Progressive ischemic stroke (PIS) is a therapeutic challenge in clinical practice. The present retrospective study aimed to investigate the safety and effectiveness of eptifibatide in the treatment of PIS. The present study enrolled patients with PIS admitted to Xiangtan Central Hospital (Xiangtan, China) between March 2020 and March 2021 with National Institutes of Health Stroke Scale (NIHSS) progression scores of ≥2 points during the initial 72 h. Patients were then divided into two groups according to their different anti-platelet treatment regimens. The control group was administered anti-platelet aggregation with aspirin 100 mg/day, or aspirin 100 mg/day in combination with clopidogrel 75 mg/day, whilst eptifibatide was administered in the eptifibatide group in addition to the treatment regimen used in the control group. Changes in NIHSS scores at the time of progression and 7 days after treatment (∆NIHSS) were used to assess early neurological recovery, and there were no significant differences in ∆NIHSS and adverse reactions between the groups (P>0.05). Subgroup analysis was subsequently performed according to the type of blood vessel that was involved [large artery atherosclerosis (LAA) or small artery occlusion (SAO)]. For the SAO subgroup, the ∆NIHSS in the eptifibatide group was significantly superior to that of the control group (P=0.008), while for the LAA subgroup, there were no significant differences in ∆NIHSS between groups (P=0.334). The present retrospective study found that patients with PIS tolerated eptifibatide treatment well. Eptifibatide exerted different effects on patients with acute PIS involving different types of blood vessels compared with oral antiplatelet drugs. In addition, application of eptifibatide may lead to faster and earlier recovery in patients with SAO, but not in those with LAA. Low-dose eptifibatide is a safe and effective treatment option for patients with PIS caused by SAO.
The deterioration of neurological deficits is a frequent complication in acute stroke (
Patients with PIS have been extensively treated using high-dose heparin (
It has been previously shown that platelet GP IIb/IIIa receptor inhibitors could be used for treating thrombosis mediated by activated platelets (
The present report aimed to provide evidence regarding the safety and validity of a specific low-dose eptifibatide antiplatelet strategy for the treatment of PIS. In addition, another aim of the present study was to test whether the efficacy of eptifibatide in patients with PIS is related to vascular classification.
A total of 74 patients [mean age, 64.3±11.4 years; 53 males (71.6%)] with clinically confirmed PIS were enrolled in Xiangtan Central Hospital (Xiangtan, China) between March 2020 and March 2021. PIS was diagnosed as the condition worsening by ≥2 points according to the NIHSS within 72 h after stroke onset (
Patients were divided into the eptifibatide group (n=32) and the control group (n=42) according to the different treatment regimens they received. For the eptifibatide group, eptifibatide was given to patients as a bolus injection at a loading dose of 135 µg/kg at the time of stroke progression, followed by a maintenance dose of 0.75 µg/kg/min for 48 h. In addition, oral antiplatelet agents were also given 4 h before eptifibatide administration was stopped. Patients in the control group received oral antiplatelet medication. For the specific oral antiplatelet drug regimens, patients with mild ischemic stroke (NIHSS score=3) were given dual-antiplatelet medication (aspirin 100 mg/day + clopidogrel hydrochloride 75 mg/day) for 21 days (
The present study was approved by the Xiangtan Central Hospital ethics committee (Xiangtan, China). All patients signed informed consent and all data were anonymized.
The patients' demographic data (age and sex), lesion location, hypertension, diabetes, hypercholesterinaemia, current smoking habit, drinking history, coronary heart disease, hyperhomocysteinemia, classification for ischemic stroke based on the Trial of ORG 10172(
Categorical data are shown as numbers and percentages (%), whereas continuous data are shown as the means ± standard deviation or median with interquartile range (IQR). The continuous and categorical variables were compared using a two-tailed independent samples t-test or Mann-Whitney U test and the χ2 test or Fisher's exact test, respectively. SPSS version 26.0 software (IBM Corp.) was used for analyses. P<0.05 was considered to indicate a statistically significant difference.
