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Use of Thrombolysis in Acute Ischemic Stroke: Analysis of the Nationwide Inpatient Sample 1999 to 2004
NEUROLOGY/ORIGINAL RESEARCH
Use of Thrombolysis in Acute Ischemic Stroke: Analysis of the Nationwide Inpatient Sample 1999 to 2004 H. Christian Schumacher, MD Brian T. Bateman, MD Bernadette Boden-Albala, PhD Mitchell F. Berman, MD, MPH J. P. Mohr, MD, MS Ralph L. Sacco, MD, MS John Pile-Spellman, MD
From the Doris and Stanley Tananbaum Stroke Center, Neurological Institute, New York– Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, NY (Schumacher, Boden-Albala, Mohr, Sacco); Department of Anesthesiology (Berman), College of Physicians and Surgeons (Bateman), Department of Epidemiology, Mailman School of Public Health, Columbia University (Sacco), New York, NY; and Interventional Neuroradiology, Departments of Radiology, Neurology, and Neurosurgery, New York Presbyterian Hospital, College of Physicians and Surgeons of Columbia University, New York, NY (Pile-Spellman).
Study objective: The aim of this study is to characterize hospital and patient characteristics associated with administration of thrombolysis in acute ischemic stroke patients in the United States. Methods: This retrospective, observational, cohort study used data from the Nationwide Inpatient Sample, an administrative discharge database. A total of 366,194 hospitalizations admitted through the emergency department with a primary diagnosis of acute ischemic stroke were selected for analysis. The primary outcome considered in this study is whether the patient received thrombolytic therapy on hospital day 0 or 1. Results: Thrombolysis was used in 1.12% (95% confidence interval [CI] 0.95% to 1.32%) of ischemic stroke hospitalizations. Most hospitals (69.5%; 95% CI 68.4% to 70.6%) treating ischemic stroke patients did not use thrombolysis during the study period. For the hospitals that used thrombolysis, the mean annual number of patients treated with thrombolysis per hospital was 3.06 (95% CI 2.68 to 3.44). In the binary logistic regression analysis, hospital characteristics associated with high use of thrombolysis were teaching hospital status and increasing number of stroke patients treated annually. Patient characteristics associated with higher use of thrombolysis were age younger than 55 years, male sex, and low comorbidity as measured by the modified Charlson Index; white race; and private self-pay health insurance. Conclusion: Use of thrombolysis for ischemic stroke in the United States from 1999 to 2004 was infrequent and showed significant differences, depending on hospital and patient demographic characteristics. [Ann Emerg Med. 2007;50:99-107.] 0196-0644/$-see front matter Copyright © 2007 by the American College of Emergency Physicians. doi:10.1016/j.annemergmed.2007.01.021
INTRODUCTION
MATERIALS AND METHODS
Intravenous thrombolysis with recombinant tissue plasminogen activator is the established treatment for acute ischemic stroke patients presenting within 3 hours after stroke onset.1,2 But despite US Food and Drug Administration approval in June 1996, intravenous thrombolysis remains underused in the United States. We performed an analysis of hospital and patient characteristics associated with thrombolysis usage from 1999 to 2004 in the National Inpatient Sample, an administrative database collecting discharge information of inpatients in a representative sample of 20% of US hospitals.
Study Design This retrospective analysis used data from the Nationwide Inpatient Sample, the largest all-payer inpatient care database in the United States, from 1999 to 2004. The Nationwide Inpatient Sample contains discharge-level information, including diagnoses, procedures, admission source, discharge destination, patient demographics, and hospital characteristics, and is maintained as part of the Healthcare Utilization Project of the Agency for Healthcare Research and Quality. Information on the database is available at http://www.hcup-us.
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Thrombolysis in Acute Ischemic Stroke Editor’s Capsule Summary
What is already known on this topic Intravenous thrombolysis within 3 hours of stroke onset was approved by the US Food and Drug Administration in 1996. It has been reported that few stroke patients actually receive this treatment. What question this study addressed This study used the Nationwide Inpatient Sample to estimate the use of thrombolysis in more than 360,000 stroke patients admitted through the emergency department from 1999 to 2004. The data could not address whether thrombolysis was indicated or not. What this study adds to our knowledge Sixty-nine percent of hospitals did not use thrombolysis at all. Only 1% of stroke patients received thrombolytics, mostly at hospitals with a high volume of stroke patients. How this might change clinical practice Thrombolytic therapy for stroke is rarely used in the United States. It remains to be seen whether measures such as Joint Commission on Accreditation of Health Care Organizations certification of primary stroke centers will increase use. ahrq.gov/nisoverview.jsp. The Nationwide Inpatient Sample represents an approximately 20% stratified sample of all patients admitted at community hospitals in the United States each year. Five hospital characteristics— geographic region, ownership, location (urban or rural), teaching status, and bed size—are used to create a stratified sample that is maximally representative of hospitalizations in the United States. For the years considered in our study, between 984 and 1,004 hospitals from between 24 and 37 states contributed discharges to the database. Participating hospitals reported 100% of their discharges to the database. The annual number of total discharges contained in the database ranged from 7,198,929 to 8,004,571 for the years considered. The Nationwide Inpatient Sample is a restrictedaccess, public use database. It contains clinical and resource use information included in a typical discharge abstract, with safeguards to protect the privacy of individual patients: (1) it contains no personal patient identifiers; (2) one of the provisions of the Data Use Agreement, which we signed when purchasing the data set, is that no cross-tabulated data involving less than or equal to 10 observations are to be published. Because of these measures, the database fulfills all criteria for exception from a formal institutional review board approval, and for this reason we did not seek institutional review board approval for the current study. Setting and Selection of Participants Patients with acute ischemic stroke were identified by querying the database for all patients admitted through the 100 Annals of Emergency Medicine
Schumacher et al Table 1. ICD-9-CM code and number of observations included for analysis, stratified by use of thrombolysis.* Treated With Thrombolysis Principal Diagnosis 433.01
433.11
433.21
433.31
433.81
433.91
434.01 434.11 434.91
436
Description
Yes (Nⴝ4,104), No. (%)
No (Nⴝ362,090), No. (%)
Occlusion and stenosis of 46 (1.1) 1,550 (0.4) basilar artery with infarction Occlusion and stenosis of 320 (7.8) 14,818 (4.1) carotid artery with infarction Occlusion and stenosis of ⱕ10† 1,004 (0.3) vertebral artery with infarction Occlusion and stenosis of 59 (1.4) 4,599 (1.3) multiple or bilateral precerebral arteries with infarction Occlusion and stenosis of 15 (0.4) 1,377 (0.4) other precerebral artery with infarction Occlusion and stenosis of ⱕ10† 226 (0.1) not specified precerebral artery with infarction Occlusion of cerebral 302 (7.4) 8,675 (2.4) arteries with infarction Cerebral embolism with 803 (19.6) 30,411 (8.4) infarction Cerebral artery occlusion, 2,032 (49.5) 212,364 (58.6) unspecified, with infarction Acute, but ill-defined, 515 (12.5) 87,066 (24.0) cerebrovascular disease
*Percentages are calculated to the total of number of observations in each column. † The exact number of observations is suppressed in compliance with the requirements of the Agency for Healthcare Research and Quality to protect individual personal patient information.
emergency department (ED) with a primary diagnosis of ischemic stroke (International Classification of Diseases, Clinical Modification, Ninth Revision [ICD-9-CM] codes 433.01, 433.11, 433.21, 433.31, 433.81, 433.91, 434.01, 434.11, 434.91, or 436).3-5 The most common cause for hospitalization in patients who were incorrectly assigned these diagnostic codes (ie, who did not have an acute ischemic stroke) was for cerebral angiogram or for carotid endarterectomy, both of which, in the absence of acute stroke, are generally elective procedures.3 We attempted to exclude these miscoded patients by selecting only those patients who are admitted through the ED. Further, because the purpose of this study was to access the use of thrombolysis for acute ischemic stroke, we excluded patients who carried a diagnosis of acute myocardial infarction (ICD-9CM codes 410.XX) or pulmonary embolus (ICD-9-CM codes 415.XX) because these are other major indications for thrombolysis, which may have confounded our analysis. Table 1 lists the number of patients for each of the ICD-9-CM codes Volume , . : August
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included in the analysis. Data from Kansas do not code admission source and were therefore excluded from analysis. Data from Illinois, Ohio, Utah, Washington, and West Virginia were also excluded because these states do not code the hospital day on which procedures are performed. Some states do not report the day of all hospital procedures; these states were included in the analysis. The total acute ischemic stroke cohort for our study included 366,194 hospitalizations. Each hospital in the database is assigned a unique, encrypted identifier. The annual acute ischemic stroke volume was determined for each hospital by using this identifier. Because the hospitals that contribute to the database change yearly, the annual volume was calculated separately for each year that a hospital was in the database (ie, it was not calculated as the mean annual volume across years). The hospitals were divided into groups based on annual ischemic stroke volume (1 to 50, 51 to 150, 151 to 300, and 301 and above). This identifier was also used to calculate the annual mean, median, percentiles, and range of thrombolysis cases for each hospital that administered thrombolysis. The teaching status and location (urban/rural) were recorded directly from the database. Data Collection and Processing We obtained demographic variables, including age, sex, and race or ethnicity as coded in the database. All hospital sites supplied information on race of the patient, and some provided it by race and ethnicity in separate data elements. When both race and ethnicity were supplied, ethnicity (specifically Hispanic) took precedence over race in setting the value for a race or ethnicity variable. Categories of race-ethnicity included white, black, Hispanic, Native American, Asian Pacific Islander, and other. Race was missing for 14.7% of patients. Primary health insurance was obtained for all stroke patients. The database provides insurance type for the expected primary payer (Medicare, Medicaid, private insurance, etc). The primary payer was missing for 0.2% of patients. To ensure uniformity of coding across data sources, this variable combined detailed categories within more general groups. The category “Medicare” includes both fee-for-service and managed-care Medicare patients. “Medicaid” included fee-for-service and managed-care Medicaid patients. “Private insurance” includes Blue Cross, commercial carriers, and private health maintenance organizations and preferred provider organizations. The category of “Other” included worker’s compensation, CHAMPUS, CHAMPVA, Title V, and other government programs. Outcome Measures The primary outcome considered in this study is whether the patient received thrombolytic therapy on hospital day 0 or 1. If thrombolysis was administered on a hospital day other than 0 or 1 or if the hospital day on which thrombolysis was administered was not coded, then the patient was not counted as having received thrombolysis for stroke. Querying all procedure code fields for the ICD-9-CM procedure code 99.10 identified Volume , . : August
Figure. Selection of study population from the original Nationwide Inpatient Sample database for 1999 to 2004. AIS, Acute ischemic stroke; AMI, acute myocardial infarction; PE, pulmonary embolism.
