0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Outcomes in Mild Acute Ischemic Stroke Treated With Intravenous Thrombolysis A Retrospective Analysis of the Get With the Guidelines–Stroke Registry FREE

Jose G. Romano, MD1; Eric E. Smith, MD, MPH2; Li Liang, PhD3; Hannah Gardener, ScD1; Sara Camp, RN, MSN4; Laura Shuey, RN, MSN4; Alison Cook, BS4; Iszet Campo-Bustillo, MD, MPH1; Pooja Khatri, MD5; Deepak L. Bhatt, MD, MPH6; Gregg C. Fonarow, MD7; Ralph L. Sacco, MD, MS1; Lee H. Schwamm, MD8
[+] Author Affiliations
1Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida
2Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
3Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
4American Heart Association, Dallas, Texas
5Department of Neurology, University of Cincinnati, Cincinnati, Ohio
6Department of Medicine, Brigham and Women’s Hospital Heart & Vascular Center/Harvard Medical School, Boston, Massachusetts
7Department of Medicine, University of California, Los Angeles
8Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston
JAMA Neurol. 2015;72(4):423-431. doi:10.1001/jamaneurol.2014.4354.
Text Size: A A A
Published online

Importance  Mild strokes have been poorly represented in thrombolytic trials and only a few series have reported outcomes after treatment with intravenous (IV) recombinant tissue plasminogen activator (rtPA) after mild stroke.

Objective  To report treatment complications and short-term outcomes in patients with mild stroke who have received treatment with IV rtPA.

Design, Setting, and Participants  Retrospective analysis of patients treated in the emergency department of hospitals that use the Get With the Guidelines–Stroke registry, a prospectively collected quality improvement registry used by hospitals across the United States. Patients were those admitted between May 1, 2010, and October 1, 2012, with acute ischemic stroke within 4.5 hours from symptom onset and a baseline National Institutes of Health Stroke Scale score of 5 or less. Univariable and multivariable analyses were performed to identify factors independently associated with discharge outcomes and treatment complications.

Intervention  Intravenous rtPA.

Main Outcomes and Measures  Treatment complications included symptomatic intracranial hemorrhage, life-threatening or serious systemic hemorrhage, other serious complications, and undetermined complications. The short-term outcomes analyzed were in-hospital mortality, discharge to home, independent ambulation at discharge, and length of stay.

Results  Among 33 995 patients who arrived within 4.5 hours of symptom onset and were treated with IV rtPA, 7621 (22.4%) had a National Institutes of Health Stroke Scale score of 5 or less and 5910 had complete data for analysis. Treatment complications were infrequent: symptomatic intracranial hemorrhage, 1.8%; life-threatening or serious systemic hemorrhage, 0.2%; other serious complications, 1.8%; and complications of undetermined cause, 2.4%. Mortality was low (1.3%), but at discharge 30.3% could not ambulate independently, 29.4% could not go directly home, and 73.0% had a length of stay of 3 days or longer. Worse short-term outcomes were seen in older patients, African American patients, diabetic patients, and those who arrived by ambulance, after hours, or with a higher National Institutes of Health Stroke Scale score.

Conclusions and Relevance  Many patients with ischemic stroke treated with IV rtPA have a mild stroke. Symptomatic intracranial hemorrhage is infrequent, but approximately 30% of these patients are unable to return directly home or ambulate independently at discharge. Additional studies are needed to identify strategies to improve the outcomes in patients with mild stroke who receive thrombolysis.

Compelling evidence and current guidelines recommend treatment with intravenous (IV) thrombolysis for eligible patients with acute ischemic stroke,13 but recent reports suggest that fewer than 5% of all patients with ischemic stroke receive thrombolytics.4 Mild or rapidly improving stroke symptoms are the most common reasons for lack of treatment in otherwise eligible patients, present in 31% to 43% of patients who arrive within 3 hours of symptom onset.58Although thrombolytic administration in patients with mild stroke has increased during the last decade in the United States,9 the efficacy and safety outcomes of thrombolysis in mild stroke remain poorly understood, as only small series are available.

The objectives of this study were to characterize treatment complications and short-term outcomes of patients with mild acute ischemic stroke treated with IV recombinant tissue plasminogen activator (rtPA) within 4.5 hours from symptom onset in the Get With the Guidelines–Stroke (GWTG-Stroke) registry and to analyze complications and outcomes by treatment window (0-3 vs 3-4.5 hours). Secondarily, we aimed to determine the proportion of mild strokes treated with thrombolytics.

The GWTG-Stroke registry, designed as a quality improvement registry and sponsored by the American Heart Association, is used by almost 1700 hospitals across the United States. Trained hospital personnel use an Internet-based tool (Quintiles Outcome) to enter deidentified data into the GWTG-Stroke registry. The Duke Clinical Research Institute serves as the data analysis center. The Duke Clinical Research Institute has institutional review board approval to analyze these data; the University of Miami Institutional Review Board also approved this analysis. This retrospective analysis of previously collected data does not require informed consent as all data are deidentified.

The study population included GWTG-Stroke registry participants with a final diagnosis of acute ischemic stroke admitted between May 1, 2010, and October 1, 2012 (n = 574 342 from 1682 hospitals). We excluded patients from hospitals that had less than 75% completion on medical history variables, which reflects suboptimal documentation (n = 19 288); those who arrived beyond 4.5 hours from symptom onset (n = 407 137); those not treated with IV rtPA (n = 108 096); those with a National Institutes of Health Stroke Scale (NIHSS) score higher than 5 (n = 28 402); those missing an NIHSS score (n = 3176); those who did not arrive through the emergency department or were not discharged from the same hospital, which limits the availability of baseline information and discharge outcomes (n = 1922); and those with a time to treatment that was longer than 4.5 hours or missing (n = 411). A total of 5910 patients from 966 hospitals were included.

The characterization of mild stroke as an NIHSS score between 0 and 5 is based on the commonly accepted practice of using this range to exclude patients from acute treatment trials1012 and to define mild stroke in population-based studies.13 The GWTG-Stroke hospitals are instructed to record the first NIHSS score obtained; subsequent changes in the degree of disability are not recorded.

