a b s t r a c t

Background: Intravenous (IV) tissue plasminogen activator administration for ischemic stroke between 3 and 4.5 hours after onset was found to be safe and beneficial in the ECASS III trial. However, its use has remained controversial, and its benefit as applied in routine practice at community stroke centers is less well defined.

Methods: This retrospective database study compared safety and clinical outcomes in 500 patients given IV tPA either from 0 to 3 or 3 to 4.5 hours after onset at a high-volume community center from January 2008 to October 2012. Additional independent variables included for univariate and multivariate analysis were age, sex, hypertension, diabetes mellitus, National Institutes of Health Stroke Scale on arrival.

Results: There were no significant differences seen in rates of symptomatic intracranial hemorrhage (3.8% vs 5.8%, P N .05), in-hospital mortality, or Barthel index at 3 months between groups. In addition, tPA administration despite ECASS III contraindications did not appear to be an independent predictor of hemorrhage in the first 24 hours.

Discussion: Our results show that the conclusions of the ECASS III trial can be applied to routine stroke treatment at a community center and that IV thrombolysis in the 3- to 4.5-hour window results in similar safety and efficacy functional outcome at 3 months compared with administration before 3 hours after onset.

(C) 2013

1. Introduction

The use of intravenous (IV) tissue plasminogen activator (tPA) for acute stroke 3 to 4.5 hours after onset remains controversial. In 2008, ECASS III showed a significant treatment benefit for patients receiving tPA in the 3- to 4.5-hour window compared with placebo, along with increased rate of symptomatic intracranial hemorrhage (sICH) [1]. Other studies have shown similar findings [2,3]. In 2009, the American Stroke Association recommendations encouraged the use of IV tPA in the 3- to 4.5-hour window [4]. However, in May 2012, the Food and Drug Administration rejected an application to extend the window for tPA, stating that the ECASS III results were not compelling enough to warrant label expansion [5]. Given the hurdles in translation of therapies from large trials to community practice, further studies on the efficacy and safety of tPA use in the 3- to 4.5-hour window in the community setting are needed. A previous study at our center compared patients treated in the 0- to 3-hour and 3- to 4.5-hour windows and found no significant difference in sICH rates or functional outcome at 3 months [6]. Similar results have been reported elsewhere [7], but both studies were limited

? Disclosures: None.

* Corresponding author.

E-mail address: [email protected] (A. Montano).

by small sample size in the 3- to 4.5-hour group. The aim of this study is to determine how administration of tPA to patients in the 3- to 4.5-hour window compares to the 0- to 3-hour window in a community setting in terms of safety and benefit.

1. Materials and methods

This is a retrospective analysis of data collected from patients treated with tPA for ischemic stroke at Hartford Hospital, Hartford, CT, between January 2008 and October 2012. This study was reviewed and approved by the Institutional Review Board of Hartford Hospital. All data were extracted from the Stroke Database of the Stroke Center at Hartford Hospital. Patients were categorized into 1 of 2 groups either receiving tPA during the 0- to 3-hour or the 3- to 4.5- hour window. Time elapsed from symptom onset to emergency department (ED) arrival was recorded. Noncontrast head computed tomography was obtained for all patients, both on arrival in the ED and, in patients treated with rt-PA, within 24 hours of thrombolytic therapy. Baseline characteristics, rates of sICH, Barthel index (BI) at 3 months, and in-hospital mortality were compared between the 2 groups. Symptomatic intracranial hemorrhage was defined as new hemorrhage on head computed tomography within 24 hours of

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1708 A. Montano et al. / American Journal of Emergency Medicine 31 (2013) 1707–1709

treatment associated with increase in NIHSS of 4 points or higher, per the NINDS stroke study group definition [8]. The BI is a measure of ability to perform specific activities of daily living, with values ranging

Table 2

Outcome measures among patients given IV tPA in the 0- to 3-hour or 3- to 4.5-hour treatment windows

from 0 to 20. We dichotomized BI into poor functional status (BI <=17) and favorable functional status (BI >=18). In a comparison of outcome measures used in various stroke trials, a cutoff of 90/100 on the modified BI (roughly 18/20 on our scale) has been shown to be most sensitive and specific for a Modified Rankin scale score of 2 [9]. Presenting NIHSS was dichotomized with 7 as a cutoff. A presenting NIHSS less than or equal to 7 has been associated with better clinical outcome [10]. Various ECASS III exclusion criteria, including age 80

Outcome IV tPA within

0-3 h

IV tPA within P

3-4.5 h

years or older, combination of prior stroke and diabetes mellitus, anticoagulation at time of stroke, and NIHSS greater than 25 were also examined as independent predictors of sICH.

1. Results

A total of 3129 patients who were treated at Hartford Hospital for acute ischemic stroke between January 2008 and October 31, 2012, were available for analysis. Of these, 500 patients received IV tPA. There were 396 patients in the 0- to 3-hour group and 104 in the 3- to 4.5-hour group. There were no significant differences in baseline characteristics (Table 1). The number of patients treated in the 3- to 4.5-hour window increased annually from 1 in 2008 to 32 in 2011.

The rate of sICH was not significantly different between patients treated from 0 to 3 hours and from 3 to 4.5 hours (3.9% vs 5.9%, P =

.313) (Table 2). There was no difference in proportion of patients with improvement in NIHSS during hospitalization (P = .783) or in- hospital mortality (P = .998). Barthel index at 3 months was available for 339 patients, with 69.1% of patients in the 0- to 3-hour group and 67.5% in the 3- to 4.5-hour group having favorable outcome (BI >=18) at 3 months (P = .232).

