, 

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1995;26(7):1289-1292. No original empirical evidence 

presented. 

Saver JL, Kalafut M. Combination therapies and the 

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[Review] [53 refs]. Neuroepidemiology 

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Saver JLK. Prehospital neuroprotective therapy for 

acute stroke: results of the Field Administration of 

Stroke Therapy-Magnesium (FAST-MAG) pilot trial. 

Stroke 2004;35(5):e106-e108. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Saxena R, Wijnhoud AD, Carton H et al. Controlled 

safety study of a hemoglobin-based oxygen carrier, 

DCLHb, in acute ischemic stroke.[see comment]. 

Stroke 1999;30(5):993-996. No intervention of interest 

studied. 

Sbarigia E, Toni D, Speziale F et al. Emergency and 

early carotid endarterectomy in patients with acute 

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prospective pilot study. Int Angiol 2003;22(4):426-

430. No intervention of interest studied. 

Schaefer E, Hacke W, Fieschi C et al. ECASS-II: a 

placebo controlled trial of alteplase (rt-PA) in acute 

ischemic hemispheric stroke where thrombolysis is 

initiated up to 6 hours following the onset of 

symptoms. Cerebrovasc Dis 1996;6(suppl 2):74No 

intervention of interest studied. 

Schellinger PD, Fiebach JB, Hacke W. Imaging-based 

decision making in thrombolytic therapy for ischemic 

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refs]. Stroke 2003;34(2):575-583. No original 

empirical evidence presented. 

Schellinger PD, Fiebach JB, Mohr A et al. 

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Part II--Intra-arterial thrombolysis, vertebrobasilar 

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[83 refs]. Crit Care Med 2001;29(9):1819-1825. No 

original empirical evidence presented. 

Schellinger PD, Fiebach JB, Mohr A et al. 

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empirical evidence presented. 
144

Schenkel J, Weimar C, Knoll T et al. R1--systemic 

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studied. 

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population [defined as adult (>16) with acute stroke]. 

Schmidt SM, Guo L, Scheer SJ. Changes in the status 

of hospitalized stroke patients since inception of the 

prospective payment system in 1983. Archives of 

Physical Medicine & Rehabilitation 2002;83(7):894-

898. No intervention of interest studied. 

Schmulling S, Grond M, Rudolf J et al. One-year 

follow-Up in acute stroke patients treated with rtPA in 

clinical routine. Stroke 2000;31(7):1552-1554. No 

intervention of interest studied. 

Schneider AT, Pancioli AM, Khoury JC et al. Trends 

in community knowledge of the warning signs and 

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Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Schoser BG, Becker VU, Eckert B et al. Clinical and 

ultrasonic long-term results of percutaneous 

transluminal carotid angioplasty. A prospective 

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1998;8(1):38-41. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Schrader J. Early antihypertensive therapy cuts risk 

after stroke. Medscape (neurology 2001;Unable to 

obtain by final date for inclusion. 

Schrader J. Acute Candesartan Cilexetil Evaluation in 

Stroke Survivors (ACCESS Study). Stroke 

1999;30(2):487. No intervention of interest studied. 

Schrader J, Luders S, Kulschewski A et al. ACCESS 

Study: Acute Candesartan Cilexetil Evaluation in 

Stroke Survivors. Am J Hypertens 2002;15(4 Part 

2):17ANo intervention of interest studied. 

Schrader J, Luders S, Kulschewski A et al. ACCESSstudy: acute candesartan cilexetil evaluation in stroke 

survivors - final results. Dtsch Med Wochenschr 

2001;126(Suppl 3):S155Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Schrader J, Rothemeyer M, Luders S et al. 

Hypertension and stroke--rationale behind the 

ACCESS trial. Acute Candesartan Cilexetil Evaluation 

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Cardiol 1998;93 Suppl 269-78. No original empirical 

evidence presented. 

Schrader J, Diener H C, Luders S. [Treating high 

blood pressure in acute stroke]. [German]. MMW 

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obtain by final date for inclusion. 

Schretzman D. Acute ischemic stroke. [Review] [34 

refs]. J Am Acad Nurse Pract 1975;24(2):71-72. No 

original empirical evidence presented. 

Schroeder EB, Rosamond WD, Morris DL et al. 

Determinants of use of emergency medical services in 

a population with stroke symptoms: the Second Delay 

in Accessing Stroke Healthcare (DASH II) Study. 

Stroke 2000;31(11):2591-2596. No intervention of 

interest studied. 

Schroth G, Berlis A, Mayer T et al. [Therapeutic 

interventional neuroradiology in acute stroke]. 

[Review] [32 refs] [German]. Ther Umsch 

2003;60(9):569-583. Non-English publication. 

Schwab S, Steiner T, Aschoff A et al. Early 

hemicraniectomy in patients with complete middle 

cerebral artery infarction. Stroke 1998;29(9):1888-

1893. No intervention of interest studied. 

Schwammenthal Y, Drescher MJ, Merzeliak O et al. 

Intravenous recombinant tissue plasminogen activator 

therapy for acute ischemic stroke: Initial israeli 

experience. Israel Medical Association Journal: Imaj 

2004;6(2):70-74. No intervention of interest studied. 

Scott JF, Robinson GM, French JM et al. Blood 

pressure response to glucose potassium insulin therapy 

in patients with acute stroke with mild to moderate 

hyperglycaemia. J Neurol Neurosurg Psychiatry 

2001;70(3):401-404. No intervention of interest 

studied. 

Scott PA, Silbergleit R. Misdiagnosis of stroke in 

tissue plasminogen activator-treated patients: 

characteristics and outcomes. Ann Emerg Med 

2003;42(5):611-618. No intervention of interest 

studied. 

Seestedt RCF. Intracerebral Hemorrhage. Curr Treat 

Options Neurol 1999;1(2):127-137. No original 

empirical evidence presented. 

Segura T, Vega G, Lopez S et al. Public perception of 

stroke in Spain. Cerebrovasc Dis 2003;16(1):21-26. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Selim M, Fink JN, Kumar S et al. Predictors of 

hemorrhagic transformation after intravenous 

recombinant tissue plasminogen activator: prognostic 

value of the initial apparent diffusion coefficient and 

diffusion-weighted lesion volume. Stroke 

2002;33(8):2047-2052. No intervention of interest 

studied. 
145

Selim M, Kumar S, Fink J et al. Seizure at stroke 

onset: should it be an absolute contraindication to 

thrombolysis? Cerebrovasc Dis 2002;14(1):54-57. No 

intervention of interest studied. 

Semplicini A, Maresca A, Simonella C et al. Cerebral 

perfusion in hypertensive patients: effects of lacidipine 

and hydrochlorothiazide. J Cardiovasc Pharmacol 

2000;35(3 Suppl 1):S13-S18. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Sever P. ALLHAT: Definitive answers or continuing 

uncertainty? J Renin Angiotensin Aldosterone Syst 

2003;4(1):3-5. No original empirical evidence 

presented. 

Shafqat S. Clinical Practice Guidelines for the 

Management of Ischemic Stroke in Pakistan. J Pak 

Med Assoc 2003;53(12):600-603. No original 

empirical evidence presented. 

Shapiro J, Bessette M, Levine SR et al. HandiStroke: a 

handheld tool for the emergent evaluation of acute 

stroke patients. Acad Emerg Med 2003;10(12):1325-

1328. No intervention of interest studied. 

Shaughnessy AS, Scow DT. t-PA for treating acute 

ischemic stroke. J Fam Pract 1996;42(5):458-459. No 

original empirical evidence presented. 

Shih LC, Saver JL, Alger Starkman S et al. Perfusionweighted magnetic resonance imaging thresholds 

identifying core, irreversibly infarcted tissue. Stroke 

2003;34(6):1425-1430. No intervention of interest 

studied. 

Shintani S, Tsuruoka S, Satoh Y. Spurious 

hyperfixation of hexamethylpropyleneamine oxime in 

acute embolic stroke.[see comment]. Ajnr: American 

Journal of Neuroradiology 1995;16(7):1532-1535. No 

intervention of interest studied. 

Silagy CA, Weller DP, Lapsley H et al. The 

effectiveness of local adaptation of nationally 

produced clinical practice guidelines. Fam Pract 

2002;19(3):223-230. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Silliman SL, Quinn B, Huggett V et al. Use of a fieldto-stroke center helicopter transport program to extend 

thrombolytic therapy to rural residents. Stroke 

2003;34(3):729-733. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Silver B, Weber J, Fisher M. Medical therapy for 

ischemic stroke. [Review] [272 refs]. Clin 

Neuropharmacol 1996;19(2):101-128. No original 

empirical evidence presented. 

Silver FL, Rubini F, Black D et al. Advertising 

strategies to increase public knowledge of the warning 

signs of stroke.[see comment]. Stroke 

2003;34(8):1965-1968. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Simon JE, Sandler DL, Pexman JHW et al. Is 

intravenous recombinant tissue plasminogen activator 

(rt-PA) safe for use in patients over 80 years old with 

acute ischaemic stroke? - The Calgary experience. 

Age & Ageing 2004;33(2):143-149. No intervention 

of interest studied. 

Singer RB. Stroke in the elderly treated for systolic 

hypertension (SHEP). Journal of Insurance Medicine 

(Seattle) 1991;23(4):265-269. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Singh V. Critical Care Assessment and Management 

of Acute Ischemic Stroke. Journal of Vascular & 

Interventional Radiology 2004;15(1 II):S21-S27. No 

original empirical evidence presented. 

Skolnick BE. Guidelines for acute stroke treatment 

centers. [Review] [35 refs]. Physical Medicine & 

Rehabilitation Clinics of North America 

1999;10(4):801-813. No original empirical evidence 

presented. 

Sloan MA, Price TR, Petito CK et al. Clinical features 

and pathogenesis of intracerebral hemorrhage after rtPA and heparin therapy for acute myocardial 

infarction: the Thrombolysis in Myocardial Infarction 

(TIMI) II Pilot and Randomized Clinical Trial 

combined experience. Neurology 1995;45(4):649-658. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Sloan MA, Price TR, Terrin ML et al. Ischemic 

cerebral infarction after rt-PA and heparin therapy for 

acute myocardial infarction. The TIMI-II pilot and 

randomized clinical trial combined experience. Stroke 

1997;28(6):1107-1114. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Sloan MA, Sila CA, Mahaffey KW et al. Prediction of 

30-day mortality among patients with thrombolysisrelated intracranial hemorrhage. Circulation 

1998;98(14):1376-1382. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Smalling RW. Molecular biology of plasminogen 

activators: what are the clinical implications of drug 

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1996;78(12A):2-7. No original empirical evidence 

presented. 

Smith RD. Extracranial-intracranial bypass in cerebral 

ischemia. Ochsner Journal 2003;5(1):31-36. No 

original empirical evidence presented. 
146

Smith RG, McLeod I, Clark DH. Evaluation of the 

volunteer stroke service in Scotland. Health Bull 

(Edinb) 1997;55(5):285-289. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Snyder DW. The American Heart Association. Focus 

on public advocacy issues. J La State Med Soc 

1997;149(5):161-163. No human participants. 

Sobel BE, Collen D. Strokes, statistics and sophistry 

in trials of thrombolysis for acute myocardial 

infarction. Am J Cardiol 1993;71(5):424-427. No 

original empirical evidence presented. 

Song S J, Fei Z, Zhang X. [Comparison of the 

intracranial pressure value in patients with 

hypertensive intracerebral hemorrhage treated with 

traditional craniotomy and puncture drainage]. 

[Chinese]. Zhongguo Wei Zhong Bing Ji Jiu Yi 

Xue/Chinese Critical Care Medicine/Zhongguo 

Weizhongbing Jijiuyixue 2003;15(9):532-534. NonEnglish publication. 

SoRelle R. Recent clinical trial updates.[comment]. 

Circulation 2002;106(12):e9029-e9032. No original 

empirical evidence presented. 

Spedding M. Reasons why stroke trials underestimate 

the neuroprotective effects of drugs. Stroke 

2002;33(1):324-325. No human participants. 

Spreadborough J, Atkinson D. The Chest, Heart and 

Stroke Association. Br J Hosp Med 1991;46(6):360No 

human participants. 

Srivastava AK, Prasad K. A study of factors delaying 

hospital arrival of patients with acute stroke. Neurol 

India 2001;49(3):272-276. No intervention of interest 

studied. 

Staessen JA, Fagard R, Thijs L et al. Randomised 

double-blind comparison of placebo and active 

treatment for older patients with isolated systolic 

hypertension. The Systolic Hypertension in Europe 

(Syst-Eur) Trial Investigators.[see comment]. Lancet 

1997;350(9080):757-764. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Stahl JE, Furie KL, Gleason S et al. Stroke: Effect of 

implementing an evaluation and treatment protocol 

compliant with NINDS recommendations. [Review] 

[83 refs]. Radiology 2003;228(3):659-668. No original 

empirical evidence presented. 

Stamler J, Stamler R, Neaton JD. Blood pressure, 

systolic and diastolic, and cardiovascular risks. US 

population data. [Review] [77 refs]. Arch Intern Med 

1993;153(5):598-615. No original empirical evidence 

presented. 

Stavropoulos SW, Solomon JA, Soulen MC et al. Use 

of abciximab during infrainguinal peripheral vascular 

interventions: Initial experience. Radiology 

2003;227(3):657-661. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Stead LG. Blood Pressure Control in Acute Stroke. 

Ann Emerg Med 2004;43(1):129-132. No original 

empirical evidence presented. 

Steg PG, Bonnefoy E, Chabaud S et al. Impact of time 

to treatment on mortality after prehospital fibrinolysis 

or primary angioplasty: data from the CAPTIM 

randomized clinical trial.[see comment]. Circulation 

2003;108(23):2851-2856. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Stegmayr B, Asplund K, Hulter-Asberg K et al. Stroke 

units in their natural habitat: can results of randomized 

trials be reproduced in routine clinical practice? RiksStroke Collaboration. Stroke 1999;30(4):709-714. No 

original empirical evidence presented. 

Steiger HJ. Carotid endarterectomy--when to do it, 

how to do it? [Review] [65 refs]. Acta Neurochir 

(Wien) 1995;137(3-4):121-127. No original empirical 

evidence presented. 

Steiner I, Gomori JM, Melamed E. The prognostic 

value of the CT scan in conservatively treated patients 

with intracerebral hematoma. Stroke 1984;15(2):279-

282. No intervention of interest studied. 

Steiner MM, Brainin M, Austrian Stroke et al. The 

quality of acute stroke units on a nation-wide level: 

the Austrian Stroke Registry for acute stroke units. 

[Review] [17 refs]. Eur J Neurol 2003;10(4):353-360. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Stern EB, Berman M, Thomas JJ et al. Community 

education for stroke awareness: An efficacy study. 

Stroke 1999;30(4):720-723. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Sterzi R V. Treatment of intracerebral hemorrhage: the 

clinical evidences. Neurol Sci 2004;25 Suppl 1S12No 

original empirical evidence presented. 

Stijnen T. Tutorial in biostatistics. Meta-analysis: 

formulating, evaluating, combining, and reporting by 

S-L. Normand, Statistics in Medicine, 18, 321-359 

(1999). Stat Med 2000;19(5):759-761. No human 

participants. 

Stingele R, Bluhmki E, Hacke W. Bootstrap statistics 

of ECASS II data: just another post hoc analysis of a 

negative stroke trial? Cerebrovasc Dis 2001;11(1):30-

33. No original empirical evidence presented. 
147

Stingele R, Hacke W. Results of the Second 

European-Australasian Acute Stroke Study (ECASS 

II): How do they influence the use of thrombolytic 

therapy in acute ischemic stroke? Intensivmedizin und 

Notfallmedizin 1999;36(7):606-611. Non-English 

publication. 

Stollberger C, Slany J, Brainin M et al. Angiotensinconverting enzyme inhibitors and stroke prevention: 

what about the influence of atrial fibrillation and 

antithrombotic therapy? Stroke 2003;34(11):e208. No 

original empirical evidence presented. 

Stolz E, Trittmacher S, Rahimi A et al. Influence of 

recanalization on outcome in dural sinus thrombosis: a 

prospective study. Stroke 2004;35(2):544-547. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Stone GW, Cox DA, Low R et al. Safety and efficacy 

of a novel device for treatment of thrombotic and 

atherosclerotic lesions in native coronary arteries and 

saphenous vein grafts: Results from the multicenter Xsizer for treatment of thrombus and atherosclerosis in 

coronary applications trial (X-TRACT) study. 

Catheterization & Cardiovascular Interventions 

2003;58(4):419-427. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Stone S. Stroke units: more trials needed. Age & 

Ageing 1999;28(2):95-97. No original empirical 

evidence presented. 

Stone SP. A trial of stroke unit (SU) versus 

comprehensive geriatric service (CGS) management 

of all stroke patients. Neurorehabilitation & Neural 

Repair 1999;13(1):49. Unable to obtain by final date 

for inclusion. 

Stordahl NJ, Back MR. The efficacy of carotid 

endarterectomy: a vascular surgery perspective 

reducing hospital stay.[erratum appears in Medsurg 

Nurs 2000 Aug;9(4):207]. [Review] [29 refs]. 

Medsurg Nurs 2000;9(3):113-121. No original 

empirical evidence presented. 