The study population was described with respect to demographic characteristics, insurance, arrival and admission data, medical history, vital signs at presentation, laboratory test results, prior medication use, initial examination findings (GWTG-Stroke collects the baseline NIHSS score and separately collects 4 reported stroke symptoms: weakness or paresis, aphasia, altered consciousness, and other symptoms), in-hospital treatments, acute care (involvement of the neurology service, involvement of a stroke team, or admission to a stroke unit), hospital characteristics and quality measures, treatment complications, and short-term outcomes of interest stratified by treatment window (0-3 vs 3-4.5 hours). Stroke unit care was defined according to the Brain Attack Coalition recommendations.14 Treatment complications were coded in the following manner: (1) symptomatic intracerebral hemorrhage (ICH): brain hemorrhage confirmed by computed tomography within 36 hours of IV rtPA and physician’s notes indicating clinical deterioration due to the hemorrhage; (2) life-threatening or serious systemic hemorrhage: bleeding within 36 hours of IV rtPA requiring transfusion of more than 3 units of blood; (3) other serious complications: complications unexpected or out of proportion to the patient’s expected course, documented as complications of reperfusion therapy such as rapid development of malignant edema, angioedema, or recurrent stroke, and requiring additional medical interventions or prolonged length of stay (LOS); and (4) complications of undetermined cause: worsening stroke symptoms after thrombolysis without definitive evidence to classify the nature of the complication and without death. Short-term outcomes at discharge included discharge to home, ability to walk independently, LOS, and in-hospital mortality. For the outcome of independent ambulation, we restricted the population to those with documented ability to ambulate independently at baseline.

In a separate analysis, we described the proportion of mild strokes among all patients treated with IV rtPA during the same 29-month study period, including all patients treated with IV rtPA 4.5 hours or sooner from symptom onset and with a documented baseline NIHSS score, excluding hospitals with less than 75% completion of medical history variable documentation.

We used χ2 tests to compare categorical variables and Wilcoxon rank sum tests for continuous and ordinal variables. We evaluated the association of patient and hospital variables with short-term outcomes at discharge and treatment complications in a multivariable logistic regression model using a generalized estimating equations approach to account for within-hospital clustering. Covariates in the model include patient baseline characteristics (age, sex, race/ethnicity, insurance, calendar year), medical history (atrial fibrillation or flutter, prosthetic heart valve, previous stroke or transient ischemic attack, coronary artery disease or prior myocardial infarction, carotid stenosis, peripheral vascular disease, hypertension, diabetes mellitus, dyslipidemia, heart failure, and smoking), arrival characteristics (time from symptom onset to arrival, arrival at off hours [between 6 pm and 7 am Monday through Friday; weekends; and holidays], ambulance transport), admission findings (NIHSS score, symptoms of aphasia, hemiparesis, altered consciousness), care unit (admission by neurology service, stroke consultation, stroke unit care), medications prior to admission (anticoagulant, antiplatelet, antihypertensive, cholesterol reducer, and diabetic medications), and hospital characteristics (region, hospital size, stroke volume, IV rtPA volume, teaching status, rural vs urban location). All P values were 2-sided and statistical significance was defined as P < .05. All statistical analyses were performed with SAS version 9.1 software (SAS Institute Inc).

Most variables had missing values in fewer than 5% of cases, except the following categories: symptoms at presentation (18.0%), mode of emergency medical services arrival (9.8%), care unit (14.5%), and medications prior to admission (11.3%-12.4%) except cholesterol reducer. Missing data were imputed to the dominant category for categorical variables and to the median for continuous variables. Missing insurance status for those aged 65 years or older was imputed to Medicare. Missing hospital variables such as teaching status and number of beds (<2%) were excluded.

The baseline patient and hospital characteristics of the 5910 patients from 966 hospitals are described in Table 1. Overall, 98.2% arrived within 3 hours of onset; 78.6% were treated in the 0- to 3-hour window and 21.4% in the 3- to 4.5-hour window. The time from symptom onset to treatment was about 1 hour longer for those treated in the 3- to 4.5-hour window (P < .001). Patients treated in the first 3 hours more commonly were older (P < .001), were men (P = .02), were non-Hispanic white (P = .03), had more atrial fibrillation (P < .001), had more dyslipidemia (P = .003), were more likely to be taking prophylactic medications (anticoagulant, P = .01; antihypertensive, P = .001; antilipidemic, P = .02), and were more likely to arrive by ambulance (P < .001). However, the NIHSS score was similar for those treated in the early and extended windows (P = .31).

Table Graphic Jump LocationTable 1.  Patient and Hospital Characteristics by Treatment Window

Treatment complications and discharge outcomes are detailed in Table 2. Mortality was 1.3%, 1.8% had symptomatic ICH, 0.2% had life-threatening or serious systemic hemorrhage, 1.8% had other serious complications, and 2.4% had complications of undetermined cause. However, 29.4% of patients could not be discharged directly home, 30.3% were not able to ambulate independently, and 73.0% had LOS of 3 days or longer. The outcome of independent ambulation at discharge was similar for the 2 treatment windows (0-3 vs 3-4.5 hours) among those with documented ability to ambulate independently prior to the index stroke only (P = .72) and in a sensitivity analysis including those with missing or undocumented baseline ambulation. There were no differences in short-term outcomes and treatment complications among those treated at 0 to 3 hours compared with those treated at 3 to 4.5 hours, except for a lower rate of treatment complications of undetermined cause in those treated in the 0- to 3-hour window than in the 3- to 4.5-hour window (2.1% vs 3.3%, respectively; P = .01). When outcomes were categorized by NIHSS score (Table 3), worse discharge outcomes were noted with increasing NIHSS score, but symptomatic ICH and other treatment complications were similar across this range of NIHSS scores.