The present retrospective study enrolled 74 participants, all patients received routine basic treatment, including routine nursing, oxygen inhalation, management of blood pressure and blood sugar, intensive lipid lowering, maintenance of water electrolyte balance and rehabilitation treatment. Among them, 32 patients received eptifibatide whereas 42 patients did not. At baseline, the mean age in the eptifibatide group was 64.0±2.2 years, where 23 (71.9%) of the patients were male. The mean age and number of male patients in the control group was 65.7±1.9 years and 30 (71.4%), respectively (
There were 30 patients in the SAO subgroup, 11 patients were treated with eptifibatide whereas 19 patients were not. At baseline, in the eptifibatide group, the mean age was 64.1±15.7 years and 9 (81.8%) of the patients were male, whereas in the control group the mean age was 63.0±12.8 with 12 (63.2%) male patients (
There were 44 patients in the LAA subgroup. In total, 21 patients were treated with eptifibatide whereas 23 patients were not. At baseline, in the eptifibatide group, the mean age was 63.9±10.9 years and 14 (66.7%) of the patients were male, whereas in the control group the mean age was 68.0±11.4 years with 18 (78.3%) male patients (
The selection of the eptifibatide dosage for the present study was based on limited evidence (
In the present study, ∆NIHSS in the eptifibatide group was not significantly different compared with that in the control group. Further subgroup analysis revealed that in the eptifibatide group, the ∆NIHSS was significantly higher compared with that in the control group in patients with SAO, but not in patients with LAA. This suggests that treatment with eptifibatide could promote the early recovery of patients with PIS, specifically with SAO. Compared with previous studies using eptifibatide in patients with PIS, the present study established the control group as a reference and subgroup analyses were conducted according to different blood vessel types involved. The establishment of a control group can exclude other factors except the anti-platelet aggregation program. Subgroup analyses based on vascular type further helped to identify the population that can benefit the most from this treatment. The present study showed that eptifibatide may exert different effects on acute PIS caused by different types of vessels, where it appeared to significantly improve the early neurological deficits in patients with SAO.
Unlike SAO, early efficacy of eptifibatide in LAA could not be found in the present study and the reason for this remains unclear. SAO-associated stroke is known to be caused by small arterial hyalinosis, endothelial dysfunction and/or intracranial perforator atherosclerosis (
In the present retrospective study of 74 patients with PIS, the rates of complications, including ecchymosis, gastrointestinal bleeding and asymptomatic intracranial haemorrhage, did not differ between the eptifibatide and control group. In addition, no symptomatic intracranial haemorrhage occurred in either group. This suggests that the patients who received eptifibatide tolerated this drug well, consistent with a previous study (
There are several limitations in the present study. The possibility of selection bias cannot be excluded, since eptifibatide therapy was provided to the patients based on their preferences. Additionally, the sample size is relatively small, and the present study was a single-centre study in China. Due to the relatively high cost of eptifibatide, only a small proportion of individuals with PIS could afford this medication. With the reform of the national medical insurance policy, non-cerebral vascular interventional treatment using eptifibatide has become increasingly difficult. This has prevented the increase in sample size. In addition, methodological biases, such as the heterogeneity of individuals and potential drug interactions, may influence the efficacy of eptifibatide. Due to the difficulty in obtaining valid post-discharge assessments, long-term follow-up analysis was not performed in the present study.
In conclusion, the present study showed that eptifibatide treatment was well tolerated in patients with PIS. Furthermore, compared with oral antiplatelet regimen alone, adding eptifibatide promoted early recovery in patients with SAO but not in patients with LAA. Due to the limitations of the retrospective study design itself, more multi-center, randomized controlled trials are needed in the future to study the effect of eptifibatide on progressive stroke.
Not applicable.
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
LL and JL designed the study. YD, ZL, YY and WZ collected the data. LL and JL confirm the authenticity of all the raw data. LL and YD analysed the data, and ZL, JL, YY and WZ helped perform the analysis, with constructive discussions. LL and JL wrote the manuscript. All authors have read and approved the final manuscript.
The studies involving human participants were reviewed and approved by the Ethics Committee of Xiangtan Central Hospital (Xiangtan, China). All participants in this study provided written informed consent for the use of their samples and publication of their data.
Not applicable.
The authors declare that they have no competing interests.
Representative CT and MRI images of two patients enrolled into the present study. A 64-year-old patient in the eptifibatide group. (A) Head CT at 13 h after progressive ischemic stroke onset (eptifibatide was administered at 17 h after onset). Head MRI (B) T1 and (C) T2 sequences on day 4 after onset showing patchy haemorrhagic areas (arrow). Head routine CT scans of a 70-year-old man in the control group on (D) day 2 and (E) day 5 after onset, with punctate haemorrhagic areas (arrow).
Baseline clinical characteristics and clinical course of patients.
