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Journal of Neurological Disorders & Stroke

Cite this article: Fazzone B, Morris G, Black LA, Williams JA, Leacock R, et al. (2016) Exclusion and Inclusion Criteria for Thrombolytic Therapy in an Isch-emic Stroke Population. J Neurol Disord Stroke 4(2): 1112. 1/5

*Corresponding authorThomas I Nathaniel, University of South Carolina School of Medicine-Greenville, Greenville, SC 29605, USA, Tel: 001-864 4559846; Fax: 001-8644558404; Email:

Submitted: 18 May 2016

Accepted: 25 May 2016

Published: 26 May 2016

Copyright© 2016 Nathaniel et al.

OPEN ACCESS

Keywords•History of smoking, previous stroke•Hypertension•Ischemic stroke•Thrombolytic therapy

Research Article

Exclusion and Inclusion Criteria for Thrombolytic Therapy in an Ischemic Stroke PopulationBrian Fazzone1, Gabrielle Morris1, Leigh-Ann Black1, Jessica-Ashley Williams1, Rodney Leacock2, Shannon Sternberg2, Dawn Blackhurst2, Afred Nelson2, and Thomas I. Nathaniel1*1Department of Neuroscience, University of South Carolina School of Medicine Greenville, USA2Greenville Health System, USA

Abstract

Background: Many of the exclusiveand inclusivecontraindications for recombinant tissue plasminogen activator (rt-PA) in the treatment of acute ischemic strokeare based on safety. While some contraindications have strongly been supported by both scientific and clinical data, including the clear benefit of rt-PA, there are several clinical controversies about others. We examined clinical characteristics related to rt-PA treated versus non-treated patients according to specific contraindications in a stroke population.

Methods: We utilized data from the Greenville Health System (GHS) stroke registry on rt-PA administration between January 2010 and December 2013. We evaluated patients who received rt-PA within 4.5 hours following the onset of acute ischemic stroke symptoms. Our analysis compared the clinical characteristics and demographics of eligible patients receiving rt-PA with those not receiving rt-PA.

Results: A total of 663 ischemic stroke patients were eligible to receive rt-PA. Out of the 663, 241 received rt-PA and 422 did not. A significant (P<0.05) number of patients with acute myocardial infarction in the 3 months prior to stroke,uncontrolledhypertensionwere excluded from rt-PA when compared to the few that received rt-PA. A significant (P<0.05) numberof patients with history of smoking received rt-PA when compared to the patient population who did not receive rt-PA. A combination of old age, and baseline NIHSS is important in making a decision about whether to administer rt-PA to patients with a combined prior history of stroke and diabetes mellitus.

Conclusion: The study provides a basis to generate a hypothesis that could be investigated to allow more eligible patients to be considered for rt-PA for the treatment of acute ischemic stroke.

INTRODUCTION With both its high fatality and ability to detrimentally affect

multiple facets of an individual’s life, stroke has arguably been proposed as the most feared vascular event [1]. Recombinant tissue plasminogen activator (rt-PA) is an approved medication therapy for acute ischemic stroke and represents the standard of acute stroke care [2]. Initially, multiple studies demonstrated the effectiveness of rt-PA as a treatment for ischemic stroke patients if given within three hours of symptom onset [3-5]. Subsequently, rt-PA showed favorable outcomes if administered up to 4.5 hours after symptoms started, though several studies recommended earlier treatment if possible as more risks were associated with later doses [6-8]. Moreover, medical history of the patient can

create a complicated clinical picture and make the decision to utilize rt-PA more complex. For example, pre-stroke dementia has recently been independently able to predict poor outcomes with rt-PA, specifically predicting in-hospital mortality[9], though, a history of dementia may not be a documented contraindication to rt-PA use in most hospitals. Conversely, a history of smoking has been associated with decreased risk of in-hospital mortality in acute ischemic strokes patients, including those patients treated with rt-PA [10-12]. Other studies have shown that better outcomes with rt-PA are associated with lower presenting stroke symptom severity, lack of diabetes history, and normal glucose and blood pressure levels before rt-PA treatment [13,14].These findings add proof to the exclusion criteria outlined in the

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NINDS and ECASS III studies in regards to stroke severity. The recent AHA guideline [15] is proposed to relax the NINDS and ECASS exclusion criteria to increase the rt-PA rate up to 20% [16]. However, majority of the proposed contraindications are grounded on expert opinion, with little to no experiential support. With so much still unknown regards to rt-PA use, it becomes harder for physicians to utilize the thrombolytic with confidence, especially in regards to complicating prognostic exclusion and inclusion clinical factors of the patient. Using a prospective registry data of ischemic stroke patients admitted between 2010 and 2013 in primary stroke center, were trospectively analyzed the clinical characteristics of eligible patients for thrombolysis who received rt-PA compared to those who did not. We identified significant clinical risk factors and discussed our findings in the context of the recent AHA/ASA guideline and the increase in rt-PA use.

