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Treatment With Tissue Plasminogen Activator and Inpatient Mortality Rates for Patients With Ischemic Stroke Treated in Community Hospitals

Originally publishedhttps://doi.org/10.1161/01.STR.32.8.1832Stroke. 2001;32:1832–1840

    Abstract

    Background and Purpose Most analyses of intravenous tissue plasminogen activator (IV tPA) use for acute stroke in routine practice have been limited by sample size and generally restricted to patients treated in large academic medical facilities. In the present study, we sought to estimate among community hospitals the use of IV tPA and to identify factors associated with the use of IV tPA and inpatient mortality.

    Methods We evaluated a retrospective cohort of 23 058 patients with ischemic stroke from 137 community hospitals.

    Results Three hundred sixty-two (1.6%) patients were treated with IV tPA, and 9.9% of those patients died during the hospitalization period. In 35.0% of the hospitals, no patients were treated with IV tPA, whereas 14.6% of hospitals treated ≈3.0% with IV tPA. After control for multiple factors, younger patients, more severely ill patients (OR 2.02, 95% CI 1.36 to 3.01), and patients treated in rural hospitals (OR 1.80, 95% CI 0.99 to 3.26) were more likely to receive IV tPA, whereas black patients were less likely (OR 0.54, 95% CI 0.31 to 0.95). There also was a trend showing that women were less likely to receive IV tPA (OR 0.84, 95% CI 0.69 to 1.03). Factors associated with an increased odds of inpatient mortality included receipt of IV tPA among men (OR 2.81, 95% CI 1.72 to 4.58) and increased age. Black patients were 27% less likely to die during hospitalization (95% CI 0.60 to 0.90).

    Conclusions In this large, retrospective evaluation of community hospital practice, the use IV tPA and inpatient mortality rates among IV tPA–treated patients were consistent with those of other studies. The likelihood of receiving IV tPA varies by race, age, disease severity, and possibly gender. These factors may influence mortality rates.

    Intravenous tissue plasminogen activator (IV tPA) was approved for the treatment of acute ischemic stroke in 1996 by the US Food and Drug Administration on the basis of findings from the National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator Trial.1 Patients who were randomized to the IV tPA arm of the trial were ≥30% more likely than placebo-treated patients to have minimal or no disability at 3 and 12 months of follow-up, although there was no difference in mortality rates.1,2

    Although these findings represent a major therapeutic breakthrough, the impact on the general population of stroke patients has been limited primarily because IV tPA must be administered within 3 hours of the onset of stroke symptoms. There are many other factors that can render a patient ineligible for treatment with IV tPA. These restrictions resulted in only 1% to 2% of patients being eligible for

    See Editorial Comment, page 1840

    intravenous thrombolysis in clinical trials.3 Reports based on clinical practice also show that only a small proportion of patients receive intravenous thrombolytic treatment, although there is wide variation (0%4 to 10.2%5) in the proportion of stroke patients who receive thrombolytic agents at individual hospitals.4–6

    A number of studies that followed the NINDS IV tPA trial demonstrated that successful clinical outcomes and low complication rates could be achieved with IV tPA outside the clinical trial setting.4,7–10 In the prospective Phase 4 STARS (Standard Treatment with Alteplase to Reverse Stroke) study of consecutive acute stroke patients who were treated with IV tPA, 13.1% died by 30 days of follow-up and 11.5% had an intracerebral hemorrhage.7 Almost all of these studies involved physicians who had previous experience with IV tPA in the NINDS or ATLANTIS (Alteplase Thrombolysis Acute Noninterventional Therapy in Ischemic Stroke) clinical trials.6,7,9–11 Recent evidence, however, suggests a higher incidence of adverse events among physicians who have less experience with thrombolytic treatment for acute ischemic stroke.5 Among a cohort of patients treated in 29 Cleveland area hospitals, the inpatient mortality rate was 15.7%, and 22.9% of patients had an intracerebral hemorrhage.5

    Although guidelines exist for patient selection for thrombolytic treatment of stroke, there are no published analyses of patient, hospital, and provider characteristics that are associated with greater or lesser use of IV tPA in routine practice. The primary aim of the present study was to estimate the proportion of patients treated with IV tPA and the incidence of in-hospital death using a large cohort of stroke patients treated in community hospitals throughout the United States. We then assessed which types of patients and providers were most likely to receive or provide treatment with IV tPA and examined factors independently associated with inpatient deaths.

