Comparative study on the efficacy and safety of alteplase and urokinase in the treatment of acute cerebral infarction

Abstract

BACKGROUND:

Acute cerebral infarction (ACI) is a common cerebrovascular disease in clinical practice.

OBJECTIVE:

The present study aims to investigate the efficacy and safety of alteplase and urokinase in treating ACI.

METHODS:

A total of 96 patients with ACI, who were treated with alteplase and urokinase, were selected as the main subjects. Among these patients, 45 patients with ultra-early acute cerebral infarction, who received intravenous thrombolysis with RT-PA (alteplase), were included in the treatment group, while 51 patients with acute cerebral infarction, who were treated with urokinase in the same time period, were included in the control group.

RESULTS:

The National Institute of Health Stroke Scale (NIHSS) scores were significantly lower in the treatment group and control group ( $P<$ 0.05) at two hours, seven days and 14 days after thrombolysis, when compared to those before thrombolysis. The bleeding rate was significantly lower in the control group, when compared to the treatment group ( $P<$ 0.05).

CONCLUSION:

The intravenous thrombolysis with urokinase or alteplase in the ultra-early stage of acute cerebral infarction can reduce the neurological injury symptoms and effectively improve the prognosis of patients with stroke. Urokinase is lower in risk of bleeding, but better in safety, when compared to alteplase.

Keywords

Alteplase urokinase thrombolytic therapy cerebral infarction stroke

1. Introduction

Acute cerebral infarction (ACI) is a common cerebrovascular disease in clinical practice, which has a high incidence rate, disability rate and mortality rate, and is more common in middle-age and elderly people [1, 2, 3]. Since most cerebral infarction diseases cause cerebral blood flow circulation disorder due to the formation of thrombus in the arterial blood vessels, the recanalization of blocked blood vessels, the improvement of cerebral perfusion, and saving the penumbra have been recognized as the first goal in the treatment of early ischemic stroke. The present ultra-early intravenous thrombolysis is the most effective method [4, 5, 6].

The most common drugs for early intravenous thrombolysis include alteplase and urokinase. At present, few comparative studies have been conducted on the efficacy of alteplase and urokinase in treating acute cerebral infarction. Therefore, the present study aims to investigate the efficacy and safety of two intravenous thrombolysis drugs, alteplase and urokinase, for treating acute cerebral infarction.

2. Methods

2.1 Case selection

In the present study, a total of 45 patients with acute ischemic stroke, who were treated with alteplase from December 2016 to July 2018 in our hospital, were included in the treatment group, while 51 patients with the same conditions, who were treated with urokinase in the same time period, were included in the control group. The present study was approved by the Ethics Committee of our hospital, and all patients provided written informed consent.

2.2 Inclusion and exclusion criteria

Inclusion criteria: (1) patients who have a clear diagnosis of acute ischemic stroke; (2) patients within 18–80 years old; (3) patients who had an incidence within 4.5 hours; (4) patients with a cranial computed tomography (CT) scan showing no intracranial hemorrhage or low density shadows, and none of the images revealed any signs of early cerebral infarction; (5) patients with no any clear signs of nervous system involvement; (6) patients with NIHSS scores within 7–22; (7) patients who had clear consciousness or experienced drowsiness; (8) patients who provided a signed informed consent.

Exclusion criteria: (1) patients with a past history of intracranial hemorrhage; (2) patients who had gastrointestinal or urinary bleeding in the past three weeks, or arterial puncture has been conducted in the site where it is not easy for hemostasis by compression in the past one week; (3) patients who had a history of cerebral infarction and myocardial infarction, and major head trauma in the past three months; (4) patients who suffered from the intracranial tumors, arteriovenous malformations and aneurysms; (5) patients who will undergo intracranial or vertebral canal surgery in the near future; (6) patients with an acute bleeding tendency, including a total platelet count of less than 100 $\times$ 10 ${}^{9}$ L; (7) patients with a blood glucose of $<$ 2.7 mmol/L; (8) patients who received an oral anticoagulant, INR $>$ 1.7 or PT $>$ 15 seconds; (9) patients with a systolic pressure of $>$ 180 mmHg or diastolic pressure of 100 mmHg; (10) patients with incomplete clinical data.

2.3 Therapeutic methods

In the treatment group, the RT-PA dose was 0.6–0.9 mg/kg (the maximum dose was 90 mg), and 10% of the total dose was intravenously injected within one minute. The remaining 90% of the total dose was added to the solution, and intravenously injected by infusion pump, which lasted for one hour. The CT image of the head was reviewed to exclude intracranial hemorrhage at 24 hours after thrombolysis. Aspirin of 100 mg/d was orally taken. The routine improvement of circulation and brain protection treatment were given. In the control group, patients received an intravenous drip of urokinase of 1,000,000–1,500,000 U, which lasted for 30 minutes. The CT image of the head was reviewed to exclude intracranial hemorrhage at 24 hours after thrombolysis. Aspirin of 100 mg/d was orally taken. The remaining treatments were the same as that of the treatment group. The drug information used in the present study is as follows: alteplase (Boehringer Ingellheim Pharama GmbH & Co. KG, Germany; Import Commodity Registration Certificate nos S20160054 and S20160055) and urokinase (Nanjing Nanda Pharmaceutical Co., Ltd., China; Approval no. GYZ Zi H10920040).