STUDY DESIGNThe study was performed using a registry of stroke patients

from the Greenville Health Care System (GHS) Stroke Registry. The GHS stroke registry contributes to the Get With The Guidelines (GWTG)–Stroke, a national registry launched by the American Heart Association and American Stroke Association to support continuous quality improvement of hospital systems’ care for patients with stroke and transient ischemic attack [17]. Patients with signs and symptoms suggestive of acute ischemic attack who arrived at the hospital within 4.5 hours of onset were enrolled in the study.

Data from the GHS stroke registry study regarding rt-PA administration between January 2010 and December 2013 were used to investigate the eligibility, rate of treatment, and reasons for excluding treatment with rt-PA. Exclusion criteria included: final discharge diagnoses other than ischemic stroke or transient ischemic attack, onset of stroke symptoms greater than 4.5 hours upon arrival at GHS, and administration of rt-PA at an outside facility. These patients that are not included if they receive rt-PA in another hospital.

We determined the rate of rt-PA use according to the eligibility criteria and calculated the rate of receipt of rt-PA among patients arriving within 4.5 hours of stroke symptom onset. Among patients meeting rt-PA eligibility, we compared the characteristics of patients receiving rt-PA with the characteristics of patients not receiving rt-PA. Specifically, we examined: demographic characteristics, stroke severity as measured by the retrospective NIH Stroke Scale (NIHSS), brain imaging, and major concomitant or comorbid conditions. The main outcome measure was the assessment of clinical eligibility for rt-PA treated patients after implementing the less restrictive criteria of 4.5 hours prior to onset of stroke. The GHS Ethics Committee approved this study. Procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) or with the Declaration of Helsinki 1975, revised Hong Kong 1989.

Statistical Analysis

Comparisons between the rt-PA and no rt-PA groups were presented as differences in proportions with 95% confidence

intervals (CIs). These comparisons included demographic factors, medical history, NIH Stroke Scale on admission, risk of mortality, medications prior to admission, and initial exam findings. Comparisons of clinical characteristics between the patients who received rt-PA and those who do not receive rt-PAand comparisons of the number of stroke patients admitted to GHS who received rt-PA between 2010-2011 and 2012-2013 were made. All analyses were descriptive - involving means, standard deviations, and other descriptive statistics. Data were examined using chi-square test, with a level of significance (P <0.05). Values are presented as Mean ± SD.Mauchly’s test was used to test for sphericity to meet the assumption that the relationships between pairs are equal in parametric test. We tested the normal distribution of all data using the exploratory data analysis (EDA) before use of parametric test.All statistical analyses were performed using SAS Statistical Software (Cary, North Carolina).

RESULTSBetween January 1, 2010 and June 30, 2013, a total of 2138

ischemic stroke patients were admitted to GHS. Of the 2,138 patients, 633 were eligible for receipt of rt-PA, excluding 62 patients who received rt-PA at an outside facility. As shown in figure 1, less than half of the eligible patients received rt-PA (n=241).11.2% of the total ischemic stroke patient population received rt-PA; and ~36% of eligible patient population actually received rt-PA. Table 1 presents demographic characteristics of patients treated with rt-PA between 2010-2013. Table 2 compares the clinical characteristics of patients receiving and not receiving rt-PA. Clinical characteristics for the stroke group included a history of hypertension, prior stroke with diabetes,

2138 Total Patients

725 (33.9%) arrival time < 4.5 hours

62 (8.5%) excluded663 (91.5%) eligible

patients

422 (63.7%) did not receive tPA

241 (36.3%) received tPA

1413 (66.1%) arrival time > 4.5 hours

Figure 1 Excluded and included acute ischemic stroke patients from January 2010 to June 2013.

