Dual Antiplatelet Therapy after Intravenous Thrombolysis for Acute Minor Ischemic Stroke

Guangjian Zhaoa Fanzhen Linb Ziran Wanga Xiaolin Shaoc Yanxue Gonga Shirui Zhanga Yansen Cuia Daiqun Yanga Hongyan Leia Zhongrong Chenga Liquan Wanga Dongdong Guoa Qinghua Zhanga
a Department of Neurology, Linyi People’s Hospital, Linyi, China; b General Medicine, Linyi People’s Hospital, Linyi, China; c Diagnostics Teaching and Research Office, Shandong Medical College, Linyi, China

 

Keywords

Dual antiplatelet therapy · Intravenous thrombolysis · Acute minor ischemic stroke · Safety
Abstract
Objective: To verify the efficacy and safety of dual antiplate- let therapy after intravenous thrombolysis for acute minor ischemic stroke (AMIS). Methods: AMIS patients who re- ceived recombinant tissue plasminogen activator (rt-PA) in- travenous thrombolysis from January to October 2018 were retrospectively analyzed and divided into the aspirin (ASP) and ASP + clopidogrel (ASP-CLO) groups based on the type of antiplatelet therapy to compare the rates of good clinical outcome, symptomatic intracranial hemorrhage (SICH) after thrombolysis, and mortality in 90 days. Results: A total of 207 patients were included (group ASP, 105 patients; group ASP-CLO, 102 patients). There was no significant difference in the baseline clinical data between the 2 groups. The 90-day modified Rankin scale scores (66.7 vs. 82.4%, p = 0.009) showed a statistically significant difference, but SICH (1.0 vs. 1.0%, p = 0.917) and 90-day mortality (1.9 vs. 1.0%, p = 0.585) showed no significant difference between the 2 groups. Conclusions: Short-term (21 days) dual antiplatelet

therapy after rt-PA intravenous thrombolysis for AMIS can improve the prognosis, reduce the risk of stroke recurrence, without increasing the risk of bleeding and mortality.
© 2020 S. Karger AG, Basel

 

Introduction

Stroke impairs human health and has high morbidity, disability, and mortality, especially in China [1–3]. Intra- venous thrombolysis with recombinant tissue plasmino- gen activator (rt-PA) within 4.5 h of onset has proven to reduce disability and mortality in patients with acute ischemic stroke (AIS). After intravenous thrombolysis, patients may have worsening of symptoms, which is as- sociated with vascular re-occlusion [4, 5]. Therefore, timely and effective treatment and follow-up are essen- tial. Antiplatelet therapy, especially combined with aspi- rin (ASP)/clopidogrel (CLO), is used for the secondary prevention of ischemic stroke, which can reduce the re- currence of stroke. The efficacy and safety of dual anti- platelet therapy in minor strokes have been confirmed by the CHANCE and POINT studies [6, 7]. Considering that intravenous thrombolysis and dual antiplatelet therapy

Qinghua Zhang

Department of Neurology, Linyi People’s Hospital Intersection of Wuhan Road and Wohushan Road Linyi, Shandong 276003 (China)
E-Mail cnqinghuazhang @ 163.com

have a high risk of bleeding [8–10], post-thrombolytic monoclonal antiplatelet therapy is widely used in clinical practice. It is still unknown whether ASP and CLO are safe and effective after rt-PA intravenous thrombolysis. The purpose of this study was to verify the efficacy and safety of dual antiplatelet therapy after rt-PA intravenous thrombolysis for acute minor ischemic stroke (AMIS).