Strand T, Asplund K, Eriksson S et al. A non-intensive 

stroke unit reduces functional disability and the need 

for long-term hospitalization. Stroke 1985;16(1):29-

34. No intervention of interest studied. 

Straub S, Junghans U, Jovanovic V et al. Systemic 

thrombolysis with recombinant tissue plasminogen 

activator and tirofiban in acute middle cerebral artery 

occlusion. Stroke 2004;35(3):705-709. No 

intervention of interest studied. 

Straznicky I, White HD, Granger CB et al. Effects of 

four thrombolytic regimens in elderly patients. 

Cardiology Review 1998;15(1):22-28. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Stroke centers can cut LOS, boost outcomes. 

Healthcare Benchmarks & Quality Improvement 

2003;10(11):127-129. No original empirical evidence 

presented. 

Stroke centers can cut LOS, boost outcomes: 

complicated process needs multidisciplinary team. 

Hosp Case Manag 2003;11(12):185-186. No original 

empirical evidence presented. 

Stroke victims need to get to the hospital faster. Minn 

Med 1998;81(9):43. No original empirical evidence 

presented. 

Sudlow C, Gubitz G, Sandercock P et al. Stroke 

prevention.[update in Clin Evid. 2002 Dec;(8):184-

208; PMID: 12603877]. [Review] [91 refs]. Clin Evid 

2002;(7):175-198. No original empirical evidence 

presented. 

Sug YS, Heller RF, Levi C et al. Knowledge of stroke 

risk factors, warning symptoms, and treatment among 

an Australian urban population.[see comment]. Stroke 

2001;32(8):1926-1930. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Sugiyama T, Lee JD, Shimizu H et al. Influence of 

treated blood pressure on progression of silent cerebral 

infarction. J Hypertens 1999;17(5):679-684. Study did 

not involve relevant population [defined as adult (>16) 

with acute stroke]. 

Sulch D, Evans A, Melbourn A et al. Does an 

integrated care pathway improve processes of care in 

stroke rehabilitation? A randomized controlled trial. 

Age & Ageing 2002;31(3):175-179. No intervention 

of interest studied. 

Sulch D, Melbourn A, Perez I et al. Integrated care 

pathways and quality of life on a stroke rehabilitation 

unit. Stroke 2002;33(6):1600-1604. No intervention of 

interest studied. 

Sulch D, Perez I, Melbourn A et al. Evaluation of an 

integrated care pathway for stroke unit rehabilitation 

[4]. Age & Ageing 2000;29(1):87No original 

empirical evidence presented. 

Summers D, Soper PA. Implementation and 

evaluation of stroke clinical pathways and the impact 

on cost of stroke care. Can J Cardiovasc Nurs 

1998;13(1):69-87. No original empirical evidence 

presented. 

Suyama J, Crocco T. Prehospital care of the stroke 

patient. [Review] [50 refs]. Emerg Med Clin North 

Am 2002;20(3):537-552. No original empirical 

evidence presented. 
148

Suzuki S, Kelley RE, Dandapani BK et al. Acute 

leukocyte and temperature response in hypertensive 

intracerebral hemorrhage. Stroke 1995;26(6):1020-

1023. No intervention of interest studied. 

Swarnkar AS, Jungreis CA, Wechsler LR et al. 

Combined intravenous and intraarterial thrombolytic 

therapy for treatment of an acute ischemic stroke: a 

case report. Journal of Stroke & Cerebrovascular 

Diseases 1999;8(4):264-267. Unable to obtain by final 

date for inclusion. 

Szoeke CE, Parsons MW, Butcher KS et al. Acute 

stroke thrombolysis with intravenous tissue 

plasminogen activator in an Australian tertiary 

hospital.[see comment]. Med J Aust 2003;178(7):324-

328. No intervention of interest studied. 

Taguchi J, Freis ED. Partial versus complete control of 

blood pressure in the prevention of hypertensive 

complications. Circ Res 1975;36(6 Suppl 1):257-260. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Takagi R, Kobayashi H, Hayashi H et al. [A new 

three-dimensional CT reconstruction method for 

cerebral arteriovenous malformation: development and 

clinical evaluation of see-through view method]. 

[Japanese]. Nippon Igaku Hoshasen Gakkai Zasshi - 

Nippon Acta Radiologica 1996;56(9):676-678. NonEnglish publication. 

Takayasu M, Nagatani T, Noda A et al. Clinical safety 

and performance of Sugita titanium aneurysm clips. 

Acta Neurochir (Wien) 2000;142(2):159-162. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Tan LB. Interpretation of IST and CAST stroke trials. 

International Stroke Trial. Chinese Acute Stroke 

Trial.[comment]. Lancet 1997;350(9075):443-444. No 

human participants. 

Tang Y, Chen S. Health promotion behaviors in 

Chinese family caregivers of patients with stroke. 

Health Promot Int 2002;17(4):329-339. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Tanne D, Reicher-Reiss H, Boyko V et al. Stroke risk 

after anterior wall acute myocardial infarction. 

SPRINT Study Group. Secondary Prevention 

Reinfarction Israeli Nifedipine Trial. Am J Cardiol 

1995;76(11):825-826. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Tanne D, Schwammenthal Y. Hyperglycemia and 

early reperfusion therapy.[comment]. Stroke 

2003;34(5):1235-1241. No intervention of interest 

studied. 

Tanne D, Turgeman D, Adler Y. Management of acute 

ischaemic stroke in the elderly: tolerability of 

thrombolytics. [Review] [97 refs]. Drugs 

2001;61(10):1439-1453. No original empirical 

evidence presented. 

Taylor DW, Barnett HJ, Haynes RB et al. Low-dose 

and high-dose acetylsalicylic acid for patients 

undergoing carotid endarterectomy: a randomised 

controlled trial. ASA and Carotid Endarterectomy 

(ACE) Trial Collaborators.[see comment]. Lancet 

1999;353(9171):2179-2184. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Taylor KS. Patient software: consultation at the stroke 

of a key. Hosp Health Netw 1994;68(17):72. No 

human participants. 

Tellez H, Bauer RB. Dexamethasone as treatment in 

cerebrovascular disease. 1. A controlled study in 

intracerebral hemorrhage. Stroke 1973;4(4):541-546. 

No intervention of interest studied. 

Teach patients to recognize warning signs of stroke. 

[Review] [0 refs]. RN 2002;65(10):24hf16-24hf18. No 

original empirical evidence presented. 

Terashi A, Kobayashi Y, Katayama Y et al. Clinical 

effects and basic studies of thrombolytic therapy on 

cerebral thrombosis. Seminars in Thrombosis & 

Hemostasis 1990;16(3):236-241. No intervention of 

interest studied. 

The PROGRESS trial was it unfairly reported by 

prescrire? Prescrire Int 2003;12(63):38-39. Unable to 

obtain by final date for inclusion. 

Thijs VN. Imaging strategy for acute stroke therapy. 

[Review] [26 refs]. Jbr-Btr: Organe de la Societe 

Royale Belge de Radiologie 2003;86(6):350-353. No 

original empirical evidence presented. 

Thomas SH, Kociszewski C, Schwamm LH et al. The 

evolving role of helicopter emergency medical 

services in the transfer of stroke patients to specialized 

centers. Prehosp Emerg Care 2002;6(2):210-214. No 

intervention of interest studied. 

Thomas V. An open evening for stroke patients and 

relatives. Br J Nurs 1992;1(11):557-559. No original 

empirical evidence presented. 

Thomas WA, Cole PV, Etherington NJ et al. Electrical 

activity of the cerebral cortex during induced 

hypotension in man. A comparison of sodium 

nitroprusside and trimetaphan. Br J Anaesth 

1985;57(2):134-141. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 
149

Thomassen L, Waje-Andreassen U, Morsund AH et al. 

Thrombolytic therapy in acute ischaemic stroke. 

Cerebrovasc Dis 2002;13(3):163-167. No intervention 

of interest studied. 

Thompson PL. Thrombolytic therapy for coronary 

occlusion.[comment]. Med J Aust 1992;157(2):75-77. 

No original empirical evidence presented. 

Thornton H. Thrombolysis for acute ischaemic stroke. 

Good quality research that addresses patients'' needs is 

required.[comment]. BMJ 2002;325(7376):1363. No 

original empirical evidence presented. 

Thurston SE. Neuroprotective therapy in acute 

ischemic stroke. [Review] [10 refs]. Va Med Q 

1998;125(2):131-132. No original empirical evidence 

presented. 

Tiffany BR, Carrubba CL. Emergency medical 

services and the acute stroke: changing the paradigm. 

J Fla Med Assoc 1997;84(4):253-257. No original 

empirical evidence presented. 

Tilley BC, Marler J, Geller NL et al. Use of a global 

test for multiple outcomes in stroke trials with 

application to the National Institute of Neurological 

Disorders and Stroke t-PA Stroke Trial. Stroke 

1996;27(11):2136-2142. No intervention of interest 

studied. 

Tilling K, Wolfe C. Re: Randomized controlled study 

of stroke unit versus stroke team care in different 

stroke subtypes.[comment]. Stroke 2002;33(7):1741-

1742. No original empirical evidence presented. 

Timsit SG, Sacco RL, Mohr JP et al. Brain infarction 

severity differs according to cardiac or arterial 

embolic source. Neurology 1993;43(4):728-733. No 

intervention of interest studied. 

Timsit SG, Sacco RL, Mohr JP et al. Early clinical 

differentiation of cerebral infarction from severe 

atherosclerotic stenosis and cardioembolism. Stroke 

1992;23(4):486-491. No intervention of interest 

studied. 

Tissue plasminogen activator for acute ischemic 

stroke. The National Institute of Neurological 

Disorders and Stroke rt-PA Stroke Study Group.[see 

comment]. N Engl J Med 1995;333(24):1581-1587. 

No intervention of interest studied. 

Todo K, Watanabe M, Fukunaga R et al. Imaging of 

distal internal carotid artery by ultrasonography with a 

3.5-MHz convex probe. Stroke 2002;33(7):1792-1794. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

Tohmo H, Karanko M, Scheinin M et al. Enalapril 

premedication attenuates the blood pressure response 

to tracheal intubation and stabilizes postoperative 

blood pressure after controlled hypotension with 

sodium nitroprusside in neurovascular patients. J 

Neurosurg Anesthesiol 1993;5(1):13-21. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Tong DC. Intravenous rt-PA for stroke. [Review] [41 

refs]. Current Medical Research & Opinion 2002;18 

Suppl 2s35-s43. No original empirical evidence 

presented. 

Toni D, Argentino C, Gentile M et al. Circadian 

variation in the onset of acute cerebral ischemia: 

ethiopathogenetic correlates in 80 patients given 

angiography. Chronobiol Int 1991;8(5):321-326. No 

intervention of interest studied. 

Toni D, Chamorro A, Kaste M et al. Acute treatment 

of ischaemic stroke. Cerebrovasc Dis 

2004;17(SUPPL. 2):30-46. No original empirical 

evidence presented. 

Toni D, Fiorelli M, De Michele M et al. Clinical and 

prognostic correlates of stroke subtype misdiagnosis 

within 12 hours from onset.[erratum appears in Stroke 

1996 Jan;27(1):152]. Stroke 1995;26(10):1837-1840. 

No intervention of interest studied. 

Toni D, Gallo V, Falcou A et al. Treatment of 

cerebrovascular diseases: state of the art and 

perspectives. J Cardiovasc Pharmacol 2001;38 Suppl 

2S83-S86. No original empirical evidence presented. 

Toni D, Iweins F, von Kummer R et al. Identification 

of lacunar infarcts before thrombolysis in the ECASS I 

study. Neurology 2000;54(3):684-688. No 

intervention of interest studied. 

Traub YM, Ayache AS, Groshar D. The effect of 

enalapril and calcium antagonists on blood pressure 

and cerebral perfusion in elderly hypertensives. 

Journal of Hypertension - Supplement 

1991;9(6):S378-S379. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Travis LH, Flemming KD, Brown RD et al. 

Awareness of Stroke Risk Factors, Symptoms, and 

Treatment is Poor in People at Highest Risk. Journal 

of Stroke & Cerebrovascular Diseases 

2003;12(5):221-227. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Trenkwalder P. Antihypertensive treatment with 

calcium channel blockers: Pharmacological 

pornography or useful intervention? Nephrology 

Dialysis Transplantation 2004;19(1):17-20. No 

original empirical evidence presented. 

Trial of secondary prevention with atenolol after 

transient ischemic attack or nondisabling ischemic 

stroke. The Dutch TIA Trial Study Group. Stroke 
150

1993;24(4):543-548. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Trotter G. Why were the benefits of tPA exaggerated? 

West J Med 2002;176(3):194-197. No original 

empirical evidence presented. 

Trouillas P, Nighoghossian N, Getenet JC et al. Open 

trial of intravenous tissue plasminogen activator in 

acute carotid territory stroke. Correlations of outcome 

with clinical and radiological data. Stroke 

1996;27(5):882-890. No intervention of interest 

studied. 

Tubler T, Schluter M, Dirsch O et al. Balloonprotected carotid artery stenting: relationship of 

periprocedural neurological complications with the 

size of particulate debris. Circulation 

2001;104(23):2791-2796. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Tuomilehto J, Puska P, Nissinen A. Hypertension 

programme of the North Karelia Project. Scand J Soc 

Med 1976;4(2):67-70. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Turnbull G B. The power of knowledge. Ostomy 

Wound Management 2004;50( 6):14-16. Unable to 

obtain by final date for inclusion. 

Turner JM, Powell D, Gibson RM et al. Intracranial 

pressure changes in neurosurgical patients during 

hypotension induced with sodium nitroprusside or 

trimetaphan. Br J Anaesth 1977;49(5):419-425. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Ueda T, Yuh WT, Taoka T. Clinical application of 

perfusion and diffusion MR imaging in acute ischemic 

stroke. [Review] [51 refs]. J Magn Reson Imaging 

1999;10(3):305-309. No original empirical evidence 

presented. 

Umemura K, Kondo K, Ikeda Y et al. 

Pharmacokinetics and safety of the novel amino-3-

hydroxy-5-methylisoxazole-4-propionate receptor 

antagonist YM90K in healthy men. J Clin Pharmacol 

1997;37(8):719-727. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Ushering in a new era in stroke care. Hosp Technol 

Ser 1997;16(12):8-9. No original empirical evidence 

presented. 

van den, Bos GA, Smits JP et al. Socioeconomic 

variations in the course of stroke: unequal health 

outcomes, equal care? Journal of Epidemiology & 

Community Health 2002;56(12):943-948. Study did 

not involve relevant population [defined as adult (>16) 

with acute stroke]. 

Van Der, LH Boers G, Tange H et al. PropeR: A multi 

disciplinary EPR system. Int J Med Inf 2003;70(2-

3):149-160. No human participants. 

van der, Worp HB, Kappelle LJ et al. The effect of 

tirilazad mesylate on infarct volume of patients with 

acute ischemic stroke. Neurology 2002;58(1):133-135. 

No intervention of interest studied. 

van Gijn J. Thrombolysis in ischemic stroke: double 

or quits? [Review] [21 refs]. Circulation 

1996;93(9):1616-1617. No original empirical evidence 

presented. 

van Heesewijk, HP Vos, JA Louwerse et al. New brain 

lesions at MR imaging after carotid angioplasty and 

stent placement. Radiology 2002;224(2):361-365. 

Study did not involve relevant population [defined as 

adult (>16) with acute stroke]. 

van Loon J, Waerzeggers Y, Wilms G et al. Early 

endovascular treatment of ruptured cerebral 

aneurysms in patients in very poor neurological 

condition. Neurosurgery 2002;50(3):457-464. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

van Veenendaal H, Grinspun DR, Adriaanse HP. 

Educational needs of stroke survivors and their family 

members, as perceived by themselves and by health 

professionals. Patient Education & Counseling 

1996;28(3):265-276. No original empirical evidence 

presented. 

Vanderschueren S, Dens J, Kerdsinchai P et al. 

Randomized coronary patency trial of double-bolus 

recombinant staphylokinase versus front-loaded 

alteplase in acute myocardial infarction. Am Heart J 

1997;134(2 Pt 1):213-219. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Venketasubramanian N. Stroke in Singapore--an 

overview. Singapore Med J 1999;40(1):48-52. No 

original empirical evidence presented. 

Venketasubramanian N, Chan BP, Lim E et al. Stroke 

disease management--a framework for comprehensive 

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Singapore 2002;31(4):452-460. No original empirical 

evidence presented. 

Verdecchia P, Schillaci G, Reboldi G et al. 

Ambulatory monitoring for prediction of cardiac and 

cerebral events. Blood Press Monit 2001;6(4):211-

215. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Vlcek M, Schillinger M, Lang W et al. Association 

between course of blood pressure within the first 24 

hours and functional recovery after acute ischemic 

stroke. Ann Emerg Med 2003;42(5):619-626. No 

intervention of interest studied. 
151

Vo KD, Santiago F, Lin W et al. MR imaging 

enhancement patterns as predictors of hemorrhagic 

transformation in acute ischemic stroke. AJNR Am J 

Neuroradiol. 2003;24(4):674-679. No intervention of 

interest studied. 

von Kummer R. Brain hemorrhage after thrombolysis: 

good or bad?[comment]. Stroke 2002;33(6):1446-

1447. No original empirical evidence presented. 

von Kummer R, Forsting M, Hutschenreuter M et al. 