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Table 1: Demographic characteristics of stroke patients that received rt-PA by timeframe (N=241 patients that received tPA).

CharacteristicHospital Admission Date2010-2013(N=241)

p-value

Age Group: No. (%) 0.448

<50years 31 (12.9)

50-59 41 (17)

60-69 61 (25)

70-79 55 (23)

≥80 53 (22)

Gender: No. (%) 0.426

Female 119 (49.0)

Male 122 (51.0)

Race: No. (%) 0.091

Caucasian 199 (82.6)

African-American 39 (16.25)

Other 3 (1.2) Initial NIH Stroke Scale Group: No. (%) 0.183

0-9 125 (52.0)

10-14 51 (21.1)

15-20 37 (15.0)

20-25 28 (12.0)

Table 2: Clinical characteristics of patients receiving and not receiving rt-PA at GHS.

Characteristic tPA (N=241) No tPA (N=422) p-value

Clinical characteristics Atrial Fib/Flutter 49 (20.3) 99 (23.5) 0.352CAD (Coronary Artery Dz) 72 (29.9) 134 (31.8) 0.615Myocardial infarction (<3 months) 5 (2.1) 23 (5.5) 0.038*

Dyslipidemia 59 (24.5) 129 (30.6) 0.094Prior stroke (<3 months) 119 (49.4) 208 (49.3) 0.983Hypertension 20 (8.7) 62 (14.7) 0.016*CHF 191 (79.3) 326 (77.3) 0.55Prior stroke & diabetes 45 (18.7) 123 (29.1) 0.003*Previous TIA 28 (11.6) 55 (13.0) 0.596Peripheral Vascular Dz (PVD) 14 (5.8) 17 (4.0) 0.296Smoking history 81 (33.6) 100 (23.7) 0.006*Initial NIH Stroke Scale (Actual) <0.001*Mean ± SD 10.7 ± 6.5 8.1 ± 6.9 Range 0.25 0.25 Initial NIH Stroke Scale Group: No. (%) 0.002*

0-9 125 (51.9) 274 (64.9) 10-14 51 (21.2) 54 (12.8) 15-20 37 (15.4) 64 (15.2) 20-25 28 (11.6) 30 (7.1) Risk of Mortality GWTG Ischemic Stroke 0.057Mean ± SD 6.47 ± 6.3 5.53 ± 5.6 Range 0.7, 35.6 0.4, 36.4

coronary artery discharge, atrial fib/flutter, previous stroke, previous TIA, peripheral vascular disease, congestive heart failure (CHF), myocardial infarction, dyslipidemia, and history of smoking. Baseline characteristics of patients with myocardial infarction less than 3 months reveals that more patients (5.5%;P<0.05) were excluded from rt-PA compared to those that receivedrt-PA (2.1%). A significant (P<0.05) number of patients with uncontrolled hypertension were excluded from rt-PA, while elderly patients (>80yrs) with baseline NIHSS>24.0 had a history of combined prior stroke and diabetes (29.1%: P=0.003) and were excluded from rt-PA. The data also showed that a significant (P<0.006) and higher number of patients with history of smoking (33.6%) received rt-PA when compared to the 23.7% patients population who did not receive rt-PA. The mean admission NIHSS score was significant (P<0.001), and higher (10.7 ± 6.5) for rt-PA receiving group when compared with patients who did not receive rt-PA (8.1 ± 6.9).

DISCUSSIONOur study represents a retrospective data set comparing

clinical risk factors of patients eligible to thrombolysis to those who were not.The primary finding of our study is that i) a significant number of patients with acute myocardial infarction in the three months prior to stroke and uncontrolled hypertension were excluded from rt-PA when compared to the few that received rt-PA. ii) a higher number of patients with history of smoking receivedrt-PA when compared to the patients’ population who did not receive rt-PA. iii) a combination of old age and baseline NIHSS is important in making a decision about whether to administer rt-PA to patients with a combined prior history of stroke and diabetes mellitus.