    Subjects and Methods

    Data Collection

    The patient sample for this study was derived from the Healthcare Benchmarking Systems International (HBSI) EXPLORE database. HBSI is a private healthcare data warehousing company that systematically collects comprehensive administrative data for all patients admitted to community hospitals, representing profit and nonprofit community hospitals located throughout the United States. From the EXPLORE database, we identified all patients with a principal International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code of 434 (occlusion of cerebral arteries) or 436 (acute but ill-defined cerebrovascular disease) who were admitted to the hospital between January 1998 and July 1999.

    The data included patient demographic variables (age, sex, race, and insurance type), the principal diagnosis and up to 10 secondary diagnoses, length of stay, discharge disposition, admission source, and number of days in the intensive care unit. Two additional measures were available to adjust for severity of illness and risk of mortality using All Patient Refined Diagnosis-Related Groups (APR-DRGs; 3M Health Information Systems).12 These were the APR-DRG Risk of Mortality and APR-DRG Severity of Illness measures. Both measures are constructed from standard discharge abstract data and coded on a scale from 1 to 4, representing minor, moderate, major, and extreme levels, respectively. The APR-DRG system has been shown to more reliably predict death and have better clinical validity than other severity measures using administrative data.13,14

    A variable that corresponds to the specialty of the attending physician was also available. This physician cared for the patient during the hospitalization but played an uncertain role in the decision of whether to administer IV tPA. Hospital characteristics included the number of hospital beds, number of skilled nursing beds and of rehabilitation beds, teaching status, whether the hospital was located in a rural or an urban area, and whether the hospital was the sole provider of medical care in the community. Hospital-related data were self-reported by the institution. The database also contained detailed charge data for each patient. Data included the name, dose, and dosage form of medications. A charge for IV tPA was used as a proxy to identify patients treated with IV tPA.

    We excluded patients who were younger than 18 years on the day of admission. We also excluded patients who had a secondary diagnosis that corresponded to an acute myocardial infarction (n=295) and patients treated with urokinase (n=68) to avoid confounding with regard to thrombolytic treatment. Finally, we excluded from the analysis patients for whom the total cost was <$100 (n=37) because these cases likely had cost data that were missing, inaccurate, or miscoded.

    Statistical Analysis

    Mean values and 95% CIs were used to describe continuous variables, and proportions and 95% CIs were used to describe categorical variables. For comparisons at the level of the hospital, Pearson χ2 tests were used to compare hospital characteristics that were categorical, and t tests were used to compare characteristics that were measured as continuous variables. For statistical comparisons at the level of the patient, we used a generalized estimating equation (GEE) to account for correlation among patients within individual hospitals. For inpatient length-of-stay comparisons, we used a model based on the Poisson family of distributions. To examine factors associated with IV tPA treatment and inpatient death, we used a model based on the binomial family of distributions.

    In the multivariate analyses, all variables were entered into the model simultaneously. To control for severity of illness and risk of death, both APR-DRG risk adjustment systems were included in the multivariate model at the same time and separately to explore their effects on the results. We encountered problems with multicollinearity and interpretation of the ORs for these variables when both risk adjustment systems were included in the model, so we used APR-DRG Severity of Illness in the model for treatment with IV tPA and APR-DRG Risk of Mortality in the model for inpatient death, although final results were consistent with the use of either risk adjustment system.

    To test for an effect of hospital experience, data for all patients with acute ischemic stroke treated in 1998 were used to construct variables that represented the annual volume of stroke patients treated at each hospital. We coded each hospital according to whether it treated <100 stroke patients, 100 to 299 stroke patients, or ≥300 stroke patients per year. Age was coded to represent patients younger than 60, 60 to 69, 70 to 79, 80 to 89, and 90 years old or older. Race was categorized as white, black, or other (consisting of Hispanic, Asian, other, or unknown race). Other variables included in the final model were hospital teaching status and rural location, patient sex, and physician specialty. We considered including the type of insurance coverage and availability of neurology or neurosurgery services at individual hospitals, but these variables were not significant and did not affect the results of the final models. Interactions between sex and race were tested in the model for treatment with IV tPA. A Wald test with 2 df was undertaken to determine whether interactions significantly contributed to the fit of the model. Interactions between IV tPA and sex as well as between IV tPA and race were tested in the model for inpatient death. The resulting ORs should be interpreted as the odds of the event (receiving IV tPA or dying) among the group under examination relative to the odds of the event in the comparison group, after adjustment for all covariates in the model.

