Factors predicting functional outcome after rtPA for patients with acute ischemic stroke

Background Accurate outcome prediction for patients with acute ischemic stroke after intravenous recombinant tissue plasminogen activator (rtPA) treatment is essential for optimizing patients’ management. We aimed to identify factors associated with unfavorable outcomes following intravenous rtPA treatment. This study was carried out on 162 patients who presented with acute ischemic stroke within 4.5 h from onset of neurological symptoms and were eligi‑ ble for intravenous rtPA. After exclusion of 48 patients, 114 patients were finally eligible for follow‑up. After complete medical and neurological history, complete medical and neurological examination and brain image (CT and or MRI brain) were collected from the patients. patients eligible were included in the study. NIHS scale was assessed for all patients at time of admission, after 24 h, and follow‑up for 3 months. Results After a 90‑day follow‑up period for 114 patients with acute ischemic stroke after rtPA, 35.8% had good outcome (MRS; 0–2), 18.5% had partial outcome (MRS; 3–4) and 12.5% had poor outcome (MRS; 5–6). Atrial fibrilla‑ tion (AF), PH of stroke, stroke severity, and severity of symptom (NIHSS) score were significantly ( P : 0.004, 0.001, 0.007 and 0.001) correlated with poor outcome after rtPA. Similarly, old age, high blood pressure at time of presentation, hypertension, and dyslipidemia were showed to carry poor outcome.


Background
Stroke is one of the most frequent causes of death and disability in developed countries, having an estimated overall adult prevalence of 2.5% [1].The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 showed that stroke was the third-leading cause of death and disability combined and the second-leading cause of death worldwide in 2017 [2,3].Treatment on specialized stroke units is essential in secondary prevention leading to an 18-46% reduction of relative mortality and 29% reduction of assistance-depending disability [4].Rapid administration of intravenous recombinant tissue-type plasminogen activator (rtPA) to appropriate patients remains the mainstay of early treatment of acute ischemic stroke [5].The benefit of the treatment diminishes significantly and is lost after 4.5 h [5].
The benefit of intravenous thrombolysis for acute ischemic stroke decreases continuously over time from symptom onset, as shown in meta-analyses of randomized trials [6,7].However, there is still large proportion of patients with unfavorable outcome after IV rtPA treatment [8].Accurate and early prediction of the clinical outcome for individual AIS patients who receive rtPA treatment is needed to provide a reasonable approach to patient management [9].
It is well-known that factors, such as age, initial NIHSS score, and systolic blood pressure, are of predictive value for clinical outcome and symptomatic intracerebral hemorrhage (SICH) [6].Magnetic resonance imaging (MRI), computed tomography (CT), and carotid duplex have also been used as possible prognostic determinant tools.Particularly, many factors, including arterial occlusion, re-occlusion, and recanalization among other factors, have been reported to have predictor effect [10].This study was prospective aimed to identify factors associated with unfavorable outcome following intravenous rtPA treatment.

Methods
The study was carried out as a prospective observational cohort study on 162 patients presented with acute ischemic stroke aged between 18 and 80 years and who presented in the first 4.5 h time window from the onset of stroke symptoms attended the Neurology Department of Al Jedaani Hospitals, KSA during the period from February 2019 to the end November of 2022. 10 patients were expired (six patients due to massive intracerebral hemorrhage as adverse effect of rtPA and four patients from extensive infarction), about 38 patients were shifted to another hospital for endovascular treatment, and remaining 114 patients completed follow-up for 3 months (Fig. 1).
This study has been approved by ethical committee of Aljedaani Hospitals belong of Ibn Sina faculty of medicine hospitals, KSA.All patients eligible for rtPA were included in the study.Eligibility criteria and contraindications for IV rtPA at our study were the same as those Guidelines for the Early Management of Patients with Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association [11].Patients who did not received the full dosage of IV rtPA due to acute adverse side effect during infusion, patients did not complete follow-up for 3 months or patients who refused participation in the study were omitted.
After complete medical and neurological history (age, sex, body weight, height, body mass index (BMI), smoking status, history of hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, atrial fibrillation and past history of stroke) and examination (initial National Institutes of Health Stroke Scale (NIHSS) score (NIHSS score before rtPA and 24 h after rtPA, admission SBP and DBP (patients with SBP higher than 185 were lowered by IV Na nitroprusside to lower than 185 before start rtPA), CT brain and or MRI brain (at time of admission and 24 h after infusion of rtPA), cardiac workup (ECG, Echocardiography, troponin, CK mb), carotid duplex and some laboratory (hemoglobin, white blood cell count, platelet count, capillary blood glucose at presentation, fasting blood glucose, hemoglobin A1C (HbA1C), lipid profiles and prothrombin time) were done for all patient immediately at time of arrival.The etiologic classification of stroke was conducted according to TOAST classification [12].All patients were administered with standard dose IV rtPA 0.9 mg/kg (adjusted by weight of patient, maximum 90 mg, 10% of dose IV bolus and remaining 90% IV infusions over 1 h) within 4.5 h of symptom onset, based on United States Food and Drug Administration-approved indications [13].
Stroke severity was categorized based on NIHSS and the size of the infarction into mild stroke, when the NIHSS score ≤ 8 with lacunar infarction or small vessel disease; moderate stroke when the NIHSS score 9 to 15 with infarction less than third of the brain; and severe stroke when the NIHSS score ≥ 16 with massive infarction more than the third of the brain [14].
The follow-up assessment was conducted after 3 months from the stroke onset.The primary outcome measures the functional outcome according to Modified Rankin Score (MRS).It was classified into good outcome (MRS scores of 0-2), partial outcome (MRS scores of 3-4) and poor outcome (MRS scores of 5-6) that indicating major disability or death [15].Hemorrhagic transformation post thrombolysis was graded according to the ECASS I (European Cooperative Acute Stroke Study I) criteria [16].Symptomatic intracerebral hemorrhage (SICH) was defined as the presence of intracerebral hemorrhage with worsening of NIHSS score by > 4 points occurring within 48 h of administration of rtPA [16].Delayed hemorrhage was defined as intracerebral hemorrhage occurring ≥ 48 h after the administration of rtPA [17].Mortality due to any cause was also recorded.
Appropriate statistical methods were applied and the results were tabulated and presented accordingly.P < 0.05 was considered significant.

