The Relationship Between Intracranial Hemorrhage After Intravenous Thrombolytic Therapy and the Need for Antihypertensive Treatment During and After Infusion in Acute Ischemic Stroke

Eda Aslanbaba Bahadir; Mine Hayriye Sorgun; Canan Togay Isikay

doi:10.4103/nsn.nsn_30_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 39 | Issue : 4 | Page : 177-182

The Relationship Between Intracranial Hemorrhage After Intravenous Thrombolytic Therapy and the Need for Antihypertensive Treatment During and After Infusion in Acute Ischemic Stroke

Eda Aslanbaba Bahadir, Mine Hayriye Sorgun, Canan Togay Isikay
Department of Neurology, Ankara University School of Medicine, Ibni Sina Hospital, Ankara, Turkey

Date of Submission	15-Feb-2022
Date of Decision	24-Jul-2022
Date of Acceptance	25-Jul-2022
Date of Web Publication	19-Dec-2022

Correspondence Address:
Eda Aslanbaba Bahadir
Department of Neurology, Ankara University School of Medicine, Ibni Sina Hospital, Samanpazari, Ankara
Turkey

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/nsn.nsn_30_22

Abstract

Background: This study aims to determine which factors increase the risk of intracerebral hemorrhage after tissue plasminogen activator (tPA) treatment in patients with acute ischemic stroke and to investigate whether there is a relationship between the need for antihypertensive therapy during and after tPA infusion and the risk of intracerebral hemorrhage. Materials and Methods: Consecutive patients who applied to our stroke center with acute ischemic stroke and received IV tPA treatment in the first 4.5 h between 2012 and 2020 were included in the study. The demographic data of patients, stroke risk factors, drugs used before the stroke, neurological examinations, cranial computed tomographys (CTs) before and after tPA, antihypertensive usage during IV tPA and in the 24-h period after treatment, hospital mortality rates, and modified Rankin Scale scores in the 3^rd month were evaluated retrospectively. Patients with intracerebral bleeding were divided into groups according to bleeding subtypes and whether they were symptomatic. Results: Intracranial bleeding was detected in 48 of 214 patients included in this study. Nineteen of these (8.8%) were classified as symptomatic intracerebral hemorrhage according to the National Institute of Neurological Disorders and Stroke and 14 (6.5%) according to the definition of the European Cooperative Acute Stroke Study. In the multiple logistic regression analysis, intracranial bleeding was significantly associated with 24^th h systolic blood pressure and the need for antihypertensive usage. Conclusions: Blood pressure regulation should be done carefully during tPA infusion and in the first 24 h. In addition, cranial CT scanning in patients who need antihypertensive usage may enable earlier detection of intracranial bleeding.

Keywords: Acute ischemic stroke, alteplase, intravenous tPA, symptomatic intracerebral hemorrhage, thrombolytic

How to cite this article:
Bahadir EA, Sorgun MH, Isikay CT. The Relationship Between Intracranial Hemorrhage After Intravenous Thrombolytic Therapy and the Need for Antihypertensive Treatment During and After Infusion in Acute Ischemic Stroke. Neurol Sci Neurophysiol 2022;39:177-82

How to cite this URL:
Bahadir EA, Sorgun MH, Isikay CT. The Relationship Between Intracranial Hemorrhage After Intravenous Thrombolytic Therapy and the Need for Antihypertensive Treatment During and After Infusion in Acute Ischemic Stroke. Neurol Sci Neurophysiol [serial online] 2022 [cited 2023 May 29];39:177-82. Available from: http://www.nsnjournal.org/text.asp?2022/39/4/177/364421