    Results

    The analytic data set consisted of records for 23 058 patients with ischemic stroke treated in 137 community hospitals from 32 states in the United States. Almost three fourths (72.5%) of the cohort had an ICD-9-CM code of 434, corresponding to occlusion of the cerebral arteries. The mean age of the cohort was 72.6 years (median 75 years), and 44.6% were male. Most patients (65.9%) were treated in nonteaching community hospitals. Hospital characteristics are summarized in Table 1.

    Hospital Characteristics

    Variable
    n=137.
    Teaching hospital29.9%
    Rural location16.8%
    Sole-community provider13.1%
    Neurology services available92.0%
    Neurosurgery services available78.8%
    Operational beds, mean n292
    Stroke patients treated in 1998, n
        <10060.6%
        100–29934.3%
        ≥3005.1%

    Use of tPA

    The proportion of patients who received treatment with IV tPA was 1.6% (95% CI 1.4% to 1.7%). Proportions were nearly equivalent in teaching and nonteaching community hospitals (1.6% versus 1.6%, P=0.929). When limiting the analysis to patients with a principal diagnosis code corresponding to occlusion of cerebral arteries (ICD-9-CM code 434), the proportion of patients receiving IV tPA was 1.8% (303 of 16 725). Among those with code 436 (acute but ill-defined cerebrovascular disease), the proportion was 0.9% (59 of 6333).

    Approximately one third (35.0%) of the hospitals did not treat 1 patient with IV tPA during the study period, whereas 14.6% of hospitals treated at least 3.0% and 5.1% of hospitals treated at least 5.0% of acute stroke patients with IV tPA. The hospitals in which no patients were treated with IV tPA admitted a smaller volume of stroke patients during the study period compared with hospitals in which at least 1 patient was treated with IV tPA (74 versus 219, P<0.001). However, the hospitals did not significantly differ with regard to the average number of operational beds (227 versus 327, P=0.127), teaching status (31.5% versus 27.1%, P=0.593), or rural location (16.7% versus 16.9%, P=0.978) between those in which no patients were treated with IV tPA and those in which at least 1 patient was treated with IV tPA, respectively.

    Use of IV tPA remained relatively constant over time: 1.6% of patients were treated with IV tPA in the first 6 months of 1998, 1.5% were treated in the last 6 months of 1998, and 1.8% were treated in the first 7 months of 1999. In the first 6 months of 1998, the inpatient mortality rate was 11.6%. The rate decreased to 9.0% in the last 6 months of 1998 and further decreased to 8.6% in the first 7 months of 1999, but these differences did not approach statistical significance (P=0.479 and P=0.452, respectively). Among IV tPA–treated patients, the mean length of stay was ≈1 day shorter for those who died during the hospitalization than for those who lived (5.2 versus 6.5 days, P=0.149).

    Bivariate, unadjusted analyses revealed that male patients tended to be treated with IV tPA more often than female patients (P<0.001) (Table 2). Black patients represented 8.0% of patients who received IV tPA and 15.5% of patients who did not receive thrombolytic therapy (P<0.001). About one fifth (19.1%) of stroke patients who were treated with IV tPA had diabetes compared with about one third (30.6%) of those who did not receive IV tPA (P<0.001). Also, more than twice the proportion of patients who received IV tPA had a neurologist recorded as their attending physician (47.2%) compared with those who did not receive IV tPA (18.2%) (P<0.001). Average inpatient length of stay was about one-half day longer for patients treated with IV tPA compared with those not treated with IV tPA (6.3 versus 5.8 days, P=0.025).

    Patient and Provider Characteristics

    VariableIV tPA–Treated Patients (n=362)Patients Not Treated With IV tPA (n=22 696)
    Male, %53.044.4
    Mean age (median), y67.3 (70)72.7 (75)
        <6025.9%15.5%
        60–6921.3%18.7%
        70–7936.5%32.7%
        80–8915.2%26.8%
        90+1.4%6.2%
    Race, %
        White83.479.1
        Black8.015.5
        Other8.65.4
    Comorbidities, %
        Diabetes mellitus19.130.6
        Hypertension55.059.6
        Congestive heart failure11.312.3
        Atrial fibrillation24.018.7
    APR-DRG severity of illness, %
        Minor12.711.4
        Moderate51.455.1
        Major22.924.2
        Extreme13.09.4
    APR-DRG risk of death, %
        Minor49.235.8
        Moderate28.240.2
        Major14.918.6
        Extreme7.75.4
    Insurance, %
        Private, fee-for-service18.510.2
        Health maintenance  organization8.38.8
        Preferred provider organization3.91.7
        Medicare60.872.3
        Medicaid3.93.0
        Other4.64.0
    Physician specialty, %
        Neurology47.218.2
        General internal medicine21.834.7
        Other30.947.1
    Discharge disposition, %
        Home35.639.2
        Home health service5.08.2
        Skilled nursing facility18.523.7
        Other facility24.917.4
    Inpatient death (95% CI), %9.9 (6.9–13.0)6.8 (6.4–7.1)
    Mean length of stay, d6.35.8
    Median length of stay, d54