Angiography in acute stroke due to occlusions of 

intracerebral arteries before and after treatment with 

intravenous recombinant tissue plasminogen activator. 

Stroke 1990;21(Suppl I):94-95. No intervention of 

interest studied. 

von Kummer R, Hacke W. Safety and efficacy of 

intravenous tissue plasminogen activator and heparin 

in acute middle cerebral artery stroke. Stroke 

1992;23(5):646-652. No intervention of interest 

studied. 

Wachters-Kaufmann CS. A Dutch ''Poststroke Guide'': 

distribution and use. Patient Education & Counseling 

1999;37(1):81-88. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Wade DT. Cognitive assessment and neurological 

rehabilitation. Clin Rehabil 2002;16(2):117-118. No 

original empirical evidence presented. 

Waigand J, Gross CM, Uhlich F et al. Elective 

stenting of carotid artery stenosis in patients with 

severe coronary artery disease.[see comment]. Eur 

Heart J 1998;19(9):1365-1370. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Warach S. Stroke neuroimaging. [Review] [20 refs]. 

Stroke 2003;34(2):345-347. No original empirical 

evidence presented. 

Wardlaw JM. The place of thrombolysis in the 

management of cerebral embolism after heart valve 

replacement. [Review] [8 refs]. J Heart Valve Dis 

1994;3(6):611-612. No original empirical evidence 

presented. 

Wardlaw JM, Lewis SC, Sandercock PA et al. Why do 

Italian stroke patients receive CT scans earlier than 

UK patients? International Stroke Trial Collaborators 

in Italy and the UK. Postgrad Med J 1999;75(879):18-

21. No intervention of interest studied. 

Wardlaw JM, Lindley RI, Lewis S. Thrombolysis for 

acute ischemic stroke: still a treatment for the few by 

the few. West J Med 2002;176(3):198-199. No 

original empirical evidence presented. 

Wardlaw JM, Sandercock PA, Berge E. Thrombolytic 

therapy with recombinant tissue plasminogen activator 

for acute ischemic stroke: where do we go from here? 

A cumulative meta-analysis. Stroke 2003;34(6):1437-

1442. No original empirical evidence presented. 

Wardlaw JM, Warlow CP, Counsell C. Systematic 

review of evidence on thrombolytic therapy for acute 

ischaemic stroke.[see comment]. Lancet 

1997;350(9078):607-614. No original empirical 

evidence presented. 

Wardlaw JM, Zoppo G, Yamaguchi T et al. 

Thrombolysis for acute ischaemic stroke.[update of 

Cochrane Database Syst Rev. 2000;(2):CD000213; 

PMID: 10796329]. [Review] [54 refs]. Cochrane 

Database Syst Rev 2003;(3):CD000213No original 

empirical evidence presented. 

Warlow C, Sudlow C, Dennis M et al. Stroke.[see 

comment]. [Review] [101 refs]. Lancet 

2003;362(9391):1211-1224. No original empirical 

evidence presented. 

Wasay M. Neurological Care in Pakistan: Actions are 

needed. J Pak Med Assoc 2003;53(12):576. No 

original empirical evidence presented. 

Weaver WD, White HD, Wilcox RG et al. 

Comparisons of characteristics and outcomes among 

women and men with acute myocardial infarction 

treated with thrombolytic therapy. GUSTO-I 

investigators.[comment]. JAMA 1996;275(10):777-

782. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Weber CE. Stroke: brain attack, time to react. 

[Review] [36 refs]. AACN Clin Issues 1995;6(4):562-

575. No original empirical evidence presented. 

Weber J, Remonda L, Mattle HP et al. Selective intraarterial fibrinolysis of acute central retinal artery 

occlusion. Stroke 1998;29(10):2076-2079. Study did 

not involve relevant population [defined as adult (>16) 

with acute stroke]. 

Weber MA. The ALLHAT report: a case of 

information and misinformation. J Clin Hypertens 

2003;5(1):9-13. No original empirical evidence 

presented. 

Wechsler LR. Innovative strategies in the management 

of acute stroke. [Review] [42 refs]. Curr Cardiol Rep 

2002;4(2):135-140. No original empirical evidence 

presented. 

Weder AB. Best bang for the buck? Curr Hypertens 

Rep 2003;5(1):3-5. No original empirical evidence 

presented. 
152

Wein TH, Hickenbottom SL, Morgenstern LB et al. 

Safety of tissue plasminogen activator for acute stroke 

in menstruating women. [Review] [11 refs]. Stroke 

2002;33(10):2506-2508. No intervention of interest 

studied. 

Wein TH, Staub L, Felberg R et al. Activation of 

emergency medical services for acute stroke in a 

nonurban population: the T.L.L. Temple Foundation 

Stroke Project. Stroke 2000;31(8):1925-1928. No 

intervention of interest studied. 

Weir CJ, Lees KR. Comparison of stratification and 

adaptive methods for treatment allocation in an acute 

stroke clinical trial. Stat Med 2003;22(5):705-726. No 

human participants. 

Weir CJ, Murray GD, Dyker AG et al. Is 

hyperglycaemia an independent predictor of poor 

outcome after acute stroke? Results of a long-term 

follow up study.[see comment]. BMJ 

1997;314(7090):1303-1306. No intervention of 

interest studied. 

Weisberg LA. ''Stroke and struck'': Protecting the 

brain from cerebrovascular disease. South Med J 

2003;96(4):331. No original empirical evidence 

presented. 

Weiss PLT, Naveh Y, Katz N. Design and testing of a 

virtual environment to train stroke patients with 

unilateral spatial neglect to cross a street safely. Occup 

Ther Int 2003;10(1):39-55. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Wester P, Strand T, Wahlgren NG et al. An open 

study of clomethiazole in patients with acute cerebral 

infarction. Cerebrovasc.Dis 1998;8(3):188-190. No 

intervention of interest studied. 

Westrick E. National initiatives: management of heart 

disease and stroke. [Review] [3 refs]. Medicine & 

Health, Rhode Island 1999;82(5):176-177. No original 

empirical evidence presented. 

Whisnant JP. Effectiveness versus efficacy of 

treatment of hypertension for stroke prevention. 

[Review] [22 refs]. Neurology 1996;46(2):301-307. 

No original empirical evidence presented. 

White HD, Barbash GI, Califf RM et al. Age and 

outcome with contemporary thrombolytic therapy: 

Results from the GUSTO-I trial. Circulation 

1996;94(8):1826-1833. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

White WB, LaRocca GM. Chronopharmacology of 

cardiovascular therapy. [Review] [65 refs]. Blood 

Press Monit 2002;7(4):199-207. No original empirical 

evidence presented. 

Whitney F. Drug therapy for acute stroke. [Review] 

[21 refs]. J Neurosci Nurs 1994;26(2):111-117. No 

original empirical evidence presented. 

Widjaja LS, Chan BP, Chen H et al. Variance analysis 

applied to a stroke pathway: how this can improve 

efficiency of healthcare delivery. Ann Acad Med 

Singapore 2002;31(4):425-430. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Wiegand N, Luthy R, Vogel B et al. Intravenous 

thrombolysis for ischaemic stroke is also safe and 

efficient without a specialised neuro-intensive care 

unit. Swiss Med Wkly 2004;134(1-2):14-17. No 

intervention of interest studied. 

Wiegand N, Luthy R, Vogel B et al. Intravenous 

thrombolysis for acute ischaemic stroke in a hospital 

without a specialised neuro-intensive care unit. Swiss 

Med Wkly 1-10-2004;134( 1-2):14-17. Unable to 

obtain by final date for inclusion. 

Wilcox RG. Clinical trials in thrombolytic therapy: 

what do they tell us? INJECT 6-month outcomes data. 

[Review] [8 refs]. Am J Cardiol 1996;78(12A):20-23. 

No original empirical evidence presented. 

Wildemann B, Hutschenreuter M, Krieger D et al. 

Infusion of recombinant tissue plasminogen activator 

for treatment of basilar artery occlusion. Stroke 

1990;21(10):1513-1514. No original empirical 

evidence presented. 

Wildermuth S, Knauth M, Brandt T et al. Role of CT 

angiography in patient selection for thrombolytic 

therapy in acute hemispheric stroke.[see comment]. 

Stroke 1998;29(5):935-938. No intervention of interest 

studied. 

Wiles R, Pain H, Buckland S et al. Providing 

appropriate information to patients and carers 

following a stroke. J Adv Nurs. 1998;28(4):794-801. 

No intervention of interest studied. 

Wilkinson G, Parcell M, MacDonald A. 

Cerebrovascular accident clinical pathway. J Qual 

Clin Pract 2000;20(2-3):109-112. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Williams B. Drug specific benefits and cardiovascular 

and stroke outcomes.[comment]. J Hypertens 

2003;21(9):1609-1610. No original empirical evidence 

presented. 

Williams B. Drug treatment of hypertension: 

Implications of ALLHAT. Heart 2003;89(6):589-590. 

No original empirical evidence presented. 
153

Williams LS, Bruno A, Rouch D et al. Stroke patients'' 

knowledge of stroke. Influence on time to 

presentation. Stroke 1997;28(5):912-915. No 

intervention of interest studied. 

Williams LS, Rotich J, Qi R et al. Effects of admission 

hyperglycemia on mortality and costs in acute 

ischemic stroke. Neurology 2002;59(1):67-71. No 

intervention of interest studied. 

Willmot M, Leonardi-Bee J, Bath PM. High blood 

pressure in acute stroke and subsequent outcome: a 

systematic review. [Review] [57 refs]. Hypertension 

2004;43(1):18-24. No original empirical evidence 

presented. 

Willmot MR, Bath PMW. The potential of nitric oxide 

therapeutics in stroke. Expert Opin Investig Drugs 

2003;12(3):455-470. No original empirical evidence 

presented. 

Willoughby DF, Sanders L, Privette A. The impact of 

a stroke screening program. Public Health Nurs 

2001;18(6):418-423. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Wills AJ. Letter from Cuba. Journal of Neurology, 

Neurosurgery & Psychiatry 2003;74(3):285-286. No 

original empirical evidence presented. 

Wilson E. First International Conference on Women, 

Heart Disease and Stroke: science and policy in 

action. Can J Cardiol 2000;16(6):726-727. No original 

empirical evidence presented. 

Wilson E, Taylor G, Phillips S et al. Creating a 

Canadian stroke system. [Review] [21 refs]. CMAJ 

Canadian Medical Association Journal 

2001;164(13):1853-1855. No human participants. 

Wintermark M, Reichhart M, Cuisenaire O et al. 

Comparison of admission perfusion computed 

tomography and qualitative diffusion- and perfusionweighted magnetic resonance imaging in acute stroke 

patients.[see comment]. Stroke 2002;33(8):2025-2031. 

No intervention of interest studied. 

Wittkowsky AK. The stroke pharmacopeia: current 

medical therapies. [Review] [15 refs]. 

Pharmacotherapy 1998;18(3 Pt 2):94S-100S. No 

original empirical evidence presented. 

Wittkowsky AK. Pharmacists and stroke prevention. 

Am J Health Syst Pharm 1996;53(9):1009. No original 

empirical evidence presented. 

Woessner R, Grauer MT, Dieterich H-J et al. 

Influence of long-term volume therapy with 

hydroxyethyl starch on leukocytes in patients with 

acute stroke. Arzneimittelforschung 2003;53(6):402-

406. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Woisetschlager C, Kittler H, Oschatz E et al. Out-ofhospital diagnosis of cerebral infarction versus 

intracranial hemorrhage. Intensive Care Med 

2000;26(10):1561-1565. Study did not involve 

relevant population [defined as adult (>16) with acute 

stroke]. 

Wojner AW, Morgenstern L, Alexandrov AV et al. 

Paramedic and emergency department care of stroke: 

baseline data from a citywide performance 

improvement study. Am J Crit Care 2003;12(5):411-

417. No intervention of interest studied. 

Wolfe C, Rudd A, Dennis M et al. Taking acute stroke 

care seriously. In the absence of evidence we should 

manage acute stroke as a medical emergency.[see 

comment]. BMJ 2001;323(7303):5-6. No original 

empirical evidence presented. 

Wolfe CD. Studies of death and disability from stroke: 

how can they effect change in service provision? Int J 

Epidemiol 1995;24 Suppl 1S60-S64. No original 

empirical evidence presented. 

Wolpert SM. An open multicenter study of the 

radiologic changes seen after various doses of r-TPA 

in patients with acute stroke: preliminary results. 

AJNR Am J Neuroradiol 1988;9(5):1038. No 

intervention of interest studied. 

Wong W-K, Kuo C-H, Hou CJY et al. Successful 

local thrombolytic therapy and percutaneous 

transluminal angioplasty for acute brachial artery 

occlusion in a case with recent stroke. Acta 

Cardiologica Sinica 2003;19(1):48-52. Study did not 

involve relevant population [defined as adult (>16) 

with acute stroke]. 

Woo D. Ischemic versus hemorrhagic stroke: Rating 

the risk factors. J Crit Illn 2003;18(5):194-195. No 

original empirical evidence presented. 

Woo D, Broderick JP, Kothari RU et al. Does the 

National Institutes of Health Stroke Scale favor left 

hemisphere strokes? NINDS t-PA Stroke Study 

Group. Stroke 1999;30(11):2355-2359. No 

intervention of interest studied. 

Wood VA, Hewer RL. The prevention and 

management of stroke. [Review] [72 refs]. J Public 

Health Med 1996;18(4):423-431. No original 

empirical evidence presented. 

Wood-Dauphinee S. A Trial Of Team Care In The 

Treatment Of Acute Stroke [Dissertation]. 1982. 

Unable to obtain by final date for inclusion. 

Woods A. Patient-teaching aid. "Am I having a 

stroke?" Nursing (Brux) 1999;29(12):32hn8No human 

participants. 
154

Wright V, Horvath R, Baird AE. Aortic dissection 

presenting as acute ischemic stroke. Neurology 

2003;61(4):581-582. No intervention of interest 

studied. 

Xavier AR, Siddiqui AM, Kirmani JF et al. Clinical 

potential of intra-arterial thrombolytic therapy in 

patients with acute ischaemic stroke. [Review] [58 

refs]. CNS Drugs 2003;17(4):213-224. No original 

empirical evidence presented. 

Xi G, Keep RF, Hoff JT. Pathophysiology of brain 

edema formation. [Review] [107 refs]. Neurosurg Clin 

N Am 2002;13(3):371-383. No original empirical 

evidence presented. 

Yamada JY, Yee H, Fitzgerald M et al. Community 

education on stroke. World Health Forum 

1992;13(1):44-46. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Yamaguchi T, Kikuchi H, Hayakawa T et al. Clinical 

efficacy and safety of intravenous tissue plasminogen 

activator in acute embolic stroke: a randomized, 

double-blind, dose-comparison study of duteplase. 

Thrombolytic Therapy in Acute Ischemic Stroke III 

Tokyo : Springer-Verlag, 1995 1995;1st ed. 223-229p. 

Unable to obtain by final date for inclusion. 

Yamaguchi T, Kikuchi H, Hayakawa T et al. Efficacy 

and safety of tissue plasminogen activator in patients 

with acute embolic stroke. J Clin Neurosci 

1995;2(1):90-91. No intervention of interest studied. 

Yamaguchi T, Sano K, Takakura K et al. Ebselen in 

acute ischemic stroke: a placebo-controlled, doubleblind clinical trial. Ebselen Study Group. Stroke 

1998;29(1):12-17. No intervention of interest studied. 

Yamashita L F, Fukujima M M, Granitoff N et al. 

[Patients with ischemic stroke are taken care quickly 

in Sao Paulo Hospital]. [Portuguese]. Arq 

Neuropsiquiatr 2004;62( 1):96-102. Unable to obtain 

by final date for inclusion. 

Yoon PH, Kim DI, Jeon P et al. Cerebral cavernous 

malformations: serial magnetic resonance imaging 

findings in patients with and without gamma knife 

surgery. Neurol Med Chir (Tokyo) 1998;38 Suppl255-

261. Study did not involve relevant population 

[defined as adult (>16) with acute stroke]. 

Yoon SS, Byles J. Perceptions of stroke in the general 

public and patients with stroke: a qualitative study.[see 

comment]. BMJ 2002;324(7345):1065-1068. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Yoon W, Seo JJ, Kim JK et al. Contrast enhancement 

and contrast extravasation on computed tomography 

after intra-arterial thrombolysis in patients with acute 

ischemic stroke. Stroke 2004;35(4):876-881. No 

intervention of interest studied. 

York KA. Rural case management for stroke: the 

development of a community-based screening and 

education program. Lippincotts Case Manag 

2003;8(3):98-114. No intervention of interest studied. 

Young C, Summerfield R, Schwartz M et al. 

Radiosurgery for arteriovenous malformations: the 

University of Toronto experience. Can J Neurol Sci 

1997;24(2):99-105. Study did not involve relevant 

population [defined as adult (>16) with acute stroke]. 

Young J. My place or yours--what is the best place for 

early stroke care?[comment]. Age & Ageing 

2001;30(3):185-186. No original empirical evidence 

presented. 