Results
The study was carried out on 162 patients (136 males and 26 females) with mean age 60.43 ± 12.094 presented with acute ischemic stroke with duration of symptoms less than 4.50 h from onset of neurological symptoms.All patients were candidate for rtPA and received full dose of rtPA adjusted by weight of patient.The prevalence of hypertension, diabetes mellitus, hypercholesterolemia, cardiac disease, AF, PH of stroke, obesity and smoking were 56.8%, 43.2%, 45.7%, 48.2%, 30.86%, 3.7%, 16.2%, and 35.8%, respectively (Table 1).Regarding to clinical presentation, most of patients (72.8%) presented with right side hemiplegia and duration of symptoms was 2.32 ± 0.79.The degree of stroke was 80.2% of patients had severe degree, 17.3% had moderate and remaining 2.5% had mild degree.The NIHS scale at time of admission was 20.16 ± 4.08 (Table 2).After administration of rtPA, 8.6% complicated with hemorrhage and 23.5% had no response at all and MR angiography showed large artery occlusion and referred to another hospital for endovascular thrombectomy.Remaining 66.8% of patients follow-up for 3 months and outcome was 35.8% had good outcome (MRS; 0-2), 18.5% had partial outcome (MRS; 3-4) and 12.5% had poor outcome (MRS; 5-6).Old age patients, hypertensive patients and hypercholesterolemia had poor outcome (Table 3).