patients treated with thrombolytic therapy. Because there is no procedural code, the rate of intra-arterial thrombolysis was estimated indirectly by identification of patients undergoing arteriography (code 88.41) on day 0 or 1 of admission.6 Primary Data Analysis All statistics were performed using SPSS (version 14; SPSS, Inc., Chicago, IL). Descriptive statistics were used to assess the effect of the hospital characteristics on the probability of receiving thrombolytic therapy. Univariate and binary logistic regression analysis was used to calculate odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for the probability of receiving thrombolytic therapy. Binary logistic regression analysis was performed in a forced method entry. ORs and 95% CIs were generated for all variables in the model. The results of the regression analysis are tabulated as recommended.7 Indicator variable coding was used in the model for categorical explanatory variables. Because SPSS does not contain an option for producing colinearity diagnostics in logistic regression, statistics such as the tolerance and variance inflation factor were obtained by running a linear regression analysis using the same outcome and predictors as suggested.8 Annals of Emergency Medicine 101
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Table 2. Use of thrombolysis for acute ischemic stroke in the Nationwide Inpatient Sample, 1999 to 2004. Year Number of hospitals treating acute stroke patients Number of acute stroke patients treated annually Number of hospitals administering thrombolysis, No. (%) Number of AIS treated with thrombolysis, No. (%) Mean Median Range 25th–75thPercentile
1999
2000
2001
2002
2003
2004
736 61,541 210 (28.5) 546 (0.9) 2.60 2 1–22 1–3
715 59,819 221 (30.9) 649 (1.1) 2.94 2 1–15 1–4
744 61,270 236 (31.7) 711 (1.2) 3.01 2 1–22 1–4
715 63,199 221 (30.9) 637 (1.0) 2.88 2 1–20 1–4
740 61,434 227 (30.7) 749 (1.2) 3.30 2 1–67 1–4
735 59,011 223 (30.3) 812 (1.4) 3.64 2 1–76 1–4
*For hospitals where thrombolysis was administered.
RESULTS There were 366,194 hospitalizations through the ED with ischemic stroke in 1999 to 2004. An annual mean of 731 hospitals contributed stroke cases to the Nationwide Inpatient Sample. Data from states where admission source or procedure day are not recorded were excluded (Figure 1). Thrombolysis was used in 4,104 hospitalizations with acute ischemic stroke (intravenous 3,696 [90.1%], intra-arterial 408 [9.9%]) corresponding to an overall thrombolysis rate for the study period of 1.12% (95% CI 0.95% to 1.32%). The overall thrombolysis rate among ischemic stroke hospitalizations increased slightly during the study period, from 0.9% in 1999 to 1.4% in 2004 (Table 2). The majority of hospitals (69.5%; 95% CI 68.4% to 70.6%) treating ischemic stroke patients did not use thrombolysis (Table 2). For the hospitals that used thrombolysis, the mean annual number of patients treated with thrombolysis per hospital was 3.06 (95% CI 2.68 to 3.44). The highest number of thrombolyzed acute ischemic stroke patients at a single institution in a single year was 76 (Table 2). Table 3 shows the univariate analysis of various patient characteristics on the odds of receiving thrombolysis. Patients younger than 55 years were most likely to receive thrombolytic therapy, with a reported rate of 1.8%, whereas patients aged 85 years and older were the least likely to receive thrombolysis, with a reported rate of 0.6%. All age groups, except patients aged 65 to 74 years, were significantly less likely to receive thrombolysis than the youngest patients. The thrombolysis rate in women was approximately two thirds the rate in men. Increasing Charlson Comorbidity Index Score, which reflects worsening general medical condition, was associated with decreasing odds of thrombolysis. Blacks and Hispanics were less likely to receive thrombolysis in the univariate analysis compared to whites. The low numbers of Asian/Pacific Islanders, Native Americans, and others precluded a meaningful analysis, and they were therefore considered as a joined group. This group had thrombolysis rate similar to that of whites. Medicare was the primary expected payer for patients in the cohort (70.9%). Compared to Medicare patients, patients who had private insurance or who self-paid had significantly higher odds of thrombolysis therapy. 102 Annals of Emergency Medicine
Hospitals treating greater than or equal to 300 stroke patients annually treated approximately one-eighth of all stroke patients. Patients treated at these high-volume hospitals were significantly more likely to receive thrombolysis than those treated by hospitals with lower volumes (Table 3). Hospitals characterized as nonteaching treated more stroke patients than teaching hospitals, 63.8% and 36.2%, respectively. Patients treated at teaching hospitals were more likely to receive thrombolysis. Urban hospitals treated more stroke patients than rural hospitals (84.1% versus 15.8%, respectively). Thrombolysis rates were higher in urban than in rural hospitals. To identify independent predictors associated with thrombolysis use for acute ischemic stroke, we performed binary logistic regression analyses as described in detail in the Materials and Methods section. The final model is presented in Table 4. Increasing age, female sex, and increasing number of comorbid conditions as measured by the modified Charlson Comorbidity Index were associated with decreasing odds for thrombolysis use. Blacks and Hispanics were less likely to receive thrombolysis compared to whites. Self-paying patients or patients with private or other insurance were more likely to receive thrombolysis compared to Medicare- or Medicaidinsured patients. The odds for using thrombolysis decreased with decreasing mean annual number of stroke patients treated at a hospital. Nonteaching hospitals were less likely to administer thrombolysis compared to teaching hospitals. However, urban hospital location was no longer associated with higher odds of thrombolysis compared to rural hospital location. Using a classification cutoff of 0.0112, corresponding to the mean thrombolysis rate of 1.12% in our data set, the model had a sensitivity of 0.63 and a specificity of 0.99 for predicting thrombolysis. For cross-validation of the model, the data were randomly split in half and binary regression analysis was performed on both halves. Comparison of the resulting 2 models revealed similar findings of the predictors to the outcome variable (data not shown).
LIMITATIONS Our study has several limitations. Discharge codes for ischemic stroke have been shown to not be completely accurate, Volume , . : August
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Table 3. Patient and hospital characteristics associated with use of thrombolysis for ischemic stroke to univariate analysis.
Patient Characteristics Age group, y ⬍55 55–64 65–74 75–84 ⱖ85 Sex Male Female Race White Black Hispanic Asian/Pacific Islander/ Native American, or other Missing Primary payer Medicare Medicaid Private Self–pay No charge Other Modified Charlson Index score 0 1–2 ⱖ3 Annual number of stroke patients treated per hospital ⱖ300 151–300 51–150 ⱕ50 Teaching status Nonteaching Teaching Location Rural Urban
Total AIS Cohort, (N ⴝ 366,194)
Cohort Receiving Thrombolysis (N ⴝ 4,104)
No.
No. (%)
42,057 52,382 84,355 118,208 69,192
739 (1.8) 738 (1.4) 1,138 (1.3) 1,095 (0.9) 394 (0.6)
Ref 0.80 (0.72–0.89) 0.77 (0.70–0.84) 0.52 (0.48–0.57) 0.32 (0.28–0.36)
162,169 203,972
2,221 (1.4) 1,883 (0.9)
Ref 0.67 (0.63–0.71)
226,244 50,138 21,502 14,547
2,715 (1.2) 407 (0.8) 226 (1.1) 179 (1.2)
Ref 0.67 (0.61–0.75) 0.88 (0.76–1.00) 1.03 (0.88–1.19)
(95% CI)
thrombolysis using the ICD-9-CM code 99.10 in discharged stroke patients is reported to have a sensitivity of only 50% to 55% and a specificity of 98% to 100%.4,12 The combination of ICD-9-CM code 99.10 and the Clinical Procedural Terminology codes 37201 and 37202 for case detection in discharge databases results in a high sensitivity and specificity of 82% and 98%, respectively, for thrombolysis.12 Unfortunately, the Nationwide Inpatient Sample database does not contain Clinical Procedural Terminology codes. For these reasons, we likely underestimated the “true” thrombolysis rate for acute ischemic stroke during the study period. Yet even when thrombolysis rates based on this reported sensitivity and specificity are extrapolated, thrombolysis rates in the United States during the study period remained low. Further, it is likely that the miscoding would affect all of the subgroups analyzed equally, so that our findings of differential use of thrombolysis in various treatment settings and among various demographic groups are likely valid.