    Multivariate Analyses: Factors Associated With IV tPA Treatment

    Results from the multivariate analysis revealed multiple patient- and provider-related characteristics that were associated with the delivery or receipt of treatment with IV tPA (Table 3). A trend showed that women may have been slightly less likely than men to receive treatment with IV tPA (OR 0.85, P=0.094), with 1.3% of women receiving IV tPA compared with 1.9% of men. Race was significantly related to the odds of receiving IV tPA. Black patients were about half as likely as whites (OR 0.54, P=0.031) to receive IV tPA, with estimates ranging from ≈5% to ≈70% less likely. Interactions between race categories and sex were not significant. As patients aged, they were increasingly less likely to be treated with IV tPA. In comparison to those younger than 60 years, patients aged 60 to 79 years were ≈30% less likely to receive IV tPA, whereas patients ages 80 to 89 years were ≈60% less likely and those at least 90 years of age were ≈85% less likely to receive IV tPA. In addition, it appears that patients with increasing levels of severity of illness were more likely to receive thrombolytic treatment. Patients with the highest level of severity of illness were approximately 2 times more likely to receive IV tPA than were patients with the lowest level of severity of illness (OR 2.02, P=0.001).

    Multivariate Analysis of Factors Associated With Receipt of IV tPA

    ParameterOR95% CIP
    Sex
        Male1.00
        Female0.840.69–1.030.094
    Race
        White1.00
        Black0.540.31–0.950.031
        Other1.430.63–3.260.390
    Age, y
        <601.00
        60–690.710.49–1.030.069
        70–790.690.54–0.880.003
        80–890.370.23–0.59<0.001
        90+0.150.06–0.36<0.001
    Severity of illness
        Minor1.00
        Moderate1.040.74–1.480.815
        Major1.350.93–1.970.116
        Extreme2.021.36–3.010.001
    Physician specialty
        General internal medicine1.00
        Neurology3.702.51–5.46<0.001
        Other specialty0.960.64–1.430.834
    Teaching status
        Nonteaching hospital1.00
        Teaching hospital1.180.73–1.900.504
    Location
        Urban area1.00
        Rural area1.800.99–3.260.051
    Hospital experience with stroke
        <100 patients treated in 19981.00
        100–299 patients treated in 19980.860.57–1.330.491
        ≥300 patients treated in 19980.820.38–1.780.621

    An examination of provider-related characteristics revealed that patients treated in community hospitals located in rural areas were almost twice as likely to receive IV tPA as were patients treated in urban area community hospitals (OR 1.80, P=0.051). Also, patients who had a neurologist as their attending physician were ≈3.7 times more likely to have received thrombolytic treatment with IV tPA than were patients who had a general internist as their attending physician (P<0.001). There was no statistically significant relationship between hospital volume of stroke patients and IV tPA treatment or between hospital teaching status and IV tPA treatment.

    Multivariate Analyses: Factors Associated With Inpatient Death

    After adjustment for multiple provider and patient characteristics, patients who received treatment with IV tPA in the study cohort were ≈80% more likely to die during the initial hospitalization than were patients who did not receive IV tPA treatment (OR 1.81, 95% CI 1.20 to 2.72, P=0.005). A test for an interaction between sex and receipt of IV tPA revealed that the negative association between IV tPA and death was confined to male patients. We did not find an association between treatment with IV tPA and death among women (OR 1.02, P=0.757) (Table 4). Male patients who were treated with IV tPA experienced a 2.8 times higher odds of dying during the initial hospitalization compared with male patients who were not treated with IV tPA (OR 2.81, P=<0.001). The data are consistent with a 72% to 458% increase in the odds of dying. Subgroup analysis revealed that the positive association in men between inpatient death and treatment with IV tPA was consistent across levels of mortality risk. The adjusted OR of inpatient death was 3.55 (95% CI 1.79 to 7.02, P=0.001) for men with minor or moderate APR-DRG Risk of Mortality levels and 2.26 (95% CI 1.15 to 4.41, P=0.017) for men with major or extreme APR-DRG Risk of Mortality levels.