Discussion
Ischemic stroke is highly prevalent worldwide.Thrombolysis has been found to be the most effective medical treatment for acute ischemic stroke (AIS) patients [18].Unfortunately, some patients still experience functional deficits after rtPA thrombolysis.Accurate and early prediction of the clinical outcome for individual AIS patients who receive rtPA treatment is needed to provide a reasonable approach to patient management [9].The present study was a prospective observational study aimed to study the predictors for favorable and unfavorable outcome of stroke patients after rtPA (Tables 4, 5).
The prevalence of hypertension, diabetes mellitus (DM), hypercholesterolemia and dyslipidemia, cardiac disease, AF, past history (PH) of stroke, obesity and smoking in our study were 56.8%, 43.2%, 45.7%, 48.2%, 30.86%, 3.7%, 16.2%, and 35.8%, respectively, came in partial agreement with Emad et al. [19], they concluded the prevalence of HTN, DM, Dyslipidemia, IHD and smoking   Our study like many studies [19][20][21][22] showed a highly significant association between the severity of stroke, assessed by NIHSS score and infarction size on admission and an unfavorable outcome was detected (P = 0.007).The NIHSS score was a good predictor of stroke outcome and that a remarkable neurologic impairment assessed by NIHSS score was associated with less favorable outcome The NIHSS score is significantly and strongly correlated with poor outcome after rtPA for acute ischemic stroke.
In addition to stroke severity, past history of stroke was associated with poor outcome and increase risk of SICH and this result agree with Wafaa [23] who reported the same results, while other studies [20,24] reported no significant correlation between history of previous stroke and poor outcome.Patient who had recurrent stoke commonly had multiple risk factors for stroke, poor control of risk factors, poor compliance on medications and advanced atherosclerosis that have unfavorable outcome after rtPA.
Regarding patients with AF, our study showed significant (P = 0.004) correlation to poor outcome, this result came in agreement with previous literature [20,[25][26][27][28].All of the previous studies reported significant correlation between AF and poor outcome after rtPA and concluded that it is mostly due to high incidence of associated SICH.The thrombus formed in AF patient was formed inside heart and carried with blood to brain; it may take time inside heart makes it hard thrombus and difficulty to dissolve by fibrinolytic effect of rtPA.Other studies [19,23] reported that no significant correlation between AF and outcome.The presence of AF among these studies were very low (5/131 and 7/40, respectively).The exact mechanisms of AF on the outcomes of stroke patients were not clear, and stroke patients with AF may have large and old thrombi, which are not sensitive to the treatment of thrombolytic therapy [29].
Regarding to blood pressure at time of presentation, the result of our study showed that patients with high blood pressure at time of presentation carried poor outcome that agree with Leonardi Bee et al. [30] and Okumura et al. [31], they reported that patients presenting with AIS who have an extremely elevated BP have worse outcomes, which is likely due to the baseline increased severity in stroke symptoms.Darger et al. [32] reported that there was a statistically significant difference in adverse events between patients requiring any method of BP control prior to thrombolysis versus those who did not, when adjusting for the baseline severity of the stroke.Previous studies have revealed that both high and low blood pressure were independent prognostic factors for poor outcome in ischemic stroke patients [30,33].
Regarding to risk factors of stroke, results of our study showed that, the patient had hypertension, dyslipidemia and ischemic heart disease carried poor outcome and high risk for ICH.Bhardwaj et al. [34], who found that risk factors such as hypertension, diabetes, dyslipidemia, smoking, alcohol intake, coronary artery disease and valvular heart disease did not influence outcome in patients of acute ischemic stroke receiving rtPA [34].Patients with chronic hypertension have shifts in perfusion autoregulation parameters as well as changes in collateral blood supplies and this, in conjunction with other considerations, such as carotid artery stenosis, put hypertensive stroke patients at a unique risk special consideration should be considered when determining rtPA eligibility in these patients [35,36].
Our study showed significant negative correlation between DM and the functional outcome.This was present in the univariate analysis and when tested as independent predictors of the functional outcome among risk factors using the multivariate analysis, it was a strong independent predictor of poor functional outcome.This was in agreement with many studies which had identified DM as a predictor of poor functional outcome after receiving IV rtPA among stroke patients like that conducted by Roquer and et al. [37] and that was conducted by Saposnik et al. [38].However, other studies did not show significant correlations between DM and functional outcome after receiving IV rtPA, but had showed a significant correlation between admission hyperglycemia and poor functional outcome after receiving IV rtPA [37,39].Our study showed non-significant correlation between smoking and the functional outcome 3 months after receiving IV rtPA, and this was in agreement with previous studies [39,40].In contrary to other studies which revealed significant negative correlation between recent or current smoking and functional outcome 3 months after IV rtPA [41].
In addition to modifiable risk factors of stroke, age is one of the major determinants of stroke outcomes [38,42].Elderly patients were prone to have poorer outcomes compared with young patients after rtPA thrombolysis treatment [43,44].Besides, elderly patients were more likely to have complications, such as AF and hypertension, as well as higher NIHSS score, all of which may influence stroke outcomes [44,45].In the present study, patients with an unfavorable outcome had a higher median age than those with a favorable outcome; the effect of age on outcome was not significant after adjusting for confounding variables.
Despite this study illustrated the factor associated with post-rtPA outcomes, it has some limitations.One of these limitations is the small sample size of the included patients that did not enable us to make more advanced statistical analysis.In addition, the shortness of the follow-up duration may be a contributing factor that prevent some clarity in the association.It is known that, the MRS improves with time after stroke; therefore, the time provide a chance for positive outcome.Moreover, we did not use the serum stroke biomarkers to test their association with post-stroke functional outcomes.

Conclusions
AF, PH of stroke, stroke severity, and severity of symptom (NIHSS) score were significantly correlated with poor outcome after rtPA.In addition, old age, high blood pressure at time of presentation, hypertension, dyslipidemia were the demographics that carried poor outcome.Patients with acute ischemic stroke who are eligible for rtPA and have one or more of these variables should be monitored carefully on both short and long term.

Fig. 1
Fig. 1 Flow diagram of all included patients showing the selection of the included patients for follow-up and the omitted patients

Table 1
Demographic data of the studied patients HTN hypertension, DM diabetes mellitus, AF atrial fibrillations, PH past history *Data were presented as number and frequency except the age was presented and mean ± standard deviation

Table 2
Clinical presentation of the studied patients NIHS scale National Institute of Health Stroke Scale

Table 3
Outcome after rtPA according to Modified Rankin Scale (MRS)

Table 4
Correlation between demographic data and outcome after rtPA based on Modified Rankin Scale (MRS) HTN hypertension, DM diabetes mellitus, AF atrial fibrillations, PH past history *P value was considered significant if it was <0.

Table 5
Correlation between clinical presentation and outcome after rtPA based on Modified Rankin Scale (MRS)NIHS scale National Institute of Health Stroke Scale, BP blood pressure *P value was considered significant if it was < 0.05