Ischemic stroke with a preceding Trans ischemic attack(TIA) less than 24 hours: Predicting clinical risk factors for thrombolytic therapy

Background Acute ischemic stroke attack with and without a recent TIA within or less than 24 hours may differ in clinical risk factors, and this may affect treatment outcomes following thrombolytic therapy. We examined whether the odds of exclusion or inclusion for thrombolytic therapy are greater in ischemic stroke with TIA less than 24 hours preceding ischemic stroke(TIA-24hr-ischemic stroke patients) as compared to those without recent TIA or non-TIA <24 hours. Methods A retrospective hospital-based analysis was conducted on 6,315 ischemic stroke patients, of whom 846 had proven brain diffusion-weighted magnetic resonance imaging (DW-MRI) of an antecedent TIA within 24 hours prior to ischemic stroke. The logistic regression model was developed to generate odds ratios (OR) to determine clinical factors that may increase the likelihood of exclusion or inclusion for thrombolytic therapy. The validity of the model was tested using a Hosmer-Lemeshow test, while the Receiver Operating Curve (ROC) was used to test the sensitivity of our model. Results In TIA-24hr-ischemic stroke population, patients with a history of alcohol abuse (OR = 5.525, 95% CI, 1.003-30.434, p = 0.05), migraine (OR=4.277, 95% CI, 1.095-16.703, p=0.037), and increasing NIHSS score (OR=1.156, 95% CI, 1.058-1.263, p = 0.001) were associated with the increasing odds of receiving rtPA, while older patients (OR = 0.965, 95% CI, 0.934‐0.997, P = 0.033) were associated with the increasing odds of not receiving rtPA. Conclusion In TIA-24hr-ischemic stroke patients, older patients with higher INR values are associated with increasing odds of exclusion from thrombolytic therapy. Our findings demonstrate clinical risks factors that can be targeted to improve the use and eligibility for rtPA in in TIA-24hr-ischemic stroke patients.


Introduction
There is a general concern that Transient Ischemic Attack (TIA) patients with focal lesions, which may appear normal on computed tomography (CT), may be at higher risk for hemorrhage post-thrombolysis treatment following onset of ischemic stroke [1][2][3][4][5]. More than one third of symptomatic patients within the 24-hour time frame may present with a number of cerebral infarcts and could be misdiagnosed and classified as a TIA [6], especially if no lesion is observed on the CT scan [7]. It has been shown that the use of CT as a diagnostic tool may not detect TIA-associated focal lesions prior to rtPA therapy in TIA-ischemic stroke patients [8]. This is because in some patients with a TIA preceding acute ischemic stroke (TIA-ischemic stroke) especially within 24 hour of stroke onset, the TIA may appear invisible on CT scans, even with ischemic lesions, and this could affect treatment outcome with thrombolytic therapy [9][10][11].
The presence of a focal lesion on DW-MRI is an important factor in the classification of transitory focal neurological dysfunction as a TIA [12][13][14][15], and represents a contraindication for rtPA therapy [16]. The new tissue-based description of a TIA as a transient episode of neurological dysfunction without acute infarction is not a contraindication for rtPA in TIA-ischemic stroke patients [17]. We know that ischemic patients with an established TIA less than 24 hours differ in clinical variables when compared with those without a TIA [2]. Patients with an established TIA more than 24 hours prior to stroke will normally receive treatment and may be admitted because of the TIA, allowing a timely administration of rtPA [1,2]. We also know that baseline clinical risk factors in TIA-24hr-ischemic stroke patients may affect treatment outcomes following thrombolytic therapy [18]. It is unknown whether specific clinical risk factors in ischemic stroke patients with a TIA within 24 hours preceding an acute ischemic stroke may contribute to the inclusion or exclusion from rtPA therapy.
