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  • ISSN: 2334-2307
    J Neurol Disord Stroke 1(2): 1015.
    Submitted: 03 September 2013; Accepted: 13 September 2013; Published: 13 September 2013
    Research Article
    The Potential Impact of Maintaining a 3-Hour IV Thrombolysis Window: How Many More Patients can we Safely Treat?
    Michael J. Lyerly1,2*, Karen C. Albright3,4,5, Amelia K. Boehme3, Reza Bavarsad Shahripour1, James T. Houston1, Pawan V. Rawal1, Niren Kapoor1, Muhammad Alvi1, April Sisson1, Anne W. Alexandrov1,6, and Andrei V. Alexandrov1
    1Department of Neurology, School of Medicine, University of Alabama at Birmingham, USA
    2Stroke Center, Birmingham Veterans Affairs Medical Center, USA
    3Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, USA
    4Health Services and Outcomes Research Center for Outcome and Effectiveness Research and Education (COERE), University of Alabama at Birmingham, USA
    5Center for Excellence in Comparative Effectiveness Research for Eliminating Disparities (CERED) Minority Health & Health Disparities Research Center (MHRC), University of Alabama at Birmingham, USA
    6School of Nursing, University of Alabama at Birmingham, USA
    *Corresponding author: Michael J. Lyerly, University of Alabama at Birmingham Stroke Program, Department of Neurology, 1813 6th Avenue South, RWUH M226, Birmingham, AL, 35294, USA, Tel: 205-934-2401, Fax: 205-975-6785; Email: mjlyerly@uab.edu
    Abstract
    Background: In 2008, the European Cooperative Acute Stroke Study-3 (ECASS-3) demonstrated that intravenous-tissue plasminogen activator could be safely administered for acute stroke patients presenting between 3 and 4.5 hours from symptom onset. Recently, the Food and Drug Administration rejected expansion of this time window in the United States. We sought to determine how many fewer patients would be treated by maintaining this restricted time window.
    Methods: We reviewed charts from patients who received intravenous thrombolysis at the University of Alabama at Birmingham between January 2009 and December 2011. Patients were divided into two groups (treated within 3 hours of onset, treated between 3 and 4.5 hours from onset). Demographics, stroke severity and protocol deviations according to the ECASS-3 trial were collected. Our safety measures were any hemorrhagic transformation, symptomatic intracerebral hemorrhage and systemic hemorrhage.
    Results: Two hundred and twelve patients were identified, of whom 192 were included in our analysis. A total of 36 patients (19%) were treated between 3 and 4.5 hours. No statistical differences were seen between age (p=0.633), gender (p=0.677), race (p=0.207) or admission stroke severity (p=0.737). Protocol deviations from the ECASS-3 criteria were found in 20 patients (56%). These were primarily age > 80 and aggressive blood pressure management. Despite these deviations, we did not see significant increases in the rates of adverse events in patients treated in the extended time window.
    Conclusions: Our data are consistent with previously reported international data that IV thrombolysis can safely be used up to 4.5 hours from symptom onset. Restricting the time window to 3 hours would have resulted in almost one-fifth fewer patients treated at our center.
    Keywords: Ischemic Stroke; Thrombolysis; Safety; Hemorrhage
    Introduction
    Currently, intravenous tissue plasminogen activator (IV-tPA) is the only FDA approved treatment for acute ischemic stroke (AIS) in the United States [1]. In 2008, the European Cooperative Acute Stroke Study-3 (ECASS-3) trial demonstrated that tPA could be safely administered in patients presenting between 3 and 4.5 hours from symptom onset [2]. Despite a higher rate of symptomatic intracranial hemorrhage (sICH) in this group (2.4% vs. 0.2%), patients treated beyond 3 hours demonstrated improved clinical outcomes. Since ECASS-3, additional international trials have provided further support for the expansion of the tPA time window [3-6].
    Although these trials have resulted in a modest increase (2%) in IV thrombolysis use in the United States, [7] overall tPA utilization rates remain below five percent [8]. While there are many factors that influence tPA use including drug label contraindications, [9] the majority of patients are excluded because of presentation to emergency rooms beyond the 3 hour treatment window [10]. This may be due to lack of symptom awareness by the patient, [11,12] failure to access emergency services [13] or geographic inaccessibility to hospitals capable of delivering acute stroke care [14].