Table Graphic Jump LocationTable 2.  Outcomes and Treatment Complications by Treatment Window
Table Graphic Jump LocationTable 3.  Outcomes and Treatment Complications by NIHSS Score

Multivariable-adjusted associations between covariates and select discharge outcomes and treatment complications are provided in Table 4. Only covariates with significant associations are included. Heart failure and altered consciousness on arrival were strongly associated with in-hospital mortality (odds ratio [OR] = 2.21 [95% CI, 1.06-4.61] and OR = 3.53 [95% CI, 1.93-6.46], respectively), although these variables did not occur commonly. Symptomatic intracranial hemorrhage occurred more often in older individuals (OR = 1.35 [95% CI, 1.12-1.63]), in those with a history of carotid stenosis (OR = 2.35 [95% CI, 1.07-5.18]), and when altered consciousness was reported as a presenting symptom (OR = 2.70 [95% CI, 1.55-4.71]); dyslipidemia and care in a stroke unit were associated with a lower risk of symptomatic ICH (OR = 0.62 [95% CI, 0.41-0.93] and OR = 0.57 [95% CI, 0.38-0.86], respectively). Older age, being African American, history of diabetes mellitus, arrival by ambulance, arrival at off hours, worse stroke severity, and hemiparesis were independently associated with inability to be discharged home and/or inability to ambulate (Table 4).

Table Graphic Jump LocationTable 4.  Multivariable-Adjusted Associations Between Covariates and Select Outcomesa

During the study period, GWTG-Stroke hospitals collectively treated 36 552 patients with IV rtPA within 4.5 hours from symptom onset, of whom 33 995 had a documented baseline NIHSS score. Of these 33 995 patients, 7621 (22.4%) had a baseline NIHSS score between 0 and 5. Conversely, among all patients with a baseline NIHSS score between 0 and 5 who arrived at the hospital within 4.5 hours from symptom onset, only 13.5% received IV rtPA.

We have characterized a cohort of patients with mild stroke treated with IV rtPA, of whom one-fifth were treated in the expanded treatment window of 3 to 4.5 hours. To our knowledge, this is the largest report of patients with mild stroke who received thrombolysis. This report adds to the characterization of mild treated strokes as most prior data come from small series. There is a paucity of data from randomized clinical trials on the efficacy and safety of IV rtPA in this population. For example, a total of 108 patients with an NIHSS score of 5 or less received thrombolytics in the National Institute of Neurological Disorders and Stroke and European Cooperative Acute Stroke Study 3 trials combined,15,16 while 304 were treated in the third International Stroke Trial.17 A recent pooled analysis of individual patient data from randomized trials showed better outcome in patients with mild ischemic stroke (NIHSS score 0-4) treated with rtPA (OR = 1.48; 95% CI, 1.07-2.06); however, only 9.9% of enrolled patients had mild stroke.18

The relatively low complication rates associated with use of IV rtPA in mild stroke, with a symptomatic ICH rate of 1.8% and systemic hemorrhage rate of 0.2%, are an important finding in this study. Treatment complications were similar between the 0- to 3-hour and 3- to 4.5-hour windows except those of undetermined cause, which were more common in the 3- to 4.5-hour window than in the 0- to 3-hour window (3.3% vs 2.1%, respectively; P = .01), and treatment complications were similar across all 6 NIHSS categories studied. The symptomatic ICH rate of 1.8% is much lower than in patients enrolled in clinical trials with a higher NIHSS score, where it has been reported to be 6.4% to 7.9%.1,2,19 While the definition of symptomatic ICH used in GWTG-Stroke is not identical to the National Institute of Neurological Disorders and Stroke criteria,1,20 it is similar and reasonably comparable. In smaller series of mild stroke treated with IV rtPA (27-488 patients), the risk of symptomatic ICH varied from 0% to 5%,10,2128 and similar to our results, no increased risk was found in those treated in the extended window.19,24

We identified a higher risk of thrombolytic treatment in older individuals, with an OR of 1.35 (95% CI, 1.12-1.63) for symptomatic ICH for each 10 years of age, consistent with the known association of advancing age and symptomatic ICH.29 A higher risk of symptomatic ICH was also found in those presenting with altered level of consciousness and in patients with a history of carotid stenosis, although it should be noted that 2.7% had a history of carotid disease, 6.6% had altered consciousness at presentation, and there was a high rate of missing presentation symptoms. While altered consciousness is not normally associated with mild stroke, one could envision scenarios in which altered consciousness was present on arrival but improved rapidly prior to the first NIHSS score being obtained.

Care in a stroke unit and history of dyslipidemia were associated with a lower risk of symptomatic ICH. Stroke unit admission was present in only two-thirds of patients, although care in a specialized unit has been clearly shown to reduce complications and improve outcomes and is recommended for all patients who have received thrombolysis.3 However, it should be recognized that patient trajectories across different units in the hospital (emergency department, intensive care unit, stroke unit, general ward, and rehabilitation) are complex and influenced by various patient-related factors as well as hospital resources, and the nomenclature of units may vary across institutions. The association with dyslipidemia deserves further discussion. In GWTG-Stroke, a history of dyslipidemia is based on self-report, prior documentation, or the use of antilipidemic medication. Although better outcomes in acute ischemic stroke have been reported in those with prior statin therapy,30 a number of studies have failed to demonstrate an association between total cholesterol or low-density lipoprotein cholesterol level and symptomatic ICH,31 although contradictory results have been reported for high-density lipoprotein cholesterol and triglycerides levels.32,33 Similar to other studies,3234 we did not find an association between symptomatic ICH after thrombolysis and the use of lipid-lowering agents.

Our results also demonstrate that a significant proportion of patients with mild stroke treated with IV rtPA have suboptimal outcomes at discharge. Overall, 30.3% did not achieve independent ambulation by discharge, 29.4% could not return directly home, 73.0% had a prolonged LOS of 3 days or longer, and 1.3% died. With the exception of death, these short-term outcomes were worse with increasing NIHSS score, reflecting greater stroke severity. A small number of patients with an NIHSS score of 0 were treated; this is probably related to the inability of the NIHSS to capture certain cerebellar and brainstem symptoms.35 In addition, as the GWTG-Stroke registry records only 1 point of stroke severity assessment at baseline, it is possible that some patients may have worsened before treatment. However, treatment in the extended window of 3 to 4.5 hours resulted in outcomes similar to those treated earlier. Others have reported similar short-term outcomes.36 Longer-term poor outcomes, defined as a modified Rankin Scale score of 2 to 6 at 3 months, have been reported in 17% to 42%, although these reports come from smaller series.15,21,22,24,25,27 Recent reports suggest that IV rtPA is associated with better delayed outcomes than controls.18,28

We found worse short-term discharge outcomes in older individuals, African American individuals, women, and those with diabetes mellitus, higher baseline NIHSS scores, reported altered level of consciousness on arrival, hemiparesis on arrival, arrival by ambulance, and arrival at off hours. These associations are expected as worse outcomes are expected in older and diabetic patients, while the arrival symptoms and mode of transportation probably reflect larger and more severe strokes.