Data are lacking on the effect of specific clinical risk factors associated with inclusion or exclusion for rtPA therapy in ischemic stroke patients of a TIA that sets in within or less than 24 hours preceding ischemic stroke TIA-24hr-ischemic stroke patients). It is possible that clinical risk factors associated with ischemic stroke patients with a TIA within or less than 24 hours preceding an acute ischemic stroke may be different from ischemic stroke patients without a TIA or with an established TIA. Since a TIA within 24 hours preceding ischemic stroke is not an established contraindication for rtPA, it implies that the presence or absence of specific clinical risk factors in acute ischemic stroke patients with TIA may contribute to the exclusion or inclusion of patients for rtPA therapy. In this study, we tested the hypothesis that specific baseline clinical risk factors may impact the inclusion or exclusion of TIA-24hr-ischemic stroke patients for rtPA therapy. The objective of the present study was to identify specific demographic and clinical risk factors associated with inclusion or exclusion from rtPA therapy in an ischemic stroke population with a TIA within 24 hours preceding an acute ischemic stroke. Knowledge of such clinical risk factors would be clinically relevant in decision making, especially in developing management and treatment strategy in the population of stroke patients with established TIA within or less than 24 hours preceding ischemic stroke.

| Study population
Data from ischemic stroke patients admitted to the PRISMA Health Greenville, SC, USA between January 2010 and June 2016 were used for this study. The ethics committee of PRISMA Health approved this retrospective study. Patients that presented with ischemic stroke within 24 hours of symptom onset, based on relevant ischemic lesions on CT or brain MRI, were included in the analysis. Ischemic stroke patients were divided into two groups: the first group comprises of those with a TIA within or less than 24 hours preceding ischemic stroke (TIA-24hr-ischemic stroke patients), while the second group consists of those with previously diagnosed TIA (at least one month) or no history of TIA (non-TIA <24 hours). For the first group, identified TIA patients prior to stroke with DWI abnormalities consistent with focal neurological dysfunction were excluded. In both groups, patients with symptomatic intracerebral hemorrhage (SICH) were excluded.
Data on clinical characteristics and laboratory analysis were collected directly from the stroke registry, which has been described in previous studies [19][20][21][22]. Collected data included patients' medical history, including atrial fibrillation/atrial flutter, coronary artery disease (CAD), carotid stenosis, pregnancy, depression, diabetes, drug or alcohol abuse, dyslipidemia, family history of stroke, congestive heart failure (CHF), hormone replacement therapy (HRT), hypertension, migraine, obesity, prior stroke, prior TIA, prosthetic heart valve, peripheral vascular disease (PVD), chronic renal disease, sickle cell, sleep apnea, and history of smoking. Demographic variables data were collected include age, race and gender. Further, data on medication history and stroke severity (NIHSS) score were also obtained.

| Statistical analysis
All statistical analyses were performed using the SPSS Statistics Software version 15.0 (Chicago, IL). Descriptive statistics were used to analyze demographic and clinical risk factors in ischemic stroke patients characterized based on a TIA-24hr-ischemic stroke patients and non-TIA <24-hour patients. The Pearson χ2 test or Student's t test was utilized to perform a bivariate group comparison of baseline characteristics between the two groups. For continuous variables, a Student-t test was used, while Pearson's chi squared analyses was considered for analyzing discrete variables. In order to examine clinical factors associated with inclusion for rtPA, a multivariable binary logistic regression was performed. Our primary outcome measures for regression analysis were clinical risk factors that are significantly associated with exclusion of inclusion for rtPA therapy. This approach provided the opportunity to determine whether the association between specific clinical risk factors in the TIA-24hr-ischemic stroke patients and the non-TIA <24-hour patients are associated with inclusion or exclusion for rtPA(the non-TIA <24hour group). For the logistic regression, the variable selection for a multivariate model was not based on univariate p-values, because we considered clinical knowledge to supersede univariate statistical analysis of p-values when selecting variables for model building [23]. Therefore, the backward selection method allowed all of our variables to be selected, while removing the least significant one at each step. In general, our analysis identified variables independently associated with the increasing odds (odds ratios [OR]) and their 95% Cis of exclusion or inclusion for thrombolytic therapy in patients with and without a TIA 24 hours prior to ischemic stroke.