DISCUSSION 53,763
577 (1.1)
0.89 (0.82–0.98)
259,533 20,181 66,893 11,765 1,140 5,848
2,388 (0.9) 206 (1.0) 1,204 (1.8) 184 (1.6) 15 (1.3) 94 (1.6)
Ref 1.11 (0.96–1.28) 1.97 (1.84–2.12) 1.71 (1.47–1.99) 1.44 (0.86–2.39) 1.76 (1.43–2.17)
150,426 177,378 38,390
2,128 (1.4) 1,742 (1.0) 234 (0.6)
Ref 0.69 (0.65–0.74) 0.43 (0.37–0.49)
51,799 144,836 127,897 41,662
859 (1.7) 1,805 (1.2) 1,231 (1.0) 209 (0.5)
Ref 0.75 (0.69–0.81) 0.58 (0.53–0.63) 0.30 (0.26–0.35)
233,655 132,412
2,239 (1.0) 1,862 (1.4)
Ref 1.47 (1.39–1.57)
57,994 308,073
443 (0.8) 3,658 (1.2)
Ref 1.56 (1.41–1.72)
because of inclusion of conditions other than ischemic stroke, although there are measures in our analysis used to exclude such patients.3,9-11 Also, in an effort to increase the specificity of our search strategy, we included only patients with a primary diagnosis of acute ischemic stroke, excluding those patients with a secondary diagnosis of ischemic stroke. Further, coding of Volume , . : August
Our main finding is a mean thrombolysis rate of only 1.12%, with only a slight increase in usage rate during the study period, in a large US cohort of acute ischemic stroke patients hospitalized between 1999 and 2004. This finding reflects the rates reported for the United States in other hospital- and population-based studies.4,5,13-19 The most commonly reported reasons for deferring thrombolysis are presentation beyond 3 hours after stroke onset and mild or rapidly improving stroke symptoms.13,17,20,21 Because we are constrained by the data contained in the Nationwide Inpatient Sample, we are unable to provide any information about why stroke patients were excluded from thrombolysis in this cohort. Other reasons for deferring from thrombolysis for ischemic stroke are concerns about its safety and efficacy, as have been expressed by the American Academy of Emergency Medicine Work Group on Thrombolytic Therapy in Stroke, and its rare usage may be a lack of belief in its efficacy on the part of the medical community.22 Our data further indicate that a large number of US hospitals, between 1999 and 2004, had limited or no experience in thrombolysis for acute ischemic stroke, despite proven clinical efficacy,23 US Food and Drug Administration approval of recombinant tissue plasminogen activator for intravenous thrombolysis in June 1996,2 and cost-effectiveness.24,25 This finding is concordant with a recent survey showing that only 44% of US hospitals provided most of the acute stroke services recommended by the Brain Attack Coalition for primary stroke centers,26 and only 7% met all Brain Attack Coalition criteria for primary stroke centers.27 Furthermore, in a survey of physicians, 45% of respondents had not thrombolyzed any stroke patient, and another 20% did so in only 1 or 2 patients during the 12 months before the survey.27 The annual number of stroke cases per hospital correlated strongly with thrombolysis rates in our study. Published patient series using different cut points for stratifying hospital volumes have Annals of Emergency Medicine 103
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Table 4. Patient and hospital characteristics associated with use of thrombolysis for ischemic stroke to binary logistic regression analysis.*
Patient Characteristics Age group, y ⬍55 55–64 65–74 75–84 ⱖ85 Sex Male Female Race White Black Hispanic Asian/Pacific Islander/Native American/other Missing Primary payer Medicare Medicaid Private Self–pay No charge Other Modified Charlson Index score 0 1–2 ⱖ3 Number of stroke patients treated per hospital annually ⱖ300 151–300 51–150 ⱕ50 Teaching status Nonteaching Teaching Location Rural Urban Intercept
Coefficient ()
Standard Error of Coefficient
⫺0.176 ⫺0.022 ⫺0.386 ⫺0.845
0.053 0.058 0.061 0.074
⫺0.263
Wald Test Statistic, 2
OR
95% CI
10.08 0.14 39.72 129.30
Ref 0.84 0.98 0.68 0.43
0.76–0.93 0.87–1.10 0.60–0.77 0.37–0.50
0.032
66.98
Ref 0.77
0.72–0.82
⫺0.608 ⫺0.238 ⫺0.112
0.055 0.071 0.079
122.75 11.31 2.03
Ref 0.54 0.79 0.89
0.49–0.61 0.69–0.91 0.77–1.04
⫺0.118
0.047
6.24
0.89
0.81–0.97
⫺0.028 ⫹0.365 ⫹0.258 ⫹0.058 ⫹0.354
0.082 0.048 0.087 0.264 0.112
0.11 57.03 8.75 0.05 10.04
Ref 0.97 1.44 1.29 1.06 1.42
0.83–1.14 1.31–1.58 1.09–1.54 0.63–1.78 1.14–1.77
⫺0.320 ⫺0.817
0.033 0.070
94.81 137.84
Ref 0.73 0.44
0.68–0.77 0.39–0.51
⫺0.241 ⫺0.482 ⫺1.041
0.043 0.048 0.087
31.07 99.47 143.87
Ref 0.79 0.62 0.35
0.72–0.86 0.56–0.68 0.30–0.42
0.209
0.035
36.26
Ref 1.23
1.15–1.32
⫺0.024 ⫺3.586
0.058 0.089
0.17 1,623.85
Ref 0.98 0.03
0.87–1.09
*Model diagnostics: Percentage of cases with a standardized residual less than –2 and greater than ⫹2: 1.12%. Durbin to Watson test statistic: 1.955. Variance inflation factor (VIF) ranged between 1.04 and 3.98 (mean 1.72). Model discrimination: C statistic: 0.662 (95% CI 0.654 to 0.670). Using a cutoff corresponding to a mean thrombolysis rate of 1.12%, sensitivity and specificity were 0.63 and 0.99 for prediction of thrombolysis, respectively. Model calibration: Hosmer and Lemeshow goodness-of-fit test: 2⫽7.141, df⫽8, P⫽.521.
had conflicting results about the association between the total number of stroke patients treated and the number of patients receiving thrombolysis annually. Although a German study was able to demonstrate a correlation between increasing number of thrombolyzed patients with increasing number of total stroke patients treated annually, stratified as less than 50, greater than or equal to 50 to 99, 100 to 199, and greater than or equal to 200 patients,28 a US study stratifying as less than 100, greater than or equal to 100 to 299, and greater than 300 total stroke patients 104 Annals of Emergency Medicine
treated annually failed to demonstrate similar findings.5 Our results suggest that higher numbers of stroke patients treated annually results in higher rates of patients treated with thrombolysis, and this, in turn, may imply that immediate referral of stroke patients to strategically placed, certified, high-volume stroke centers with continuously available, dedicated, and sophisticated stroke teams, analogous to the manner in which trauma patients are routed to certified trauma centers, leads to an increase of thrombolysis rates in the United States.29 Volume , . : August
Schumacher et al There are many published examples of centers with thrombolysis rates much higher than the overall rate reported in our study. These centers, which are typically academic or community medical facilities with an institutional commitment to stroke care, have reported thrombolysis rates ranging from 3% to 22%.4,28,30-35 The experience of these centers confirms that, with well-organized hospital programs to ensure thrombolysis in eligible patients, much higher treatment rates than those observed in our survey are possible. Although in the univariate analysis patients were more likely to receive thrombolysis in urban compared to rural hospitals, this association lost statistical significance when adjustment was made for other factors in the multivariate analysis. This finding confounds the common assumption that in rural areas transportation of patients to hospitals may take longer compared to that in urban areas and adds to the out-of-hospital treatment delay, as has been described by others.36 Less surprising was the finding that teaching hospitals had higher thrombolysis use compared to nonteaching hospitals when adjustment was made for other characteristics. As might be expected, elderly patients and those with many comorbid conditions, as assessed by the Charlson Index, were less likely to receive thrombolysis. Physicians may defer from thrombolysis in elderly patients because of the fear of hemorrhagic or other complications, which may explain the observed lower thrombolysis rates in our cohort for patients 85 years or older. However, current evidence suggests that thrombolysis in carefully selected elderly patients is not associated with higher rates of hemorrhagic complications.37,38 More striking was that socioeconomic factors, including nonwhite race and nonprivate insurance, were associated with lower thrombolysis rates in our study. Several studies suggest that social variables exert pressure on patients’ interaction with the health care system by creating differentials in access to knowledge, wealth, power, and prestige,39 which may in turn cause language barriers, economic barriers, mistrust of medical professionals, poor health status, or poor access to health services,40-43 all of which may decrease the probability that a patient receives thrombolysis in the setting of acute stroke. Whatever the underlying mechanism, our study, reflecting the results of the large survey of academic centers reported by Johnston et al,4 identifies access to thrombolysis as an area of significant health care disparity. However, a study from the Greater Cincinnati/Northern Kentucky Stroke Study did not observe a racial disparity of thrombolysis use for ischemic stroke.44 Future studies using large-scale prospective case surveillance are more appropriate to provide reliable data to evaluate for racial disparities. For the reasons stated above, our study has several limitations that apply to all discharge databases. The ongoing creation of a nationwide US acute stroke registry under the supervision of the Centers for Disease Control and Prevention, the Paul Coverdell National Acute Stroke Registry,45,46 will provide more accurate nationwide information on acute stroke management and Volume , . : August
Thrombolysis in Acute Ischemic Stroke outcome after its full implementation and, it is hoped, will overcome the deficiencies of current administrative databases.45,46 Until the full implementation of the Paul Coverdell National Acute Stroke Registry, most data on thrombolysis rates will be obtained from ongoing and newly established regional stroke networks.11,18,19,34,47-50 In addition, the introduction of a new diagnosis-related group code (DRG 559) for treating acute ischemic stroke patients with a thrombolytic drug51 is likely to result in more accurate recording of thrombolysis in administrative data sets because hospitals will have a financial incentive to code the thrombolysis procedure in patients’ discharge abstracts.52 In summary, use of thrombolysis for ischemic stroke in the United States from 1999 to 2004 was infrequent and showed significant differences, depending on hospital and patient demographic characteristics. The substantial morbidity and mortality associated with stroke, and the high cost to society for caring for disabled stroke patients, demands that this proven therapy be more widely used. Efforts to improve community and patient education about stroke symptoms and the best response if they occur,18,53,54 to establish certified acute stroke centers by the Joint Commission on Accreditation of Healthcare Organizations (JACHO),55 and to implement current guidelines for acute ischemic stroke management26,56 are likely to improve patient access to thrombolysis.29 We thank Claudia Steiner, MD, MPH, Healthcare Cost and Utilization Project, Center for Delivery, Organization and Markets, Agency for Healthcare Quality and Research, for critical review of the article. Supervising editor: William G. Barsan, MD Author contributions: HCS and BTB were responsible for study concept and design, acquisition of data, statistical analysis and interpretation of the data, and drafting of the article. HCS, BTB, BB-A, MFB, JPM, RLS, and JP-S were responsible for critical revision of the article for important intellectual content. BTB and JP-S obtained funding. HCS takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. HCS was supported by the NIH training grant PHS 5-T32-NS007155-26. BTB was supported by the Doris Duke Charitable Foundation. JPS was supported in part by a grant from NYSTAR. BBA, JPM, and RLS are supported by grants from NINDS (Specialized Program on Translational Research in Acute Stroke, P50 049060). Publication dates: Received for publication April 1, 2006. Revision received January 24, 2007. Accepted for publication January 26, 2007. Available online May 3, 2007. Annals of Emergency Medicine 105