There are many possible explanations for poor functional outcomes in mild stroke. First, a low NIHSS score does not exclude disabling symptoms37: isolated aphasia, hemianopsia, or monoplegia may result in a low NIHSS score but these symptoms may be disabling. Also, early progression of symptoms and infarct growth may affect 9% to 10% of those with minor stroke and are associated with large-vessel occlusion and hypoperfusion.3840 Moreover, early recurrence after rapid improvement has been described41; this may represent vascular reocclusion, described in up to 12% of those treated with IV rtPA,42 failure of collateral flow to sustain penumbral tissue, or even small-vessel occlusion as in the capsular warning syndrome.43 We found subsequent deterioration in 2.4% that was not explained by symptomatic ICH; this was more frequent in the 3- to 4.5-hour treatment window. One may hypothesize that this low rate of worsening may correspond to a lower frequency of large-vessel occlusion. However, this cannot be ascertained from our data.

Although we have characterized short-term outcomes in mild stroke, the long-term outcomes have not yet been well studied in a large controlled cohort. As most individuals who go to rehabilitation achieve their highest level of independence at 12 weeks,44 3-month outcome is a better measure of disability. As noted, smaller series have reported on the modified Rankin Scale, the most common outcome measure used in stroke studies, but this scale has limitations such as high interrater variability45 and unequal disability weight for each level of the scale.46 Also, it does not interrogate quality of life and activities of daily living and therefore may not capture the full range of disability associated with mild stroke.47,48 We did not compare the outcomes of patients with mild stroke treated with rtPA with the outcomes of those who were not treated, owing to the important selection bias introduced by treatment decisions for which we cannot adequately adjust because of measured and unmeasured residual confounding. This will require randomized prospective trials such as the Potential for rtPA to Improve Stroke With Mild Symptoms study (PRISMS; clinicaltrials.gov identifier NCT02072226). The PRISMS trial and the Mild and Rapidly Improving Stroke Study (MaRISS; clinicaltrials.gov identifier NCT02072681), an observational study, will provide detailed multidimensional measures of the dynamic nature of mild stroke and the longer-term outcomes that will discern the impact and full range of disability associated with mild stroke.

Limitations of this study include those associated with registry-derived data. Hospital participation in the GWTG-Stroke registry is voluntary, and it is possible that our population does not fully reflect the experience across the United States. Indeed, a larger proportion of patients in our sample was treated at teaching hospitals compared with a nationwide inpatient sample.49 However, GWTG-Stroke is used by 1 in 3 acute care hospitals, and with more than 3 million patient entries, it encompasses 1 in 4 strokes in the country. Moreover, prior studies with linkage to national Medicare data suggest that data from the GWTG-Stroke registry are representative of the national Medicare stroke population.50 Another limitation is that we have only 1 fixed point of stroke severity assessment, and some patients with mild stroke may have had more or less severe deficits prior to the baseline recorded NIHSS score and rtPA administration. Residual measured or unmeasured confounding may have influenced the findings.

This study also has important strengths that need to be underscored. To our knowledge, this is the largest study to date of mild stroke treated with IV rtPA. It carefully delineates the factors associated with poor discharge outcomes and expands prior reports8 by including those treated in the expanded window of 4.5 hours.51 The period of data collection (2010-2012) and the large number of hospitals provide a current representation of the characteristics and outcomes of this population in the United States.

We have described the treatment complications and short-term outcomes and identified baseline predictors of outcomes in mild stroke treated with thrombolytics. The efficacy of thrombolytics in this population cannot be discerned from our study, for which randomized studies are needed. However, given the significant proportion of treated mild stroke and real-world safety and outcomes observed, our results provide reassurance about the safety of IV rtPA in patients with low NIHSS scores.

Corresponding Author: Jose G. Romano, MD, Department of Neurology, University of Miami Miller School of Medicine, 1120 NW 14th St, Ste 1357, Miami, FL 33136 (jromano@med.miami.edu).

Accepted for Publication: November 25, 2014.

Published Online: February 2, 2015. doi:10.1001/jamaneurol.2014.4354.

Author Contributions: Drs Romano and Liang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Romano, Smith, Gardener, Camp, Shuey, Campo-Bustillo, Sacco, Schwamm.

Acquisition, analysis, or interpretation of data: Romano, Smith, Liang, Gardener, Camp, Shuey, Cook, Khatri, Bhatt, Fonarow, Schwamm.

Drafting of the manuscript: Romano, Smith, Khatri, Bhatt, Fonarow.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Liang, Gardener.

Obtained funding: Romano.

Administrative, technical, or material support: Romano, Smith, Camp, Shuey, Cook, Campo-Bustillo, Fonarow, Sacco.

Study supervision: Romano, Shuey, Cook, Khatri, Schwamm.

Conflict of Interest Disclosures: Dr Romano reported receiving research salary support from Genentech and serving on the scientific advisory board for Vycor/NovaVision. Dr Smith reported serving on the data safety monitoring board of an alteplase trial funded by the National Institute of Neurological Disorders and Stroke. Dr Gardener reported receiving research salary support from Genentech. Dr Campo-Bustillo reported receiving research salary support from Genentech. Dr Khatri reported receiving research salary support from Genentech, Penumbra, and Biogen; honorarium from UpToDate; and book royalties from Taylor and Francis. Dr Bhatt reported serving on the advisory boards for Elsevier PracticeUpdate Cardiology, Medscape Cardiology, and Regado Biosciences; serving on the board of directors of the Boston VA Research Institute and the Society of Cardiovascular Patient Care; serving as chair on the American Heart Association Get With the Guidelines steering committee; serving on data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; receiving honoraria from the American College of Cardiology (editor, Clinical Trials, Cardiosource), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), and WebMD (continuing medical education steering committees); serving as deputy editor of Clinical Cardiology and pharmacology section editor of the Journal of the American College of Cardiology; receiving research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi-Aventis, and The Medicines Company; and performing unfunded research for FlowCo, PLx Pharma, and Takeda. Dr Fonarow is an employee of the University of California, which holds a patent on a retriever device for stroke. Dr Sacco reported serving as a consultant to Boehringer-Ingelheim. Dr Schwamm reported serving as the principal investigator of a National Institute of Neurological Disorders and Stroke–funded study for which Genentech provides alteplase and supplementary site payments and serving as a member of the international steering committee of desmoteplase trials for Lundbeck. No other disclosures were reported.