In the regression model, rtPA treatment served as the dependent variable. In addition, variables for TIA-24hr-ischemic stroke patients were included as the primary independent for the entire ischemic stroke population with or without a recent TIA (24 hours prior), established TIA (at least more than one month) or no TIA. The increasing odds of exclusion or inclusion in the sub-cohort for these groups were analyzed separately. A Hosmer-Lemeshow test examined the validity of the model, and the overall correct classification percentage as well as the area under the Receiver Operating Curve (ROC) for score prediction was determined. This allowed us to test the sensitivity, specificity and accuracy of our logistic model. Odds ratios (ORs) were determined from the logistic regression and significance was set at the probability level of 0.05. The odds ratio values were then utilized to predict the increasing odds of exclusion of inclusion in the TIA-24hrischemic stroke patients.

Results
In this study, a total of 6,315 ischemic stroke patients were identified. Of this cohort, 846 patients had a TIA within 24 hours prior to the ischemic stroke, whereas 5,469 did not. Table 1 presents the demographic and clinical variables of acute ischemic stroke patients with and without TIA within 24 hours prior to ischemic stroke. TIA-24hr-ischemic stroke patients were more likely to be white (82.2% vs. 78.4%), with lower rates of atrial fibrillation (13.9% vs 16.9%) and alcohol abuse (3.7% vs. 6.2%). The TIA-24hr-ischemic stroke group also demonstrated higher rates of carotid artery stenosis (7.9% vs 6.1%) and dyslipidemia (58.2% vs 50.4%). These patients presented with higher rates of previous stroke (32.4% vs. 26.0%) and previous TIA more than 24   The results of logistic regression showing factors associated with rtPA in the TIA-24hrischemic stroke population is presented in Table 3, while the forest plot representation is shown in Fig 1. The results indicate that TIA-24hr-ischemic stroke patients presenting  Table 4 presents factors that are associated with the odds of receiving rtPA in the non-TIA <24 hours group, while the representative forest plot is shown in Fig 3. As shown in Table   4

Discussion
The current study investigated clinical risk factors associated with inclusion or exclusion from rtPA therapy in an ischemic stroke population presenting with a TIA within 24 hours preceding an acute ischemic stroke. First, a frequency of only 13% of an antecedent TIA within 24 hours in the ischemic stroke population was found. Second, a greater percentage of TIA-24hr-ischemic stroke patients were excluded from rtPA when compared to the non-TIA <24-hour patients. Third, more clinical risk factors were associated with inclusion than exclusion for rtPA, while increasing age and INR were associated with increasing odds of exclusion from thrombolytic therapy in the TIA-24hr-ischemic stroke patients. Finally, more clinical risk factors were associated with exclusion than inclusion from rtPA in the ischemic stroke population in the non-TIA <24-hour group.
The non-TIA <24-hour ischemic stroke group analyzed in this study was older (68.08 ± 14.47) than patients reported in other studies (mean age of 63) [1]. Moreover, the TIA-24hr-ischemic stroke population in this study consists of a significant proportion of patients > 80 years, not excluded from rtPA in line with AHA guidelines [24] and reported to be safe by several studies [25][26][27]. The prevalence of a prior TIA in patients with ischemic stroke in the general population is between 7% to 40% [13,28,29]. The frequency of occurrence of a TIA in our TIA-24hr-ischemic population was 13%, which falls within the low range of occurrence among those reported [13,28,29]. The occurrence of a TIA within 24 hours preceding the onset of acute ischemic stroke was not a contraindication for thrombolytic therapy in this study population, therefore, it is not possible that the exclusion of this group of patients is the reason for the low occurrence of TIAs observed. Since this is a retrospective study, there is the possibility of bias in data input which could potentially account for the low occurrence. However, the analysis of TIAs occurring within 24 hours preceding the onset of acute ischemic stroke is mainly done by retrospective data analysis, and this method is supported by several studies as the best approach to determine an antecedent TIA. [30,31]. It is also possible that the main etiology of the ischemic stroke population with a TIA in this study is cardioembolism, which is often more severe than atherothrombotic strokes [1,2]. Therefore, the low frequency could be attributed to lesser occurrence of stroke in a large vessel, which is more commonly indicated by temporary symptoms in contrast to stroke from cardioembolism [1].