Thrombolysis in Acute Ischemic Stroke Reprints not available from the authors. Address for correspondence: H. Christian Schumacher, MD, Doris and Stanley Tananbaum Stroke Center, Neurological Institute, New York Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, 710 West 168th Street, Box 163, New York, NY 10032; 212-305 8033, fax 212-305 5796; E-mail [email protected]. REFERENCES 1. The National Institute of Neurological Disorders rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587. 2. US Food and Drug Administration. Product approval information— licencing action: alteplase (Activase). Available at: http://www. fda.gov/cder/foi/appletter/1996/altegen061896l.pdf. Accessed January 24, 2007. 3. Goldstein LB. Accuracy of ICD-9-CM coding for the identification of patients with acute ischemic stroke: effect of modifier codes. Stroke. 1998;29:1602-1604. 4. 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. Stroke. 2001;32: 1061-1068. 5. Reed SD, Cramer SC, Blough DK, et al. Treatment with tissue plasminogen activator and inpatient mortality rates for patients with ischemic stroke treated in community hospitals. Stroke. 2001;32:1832-1840. 6. Choi JH, Bateman BT, Mangla S, et al. Endovascular recanalization therapy in acute ischemic stroke. Stroke. 2006;37: 419-424. 7. Lang TA, Secic M. Analyzing Multiple Variables. I. Reporting Regression Analyses. How to Report Statistics in Medicine. Philadelphia, PA: American College of Physicians; 1997:105-125. 8. Field A. Logistic regression. In: Wright DB, ed. Discovering Statistics Using SPSS for Windows. Thousand Oaks, CA: SAGE Publications; 2000:163-204. 9. Leibson CL, Naessens JM, Brown RD, et al. Accuracy of hospital discharge abstracts for identifying stroke. Stroke. 1994;25:23482355. 10. Benesch C, Witter DM Jr, Wilder AL, et al. Inaccuracy of the International Classification of Diseases (ICD-9-CM) in identifying the diagnosis of ischemic cerebrovascular disease. Neurology. 1997;49:660-664. 11. Broderick J, Brott T, Kothari R, et al. The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke. 1998; 29:415-421. 12. Qureshi AI, Harris-Lane P, Siddiqi F, et al. International classification of diseases and current procedural terminology codes underestimated thrombolytic use for ischemic stroke. J Clin Epidemiol. 2006;59:856-858. 13. Barber PA, Zhang J, Demchuk AM, et al. Why are stroke patients excluded from TPA therapy? an analysis of patient eligibility. Neurology. 2001;56:1015-1020. 14. Katzan IL, Hammer MD, Hixson ED, et al. Utilization of intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol. 2004;61:346-350. 15. Qureshi AI, Suri MF, Nasar A, et al. Thrombolysis for ischemic stroke in the United States: data from National Hospital Discharge Survey 1999-2001. Neurosurgery. 2005;57:647-654. 16. Brown DL, Lisabeth LD, Garcia NM, et al. Emergency department evaluation of ischemic stroke and TIA: the BASIC Project. Neurology. 2004;63:2250-2254.
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Schumacher et al 17. Kleindorfer D, Kissela B, Schneider A, et al. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke. 2004;35:e27-e29. 18. California Acute Stroke Pilot Registry (CASPR) Investigators. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology. 2005;64:654-659. 19. Deng YZ, Reeves MJ, Jacobs BS, et al. IV tissue plasminogen activator use in acute stroke: experience from a statewide registry. Neurology. 2006;66:306-312. 20. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA. 2000;283:1151-1158. 21. Garcia-Monco JC, Pinedo A, Escalza I, et al. Analysis of the reasons for exclusion from tPA therapy after early arrival in acute stroke patients. Clin Neurol Neurosurg. 2007;109:50-53. 22. Goyal DG, Li J, Mann J, et al. Position statement of the American Academy of Emergency Medicine on the use of intravenous thrombolytic therapy in the treatment of stroke. Available at: http:// www.aaem.org/positionstatements/thrombolytictherapy.shtml. Accessed January 24, 2007. 23. 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;363:768-774. 24. Fagan SC, Morgenstern LB, Petitta A, et al. Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke Study Group. Neurology. 1998;50:883-890. 25. Sandercock P, Berge E, Dennis M, et al. Cost-effectiveness of thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke assessed by a model based on UK NHS costs. Stroke. 2004;35:1490-1497. 26. Alberts MJ, Latchaw RE, Selman WR, et al. Recommendations for comprehensive stroke centers: a consensus statement from the Brain Attack Coalition. Stroke. 2005;36:1597-1616. 27. Kidwell CS, Shephard T, Tonn S, et al. Establishment of primary stroke centers: a survey of physician attitudes and hospital resources. Neurology. 2003;60:1452-1456. 28. 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. Stroke. 2003;34:1106-1113. 29. Douglas VC, Tong DC, Gillum LA, et al. Do the Brain Attack Coalition’s criteria for stroke centers improve care for ischemic stroke? Neurology. 2005;64:422-427. 30. Grond M, Stenzel C, Schmulling S, et al. Early intravenous thrombolysis for acute ischemic stroke in a community-based approach. Stroke. 1998;29:1544-1549. 31. Grotta JC, Burgin WS, El Mitwalli A, et al. Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000. Arch Neurol. 2001;58:2009-2013. 32. Morgenstern LB, Staub L, Chan W, et al. Improving delivery of acute stroke therapy: the TLL Temple Foundation Stroke Project. Stroke. 2002;33:160-166. 33. 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:e55-e57. 34. Qureshi AI, Kirmani JF, Sayed MA, et al. Time to hospital arrival, use of thrombolytics, and in-hospital outcomes in ischemic stroke. Neurology. 2005;64:2115-2120. 35. Wojner-Alexandrov AW, Alexandrov AV, Rodriguez D, et al. Houston paramedic and emergency stroke treatment and outcomes study (HoPSTO). Stroke. 2005;36:1512-1518. 36. Merino JG, Silver B, Wong E, et al. Extending tissue plasminogen activator use to community and rural stroke patients. Stroke. 2002;33:141-146.
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37. Vatankhah B, Dittmar MS, Fehm NP, et al. Thrombolysis for stroke in the elderly. J Thromb Thrombolysis. 2005;20:5-10. 38. Sylaja PN, Cote R, Buchan AM, et al. Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol Neurosurg Psychiatry. 2006;77:826-829. 39. Link BG, Phelan J. Social conditions as fundamental causes of disease. J Health Soc Behav. 1995;Spec No:80-94. 40. Howard G, Anderson R, Sorlie P, et al. Ethnic differences in stroke mortality between non-Hispanic whites, Hispanic whites, and blacks. The National Longitudinal Mortality Study. Stroke. 1994;25:2120-2125. 41. Davey Smith G, Neaton JD, Wentworth D, et al. Mortality differences between black and white men in the USA: contribution of income and other risk factors among men screened for the MRFIT. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Lancet. 1998;351:934-939. 42. Lynch J, Harper S, Kaplan GA, et al. Associations between income inequality and mortality among US states: the importance of time period and source of income data. Am J Public Health. 2005;95:1424-1430. 43. Brunner E, Shipley MJ, Blane D, et al. When does cardiovascular risk start? past and present socioeconomic circumstances and risk factors in adulthood. J Epidemiol Community Health. 1999; 53:757-764. 44. Kleindorfer D, Schneider A, Kissela BM. The effect of race and gender on patterns of rt-PA use within a population. J Stroke Cerebrovasc Dis. 2003;12:217-220. 45. Wattigney WA, Croft JB, Mensah GA, et al. Establishing data elements for the Paul Coverdell National Acute Stroke Registry: Part 1: proceedings of an expert panel. Stroke. 2003;34:151-156. 46. Arora S, Broderick JP, Frankel M, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke. 2005;36:1232-1240.
47. Ruland S, Gorelick PB, Schneck M, et al. Acute stroke care in Illinois: a statewide assessment of diagnostic and treatment capabilities. Stroke. 2002;33:1334-1339. 48. Rymer MM, Thrutchley DE. Organizing regional networks to increase acute stroke intervention. Neurol Res. 2005;27(suppl 1):S9-S16. 49. Howard VJ, Acker J, Gomez CR, et al. An approach to coordinate efforts to reduce the public health burden of stroke: the Delta States Stroke Consortium. Prev Chronic Dis. 2004;1:1-7. 50. Hedworth AB, Smith CS. The Great Lakes Regional Stroke Network experience. Prev Chronic Dis. 2006;3:A128. 51. American Stroke Association. Centers for Medicare and Medicaid create new reimbursement category for stroke patients. Stroke news. Available at: http://www.strokeassociation.org/presenter. jhtml?identifier⫽3032721. Accessed January 24, 2007. 52. Kleindorfer D, Hill MD, Woo D, et al. A description of Canadian and United States physician reimbursement for thrombolytic therapy administration in acute ischemic stroke. Stroke. 2005; 36:682-687. 53. Silverman IE, Beland DK, Bohannon RW, et al. Expanding the range of therapies for acute ischemic stroke: the early experience of the Regional Stroke Center at Hartford Hospital. Conn Med. 2004;68:419-429. 54. Silver FL, Rubini F, Black D, et al. Advertising strategies to increase public knowledge of the warning signs of stroke. Stroke. 2003;34:1965-1968. 55. Joint Commission on Accreditation of Healthcare Organizations. Stroke performance implementation guide. Available at: http://www.jointcommission.org/CertificationPrograms/ PrimaryStrokeCenters/implementation_guide.htm. Accessed January 24, 2007. 56. National Stroke Association. Stroke: The First Hours. Englewood, CO: National Stroke Association; 2005.