Introduction

Recombinant tissue plasminogen activator (tPA [alteplase]) has been used in acute ischemic stroke treatment since it was approved by the Food and Drug Administration in the United States in 1996. Its effectiveness has been proven in large patient series in studies such as the European Cooperative Acute Stroke Study (ECASS) and the National Institute of Neurological Disorders and Stroke (NINDS).^[1],[2] However, because it can lead to fatal complications such as intracerebral hemorrhage, alteplase can be used in selected patients. Although different rates have been determined due to the use of different definitions of symptomatic hemorrhage in studies, the rates of symptomatic intracranial hemorrhage have been reported at 6%–8%.^{[1],[2],[3],[4]} Some risk factors that may lead to intracranial hemorrhage have been blamed in different studies. These are hypodensity detected on cranial computed tomography (CT), dense middle cerebral artery (MCA) sign, high serum glucose or history of diabetes mellitus, hypercholesterolemia, statin usage, previous transient ischemic attack (TIA) or stroke history, smoking, high blood pressure, high stroke severity, age, renal failure, congestive heart failure, atrial fibrillation, using antiaggregant or anticoagulant before tPA.^{[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15]} In thrombolysis studies involving cerebral and myocardial infarction, it was emphasized that hypertension within the first 24 h was an independent predictive factor for symptomatic intracranial hemorrhage.^[7] Therefore, it is recommended that the blood pressure of patients who will receive intravenous tPA be kept below 185/110 mmHg (Class I-Evidence Level B).^[16] In the ENCHANTED study, although there was no difference in functional improvement in patients whose blood pressure was lowered more intensely than recommended in the guidelines, a significant decrease was found in the rate of total intracranial hemorrhage. However, there was no significant decrease in major intracranial bleeding rates.^[17] The SITSMOST study showed that high systolic blood pressure rather than diastolic blood pressure is associated with symptomatic intracerebral hemorrhage (sICH).^[14] Ahmed et al. reported that discontinuation of antihypertensive treatment for up to 7 days in patients with a history of hypertension was associated with a worse outcome, while the initiation of antihypertensive treatment in newly diagnosed moderate hypertension was associated with a good outcome.^[18] Previous studies have not reported the relationship between the need for antihypertensive treatment during and after tPA infusion and the risk of intracerebral hemorrhage. This study aims to determine which factors increase the risk of intracerebral hemorrhage after tPA treatment in patients with acute ischemic stroke and to investigate whether there is a relationship between the need for antihypertensive therapy during and after tPA infusion and the risk of intracerebral hemorrhage.

Materials and Methods

The study included 214 patients who applied to Ankara Medical Faculty Ibni Sina Hospital with acute ischemic stroke in the first 4.5 h and received intravenous tPA treatment between January 2012 and July 2020. The demographic data of the patients, stroke risk factors, drugs used before the stroke, neurological and physical examination characteristics of the patients were reviewed retrospectively. tPA eligibility criteria were used for inclusion criteria. Neurological examinations at the time of admission to the hospital and 24 h after tPA treatment were recorded according to the National Institutes of Health Stroke Scale (NIHSS) score. Admission blood pressure, blood glucose, routine biochemistry, hemogram, and hemostasis values were scanned. Since the blood pressure was 185/110 mmHg and above, the patients started antihypertensive treatment during tPA infusion and in the first 24 h after it was determined. The HbA1c and lipid profiles of the patients during their hospitalization were recorded. Cranial CT scans were examined both at admission and the 24^th h. Those who were found to have bleeding were divided into groups by the bleeding classification in the ECASS studies. According to this classification, petechial hemorrhages without mass effect were defined as hemorrhagic transformation. This hemorrhagic transformation group was also divided into 1 and 2 according to their small and confluent nature. Hemorrhages with mass effect were classified as a parenchymal hematoma (PH). Bleeding <30% of the infarct area was classified as PH 1, over 30% as PH 2.^[19] In terms of symptomatic intracranial hemorrhage, the definitions in both the NINDS and ECASS studies were specified separately. According to the NINDS definition, symptomatic intracranial hemorrhage was defined as clinical deterioration with newly detected hemorrhage on brain CT in the first 36 h and a decline of ≥4 in the NIHSS score or death associated with the ECASS definition. Mortality rates at hospitalization and modified Rankin Scale (mRS) at 3^rd months were evaluated in prognosis. Patients with no or minimal deficits (mRS 0 and 1) were considered a favorable outcome. Those with and without symptomatic hemorrhage were compared in terms of risk factors.