    Multivariate Analysis of Factors Associated With Inpatient Mortality

    ParameterOR95% CIP
    Treatment with IV tPA
        Men2.811.72–4.58<0.001
        Women1.010.49–2.090.974
    Sex
        Male1.00
        Female1.020.90–1.150.757
    Race
        White1.00
        Black0.730.60–0.900.004
        Other0.950.73–1.240.688
    Age, y
        <601.00
        60–691.291.02–1.640.036
        70–791.110.91–1.370.295
        80–891.511.23–1.84<0.001
        90+2.421.90–3.07<0.001
    Risk of death
        Minor1.00
        Moderate2.962.29–3.82<0.001
        Major10.768.09–14.30<0.001
        Extreme99.7875.63–131.63<0.001
    Physician specialty
        General internal medicine1.00
        Neurology0.960.73–1.270.795
        Other specialty1.191.04–1.360.013
    Teaching status
        Nonteaching hospital1.00
        Teaching hospital0.880.70–1.100.245
    Location
        Urban area1.00
        Rural area0.960.77–1.200.733
    Hospital experience with stroke
        <100 patients treated in 19981.00
        100–299 patients treated in 19980.930.76–1.140.489
        ≥300 patients treated in 19980.930.67–1.290.663

    Other factors emerged in relation to mortality risk. Relative to whites, blacks were ≈30% less likely to die during the hospitalization, with estimates ranging from ≈10% to 40% (P=0.004). Interactions between race categories and treatment with IV tPA were not statistically significant (Wald test, P=0.478). With the exception of patients aged 70 to 79, patients who were at least 60 years old were more likely to die while in the hospital relative to patients younger than 60 years. Patients who were at least 90 years old were ≈2.5 times more likely to die than were patients younger than 60 years (P<0.001). The APR-DRG Risk of Mortality levels were strongly associated with observed inpatient death. Among patients with the lowest level of APR-DRG Risk of Mortality, 1.0% died, compared with 3.6%, 11.7%, and 52.9% among those with increasing levels of Risk of Mortality. Patients who were cared for by attending physicians outside of general internal medicine and with specialties in fields other than neurology were, on average, ≈20% more likely to die during the hospitalization compared with patients for whom a general internist was the attending physician (P=0.013). In terms of hospital-related characteristics, neither hospital teaching status, rural location, nor annual volume of stroke patients treated was significantly associated with inpatient death.

    Discussion

    This study documents the extent of treatment with IV tPA for acute ischemic stroke in a large cohort of community hospitals located throughout the United States and examines hospital-, physician-, and patient-level factors associated with its use. In this cohort, 1.6% of patients received treatment with IV tPA for acute ischemic stroke, which is consistent with other estimates of IV tPA use in community hospitals (Table 5).5,8 Our results also confirm observations that there is a large degree of variation in the proportion of patients who receive intravenous thrombolysis at individual hospitals.5,8,9,15,16

    Comparison of IV tPA Treatment and Mortality Estimates Among Studies

    StudyCohort DescriptionNo. Treated With IV tPAProportion Treated With IV tPA, %Inpatient Death, %Death After Discharge, %
    NR indicates not reported.
    *Percent of screened patients, reported in Katzan et al.5
    †Reported in Tanne et al.10
    ‡One-hundred of 1950 patients admitted to area hospitals with final diagnosis of ischemic stroke.
    §Seventy of 3948 patients with primary diagnosis of ischemic stroke.
    ∥Sixty-eight of 2350 patients with hemorrhagic and ischemic stroke.
    ¶Fifty-seven of 900 patients treated at hospitals that prescribed tPA to at least 1 patient.
    **Seven of 630 patients treated in 2 community hospitals.
    ††Twenty-three of 405 patients treated at 1 academic hospital.
    ‡‡Nine of 134 patients with ischemic stroke.
    Present study137 Community hospitals in United States3621.69.9
    Albers et al.724 Academic and 33 community hospitals in US389NRNR13 at 30 d
    NINDS Trial, Parts I and II18 Academic medical centers and affiliated hospitals3123.6*1113 at 30 d
    Tanne et al.105 Academic and 8 community hospitals in US189NR10NR
    Grond et al.91 Academic hospital in Cologne, Germany1005.1NR8 at 1 wk
    Katzan et al.529 Hospitals in Cleveland, Ohio701.8§15.7NR
    Buchan et al.161 Academic hospital in Calgary, Canada682.9NR16 at 3 mo
    Wang et al.420 Hospitals in central Illinois576.39NR
    Chiu et al.81 Academic and 2 community hospitals in Houston, Tex301.1**NR20 at 3 mo
    5.7††
    Zweifler et al.61 Academic hospital in Mobile, Ala96.7‡‡NRNR