The univariate analysis revealed that the TIA-ischemic stroke population that received rtPA was younger, more likely to have atrial fibrillation, have a history of alcohol abuse, be obese, present with a migraine, and have lower INR and NIH scores. Ischemic stroke patients receiving rtPA without a diagnosed TIA were younger, more likely to be depressed, have dyslipidemia, be on hormonal replacement therapy, present with a migraine, have a previous TIA, be obese, use cholesterol reducers or antidepressants, and have higher NIH scores. Following adjustment for the effect of confounding variables, hormonal replacement therapy, obesity, history of a previous TIA, and anti-depressant use were factors found to be associated with inclusion for rtPA in the non-TIA <24-hour patients, while increasing age, female gender, carotid artery stenosis, diabetes, history of previous stroke and alcohol use, cholesterol, serum creatinine, INR, and increased systolic blood pressure were associated with exclusion from rtPA. The identified comorbidities associated with exclusion from thrombolytic therapy are comparable to existing prospective and retrospective studies, such as increasing age associated with worse outcomes [32], female gender corresponding with significantly higher percentages of cardioembolic strokes [33], and severe carotid artery stenosis, which predicts poor outcome [34]. Other identified comorbidities reported in previous studies are diabetes; due to hyperglycemia, which increases the risk of cerebral hemorrhage with rtPA treatment [35], and chronic alcohol use; which increases excitotoxic/ischemic damage, leading to poor outcomes [36]. History of previous stroke represents an exclusion criteria, especially in patients with large infarctions and concern of bleeding [37]. Furthermore, high levels of serum creatinine as an exclusion criteria is due to risk of symptomatic intracranial hemorrhage [38], while elevated INR is due to the risk of intracranial hemorrhage [39]. Finally, higher peak values of systolic blood pressure may lead to higher rates of hemorrhagic complications [40].
A transient ischemic attack preceding ischemic stroke does not appear to have a major influence on outcomes following rtPA, and may actually induce neuroprotection in patients with ischemic stroke [41]. This argues for the necessity to understand the other clinical risk factors which might affect thrombolytic treatment outcome. This study revealed that TIA-24hr-ischemic stroke patients with a history of alcohol abuse are more likely to be included for rtPA. Alcohol consumption as a risk factor for stroke is known to follow a Jshaped curve, such that modest drinkers (<15 g/d) have the lowest risk, and heavy drinkers (>60 g/d) have the highest [42]. The signs and symptoms of acute alcohol intoxication are similar to those of vertebrobasilar stroke [43]. Due to similarities in symptoms such as double vision, nystagmus, dysarthria, and ataxia, the differential diagnosis of alcohol intoxication versus vertebrobasilar stroke may constitute a major diagnostic challenge. Moreover, if alcohol intoxication and stroke occur concurrently, the signs and symptoms of stroke may be linked to the effects of alcohol, resulting in a delayed stroke diagnosis and failure to administer thrombolytic therapy. In the case of uncertainty, and if stroke cannot be excluded, thrombolytic therapy can be administered [43]. It is possible that the TIA-24hr-ischemic stroke patients with a history of alcohol abuse arrived at the hospital early, allowing stroke diagnosis to be established within the therapeutic time window. Therefore, the TIA-24hr-ischemic stroke patients with a simultaneous history of alcohol abuse were more likely to be eligible for rtPA therapy.