Funding/Support: This work was supported by a grant from Genentech to the University of Miami.

Role of the Funder/Sponsor: Genentech had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: This work was presented in part as a poster at the International Stroke Conference 2014; February 12, 2014; San Diego, California.

National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group.  Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587.
PubMed   |  Link to Article
Hacke  W, Kaste  M, Bluhmki  E,  et al; ECASS Investigators.  Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.
PubMed   |  Link to Article
Jauch  EC, Saver  JL, Adams  HP  Jr,  et al; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology.  Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.
PubMed   |  Link to Article
Adeoye  O, Hornung  R, Khatri  P, Kleindorfer  D.  Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke. 2011;42(7):1952-1955.
PubMed   |  Link to Article
Barber  PA, Zhang  J, Demchuk  AM, Hill  MD, Buchan  AM.  Why are stroke patients excluded from TPA therapy? an analysis of patient eligibility. Neurology. 2001;56(8):1015-1020.
PubMed   |  Link to Article
Kleindorfer  D, Kissela  B, Schneider  A,  et al; Neuroscience Institute.  Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke. 2004;35(2):e27-e29.
PubMed   |  Link to Article
George  MG, Tong  X, McGruder  H,  et al; Centers for Disease Control and Prevention.  Paul Coverdell National Acute Stroke Registry surveillance: four states, 2005-2007. MMWR Surveill Summ. 2009;58(7):1-23.
PubMed
Smith  EE, Fonarow  GC, Reeves  MJ,  et al.  Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue-type plasminogen activator: findings from Get With the Guidelines-Stroke. Stroke. 2011;42(11):3110-3115.
PubMed   |  Link to Article
Schwamm  LH, Ali  SF, Reeves  MJ,  et al.  Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With the Guidelines-Stroke hospitals. Circ Cardiovasc Qual Outcomes. 2013;6(5):543-549.
PubMed   |  Link to Article
Ginsberg  MD, Palesch  YY, Hill  MD,  et al; ALIAS and Neurological Emergencies Treatment Trials (NETT) Investigators.  High-dose albumin treatment for acute ischaemic stroke (ALIAS) part 2: a randomised, double-blind, phase 3, placebo-controlled trial. Lancet Neurol. 2013;12(11):1049-1058.
PubMed   |  Link to Article
Pancioli  AM, Adeoye  O, Schmit  PA,  et al; CLEAR-ER Investigators.  Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial. Stroke. 2013;44(9):2381-2387.
PubMed   |  Link to Article
Shuaib  A, Lees  KR, Lyden  P,  et al; SAINT II Trial Investigators.  NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357(6):562-571.
PubMed   |  Link to Article
Dhamoon  MS, Moon  YP, Paik  MC,  et al.  Long-term functional recovery after first ischemic stroke: the Northern Manhattan Study. Stroke. 2009;40(8):2805-2811.
PubMed   |  Link to Article
Alberts  MJ, Hademenos  G, Latchaw  RE,  et al; Brain Attack Coalition.  Recommendations for the establishment of primary stroke centers. JAMA. 2000;283(23):3102-3109.
PubMed   |  Link to Article
Khatri  P, Kleindorfer  DO, Yeatts  SD,  et al.  Strokes with minor symptoms: an exploratory analysis of the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator trials. Stroke. 2010;41(11):2581-2586.
PubMed   |  Link to Article
Bluhmki  E, Chamorro  A, Dávalos  A,  et al.  Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009;8(12):1095-1102.
PubMed   |  Link to Article
IST-3 Collaborative Group.  Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial. Lancet Neurol. 2013;12(8):768-776.
PubMed   |  Link to Article
Emberson  J, Lees  KR, Lyden  P,  et al; Stroke Thrombolysis Trialists’ Collaborative Group.  Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384(9958):1929-1935.
PubMed   |  Link to Article
Wardlaw  JM, Murray  V, Berge  E,  et al.  Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet. 2012;379(9834):2364-2372.
PubMed   |  Link to Article
NINDS t-PA Stroke Study Group.  Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28(11):2109-2118.
PubMed   |  Link to Article
Urra  X, Ariño  H, Llull  L,  et al.  The outcome of patients with mild stroke improves after treatment with systemic thrombolysis. PLoS One. 2013;8(3):e59420.
PubMed   |  Link to Article
Steffenhagen  N, Hill  MD, Poppe  AY, Buchan  AM, Coutts  SB.  Should you thrombolyse all or any stroke patients with baseline National Institutes of Health stroke scale scores < or = 5? Cerebrovasc Dis. 2009;28(2):201-202.
PubMed   |  Link to Article
Tanne  D, Kasner  SE, Demchuk  AM,  et al.  Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the Multicenter rt-PA Stroke Survey. Circulation. 2002;105(14):1679-1685.
PubMed   |  Link to Article
Wendt  M, Tütüncü  S, Fiebach  JB, Scheitz  JF, Audebert  HJ, Nolte  CH.  Preclusion of ischemic stroke patients from intravenous tissue plasminogen activator treatment for mild symptoms should not be based on low National Institutes of Health Stroke Scale Scores. J Stroke Cerebrovasc Dis. 2013;22(4):550-553.
PubMed   |  Link to Article
Strbian  D, Piironen  K, Meretoja  A,  et al; Helsinki Stroke Thrombolysis Registry Group.  Intravenous thrombolysis for acute ischemic stroke patients presenting with mild symptoms. Int J Stroke. 2013;8(5):293-299.
PubMed   |  Link to Article
Hassan  AE, Hassanzadeh  B, Tohidi  V, Kirmani  JF.  Very mild stroke patients benefit from intravenous tissue plasminogen activator without increase of intracranial hemorrhage. South Med J. 2010;103(5):398-402.
PubMed   |  Link to Article