Young J, Murray J, Forster A. Review of longer-term 

problems after disabling stroke. Rev Clin Gerontol 

2003;13(1):55-65. No original empirical evidence 

presented. 

Young JB. The primary care stroke gap. Br J Gen 

Pract 2001;51(471):787-788. No original empirical 

evidence presented. 

Yu RF, San Jose, MC Manzanilla et al. Sources and 

reasons for delays in the care of acute stroke patients. 

J Neurol Sci 2002;199(1-2):49-54. No intervention of 

interest studied. 

Yudkin JS. Preventing stroke with ramipril. 

Superiority of particular class of antihypertensive 

agent remains to be shown.[see comment][comment]. 

BMJ 2002;325(7361):439. No original empirical 

evidence presented. 

Yuh WT, Taoka T, Ueda T et al. Imaging helps 

identify who benefits from stroke intervention. Diagn 

Imaging (San Franc) 1999;21(12):77-82. No original 

empirical evidence presented. 

Yusuf S, Lonn E. Anti-ischaemic effects of ACE 

inhibitors: review of current clinical evidence and 

ongoing clinical trials.[erratum appears in Eur Heart J 

1998 Nov;19(11):1742]. [Review] [44 refs]. Eur Heart 

J 1998;19 Suppl JJ36-J44. No original empirical 

evidence presented. 

Zahn D. Preventing and treating stroke. Can Pharm J 

2003;136(10):32. No original empirical evidence 

presented. 

Zahn D. Stroke - A medical emergency. Can Pharm J 

2003;136(10):3. No human participants. 
155

Zetterling MR-E. High intraoperative blood loss may 

be a risk factor for postoperative hematoma. J 

Neurosurg Anesthesiol. 2004;16(2):151-155. Study 

did not involve relevant population [defined as adult 

(>16) with acute stroke]. 

Zhang S F, He M D, Li C. [Clinical curative effect of 

dengzhanhua injection on acute cerebral infarction: a 

report of 100 cases]. [Chinese]. Hunan Yi Ke Da Xue 

Xue Bao 6-28-2002;27(3):235-238. Non-English 

publication. 

Zhu XL, Chan MS, Poon WS. Spontaneous 

intracranial hemorrhage: which patients need 

diagnostic cerebral angiography? A prospective study 

of 206 cases and review of the literature. [Review] [27 

refs]. Stroke 1997;28(7):1406-1409. No intervention 

of interest studied. 

Zingmark P-H, Ekblom M, Odergren T et al. 

Population pharmacokinetics of clomethiazole and its 

effect on the natural course of sedation in acute stroke 

patients. Br J Clin Pharmacol 2003;56(2):173-183. No 

intervention of interest studied. 

Zivin JA. Diffusion-weighted MRI for diagnosis and 

treatment of ischemic stroke.[comment]. Ann Neurol 

1997;41(5):567-568. No original empirical evidence 

presented. 

Zivin JA, Choi DW. Stroke therapy. Sci Am 

1991;265(1):56-63. No original empirical evidence 

presented. 

Zuger A. A big study yields big questions. N Engl J 

Med 2003;349(3):213-214. No original empirical 

evidence presented. 

 
156
A-1

Appendix A. Search Strategies 

Search Strategy 1 

Ovid Medline 

1. Intracranial Thrombosis/ or Cerebral Infarction/ or Cerebral Hemorrhage/ or Cerebrovascular 

Accident/ 

2. "Intracranial Embolism and Thrombosis"/ 

3. Intracranial Embolism/ 

4. Brain Ischemia/ 

5. ischemic stroke$.tw. 

6. cva.mp. 

7. or/1-6 

8. Intracranial Thrombosis/ or Cerebral Infarction/ or Cerebral Hemorrhage/ or Cerebrovascular 

Accident/ or "Intracranial Embolism and Thrombosis"/ or Intracranial Embolism/ or Stroke/ or 

Brain Ischemia/ 

9. (stroke or cva).mp. 

10. or/8-9 

11. Intracranial Thrombosis/ or Cerebral Infarction/ or Cerebral Hemorrhage/ or Cerebrovascular 

Accident/ or "Intracranial Embolism and Thrombosis"/ or Intracranial Embolism/ 

12. stroke/ 

13. exp Intracranial Hemorrhages/ 

14. (cerebrovascular$ or cerebral vascular or stroke).tw. 

15. (haemorrhag$ or hemorrhag$ or haematom$ or hematom$).mp. 

16. (ich or cva).mp. 

17. (primary intracerebral hemorrhage or pich).mp. 

18. (haemorrhag$ or hemorrhag$ or haematom$ or hematom$).mp. 

19. exp brain/ 

20. (cerebr$ or intracerebral or intracran$ or parenchymal or brain).tw. 

21. 18 and (19 or 20) 

22. or/11-17,21 

23. *subarachnoid hemorrhage/ or *subarachnoid hemorrhage, traumatic/ 

24. *Tissue Plasminogen Activator/ 

25. 22 not (23 or 24) 

26. exp surgery/ 

27. surgery.hw. or surgery.kw. 

28. surg$.mp. 

29. endoscop$.mp. 

30. craniotom$.mp. 

31. stereotactic.mp. 

32. ventricular drain$.mp. 

33. intraoperative ultras$.mp. 

34. neuroprotective.mp. 

35. or/26-34 

36. 25 and 35 

37. *Cardiac Surgical Procedures/ 

38. *Coronary Artery Bypass/ 

39. *Coronary Disease/ 

40. *Aortic Valve Stenosis/ 

41. *Endarterectomy, Carotid/ 

42. or/37-41 

43. 42 not (11 or 12 or 13) 

44. 36 not 43 

45. Antihypertensive Agents/ or Hypertension/ or Angiotensin-Converting Enzyme Inhibitors/ 
A-2

46. antihypertensive treatment.mp. 

47. antihypertensive$.tw. 

48. (angiotensin-converting enzyme or ace).tw. 

49. Labetalol/ 

50. 36894-69-6.rn. 

51. (Chlortalidone or Hydrochlorotiazide).tw. 

52. (Atenolol or Propranolol or metoprolol or carvedilol or labetalol or pindolol or bisoprolol).tw. 

53. (Enalapril or lisinopril or captopril or ramipril or benazepril).tw. 

54. (losartan or candesartan or valsartan).tw. 

55. (nifedipine or nicardipine or amlodipine or isradipine or varapamil or felodipine or 

diltiazem).tw. 

56. (nitroprusside or clonidine or terazosin$ or doxazosin$).tw. 

57. or/45-56 

58. *subarachnoid hemorrhage/ or *subarachnoid hemorrhage, traumatic/ 

59. *Tissue Plasminogen Activator/ 

60. 57 not (58 or 59) 

61. 60 and 25 

62. injections, intra-arterial/ 

63. intraarterial.tw. 

64. intra arterial.tw. 

65. or/62-64 

66. thromboly$.tw. 

67. thrombolytic therapy/ 

68. (iat or ia).tw. 

69. exp Tissue Plasminogen Activator/ 

70. tPA.mp. 

71. Activase.tw. 

72. alteplase.tw. 

73. clot dissolv$.tw. 

74. reperfusion therapy.tw. 

75. reteplase.tw. 

76. tenecteplase.tw. 

77. tissue plasminogen activator.tw. 

78. tPA.tw. 

79. EC-3-4-21-68.rn. 

80. or/66-79 

81. 65 and 80 

82. blood glucose.mp. 

83. Blood Glucose/ 

84. serum glucose.mp. 

85. blood sugar.tw. 

86. ((blood or serum) adj2 (sugar or glucose)).mp. 

87. Hyperglycemia/ 

88. Hypoglycemia/ 

89. or/82-88 

90. ((mechanical or ultrason$) adj (clot$ or disrupt$)).mp. 

91. ultrasonic therapy/ 

92. Angioplasty/ or Angioplasty, Balloon/ 

93. endovascular intervention$.tw. 

94. snare manipulation.tw. 

95. guidewire.tw. 

96. mechanical thromboly$.tw. 

97. mechanical recanalization.mp. 

98. (percutaneous transluminal angioplast$ or pta).tw. 

99. cerebral angiograph$/ 

100. or/90-99 
A-3

101. exp Tissue Plasminogen Activator/ 

102. tPA.mp. 

103. Activase.tw. 

104. alteplase.tw. 

105. clot dissolv$.tw. 

106. reperfusion therapy.tw. 

107. reteplase.tw. 

108. tenecteplase.tw. 

109. tissue plasminogen activator.tw. 

110. tPA.tw. 

111. EC-3-4-21-68.rn. 

112. or/101-111 

113. exp Tissue Plasminogen Activator/ 

114. tPA.mp. 

115. Activase.tw. 

116. alteplase.tw. 

117. clot dissolv$.tw. 

118. reperfusion therapy.tw. 

119. reteplase.tw. 

120. tenecteplase.tw. 

121. tissue plasminogen activator.tw. 

122. tPA.tw. 

123. EC-3-4-21-68.rn. 

124. or/113-123 

125. mri.mp. 

126. mr imag$.mp. 

127. magnetic resonance imag$.mp. 

128. magnetic resonance imaging/ 

129. 124 and (or/125-128) 

130. health promotion/ 

131. health education/ 

132. Health Knowledge, Attitudes, Practice/ 

133. health behavior/ 

134. Attitude to Health/ 

135. delivery of health care/ 

136. program evaluation/ 

137. Marketing of Health Services/ 

138. Information Services/ 

139. advertising/ 

140. patient education/ 

141. community health planning/ 

142. area health education centers/ 

143. outreach.tw. 

144. communications media/ 

145. health promotion.tw. 

146. (community adj8 intervention).tw. 

147. (advocacy adj5 program).tw. 

148. ((public or communty) adj2 (aware$ or promot$ or educat$)).mp. 

149. or/130-148 

150. Patient Care Team/ 

151. (psc or primary stroke cent$).tw. 

152. (stroke adj3 (service$ or center$ or centre$ or team$)).tw. 

153. stroke centre.mp. 

154. Intensive Care Units/ 

155. Hospital Units/ 

156. or/150-155 
A-4

157. emergency medical services/ 

158. Emergency Medicine/ 

159. (ems or emergency medical services).tw. 

160. Emergency Service, Hospital/ 

161. emergency care/ 

162. (emergency room or er).tw. 

163. emergency treatment/ 

164. ("911" or "999").tw. 

165. Paramedic$.mp. 

166. or/157-165 

167. clinical protocols/ 

168. program evaluation/ 

169. exp patient care planning/ 

170. (protocol$ or care plan$).mp. 

171. ((critical or clinical) adj2 path$).mp. 

172. treatment plan$.mp. 

173. or/167-172 

174. 166 and 173 

175. RANDOMIZED CONTROLLED TRIAL.pt. 

176. CONTROLLED CLINICAL TRIAL.pt. 

177. RANDOMIZED CONTROLLED TRIALS.sh. 

178. RANDOM ALLOCATION.sh. 

179. DOUBLE BLIND METHOD.sh. 

180. SINGLE-BLIND METHOD.sh. 

181. or/175-180 

182. (ANIMALS not HUMAN).sh. 

183. 181 not 182 

184. CLINICAL TRIAL.pt. 

185. exp CLINICAL TRIALS/ 

186. (clin$ adj25 trial$).ti,ab. 

187. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. 

188. PLACEBOS.sh. 

189. placebo$.ti,ab. 

190. random$.ti,ab. 

191. versus.tw. 

192. RESEARCH DESIGN.sh. 

193. or/184-192 

194. 193 not 182 

195. 194 not 183 

196. 183 or 195 

197. 44 and 196 

198. 61 and 196 

199. 81 and 7 and 196 

200. 89 and 10 and 196 

201. 100 and 7 and 196 

202. 112 and 7 and 196 

203. 129 and 7 

204. 149 and 10 

205. 156 and 10 and 196 

206. 174 and 10 

207. or/197,199-203 

208. limit 207 to all adult <19 plus years> 

209. or/198,204-206 

210. or/208-209 
A-5

Appendix B. Correspondence to Targeted Trial 

Investigators 

October 1, 2004 

Dear Dr. _________, 

I am writing on behalf of the University of Ottawa’s Evidence-based Practice Center 

(UO-EPC). We are conducting a systematic review on Acute Stroke, Evaluation & 

Treatment under the clinical leadership of Dr. Mukul Sharma. This review is being 

conducted under a contract from the Agency for Healthcare Research and Quality 

(AHRQ). 

The task involves the following three objectives: 

• To determine what interventions for acute stroke (delivered within the first 24 

hours from onset of symptoms) are effective in reducing stroke-related 

morbidity or mortality. 

• To review how the safety and effectiveness of these interventions vary with the 

timing of intervention in relation to onset of symptoms. 

• To determine what is the evidence that specific systems of care (i.e., dedicated 

stroke programs) improve outcomes of acute stroke. 

We are seeking out principle investigators, such as you, for additional evidence 

including unpublished trials that may have been terminated early, in event these trials 

may yield some valuable data pertinent to our review. We understand that permission 

would be required to cite any information provided to us and introduced into the public 

domain. 

We look forward to receiving any information you would deem appropriate for 

inclusion in this review at your earliest convenience. 

Kind regards, 

Chantelle Garritty, on behalf of Dr. Mukul Sharma & the University of Ottawa Evidencebased Practice Center (UO-EPC) 
A-6

Appendix C. Data Assessment and Data 

Abstraction Forms 

Relevance Assessment Forms 

Level 1 Screening of Titles and Abstracts—Eligibility Criteria 

Inclusion Criteria 

1. Does this report describe a study involving human participants? 

- Yes 

- No 

- Can’t tell 

2. Does this study include adults (>16 years old) with Acute Stroke (i.e., intracerebral 

hemorrhage [ICH] or ischemic stroke [IS])? 

- Yes 

- No 

- Can’t tell 

3. Is the purpose of the study to investigate the effect (e.g., efficacy, effectiveness, mortality, 

adverse events) of the following interventions: 

a) surgery for ICH, or 

b) antihypertensive therapy for ICH, or 

c) intra-arterial thrombolytic therapy for IS, or 

d) normalization of blood glucose levels for IS, or 

e) mechanical clot disruption for IS, or 

f) timing of thrombolytic therapy in IS, or 

g) pretreatment CT scoring system for IS, or 

h) pretreatment MRI scoring system for IS, or 

i) CT perfusion/angiography for IS, or 

j) community education programs for acute stroke, or 

k) use of designated centers for acute stroke, or 

l) use of ER protocols for management of acute stroke? 

- Yes 

- No 

- Can’t tell 

Exclusion Criteria 

4. If this is a narrative or systematic review opinion piece or editorial, letter, guideline or policy 

paper, etc., does it exclusively describe studies already reported elsewhere (i.e., it does not 

present any empirical evidence published for the first time)? 

- Yes 
A-7

- No 

- Can’t tell 

5. Is this study reported in English? 

- Yes 

- No 

- Can’t tell 

6. Comments:

Level 2 Screening of Full Articles—Eligibility Criteria 

Inclusion Criteria 

1. Is this study reported in English? 

- Yes 

- No 

2. Does this report describe a study involving human participants? 

- Yes 

- No 

- Can’t tell 

3. Does this study include adults (>16 years old) with Acute Stroke (i.e., intracerebral 

hemorrhage [ICH] or ischemic stroke [IS])? 

- Yes 

- No 

- Can’t tell 

4. Is the purpose of the study to investigate the effect (e.g., efficacy, effectiveness, mortality, 

adverse events) of the following interventions: 

a) Surgery for ICH, or 

b) Antihypertensive therapy for ICH, or 

c) Intra-arterial thrombolytic therapy for IS, or 

d) Normalization of blood glucose levels for IS, or 

e) Mechanical clot disruption for IS, or 

f) Timing of thrombolytic therapy in IS, or 

g) Pretreatment CT scoring system for IS, or 

h) Pretreatment MRI scoring system for IS, or 

i) CT perfusion/angiography for IS, or 

j) Community education programs for acute stroke, or 

k) Use of designated centers for acute stroke, or 

l) Use of ER protocols for management of acute stroke? 

- Yes 

- No 

- Can’t tell 

5. To which of the following topics does this study belong? 
A-8

(Check all that apply)

- a) Surgery for ICH 

- b) Antihypertensive therapy for ICH 

- c) Intra-arterial thrombolytic therapy for IS 

- d) Normalization of blood glucose levels for IS 

- e) Mechanical clot disruption for IS 

- f) Timing of thrombolytic therapy in IS 

- g) Pretreatment CT scoring system for IS 

- h) Pretreatment MRI scoring system for IS 

- i) CT perfusion/angiography for IS 

- j) Community education programs for acute stroke 

- k) Use of designated centers for acute stroke 

- l) Use of ER protocols for management of acute stroke 

Exclusion Criteria 

6. Is this study one of the following? 

• Narrative review, or 

• Systematic review, or 

• Opinion piece, or 

• Editorial, or 

• Letter, or 

• Guideline, or 

• Policy paper etc. 