Materials and Methods

Objects
The clinical data of AMIS patients treated with rt-PA intrave- nous thrombolysis from January to October 2018 at the Neuro- logical Emergency Department of Linyi People’s Hospital were retrospectively analyzed. The inclusion criteria were: (1) age (>18 years); (2) clinical diagnosis of AMIS (3) signed informed con- sent. Patients who underwent bridging therapy after the thrombo- lytic therapy were excluded. The indications and contraindications of intravenous thrombolysis were the same as the American Heart Association and the American Stroke Association (AHA/ASA) guidelines for early management of patients with AIS [3].
AMIS was defined as a score of ≤5 points on the National In- stitutes of Health Stroke Scale (NIHSS, scores range from 0 to 42 points, where a higher score signifies higher severity). This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Ethics Committee of Linyi People’s Hospital. Written informed consent was obtained from all participants.
Treatment and Grouping
The patients were administered with rt-PA (Actilyse®, Boeh- ringer Ingelheim, Germany) intravenous thrombolysis within 4.5 h of onset, in which 10% of the total dose was injected intravenously for 1 min, and the remaining 90% of the dose was injected intrave- nously via an infusion pump for 1 h. A day after the thrombolytic therapy, each patient was reexamined on computed tomography and magnetic resonance angiography; after eliminating intracranial hemorrhage (ICH), oral antiplatelet therapy was administered in each patient. The patients were divided into the ASP and ASP-CLO groups based on the type of antiplatelet drug administrated. The ASP group was administrated with 100 mg of oral ASP q.d. for 90 days (Bayer, Germany), and the ASP-CLO group was adminis- trated with 100 mg of oral ASP q.d. for 90 days and 75 mg of oral CLO (Sanofi Winthrop Industrie, Paris, France) q.d. for 21 days.

Comparison of Effectiveness and Safety
The main effective outcomes were evaluated using the modified Rankin Scale (mRS) score, 90 days after the thrombolysis [11]. The mRS scores were defined as: 0–1, good clinical outcomes; 2–5, vary- ing degrees of dysfunction; 6, death. The secondary outcomes were evaluated based on stroke recurrence within 90 days, including ischemic and hemorrhagic strokes. The safety outcomes were eval- uated based on symptomatic ICH (SICH) after thrombolysis and mortality in 90 days. The study criteria referred to The European Cooperative Acute Stroke Study II [12]. SICH was defined as hem- orrhage suggested by head computed tomography review after the thrombolytic therapy, accompanied with increase in the NIHSS

score by 4 points or more from the baseline NIHSS score or the minimum NIHSS score from baseline to 24–36 h after the throm- bolytic therapy. The secondary safety outcomes were evaluated based on various bleeding events. Bleeding events were defined based on the Global Utilization of Streptokinase and Tissue Plas- minogen Activator for Occluded Coronary Arteries criteria. Severe bleeding was defined as fatal or ICH or other hemorrhage causing hemodynamic compromise that required blood or fluid replace- ment, inotropic support, or surgical intervention. Moderate bleed- ing was defined as bleeding that required blood transfusion but did not lead to hemodynamic compromise requiring intervention. Mi- nor bleeding was defined as bleeding neither requiring transfusion nor causing hemodynamic compromise [6, 13].
Statistical Analysis
The Statistical Package for the Social Sciences 22.0 software was used for statistical analysis. The measurement data were expressed as median and interquartile ranges, and the Mann-Whitney U test was used to analyze the differences between the groups; the count data were expressed as frequency and percentage, and the χ2 test was used to compare differences between the groups; the OR/95% CI and corrected OR/95% CI used single- and multiple-compo- nent logistic regression analyses for comparing the safety and ef- fectiveness between the groups, with p < 0.05 considered statisti- cally significant.
Results

General Information and Baseline Characteristics
A total of 661 AIS patients treated with rt-PA intrave- nous thrombolysis from January to October 2018 at Linyi People’s Hospital were retrospectively analyzed, among whom 75 were excluded because of a bridging treatment. Of the 215 AMIS patients, 8 were excluded because of in- complete data or loss of contact. Finally, a total of 207 people were included in the study, among whom 105 were placed in the ASP group and 102 in the ASP-CLO group. There were no statistical differences in baseline char- acteristics between the 2 groups, including the age, sex, NIHSS score, history of hypertension, diabetes mellitus, atrial fibrillation, and ischemic heart disease, habit of smoking/alcohol consumption, baseline blood pressure, blood sugar, and blood lipid level, median rt-PA dose, onset-to-treatment time, door-to-needle time, and stroke
etiology (Table 1).