    Expanding the tPA window has the potential to increase the proportion of patients who are eligible for treatment in the United States [15]. However, without an FDA approval of treatment beyond 3 hours, many providers, particularly those outside major stroke centers, may be reluctant to offer this therapy. The objective of this study was to determine the safety of expanding the tPA window to 4.5 hours in a tertiary care hospital in the US Stroke Belt, including patients with and without ECASS-3 protocol deviations, and to assess how many patients would have been denied treatment by restricting time window to 3 hours.
    Methods
    Study Population
    After approval by the University of Alabama at Birmingham (UAB) Institutional Review Board, we retrospectively analyzed all AIS patients treated at UAB between January 2009 and December 2011. Our center utilizes an expanded IV tPA treatment protocol that includes use of the 4.5 hour window. Informed consent (from patient or surrogate) was obtained prior to treatment on all patients who received tPA after 3 hours. Demographic data, stroke severity as measured by the National Institute of Health Stroke Scale (NIHSS), and IV thrombolytic data were obtained from our prospectively collected stroke registry. Retrospective chart review was performed on all patients who received IV tPA at our center to obtain additional clinical, laboratory, imaging, and treatment data. In addition, charts were reviewed to determine when IV thrombolysis was initiated relative to symptom onset and to determine if there were any deviations from the published inclusion and exclusion criteria in the ECASS-3 trial [2].
    Patients with an uncertain time of symptom onset (i. e., wake up strokes) and those who received tPA beyond the 4.5 hour window were excluded from the analysis. We also excluded patients treated at other institutions and then transferred to our center since documentation of treatment times and management of blood pressure during transfer were inconsistently documented. Use of aggressive blood pressure control was defined in the ECASS-3 trial as the need for continuous infusion of an antihypertensive agent.
    Safety Outcomes
    Our primary safety outcome was symptomatic intracerebral hemorrhage (sICH). We defined sICH as a hemorrhage not seen on previous imaging coupled with >4 point neurologic deterioration on the NIH Stroke Scale [16]. Our two secondary outcomes were any hemorrhagic transformation (HT) on CT or MRI and systemic hemorrhage.
    Statistical Analysis
    Categorical data were compared using Pearson Chi-squared or Fisher exact test where appropriate. Continuous data were compared using Wilcoxon Rank Sum test. All tests were two sided and an alpha of 0.05 was considered significant. As this was an exploratory analysis, no adjustments were made for multiple comparisons [17].
    Results
    We identified 212 patients in our registry who received tPA from 2009 to 2011. We excluded 20 patients because of missing data. Of the 192 patients with complete data, 156 patients were treated within 3 hours and 36 patients were treated between 3 and 4.5 hours. Table 1 compares the baseline demographics between these groups. Fewer patients in the extended time window group were on an antiplatelet agent prior to admission, otherwise there were no significant differences between groups.
    We assessed the 36 patients in the extended time window group for protocol deviations according to the ECASS-3 trial. One or more deviations were found in 20 patients (56%, Table 2). The two most frequent deviations were age greater than 80 (22%) and aggressive blood pressure management using nicardipine hydrochloride (14%). Four patients were on oral anticoagulation therapy with warfarin; however, only one of these patients had an INR greater than 1.7. There were no patients on novel anticoagulants (e. g. , dabigatran). Two patients had a clinically severe stroke as defined by the ECASS-3 trial involving more than a third of the MCA territory on the initial CT scan. One patient was treated when their glucose was 536 mg/dL and one patient had recent gastrointestinal bleeding.
    The proportion of patients in each group with sICH, HT and systemic hemorrhage is displayed in Table 3. Symptomatic ICH was rare and occurred in only one patient (3%) in the extended time window group, compared to two patients (1%, p=0.468) in the group treated within three hours. Similarly, HT without clinical deterioration was noted in 8 patients (22%) in the extended time window group, compared to 22 patients (14%, p=0.233) in the group treated within three hours. No patients developed systemic hemorrhage in the extended time window group.
    Table 1 Comparison of the Demographics and Baseline Characteristics of Treatment Groups. IQR=Interquartile Range; HTN=Hypertension; HLD=Hyperlipidemia; Afib=Atrial Fibrillation; CHF=Congestive Heart Failure; CKD=Chronic Kidney Disease; NIHSS= National Institutes of Health Stroke Scale.