- Yes 

- No 

- Can’t tell 

7. If answer to the above question is YES, does this article report original research data? (i.e., 

presents any empirical evidence published for the first time) 

- Yes 

- No 

- Can’t tell 

8. Was this full reference available by the stop date for relevance assessment at Level II? 

- unable to obtain for review by inclusion deadline 

- able to obtain for review by inclusion deadline 

9. Comments 

Study Type Classification 

1. Does this report belong to the following Levels of Evidence (see below)? 

- yes 

- no 
A-9

2. Level of Evidence of this report (select one) 

-RCT parallel design 

 -RCT crossover design 

 -RCT factorial design 

 -Controlled clinical trial (non-RCT) 

 -Multiple prospective cohorts 

 -At least one prospective cohort & one retrospective cohort 

 -Case-control 

 -Cross-sectional 

 -Before-after (pre-post) 

 -Single prospective cohort 

 -Single retrospective cohort 

 -Case series (noncomparative) 

 -Case study 

 -Sequential 

 -Cross-national ecological analysis 

 -Other: 

Data Abstraction Forms 

General Stroke Data Extraction 

1. Initials of reviewer:

2. Reference identification # (Refid): 

3. Author, Year, Location [number of sites]: 

4. Number of unique studies that this report describes: 

5. If other included reports refer to this same study, provide the Refid(s): 

6. Publication status (select one): 

 - Journal publication 

- Grey Literature (e.g., conference paper/abstract, internet document, Book chapter, 

thesis, etc) 

- Other 

7. Funding source type (select all that apply): 

- Government (Specify) 

- Industry (Specify) 

- Private (non-industry) (Specify) 

- Hospital (Specify) 

- Other (Specify) 

- Not reported 

8. Total # of individuals screened: 

9. Full sample size (enrolled in study): 

10. Full sample size (completing study): 

11. Full sample’s percentage of male participants: 

12. Comments, including notable differences between study arms / cohorts re ‘% male 

participants’: 

13. Mean age (SD/SE; range) of all study participants: 

14. Comments, including notable differences between study arms/cohorts re age: 

15. From which racial groups were participants drawn (select all that apply)?
A-10

- Black/African ancestry 

- Native North American 

- Hispanic 

- Asian 

- Caucasian/European 

- Other (specify) 

- Not reported 

- Can’t tell 

16. Specify each racial group’s percentage/proportion of full sample: 

17. Comments, including notable differences between study arms/cohorts re racial composition:

18. Specify each socioeconomic status (i.e., employment status, insurance, income, education, 

married) group’s percentage/proportion of full sample: 

19. Comments, including notable differences between study arms/cohorts re socioeconomic 

status: 

20. Eligibility criteria (select all): 

- List of study’s inclusion criteria: 

- List of study’s exclusion criteria: 

21. Type of setting where study was conducted (e.g., Emergency room, Teaching Hospital, etc):

22. Adverse events/ side effects reported in the present, per study arm/cohort: 

23. Number of drop outs/withdrawals, per study arm/cohort: 

24. Study duration, including units (includes run-in period duration, washout duration, 

intervention length, etc.): 

25. Comment box (optional): 

Specific Acute Stroke Data Extraction 

1. Initials of reviewer:

2. Reference identification # (Refid): 

3. Author, Year, Location [number of sites]: 

4. Number of unique studies that this report describes: 

5. If other included reports refer to this same study, provide the Refid(s): 

6. How was acute stroke defined? 

7. How was acute stroke diagnosed?

8. How was Acute Stroke classified (e.g. Ischemic, Hemorrhagic)? 

9. How was the severity of Acute Stroke defined? 

10. Describe the full sample’s baseline level of Acute Stroke symptoms and/or signs severity: 

11. Comments, including notable differences between arms/cohorts re participants’ baseline level 

of Acute Stroke symptoms and/or signs severity: 

12. Time since Stroke onset to intervention (specify: mean; range): 

13. Comments, including notable differences between arms/cohorts re participants’ baseline 

disease duration: 

14. Pre-study medication(s) or treatments for Acute Stroke, including dose/ frequency: 

15. Concurrent/antecedent conditions (select all that apply) 

- Arterial Hypertension 

- Diabetes Mellitus 

- Dyslipidemia 

- Smoking 

- Other 

- Not Reported 
A-11

16. Specify the percentage/proportion of the whole sample re each type of each 

concurrent/antecedent condition: 

17. Comments, including notable differences between study arms/cohorts re 

concurrent/antecedent conditions: 

18. Specify pre-study medications or treatments for each concurrent/antecedent condition, with 

dose/frequency: 

19. Comments, including notable differences between study arms/cohorts re pre-study 

medications/treatments: 

20. Which question(s) this study answer (select all that apply): 

- (A) Surgery for ICH 

- (B) Antihypertensive therapy for ICH 

- (C) Intra-arterial thrombolytic therapy for IS 

- (D) Normalization of blood glucose levels for IS 

- (E) Mechanical clot disruption for IS 

- (F) Timing of Thrombolytic therapy for IS 

- (G) Pretreatment CT scoring system for IS 

- (H) Pretreatment MRI scoring system for IS 

- (I) CT perfusion/angiography for IS 

- (J) Community education programs for acute stroke 

- (K) Use of designated centres for acute stroke 

- (L) Use of ER protocols for management of acute stroke 

21. Participants were enrolled according to which criterion (select one)? 

- Intention-to-treat (all randomized/enrolled) 

- Those receiving at least one dose 

- Those completing the study (i.e., with follow-up data) 

- Can’t tell 

- Not applicable 

- Other: 

22. Cointerventions: Medications and/or treatments allowed or permitted during the study period: 

23. Comments, including notable differences between study arms/cohorts re on-study 

medications/treatments: 

24. Type of intervention (Select one if applicable) 

Answer for Interventions 

(B) Antihypertensive Therapy for ICH &/or 

(D) Normalization of blood glucose levels for IS 

- Drug (see below) 

- Target (give target i.e., blood pressure, glucose level) 

- Not applicable 

25. Imaging tests performed on-study: (check all that apply) 

Answer for Interventions 

(G) Pretreatment CT scoring system for IS, 

(H) Pretreatment MRI scoring system for IS, &/or 

(I) CT perfusion/angiography for IS 

- CT 

- CT perfusion 

- CT angio 

- MRI (other than DWI/PWI) 

- MRI DWI/PWI 

- Other 

- Not reported 

- Not applicable 
A-12

26. Describe listed characteristics of imaging tests (see above question) used to make the 

intervention decision. 

Answer for Interventions 

(G) Pretreatment CT scoring system for IS, 

(H) Pretreatment MRI scoring system for IS, &/or 

(I) CT perfusion/angiography for IS 

27. ‘Centre’ definition used: (select all that apply) 

Answer for Intervention 

(K) Use of designated centres for acute stroke 

- Brain Attack Coalition (BAC) (definition at bottom) 

- Other (describe) 

28. Intervention components (check all that apply) 

Answer for Intervention 

(L) Use of ER protocols for management of acute stroke 

- Stroke team 

- 24 hour CT 

- Written protocol orders 

- Professional education 

- Drug storage in ER 

- Other 

29. Study GROUP 1: Intervention of interest (e.g., Surgery for ICH): (Select all) 

- Define study group (e.g., by time window since stroke onset): 

- Intervention/ exposure/ procedure type: 

- Dose/ frequency/ timing (if apply): 

- Intervention Length: 

- N enrolled/completed: 

30. Study GROUP 2: first comparator (e.g., placebo, other type of intervention): (Select all): 

- Define study group (e.g., by time window since stroke onset): 

- Intervention/ exposure/ procedure type: 

- Dose/ frequency/ timing (if apply): 

- Intervention Length: 

- N enrolled/completed: 

31. Study GROUP 3: (if applicable) 

- Define study group (e.g., by time window since stroke onset): 

- Intervention/ exposure/ procedure type: 

- Dose/ frequency/ timing (if apply): 

- Intervention Length: 

- N enrolled/completed: 

32. Study GROUP 4: (if applicable) 

- Define study group (e.g., by time window since stroke onset): 

- Intervention/ exposure/ procedure type: 

- Dose/ frequency/ timing (if apply): 

- Intervention Length: 

- N enrolled/completed: 

33. Outcome measures with significance (e.g., Surgery S better than no surgery) 

(select all that apply) 

- NIHSS 

- mRS (Modified Rankin Scale) 

- Barthel 

- FIM 

- Time to treatment 
A-13

- Time to presentation to ER (arrival) 

- Other (describe all the outcomes assessed not mentioned above) 

34. Identify any problems with the research design (e.g., definition of placebo/control(s); 

inappropriateness of run-in and washout periods), or its implementation:

35. Comment box (optional): 

Quality Assessment Forms—RCTs 

Jadad Scale 

Descriptor Yes No 

Was the study described as randomized (this includes the use of words such 

as randomly, random, and randomization)? 

 

The method used to generate the sequence of randomization was described 

and it was appropriate (table of random numbers, computer generated, etc) 

 

Was the report of allocation 

concealment: 

Adequate 1 Inadequate 1 Unclear 1

Was the study described as double blind? 

 

The method of double blinding was described and it was appropriate

(identical placebo, active placebo, dummy, etc)? 

 

Was there a description of withdrawals and dropouts? 

 

Note: Clinical controlled trials were assessed out of a possible score of 3 according to a modified 

Jadad scale 

Allocation Concealment - Refers to the technique used to implement the randomization sequence, 

not to generate it. 

Adequate 

• Sequentially numbered, opaque, sealed envelopes (SNOSE) 

• Pharmacy controlled 

• Numbered or ordered containers 

• Central randomization – for example by telephone to a trials office or other method 

whose description contained elements convincing of concealment – for example a secure 

computer assisted method.

Inadequate 

• Alternation 

• Reference to case record numbers or to dates of birth 
A-14

Unclear 

• No mention of an allocation concealment approach at all 

• An approach that does not fall into either adequate or inadequate allocation concealment 
A-15

Quality Assessment Forms—Case-Control and Cohort 

Studies 

Newcastle-Ottawa Scale (NOS) 

Descriptor Yes No Can’t tell 

Was the therapeutic intervention reported? 

Were the inclusion/exclusion criteria reported? 

Was follow-up reported as an inclusion criterion? 

Was the sample size determination reported (cases accrued consecutively 

or non consecutively over a specified time period)? 

 

Were the sample size calculations (and any assumptions) reported? 

Was the time period for accrual of cases and whether they were 

accumulated prospectively or retrospectively reported? 

 

Were the sources of participants (same or different clinicians, one or more 

center) reported? 

 

Were how the outcome assessments made and who made them reported? 

Was blinding reported? 

Were the primary and secondary measures reported? 

Was the timing of the outcome measures reported? 

Was a follow-up schedule reported? 

Were efforts used to maintain follow-up with participants reported? 

Did the authors report on compliance with follow-up? 

Was the method of data collection reported? 

Were any participant exclusions from data analysis reported? 

Was the statistical approach for analyzing the data reported? 

Did the authors report any missing data and how it was handled in the 

data analysis? 

 

Did the authors report any adverse events? 
A-16

Quality Assessment Forms—Noncomparative CaseSeries Studies 

Quality assessment Yes Partial No N/A

1. Question / objective sufficiently described? 

2. Design evident and appropriate to answer study question? 

3. Subject characteristics sufficiently described? 

4. Subjects appropriate to the study question? 

5. Controls used and appropriate? (if no control, check no) 

6. Method of subject selection described and appropriate? 

7. If random allocation to treatment groups was possible, is it 

described? (if not possible, check n/a) 

 

8. If blinding of investigators to intervention was possible, is it 

reported? (If not possible, n/a) 

 

9. If blinding of subjects to intervention was possible, is it reported? 

(If not possible, n/a)1

 

10. Outcome measure well defined and robust to measurement bias? 

Means of assessment reported? 

 

11. Confounding accounted for? 

12. Sample size adequate? 

13. Post hoc power calculations or confidence intervals reported for 

statistically non-significant results? 

 

14. Statistical analyses appropriate? 

15. Statistical tests stated? 

16. Exact p-values or confidence intervals stated? 

17. Attrition of subjects and reason for attrition recorded? 

18. Results reported in sufficient detail? 

19. Do the results support the conclusions? 

Sum (items 1-19) 
A-17

Appendix D. Modified QUOROM Flow Chart 

Modified QUOROM Flow Chart 

*Note: some items were eligible for both reviews, therefore, the sum does not add up to 

the number of included studies. 

7487 - Screened at Level 1 

6098 - Failed to meet inclusion criteria: 

255 - No human participants 

5549 - No adult (>16) or acute stroke 

67 - No original empirical evidence presented 

227 - No intervention of interest studied 

1389 Eligible for assessment of relevance at Level 2 

N= 36 records (but reporting on 37 studies) 

9994 - Records identified 

2511 - Duplicate records removed 

100 records did not provide sufficient level of 

evidence for related question

11253 - Failed to meet inclusion criteria: 

15 – Non-English publication 

87 - No human participants 

286 – No adult (>16) or acute stroke 

486 - No original empirical evidence presented 

322 - No intervention of interest studied 

57 – Unable to obtain by final date for inclusion 

136 Eligible for assessment of relevance at Level 3 
E-18

Appendix E. Evidence Tables 

Experimental Studies 

Evidence Table 1: Randomized clinical trials 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Albers, 2002, US1

Design: RCT Parallel 

n= 61 Age: IG 66 (10)y; CG; 66 (11)y % Male: IG 82.6; CG 57.9 Race: White IG 95.7%; CG 84.2%e; Black IG 0%; CG 10.5%; Hispanic IG 0%; CG 5.3%; Asian IG 4.3%; CG 0% 

Inclusion Criteria: Acute IS defined by sudden onset of an acute focal neurological deficit due to ischemia with no sign of hemorrhage by CT; MCA origin with measurable focal neurological deficit; age 18-79y; within 3-5 hr post onset 

Exclusion Criteria: ICH by CT; sign of ischemia in > 1/3 of the territory of MCA; other exclusion as ATLANTIS A trial2

I: Timing of thrombolytic therapy in IS (n=23) C: Control (n=38) 

I: tPA / 0.9 mg/kg C: Placebo 

• Mortality (90 d) • NIHSS, mRS, BI, 

GCS (30, 90d) 

• Rate of ICH 

1

US = United States; RCT = randomized controlled trial; NR = not reported; NA = not available; n = number of participants; pts = patien

hr = hour; min = minutes; s = seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = internatio

millimoles / litre; MHz = megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic 

hemorrhage; ER = emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatme

intravenous; IA = intra arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical anacerebral artery; AVM = arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurol

Stroke; NIHSS = National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow 

Modified Rankin Scale; GCS = Glasgow Coma Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS 

NIH = National Institutes of Health NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-19

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Alexandrov, 2004, US & Canada3

Design: RCT Parallel 

n=126 Age: IG 67(12)y; CG 70(13)y % Male: NR Race: NR Inclusion Criteria: Acute IS of MCA, within 3 hr post onset; IG Abnormal flow through MCA, with TIBI scale grade 0-3 (Thrombolysis in Brain Ischemia flow-grading system) before TPA tx Exclusion Criteria: NR 

I: Mechanical clot disruption for IS (n=63) C: Control (n=63) 

I: Continuous 2-MHz transcranial Doppler ultrasonography / 750 mW & 3-6 mm insonation for 2hr + tPA/ 0.9 mg/kg, up to 90 mg/ within 3 hr post onset 

C: tPA/ same as IG + placebo (inactive channel with no continuous insonation) 

• Complete 

recanalization rate 

• Clinical recovery 

4/

US = United States; RCT = randomized controlled trial; NR = not reported; NA = not available; n = number of participants; pts = patien

month; hr = hour; min = minutes; s = seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = in

= millimoles / litre; MHz = megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemi

intracranial hemorrhage; ER = emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; t

history; IV = intravenous; IA = intra arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of stmiddle cerebral artery; AVM = arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute o

and Stroke; NIHSS = National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glas= Modified Rankin Scale; GCS = Glasgow Coma Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS 

Service; NIH = National Institutes of Health NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-20

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Auer, 1989, Austria4

Design: RCT Parallel 

n=100 Age: 30-80y % Male: IG 56; CG 66 Race: NR Inclusion Criteria: Acute, hematoma > 10 cm3; within 48 hr of hemorrhage 

with neurological deficits, consciousness impairment, approved for surgery / angiography, Exclusion Criteria: aneurysm, arteriovenous malformation, tumor as the bleeding source, post-traumatic intracerebral hematomas 

I: Surgery for ICH, (n=50) C: Medical tx (n=50) 

I: Hematoma evacuation through burr hole/<24h C: Medical tx, endoscopy 

• Mortality rate (1 wk*, 

6 mo*) 

• Neurological recovery 

by clinical & CT signs 

(6 wk, 6 mo) 

1/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

= recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NH

Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-21

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Batjer, 1999, US5

Design: RCT Parallel 

n=21 Age: IG 53.3 (3.4)y; CG1 54.9 (3.5) y; CG2 53.3 (5.9) y % Male: NR Race: NR Inclusion Criteria: Acute hypertensive putaminal ICH ≥3cm in diameter, moderate to severe hemiparesis/ uniform hemiplegia (grade 1-3)< 24hr post onset Exclusion Criteria: Un-associated neurologic illness, end-stage systemic disease; coagulopathy of any cause; aneurysm; arterioveous malformation, or tumour; decorticate or decerebrate posturing 