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Use of Thrombolysis in Acute Ischemic Stroke: Analysis of the Nationwide Inpatient Sample 1999 to 2004 H. Christian Schumacher, MD Brian T. Bateman, MD Bernadette Boden-Albala, PhD Mitchell F. Berman, MD, MPH J. P. Mohr, MD, MS Ralph L. Sacco, MD, MS John Pile-Spellman, MD
From the Doris and Stanley Tananbaum Stroke Center, Neurological Institute, New York– Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, NY (Schumacher, Boden-Albala, Mohr, Sacco); Department of Anesthesiology (Berman), College of Physicians and Surgeons (Bateman), Department of Epidemiology, Mailman School of Public Health, Columbia University (Sacco), New York, NY; and Interventional Neuroradiology, Departments of Radiology, Neurology, and Neurosurgery, New York Presbyterian Hospital, College of Physicians and Surgeons of Columbia University, New York, NY (Pile-Spellman).
Study objective: The aim of this study is to characterize hospital and patient characteristics associated with administration of thrombolysis in acute ischemic stroke patients in the United States. Methods: This retrospective, observational, cohort study used data from the Nationwide Inpatient Sample, an administrative discharge database. A total of 366,194 hospitalizations admitted through the emergency department with a primary diagnosis of acute ischemic stroke were selected for analysis. The primary outcome considered in this study is whether the patient received thrombolytic therapy on hospital day 0 or 1. Results: Thrombolysis was used in 1.12% (95% confidence interval [CI] 0.95% to 1.32%) of ischemic stroke hospitalizations. Most hospitals (69.5%; 95% CI 68.4% to 70.6%) treating ischemic stroke patients did not use thrombolysis during the study period. For the hospitals that used thrombolysis, the mean annual number of patients treated with thrombolysis per hospital was 3.06 (95% CI 2.68 to 3.44). In the binary logistic regression analysis, hospital characteristics associated with high use of thrombolysis were teaching hospital status and increasing number of stroke patients treated annually. Patient characteristics associated with higher use of thrombolysis were age younger than 55 years, male sex, and low comorbidity as measured by the modified Charlson Index; white race; and private self-pay health insurance. Conclusion: Use of thrombolysis for ischemic stroke in the United States from 1999 to 2004 was infrequent and showed significant differences, depending on hospital and patient demographic characteristics. [Ann Emerg Med. 2007;50:99-107.] 0196-0644/$-see front matter Copyright © 2007 by the American College of Emergency Physicians. doi:10.1016/j.annemergmed.2007.01.021
INTRODUCTION
MATERIALS AND METHODS
Intravenous thrombolysis with recombinant tissue plasminogen activator is the established treatment for acute ischemic stroke patients presenting within 3 hours after stroke onset.1,2 But despite US Food and Drug Administration approval in June 1996, intravenous thrombolysis remains underused in the United States. We performed an analysis of hospital and patient characteristics associated with thrombolysis usage from 1999 to 2004 in the National Inpatient Sample, an administrative database collecting discharge information of inpatients in a representative sample of 20% of US hospitals.
Study Design This retrospective analysis used data from the Nationwide Inpatient Sample, the largest all-payer inpatient care database in the United States, from 1999 to 2004. The Nationwide Inpatient Sample contains discharge-level information, including diagnoses, procedures, admission source, discharge destination, patient demographics, and hospital characteristics, and is maintained as part of the Healthcare Utilization Project of the Agency for Healthcare Research and Quality. Information on the database is available at http://www.hcup-us.
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Thrombolysis in Acute Ischemic Stroke Editor’s Capsule Summary
What is already known on this topic Intravenous thrombolysis within 3 hours of stroke onset was approved by the US Food and Drug Administration in 1996. It has been reported that few stroke patients actually receive this treatment. What question this study addressed This study used the Nationwide Inpatient Sample to estimate the use of thrombolysis in more than 360,000 stroke patients admitted through the emergency department from 1999 to 2004. The data could not address whether thrombolysis was indicated or not. What this study adds to our knowledge Sixty-nine percent of hospitals did not use thrombolysis at all. Only 1% of stroke patients received thrombolytics, mostly at hospitals with a high volume of stroke patients. How this might change clinical practice Thrombolytic therapy for stroke is rarely used in the United States. It remains to be seen whether measures such as Joint Commission on Accreditation of Health Care Organizations certification of primary stroke centers will increase use. ahrq.gov/nisoverview.jsp. The Nationwide Inpatient Sample represents an approximately 20% stratified sample of all patients admitted at community hospitals in the United States each year. Five hospital characteristics— geographic region, ownership, location (urban or rural), teaching status, and bed size—are used to create a stratified sample that is maximally representative of hospitalizations in the United States. For the years considered in our study, between 984 and 1,004 hospitals from between 24 and 37 states contributed discharges to the database. Participating hospitals reported 100% of their discharges to the database. The annual number of total discharges contained in the database ranged from 7,198,929 to 8,004,571 for the years considered. The Nationwide Inpatient Sample is a restrictedaccess, public use database. It contains clinical and resource use information included in a typical discharge abstract, with safeguards to protect the privacy of individual patients: (1) it contains no personal patient identifiers; (2) one of the provisions of the Data Use Agreement, which we signed when purchasing the data set, is that no cross-tabulated data involving less than or equal to 10 observations are to be published. Because of these measures, the database fulfills all criteria for exception from a formal institutional review board approval, and for this reason we did not seek institutional review board approval for the current study. Setting and Selection of Participants Patients with acute ischemic stroke were identified by querying the database for all patients admitted through the 100 Annals of Emergency Medicine
Schumacher et al Table 1. ICD-9-CM code and number of observations included for analysis, stratified by use of thrombolysis.* Treated With Thrombolysis Principal Diagnosis 433.01
433.11
433.21
433.31
433.81
433.91
434.01 434.11 434.91
436
Description
Yes (Nⴝ4,104), No. (%)
No (Nⴝ362,090), No. (%)
Occlusion and stenosis of 46 (1.1) 1,550 (0.4) basilar artery with infarction Occlusion and stenosis of 320 (7.8) 14,818 (4.1) carotid artery with infarction Occlusion and stenosis of ⱕ10† 1,004 (0.3) vertebral artery with infarction Occlusion and stenosis of 59 (1.4) 4,599 (1.3) multiple or bilateral precerebral arteries with infarction Occlusion and stenosis of 15 (0.4) 1,377 (0.4) other precerebral artery with infarction Occlusion and stenosis of ⱕ10† 226 (0.1) not specified precerebral artery with infarction Occlusion of cerebral 302 (7.4) 8,675 (2.4) arteries with infarction Cerebral embolism with 803 (19.6) 30,411 (8.4) infarction Cerebral artery occlusion, 2,032 (49.5) 212,364 (58.6) unspecified, with infarction Acute, but ill-defined, 515 (12.5) 87,066 (24.0) cerebrovascular disease
*Percentages are calculated to the total of number of observations in each column. † The exact number of observations is suppressed in compliance with the requirements of the Agency for Healthcare Research and Quality to protect individual personal patient information.
emergency department (ED) with a primary diagnosis of ischemic stroke (International Classification of Diseases, Clinical Modification, Ninth Revision [ICD-9-CM] codes 433.01, 433.11, 433.21, 433.31, 433.81, 433.91, 434.01, 434.11, 434.91, or 436).3-5 The most common cause for hospitalization in patients who were incorrectly assigned these diagnostic codes (ie, who did not have an acute ischemic stroke) was for cerebral angiogram or for carotid endarterectomy, both of which, in the absence of acute stroke, are generally elective procedures.3 We attempted to exclude these miscoded patients by selecting only those patients who are admitted through the ED. Further, because the purpose of this study was to access the use of thrombolysis for acute ischemic stroke, we excluded patients who carried a diagnosis of acute myocardial infarction (ICD-9CM codes 410.XX) or pulmonary embolus (ICD-9-CM codes 415.XX) because these are other major indications for thrombolysis, which may have confounded our analysis. Table 1 lists the number of patients for each of the ICD-9-CM codes Volume , . : August
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included in the analysis. Data from Kansas do not code admission source and were therefore excluded from analysis. Data from Illinois, Ohio, Utah, Washington, and West Virginia were also excluded because these states do not code the hospital day on which procedures are performed. Some states do not report the day of all hospital procedures; these states were included in the analysis. The total acute ischemic stroke cohort for our study included 366,194 hospitalizations. Each hospital in the database is assigned a unique, encrypted identifier. The annual acute ischemic stroke volume was determined for each hospital by using this identifier. Because the hospitals that contribute to the database change yearly, the annual volume was calculated separately for each year that a hospital was in the database (ie, it was not calculated as the mean annual volume across years). The hospitals were divided into groups based on annual ischemic stroke volume (1 to 50, 51 to 150, 151 to 300, and 301 and above). This identifier was also used to calculate the annual mean, median, percentiles, and range of thrombolysis cases for each hospital that administered thrombolysis. The teaching status and location (urban/rural) were recorded directly from the database. Data Collection and Processing We obtained demographic variables, including age, sex, and race or ethnicity as coded in the database. All hospital sites supplied information on race of the patient, and some provided it by race and ethnicity in separate data elements. When both race and ethnicity were supplied, ethnicity (specifically Hispanic) took precedence over race in setting the value for a race or ethnicity variable. Categories of race-ethnicity included white, black, Hispanic, Native American, Asian Pacific Islander, and other. Race was missing for 14.7% of patients. Primary health insurance was obtained for all stroke patients. The database provides insurance type for the expected primary payer (Medicare, Medicaid, private insurance, etc). The primary payer was missing for 0.2% of patients. To ensure uniformity of coding across data sources, this variable combined detailed categories within more general groups. The category “Medicare” includes both fee-for-service and managed-care Medicare patients. “Medicaid” included fee-for-service and managed-care Medicaid patients. “Private insurance” includes Blue Cross, commercial carriers, and private health maintenance organizations and preferred provider organizations. The category of “Other” included worker’s compensation, CHAMPUS, CHAMPVA, Title V, and other government programs. Outcome Measures The primary outcome considered in this study is whether the patient received thrombolytic therapy on hospital day 0 or 1. If thrombolysis was administered on a hospital day other than 0 or 1 or if the hospital day on which thrombolysis was administered was not coded, then the patient was not counted as having received thrombolysis for stroke. Querying all procedure code fields for the ICD-9-CM procedure code 99.10 identified Volume , . : August
Figure. Selection of study population from the original Nationwide Inpatient Sample database for 1999 to 2004. AIS, Acute ischemic stroke; AMI, acute myocardial infarction; PE, pulmonary embolism.