Statistical analysis

For data analysis, IBM SPSS Windows 15 package program (USA) program was used. Descriptive statistics were shown as mean ± standard deviation for variables with normal distribution, median (min–max) for variables with nonnormal distribution, and several cases and (%) nominal variables. When the number of groups was two, the significance of the difference between the groups in terms of means was investigated with the t-test. The significance of the difference in terms of median values was investigated with the Mann–Whitney U test. When the number of groups was more than two, the significance of the difference between the groups in terms of means was determined by one-way analysis of variance. The Kruskal–Wallis test determined the significance of the difference in terms of median values. Nominal variables were evaluated with Pearson Chi-square or Fisher's exact test. Risk factors affecting the dependent variable were investigated by logistic regression analysis.

Results

In our study, 214 patients who were treated with IV thrombolytic therapy were retrospectively screened. Intracranial hemorrhage after tPA was detected in 48 patients (22.5%; mean age 74 ± 12; female n = 21, 44%), 4 of them hemorrhagic infarction HI1 (1.8%, mean age 75 ± 8, female n = 2, 50%), 7 HI2 (3.2%, mean age 77 ± 12, female n = 2, 28.6%), 12 PH1 (5.6%, mean age 71 ± 12, female n = 6, 50%), and 19 PH2 (8.8%, mean age was 73 ± 12, female n = 10, 52.6%). Furthermore, PH outside the infarct area remote parenchymal hematoma in three patients (1.4%), subarachnoid hemorrhage (SAH) in 1 patient (0.4%), and SAH that opened into the ventricle with hematoma outside the infarct area in two patients (0.9%) were detected [Table 1]. Considering the number of sICH; There were 19 patients (8.8%, mean age 71.5 ± 15, female n = 9, 47.4%) according to the NINDS definition and 14 patients (6.5%, mean age was 73.1 ± 15, female n = 10, 42.9%) according to the ECASS definition.

Table 1: Rates of intracranial bleeding subtypes

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There was no statistically significant difference between groups with and without intracranial bleeding in age, gender, and ischemic stroke risk factors (hypertension, diabetes mellitus, atrial fibrillation, previous stroke/TIA, coronary artery disease, dyslipidemia, congestive heart failure, renal failure, malignancy, and smoking). In addition, there was no significant difference between the groups in terms of antiaggregant, anticoagulant, statin, and antidepressant usage before stroke [Table 2]. Cranial CT scans taken during admission to the emergency department were evaluated for the presence of hypodensity and dense MCA sign. In the groups with and without intracranial hemorrhage, CT hypodensity was 2% and 4%, respectively; dense MCA sign was found in 19% and 13%, respectively (P > 0.05) [Table 3].

Table 2: Prestroke risk factors in patients with and without intracranial hemorrhage

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Table 3: Admission characteristics in patients with and without intracranial hemorrhage

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There was no statistically significant difference in admission NIHSS scores between the group with hemorrhage (median = 14) and the group without hemorrhage (median = 11) (P = 0.298). However, NIHSS scores measured 24 h after tPA administration were statistically higher in the group with hemorrhage (P < 0.001) [Table 3].

When the systolic and diastolic blood pressures measured in the emergency room were compared, there was no significant difference in the group with intracranial bleeding. Antihypertensive treatment was started in 25 patients (15%) in the group without intracranial hemorrhage and 24 patients (50%) in the group with intracranial hemorrhage because their blood pressure was 185/110 mmHg and above during and in the first 24 h after IV tPA infusion. Intravenous esmolol was used in these patients. The need for antihypertensive treatment during and in the first 24 h after IV tPA infusion was significantly higher in patients with intracranial hemorrhage (P = 0.001) [Table 3]. Mortality rates of the patients during their hospitalization and mRS at the 3^rd month after discharge were evaluated. The hospital mortality rate was 46% (n = 22) in patients with intracranial hemorrhage and 14% (n = 24) in patients without bleeding (P < 0.001). The functional status of the patients at the 3^rd month was evaluated by mRS. mRS could not be evaluated because 117 of the patients were excluded from our follow-up. The scores of the remaining 97 patients were calculated according to their neurological examinations and functional status. In the group with intracranial hemorrhage, the favorable outcome was 4%, and functional independence was 6%, whereas in the group without hemorrhage, the favorable outcome was 16%, and functional independence was 19%. This difference between the groups was also statistically significant (P = 0.002) [Table 4].