I: Surgery for ICH (n=8) C1: Best medical management (n=9) C2: Best medical management + intracranial pressure monitoring (n=4) 

I: Frontotemporal or pterional craniotomy C1: IV dexamethasone/ 4mg tapered over 7-14 d C2: Antihypertensive same as C1 arm + placement of frontal ventriculostomy 

• Mortality rate (6 mo) • Functional recovery (6 

mo) 

1/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-22

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics 

Intervention (I) 

/Comparator 

(C) 

Technique /Dose 

/Timing 

Reported Outcomes 

(follow-up interval)

Qu

Asses

(Ja

Clark, 1999, US6

Design: RCT Parallel 

n= 547 

Age: IG: 66 (12)y; CG; 65 (11)y % Male: IG: 54.8; CG: 63.6 Race: White IG: 84.6%; CG: 83.6% Inclusion Criteria: Acute IS defined by sudden onset of an acute focal neurological deficit due to ischemia with no sign of hemorrhage by CT; MCA origin with measurable focal neurological deficit; age 18-79y; within 3-5 hr post onset 

Exclusion Criteria: ICH by CT; sign of ischemia in > 1/3 of the territory of MCA; other exclusion as ATLANTIS A trial2

I: Timing of thrombolytic therapy in IS (n=272) C: Control (n=275) 

I: TPA / 0.9 mg/kg, up to 90 mg (10% IV bolus over 1-2 min & 90% IV infusion over 1 hr)/ 1 hr C: Placebo/ matching dose for 1 hr 

• Mortality (90 d) • NIHSS, mRS, BI, 

GCS (30, 90d) 

2

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

 NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-23

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qu

Asses

(Ja

Clark, 2000, US2

Design: RCT Parallel 

n=142 Age: I 67 (13)y; C 65 (12)y % Male: NR Race: I = 82% White; C = 86% White Inclusion Criteria: Acute stroke with neurological deficit, within 6 hr post symptom onset Exclusion Criteria: Coma, severe obtundation, fixed eye deviation, complete hemiplegia; NIHSS <4; seizure; known ICH; hypertension; septicembolus; pericarditis or ventricular thrombus or aneurysm; trauma within 30 d; head trauma within 90 d; diathesis; pregnancy, lactation or parturition within 30 d; glucose <50 or >400, platelets <100,000, hematocrit <25; terminal illness; S hazard to tx 

I: Timing of thrombolytic therapy in IS (n=71) C: Control (n=71) 

I: TPA / 0.9 mg/kg, up to 90 mg (10% IV bolus over 1-2 min & 90% IV infusion over 1 hr)/ 1 hr C: Placebo/ matching dose for 1 hr 

• Recanalization* 

(negative effect of TPA) 

• NIHSS, mRS, 

Barthel Index 

• Mortality 

(90 d) 

• Symptomatic ICH 

rate 

2

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-24

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) 

del Zoppo, 1998, US & Canada7

Design: RCT parallel 

n=40 Age: full 64.2 (12.1)y; IG 66.5 (11)y, CG 69.6 (11.1)y % Male: IG 54; CG 36 Race: White IG 77%; CG 71% Inclusion Criteria: Acute carotid artery stroke; new focal neurological signs in the MCA within 6 hr of onset, NIHSS score ≥4; (except for isolated aphasia or hemianopsia; age 18-85y Exclusion Criteria: NIHSS score >30; coma; minor stroke symptoms; history of stroke within 6 wk; seizure; hypertension; head trauma within 90 d; active or recent hemorrhage within 14 d; diathesis; oral anticoagulation international normalized ratio >1.5 

I: Timing of thrombolytic therapy in IS (n=26) C: Placebo (n=14)

I: IA Pro-Urokinase/ 6 mg + Heparin/ 100 IU/kg bolus + 1000-2000 I.U./hr infusion/ median 5.5 hr post symptom onset 

C: Saline placebo/ matching heparin/ matching time 

• MCA recanalization* • Hemorrhage 

frequencies 

• Mortality • Functional outcomes 

(mRS, Barthel Index, NIHSS) 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

= milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles / litre; MHz = group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhage; ER = emergen

computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = intra arterial; tPA = rec

activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; AVM = arteriovenous malformatio

cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = National Institute of Health and Stroke Sca

Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rankin Scale; GCS = Glasgow Coma Scale; NOS = 

Heart and Stroke Foundation; AHA = American Heart Association; NHS = National Health Service; NIH = National Institutes of Health

Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-25

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Eggers, 2003, Germany8

Design: RCT Parallel 

n=25 Age: full 61.3 (9.1)y; IG 60.3 (10.3)y; CG 62.1 (8.3)y % Male: full 76; IG 73; CG 79 Race: NR Inclusion Criteria: Acute IS in MCA/ M1; 18-80y, within 3 hr symptom onset (according to NINDS criteria)Exclusion Criteria: age <18y; pregnancy or lactation; insufficient acoustic window no allowing identification of the main basal cerebral arteries 

I: Mechanical clot disruption for IS (n=11) C: Control (n=14) 

I: Ultrasound/ continues 2 MHz transcranial Doppler mode + TPA/ 0.9 mg/kg IV over 1 hr C: Matching IV TPA tx for 1 hr 

• Barthel Index (90 d)* • NIHSS/ mRS • Mortality 

1/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated
E-26

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qu

Asse

(Ja

Furlan, 1999, US & Canada9

Design: RCT parallel 

n=180 Age: full 64 (14)y (groups identical in age) % Male: full 59; IG 58, CG 61 Race: White 80% Inclusion Criteria: Acute IS (MCA), 18-85y, with new neurological symptoms < 6 hr post symptom onset; NIHSS score ≥4 Exclusion Criteria: NIHSS score >30; coma; improving neurological signs; history of stroke; seizure at onset; subarachnoid hemorrhage; history of ICH; neoplasm or subarachnoid hemorrhage; septic embolism; lacunar stroke; surgery; organ biopsy; head trauma within 90 d; active or recent hemorrhage within 30 d; known hemorrhagic diathesis; uncontrolled hypertension 

I: Timing of thrombolytic therapy in IS: IA Urokinase tx (n=121) C: Placebo (n=59) 

I: IA Urokinase/ 9 mg + heparin/NR for 2 hr C: Saline + Heparin for 2 hr 

• mRS (90 d) • MCA recanalization* • Frequency of ICH • Mortality (90 d)

3

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-27

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Gray, 2004 UK10

Design: RCT Parallel 

n=452 Age: IG 75.2y; CG 74.4y % Male: IG 50.6; CG 54.1 Race: NR Inclusion Criteria: Acute stroke< 24 hr post symptom onset, with admission glucose level >6 to <17 mmol/L Exclusion Criteria: Coma; hx of insulin-requiring diabetes; anemia; renal failure; congestive heart failure; S pre-existing disability 

I: Normalization of blood glucose levels for IS (n=221) C: Control (n=231) 

I: (GKI) Dextrose / continuous IV of 10% + Potassium chloride /20 mmol + Human soluble Actrapid / variable dose starting with 16 U/L for 24 hr C: Saline/ 0.9% at 100 mL/hr for 24 hr 

• Difference in mean 

plasma glucose values at subsequent time intervals in 24 h 

1/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-28

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identificatio

n 

Population Characteristics 

Intervention (I) 

/Comparator 

(C) 

Technique /Dose 

/Timing 

Reported 

Outcomes 

(follow-up 

interval) 

Qua

Asses

(Jad

Hacke, 1998, Europe, Austrialia, New Zealanc11Design: RCT Parallel 

n=800 Age: median, IG=CG 68 y % Male: IG 60.6; CG 56.2 Race: NR Inclusion Criteria: Acute ischemic stroke within 6 hrs of onset, early infarct change on CT less than 33% of the MCA territory Exclusion Criteria: signs of ICH or parenchymal hypoattenuation > 1/3 MCA territory; brain swelling > 33% of MCA; subarachnoid haemorrhage; unknown time of onset; coma or stupor; hemiplegia + fixed eye deviation; minor stroke symptoms (> 50 of the maximum 58 points on the SSS before randomization, or rapid improvement of symptoms); seizure < 6 mo; hypertension at randomization; traumatic brain injury < 14 d; recent surgery on the central nervous system; gastrointestinal or urinary tract haemorrhage; current tx with IA or subcutaneous heparin to raise the clotting time; known hereditary or acquired haemorrhagic diathesis; lactation; pregnancy or recent parturition < 30 d; lack of medically approved means of concentrations 

I: rtPA (n=409) C: Placebo (n=391) 

I: Alteplase 0.9 mg/kg bodyweight, maximum of 90 mg/pts; bolus of 10% of the total dose over 1-2 min followed by a 60 min IV infusion of the remaining dose. (admin of anticoagulants, antiplatelet agents, haemorrheological agents, potential neuroprotective drugs & volume expanders were prohibited during 1st 24 

hr) C: Identical tx with placebo agent 

• Mortality • mRS • ICH rate 

4/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-29

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics 

Intervention 

(I) 

/Comparator 

(C) 

Technique /Dose 

/Timing 

Reported Outcomes 

(follow-up interval) 

Qua

Asses

(Jad

Hacke, 1995, Europe 12

Design: RCT Parallel 

n=620 Age: IG 65 (12)y; CG 65 (11) % Male: IG 60.1; CG 65.5 Race: NR Inclusion Criteria: Acute ischemic stroke, 18-80 y; 0-6 hrs, early infarct change on CT less than 33% of the MCA territory Exclusion Criteria: See the eligibility criteria listed for Hacke 199811

I: rtPA (n=313) C: Placebo (n=307) 

I: rtPA 1.1 mg/kg C: Placebo 

• Primary: Barthel, mRS 

(90 d) 

• Secondary: Combined 

Barthel & mRS, SSS (90 d)/ Mortality (30 d) 

• Tertiary: Early 

neurological recovery (SSS), and duration of hospital stay 

4/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-30

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qu

Asse

(Ja

Haley, 1993, US13

Design: RCT Parallel 

n=27 Age: Within 90 min: IG 65 (11)y; CG 64 (8) y; 91-180 min: IG 72 (1)y, CG 67 (9)y% Male: NR Race: NR Inclusion Criteria: Acute IS causing neurological deficit, age 18-80, within 90 min or 91-180 min post symptom onset Exclusion Criteria: Mild stroke; symptoms only of sensory loss or ataxia; IC or subarachnoid hemorrhage; pregnancy, lactation; platelet < 100 000/mm3; protrombin time >15 s; elevated partial thromboplastin time due to heparin tx; major surgery or serious trauma within 14 d; gastrointestinal or urinary tract hemorrhage within 21d; arterial puncture at noncompressible site within 7 d; mean BP ≥135 mmHg; brain infarction within 90 d; serious medical illness 

I: Timing of thrombolytic therapy in IS (n=14) C: Control (n=13) 

I: IV tPA / 0.85 mg/kg for 1 hr C: IV placebo/ matching dose for 1 hr 

• NIHSS (baseline, 30 

min, 1, 2 hr post infusion & 24 hr* post stroke), mRS, Barthel Index, GCS 

• Mortality • Onset to treatment 

time (OTT) interaction

5

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-31

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Juvela, 1989, Finland{1124} Design: RCT Parallel 

n=52 Age: IG 54 (8.9)y, CG 49.3 (10.1)y % Male: full 58; IG 65; CG 50 Race: NR Inclusion Criteria: Acute ICH within 24 hr post bleed; unconscious &/or severe hemiparesis or dysphasia Exclusion Criteria: Cerebellar hematomas; traumatic hemorrhages; hemorrhages into brain tumors, & hemorrhages from cerebral aneurysms & arteriovenous malformations; malignant diseases; severe heart, lung or endocrine diseases; improving clinical condition or no reaction to pain 

I: Surgery for ICH (n=26) C: Conservative tx (n=26) 

I: Surgery within 48 hr post bleeding (methods NR) C1: NR/ within 48 hr post bleeding 

• Mortality rate (6 mo) • Morbidity • GCS 

1

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Ranki

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-32

Evidence Table 1 (cont’d): Randomized clinical trial

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qual

Assess

(Jada

Kase, 2001, US14

Design: RCT Parallel 

n=174 Age: 64.2 (12.1)y % Male: NR Race: NR Inclusion Criteria: Acute IS M1 or M2 segments of MCA <6 hr post symptom onset; NIHSS score 4-30Exclusion Criteria: NR 

I: Timing of thrombolytic therapy in IS (n=110) C: Placebo (n=64) 

I: IA Urokinase/ 9 mg directly into clot for 2 hr + Heparin/2000 IU bolus followed by 500 IU/hr for 2 hr C: Saline + Heparin/ matching dose & timing 

• Symptomatic ICH 

(relationship with baseline characteristics) 

• Mortality following 

symptomatic ICH 

• Serum glucose level

2/5 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-33

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Keris, 2001, Latvia15

Design: RCT Parallel 

n=45 Age: IG 53 (9)y; CG 65 (8)y % Male: IG 83; CG 51.5 Race: NR Inclusion Criteria: Acute severe hemiparetic IS within 6 hr post symptom onset Exclusion Criteria: sulcal effacement, mass effect, edema, or possible hemorrhage on CT 

I: Timing of thrombolytic therapy in IS (n=12) C: Conventional tx (n=33) 

I: IA TPA/ 25 mg for 5-10 min; IV TPA/25 mg for 60 min + Heparin/ 5000 U initially & twice a day for several days C: Heparin/ matching dose & frequency 

• mRS (1, 12 mo, rated 

as good/poor) 

• Mortality 

1/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracrania

emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV 

arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle ce

arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and S

National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; m

Scale; GCS = Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart A

National Health Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-34

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Lewandowski, 1999, US16

Design: RCT Parallel 

n=35 Age: IG 65.6 (11.2)y; CG 67.3 (12.3)y % Male: full 54.3; IG 53; CG 56 Race: White, full 48.6%; IG 41%; CG 56% Inclusion Criteria: Acute focal IS within 3 hr of symptom onset (based on NINDS TPA stroke study) Exclusion Criteria: based on NINDS tPA stroke study, also excluded pts with hx of stroke within 6 wk; surgery biopsy or haemorrhage within 30 d of randomization 

I: Timing of thrombolytic therapy in IS (n=17) C: Placebo+ IA thrombolytic tx (n=18) 

I: IV TPA/ 0.6 mg/kg for 30 min; IA TPA/ 0.6 mg/kg max 20 mg for max 2 hr C: IV placebo + IA TPA/ matching dose for 2 hr max 

• NIHSS (7-10 d) • Barthel Index, mRS, 

GCS (3mo) 

• ICH & recanalization 

rate 

4/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracrania

emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV 

arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle ce

arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and S

National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; m

Scale; GCS = Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart A

National Health Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-35

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Marler, 2000, US17

(Part A) Design: RCT Parallel 

n=302 Age: NR % Male: NR Race: NR Inclusion Criteria: Acute stroke 0-90 min post symptom onset (based on NINDS TPA study for stroke) Exclusion Criteria: based on NINDS TPA study for stroke 

I: Timing of thrombolytic therapy in IS (n=157) C: Control (n=145) 

I: IV TPA/ 0.9 mg/kg (10% bolus & 90% as infusion), max 90 mg, for 1 hr C: Placebo powder/ 0.9 mg/kg 10% bolus & 90% as IV infusion for 1 hr 

• NIHSS mRS, Barthel 

Index, GCS (baseline, 24 hr, 3 mo) 

• Time to tx & outcome

1/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracrania

emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV 

arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle ce

arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and S

National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; m

Scale; GCS = Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart A

National Health Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-36

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qual

Assess

(Jada

Marler, 2000, US17

Part B Design: RCT Parallel 

n=320 Age: NR % Male: NR Race: NR Inclusion Criteria: Acute stroke 91-180 min post symptom onset (based on NINDS TPA study for stroke) Exclusion Criteria: based on NINDS TPA study for stroke 

I: Timing of thrombolytic therapy in IS (n=153) C: Control (n=167) 

I: IV TPA/ 0.9 mg/kg (10% bolus & 90% as infusion), max 90 mg, for 1 hr C: Placebo powder/ 0.9 mg/kg 10% bolus & 90% as IV infusion for 1 hr 

• NIHSS, mRS, Barthel 

Index, GCS (baseline, 24 hr, 3 mo), 

• Time to tx & outcome 

1/5 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracrania

emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV 

arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle ce

arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and S

National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; m

Scale; GCS = Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart A

National Health Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-37

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Mendelow, 2005, UK18

Design: RCT Parallel (Reviewer nominated; published beyond search dates) 

n=1033 Age: IG 62 (52-70)y; CG 62 (53-71)y % male: full 57.2; IG 57; 58CG Race: NR Inclusion Criteria: CT evidence of spontaneous supratentorial ICH, within 72 hr; uncertainty by neurosurgeon about benefits of either tx; hematoma ≥2 cm; GCS >=5 Exclusion Criteria: haemorrhage due to an aneurysm or an angiographically proven arterobenous malformation; haemorrhage secondary ot a tumour or trauma; pts with cerebellar haemorrhage or extension of a supratentorial haelorrhage intor the brainstem; pts with severe pre-existing physical or mental diability or severe comorbidity that might intrerfer with the assessment of outcome;or if the surgery could not be undertaken within 24 hr of randomization