patients treated with thrombolytic therapy. Because there is no procedural code, the rate of intra-arterial thrombolysis was estimated indirectly by identification of patients undergoing arteriography (code 88.41) on day 0 or 1 of admission.6 Primary Data Analysis All statistics were performed using SPSS (version 14; SPSS, Inc., Chicago, IL). Descriptive statistics were used to assess the effect of the hospital characteristics on the probability of receiving thrombolytic therapy. Univariate and binary logistic regression analysis was used to calculate odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for the probability of receiving thrombolytic therapy. Binary logistic regression analysis was performed in a forced method entry. ORs and 95% CIs were generated for all variables in the model. The results of the regression analysis are tabulated as recommended.7 Indicator variable coding was used in the model for categorical explanatory variables. Because SPSS does not contain an option for producing colinearity diagnostics in logistic regression, statistics such as the tolerance and variance inflation factor were obtained by running a linear regression analysis using the same outcome and predictors as suggested.8 Annals of Emergency Medicine 101
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Table 2. Use of thrombolysis for acute ischemic stroke in the Nationwide Inpatient Sample, 1999 to 2004. Year Number of hospitals treating acute stroke patients Number of acute stroke patients treated annually Number of hospitals administering thrombolysis, No. (%) Number of AIS treated with thrombolysis, No. (%) Mean Median Range 25th–75thPercentile
1999
2000
2001
2002
2003
2004
736 61,541 210 (28.5) 546 (0.9) 2.60 2 1–22 1–3
715 59,819 221 (30.9) 649 (1.1) 2.94 2 1–15 1–4
744 61,270 236 (31.7) 711 (1.2) 3.01 2 1–22 1–4
715 63,199 221 (30.9) 637 (1.0) 2.88 2 1–20 1–4
740 61,434 227 (30.7) 749 (1.2) 3.30 2 1–67 1–4
735 59,011 223 (30.3) 812 (1.4) 3.64 2 1–76 1–4
*For hospitals where thrombolysis was administered.
RESULTS There were 366,194 hospitalizations through the ED with ischemic stroke in 1999 to 2004. An annual mean of 731 hospitals contributed stroke cases to the Nationwide Inpatient Sample. Data from states where admission source or procedure day are not recorded were excluded (Figure 1). Thrombolysis was used in 4,104 hospitalizations with acute ischemic stroke (intravenous 3,696 [90.1%], intra-arterial 408 [9.9%]) corresponding to an overall thrombolysis rate for the study period of 1.12% (95% CI 0.95% to 1.32%). The overall thrombolysis rate among ischemic stroke hospitalizations increased slightly during the study period, from 0.9% in 1999 to 1.4% in 2004 (Table 2). The majority of hospitals (69.5%; 95% CI 68.4% to 70.6%) treating ischemic stroke patients did not use thrombolysis (Table 2). For the hospitals that used thrombolysis, the mean annual number of patients treated with thrombolysis per hospital was 3.06 (95% CI 2.68 to 3.44). The highest number of thrombolyzed acute ischemic stroke patients at a single institution in a single year was 76 (Table 2). Table 3 shows the univariate analysis of various patient characteristics on the odds of receiving thrombolysis. Patients younger than 55 years were most likely to receive thrombolytic therapy, with a reported rate of 1.8%, whereas patients aged 85 years and older were the least likely to receive thrombolysis, with a reported rate of 0.6%. All age groups, except patients aged 65 to 74 years, were significantly less likely to receive thrombolysis than the youngest patients. The thrombolysis rate in women was approximately two thirds the rate in men. Increasing Charlson Comorbidity Index Score, which reflects worsening general medical condition, was associated with decreasing odds of thrombolysis. Blacks and Hispanics were less likely to receive thrombolysis in the univariate analysis compared to whites. The low numbers of Asian/Pacific Islanders, Native Americans, and others precluded a meaningful analysis, and they were therefore considered as a joined group. This group had thrombolysis rate similar to that of whites. Medicare was the primary expected payer for patients in the cohort (70.9%). Compared to Medicare patients, patients who had private insurance or who self-paid had significantly higher odds of thrombolysis therapy. 102 Annals of Emergency Medicine
Hospitals treating greater than or equal to 300 stroke patients annually treated approximately one-eighth of all stroke patients. Patients treated at these high-volume hospitals were significantly more likely to receive thrombolysis than those treated by hospitals with lower volumes (Table 3). Hospitals characterized as nonteaching treated more stroke patients than teaching hospitals, 63.8% and 36.2%, respectively. Patients treated at teaching hospitals were more likely to receive thrombolysis. Urban hospitals treated more stroke patients than rural hospitals (84.1% versus 15.8%, respectively). Thrombolysis rates were higher in urban than in rural hospitals. To identify independent predictors associated with thrombolysis use for acute ischemic stroke, we performed binary logistic regression analyses as described in detail in the Materials and Methods section. The final model is presented in Table 4. Increasing age, female sex, and increasing number of comorbid conditions as measured by the modified Charlson Comorbidity Index were associated with decreasing odds for thrombolysis use. Blacks and Hispanics were less likely to receive thrombolysis compared to whites. Self-paying patients or patients with private or other insurance were more likely to receive thrombolysis compared to Medicare- or Medicaidinsured patients. The odds for using thrombolysis decreased with decreasing mean annual number of stroke patients treated at a hospital. Nonteaching hospitals were less likely to administer thrombolysis compared to teaching hospitals. However, urban hospital location was no longer associated with higher odds of thrombolysis compared to rural hospital location. Using a classification cutoff of 0.0112, corresponding to the mean thrombolysis rate of 1.12% in our data set, the model had a sensitivity of 0.63 and a specificity of 0.99 for predicting thrombolysis. For cross-validation of the model, the data were randomly split in half and binary regression analysis was performed on both halves. Comparison of the resulting 2 models revealed similar findings of the predictors to the outcome variable (data not shown).
LIMITATIONS Our study has several limitations. Discharge codes for ischemic stroke have been shown to not be completely accurate, Volume , . : August
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Thrombolysis in Acute Ischemic Stroke
Table 3. Patient and hospital characteristics associated with use of thrombolysis for ischemic stroke to univariate analysis.
Patient Characteristics Age group, y ⬍55 55–64 65–74 75–84 ⱖ85 Sex Male Female Race White Black Hispanic Asian/Pacific Islander/ Native American, or other Missing Primary payer Medicare Medicaid Private Self–pay No charge Other Modified Charlson Index score 0 1–2 ⱖ3 Annual number of stroke patients treated per hospital ⱖ300 151–300 51–150 ⱕ50 Teaching status Nonteaching Teaching Location Rural Urban
Total AIS Cohort, (N ⴝ 366,194)
Cohort Receiving Thrombolysis (N ⴝ 4,104)
No.
No. (%)
42,057 52,382 84,355 118,208 69,192
739 (1.8) 738 (1.4) 1,138 (1.3) 1,095 (0.9) 394 (0.6)
Ref 0.80 (0.72–0.89) 0.77 (0.70–0.84) 0.52 (0.48–0.57) 0.32 (0.28–0.36)
162,169 203,972
2,221 (1.4) 1,883 (0.9)
Ref 0.67 (0.63–0.71)
226,244 50,138 21,502 14,547
2,715 (1.2) 407 (0.8) 226 (1.1) 179 (1.2)
Ref 0.67 (0.61–0.75) 0.88 (0.76–1.00) 1.03 (0.88–1.19)
(95% CI)
thrombolysis using the ICD-9-CM code 99.10 in discharged stroke patients is reported to have a sensitivity of only 50% to 55% and a specificity of 98% to 100%.4,12 The combination of ICD-9-CM code 99.10 and the Clinical Procedural Terminology codes 37201 and 37202 for case detection in discharge databases results in a high sensitivity and specificity of 82% and 98%, respectively, for thrombolysis.12 Unfortunately, the Nationwide Inpatient Sample database does not contain Clinical Procedural Terminology codes. For these reasons, we likely underestimated the “true” thrombolysis rate for acute ischemic stroke during the study period. Yet even when thrombolysis rates based on this reported sensitivity and specificity are extrapolated, thrombolysis rates in the United States during the study period remained low. Further, it is likely that the miscoding would affect all of the subgroups analyzed equally, so that our findings of differential use of thrombolysis in various treatment settings and among various demographic groups are likely valid.
