The Efficacy and Safety of Intravenous Thrombolysis in Older Chinese Patients with Acute Ischemic Stroke
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.310086
Source of Support: None, Conflict of Interest: None
Keywords: Acute ischemic stroke, adverse effect, efficacy, intravenous thrombolysis, older patient
Ming Xu and Jiamei Guo contributed equally to this work.
Stroke, which has become an increasing global health problem, refers to a group of acute cerebrovascular events in which the primary clinical manifestations are cerebral ischemia or hemorrhage, characterized by high morbidity, disability, and mortality. Furthermore, the proportion of ischemic stroke has escalated to over 80% of patients with stroke admitted into a medical center, with incidence markedly increasing with age. According to statistics, almost 30% of ischemic stroke patients are over 80 years, with a higher risk of disability and mortality than younger patients.
Recombinant tissue plasminogen activator (rt-PA) was first introduced in 1985. Intravenous thrombolysis treatment with rt-PA has been recognized as an effective method for the treatment of acute ischemic stroke and widely recommended by American guidelines. Chinese stroke guidelines also recommend intravenous thrombolysis with rt-PA for acute ischemic stroke patients less than 80 years during the first 4.5 h from symptom onset. However, the efficacy and safety of intravenous thrombolysis for the older acute ischemic stroke patients (i.e., age >80 years) is still controversial,,,,,,,, with few empirical reports examining the efficacy and safety of thrombolysis for older patients being conducted in China. Therefore, the current study aimed to evaluate the efficacy and safety of thrombolysis treatment with rt-PA in a sample of older Chinese patients with acute ischemic stroke, via analyses of clinical features, complications, and prognosis.
Study design was approved by The People's Hospital of Dazu District and Chongqing Medical University. Clinical data were prospectively analyzed from 168 patients with acute ischemic stroke hospitalized in the Department of Neurology of The People's Hospital of Dazu District, from January 2013 to March 2018. All patients met both inclusion and exclusion criteria. Inclusion criteria included (1) reference to the 2013 American Stroke Association guidelines for thrombolysis of a therapy onset time of less than 4.5 h following event; (2) a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 25 points before therapy; (3) cerebral CT scan to exclude intracerebral hemorrhage (i.e., imaging change without fresh large area cerebral infarction); and (4) informed consent signed by patients or family members before therapy. Exclusion criteria included (1) mild neurological deficits, significant improvements prior to therapy, and/or neurological deficits after seizures; (2) a history of intracranial hemorrhage (ICH), brain trauma, cerebral infarction, and/or myocardial infarction in the last three months; (3) history of gastrointestinal or urinary tract bleeding in the last three weeks; (4) surgical operation history within the last two weeks; (5) evidence of active bleeding, trauma (fracture), or history of arterial puncture in last seven days; (6) systolic blood pressure =185 mmHg or diastolic blood pressure =105 mmHg, and/or above the target value after treatment; (7) oral anticoagulants, an INR >1.5, or heparin treatment within 48 h (activated partial thromboplastin time exceeding the normal range); (8) blood platelet less than 100*109/L, blood glucose <2.7 mmol/L, or >22.2 mmol/L; and (9) severe heart, lung, liver, or kidney dysfunction, malignancy, and/or pregnancy.
All patients received identical care, with the exception of intravenous thrombolysis with rt-PA, from the time they were admitted to the hospital. Referring to the SITS-MOST study: Alteplase for injection, an rt-PA (Boheringer Ingelheim International Corporation, Germany) was used during the first 4.5 h following stroke symptom onset in acute ischemic stroke patients. Total dose was calculated by 0.9 mg/kg (body weight), 10% of which was first given within 5 min, and the remaining dissolved in 250 ml isotonic saline intravenous infusion over the course of 45 - 60 min. All patients treated with thrombolytic treatment received a CT scan to detect ICH 24 h after thrombolytic treatment.
After thrombolytic treatment, patients without any ICH were given aspirin or clopidogrel to address antiplatelet aggregation. Patients with atrial fibrillation were administered warfarin anticoagulant therapy. Patients without thrombolytic treatment could be treated with antiplatelet aggregation or anticoagulation treatment immediately after admission. The 168 ischemic stroke patients were classified into three groups according to age and the differing treatment: 42 older adult patients (age >80 years), treated with intravenous rt-PA (ET group); 66 younger patients (aged 18–80), treated with intravenous rt-PA (NET group); and 60 older adult patients, treated without intravenous rt-PA (ENT group).