    Our estimate of inpatient death for patients treated with IV tPA is consistent with estimates reported in the literature based on clinical trial data as well as on data collected during routine practice (Table 5). Our point estimate of an inpatient mortality rate of 9.9% among 362 patients treated with IV tPA is 37% lower than that reported by Katzan et al,5 which was based 70 patients treated with IV tPA in hospitals located in the Cleveland area. The 95% CI calculated for inpatient death in this study (6.9% to 13.0%) is consistent with the 95% CI for inpatient death in the NINDS trial, Parts I and II (7.4% to 14.4%). Thus, our analysis provides no evidence that the incidence of inpatient death among patients receiving IV tPA in community hospitals is higher than that among stroke patients enrolled in randomized trials of IV tPA.

    Factors Associated With Use of IV tPA

    Because information regarding which patients were eligible for thrombolysis was not available, it is critical to acknowledge that we are measuring a combination of processes when examining factors related to the administration of IV tPA, including eligibility for IV tPA and the decision to treat with IV tPA. Therefore, we cannot discern whether lower utilization of IV tPA in certain subgroups is inappropriate. Nevertheless, our multivariate analyses unveiled a number of provider- and patient-related characteristics associated with higher or lower use of IV tPA that may warrant further study in other patient cohorts.

    Certain subgroups were less likely to receive IV tPA. A number of studies have documented that women are less likely to receive thrombolytic therapy for acute myocardial infarction.17–19 Although our study does not clearly establish this finding for the treatment of acute ischemic stroke, the data suggest a lower odds of receiving IV tPA among women. We also found that black patients were only half as likely as white patients to receive treatment with IV tPA. Numerous studies in the literature report that black patients are less likely to receive various procedures for the diagnosis and treatment of cerebrovascular disease.20–22 Although our study revealed similar findings for the receipt of IV tPA, other reports suggest alternative explanations. The most common reason patients are ineligible for thrombolytic therapy is that they have exceeded the recommended 3-hour time window for treatment.15,23,24 In a prospective study, Kothari et al25 found that white stroke patients were 3.5 times more likely than black stroke patients to arrive in the emergency department within 3 hours of symptom onset. Other researchers have suggested that treatment differences between black and white patients are in part due to physician differences.21 Although the precise role of the attending physician in the decision to treat with IV tPA was unavailable, we estimated that patients treated by attending physicians who were neurologists were 3.7 times more likely to receive IV tPA. This finding was consistent among black and white patients. However, only 10.6% of black patients had a neurologist as their attending physician compared with 20.3% of white patients.

    Although the benefit the elderly receive from IV tPA is reported to be similar to that of younger patients,26 in our study, older patients were less likely to receive intravenous thrombolytic treatment. Among those younger than 60 years, 2.6% received IV tPA, and the proportion decreased to 0.4% for those 90 years old or older. The elderly are less likely to recognize stroke symptoms,27 which could lead to longer delays in seeking medical attention,28 thereby decreasing the likelihood of meeting the 3-hour time window for treatment with IV tPA. In addition, older patients may be eligible for thrombolysis less often than younger patients due to higher utilization of anticoagulants29 and a higher prevalence of systolic hypertension.30 However, even when eligible for treatment, elderly patients often receive less aggressive therapy than do younger patients.10,19,31–33

    The finding that patients treated by neurologists were more likely to have received IV tPA may be in large part due to practice and referral patterns. Patients who are identified as candidates for IV tPA administration are more likely to have a neurologist called in for consultation or direct patient care. Also, patients treated with IV tPA in the emergency department by physicians who are not neurologists may be more likely to be referred to a neurologist for inpatient follow-up.

    The finding that rural area community hospitals were more likely to provide thrombolytic treatment was a bit surprising. Among patients treated in rural area hospitals, 2.3% received IV tPA compared with 1.5% in urban area hospitals. This finding was consistent across many different specifications of the statistical model. Physicians practicing in rural area hospitals may not have direct access to consultation with stroke specialists and therefore may make the decision of whether to treat with IV tPA without benefit of such consultation; this may eliminate time delays incurred when waiting for consultations before proceeding with treatment,34,35 increasing the likelihood that a patient would meet the 3-hour time restriction for treatment. Other potential explanations may be that patients admitted to smaller, rural area hospitals encounter less traffic when traveling to the hospital and are triaged more quickly in the emergency department to meet time constraints for treatment with IV tPA. The finding that patients treated in rural area hospitals are more likely to receive IV tPA requires further evaluation.