Effectiveness and Safety Evaluation
In the effectiveness evaluation, good prognosis was ev- ident on day 90 in 70 patients in the ASP group and 84 patients in the ASP-CLO group. There was a significant difference in the day 90 mRS score between the 2 groups (66.7 vs. 82.4%, p = 0.009). Stroke recurrence within 90 days was more serious, with 10 cases of in the ASP
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Table 1. Comparison of demographic and baseline clinical data between groups

Demographic factors
Age, years, median (IQR) 61 (54–68) 60 (51–67) 0.304
Gender, male, n (%) 73 (69.5) 68 (66.7) 0.659
tPA dose, mg/kg, median (IQR) 0.75 (0.69–0.84) 0.75 (0.67–0.83) 0.799
Before stroke mRS 0–1 scores, n (%) 103 (98.1) 101 (99.0) 0.812
Vascular risk factors, n (%)
Hypertension 63 (60.0) 65 (63.7) 0.581
Hypercholesterolemia 25 (23.8) 27 (26.5) 0.659
DM 16 (15.2) 19 (18.6) 0.515
Ischemic heart disease 4 (3.8) 5 (4.9) 0.745
Atrial fibrillation 7 (6.7) 5 (4.9) 0.587
Previous cerebral infarction 20 (19.0) 23 (22.5) 0.535
Smoking 31 (29.5) 27 (26.5) 0.625
Drinking 27 (25.7) 27 (26.5) 0.901
Baseline BP, mm Hg, median (IQR)
SBP 152 (137–165) 152 (136–166) 0.845
DBP 90 (80–98) 90 (80–97) 0.744
Laboratory examination, mmol/L, median (IQR)
Total cholesterol 4.5 (3.98–5.11) 4.7 (4.13–5.26) 0.268
Triglyceride 1.33 (0.98–1.88) 1.42 (0.96–2.01) 0.702
LDL-C 2.93 (2.45–3.58) 3.04 (2.67–3.52) 0.411
HDL-C 1.0 (0.89–1.15) 1.07 (0.92–1.25) 0.066
Fasting blood glucose
Etiological classification of stroke, n (%) Large artery atherosclerosis 5.44 (4.94–6.29)
27 (25.7) 5.36 (4.89–6.01)
23 (22.5) 0.507
0.595
Arteriolar occlusion 63 (60.0) 68 (66.7) 0.32
Cardiogenic embolism 9 (8.6) 7 (6.9) 0.32
Other definite causes 3 (2.9) 2 (2.0) 0.93
Undetermined etiology 3 (2.9) 2 (2.0) 0.93
DNT, min, median (IQR) 32 (28–39.5) 30 (26–37.8) 0.06
OTT, min, median (IQR) 160 (120–195) 150 (105–192) 0.447
Baseline NIHSS score, score, median (IQR) 4 (3–4) 4 (3–5) 0.067
ASP, aspirin; ASP-CLO, ASP + clopidogrel; IQR, interquartile range; t-PA, tissue plasminogen activator; mRS, modified Rankin Scale; DM, diabetes mellitus; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; OTT, onset-to-treatment time; DNT, door-to-needle time; NIHSS, National Institutes of Health Stroke Scale.

group and 5 in the ASP-CLO group. The stroke recur- rence rate showed no significant differences between the 2 groups (9.5%, ASP-CLO; 4.9%, ASP; p = 0.207). Figure
1 shows the distribution of mRS scores in the 2 groups.
In the safety evaluation, ICH was found within 90 days in 3 patients in the ASP group and in 4 patients in the ASP-CLO group. There was one case of SICH in each group, showing no significant difference between the 2 groups (1.0 vs. 1.0%, p = 0.917). Two patients in the ASP group and 1 patient in the ASP-CLO group died. There was no significant difference in 90-day mortality between the 2 groups (1.9 vs. 1.0%, p = 0.585). Based on the Glob- al Strategies for Opening Occluded Coronary Arteries

criteria, there were no severe or moderate bleeding events in either group. There were 2 cases of minor bleeding in each group, showing no significant difference (1.9 vs. 2.0%, p = 0.855; Table 2).