Huisa  BN, Raman  R, Neil  W, Ernstrom  K, Hemmen  TM.  Intravenous tissue plasminogen activator for patients with minor ischemic stroke. J Stroke Cerebrovasc Dis. 2012;21(8):732-736.
PubMed   |  Link to Article
Greisenegger  S, Seyfang  L, Kiechl  S, Lang  W, Ferrari  J; Austrian Stroke Unit Registry Collaborators.  Thrombolysis in patients with mild stroke: results from the Austrian Stroke Unit Registry. Stroke. 2014;45(3):765-769.
PubMed   |  Link to Article
Whiteley  WN, Slot  KB, Fernandes  P, Sandercock  P, Wardlaw  J.  Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies. Stroke. 2012;43(11):2904-2909.
PubMed   |  Link to Article
Ní Chróinín  D, Asplund  K, Åsberg  S,  et al.  Statin therapy and outcome after ischemic stroke: systematic review and meta-analysis of observational studies and randomized trials. Stroke. 2013;44(2):448-456.
PubMed   |  Link to Article
Hackam  DG, Woodward  M, Newby  LK,  et al.  Statins and intracerebral hemorrhage: collaborative systematic review and meta-analysis. Circulation. 2011;124(20):2233-2242.
PubMed   |  Link to Article
Uyttenboogaart  M, Koch  MW, Koopman  K, Vroomen  PC, Luijckx  GJ, De Keyser  J.  Lipid profile, statin use, and outcome after intravenous thrombolysis for acute ischaemic stroke. J Neurol. 2008;255(6):875-880.
PubMed   |  Link to Article
Messé  SR, Pervez  MA, Smith  EE,  et al.  Lipid profile, lipid-lowering medications, and intracerebral hemorrhage after tPA in get with the guidelines-stroke. Stroke. 2013;44(5):1354-1359.
PubMed   |  Link to Article
Engelter  ST, Soinne  L, Ringleb  P,  et al.  IV thrombolysis and statins. Neurology. 2011;77(9):888-895.
PubMed   |  Link to Article
Martin-Schild  S, Albright  KC, Tanksley  J,  et al.  Zero on the NIHSS does not equal the absence of stroke. Ann Emerg Med. 2011;57(1):42-45.
PubMed   |  Link to Article
Willey  JZ, Khatri  P, Khoury  JC,  et al.  Variability in the use of intravenous thrombolysis for mild stroke: experience across the SPOTRIAS network. J Stroke Cerebrovasc Dis. 2013;22(4):318-322.
PubMed   |  Link to Article
Köhrmann  M, Nowe  T, Huttner  HB,  et al.  Safety and outcome after thrombolysis in stroke patients with mild symptoms. Cerebrovasc Dis. 2009;27(2):160-166.
PubMed   |  Link to Article
Coutts  SB, Hill  MD, Eliasziw  M, Fischer  K, Demchuk  AM; VISION Study Group.  Final 2 year results of the vascular imaging of acute stroke for identifying predictors of clinical outcome and recurrent ischemic events (VISION) study. BMC Cardiovasc Disord. 2011;11:18.
PubMed   |  Link to Article
Rajajee  V, Kidwell  C, Starkman  S,  et al.  Early MRI and outcomes of untreated patients with mild or improving ischemic stroke. Neurology. 2006;67(6):980-984.
PubMed   |  Link to Article
Asdaghi  N, Hill  MD, Coulter  JI,  et al.  Perfusion MR predicts outcome in high-risk transient ischemic attack/minor stroke: a derivation-validation study. Stroke. 2013;44(9):2486-2492.
PubMed   |  Link to Article
Smith  EE, Abdullah  AR, Petkovska  I, Rosenthal  E, Koroshetz  WJ, Schwamm  LH.  Poor outcomes in patients who do not receive intravenous tissue plasminogen activator because of mild or improving ischemic stroke. Stroke. 2005;36(11):2497-2499.
PubMed   |  Link to Article
Rubiera  M, Alvarez-Sabín  J, Ribo  M,  et al.  Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke. Stroke. 2005;36(7):1452-1456.
PubMed   |  Link to Article
Donnan  GA, O’Malley  HM, Quang  L, Hurley  S, Bladin  PF.  The capsular warning syndrome: pathogenesis and clinical features. Neurology. 1993;43(5):957-962.
PubMed   |  Link to Article
Jørgensen  HS, Nakayama  H, Raaschou  HO, Vive-Larsen  J, Støier  M, Olsen  TS.  Outcome and time course of recovery in stroke, part II: time course of recovery: the Copenhagen Stroke Study. Arch Phys Med Rehabil. 1995;76(5):406-412.
PubMed   |  Link to Article
Quinn  TJ, Dawson  J, Walters  MR, Lees  KR.  Reliability of the modified Rankin Scale: a systematic review. Stroke. 2009;40(10):3393-3395.
PubMed   |  Link to Article
Hong  KS, Saver  JL.  Quantifying the value of stroke disability outcomes: WHO global burden of disease project disability weights for each level of the modified Rankin Scale. Stroke. 2009;40(12):3828-3833.
PubMed   |  Link to Article
Dromerick  AW, Edwards  DF, Diringer  MN.  Sensitivity to changes in disability after stroke: a comparison of four scales useful in clinical trials. J Rehabil Res Dev. 2003;40(1):1-8.
PubMed   |  Link to Article
Harrison  JK, McArthur  KS, Quinn  TJ.  Assessment scales in stroke: clinimetric and clinical considerations. Clin Interv Aging. 2013;8:201-211.
PubMed
Moradiya  Y, Crystal  H, Valsamis  H, Levine  SR.  Thrombolytic utilization for ischemic stroke in US hospitals with neurology residency program. Neurology. 2013;81(23):1986-1995.
PubMed   |  Link to Article
Reeves  MJ, Fonarow  GC, Smith  EE,  et al.  Representativeness of the Get With the Guidelines-Stroke Registry: comparison of patient and hospital characteristics among Medicare beneficiaries hospitalized with ischemic stroke. Stroke. 2012;43(1):44-49.
PubMed   |  Link to Article
Del Zoppo  GJ, Saver  JL, Jauch  EC, Adams  HP  Jr; American Heart Association Stroke Council.  Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009;40(8):2945-2948.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Patient and Hospital Characteristics by Treatment Window
Table Graphic Jump LocationTable 2.  Outcomes and Treatment Complications by Treatment Window
Table Graphic Jump LocationTable 3.  Outcomes and Treatment Complications by NIHSS Score
Table Graphic Jump LocationTable 4.  Multivariable-Adjusted Associations Between Covariates and Select Outcomesa