    Variable

    Less than 3 Hours (n=156)

    3-4.5 Hours(n=36)

    P-value

    Age

    68 (IQR 55, 82)

    68 (IQR 54, 79)

    0.633

    Gender (Male)

    54% (84)

    50% (18)

    0.677

    Race

     

     

    0.207

        White

    57% (89)

    72% (26)

     

        Black

    41% (64)

    14% (10)

     

        Asian/Pacific Islander

    2% (3)

    0% (0)

     

    Ethnicity

     

     

     

        Non-Hispanic

    100% (156)

    100% (36)

    N/A

    Past Medical History

     

     

     

        Diabetes

    28% (43)

    14% (5)

    0.133

        HTN

    77% (120)

    67% (24)

    0.200

        HLD

    32% (50)

    28% (10)

    0.618

        Afib

    18% (28)

    31% (11)

    0.090

        CHF

    15% (23)

    6% (2)

    0.176

        CKD

    6% (10)

    0% (0)

    0.213

    Medications

     

     

     

        Oral Hypoglycemics

    16% (25)

    11% (4)

    0.608

        Antihypertensives

    64% (100)

    50% (18)

    0.117

        Antiplatelet Agent

    41% (64)

    22% (8)

    0.036

    Current Smoker

    28% (44)

    33% (12)

    0.542

    Admission NIHSS

    8 (IQR 5, 15)

    8 (IQR 5,13)

    0.737

    Table 1 Comparison of the Demographics and Baseline Characteristics of Treatment Groups. IQR=Interquartile Range; HTN=Hypertension; HLD=Hyperlipidemia; Afib=Atrial Fibrillation; CHF=Congestive Heart Failure; CKD=Chronic Kidney Disease; NIHSS= National Institutes of Health Stroke Scale.

    ×
    Table 2 Frequency of ECASS-3 Protocol Deviations in Patients Treated between 3-4.5 Hours. MCA=Middle Cerebral Artery; NIHSS=National Institutes of Health Stroke Scale; PT=Prothrombin Time; PTT= Partial Thromboplastin Time; SBP=Systolic Blood Pressure; DBP=Diastolic Blood Pressure; SAH= Subarachnoid Hemorrhage.

    Deviation Type

    Percentage of Patients with Deviations (n=36)

    Age >80

    22% (8)

    Aggressive Blood Pressure Treatment Required

    14% (5)

    Oral Anticoagulant Treatment

    11% (4)

    Imaging with >33% MCA Territory Involvement

    6% (2)

    Seizure at Onset

    3% (1)

    Combination of Diabetes and Previous Stroke

    3% (1)

    Other Disorders with an Increased Bleeding Risk

    3% (1)

    Platelets <100,000

    3% (1)

    Glucose <50 or >400

    3% (1)

    NIHSS >25

    0% (0)

    Trauma or Major Surgery within 3 Months

    0% (0)

    Stroke or Serious Head Trauma within 3 Months

    0% (0)

    Elevated PT/PTT

    0% (0)

    SBP >185 or DBP >110

    0% (0)

    Symptoms Resemble SAH

    0% (0)

    Table 2 Frequency of ECASS-3 Protocol Deviations in Patients Treated between 3-4.5 Hours. MCA=Middle Cerebral Artery; NIHSS=National Institutes of Health Stroke Scale; PT=Prothrombin Time; PTT= Partial Thromboplastin Time; SBP=Systolic Blood Pressure; DBP=Diastolic Blood Pressure; SAH= Subarachnoid Hemorrhage.

    ×
    Table 3 Safety Outcomes based on Treatment Times. ICH=Intracerebral Hemorrhage; HT= Hemorrhagic Transformation; MRI=Magnetic Resonance Imaging; CT=Computed Tomography.

    Deviation Type

    Percentage of Patients with Deviations  (n=36)

    Age >80

    22% (8)

    Aggressive Blood Pressure Treatment Required

    14% (5)

    Oral Anticoagulant Treatment

    11% (4)

    Imaging with >33% MCA Territory Involvement

    6% (2)

    Seizure at Onset

    3% (1)

    Combination of Diabetes and Previous Stroke

    3% (1)

    Other Disorders with an Increased Bleeding Risk

    3% (1)

    Platelets <100,000

    3% (1)

    Glucose <50 or >400

    3% (1)

    NIHSS >25

    0% (0)

    Trauma or Major Surgery within 3 Months

    0% (0)

    Stroke or Serious Head Trauma within 3 Months

    0% (0)

    Elevated PT/PTT

    0% (0)

    SBP >185 or DBP >110

    0% (0)

    Symptoms Resemble SAH

    0% (0)

    Table 3 Safety Outcomes based on Treatment Times. ICH=Intracerebral Hemorrhage; HT= Hemorrhagic Transformation; MRI=Magnetic Resonance Imaging; CT=Computed Tomography.

