|Year : 2021 | Volume
| Issue : 1 | Page : 285-290
Safety and efficacy of low-dose alteplase in the treatment of acute ischemic stroke in Egyptian patients
Wafik M El-Sheikh1, Gelan M Salim1, Khaled H Afifi1, Basma G El-Shanawany2
1 Department of Neuropsychiatry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Neuropsychiatry, El-Mataria Teaching Hospital, Cairo, Egypt
|Date of Submission||29-Aug-2019|
|Date of Decision||29-Oct-2019|
|Date of Acceptance||04-Nov-2019|
|Date of Web Publication||27-Mar-2021|
Basma G El-Shanawany
Sers El-Lian, Menoufia, 12345
Source of Support: None, Conflict of Interest: None
To evaluate the safety and efficacy of low-dose alteplase (0.6 mg/kg) in the treatment of Egyptian patients with acute ischemic stroke (AIS).
High cost and concerns associated with post-thrombolysis intracerebral hemorrhage are major obstacles that limit utilization of the standard-dose alteplase (0.9 mg/kg) in AIS in Egypt.
Patients and methods
This is a nonrandomized clinical trial conducted on 40 Egyptian patients with AIS who were eligible for intravenous alteplase. Patients were thrombolysed at a dose of 0.6 mg/kg. Primary outcomes were safety expressed in the proportion of patients who developed symptomatic intracranial hemorrhage according to European Cooperative Acute Stroke Study III definition and 3-month mortality and efficacy expressed in the proportion of patients with modified Rankin Scale of 0–1 (favorable outcome) at 3 months.
The proportion of favorable outcome (efficacy analysis) was 37.5% (n = 15). No cases developed symptomatic intracranial hemorrhage in the studied sample with an overall mortality rate of 7.5% (n = 3) with one case recorded in hospital mortality (safety analysis).
Intravenous alteplase at 0.6 mg/kg within 4.5 h of stroke onset could be safe and effective in routine clinical practice as a substitute of the standard dose (0.9 mg/kg) especially in developing countries like Egypt.
Keywords: ischemic stroke, low-dose alteplase, symptomatic intracranial hemorrhage, thrombolysis
|How to cite this article:|
El-Sheikh WM, Salim GM, Afifi KH, El-Shanawany BG. Safety and efficacy of low-dose alteplase in the treatment of acute ischemic stroke in Egyptian patients. Menoufia Med J 2021;34:285-90
|How to cite this URL:|
El-Sheikh WM, Salim GM, Afifi KH, El-Shanawany BG. Safety and efficacy of low-dose alteplase in the treatment of acute ischemic stroke in Egyptian patients. Menoufia Med J [serial online] 2021 [cited 2021 Nov 27];34:285-90. Available from: http://www.mmj.eg.net/text.asp?2021/34/1/285/312045
| Introduction|| |
Stroke is the second most common cause of death and the major global cause of disability worldwide. Most of these deaths occurred in low-income and middle-income countries .
Intravenous alteplase is the only proven effective medical treatment for acute ischemic stroke (AIS) with standard dose (0.9 mg/kg) during the past 20 years within 3 h of onset .
This time window was extended in 2008 to 4.5 h after the Stroke International Stroke Thrombolysis Registry (SITS-ISTR)  and European Cooperative Acute Stroke Study (ECASS) III study .
In Japan, low-dose (0.6 mg/kg) intravenous alteplase was approved in 2006 in the Japanese Stroke-Care Guideline as it showed similar effects on improving the neurologic functions and significantly reducing the incidence of intracranial hemorrhage and cost of treatment . Also, many other observational and registry studies had been conducted in order to prove the efficacy and safety of lower doses of intravenous rt-PA in other Asian countries ,.
In Egypt, utilization of intravenous thrombolysis for AIS remains at less than 1%, which is incompatible with the high prevalence of stroke among Egyptian population. The major obstacle against its use is the high cost .
On reviewing stroke characteristics in Egypt, a study has shown that 67.1% of Egyptian patients with AIS had intracranial stenosis , which is nearly similar to stroke characteristics in Asia where intracranial stenosis was recorded as 33–50% in China, 54% in South Asians, and 56% in Koreans .