There were no significant differences (Fisher exact test, P = 1.0 for all) in sICH rate when patients in the 3- to 4.5-hour group were separated into age 80 years or older vs younger than 80 (2/32 vs 4/72), anticoagulation vs no anticoagulation (0/12 vs 6/92), combination of prior stroke and diabetes mellitus vs absence of either (0/3 vs 6/101) or NIHSS greater than 25 vs NIHSS less than 25 (0/2 vs 6/102).

1. Discussion

To our knowledge, this is the largest study to date from a community stroke center to compare outcome and Safety measures between patients given IV tPA in the 0- to 3-hour and 3- to 4.5-hour windows. Our rate of sICH in the 3- to 4.5-hour group is similar to other studies [1] but higher than that found in ECASS III (2.4%). However, the ECASS III requirement of establishing hemorrhage as the predominant cause of deterioration likely resulted in the lower

Table 1

Baseline characteristics among patients given IV tPA in the 0- to 3-hour or 3- to 4.5-hour treatment windows

reported rate, as the sICH rate determined by the investigators when

applying the less stringent ECASS II definition was 5.4% [2].

Our study has some limitations. This was a single-center, retrospective study from a high-volume stroke center and thus may not be representative of all community centers where patients receive IV tPA for acute stroke. In addition, the small sample size of patients treated despite meeting ECASS III exclusion criteria resulted in low power for this analysis. With respect to outcome measures, the form of BI used in our database is scored out of 20 points, as opposed to the modified BI using a 100-point scale. This made extrapolating the ideal cutoff for favorable outcome difficult. Our cutoff was selected based on a study comparing modified Barthel and modified Rankin scale (mRs) values in acute stroke patients, with a modified Barthel of 90 best corresponding to mRS of 2 [8]. However, although similarly scored, it is not clear how well a BI of 18 corresponds to a score of 90 on the modified BI. The high degree of inconsistency in measures of functional outcome among various trials makes comparison with other studies difficult. One study found that among various major acute stroke trials, primary end points included BI in 7, modified Rankin scale in 6, and both in 3 [11]. While recently mRS has been used in the Stroke Center at Hartford Hospital database, we chose to use BI in this analysis as it allowed us the greatest sample size for the analysis. Use of mRS in future studies from our center may allow for a more standardized assessment of functional outcome after acute stroke.

In the last 10 years, overall utilization of IV tPA has steadily

increased as physician confidence in its use has grown [12,13]. Utilization of tPA after 3 hours has likewise expanded since 2008 [14]. Nationally, however, IV tPA continues to be underused [13], and there is a great need to expand the pool of patients benefiting from IV thrombolysis. Furthermore, 2 recent trials showing Endovascular therapy within the first 4.5 hours to have no increased benefit over IV tPA alone [15,16] should encourage clinicians to prioritize IV tPA use for patients presenting before 4.5 hours. At our center, use of tPA in the extended treatment window has increased steadily since 2008, with similar functional outcomes and rates of sICH compared with the first 3 hours. Our findings suggest that the conclusions from ECASS III are applicable in a community setting, and we recommend the continued and expanded use of IV tPA in patients presenting between 3 and 4.5 hours after the onset of acute ischemic stroke.

References

Variable Patients treated

in 0-3 h

Patients treated P

in 3-4.5 h

1. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J

n 396 104 N/A

Med 2008;359:1317-29.

1. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, et al.

association. Stroke 2009;40:2945-8.

1. Samson K. tPA appears safe for ischemic stroke patients on lower warfarin doses, investigators report. Neurology Today 2012;12(16):7-10.

A. Montano et al. / American Journal of Emergency Medicine 31 (2013) 1707–1709 1709

1. Alias M, Staff I, McCullough LD. Early experience with community implementation of thrombolysis three to 4.5 hours after acute ischemic stroke. Connecticut Medicine 2011;75:531-6.
2. Tekle WG, Chaudry SA, Fatima Z, Ahmed M, Khalil S, Hassan AE, et al. Intravenous thrombolysis in expanded time window (3-4.5 hours) in General practice with concurrent availability of endovascular treatment. J Vasc Interv Neurol 2012;5:22-7.
3. NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for acute ischemic stroke. Stroke 1997;28:2109-18.
4. Uyttenboogaart M, Stewart RE, Vroomen P, DeKeyser J, Luijckx GJ. Optimizing cutoff scores for the Barthel index and the modified Rankin Scale for defining outcome in acute stroke trials. Stroke 2005;36:1984-7.
5. DeGraba TJ, Hallenbeck JM, Pettigrew KD, Dutka AJ, Kelly BJ. Progression in acute stroke: value of the initial NIH Stroke Scale score on patient stratification in future trials. Stroke 1999;30:1208-12.
6. Sutler G, Steen C, DeKeyser J. Use of the Barthel index and modified Rankin Scale in acute stroke trials. Stroke 1999;30:1538-41.
7. Prabhakaran S, McNulty M, O’Neill K, Ouyang B. intravenous thrombolysis for stroke increases over time at primary stroke centers. Stroke 2012;43:875-7.
8. Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke 2011;42:1952-5.
9. Ahmed N, Wahlgren N, Grond M, Hennerici M, Lees KR, Mikulik R, et al, SITS investigators. Implementation and outcome of thrombolysis with alteplase 3-4.5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet Neurol 2010;9: 866-74.
10. Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, et al, for the SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368:904-13.
11. Broderick J, Palesch Y, Demchuk AM, Yeatts SD, Khatri P, Hill MD, for the interventional management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903.