Characteristic | Eptifibatide group (n=32) | Control group (n=42) | P-value |
---|---|---|---|
Age, years |
64.0±2.2 | 65.7±1.9 | 0.549 |
Sex, n (%) | |||
Male | 23 (71.9) | 30 (71.4) | 0.996 |
Female | 9 (28.1) | 12 (28.6) | |
Lesion location, n (%) | 0.877 | ||
Brainstem/cerebellum | 13 (40.6) | 13 (31.0) | |
Basal ganglia | 6 (18.8) | 10 (23.8) | |
Cortical and subcortical of MCA | 9 (28.1) | 11 (26.2) | |
Cortical and subcortical of ACA | 1 (3.1) | 3 (7.1) | |
Cortical and subcortical of PCA | 3 (9.4) | 5 (11.9) | |
Involved vessel, n (%) | |||
Small artery occlusion | 11 (34.4) | 19 (45.2) | 0.346 |
Large artery atherosclerosis | 21 (65.6) | 23 (54.8) | |
Risk factors, n (%) | |||
Hypertension | 26 (81.3) | 33 (78.6) | 0.776 |
Diabetes mellitus | 8 (25.0) | 16 (38.1) | 0.233 |
Hypercholesterinemia | 13 (40.6) | 22 (52.4) | 0.316 |
Current smoking | 9 (28.1) | 10 (23.8) | 0.674 |
Drinking | 9 (28.1) | 6 (14.3) | 0.142 |
Coronary heart disease | 8 (25.0) | 12 (28.6) | 0.732 |
Hyperhomocysteinemia | 3 (9.4) | 7 (16.7) | 0.572 |
Family history of stroke | 2 (6.3) | 4 (9.5) | 0.693 |
Antiplatelet regimen, n (%) | 0.715 | ||
Dual antiplatelet 21 days | 5 (15.6) | 4 (9.5) | |
Dual antiplatelet 90 days | 10 (31.3) | 15 (35.7) | |
Monoclonal antiplatelet | 17 (53.1) | 23 (54.8) | |
Clinical сouгse, points |
|||
NIHSS on admission | 3.0 (1.0-5.8) | 3.0 (1.8-5.0) | 0.821 |
NIHSS at progression | 7.5 (4.0-11.8) | 6.0 (5.0-9.0) | 0.588 |
∆NIHSS improvement | 2.0 (0.3-4.0) | 1.5 (0.0-2.0) | 0.053 |
NIHSS 7 days after treatment | 4 (2.0-10.0) | 5.0 (3.0-7.5) | 0.425 |
Complications, n (%) | |||
Ecchymosis | 2 (6.3) | 2 (4.8) | 1.000 |
Asymptomatic cerebral haemorrhage | 1 (3.1) | 1 (2.4) | 1.000 |
Gastrointestinal haemorrhage | 2 (6.3) | 3 (7.1) | 1.000 |
aMean ± standard deviation.
bMedian (interquartile range). Student's unpaired t-test was used for continuous variables, whereas the non-parametric Mann-Whitney U test was used when the data did not conform to a normal distribution or if the variance was uneven. χ2 or Fisher's exact test was used for categorical variables. MCA, middle cerebral artery; ACA, anterior cerebral artery; PCA, posterior cerebral artery; NIHSS, National Institutes of Health Stroke Scale; ∆NIHSS improvement, NIHSS at progression compared with 7 days after treatment; dual antiplatelet, aspirin 100 mg/day combined with clopidogrel hydrochloride 75 mg/day; monoclonal antiplatelet, aspirin 100 mg/day.
Subgroup analysis of patients with small artery occlusion.
Characteristic | Eptifibatide group (n=11) | Control group (n=19) | P-value |
---|---|---|---|
Age, years |
64.1±15.7 | 63.0±12.8 | 0.830 |
Sex, n (%) | 0.508 | ||
Male | 9 (81.8) | 12 (63.2) | |
Female | 2 (18.2) | 7 (36.8) | |
Lesion location, n (%) | 0.444 | ||
Brainstem/cerebellum | 4 (36.4) | 8 (42.1) | |
Basal ganglia | 4 (36.4) | 6 (31.6) | |
Cortical and Subcortical of MCA | 3 (27.3) | 2 (10.5) | |
Cortical and Subcortical of ACA | 0 (0.0) | 3 (15.8) | |
Cortical and Subcortical of PCA | 0 (0.0) | 0 (0.0) | |
Risk factors, n (%) | |||
Hypertension | 9 (81.8) | 15 (78.9) | 1.000 |
Diabetes mellitus | 2 (18.2) | 7 (36.8) | 0.508 |
Hypercholesterinaemia | 4 (36.4) | 12 (63.2) | 0.156 |
Current smoking | 2 (18.2) | 5 (26.3) | 0.952 |
Drinking | 4 (36.4) | 3 (15.8) | 0.403 |
Coronary heart disease | 2 (18.2) | 4 (21.1) | 1.000 |
Hyperhomocysteinemia | 0 (0.0) | 2 (10.5) | 0.520 |
Family history of stroke | 1 (9.1) | 0 (0.0) | 0.367 |
Antiplatelet regimen, n (%) | 0.520 | ||
Dual antiplatelet 21 days | 0 (0.0) | 2 (8.7) | |
Dual antiplatelet 90 days | 0 (0.0) | 0 (0.0) | |
Monoclonal antiplatelet | 11 (100.0) | 17 (89.5) | |
Clinical сouгse, points |
|||
NIHSS on admission | 3.0 (2.0-7.0) | 2.0 (1.0-3.0) | 0.094 |
NIHSS at progression | 7.0 (5.0-10.0) | 6.0 (5.0-7.0) | 0.171 |
∆NIHSS improvement | 4.0 (2.0-5.0) | 2.0 (1.0-3.0) | 0.008 |
NIHSS at 7 days after treatment | 2.0 (2.0-5.0) | 3.0 (2.0-5.0) | 0.641 |
aMean ± standard deviation.