References

National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group.  Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587.
PubMed   |  Link to Article
Hacke  W, Kaste  M, Bluhmki  E,  et al; ECASS Investigators.  Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.
PubMed   |  Link to Article
Jauch  EC, Saver  JL, Adams  HP  Jr,  et al; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology.  Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.
PubMed   |  Link to Article
Adeoye  O, Hornung  R, Khatri  P, Kleindorfer  D.  Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke. 2011;42(7):1952-1955.
PubMed   |  Link to Article
Barber  PA, Zhang  J, Demchuk  AM, Hill  MD, Buchan  AM.  Why are stroke patients excluded from TPA therapy? an analysis of patient eligibility. Neurology. 2001;56(8):1015-1020.
PubMed   |  Link to Article
Kleindorfer  D, Kissela  B, Schneider  A,  et al; Neuroscience Institute.  Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke. 2004;35(2):e27-e29.
PubMed   |  Link to Article
George  MG, Tong  X, McGruder  H,  et al; Centers for Disease Control and Prevention.  Paul Coverdell National Acute Stroke Registry surveillance: four states, 2005-2007. MMWR Surveill Summ. 2009;58(7):1-23.
PubMed
Smith  EE, Fonarow  GC, Reeves  MJ,  et al.  Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue-type plasminogen activator: findings from Get With the Guidelines-Stroke. Stroke. 2011;42(11):3110-3115.
PubMed   |  Link to Article
Schwamm  LH, Ali  SF, Reeves  MJ,  et al.  Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With the Guidelines-Stroke hospitals. Circ Cardiovasc Qual Outcomes. 2013;6(5):543-549.
PubMed   |  Link to Article
Ginsberg  MD, Palesch  YY, Hill  MD,  et al; ALIAS and Neurological Emergencies Treatment Trials (NETT) Investigators.  High-dose albumin treatment for acute ischaemic stroke (ALIAS) part 2: a randomised, double-blind, phase 3, placebo-controlled trial. Lancet Neurol. 2013;12(11):1049-1058.
PubMed   |  Link to Article
Pancioli  AM, Adeoye  O, Schmit  PA,  et al; CLEAR-ER Investigators.  Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial. Stroke. 2013;44(9):2381-2387.
PubMed   |  Link to Article
Shuaib  A, Lees  KR, Lyden  P,  et al; SAINT II Trial Investigators.  NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357(6):562-571.
PubMed   |  Link to Article
Dhamoon  MS, Moon  YP, Paik  MC,  et al.  Long-term functional recovery after first ischemic stroke: the Northern Manhattan Study. Stroke. 2009;40(8):2805-2811.
PubMed   |  Link to Article
Alberts  MJ, Hademenos  G, Latchaw  RE,  et al; Brain Attack Coalition.  Recommendations for the establishment of primary stroke centers. JAMA. 2000;283(23):3102-3109.
PubMed   |  Link to Article
Khatri  P, Kleindorfer  DO, Yeatts  SD,  et al.  Strokes with minor symptoms: an exploratory analysis of the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator trials. Stroke. 2010;41(11):2581-2586.
PubMed   |  Link to Article
Bluhmki  E, Chamorro  A, Dávalos  A,  et al.  Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009;8(12):1095-1102.
PubMed   |  Link to Article
IST-3 Collaborative Group.  Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial. Lancet Neurol. 2013;12(8):768-776.
PubMed   |  Link to Article
Emberson  J, Lees  KR, Lyden  P,  et al; Stroke Thrombolysis Trialists’ Collaborative Group.  Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384(9958):1929-1935.
PubMed   |  Link to Article
Wardlaw  JM, Murray  V, Berge  E,  et al.  Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet. 2012;379(9834):2364-2372.
PubMed   |  Link to Article
NINDS t-PA Stroke Study Group.  Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28(11):2109-2118.
PubMed   |  Link to Article
Urra  X, Ariño  H, Llull  L,  et al.  The outcome of patients with mild stroke improves after treatment with systemic thrombolysis. PLoS One. 2013;8(3):e59420.
PubMed   |  Link to Article
Steffenhagen  N, Hill  MD, Poppe  AY, Buchan  AM, Coutts  SB.  Should you thrombolyse all or any stroke patients with baseline National Institutes of Health stroke scale scores < or = 5? Cerebrovasc Dis. 2009;28(2):201-202.
PubMed   |  Link to Article
Tanne  D, Kasner  SE, Demchuk  AM,  et al.  Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the Multicenter rt-PA Stroke Survey. Circulation. 2002;105(14):1679-1685.
PubMed   |  Link to Article
Wendt  M, Tütüncü  S, Fiebach  JB, Scheitz  JF, Audebert  HJ, Nolte  CH.  Preclusion of ischemic stroke patients from intravenous tissue plasminogen activator treatment for mild symptoms should not be based on low National Institutes of Health Stroke Scale Scores. J Stroke Cerebrovasc Dis. 2013;22(4):550-553.
PubMed   |  Link to Article
Strbian  D, Piironen  K, Meretoja  A,  et al; Helsinki Stroke Thrombolysis Registry Group.  Intravenous thrombolysis for acute ischemic stroke patients presenting with mild symptoms. Int J Stroke. 2013;8(5):293-299.
PubMed   |  Link to Article
Hassan  AE, Hassanzadeh  B, Tohidi  V, Kirmani  JF.  Very mild stroke patients benefit from intravenous tissue plasminogen activator without increase of intracranial hemorrhage. South Med J. 2010;103(5):398-402.
PubMed   |  Link to Article
Huisa  BN, Raman  R, Neil  W, Ernstrom  K, Hemmen  TM.  Intravenous tissue plasminogen activator for patients with minor ischemic stroke. J Stroke Cerebrovasc Dis. 2012;21(8):732-736.