Lowering the dose of intravenous alteplase and thus lowering its economic burden will greatly increase the rate of utilization of intravenous thrombolysis in Egypt, which will subsequently result in reduction of the proportion of deaths and disability caused by stroke among Egyptian population. The aim of the current study was to evaluate if low-dose intravenous alteplase is effective and safe as a substitute of standard-dose regimen in the treatment of Egyptian patients with AIS.
| Patients and methods|| |
This study was a nonrandomized clinical trial on 40 AIS patients within 4.5 h from symptoms onset. The patients were recruited from El-Mataria Teaching Hospital and Menoufia University Hospitals during the period from November 2017 to December 2018 after approval from the Research and Ethics Committee of Faculty of Medicine, Menoufia University. Written informed consent was obtained from all participants and patients' confidentiality was assured. Patients were considered eligible for intravenous thrombolysis according to the American Heart Association and American Stroke Association guidelines . Informed written consent for alteplase was signed by patients or first-degree relatives. Data were collected from hospital records by B.G.E. and analysis of data and 3-month follow-up were performed by K.H.A. and G.M.S. All patients were subjected to complete history taking including assessment of vascular risk factors, previous treatment, time window, baseline prestroke modified Rankin Scale (mRS), and initial stroke severity using the National Institutes of Health Stroke Study (NIHSS) score. Noncontrast computed tomography (CT) brain was performed on all patients at presentation and was analyzed for the presence of intracranial hemorrhage or any abnormal findings. The Alberta Stroke Program Early CT score was used to assess early signs of ischemia . Trial of ORG 10172 in acute stroke treatment classification  and Oxfordshire community stroke project  classifications were used to clarify stroke subtypes. Nonrandomly (according to the center point of view), patients were administered a single dose of intravenous alteplase at a low dose of 0.6 mg/kg (not exceeding 60 mg). Precautions during alteplase infusion and monitoring for complications for the next 24 h were followed according to American Heart Association and American Stroke Association guidelines . Follow-up noncontrast CT brain 24 h posttreatment was assessed for intracerebral hemorrhage. NIHSS was reassessed at day 7 of admission or at discharge and in-hospital mortality was recorded. All patients were followed at 3 months from admission by a telephone call or by a face-to-face interview to assess mRS and mortality.
Safety outcome was assessed by the occurrence of symptomatic intracerebral hemorrhage (SICH) in the first 24 h posttreatment and 3-month mortality. We defined SICH according to ECASS III study definition (any hemorrhage plus a neurological deterioration of more than or equal to four points on the NIHSS baseline or from the lowest NIHSS value after baseline to 7 days or leading to death) .
Efficacy outcome was assessed by favorable outcome at 3 months (defined as mRS of 0–1).
Results were collected, tabulated, and statistically analyzed by IBM personal computer and Statistical Package for the Social Sciences (SPSS), version 22 (2013; IBM Corp., Armonk, New York, USA). Data were presented as descriptive statistics including percentage (%), mean, and SD.
| Results|| |
A total of 40 AIS Egyptian patients received intravenous alteplase at low dose (0.6 mg/kg). Demographic data and vascular risk factors of recruited patients are shown in [Table 1]. Our study sample had a mean age of 60.58 ± 14.16 with male predominance (55%). Hypertension was the most prevalent risk factor (65%) followed by diabetes mellitus (47.5%), current smoking (45%), dyslipidemia (35%), and atrial fibrillation and ischemic heart disease (both 30%). History of current warfarin anticoagulant use was noted in 10% of patients, in all of them international normalized ratio was less than 1.7 while the use of antiplatelet drugs was documented in 30%. As shown in [Table 2], the mean basal NIHSS of the studied sample was 12.58 ± 4.37 reflecting moderate stroke severity according to Hage  and Alberta Stroke Program Early CT score recorded a mean value of 5.55 ± 2.59.