DISCUSSION 53,763
577 (1.1)
0.89 (0.82–0.98)
259,533 20,181 66,893 11,765 1,140 5,848
2,388 (0.9) 206 (1.0) 1,204 (1.8) 184 (1.6) 15 (1.3) 94 (1.6)
Ref 1.11 (0.96–1.28) 1.97 (1.84–2.12) 1.71 (1.47–1.99) 1.44 (0.86–2.39) 1.76 (1.43–2.17)
150,426 177,378 38,390
2,128 (1.4) 1,742 (1.0) 234 (0.6)
Ref 0.69 (0.65–0.74) 0.43 (0.37–0.49)
51,799 144,836 127,897 41,662
859 (1.7) 1,805 (1.2) 1,231 (1.0) 209 (0.5)
Ref 0.75 (0.69–0.81) 0.58 (0.53–0.63) 0.30 (0.26–0.35)
233,655 132,412
2,239 (1.0) 1,862 (1.4)
Ref 1.47 (1.39–1.57)
57,994 308,073
443 (0.8) 3,658 (1.2)
Ref 1.56 (1.41–1.72)
because of inclusion of conditions other than ischemic stroke, although there are measures in our analysis used to exclude such patients.3,9-11 Also, in an effort to increase the specificity of our search strategy, we included only patients with a primary diagnosis of acute ischemic stroke, excluding those patients with a secondary diagnosis of ischemic stroke. Further, coding of Volume , . : August
Our main finding is a mean thrombolysis rate of only 1.12%, with only a slight increase in usage rate during the study period, in a large US cohort of acute ischemic stroke patients hospitalized between 1999 and 2004. This finding reflects the rates reported for the United States in other hospital- and population-based studies.4,5,13-19 The most commonly reported reasons for deferring thrombolysis are presentation beyond 3 hours after stroke onset and mild or rapidly improving stroke symptoms.13,17,20,21 Because we are constrained by the data contained in the Nationwide Inpatient Sample, we are unable to provide any information about why stroke patients were excluded from thrombolysis in this cohort. Other reasons for deferring from thrombolysis for ischemic stroke are concerns about its safety and efficacy, as have been expressed by the American Academy of Emergency Medicine Work Group on Thrombolytic Therapy in Stroke, and its rare usage may be a lack of belief in its efficacy on the part of the medical community.22 Our data further indicate that a large number of US hospitals, between 1999 and 2004, had limited or no experience in thrombolysis for acute ischemic stroke, despite proven clinical efficacy,23 US Food and Drug Administration approval of recombinant tissue plasminogen activator for intravenous thrombolysis in June 1996,2 and cost-effectiveness.24,25 This finding is concordant with a recent survey showing that only 44% of US hospitals provided most of the acute stroke services recommended by the Brain Attack Coalition for primary stroke centers,26 and only 7% met all Brain Attack Coalition criteria for primary stroke centers.27 Furthermore, in a survey of physicians, 45% of respondents had not thrombolyzed any stroke patient, and another 20% did so in only 1 or 2 patients during the 12 months before the survey.27 The annual number of stroke cases per hospital correlated strongly with thrombolysis rates in our study. Published patient series using different cut points for stratifying hospital volumes have Annals of Emergency Medicine 103
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Schumacher et al
Table 4. Patient and hospital characteristics associated with use of thrombolysis for ischemic stroke to binary logistic regression analysis.*
Patient Characteristics Age group, y ⬍55 55–64 65–74 75–84 ⱖ85 Sex Male Female Race White Black Hispanic Asian/Pacific Islander/Native American/other Missing Primary payer Medicare Medicaid Private Self–pay No charge Other Modified Charlson Index score 0 1–2 ⱖ3 Number of stroke patients treated per hospital annually ⱖ300 151–300 51–150 ⱕ50 Teaching status Nonteaching Teaching Location Rural Urban Intercept
Coefficient ()
Standard Error of Coefficient
⫺0.176 ⫺0.022 ⫺0.386 ⫺0.845
0.053 0.058 0.061 0.074
⫺0.263
Wald Test Statistic, 2
OR
95% CI
10.08 0.14 39.72 129.30
Ref 0.84 0.98 0.68 0.43
0.76–0.93 0.87–1.10 0.60–0.77 0.37–0.50
0.032
66.98
Ref 0.77
0.72–0.82
⫺0.608 ⫺0.238 ⫺0.112
0.055 0.071 0.079
122.75 11.31 2.03
Ref 0.54 0.79 0.89
0.49–0.61 0.69–0.91 0.77–1.04
⫺0.118
0.047
6.24
0.89
0.81–0.97
⫺0.028 ⫹0.365 ⫹0.258 ⫹0.058 ⫹0.354
0.082 0.048 0.087 0.264 0.112
0.11 57.03 8.75 0.05 10.04
Ref 0.97 1.44 1.29 1.06 1.42
0.83–1.14 1.31–1.58 1.09–1.54 0.63–1.78 1.14–1.77
⫺0.320 ⫺0.817
0.033 0.070
94.81 137.84
Ref 0.73 0.44
0.68–0.77 0.39–0.51
⫺0.241 ⫺0.482 ⫺1.041
0.043 0.048 0.087
31.07 99.47 143.87
Ref 0.79 0.62 0.35
0.72–0.86 0.56–0.68 0.30–0.42
0.209
0.035
36.26
Ref 1.23
1.15–1.32
⫺0.024 ⫺3.586
0.058 0.089
0.17 1,623.85
Ref 0.98 0.03
0.87–1.09
*Model diagnostics: Percentage of cases with a standardized residual less than –2 and greater than ⫹2: 1.12%. Durbin to Watson test statistic: 1.955. Variance inflation factor (VIF) ranged between 1.04 and 3.98 (mean 1.72). Model discrimination: C statistic: 0.662 (95% CI 0.654 to 0.670). Using a cutoff corresponding to a mean thrombolysis rate of 1.12%, sensitivity and specificity were 0.63 and 0.99 for prediction of thrombolysis, respectively. Model calibration: Hosmer and Lemeshow goodness-of-fit test: 2⫽7.141, df⫽8, P⫽.521.
had conflicting results about the association between the total number of stroke patients treated and the number of patients receiving thrombolysis annually. Although a German study was able to demonstrate a correlation between increasing number of thrombolyzed patients with increasing number of total stroke patients treated annually, stratified as less than 50, greater than or equal to 50 to 99, 100 to 199, and greater than or equal to 200 patients,28 a US study stratifying as less than 100, greater than or equal to 100 to 299, and greater than 300 total stroke patients 104 Annals of Emergency Medicine
treated annually failed to demonstrate similar findings.5 Our results suggest that higher numbers of stroke patients treated annually results in higher rates of patients treated with thrombolysis, and this, in turn, may imply that immediate referral of stroke patients to strategically placed, certified, high-volume stroke centers with continuously available, dedicated, and sophisticated stroke teams, analogous to the manner in which trauma patients are routed to certified trauma centers, leads to an increase of thrombolysis rates in the United States.29 Volume , . : August
Schumacher et al There are many published examples of centers with thrombolysis rates much higher than the overall rate reported in our study. These centers, which are typically academic or community medical facilities with an institutional commitment to stroke care, have reported thrombolysis rates ranging from 3% to 22%.4,28,30-35 The experience of these centers confirms that, with well-organized hospital programs to ensure thrombolysis in eligible patients, much higher treatment rates than those observed in our survey are possible. Although in the univariate analysis patients were more likely to receive thrombolysis in urban compared to rural hospitals, this association lost statistical significance when adjustment was made for other factors in the multivariate analysis. This finding confounds the common assumption that in rural areas transportation of patients to hospitals may take longer compared to that in urban areas and adds to the out-of-hospital treatment delay, as has been described by others.36 Less surprising was the finding that teaching hospitals had higher thrombolysis use compared to nonteaching hospitals when adjustment was made for other characteristics. As might be expected, elderly patients and those with many comorbid conditions, as assessed by the Charlson Index, were less likely to receive thrombolysis. Physicians may defer from thrombolysis in elderly patients because of the fear of hemorrhagic or other complications, which may explain the observed lower thrombolysis rates in our cohort for patients 85 years or older. However, current evidence suggests that thrombolysis in carefully selected elderly patients is not associated with higher rates of hemorrhagic complications.37,38 More striking was that socioeconomic factors, including nonwhite race and nonprivate insurance, were associated with lower thrombolysis rates in our study. Several studies suggest that social variables exert pressure on patients’ interaction with the health care system by creating differentials in access to knowledge, wealth, power, and prestige,39 which may in turn cause language barriers, economic barriers, mistrust of medical professionals, poor health status, or poor access to health services,40-43 all of which may decrease the probability that a patient receives thrombolysis in the setting of acute stroke. Whatever the underlying mechanism, our study, reflecting the results of the large survey of academic centers reported by Johnston et al,4 identifies access to thrombolysis as an area of significant health care disparity. However, a study from the Greater Cincinnati/Northern Kentucky Stroke Study did not observe a racial disparity of thrombolysis use for ischemic stroke.44 Future studies using large-scale prospective case surveillance are more appropriate to provide reliable data to evaluate for racial disparities. For the reasons stated above, our study has several limitations that apply to all discharge databases. The ongoing creation of a nationwide US acute stroke registry under the supervision of the Centers for Disease Control and Prevention, the Paul Coverdell National Acute Stroke Registry,45,46 will provide more accurate nationwide information on acute stroke management and Volume , . : August
Thrombolysis in Acute Ischemic Stroke outcome after its full implementation and, it is hoped, will overcome the deficiencies of current administrative databases.45,46 Until the full implementation of the Paul Coverdell National Acute Stroke Registry, most data on thrombolysis rates will be obtained from ongoing and newly established regional stroke networks.11,18,19,34,47-50 In addition, the introduction of a new diagnosis-related group code (DRG 559) for treating acute ischemic stroke patients with a thrombolytic drug51 is likely to result in more accurate recording of thrombolysis in administrative data sets because hospitals will have a financial incentive to code the thrombolysis procedure in patients’ discharge abstracts.52 In summary, use of thrombolysis for ischemic stroke in the United States from 1999 to 2004 was infrequent and showed significant differences, depending on hospital and patient demographic characteristics. The substantial morbidity and mortality associated with stroke, and the high cost to society for caring for disabled stroke patients, demands that this proven therapy be more widely used. Efforts to improve community and patient education about stroke symptoms and the best response if they occur,18,53,54 to establish certified acute stroke centers by the Joint Commission on Accreditation of Healthcare Organizations (JACHO),55 and to implement current guidelines for acute ischemic stroke management26,56 are likely to improve patient access to thrombolysis.29 We thank Claudia Steiner, MD, MPH, Healthcare Cost and Utilization Project, Center for Delivery, Organization and Markets, Agency for Healthcare Quality and Research, for critical review of the article. Supervising editor: William G. Barsan, MD Author contributions: HCS and BTB were responsible for study concept and design, acquisition of data, statistical analysis and interpretation of the data, and drafting of the article. HCS, BTB, BB-A, MFB, JPM, RLS, and JP-S were responsible for critical revision of the article for important intellectual content. BTB and JP-S obtained funding. HCS takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. HCS was supported by the NIH training grant PHS 5-T32-NS007155-26. BTB was supported by the Doris Duke Charitable Foundation. JPS was supported in part by a grant from NYSTAR. BBA, JPM, and RLS are supported by grants from NINDS (Specialized Program on Translational Research in Acute Stroke, P50 049060). Publication dates: Received for publication April 1, 2006. Revision received January 24, 2007. Accepted for publication January 26, 2007. Available online May 3, 2007. Annals of Emergency Medicine 105