bMedian (interquartile range). Student's unpaired t-test was used for continuous variables, whereas the non-parametric Mann-Whitney U test was used when the data did not conform to a normal distribution or the variance was uneven. χ2 or Fisher's exact test was used for categorical variables. MCA, middle cerebral artery; ACA, anterior cerebral artery; PCA, posterior cerebral artery; NIHSS, National Institutes of Health Stroke Scale; ∆NIHSS improvement, NIHSS at progression compared with 7 days after treatment; dual antiplatelet, aspirin 100 mg/day combined with clopidogrel hydrochloride 75 mg/day; monoclonal antiplatelet, aspirin 100 mg/day.
Subgroup analysis of patients with large arteries atherosclerosis.
Characteristics | Eptifibatide group (n=21) | Control group (n=23) | P-value |
---|---|---|---|
Age, years |
63.9±10.9 | 68.0±11.4 | 0.231 |
Sex, n (%) | 0.388 | ||
Male | 14 (66.7) | 18 (78.3) | |
Female | 7 (33.3) | 5 (21.7) | |
Lesion location, n (%) | 0.481 | ||
Brainstem/cerebellum | 9 (42.9) | 5 (21.7) | |
Basal ganglia | 2 (9.5) | 4 (17.4) | |
Cortical and Subcortical of MCA | 6 (28.6) | 9 (39.1) | |
Cortical and Subcortical of ACA | 1 (4.8) | 0 (0.0) | |
Cortical and Subcortical of PCA | 3 (14.3) | 5 (21.7) | |
Risk factors, n (%) | |||
Hypertension | 17 (81.0) | 18 (78.3) | 1.000 |
Diabetes mellitus | 6 (28.6) | 9 (39.1) | 0.460 |
Hypercholesterinaemia | 9 (42.9) | 10 (43.5) | 0.967 |
Current Smoking | 7 (33.3) | 5 (21.7) | 0.388 |
Drinking | 5 (23.8) | 3 (13.0) | 0.594 |
Coronary heart disease | 6 (28.6) | 8 (34.8) | 0.659 |
Hyperhomocysteinemia | 3 (14.3) | 5 (21.7) | 0.803 |
Family history of stroke | 1 (4.8) | 4 (17.4) | 0.348 |
Antiplatelet regimen, n (%) | 0.342 | ||
Dual antiplatelet 21 days | 5 (23.8) | 2 (8.7) | |
Dual antiplatelet 90 days | 10 (47.6) | 15 (65.2) | |
Monoclonal antiplatelets | 6 (28.6) | 6 (26.1) | |
Clinical сouгse, points |
|||
NIHSS on admission | 2.0 (1.0-5.0) | 4.0 (2.0-8.0) | 0.155 |
NIHSS at progression | 8.0 (3.5-14.0) | 7.0 (5.0-12.0) | 0.934 |
∆NIHSS improvement | 2.0 (0.0-2.5) | 1.0 (0.0-2.0) | 0.334 |
NIHSS at 7 days after treatment | 5.0 (2.0-12.5) | 6.0 (3.0-11.0) | 0.663 |
aMean ± standard deviation.
bMedian (interquartile range). Student's unpaired t-test was used for continuous variables, whereas the non-parametric Mann-Whitney U test was used when the data did not conform to normal distribution or the variance was uneven. χ2 or Fisher's exact test was used for categorical variables. MCA, middle cerebral artery; ACA, anterior cerebral artery; PCA, posterior cerebral artery; NIHSS, National Institutes of Health Stroke Scale; ∆NIHSS improvement, NIHSS at progression compared with 7 days after treatment; dual antiplatelet, aspirin 100 mg/day combined with clopidogrel hydrochloride 75 mg/day; monoclonal antiplatelet, aspirin 100 mg/day.