All patients underwent a standard neurological examination, electrocardiography, blood pressure, blood lipid, serum glucose, and CT/MRI scan of the head at admission. Stroke severity was assessed, with an NIHSS score given by a certified neurologist, at admission, 1 day, and 14 days after thrombolysis treatment. Functional outcomes were evaluated by the modified Rankin scale (mRS, score 0–6 points) and a Barthel index obtained at three months following stroke event. A favorable outcome was defined as an mRS score ≥2, and a poor outcome was defined as an mRS score >2. In addition to observing for bleeding of organs and other adverse reactions following thrombolytic treatment, the brain was continuously observed for hemorrhagic transformation, including hemorrhagic cerebral infarction, parenchyma hematoma (according to the ECASS II standard), and/or symptomatic ICH, for seven days following cerebral infarction. Symptomatic ICH was defined by ECASS II, with a secondary CT scan showing hemorrhage and the NIHSS score increasing by ≥4 points from baseline or the lowest NIHSS score during the 24–36 h after thrombolysis.
Data were analyzed by SPSS 20.0 (IBM). Continuous variables are presented as mean ± SD if normally distributed and were compared by t-test or median (interquartile range). If not normally distributed, data were compared by rank test between groups. Categorical variables are presented as absolute values and percentages, with differences between groups assessed by Pearson χ2 or a Fisher exact test. Single-factor analyses were performed to determine risk factors of hemorrhagic transformation. A P value of <0.05 was considered significant for all tests.
Demographic data, past medical history, and NIHSS scores are shown in [Table 1]. There were no significant differences in baseline clinical characteristics of sex; prevalence of vascular risk factors, including arterial hypertension, diabetes, coronary heart disease, atrial fibrillation, and hyperlipidemia; and onset time to therapy among the three groups. As expected, there were significant differences in age between ET/ENT and NET groups.
There were no significant differences in the median of the NHISS score at baseline, or at first day after treatment among the three groups. At the 14th day after treatment, the NIHSS score in the ET group was significantly higher (P = 0.002) than that in the NET group but not significantly different from the ENT group (P = 0.772). Results show that the median NIHSS scores of the three groups were reduced after treatment, with or without thrombolytic therapy. Specifically, no significant differences between the ET and ENT groups indicate that thrombolytic therapy may not contribute to increased short-term benefits for older patients. Scores of the mRS and Barthel index are often used to evaluate the prognosis of patients with acute stroke. [Table 2] shows the comparison of mRS and Barthel index scores between the three groups at 90 days after treatment. The rate of “good” prognosis (P = 0.004) and Barthel index scores (P = 0.005) in the NET group were significantly higher than those in the ET group, indicating that younger patients treated with intravenous rt-PA had better recovery to the normal life than older patients .There was no significant difference in mRS scores between ET and ENT groups (P = 0.392), while Barthel index scores of ET group were still significantly higher than ENT group (P = 0.026). In the ET group, two patients died of other diseases. Furthermore, this group contained three patients who recovered well within the first 14 days but worsened within 90 days, experiencing a second stroke. These individuals were classified as a “poor” prognosis. Taking this into account, the older patients with acute ischemic stroke treated with thrombolytic therapy might achieve a better prognosis and lower instances of disability than those treated without rt-PA, In addition, older patients achieved less benefit from rt-PA treatment than their younger counterparts. However, the previous studies suggested that Barthel index scores had “ceiling effect”, and mRS scores was better to reflect functional disability difference among stroke patients. The results should be confirmed by a large sample study in the future.
To analyze the relationship between long-term efficacy of thrombolytic therapy and baseline NIHSS scores, patients in the ET group were divided into three subgroups, according to different NIHSS score standards: ≥6 points (6 patients, 14.29%); 7–15 points (21 patients, 50%); and ≥16 points (15 patients, 35.71%). Favorable outcome rates at 90 days following stroke were 83%, 52%, and 6% among the three groups. This suggests that older patients with acute ischemic stroke and presenting lower NIHSS scores (i.e., ≥6 points) might hold the best prognosis after stroke.