More patients with acute myocardial infarction in the three months prior to stroke were excluded from rt-PA.The main concerns include the possibility for myocardial hemorrhage influencing myocardial wall bursting and post myocardial infarction that could become hemorrhagic. In general, data on thrombolysis for stroke for recent myocardial infarction are very few. Few case reports of patients with cardiac rupture after receiving rt-PA for stroke have been described. The first is that of an elderly woman that presents with ST-segment elevation myocardial infarction(STEMI) [18]. In a different case report, the patient had coronary artery bypass grafting surgery two days before, while another case presented a patient with dyspnea many days before an onset of a broad-spectrum of changes on electrocardiogram[19]. Fatal conditions have been associated with patients presenting with an acute myocardial infarction three months prior to stroke [18,19] including sudden hypotension, that could occur about thirty minutes totwo hours after completion of rt-PA [18]. These findings suggest that several factors, including the severity of stroke symptoms and age among others, should be factored-in in the decision-making process about rt-PA and acute infarction. This is important as there are no clear-cut data to evaluate risks in these patients [16]. Moreover, as the new AHA guideline considers recent acute myocardial infarction in the three months prior to stroke as a contraindicator to rt-PA. It is not an exclusion criterion in the NINDs trials[2,20].

A major finding in the current study is that patients 80 years old and above that had uncontrolled hypertension with values

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above a systolic of 185 mmHg or diastolic of 110 mmHg, indi-cating an extremely elevated blood pressure (BP), and NIHSS >20,indicating increased severity in stroke symptoms, were excluded. Patients presenting with acute ischemic stroke with extremely elevated BP may have worse outcomes, because of increased severity in stroke symptoms [21]. In general, there is a general complexity in the association between BP, antihyper-tensive treatment, and outcomes inthe treatment of acute stroke. Both the 2015 AHA and NINNDS guidelines, and many other pro-tocols [22,23] excluded hypertensive patients from rt-PA. On the other hand, the most current evidence [24] did not indicate a relationship between elevated BP and detrimental outcomes in patients treated with rt-PA. As part of the use of rt-PA protocol in the treatment of acute ischemic stroke, the new AHA guideline allows the use of intravenous (IV) anti-hypertensive therapy ear-lier considered aggressive. This recommendation is mainly based upon expert opinion, and underlines the need for further studies to determine the treatment of arterial hypertension [25], to al-low eligible patients to be considered for rt-PA. Our current study reveals that a higher number of patients with history of smoking receivedrt-PA when compared to the patients’ population who did not receive rt-PA.

It has been shown that a combination of priorstrokeanddia-betes mellituscan be used to determine the poor outcomes fol-lowing treatment with rt-PA [26]. Poor response of patients with prior stroke and diabetes mellitus to rt-PA is associated with a higher risk of sICH [27,28]. Because of these concerns, older age patients with higher baseline NIHSS score (>24) and combined prior history of stroke and diabetes mellitus were excluded in the current study. Patients with a combined history of prior stroke and diabetes mellitus were excluded in the ECASS III trial [29]. The AHA guideline recommends rt-PA for selected patients, who are treated in the 3- to 4.5-hour window and >80 years old. How-ever, the benefits of rt-PA for patients with a combination of old age (>80yr), higher baseline NIHSS, and a prior history of stroke and diabetes mellitus is not known [15]. An important finding in our study is that a combination of old age and baseline NIHSS is important in making a decision about whether to administer rt-PA to patients with a combined prior history of stroke and diabe-tes mellitus.There are several limitations to this study. First the data reported depended upon the small sample size. The retro-spective data sample size could not analyze outcome prognosis including modified Rankin score. This information could be use-ful to compare dragon scores on each included patient to analyze if outcome has a significant difference among groups. Third, since this was a retrospective study data recorded depended on the ac-curacy and completion of each patient’s record.

CONCLUSIONTaken together, our current study is a retrospective analysis

of prospectively collected data and does not evaluate the safety or efficacy of patients associated with acute myocardial infarc-tion and a combination of prior stroke and diabetes prior toa clinical intervention with rt-PA. However, it provides a basis to generate hypothesis that could be investigated to allow more eligible patients to be considered for rt-PA for the treatment of

acute ischemic stroke for AIS.

ACKNOWLEDGEMENTS This study was funded by GHS. We thank Dr Melinda Ingiaimo

for revising the previous versions of this manuscript.

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Fazzone B, Morris G, Black LA, Williams JA, Leacock R, et al. (2016) Exclusion and Inclusion Criteria for Thrombolytic Therapy in an Ischemic Stroke Popula-tion. J Neurol Disord Stroke 4(2): 1112.

Cite this article

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