PubMed   |  Link to Article
Greisenegger  S, Seyfang  L, Kiechl  S, Lang  W, Ferrari  J; Austrian Stroke Unit Registry Collaborators.  Thrombolysis in patients with mild stroke: results from the Austrian Stroke Unit Registry. Stroke. 2014;45(3):765-769.
PubMed   |  Link to Article
Whiteley  WN, Slot  KB, Fernandes  P, Sandercock  P, Wardlaw  J.  Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies. Stroke. 2012;43(11):2904-2909.
PubMed   |  Link to Article
Ní Chróinín  D, Asplund  K, Åsberg  S,  et al.  Statin therapy and outcome after ischemic stroke: systematic review and meta-analysis of observational studies and randomized trials. Stroke. 2013;44(2):448-456.
PubMed   |  Link to Article
Hackam  DG, Woodward  M, Newby  LK,  et al.  Statins and intracerebral hemorrhage: collaborative systematic review and meta-analysis. Circulation. 2011;124(20):2233-2242.
PubMed   |  Link to Article
Uyttenboogaart  M, Koch  MW, Koopman  K, Vroomen  PC, Luijckx  GJ, De Keyser  J.  Lipid profile, statin use, and outcome after intravenous thrombolysis for acute ischaemic stroke. J Neurol. 2008;255(6):875-880.
PubMed   |  Link to Article
Messé  SR, Pervez  MA, Smith  EE,  et al.  Lipid profile, lipid-lowering medications, and intracerebral hemorrhage after tPA in get with the guidelines-stroke. Stroke. 2013;44(5):1354-1359.
PubMed   |  Link to Article
Engelter  ST, Soinne  L, Ringleb  P,  et al.  IV thrombolysis and statins. Neurology. 2011;77(9):888-895.
PubMed   |  Link to Article
Martin-Schild  S, Albright  KC, Tanksley  J,  et al.  Zero on the NIHSS does not equal the absence of stroke. Ann Emerg Med. 2011;57(1):42-45.
PubMed   |  Link to Article
Willey  JZ, Khatri  P, Khoury  JC,  et al.  Variability in the use of intravenous thrombolysis for mild stroke: experience across the SPOTRIAS network. J Stroke Cerebrovasc Dis. 2013;22(4):318-322.
PubMed   |  Link to Article
Köhrmann  M, Nowe  T, Huttner  HB,  et al.  Safety and outcome after thrombolysis in stroke patients with mild symptoms. Cerebrovasc Dis. 2009;27(2):160-166.
PubMed   |  Link to Article
Coutts  SB, Hill  MD, Eliasziw  M, Fischer  K, Demchuk  AM; VISION Study Group.  Final 2 year results of the vascular imaging of acute stroke for identifying predictors of clinical outcome and recurrent ischemic events (VISION) study. BMC Cardiovasc Disord. 2011;11:18.
PubMed   |  Link to Article
Rajajee  V, Kidwell  C, Starkman  S,  et al.  Early MRI and outcomes of untreated patients with mild or improving ischemic stroke. Neurology. 2006;67(6):980-984.
PubMed   |  Link to Article
Asdaghi  N, Hill  MD, Coulter  JI,  et al.  Perfusion MR predicts outcome in high-risk transient ischemic attack/minor stroke: a derivation-validation study. Stroke. 2013;44(9):2486-2492.
PubMed   |  Link to Article
Smith  EE, Abdullah  AR, Petkovska  I, Rosenthal  E, Koroshetz  WJ, Schwamm  LH.  Poor outcomes in patients who do not receive intravenous tissue plasminogen activator because of mild or improving ischemic stroke. Stroke. 2005;36(11):2497-2499.
PubMed   |  Link to Article
Rubiera  M, Alvarez-Sabín  J, Ribo  M,  et al.  Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke. Stroke. 2005;36(7):1452-1456.
PubMed   |  Link to Article
Donnan  GA, O’Malley  HM, Quang  L, Hurley  S, Bladin  PF.  The capsular warning syndrome: pathogenesis and clinical features. Neurology. 1993;43(5):957-962.
PubMed   |  Link to Article
Jørgensen  HS, Nakayama  H, Raaschou  HO, Vive-Larsen  J, Støier  M, Olsen  TS.  Outcome and time course of recovery in stroke, part II: time course of recovery: the Copenhagen Stroke Study. Arch Phys Med Rehabil. 1995;76(5):406-412.
PubMed   |  Link to Article
Quinn  TJ, Dawson  J, Walters  MR, Lees  KR.  Reliability of the modified Rankin Scale: a systematic review. Stroke. 2009;40(10):3393-3395.
PubMed   |  Link to Article
Hong  KS, Saver  JL.  Quantifying the value of stroke disability outcomes: WHO global burden of disease project disability weights for each level of the modified Rankin Scale. Stroke. 2009;40(12):3828-3833.
PubMed   |  Link to Article
Dromerick  AW, Edwards  DF, Diringer  MN.  Sensitivity to changes in disability after stroke: a comparison of four scales useful in clinical trials. J Rehabil Res Dev. 2003;40(1):1-8.
PubMed   |  Link to Article
Harrison  JK, McArthur  KS, Quinn  TJ.  Assessment scales in stroke: clinimetric and clinical considerations. Clin Interv Aging. 2013;8:201-211.
PubMed
Moradiya  Y, Crystal  H, Valsamis  H, Levine  SR.  Thrombolytic utilization for ischemic stroke in US hospitals with neurology residency program. Neurology. 2013;81(23):1986-1995.
PubMed   |  Link to Article
Reeves  MJ, Fonarow  GC, Smith  EE,  et al.  Representativeness of the Get With the Guidelines-Stroke Registry: comparison of patient and hospital characteristics among Medicare beneficiaries hospitalized with ischemic stroke. Stroke. 2012;43(1):44-49.
PubMed   |  Link to Article
Del Zoppo  GJ, Saver  JL, Jauch  EC, Adams  HP  Jr; American Heart Association Stroke Council.  Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009;40(8):2945-2948.
PubMed   |  Link to Article

Correspondence

CME


You need to register in order to view this quiz.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

8,446 Views
4 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
Three Fundamental Principles of EBM

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
Best Evidence Summaries