    Factors Associated With Inpatient Death

    It is important to note that we cannot distinguish between the effect of IV tPA on death in patients who were treated with IV tPA according to NINDS guidelines from patients who were treated with IV tPA despite violation of the guidelines. Nevertheless, a note of caution is suggested by our results, which show that in routine practice, men who were treated with IV tPA had a 2.8 times higher odds of dying relative to men who were not treated with IV tPA. Katzan et al5 also reported a significantly higher incidence of inpatient death among stroke patients treated with IV tPA in a wide range of community and academic institutions, but they did not evaluate whether this difference was solely attributable to men, as in the present study. Recent studies have documented a considerable amount of deviation from NINDS guidelines for treatment with IV tPA in routine practice,5,7,36 and numerous studies report an increased risk of poor outcomes for patients treated with IV tPA outside the currently recommended guidelines.10,16,37,38 The increased incidence of IV tPA death among men may suggest that physicians are more conservative in their choice of treatment for women with stroke.

    In the multivariate model for inpatient death, black patients were found to be less likely to die than were white patients (7.1% of white patients died compared with 5.6% of black patients). This finding is not consistent with other reports in the medical literature, in which population-based studies have shown that blacks are more likely to die from strokes than are whites.39–41 However, in examination of only in-hospital death, as in the present study, previous studies have found that observed and predicted mortality rates due to stroke are indeed lower in black patients than in white patients.42 This paradoxical association could reflect a sampling bias in hospitalized patient cohorts if a higher proportion of black patients die outside of the hospital setting. Epidemiological studies show that the greatest disparity between stroke mortality rates for blacks and whites exists at younger ages, when blacks are more likely to die from strokes than are whites.39,43 At older ages, whites are more likely to die from strokes than are blacks.39,43 This trend was also observed in our cohort. Among patients younger than 65 years, 4.3% of blacks died during the hospital stay compared with 3.6% of whites, whereas among those 65 years old or older, 8.0% of white patients died and 6.6% of black patients died. Thus, in our cohort, the higher incidence of death in whites compared with blacks is likely due to our relatively aged sample, in which ≈77% of the cohort were at least 65 years old.

    The finding that attending physicians in specialties other than neurology were more likely to treat patients who died compared with general internists must be considered in light of the possibility that the specialty of the attending physician may not be reflective of the physician who was involved in the treatment of the patient with stroke. Such referrals are likely more common among patients who had other severe comorbidities, because they would be more likely to be treated by specialists in fields such as cardiology or nephrology.

    Study Limitations

    The HBSI data have several limitations. Patient deaths were not confirmed in this study but were based on discharge abstracts. We did not have information regarding the severity of stroke symptoms on admission, nor did we have information regarding which patients were eligible for treatment with IV tPA or were treated outside the NINDS criteria. Also, the reliability of using charge data from a cost accounting system as a proxy for treatment with IV tPA has not been validated. It is possible that we are underestimating the use of IV tPA because physicians could have administered the drug without a charge being generated. However, IV tPA is a relatively costly medication, and its use is likely to be closely monitored.

    The severity adjustment variables (APR-DRG Severity of Illness and Risk of Mortality) used in the multivariate analyses are based on information collected at the time of discharge. Therefore, we cannot distinguish comorbidities and clinical events that were present on admission to the hospital from events or complications that occurred after admission. Many of the factors that are used to compute the APR-DRG measures are most likely present at the time of admission (eg, atrial fibrillation, diabetes, hypertension). Nevertheless, in some cases these measures misadjust for iatrogenic complications that occurred during the hospital stay. For this reason, our analysis could be viewed as conservative in its estimation of the OR of death among IV tPA–treated patients in that patients treated with IV tPA are more likely to experience an intracerebral hemorrhage and, as a result, more likely to die. In addition, many of the patients who experienced an intracerebral hemorrhage could have been coded with a primary diagnosis of intracerebral hemorrhage (ICD-9-CM code 431) and would not have been included in our cohort. In an examination of 3968 patients with a primary diagnosis of intracerebral hemorrhage from the same HBSI database, 13.2% had a secondary diagnosis of ischemic stroke and 0.6% (n=25) had been treated with IV tPA. Of the patients treated with IV tPA, 40% died. Because these patients were not included in our analysis, again, the effect of IV tPA on inpatient death may be biased downward.