Table 4. Prognostic characteristics in patients with and without intracranial hemorrhage

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In the multiple logistic regression analysis, intracranial bleeding was significantly associated with 24^th h systolic blood pressure (beta: 0.369 [0.2–0.11], P = 0.06), antihypertensive use during and after infusion (beta: 0.593 [0.249]). −0.974, P = 0.001) [Table 5].

Table 5: Multiple logistic regression analysis in patients with and without intracranial hemorrhage

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Discussion

In this study, 214 patients who applied to Ankara Medical Faculty Ibni Sina Hospital with acute ischemic stroke clinic and received intravenous tPA between January 2012 and July 2020 were evaluated retrospectively. The overall rate of intracranial hemorrhage in patients given intravenous tPA was 22.5%. In the multiple regression analysis, intracranial bleeding was significantly associated with 24^th h systolic blood pressure and the need for antihypertensive usage during and after tPA infusion.

In the previous studies, different results have been obtained in terms of asymptomatic and sICH rates. In the tPA stroke study of the NINDS group, the rate of asymptomatic intracranial hemorrhage was 4.5%, and the rate of symptomatic intracranial hemorrhage was 6.4%. In the study which ECASS researchers investigated the effectiveness of tPA 3-4.5 hours after stroke, the rate of all intracranial hemorrhage was found to be 27%, the rate of symptomatic bleeding according to the NINDS definition 7.9%, and 5.3% according to the ECASS definition. In our study, the rate of all intracranial hemorrhage was 22.5%, while the rate of symptomatic intracranial hemorrhage was 8.8% according to the NINDS definition and 6.5% according to the ECASS definition.^[2],[4] It is thought that the determination of different rates is due to the use of different definitions in the studies.

In the ECASS II study, HI1 type hemorrhage was found at 19.6%, HI2 type hemorrhage at 15.2%, PH1 type hemorrhage at 3.7%, and PH 2 type hemorrhage at 8.1% in the group receiving tPA.^[20] Contrary to ECASS II, PH2-type bleeding was the most common in our study, while HI2-type bleeding was found more than HI1. This situation has been associated with high blood pressure that necessitates antihypertensive use during and after tPA infusion. In our study, among patients with and without intracranial hemorrhage, no difference was found in age, gender, ischemic stroke risk factors, prestroke drug use, stroke severity, and admission blood pressure values.

Butcher et al. reported that the mean systolic blood pressure elevation within 24 h after treatment was predictive of intracranial hemorrhage.^[21] In the study of Waltimo et al., blood pressure values before and after thrombolytic therapy were compared in groups with and without intracranial hemorrhage, and the patients with bleeding had higher blood pressure.^[22] The relationship between the need for antihypertensive treatment during and after tPA infusion and the risk of intracerebral hemorrhage was not reported in these studies. In our study, the rate of patients who required antihypertensive use during tPA infusion and within 24 h after receiving it was found to be significantly higher in patients with intracranial hemorrhage. Thus, blood pressure control during and after tPA administration is critical in patients who need antihypertensive and should be approached more carefully in terms of hemorrhage risk.

In a meta-analysis of 6756 patients by Emberson et al., although a higher mortality rate was observed in the early period due to intracranial hemorrhage, it was found that there was an increase in the functional independence rates of 3–6 months.^[23] In the IST-3 study, while death due to intracranial hemorrhage or enlargement of the infarct was more common in the tPA group within the 1^st week, the long-term prognosis of patients who survived the 1^st week was better than others.^[24] In our study, both hospitalization mortality rates and mRS scores at the 3^rd month were higher in the group with intracranial hemorrhage. However, these data were not statistically significant in multiple regression analysis.

There are several limitations of our study, including its retrospective design and a single medical center. In addition, this is a restriction of the cohort to a small number of patients. Hence, statistical analysis of hemorrhagic infarct and PH subtypes is insufficient. Another limitation was the lack of follow-up information for all patients.

Conclusions

The fact that the rate of patients requiring antihypertensive usage during intravenous tPA and in the 24 h after it was found to be significantly higher in the group with intracranial hemorrhage indicates that blood pressure regulation should be done carefully during tPA and in the first 24 h. In addition, being more careful in terms of bleeding and early cranial CT in these patients may enable earlier detection of intracranial bleeding.

Financial support and sponsorship

This study was supported by the authors.

Conflicts of interest

There are no conflicts of interest.

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