    ×
    Discussion
    Our study suggests that expanding the IV t-PA time window to 4.5 hours in a tertiary care hospital in the Stroke Belt of the United States is safe, although some patients had deviations from the ECASS-3 protocol. If a 3 hour cut off was used, 36 fewer patients (19% of our treatment population during this time period) would have been denied treatment. This is slightly higher than the experience reported at other centers [18]. Within these 36 patients, nearly half had ECASS-3 protocol deviations, however safety outcomes did not significantly differ from patients treated within 3 hours.
    In spite of clinical trials and guidelines [3,4,19] supporting the safety and efficacy of tPA beyond 3 hours, this practice is still considered to be "off-label" in the United States. While the percentage of patients treated between 3 and 4.5 hours has increased by 2%, [7] there may be continued reluctance to adopt this practice outside of major academic centers with stroke expertise. Since tPA is the only medical treatment available to these patients, [1] it is imperative to minimize barriers to its delivery [20]. Many of the tPA contraindications are overly restrictive [21-23]. Regardless of the other contraindications, arrival beyond the treatment window remains the largest barrier [10]. While reasons for delayed arrival certainly need to be addressed, the reality is that a 3 hour time window is going to continue to be a barrier to acute stroke treatment.
    Our data are consistent with previous research showing that tPA can be safely delivered up to 4.5 hours after symptom onset. Large international trials such as the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) and the Third International Stroke Trial (IST-3) have shown that an extended time window beyond 3 hours may be beneficial for many patients although outcomes are less favorable [3,4] The CASES registry in Canada also found that tPA is beneficial in the extended window although they found a trend towards higher sICH rates and death [5]. Similar to the contraindications used with the 3 hour window, the exclusion criteria used in the ECASS-3 trial warrant further study to determine if they should be applied to all patients in the extended time window. At our center, we found that the most common protocol deviations in the extended time window were age >80 and aggressive blood pressure control using IV agents. Currently, there are conflicting data for tPA use in elderly patients (within 3 hours) [24-27] although the IST-3 trial suggested that the benefit is not diminished [4]. Martin-Schild et al. demonstrated that aggressive IV blood pressure control for patients treated within three hours is relatively safe and does not appear to be associated with worse outcomes [23]. Prospective studies are needed to further explore the effects of aggressive blood pressure control in the setting of tPA. Overall, even with protocol deviations, patients treated in the extended time window have safety outcomes similar to those treated within 3 hours.
    Our study is limited by its retrospective design. Our small sample size may have prevented us from detecting existing differences in groups. Additionally, our sample included patients admitted to a single, tertiary care center where patients were treated following evaluation by trained stroke neurologists who are comfortable with tPA use. Our experience may not be generalizable to smaller, more rural facilities. Furthermore, we only examined patients presenting directly to our emergency room and did not consider alternate forms of tPA administration (e. g. , "drip and ship," telemedicine). Our outcomes were limited to the short-term, only accounting for morbidity occurring during the hospitalization. Additional study is needed to assess long-term outcomes in patients treated in the extended time window. Despite these limitations, our study is the first to describe the effects of an extended time window in the US Stroke Belt.
    Acknowledgement
    Dr. Albright is supported by Award numbers 5 T32 HS013852-10 from the Agency for Healthcare Research and Quality (AHRQ), 3 P60 MD000502-08S1 for the National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH). Ms. Boehme is supported by award 13PRE13830003 from the American Heart Association (AHA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ, AHA or the NIH.
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    Cite this article: Lyerly MJ, Albright KC, Boehme AK, Bavarsad Shahripour R, Houston JT, et al. (2013) The Potential Impact of Maintaining a 3-Hour IV Thrombolysis Window: How Many More Patients can we Safely Treat? J Neurol Disord Stroke 1(2): 1015.
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