Furthermore, the TIA-24hr-ischemic stroke patients that presented with migraine were more likely to receive rtPA therapy. Migraine has been established as the third most common stroke mimic and contributes to greater than 17% of poor outcomes in thrombolytic therapy [44]. Thrombolytic therapy in ischemic stroke patients with migraine is associated with a low risk of poor treatment outcome [44]. With an increased capability of accurately diagnosing a migraine attack, it is possible that a comprehensive clinical evaluation provided an accurate diagnosis of migraine with existing history in the TIAischemic stroke patients in this study. Even when a definitive diagnosis is not possible, the evidence of rtPA safety in scientific literature [45][46][47][48][49] supports its administration, as shown in the current study.
Another major finding in this study is that older TIA-24hr-ischemic stroke patients are more likely to be excluded from rtPA. A TIA is known to have negligible effects on patients 50 years below, but significantly reduces life expectancy in individuals 65 years and older [50]. Compared to patients 50 years and younger, patients that are 75-84 years old are at a greater risk. Furthermore, patients above the age of 80 have the highest risk [50].
In line with this finding, the study showed that elderly stroke patients with a TIA within 24 hours prior to stroke may be excluded from rtPA therapy, suggesting that these patients may have the most to gain from intensive cerebrovascular risk management.
A major challenge with a TIA is the uncertainty of its diagnosis, including the neurovascular implication, which is systemic in many TIA studies [51]. More than 25% of patients assumed to present with a TIA in the emergency department were further assessed and noted to have had a stroke, while 25% had an established mimic condition [52]. While we could not dependably differentiate among stroke cases misclassified as a TIA, or complications of stroke mimicking a TIA in our retrospective data, our sample best represents those progressing to stroke after a TIA presentation assessed by DW-MRI prior to onset of ischemic stroke. Therefore, our retrospective data consist of ischemic stroke patients diagnosed with a TIA within 24 hours prior to onset of ischemic stroke, reflecting real world clinical scenarios. It has been shown that an estimated 70% of patients with a diagnosis of a TIA are admitted to the hospital and, of these, only 50% retain a TIA diagnosis [52,53]. The studied cohort represents those retaining a TIA diagnosis within 24 hours prior to stroke, reducing misclassification. A major limitation of this study is that the results cannot be generalized to ischemic stroke patients with a TIA diagnosis greater than 24 hours prior to stroke. In addition, the small number of ischemic stroke patients having a TIA within 24 hours prior to onset of stroke could be considered another limitation of the study in the demonstration of differences in clinical risk factors between ischemic stroke with a TIA <24 hours prior and ischemic stroke without a TIA <24 hours prior. However, in the light of 13% occurrence of a TIA <24 hours prior to ischemic stroke in this population, which fits within the existing range of between 7% to 40% [1,2,28], it seems likely that these findings will be clinically relevant in decision making with respect to the management of clinical risk factors associated with thrombolytic therapy.

Conclusion
Patients presenting with a TIA less than 24 hours prior to an ischemic stroke were more likely to be excluded from receiving rtPA than those without a TIA 24 hours prior, with the most likely cause of exclusion criteria being increased age. Considering the small number of patients presenting with a TIA within 24 hours prior to an ischemic stroke and the high exclusion rate from rtPA within this group, this study provides vital information that can help facilitate future clinical decisions when administering rtPA to TIA-24hr-ischemic stroke patients.

Declarations
Ethics approval and consent to participate. This is a retrospective data collection. This study was approved by the institutional review board of PRISMA Health institutional committee for ethics (approval number: 00052571) Acknowledgement. We thank the stroke unit of Greenville Health system for helping in the data collection.
Authors' contribution. NP, DS and TIN designed the concept, experimental design and data analysis, while TM and AS critically revised the drafts, interprets the results, read and approved the last version of this manuscript. All authors have provided the corresponding author with permission to be named in the manuscript and approved the submission of this manuscript.
Availability of data and materials. The retrospective datasets are available by request from the corresponding author of this manuscript respectively Funding: This study was funded by the Fullerton Foundation.  Figure 1 Forest Plot representation of