2.4 Efficacy evaluation standard

The neurological impairment was evaluated using the NIHSS scale at admission, at two hours and seven days after thrombolysis, and at discharge (14 days), respectively. The modified Rankin scale (mRs) was used to score at discharge (14 days), in which 0–2 points were recorded as good and $>$ 2 points were recorded as poor. Patients who experienced cerebral hemorrhage during the treatment, or died were separately recorded.

2.5 Statistical analysis

In the present study, SPSS 22.0 statistical software was used to process the data. The measurement data were expressed as mean $\pm$ standard deviation (x $\pm$ SD). Enumeration data were expressed in percentage (%). $W$ -test was used for the normality test. $F$ -test was used for the homogeneity test of variances. $T$ -test was used for comparisons between two groups. Nonparametric test was used to compare the mean of multiple samples that did not obey the normal distribution, or obeyed the normal distribution, but the variance was uneven. Counting data were analyzed using chi-square test. $P<$ 0.05 was considered statistically significant.

3. Results

3.1 General data

In the present study, 45 patients with acute cerebral infarction, who were treated with RT-PA were included in the treatment group, while 51 patients with acute cerebral infarction, who were treated with urokinase, were included in the control group. There were 27 male and 18 female patients in the treatment group, and their age ranged between 40–80 years, with a median age of 62.97 $\pm$ 10.69 years. The course of disease was 1–44 days, with a median course of disease of 15.37 $\pm$ 8.35 days. There were 26 male and 25 female patients in the control group, and their age ranged between 42–79 years, with a median age of 61.84 $\pm$ 9.57 years. The course of disease was 2–82 days, with a median course of disease of 16.72 $\pm$ 11.51 days.

3.2 Efficacy comparison between the two patient groups

The difference in neurological function scores was not statistically significant between the two groups at two hours, seven days and 14 days (discharge) after thrombolysis. However, the neurological function scores after thrombolysis were better than those before thrombolysis in both groups, and the different was statistically significant ( $P<$ 0.05). Both RT-PA and urokinase could significantly improve brain function in stroke patients, but the difference was not statistically significant between these two groups (Tables 1 and 2).

Table 1
The NIHSIS score of the two groups in different periods

	Before thrombolysis	Two hours after thrombolysis	Seven days after thrombolysis	Fourteen days after thrombolysis
Treatment group	11.46 $\pm$ 3.17	9.13 $\pm$ 4.21	7.09 $\pm$ 4.60	6.97 $\pm$ 4.51 ${}^{\text{b}}$
Control group	11.13 $\pm$ 3.13 ${}^{\text{a}}$	8.94 $\pm$ 4.51	7.24 $\pm$ 4.92	6.72 $\pm$ 4.99 ${}^{\text{c}}$

${}^{\text{a}}$ Compared with the treatment group, $t=$ 0.512, $P=$ 0.512 $>$ 0.05; ${}^{\text{b}}$ compared with before thrombolysis, $t=$ 5.464, $P=$ 000 $<$ 0.05; ${}^{\text{c}}$ compared with before thrombolysis, $t=$ 5.347, $P=$ 0.000 $<$ 0.05.

Table 2

The effective rate of thrombolysis in the two groups

	$n$	Number of effective cases	Effective rate (%)
Treatment group	45	16	35.56 ${}^{\text{a}}$
Control group	51	16	31.35 ${}^{\text{a}}$
X ${}^{2}$			0.188
$P$			0.664

${}^{\text{a}}$ Compare with the treatment group, X ${}^{2}=$ 0.188, $P=$ 0.664 $>$ 0.05.

Table 3

Comparison on the bleeding rate and mortality in the two groups

	Bleeding rate	Mortality
Treatment group	2.23%	6.67%
Control group	1.96% ${}^{\text{a}}$	1.96% ${}^{\text{c}}$
X ${}^{2}$	0.00	0.409
$P$	1.000	0.522

${}^{\text{a}}$ Compared with the treatment group, $P=$ 1.000 $>$ 0.05; ${}^{\text{c}}$ compared with the treatment group, $P=$ 0.042 $<$ 0.05.

3.3 Comparison on occurrence rate of adverse reaction in the two groups

The bleeding rate of patients in the treatment group was 6.67% (3/45), which was higher than the control group (1.96%, 1/51), and the difference was statistically significant ( $P<$ 0.05). The mortality of patients in the treatment group was 2.23% (1/45), which was higher than the control group (1.96%, 1/51), but the difference was not statistically significant ( $P>$ 0.05, Table 3).