|Table 1: Demographic characteristics and vascular risk factors in patients treated with low-dose intravenous alteplase|
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|Table 2: Stroke characteristics (severity and subtypes) in patients treated with low-dose intravenous alteplase|
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As shown in [Table 3], the study also showed that 90% (n = 36) of patients were thrombolysed between 3 and 4.5 h of stroke onset and only 10% (n = 4) were thrombolysed within 0–3 h. Prestroke mRS ranged from 0 to 2 with majority of patients having a prestroke mRS of 0 (86%).
|Table 3: Prestroke modified Rankin Scale, previous treatment, and time to treatment in patients treated with low-dose alteplase|
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According to Oxfordshire classification  stroke subtypes were recorded as follows: lacunar infarctions (35%), partial anterior circulation infarctions (32.5%), total anterior circulation infarctions (12.5%), and posterior circulation infarctions (20%) and according to Trial of ORG 10172 in acute stroke treatment classification  stroke subtypes were recorded as follows: lacunar stroke (45%), large artery stroke (35%), cardioembolic stroke (30%), and stroke of undetermined etiology (2.5%).
Regarding efficacy outcome, a favorable outcome (mRS score of 0–1) at 3 months was achieved in 37.5% (n = 15) of patients. Of them, 14 cases were having a prestroke mRS of 0 and one case was having a prestroke mRS of 1 [Table 4].
|Table 4: Safety and efficacy outcomes in patients treated with low-dose intravenous alteplase|
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Regarding safety outcome, no cases developed SICH in the studied sample and only one case developed asymptomatic intracranial hemorrhage with parenchymal hemorrhage type 1.
The 3-month mortality was documented as 7.5% with one case having died in hospital.
| Discussion|| |
The concept of using low-dose intravenous alteplase is applicable in Egypt in certain centers (according to the center point of view). We have presented the first results of experience in thrombolysis with low-dose alteplase in the treatment of AIS in a sample of Egyptian population. Our study documented results which are comparable to that of the reported trials of both low-dose and standard-dose intravenous alteplase regarding efficacy and safety.
In the current study, time to treatment was the most prevalent basal characteristic as 90% of patients were thrombolysed between 3 and 4.5 h of stroke onset, while only 10% were thrombolysed within 0–3 h. This result reflects that the extended time window (3–4.5 h) was a strong reason for taking the decision of low-dose alteplase in the studied sample. The rationale for that was based on the fact that increased time to treatment may be associated with increasing the risk of hemorrhagic transformation as was evidenced by Wahlgren et al.  and Hacke et al. , who approved the efficacy of standard-dose alteplase in the extended window (3–4.5 h) but with higher risk of SICH.
Wahlgren et al.  and Hacke et al.  documented that 2.2% of patients treated within 3–4.5 h of AIS onset had SICH in the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Registry (SITS-ISTR) trial and 2.4% in ECASS III trial versus 1.7% in those treated within 3 h.
Regarding efficacy outcome, favorable outcome (an mRS score of 0–1) at 3 months was achieved in 37.5% (n = 15) of patients.
This result is comparable to the result of some Asian studies who approved the efficacy of low-dose alteplase ,,.
The Japan Alteplase Clinical Trial (J-ACT)  was a prospective cohort study that evaluated 103 patients within 3 h of AIS. Of these, 37% of patients in the J-ACT had a mRS score of 0–1 at 3 months. The difference is that the patients were thrombolysed within 0–3 h of stroke onset unlike in our study (within 4.5 h).
Also, the Japan post-Marketing Alteplase Registration Study  enrolled 7492 patients in 942 centers to evaluate the safety and efficacy of 0.6 mg/kg intravenous alteplase for Japanese patients. The study demonstrated 33% favorable outcome. The different value can be explained by the different sample size, racial difference, and different basal characteristics (higher mean age, higher basal NIHSS and higher atrial fibrillation, and cardioembolic patients).
J-ACT2  enrolled 58 ischemic stroke patients within 3 h of onset who had MRA-documented middle cerebral artery occlusion. The patients were thrombolysed at a dose of 0.6 mg/kg. A favorable outcome (mRS score of 0–1 at 3 months after onset) was achieved in 46.6% of patients. The different higher value can be explained by that time to treatment was within 0–3 h in comparison to extended time to treatment (3–4.5 h) in our study and also, the study was confined only to middle cerebral artery stroke.