Additionally, older thrombolytic patients were divided into three subgroups according to Oxfordshire Community Stroke Project classification and imaging findings. Specifically, patients were divided into posterior circulation infarction (5 patients, 11.91%); lacunar infarction (3 patients, 7.14%); and anterior circulation infarction, including partial anterior circulation infarction (34 patients, 80.95%). The favorable outcome rates at 90 days after stroke were 80%, 66.7%, and 29.4. These data suggest that older patients with acute ischemic stroke with posterior circulation infarction might hold the best prognosis after stroke. Nevertheless, due to the limited sample of this study, this conclusion needs to be confirmed by further studies with large sample.
Adverse reactions were also observed in the current study. Specifically, the incidence of hemorrhagic transformation and symptomatic ICH within the first week among the ET, NET, and ENT groups was 19.05%, 9.09%, and 10%, respectively. There were no significant differences among the three groups (P > 0.05). The common bleeding sites of patients with hemorrhagic transformation were oral cavity, gingiva, skin, or joints. Bleeding was not severe, which was why recovery was permitted without specific treatment. [Table 3] shows univariate regression analyses of hemorrhage transformation and symptomatic ICH in the ET group. Results show that a high NIHSS score at baseline, a longer initial treatment time, and a combined history of atrial fibrillation and diabetes mellitus increase the risk of hemorrhagic transformation after thrombolytic therapy in older patients with acute ischemic stroke (P < 0.05).
Other adverse reactions were recorded, such as coagulation dysfunction, decreased platelets, renal dysfunction, drug allergies, and rash in patients undergoing thrombolytic therapy. However, all reactions were not found to be severe. Thus, no specific treatment was needed to manage symptoms.
The most urgent need following ischemic stroke is to restore blood supply and to improve cerebral perfusion in the brain as soon as possible. Intravenous thrombolysis is a method of treatment that has been confirmed to be effective and is widely recommended. However, no consensus has been reached in the literature regarding thrombolytic therapy in older patients (i.e., individuals >80 years of age).,,,,,,, In this study, no significant differences were observed in neurological impairment between the ET and ENT groups within two weeks treatment. However, the rate of “good” prognosis assessed via mRS and mean Barthel index scores was higher in the ET group than that in the ENT group at 90 days post-stroke. The results indicated that thrombolytic therapy might improve future quality of life in older patients (i.e., >80 years), rather than decreasing disability in the short term following the stroke. These results are consistent with previous studies in patients younger than 80 years., Because of the limited amount of samples and a single center study, the conclusion should be confirmed by a large-scale and multi-center study in the future.
To further analyze the effects of thrombolysis therapy, patients were grouped according to NIHSS score at admission, which can be used to evaluate stroke severity. Changes in the NIHSS score were an important indicator of the ameliorative effects of treatment. The data showed that the overall prognosis and thrombolytic effects in patients with lower NIHSS scores were better than those with higher NIHSS scores. A previous report has shown that a 1 point increase in the NIHSS score was associated with a 24% decrease in the probability of functional improvement at 3 months; that a baseline NIHSS score higher than 16 was a predictor of death or severe disability after stroke; and that an NIHSS score less than 6 points meant a “good” prognosis. However, the ECASS II study and research by Emberson have asserted that baseline NIHSS scores do not affect the prognosis of thrombolytic therapy. Many factors may account for this discrepancy. For instance, it has been speculated that patients without serious vascular congestion might have a better response to thrombolytic drugs. Furthermore, the effect of thrombolysis therapy may differ due to the location of cerebral infarction. In the current study, intravenous thrombolytic therapy demonstrated increased efficacy in patients with acute posterior circulation ischemic stroke. A previous study showed that intravenous t-PA improved clinical outcomes at 3 months, with a primary focus on anterior circulation. However, there is a dearth of clinical trials examining the effects of thrombolytic therapy in acute posterior circulation ischemic stroke. This study found that older adult patients with posterior circulation infarctions demonstrated better recovery than those with anterior circulation infarction. Many reasons may account for this, including complicated anatomical structures, physiological function, and differences in neurovasculature. The posterior circulating compensatory vessels were often more abundant. Nevertheless, due to the limited samples of this study, this conclusion needs to be confirmed by further studies with a large sample. Some researchers, have pointed out that weight distribution of the NIHSS scoring system focuses on anterior circulation symptoms, with many of the posterior circulation symptoms, such as diplopia, dysphagia, gait abnormality, hearing loss, and nystagmus, not included. Therefore, the NIHSS scale may not be suitable for the posterior circulation infarction, making it necessary to select more suitable evaluation models in future research.