I: Surgery for ICH (n=503) C: Conservative tx (n=530) Baseline differences: NR Comments: Cross over from IG to CG n=31; from CG to IG n=140 

I: Early surgery combined haematoma evacuation within 24 hr of randomization C: Medical tx followed by evacuation if necessary 

• Mortality • Functional outcomes 

(BI, mRS) 

3/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracrania

emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV 

arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle ce

arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and S

National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; m

Scale; GCS = Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart A

National Health Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-38

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qual

Assess

(Jada

Morgenstern, 1998, US19

Design: RCT Parallel 

n=34 Age: IG 56 (22-72) y; CG 51 (37-77) y % Male: full 65; IG 29.4; CG 41 Race: 32.4 % non-White, 67.6% White Inclusion Criteria: Acute ICH > 9 mL diagnosed by CT within 3 hr screening, <12 hr; GCS 5-15 Exclusion Criteria: Secondary ICH; brainstem or cerebellar ICH, or ICH of thalamus or ventricular system; prehemorrhage low functional level; coagulopathy (>15 s; elevated partial thromboplastin time, platelet <100,000/mm3); 

precluded 6 mo survival; biopsyproved amyloid angiopathy; hematoma volume 10-19 mL; GCS >15; better than antigravity strength on the affected side; ventricular extension >1/2 of one lateral ventricle or 1/3 of both lateral ventricles 

I: Surgery for ICH (n=17) C: Standard medical tx (n=17) 

I: Open craniotomy & hematoma evacuation/ <12 hr post onset C1: Standard medical tx /NR 

• Mortality • Barthel Index, GCS 

1/5 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracrania

emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV 

arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle ce

arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and S

National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; m

Scale; GCS = Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart A

National Health Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-39

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qual

Assess

(Jada

Patel, 2001, US20

Design: RCT Parallel 

n=624 Age: 61-68y % Male: NR Race: NR Enrolment: Jan 1991–Oct 1994 Inclusion Criteria: Acute IS < 3 hr (0-90 & 91-180 min) post onset Exclusion Criteria: NR 

I: Pretreatment CT scoring system for IS(n=312) C: Control (n=312) 

I: CT/ within 3h symptom onset + IV tPA C: CT /within 3 hr symptom onset + placebo 

• Frequency of EIC on 

baseline CT/ association of EIC with other baseline variables; effect of EIC on deterioration at 24 hr 

• NIHSS, Barthel Index, 

mRS, GCS (3 mo) 

• Mortality (3 mo) • ICH rate (within 36 hr 

of tx) 

2/5 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracrania

emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV 

arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle ce

arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and S

National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; m

Scale; GCS = Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart A

National Health Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-40

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Q

Ass

(J

Roberts, 2002, US21

Design: RCT Parallel 

n=159 Age: NR % Male: NR Race: NR Inclusion Criteria: Acute IS of MCA origin within 6 hr of onset; angiography: complete occlusion or contrast penetration with minimal perfusion of M1 or and M2 (based on PROACT II trial criteria segment of MCA) Exclusion Criteria: based on PROACT II trial criteria 

I: Pre-tx CT scoring system for IS (n=107) C: Control (n=52) 

I: CT, angiography /baseline, 24 hr, 7-10 d + recombinant proUrokinase/ 9 mg + IV heparin/2000 U bolus & 500U/hr for 4 hr at beginning of angiography C: CT/ matching intervals + IV heparin/ matching dose 

• Correlation of 

baseline CT with clinical outcomes 

• NIHSS, mRS (90 d) • Mortality (90 d) 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-41

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qu

Asse

(Ja

Scott, 1999, UK22

Design: RCT Parallel 

n=53 Age: median IG 74 (11)y; CG 74 (9.6)y % Male: full 44; IG 52; CG 36 Race: NR Inclusion Criteria: Acute IS with neurological deficit lasting >24 hr, age >18 y; within 24 hr of onset Exclusion Criteria: > 24 hr post onset; coma; pneumonia; heart failure (New York Heart Association grades 3 or 4), renal failure (creatinine level of > 200 micro sing-mol/l; anemia (Hb 3); dementia; isolated posterior circulation syndromes without physical disability; pure language disorders; previously diagnosed insulin treated diabetes (type 1 or 2); or subarachnoid hemorrhage 

I: Normalization of blood glucose levels for IS (n=28) C: Control (n=25) 

I: (GKI) Dextrose/ 500 mL 10% + Potassium chloride 20 mmol + Human soluble Actrapid insulin/16 U/L C: Same as I/ glucoscans q2h for 24 hr 

• Mortality • Plasma glucose level 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-42

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Quality Assessm

(Jadad

Teernstra, 2003, The Netherlands23

Design: RCT Parallel 

n=71 Age: IG 67 (± 68, range 47-84) y; CG 69 (±71, range 49-89) y % Male: full 56.3; IG 58; CG 56 Race: NR Inclusion Criteria: Pts with expected mortality of 88%; age >45 y, ICH >10 cm3, within 72 hrs of 

ictus, Glasgow Eye Motor Score 2-10 Exclusion Criteria: Arterioveous malformation 

I: Surgery for ICH (n=36) C: No-Surgery (n=35) 

I: Stereotactic tx of ICH by plasminogen activator, Urokinase/ 5000 IU, 8 x in 6 hr intervals over 48 hr C1: Standard medical care 

• ICH volume reduction (immediate*)• mRS • Mortality (6mo) 

2/5 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracrania

emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV 

intra arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = midd

AVM = arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorder

= National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; 

Rankin Scale; GCS = Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American NHS = National Health Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-43

Evidence Table 1 (cont’d): Randomized clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) Qua

Asses

(Jad

Zuccarello, 1999, US24

Design: RCT Parallel 

n=20 Age: 62.4 (NR)y, 27-80y % Male: 55 Race: White 60%; Black 40% Inclusion Criteria: Acute supratentorial ICH >10 cm3, 

diagnosed by CT, with focal neurological deficit; age >18y; GCS >4, within 24 hr of onset; surgery within 3 hr of randomization Exclusion Criteria: Lack of neurological deficit; infratentorial ICH; vascular abnormality proven by CT; terminal illness; coagulopathy; traumatic ICH; pregnancy 

I: Surgery for ICH (n=9) C: Control (n=11) 

I: Varied techniques i.e. open craniotomy or CT-guided Stereotactic aspiration with 6000 U Urokinase in 12 hr intervals/ median 8 hr 35 min post onset C: Medical tx/ varied according to tx regiment/ median 3 hr 17 min onset to admission & 3 hr 10 min admission to randomization 

• NIHSS (median 3 

mo)* 

• Mortality • Barhel Index • ICH volume 

2/

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

megahertz; IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracrania

emergency room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV 

intra arterial; tPA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = midd

AVM = arteriovenous malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorder

= National Institute of Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; 

Rankin Scale; GCS = Glasgow Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American NHS = National Health Service; NIH = National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-44

Evidence Table 1 (cont’d): Controlled clinical trial 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes (follow-up interval) 

Qu

Asses

(Mo

Jad

Morgenstern, 2003, US25

Design: Controlled Clinical Trial 

n=1427 (for all 3 phases); phase 3 only: n=238 Age: phase 1: >21y % Male: phase 1: IG 42.6, CG 38.2; phase 2: IG 43.3, CG 41.9; phase 3: IG 43.1, CG 43.5 Race: Non-White/ phase 1: IG 23.4%, CG 34%; phase 2: IG 20.8%, CG 28%; phase 3: IG 25.4%, CG 31.5% Inclusion Criteria: County residents experience of cerebrovascular event; IV tPA inclusion according to NINDS Exclusion Criteria: non-résidents; age < 21y 

I: Community education program for acute stroke (n=748/ phase 3: n=130) C: Control (n=679/ phase 3: n=108) 

I: Community education + professional development & organizational change/ 15 mo C: No intervention/15 mo 

• Frequency of IV TPA 

tx in IS* 

• Frequency of IV TPA 

in eligible candidates* 

1

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment 

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-45

Observational Studies 

Evidence Table 2: Multiple prospective cohort 

Study 

Identification 

Population 

Characteristics Intervention Technique /Dose /Timing Reported Outcomes Qu

Asse

Suarez, 2002, US26

Design: Multiple Prospective Cohort

n =45 Age: 67 (13)y % Male: 42 Race: NR 

Inclusion Criteria: Acute IS <3hrs post symptom onset; no improvement on clinical sign; no ICH on CT; age 18-80; NIHSS score ≥4 

Exclusion Criteria: Evidence of cerebral hemorrhage or mass effect on CT; questionable diagnosis (e.g., seizure; high risk hemorrhage; pregnancy or delivery < 14 d; diastolic BP>120 mmHg) 

I: Pre-treatment MRI scoring system for IS (n=45)

I: IV TPA/ 0.6 mg/Kg /completed within 5 hr of onset + Emergency MRI (Diffusion weighted & Perfusion weighted) + Angiography in case of acute cortical infarction and when determined with vessel occlusion, IA Urokinase/ up to 750,000 units or IA tPA for maximum 0.3 mg/kg 

• Correlation between 

abnormal perfusionweighted imaging findings and cerebral angiographic findings 

• Symptomatic ICH • Mortality • NIHSS, Barthel Index (3 

mo post tx) 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Ranki

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health NOTE: Numerical values are mean (standard deviation) unless otherwise indicated; TOAST = Trial of Org 10172 in Acute Stroke Trea
E-46

Evidence Table 2 (cont’d): Single retrospective cohort 

Study 

Identification Population Characteristics Intervention Technique /Dose /Timing Reported Outcomes 

A

Akins, 2000, US27

Design: Single Retrospective Cohort

n = NR Age: 73 (11)y % Male: NR Race: NR 

Inclusion Criteria: Consecutive acute IS treated with IV TPA according to NINDS protocol treated by ER physician or neurologist Exclusion Criteria: NR 

Use of ER protocols for management of acute stroke Note: Data is broken for two groups treated by ER physician (n=23) /or by neurologist (n=20)

Observational study examining ED physicians’ ability to initiate thrombolysis 

• Protocol 

deviation for ED physicians compared to neurologists 

• Number of pts 

treated by two tx groups 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Ranki

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health NOTE: Numerical values are mean (standard deviation) unless otherwise indicated; TOAST = Trial of Org 10172 in Acute Stroke Trea
E-47

Evidence Table 2 (cont’d): Single prospective cohort 

Study 

Identification Population Characteristics Intervention Technique /Dose /Timing Reported Outcomes Quality Assessm

(NOS) 

Hermier, 2003, France28

Design: Single Prospective Cohort

n=28 Age: 65 (14)y % Male: 55.2 

Race: NR Inclusion Criteria: Acute IS, with pretx & within 6 hr MRI; NIHSS >4 & no contraindication to tPA tx; with recanalization on MRI, or persistent occlusion on MRI Exclusion Criteria: Preexisting neurologic, psychiatric, or other illness confounding neurological evaluation; contraindications to MRI; movement artifacts precluding MRI interpretation; lacunar syndromes; 

presence of factors affecting time-topeak analysis 

 Pre-treatment MRI scoring system for IS (recanalization n=18; persistent occlusion n=10) 

CT + MRI (included three dimensional time of flight tube MRA; echoplanar imaging isotropic diffusion; and Perfusion MRI)

• NIHSS (60 d) • Relative & 

absolute time to peak/ 60 d lesion volume 

Note: Observational study correlating outcome with measured parameters 

7/19 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Ranki

Coma Scale; NOS = Newcastle Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = NatioNational Institutes of Health NOTE: Numerical values are mean (standard deviation) unless otherwise indicated; TOAST = Trial of Org 10172 in Acute Stroke Trea
E-48

Evidence Table 2 (cont’d): Single prospective cohort 

Study 

Identification Population Characteristics Intervention Technique /Dose /Timing Reported Outcomes Quality Assessme

(NOS) 

Hill, 2000, Canada29 Design: Single Prospective Cohort 

n=NR Age: mean 69.3y % Male: 55 Race: NR Inclusion Criteria: Acute IS, treated within 3 hr of symptom onset 

Exclusion Criteria: TIA (transient ischemic attack) or mild stroke; hx of subarachnoid hemorrhage; hypertension; hemorrhage, mass effect or edema, tumour or AVM on pre-tx CT; major surgery or trauma within 14 d; active internal bleeding; arterial puncture at a noncompressible site in the last 7 d; hx of hematological abnormality or coagulopathy or anticoagulation (PT > 15s, INR >1.4, PTT >4s, platelets <100,000/L) 

Use of designated centers for acute stroke 

Restructuring health care services, centralizing neurosurgical & neurological staff, using a modified model of NIHSS study with the aim of decrease time to tx 

• Improvement in 

time intervals of onset to ER; onset to CT; ER to CT; ER to tx; CT to tx 

5/19 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-49

Evidence Table 2 (cont’d): Single prospective cohorts

Study Identification Population Characteristics Intervention Technique /Dose /Timing Reported Outcomes Qu

Asse

(N

Jahnke, 2003, US30

Design: Single Retrospective Cohort

Age: NR 

% Male: NR Race: NR 

Inclusion Criteria: Acute stroke with mild to severe neurological deficits Exclusion Criteria: NR 

Use of ER protocols for management of acute stroke Note: number of pts treated n=65

Observational study examining ED protocol 

• Number of pts 

treated 

• Door-to-needle time 

decreased following implementation of the protocol 

6

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-50

Evidence Table 2 (cont’d): Single prospective cohort

Study 

Identification Population Characteristics Intervention Technique /Dose /Timing Reported Outcomes 

As

Kilpatrick, 2001, US31

Design: Single Retrospective Cohort 

n =51 Age: 61.7 (19-89)y % Male: 63 Race: NR Inclusion Criteria: Acute hemispheric IS within 24 hr post symptom onset, undergone CT, CT-Angiography & XeCT(xenon-enhanced-CT ), CBF(cerebral blood flow); NIHSS score 1-26 

Exclusion Criteria: posterior circulation symptoms 

CT perfusion/ angiography for IS (n=51) 

CT+ CT-Angiography + XeCT CBF/ within 24 hr post onset / completed at mean 44.5 min, range 15-223 min post onset 

• Association of CBF, 

and infarction rates 

• Association of CT 

angiogram occlusion with infarction rate

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-51

Evidence Table 2 (cont’d): Single retrospective cohort

Study 

Identification Population Characteristics Intervention Technique /Dose /Timing Reported Outcomes 

Quali

Assessm

(NOS

Smith, 1999, US33

Design: Single Prospective Cohort

n=37 (treated pts) 

Age: 63 (16)y, 22-87y % Male: 68 Race: White 86%; Black 11%; Asian 3% Inclusion Criteria: Acute IS treated with TPA, presented to ER 64 (29) min post onsetExclusion Criteria: NR 

Use of ER protocols for management of acute stroke (n=37)

Observational study examining the ability of ED physicians to treat thrombolysis 

• Onset-to-ED; onsetto needle time 

• Door to needle time 

(also: door-to physician; door-toCT) 

8/1

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hou

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrha

room; IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenou

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-52

Evidence Table 2 (cont’d): Case-control design 

Study 

Identification Population Characteristics Intervention Technique /Dose /Timing Reported Outcomes 

As

Agarwal, 2004, US34

Design: Case Control

n=83 Age: IG 70 (15)y; CG 71 (15)y % Male: IG 61; CG 47 Race: White IG 79%; CG 88% Inclusion Criteria: Acute IS (according to TOAST) <3 hr post symptom onset (IG) or 3-6 hr post onset & pts excluded for IV TPA based on NINDS criteria (CG) Exclusion Criteria: Cerebral hemorrhage/ NINDS criteria for thrombolytic tx 

CT perfusion/ angiography for IS (n=66) C: Control (n=17) 

I: CT/ 1.4 (0.7) hr & at 24 hr post onset + IV tPA/ 46-90 mg (0.9 mg/kg, max 90 mg)/ 2.3 (15) hr post onset C: CT/ 1.8 (1.1) hr & at 24 hr post onset + IA tPA/ 14-20 mg/ 4.4 (1.1) hr post onset

• Correlation with 

hyperdense middle cerebral artery signs (HCMAS) and outcomes 

• NIHSS (baseline, 24 

hr post onset, discharge) 

• mRS (90 d)

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhagIV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health; TOAST = Trial of Org 10172 in Acute Stroke Treatment NOTE: Numerical values are mean (standard deviation) unless otherwise indicated 
E-53

Pre-Post Studies 

Evidence Table 3: Pre-post design 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes 

Kay, 1993, Hong Kong35

Design: PrePost

n=10 Age: 49-64y % Male: 50 Race: NR Inclusion Criteria: ICH confirmed by CT 8-48 hr prerecruitment; systolic BP >180 mmHg, diastolic BP >100 mmHg Exclusion Criteria: NR 

Antihypertensive therapy for ICH (n=10) 

IV Ketanserin injection/ single does up to 10 mg/ 10-52 hrs post symptom onset 

• Systolic arterial 

pressure (0-2 hr)* 

• Mean intracranial 

pressure 

• Cerebral 

perfusion pressure (0-2hr)* 

Lattimore, 2003, US32

Design: PrePost

n=327/511 pts admitted to the hospital met inclusion criteria for IS from Jan 2000 to Dec 2001 Age: 76 (range 27-95)y % Male: 51 