The proportion of favorable outcome is also comparable to that of the reported trials of 0.9 mg/kg ,.
In the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study part 2 , which compared between patients who received intravenous alteplase at a dose of 0.9 mg/kg within 3 h and those who received placebo treatment, favorable outcome at 3 months was achieved in 39% of patients.
Also, in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) , which compared between patients who received intravenous alteplase at a dose of 0.9 mg/kg within 3 h and those who received placebo treatment, the proportion of favorable outcome at 3 months was 39%.
On the other hand, there are other studies that compared low-dose alteplase with standard-dose alteplase and failed to approve its noninferiority to standard dose with respect to favorable outcome at 3 months ,.
This could be explained by racial differences, different basal characteristics of the patients recruited, and by the different sample size.
In Zhou et al. , the study compared between low-dose and standard-dose intravenous rt-PA in Chinese patients. In the 0.9 mg/kg group (n = 51), 51.1% had favorable outcome at 3 months versus 35% in the 0.6–0.7 mg/kg group (n = 23).
Sharma et al. , in a similar study in Singapore demonstrated that there was a significant difference in the outcome at 3 months 35% (n = 48) in the low-dose group versus 58.5% (n = 82) in the standard dose group.
In the current study, no cases developed symptomatic intracranial hemorrhage.
This result goes with the result of J-ACT2 , which documented also no cases of SICH and also used ECASS III definition for SICH as the current study did.
The Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) , a reported trial of 0.9 mg/kg in which SICH according to ECASS definition was 4.6%.
These results reflects that lower doses of alteplase can be associated with a lower risk of SICH.
Also, the comparative study of Anderson et al.  documented that less major SICH occurred in the low-dose group than the standard-dose group (1.0 vs. 2.1%). The difference is that they used SITS-MOST (Safe Implementation of Treatments in Stroke International Stroke Thrombolysis – Monitoring Study) definition for SICH.
Nguyen et al.  in their comparative study between low-dose and standard-dose alteplase in Vietnam also documented no difference in the occurrence of SICH (per ECASS definition) in the standard-dose group compared with the low-dose group (5 vs. 2%).
The previous data could confirm that low-dose alteplase is comparable to standard-dose strategy with respect to risk of SICH and even may be less risky.
Regarding 3-month mortality, the current study documented three (7.5%) cases. One of them died in hospital with massive cerebral infarction that resulted in malignant edema and conization at day 6 of admission and the other two cases died after hospital discharge, one with complicated aspiration pneumonia and the other with sudden cardiac arrest.
In The Japan post-Marketing Alteplase Registration Study  which used a dose of 0.6 mg/kg, the overall mortality rate was 13% while in the ECASS III , which studied the efficacy and safety of the standard dose (0.9 mg/kg) within 4.5 h of stroke onset mortality was documented as 7.7% and in the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study part 2 , mortality was recorded as 17%.
These results suggest that low-dose alteplase is comparable to standard-dose regimen with respect to mortality and this is what was reflected in most studies comparing low dose and standard dose intravenous alteplase which showed no significant difference between the two doses.
Chao et al. , in a study comparing different doses of intravenous rt-PA documented a 3-month mortality of 8% in both 0.6 and 0.9 groups.
Sharma et al.  in Singapore in a study comparing the two doses also documented that there was no significant difference in the 3-month mortality between low and standard doses (10 vs. 13%).
Anderson et al.  in a study comparing between the two doses demonstrated also that mortality at 90 days did not differ significantly between the two groups (8.5 and 10.3%).
Kim et al. , in a study comparing between the low-dose and standard-dose intravenous rt-PA in Korea found that there was no significant difference between low and standard doses (13 vs. 14%).
Our study design has limitations. First, the small sample size was the main obstacle in the current study. Second, the alteplase dose selection was not randomized. Third, the stroke team conducting outcome assessments could not be blinded to treatment, raising the possibility of observer bias.
| Conclusion|| |
Low-dose (0.6 mg/kg) intravenous alteplase could be effective and safe in the treatment of Egyptian patients with AIS. However, further future studies are needed to confirm these results.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]