    Finally, we did not have any information on functional status or quality of life. Although death clearly is an important end point, these other measures are equally important in a condition such as stroke as demonstrated by the NINDS study, which clearly demonstrated a benefit in functional status but no change in mortality rates with the use of IV tPA.1

    The present results must be interpreted within the context of a retrospective study based on automated data with its inherent limitations. However, our large sample provided sufficient power to explore numerous patient- and provider-related factors that were associated with the receipt of IV tPA and inpatient death. This analysis documented relatively low (or no) use of IV tPA at many community hospitals throughout the United States. Overall, the incidence of inpatient death in this study was typical of previous cohort studies and randomized trials. Younger patients, male patients, and patients with high levels of severity of illness were more likely to be treated with IV tPA, whereas black patients were less likely to be treated with IV tPA. Several factors were independently associated with an increased risk of death, including advanced age and treatment with IV tPA among male patients. Black patients were less likely than white patients to die during the hospitalization. The results of this study suggest that more aggressive treatment of male patients may be associated with a greater risk of death. Further research is suggested to further explore these findings in other patient cohorts.

    Footnotes

    Correspondence to Shelby D. Reed, PhD, Duke Clinical Research Institute, PO Box 17969, 2400 Pratt St, Durham, NC 27715. E-mail

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    strokeahaStrokeStrokeStroke0039-24991524-4628Lippincott Williams & Wilkins
    Editorial CommentWang David Z., , Guest Editor01082001

    IV tPA, Much Underutilized, Does Not Increase Stroke Mortality

    In the May issue of Stroke, we learned about the low rate (4.1%) of utilization of intravenous tPA (IV tPA), and the racial disparity (blacks are one fifth as likely) in receiving IV tPA among 42 academic medical centers in the United States.1 The current study discovered an even lower rate (1.6%) in delivering IV tPA, and also racial disparity (blacks are half as likely) among 137 community hospitals. By now we should have learned that these 2 problems in acute stroke care are serious and nationwide.

    The authors also concluded that the inpatient mortality rate is compatible with most other published reports. Therefore, once again it has confirmed the fact that administering IV tPA does not cause excessive death among the community hospitals. This finding is important because the survey reported that the complication physicians fear most is a hemorrhagic event associated with the use of IV tPA2 but not the mortality rate. Indeed, IV tPA is associated with a higher rate of intracerebral hemorrhage (6.4% per NINDS trial). However, IV tPA does not increase the mortality. The NINDS trial indicated that with or without IV tPA, the mortality is very similar (17% among the IV tPA group, 21% among the placebo). One therefore should not ignore the fact that stroke kills. On the other hand, if IV tPA is given to appropriate stroke patients, there is a 33% chance of improvement. This improvement includes an absolute “cure” rate of 12% (1 of every 8 patients treated).

    With the ongoing public education campaign on recognition of the signs and symptoms of stroke, we can anticipate that sooner or later more acute stroke patients will present to local emergency rooms within 3 hours. Therefore, healthcare professionals and institutions should be prepared to deliver IV tPA without any racial disparity. It is very encouraging to see that neurologists were 3.7 times more likely to give tPA in the current study. As Dr Harold Adams recently mentioned, the neurologists should assume such a leadership role in stroke care before someone else takes it.3 Much work also needs to be done to get health care institutions ready to deliver stroke care. As reported by Katzan et al on the survey of the Brain Matters Stroke Management Workshop, only 50% of the neurologists believed that their institution could meet the NINDS recommended target.2

    Despite the low rate of use of IV tPA, the current study showed that rural area hospitals did better than urban area hospitals. With the rather similar good outcome these rural area hospitals were able to achieve, it showed that delivering IV tPA can be accomplished in small hospitals. This certainly has been our experience with the OSF Stroke Network, where 21 of the 23 hospitals are located in rural areas in central Illinois and have had the experience of administering IV tPA. The authors mentioned that the reason these rural hospitals can give IV tPA is partially due to less traffic and no time delays in waiting for specialty consultation. Other reasons include no tie-up of CT scans and the fact that ERs may not be as overwhelmingly busy as at tertiary referral centers.

    The finding that older patients were less likely to receive IV tPA can be an indication of the caution exercised on the part of the treating physician who may be concerned about hemorrhagic complications. However, such caution may be excessive. Despite the likelihood of having more complex baseline medical conditions in the elderly, older patients may still improve from severe baseline neurologic deficit to a mild to moderate state.4

    The current study examined the data from patients admitted from 1998 to 1999. Since then, more stroke awareness campaigns have been conducted and are ongoing nationwide. It may be helpful to assess the result of such campaigns by conducting a similar follow-up study in the near future. Meanwhile, let us continue our effort in improving the access of IV tPA, therefore, more appropriate acute ischemic stroke patients can be benefited.

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