Race: NR Inclusion Criteria: Acute IS < 6 hr (53% within 3 hr post onset), with persistent neurological deficits, & all inclusion criteria based on NINDS & guidelines from a Special Writing Group of the AHA Exclusion Criteria: Based on NINDS & guidelines from a Special Writing Group of the AHA 

I: Use of designated centers for acute stroke 

I: Around the clock coverage by stroke team 

• Time to tx • Correlation of 

establishment of stroke center and number of pts treated with tPA 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hou

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; Amalformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = National Health Service; NIH = Nationa

NOTE: Numerical values are mean (standard deviation) unless otherwise indicated Quality of Pre-post studies was not determined. 
E-54

Evidence Table 3 (cont’d): Pre-post design 

Study 

Identification Population Characteristics Intervention (I) /Comparator (C) Technique /Dose /Timing Reported Outcomes 

A

Nishiyama, 2000, Japan36

Design: Prepost

n=22 Age: 64 (±15, range 47-79) y % Male: 50 Race: NR Inclusion Criteria: Acute putaminal hemorrhage secondary to hypertension, with surgical drainage of hematoma Exclusion Criteria: history of liver or renal damage 

I: Antihypertensive therapy for ICH (n=22) 

I: Nicardipine infusion/ 484 ± 343 (138-826) mg for 213 ± 114 (92-323) hr 

• BP*, HR, conscious 

level, Vmca, pulsatility index 

• Intracranial 

pressure 

• Cerebral perfusion 

pressure 

• Platelet counts • CT signs of change 

in bleeding and/or brain edema 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hou

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles 

IG = intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhag

IV = intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = 

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rank

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Natio

National Institutes of Health NOTE: Numerical values are mean (standard deviation) unless otherwise indicated; TOAST = Trial of Org 10172 in Acute Stroke Trea

Quality of Pre-post studies was not determined. 
E-55

Summary Table: Intervention J: Community education for stroke (excluded pre-post studies) 

Study Identification Setting Population Characteristics Intervention /Outcome 

Alberts,1992, US37

Design: Pre-post 

University Hospital (Duke/Durham) 

Cerebral infarction; stroke-inevolution; (ICH); subarachnoid hemorrhage Pre-educational: n=290 Post-educational: n=189 

Community education program, professional education and helicopter transport/ Time delay in presentation & referral 

Interventiprogram outcomesand post 

Barsan, 1994, US38

Design: Pre-post 

3 university & 9 community hospitals (including 2 teaching hospitals) 

Pts within 24 hrs post onset (NIH tPA pilot study: Feb 1987-Aug 1989) ; n=1948 

Community education program / Time of onset to hospital arrival 

Retrospetimes coiimplemensecular trnot accou

Becker, 2001, US39Design: Pre-post 

King County (Washington) resident community 

English speaking residents, randomly chosen & willing to participate in a telephone survey: n=1058 

Community base education campaign/ Stroke knowledge (questionnaire based) 

No measoutcomes 

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour; 

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles / 

= intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhage; E

= intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = int

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rankin 

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Nation

National Institutes of Health NOTE: Numerical values are mean (standard deviation) unless otherwise indicated; TOAST = Trial of Org 10172 in Acute Stroke Treat

Quality of Pre-post studies was not determined. 
E-56

Summary Table: Intervention J: Community education for stroke (excluded pre-post studies) 

Study Identification Setting Population Characteristics Intervention /Outcome 

Smith, 1999, US40

Design: Pre-post 

2 university hospitals 

Paramedic Trainees: n=22 Stroke pts transferred by paramedics: n=84 (32 were transported by trained paramedics; 29/32 had stroke dx)

 Educational program on stroke to improve paramedic accuracy in stroke recognition/ Paramedic test scores/ accuracy in 

identification of stroke victims 

No measoutcomesparamed

Weinhardt, 1999, US41

Design: Pre-post 

NR Stroke patients: n=28 Education video to improve case 

management of stroke pts Pts knowledge of stroke (4 items from NIHSS) 

No clinica

US = United States; NR = not reported; NA = not available; n = number of participants; pts = patients; y = year; mo = month; hr = hour; 

seconds; mg = milligrams; mL = millilitres; mmHg = millimetres of mercury; kg = kilogram; IU = international units; mmol/l = millimoles / 

= intervention group; CG = control group; BP = blood pressure; HR = heart rate; IS = ischemic stroke; ICH = intracranial hemorrhage; E

= intravenous; CT = computed tomography; MRI = magnetic resonance imaging; tx = treatment; hx = history; IV = intravenous; IA = int

recombinant tissue plasminogen activator; S = significance; * = Significance (S) of statistical analysis; MCA = middle cerebral artery; A

malformation; Vmca = velocity in the middle cerebral artery; NINDS = National Institute of Neurological Disorders and Stroke; NIHSS = 

Health and Stroke Scale; ECASS = European Cooperative Acute Stroke Study; GCS = Glasgow Coma Scale; mRS = Modified Rankin 

Coma Scale; NOS = Newcastle-Ottawa Scale; HSF = Heart and Stroke Foundation; AHA = American Heart Association; NHS = Nation

National Institutes of Health NOTE: Numerical values are mean (standard deviation) unless otherwise indicated; TOAST = Trial of Org 10172 in Acute Stroke Treat

Quality of Pre-post studies could not be determined. 
E-57

Listing of Studies Included in Evidence Tables

Agarwal PK. Hyperdense middle cerebral artery sign: can it 

be used to select intra-arterial versus intravenous 

thrombolysis in acute ischemic stroke? Cerebrovasc Dis 

2004;17(2-3):182-90. 

Akins PT, Delemos C, Wentworth D, Byer J, Schorer SJ, 

Atkinson RP. Can emergency department physicians safely 

and effectively initiate thrombolysis for acute ischemic 

stroke? Neurology 2000;55(12):1801-5. 

Albers GW, Clark WM, Madden KP, Hamilton SA. 

ATLANTIS trial: results for patients treated within 3 hours 

of stroke onset. Alteplase Thrombolysis for Acute 

Noninterventional Therapy in Ischemic Stroke. Stroke 

2002:33(2):493-95. 

Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford 

SR, Alvarez-Sabin J, et al. Ultrasound-enhanced systemic 

thrombolysis for acute ischemic stroke. N Engl J Med 

2004;351(21):2170-8. 

Auer LM, Deinsberger W, Niederkorn K, Gell G, Kleinert 

R, Schneider G, et al. Endoscopic surgery versus medical 

treatment for spontaneous intracerebral hematoma: a 

randomized study. J Neurosurg 1989;70(4):530-5. 

Batjer HH, Reisch JS, Allen BC, Plaizier LJ, Su CJ. Failure 

of surgery to improve outcome in hypertensive putaminal 

hemorrhage. A prospective randomized trial. Arch Neurol 

1990;47(10):1103-6. 

Clark WM, Wissman S, Albers GW, Jhamandas JH, 

Madden KP, Hamilton S. Recombinant tissue-type 

plasminogen activator (Alteplase) for ischemic stroke 3 to 5 

hours after symptom onset. The ATLANTIS Study: a 

randomized controlled trial. Alteplase Thrombolysis for 

Acute Noninterventional Therapy in Ischemic Stroke.[see 

comment]. JAMA 1999;282(21):2019-26. 

Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA 

(alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : 

results of a double-blind, placebo-controlled, multicenter 

study. Thromblytic therapy in acute ischemic stroke study 

investigators. Stroke 2000;31(4):811-6. 

del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, 

Rowley HA, Gent M. PROACT: a phase II randomized 

trial of recombinant pro-urokinase by direct arterial 

delivery in acute middle cerebral artery stroke. PROACT 

Investigators. Prolyse in Acute Cerebral 

Thromboembolism.[see comment]. Stroke 1998;29(1):4-11. 

Eggers J, Koch B, Meyer K, Konig I, Seidel G. Effect of 

ultrasound on thrombolysis of middle cerebral artery 

occlusion. Ann Neurol 2003;53(6):797-800. 

Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, 

Kase C, et al. Intra-arterial prourokinase for acute ischemic 

stroke. The PROACT II study: a randomized controlled 

trial. Prolyse in Acute Cerebral Thromboembolism.[see 

comment]. JAMA 1999;282(21):2003-11. 

Gray CS, Hildreth AJ, Alberti GK, O'Connell JE, 

Collaboration GIST. Poststroke hyperglycemia: natural 

history and immediate management. Stroke 

2004;35(1):122-6. 

Haley EJ, Brott TG, Sheppard GL, Barsan W, Broderick J, 

Marler K, et al. Pilot randomized trial of tissue 

plasminogen activator in acute ischemic stroke. The TPA 

Bridging Study Group. Stroke 1993;24(7):1000-4. 

Hermier M, Nighoghossian N, Adeleine P, Berthezene Y, 

Derex L, Yilmaz H, et al. Early magnetic resonance 

imaging prediction of arterial recanalization and late infarct 

volume in acute carotid artery stroke. J Cereb Blood Flow 

Metab 2003;23(2):240-8. 

Hill MD, Barber PA, Demchuk AM, Sevick RJ, 

Newcommon NJ, Green T, et al. Building a "brain attack" 

team to administer thrombolytic therapy for acute ischemic 

stroke. CMAJ 2000;162(11):1589-93. 

Jahnke HK, Zadrozny D, Garrity T, Hopkins S, Frey JL, 

Christopher M. Stroke teams and acute stroke pathways: 

one emergency department's two-year experience. J Emerg 

Nurs 2003;29(2):133-9. 

Juvela S, Heiskanen O, Poranen A, Valtonen S, Kuurne T, 

Kaste M, et al. The treatment of spontaneous intracerebral 

hemorrhage. A prospective randomized trial of surgical and 

conservative treatment.[see comment]. J Neurosurg 

1989;70(5):755-8. 

Kase CS, Furlan AJ, Wechsler LR, Higashida RT, Rowley 

HA, Hart RG, et al. Cerebral hemorrhage after intra-arterial 

thrombolysis for ischemic stroke: the PROACT II trial. 

Neurology 2001;57(9):1603-10. 

Kay R, Poon WS, Nicholls MG. Effect of intravenous 

ketanserin on arterial and intracranial pressures in patients 

with systemic hypertension following intracerebral 

haemorrhage. J Hum Hypertens 1993;7(4):369-71. 

Keris V, Rudnicka S, Vorona V, Enina G, Tilgale B, 

Fricbergs J. Combined intraarterial/intravenous 

thrombolysis for acute ischemic stroke. AJNR Am J 

Neuroradiol 2001;22(2):352-8. 
E-58

Kilpatrick MM, Yonas H, Goldstein S, Kassam AB, Gebel 

JJ, Wechsler LR, et al. CT-based assessment of acute 

stroke: CT, CT angiography, and xenon-enhanced CT 

cerebral blood flow.[see comment]. Stroke 

2001;32(11):2543-9. 

Lattimore SU, Chalela J, Davis L, DeGraba T, Ezzeddine 

M, Haymore J, et al. Impact of establishing a primary 

stroke center at a community hospital on the use of 

thrombolytic therapy: the NINDS Suburban Hospital 

Stroke Center experience. Stroke 2003;34(6):e55-e57. 

Lewandowski CA, Frankel M, Tomsick TA, Broderick J, 

Frey J, Clark W, et al. Combined intravenous and intraarterial r-TPA versus intra-arterial therapy of acute 

ischemic stroke: Emergency Management of Stroke (EMS) 

Bridging Trial. Stroke 1999;30(12):2598-605. 

Lin CS, Tsai J, Woo P, Chang H. Prehospital delay and 

emergency department management of ischemic stroke 

patients in Taiwan, R.O.C. Prehosp Emerg Care 1999; 

3(3):194-200. 

Marler J, Tilley BC, Lu Y, Brott TG, Lyden PC, Grotta JC, 

et al. Early stroke treatment associated with better outcome: 

the NINDS rt-PA stroke study. Neurology 

2000;55(11):1649-55. 

Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, 

Grotta JC. Surgical treatment for intracerebral hemorrhage 

(STICH): a single-center, randomized clinical trial. 

Neurology 1998;51(5):1359-63. 

Morgenstern LB, Bartholomew LK, Grotta JC, Staub L, 

King M, Chan W. Sustained benefit of a community and 

professional intervention to increase acute stroke therapy. 

Arch Intern Med 2003;163(18):2198-2202. 

Nishiyama T, Yokoyama T, Matsukawa T, Hanaoka K. 

Continuous nicardipine infusion to control blood pressure 

after evacuation of acute cerebral hemorrhage. Can J 

Anaesth 2000;47(12):1196-1201. 

Patel SC, Levine SR, Tilley BC, Grotta JC, Lu M, Frankel 

M et al. Lack of clinical significance of early ischemic 

changes on computed tomography in acute stroke.[see 

comment]. JAMA 2001;286(22):2830-2838. 

Roberts HC, Dillon WP, Furlan AJ, Wechsler LR, Rowley 

HA, Fischbein NJ, et al. Computed tomographic findings in 

patients undergoing intra-arterial thrombolysis for acute 

ischemic stroke due to middle cerebral artery occlusion: 

results from the PROACT II trial.[see comment]. Stroke 

2002;33(6):1557-65. 

Scott JF, Robinson GM, French JM, O'Connell JE, Alberti 

KG, Gray CS. Glucose potassium insulin infusions in the 

treatment of acute stroke patients with mild to moderate 

hyperglycemia: the Glucose Insulin in Stroke Trial (GIST). 

Stroke 1999;30(4):793-9. 

Smith RW, Scott PA, Grant RJ, Chudnofsky CR, 

Frederiksen SM. Emergency physician treatment of acute 

stroke with recombinant tissue plasminogen activator: a 

retrospective analysis. Acad Emerg Med 1999;6(6):618-25. 

Suarez JI, Zaidat OO, Sunshine JL, Tarr R, Selman WR, 

Landis DM. Endovascular administration after intravenous 

infusion of thrombolytic agents for the treatment of patients 

with acute ischemic strokes. Neurosurgery 2002;50(2):251-

9. 

Teernstra OP, Evers SM, Lodder J, Leffers P, Franke CL, 

Blaauw G, et al. Stereotactic treatment of intracerebral 

hematoma by means of a plasminogen activator: a 

multicenter randomized controlled trial (SICHPA). Stroke 

2003;34(4):968-74. 

Zuccarello M, Brott T, Derex L, Kothari R, Sauerbeck L, 

Tew J, et al. Early surgical treatment for supratentorial 

intracerebral hemorrhage: a randomized feasibility 

study.[see comment]. Stroke 1999;30(9):1833-9. 
E-59

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E-60

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JE, Alberti KG, Gray CS. Glucose potassium 

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Appendix F. Additional Acknowledgments 

The UO-EPC gratefully acknowledges the following individuals who served on our 

Technical Expert Panel (TEP). Acknowledgment does not reflect endorsement of this 

report. 

Lawrence Brass, MD 

Professor of Neurology, Epidemiology & 

Public Health 

Yale University School of Medicine 

New Haven, Connecticut, USA 

Richard Kok Tiong Chan, MD 

Associate Professor of Neurology, 

University of Western Ontario 

London, Ontario, Canada 

Vladimir Hachinski, MD 

Editor-in-Chief, STROKE (American Heart 

Association);

Associate Professor of Neurology, University of 

Western Ontario 

London, Ontario, Canada 

Peter Langehorne, MD 

Professor of Stroke Care, 

Academic Section of Geriatric Medicine 

Royal Infirmary

Glasgow, Scotland, UK 

Wieslaw Oczkowski, MD 

Neurologist, Hamilton Health Sciences Medical 

Centre; Director, Regional Stroke Program; 

Associate Clinical Professor, 

McMaster University

Hamilton, Ontario, Canada 

Dr.Gerald Peden, 

Medical Director 

Technology Evaluation and Medical Policy 

Claim Payment Policy Unit 

Independence Blue Cross 

Philadelphia, PA, USA 

Ashfaq Shuaib, MD 

Professor and Director, Division of Neurology

Department of Medicine 

University of Alberta 

Edmonton, Alberta, Canada 

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The UO-EPC gratefully acknowledges the following individuals who reviewed the initial 

draft of this evidence report, and provided constructive feedback. Acknowledgement does 

not reflect endorsement of this report. 

David Atkins, MD, MPH 

Chief Medical Officer 

Center for Outcomes and Evidence 

Agency for Healthcare Research Quality

Rockville, MD, USA 

Dean C.C. Johnston, MD 

Practice of Cerebrovascular/General Neurology 

St. Paul’s Hospital 

Vancouver, BC, Canada

Randall T. Higashida, MD 

Clinical Professor Radiology & Neurosurgery

U.C.S.F. Medical Center 

Department of Radiology 

University of California 

San Fransisco, CA, USA 

Peter Langehorne, MD 

Professor of Stroke Care, 

Academic Section of Geriatric Medicine 

Royal Infirmary

Glasgow, Scotland, UK 

Wieslaw Oczkowski, MD 

Neurologist, Hamilton Health Sciences Medical 

Centre; Director, Regional Stroke Program; 

Associate Clinical Professor, 

McMaster University

Hamilton, Ontario, Canada 

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