Thrombolysis in Acute Ischemic Stroke Reprints not available from the authors. Address for correspondence: H. Christian Schumacher, MD, Doris and Stanley Tananbaum Stroke Center, Neurological Institute, New York Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, 710 West 168th Street, Box 163, New York, NY 10032; 212-305 8033, fax 212-305 5796; E-mail [email protected]. REFERENCES 1. The National Institute of Neurological Disorders rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587. 2. US Food and Drug Administration. Product approval information— licencing action: alteplase (Activase). Available at: http://www. fda.gov/cder/foi/appletter/1996/altegen061896l.pdf. Accessed January 24, 2007. 3. Goldstein LB. Accuracy of ICD-9-CM coding for the identification of patients with acute ischemic stroke: effect of modifier codes. Stroke. 1998;29:1602-1604. 4. 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. Stroke. 2001;32: 1061-1068. 5. Reed SD, Cramer SC, Blough DK, et al. Treatment with tissue plasminogen activator and inpatient mortality rates for patients with ischemic stroke treated in community hospitals. Stroke. 2001;32:1832-1840. 6. Choi JH, Bateman BT, Mangla S, et al. Endovascular recanalization therapy in acute ischemic stroke. Stroke. 2006;37: 419-424. 7. Lang TA, Secic M. Analyzing Multiple Variables. I. Reporting Regression Analyses. How to Report Statistics in Medicine. Philadelphia, PA: American College of Physicians; 1997:105-125. 8. Field A. Logistic regression. In: Wright DB, ed. Discovering Statistics Using SPSS for Windows. Thousand Oaks, CA: SAGE Publications; 2000:163-204. 9. Leibson CL, Naessens JM, Brown RD, et al. Accuracy of hospital discharge abstracts for identifying stroke. Stroke. 1994;25:23482355. 10. Benesch C, Witter DM Jr, Wilder AL, et al. Inaccuracy of the International Classification of Diseases (ICD-9-CM) in identifying the diagnosis of ischemic cerebrovascular disease. Neurology. 1997;49:660-664. 11. Broderick J, Brott T, Kothari R, et al. The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke. 1998; 29:415-421. 12. Qureshi AI, Harris-Lane P, Siddiqi F, et al. International classification of diseases and current procedural terminology codes underestimated thrombolytic use for ischemic stroke. J Clin Epidemiol. 2006;59:856-858. 13. Barber PA, Zhang J, Demchuk AM, et al. Why are stroke patients excluded from TPA therapy? an analysis of patient eligibility. Neurology. 2001;56:1015-1020. 14. Katzan IL, Hammer MD, Hixson ED, et al. Utilization of intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol. 2004;61:346-350. 15. Qureshi AI, Suri MF, Nasar A, et al. Thrombolysis for ischemic stroke in the United States: data from National Hospital Discharge Survey 1999-2001. Neurosurgery. 2005;57:647-654. 16. Brown DL, Lisabeth LD, Garcia NM, et al. Emergency department evaluation of ischemic stroke and TIA: the BASIC Project. Neurology. 2004;63:2250-2254.
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Schumacher et al 17. Kleindorfer D, Kissela B, Schneider A, et al. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke. 2004;35:e27-e29. 18. California Acute Stroke Pilot Registry (CASPR) Investigators. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology. 2005;64:654-659. 19. Deng YZ, Reeves MJ, Jacobs BS, et al. IV tissue plasminogen activator use in acute stroke: experience from a statewide registry. Neurology. 2006;66:306-312. 20. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA. 2000;283:1151-1158. 21. Garcia-Monco JC, Pinedo A, Escalza I, et al. Analysis of the reasons for exclusion from tPA therapy after early arrival in acute stroke patients. Clin Neurol Neurosurg. 2007;109:50-53. 22. Goyal DG, Li J, Mann J, et al. Position statement of the American Academy of Emergency Medicine on the use of intravenous thrombolytic therapy in the treatment of stroke. Available at: http:// www.aaem.org/positionstatements/thrombolytictherapy.shtml. Accessed January 24, 2007. 23. 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;363:768-774. 24. Fagan SC, Morgenstern LB, Petitta A, et al. Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke Study Group. Neurology. 1998;50:883-890. 25. Sandercock P, Berge E, Dennis M, et al. Cost-effectiveness of thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke assessed by a model based on UK NHS costs. Stroke. 2004;35:1490-1497. 26. Alberts MJ, Latchaw RE, Selman WR, et al. Recommendations for comprehensive stroke centers: a consensus statement from the Brain Attack Coalition. Stroke. 2005;36:1597-1616. 27. Kidwell CS, Shephard T, Tonn S, et al. Establishment of primary stroke centers: a survey of physician attitudes and hospital resources. Neurology. 2003;60:1452-1456. 28. 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. Stroke. 2003;34:1106-1113. 29. Douglas VC, Tong DC, Gillum LA, et al. Do the Brain Attack Coalition’s criteria for stroke centers improve care for ischemic stroke? Neurology. 2005;64:422-427. 30. Grond M, Stenzel C, Schmulling S, et al. Early intravenous thrombolysis for acute ischemic stroke in a community-based approach. Stroke. 1998;29:1544-1549. 31. Grotta JC, Burgin WS, El Mitwalli A, et al. Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000. Arch Neurol. 2001;58:2009-2013. 32. Morgenstern LB, Staub L, Chan W, et al. Improving delivery of acute stroke therapy: the TLL Temple Foundation Stroke Project. Stroke. 2002;33:160-166. 33. 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:e55-e57. 34. Qureshi AI, Kirmani JF, Sayed MA, et al. Time to hospital arrival, use of thrombolytics, and in-hospital outcomes in ischemic stroke. Neurology. 2005;64:2115-2120. 35. Wojner-Alexandrov AW, Alexandrov AV, Rodriguez D, et al. Houston paramedic and emergency stroke treatment and outcomes study (HoPSTO). Stroke. 2005;36:1512-1518. 36. Merino JG, Silver B, Wong E, et al. Extending tissue plasminogen activator use to community and rural stroke patients. Stroke. 2002;33:141-146.
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37. Vatankhah B, Dittmar MS, Fehm NP, et al. Thrombolysis for stroke in the elderly. J Thromb Thrombolysis. 2005;20:5-10. 38. Sylaja PN, Cote R, Buchan AM, et al. Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol Neurosurg Psychiatry. 2006;77:826-829. 39. Link BG, Phelan J. Social conditions as fundamental causes of disease. J Health Soc Behav. 1995;Spec No:80-94. 40. Howard G, Anderson R, Sorlie P, et al. Ethnic differences in stroke mortality between non-Hispanic whites, Hispanic whites, and blacks. The National Longitudinal Mortality Study. Stroke. 1994;25:2120-2125. 41. Davey Smith G, Neaton JD, Wentworth D, et al. Mortality differences between black and white men in the USA: contribution of income and other risk factors among men screened for the MRFIT. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Lancet. 1998;351:934-939. 42. Lynch J, Harper S, Kaplan GA, et al. Associations between income inequality and mortality among US states: the importance of time period and source of income data. Am J Public Health. 2005;95:1424-1430. 43. Brunner E, Shipley MJ, Blane D, et al. When does cardiovascular risk start? past and present socioeconomic circumstances and risk factors in adulthood. J Epidemiol Community Health. 1999; 53:757-764. 44. Kleindorfer D, Schneider A, Kissela BM. The effect of race and gender on patterns of rt-PA use within a population. J Stroke Cerebrovasc Dis. 2003;12:217-220. 45. Wattigney WA, Croft JB, Mensah GA, et al. Establishing data elements for the Paul Coverdell National Acute Stroke Registry: Part 1: proceedings of an expert panel. Stroke. 2003;34:151-156. 46. Arora S, Broderick JP, Frankel M, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke. 2005;36:1232-1240.
47. Ruland S, Gorelick PB, Schneck M, et al. Acute stroke care in Illinois: a statewide assessment of diagnostic and treatment capabilities. Stroke. 2002;33:1334-1339. 48. Rymer MM, Thrutchley DE. Organizing regional networks to increase acute stroke intervention. Neurol Res. 2005;27(suppl 1):S9-S16. 49. Howard VJ, Acker J, Gomez CR, et al. An approach to coordinate efforts to reduce the public health burden of stroke: the Delta States Stroke Consortium. Prev Chronic Dis. 2004;1:1-7. 50. Hedworth AB, Smith CS. The Great Lakes Regional Stroke Network experience. Prev Chronic Dis. 2006;3:A128. 51. American Stroke Association. Centers for Medicare and Medicaid create new reimbursement category for stroke patients. Stroke news. Available at: http://www.strokeassociation.org/presenter. jhtml?identifier⫽3032721. Accessed January 24, 2007. 52. Kleindorfer D, Hill MD, Woo D, et al. A description of Canadian and United States physician reimbursement for thrombolytic therapy administration in acute ischemic stroke. Stroke. 2005; 36:682-687. 53. Silverman IE, Beland DK, Bohannon RW, et al. Expanding the range of therapies for acute ischemic stroke: the early experience of the Regional Stroke Center at Hartford Hospital. Conn Med. 2004;68:419-429. 54. Silver FL, Rubini F, Black D, et al. Advertising strategies to increase public knowledge of the warning signs of stroke. Stroke. 2003;34:1965-1968. 55. Joint Commission on Accreditation of Healthcare Organizations. Stroke performance implementation guide. Available at: http://www.jointcommission.org/CertificationPrograms/ PrimaryStrokeCenters/implementation_guide.htm. Accessed January 24, 2007. 56. National Stroke Association. Stroke: The First Hours. Englewood, CO: National Stroke Association; 2005.
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Annals of Emergency Medicine 107