Hemorrhage transformation was the main complication of thrombolytic therapy. While the mortality rate of symptomatic ICH is above 50%, thrombolysis did not significantly increase the risk of hemorrhagic transformation or the incidence of symptomatic ICH in older patients. In the current study, although some patients (8/34 Pts) demonstrated transformation bleeding in the gingiva, joints, and skin, all of which were not severe, there were no statistical differences among the three groups. Therefore, the main risk factors for bleeding in older patients may be age and disease, rather than the thrombolytic treatment itself. Several other factors were related to hemorrhagic transformation, such as high NIHSS score at baseline, long duration until the administration of therapy, history of atrial fibrillation and diabetes. The high NHISS score observed in many stroke patients is a predictive risk factor for symptomatic ICH after thrombolytic therapy,, which may be due to the destruction of the cerebral microvasculature in response to the severe ischemic state, resulting in increased permeability and occurrences of hemorrhagic transformation. Therefore, patients with high NHISS scores should be cautiously given thrombolytic therapy. Additionally, patients with atrial fibrillation might also be at risk for a higher rate of hemorrhagic transformation, as cardiogenic emboli are typically larger than small vascular lesions and mostly obstruct large vessels, which can cause low recanalization, and increase the risk of hemorrhage transformation. The duration from symptom onset to thrombolytic therapy was also shown to affect the rate of hemorrhage transformation. In patients with hemorrhagic transformation, the average duration from symptom onset to administration of thrombolytic therapy was longer than that in patients without hemorrhagic transformation. This may be due to more serious brain tissue damage and enlargement of the cerebral infarction area. Moreover, it may also increase reperfusion injury after blood flow recovery. Finally, the presence of diabetes, especially high blood glucose before treatment, may be a risk factor for hemorrhage transformation. There was a higher incidence of hemorrhagic transformation for stroke patients with diabetes mellitus than in patients without diabetes in the ET group. Previous research has found that if the blood glucose of ischemic stroke patients was more than 11.1 mmol/L before thrombolysis, 25% of these patients demonstrated symptomatic ICH after thrombolytic therapy, in addition to remarkably high rates of hemorrhage transformation. The reasons for these results may be that hyperglycemia accelerates anaerobic glycolysis, increasing lactic acid production and accumulation, which, in turn, causes inhibition of mitochondrial function, enzyme inactivation, and an increase in free radicals, promoting cell death in the ischemic penumbra area, resulting in infarction area enlargement and damage to the blood brain barrier.
Thrombolytic therapy was beneficial for older patients with acute ischemic stroke, especially for the patients with a lower NIHSS score (≥6 points) or who were classified as posterior circulation infarction at baseline. A higher NIHSS score at baseline, longer duration until the administration of therapy, a history of atrial fibrillation, and diabetes mellitus were risk factors of hemorrhagic transformation. Thus, thrombolytic therapy in older acute ischemic stroke patients may rarely result in severe adverse reactions and exhibit long-term efficacy, via improvement in the future quality of life. However, this therapy is most likely effective for older stroke patients with lower risk factors for bleeding and lower NIHSS scores at baseline.
Some limitations were noted in the current study. First, a single dose of rt-PA (0.9 mg/kg, maximum dose of 90 mg) was used in the study. It has been reported that rt-PA at 0.6 mg/kg for Asiatic population with acute ischemic stroke can provide benefit and reduces the risk of bleeding. Thus, the different doses of rt-PT should be considered in future studies. Second, guided by multimodal imaging, appropriate patients may be chosen to be treated with intravenous rt-PA to minimize the rate of symptomatic ICH. Some patients could benefit from treating with intravascular bridging after thrombolysis. Finally, due to small sample sizes and a single hospital involved in the study, future studies should be conducted with large samples of patients, at multiple locations.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3]