4. Discussion and conclusion

The results of the present study show that the NIHSS scores of patients in the treatment group and control group significantly decreased at two hours, seven days and 14 days after thrombolysis, when compared to those before thrombolysis, and the difference was statistically significant. However, there is no significant difference in NIHSS score, good prognosis rate and mortality between the two groups before and after thrombolysis. The bleeding rate of patients in the control group was significantly lower than that of patients in the treatment group, and the difference was statistically significant.

Cerebrovascular diseases cause a serious threat to the health and life of middle-age and elderly people, and the incidence of stroke is particularly high. Acute ischemic stroke accounts for 60%–80% of total stroke incidences, which is the highest type of stroke. The most common type of ischemic stroke is the formation of cerebral thrombus [5]. The key treatment for this disease is to re-channel the blocked intracranial blood vessels as soon as possible, and quickly restore the cerebral blood flow, in order to reduce the further ischemic necrosis of brain tissue. Ultra-early thrombolysis is the only effective way to reopen occlusive vessels and save the ischemic penumbra [7, 8]. The theory of ischemic penumbra is the theoretical basis of thrombolysis [9]. A large number of clinical studies have shown that the rapid rescue of ischemic penumbra perfusion, and the awakening of dormant and semi-dormant neurons may improve neural function. At present, urokinase and alteplase are the main drugs for ultra-early thrombolysis in acute cerebral infarction. The results reported by different scholars on these two drugs are not consistent [10, 11]. The search for safe and efficient thrombolytic drugs has been the focus of the majority of scholars.

In the present study, a retrospective analysis was carried out in 96 patients with acute cerebral infarction, who were treated in our hospital using urokinase and alteplase. We found that neurological impairment improved in both the treatment group and control group, and the difference was statistically significant before and after treatment. However, the difference in level of neurological impairment was not statistically significant between these two groups. This suggests that both alteplase and urokinase thrombolysis could reduce neurological impairment in the treatment of acute cerebral infarction, and the difference in the degree of neurological improvement is not significant within two hours, seven days and 14 days of treatment. The overall effective rate was 35.56% in the treatment group and 31.35% in the control group. However, the difference in effective rate was not statistically significant ( $P>$ 0.05) between the two groups. This suggests that both kinds of thrombolysis were effective, and that there was no difference. Since the purpose of thrombolytic drugs is to re-canalize occlusive blood vessels, the mechanism of action of these two drugs was different [12, 13, 14]. Urokinase is a human urine extract, which has no antigenicity. This can be directly applied to the endogenous fibrinolytic system, driving plasminogen to convert to plasmin. The recanalization of occlusive blood vessels would be achieved by rapidly dissolving the fresh thrombus and recanalizing the occlusive blood vessels. However, the drug has a poor effect in dissolving old thrombus [15, 16, 17, 18, 19]. RT-PA belongs to the second generation of thrombolysis drugs, which is specific, selective and targeted on plasminogen elements in the thrombus. However, this has little effect on plasminogen in the normal blood circulation. Therefore, there would be no obvious systemic fibrinolysis. The incidence of complications varies between these two experimental groups due to the different thrombolytic mechanism. In the present study, the mortality rate was 2.23% in the treatment group and 1.96% in the control group, but the difference was not statistically significant. Furthermore, the bleeding rate was 6.67% in the treatment group and 1.91% in the control group, but the difference was statistically significant. This suggests that the bleeding rate was higher in the alteplase group. By considering and analyzing the short half-life of RT-PA, continuous administration is needed to maintain the plasma concentration in vivo. However, the high-dose and long-term use of RT-PA at once would increase the risk of bleeding, which is consistent with the views of Carpenter et al. [20]. However, patients in both the treatment group and control group did not have a higher proportion of bleeding or death. Thus, these are still more ideal.

There were still shortcomings in the present study. First, the present study was an observational study, and not a randomized controlled trial, and did not set blinding. Therefore, there is still a certain risk of bias. Second, the present study is a single-center clinical study with a small sample size. Thus, there is a need to carry out further multicenter clinical studies with a larger sample size. Finally, the clinical follow-up time of the present study was short. Hence, long-term clinical observation studies are needed.

Intravenous thrombolysis with urokinase or alteplase in the ultra-early stage of acute cerebral infarction can reduce neurological injury symptoms and effectively improve the prognosis of patients with stroke. Urokinase has a lower risk of bleeding and better safety, when compared to alteplase.

Footnotes

Conflict of interest

None of the authors have any personal, financial, commercial, or academic conflicts of interest to report.

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Comparative study on the efficacy and safety of alteplase and urokinase in the treatment of acute cerebral infarction

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Methods

2.1 Case selection

2.2 Inclusion and exclusion criteria

2.3 Therapeutic methods

2.4 Efficacy evaluation standard

2.5 Statistical analysis

3. Results

3.1 General data

3.2 Efficacy comparison between the two patient groups

Table 1 The NIHSIS score of the two groups in different periods

4. Discussion and conclusion

Footnotes

Conflict of interest

References

Table 1
The NIHSIS score of the two groups in different periods