Discussion

Antiplatelet therapy is used for the secondary preven- tion of ischemic stroke, which can reduce the recurrence of stroke. The effectiveness and safety of dual antiplatelet therapy in minor ischemic stroke have been confirmed by CHANCE and POINT studies. AIS patients with initial
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Fig. 1. Functional outcomes on D90, Ac- cording to Score on the mRS. Scores on the mRS range from 0 to 6, with 0 indicating no symptoms,1 symptoms without clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability, and 6 death. mRS, modified Rankin Scale; ASP, aspirin; ASP-CLO, ASP + clopidogrel.

ASP, aspirin; ASP-CLO, ASP + clopidogrel; mRS, modified Rankin Scale; ICH, intracranial hemorrhage; SICH, symptomatic intra- cranial hemorrhage.
recanalization after intravenous thrombolysis still have the risk of re-occlusion and need further antiplatelet ther- apy [14]. The 2018 AHA/ASA guidelines for early man- agement of patients with AIS only recommend antiplate- let therapy 24 h after thrombolysis, while does not pro- vide a definite strategy for monoclonal or dual antiplatelet therapy. At present, due to the risk of bleeding after thrombolysis, most of these patients are provided monoclonal antiplatelet therapy in clinical practice [8– 10]. The effectiveness and safety of dual antiplatelet ther- apy after intravenous thrombolysis for AIS still lack clin- ical research evidence, which warrants further studies.
The results of this study indicate that short-term use of ASP/CLO-combined antiplatelet therapy after intrave- nous thrombolysis for AMIS is both effective and safe, unlike ASP alone. There was a significant difference be- tween the 2 groups in the 90-day mRS score of 0–1 (66.7 vs. 82.4%, p = 0.009), suggesting that dual-antiplatelet therapy can improve the prognosis of patients. There was

no significant difference in stroke recurrence between the 2 groups (9.5 vs. 4.9%, p = 0.207), but dual-antiplatelet therapy decreased the stroke recurrence rate. The lack of significant difference between the 2 groups may be be- cause of the small sample size of this study. In the safety evaluation, there was one case of SICH (1.0 vs. 1.0%, p = 0.917) in each group, showing no significant difference. There was no statistical significance in 90-day mortality between the 2 groups (1.9 vs. 1.0%, p = 0.585). Based on the Global Strategies for Opening Occluded Coronary Arteries criteria, there were no severe or moderate bleed- ing events in either group. There was no significant dif- ference in minor bleeding between the 2 groups (1.9 vs. 2.0%, p = 0.855). These findings are similar to those of the CHANCE study [6], suggesting that dual antiplatelet therapy is effective and safe in the short term (21 days) after intravenous thrombolysis for AMIS.
The patient selection in this study was similar, al- though not identical, to those in CHANCE and POINT
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studies. Different studies used different definitions of mi- nor stroke, and criteria for diagnosing a minor stroke have not yet been unified [15]. In our study, NIHSS <5 points was defined as minor stroke [16–18]. Therefore, patients with NIHSS of 4–5 points were included in this study. In addition, we only included patients with minor stroke and not those with high-risk TIA. The duration of dual-antiplatelet therapy varies among studies [19]. In the CHANCE study [6], dual-antiplatelet therapy lasted 21 days and was found to significantly reduce the recur- rence risk of minor stroke within 90 days without increas- ing the risk of bleeding. In the POINT study [7], dual- antiplatelet therapy lasted for 90 days, which can signifi- cantly reduce the recurrence rate of new ischemic vascular events and ischemic stroke within 90 days while increasing major bleeding events. Rahman et al. [20] per- formed a meta-analysis and compared the effectiveness and safety of monoclonal antiplatelets and dual-anti- platelets for different medication durations (short-term,
<1 month; medium-term, <3 months; long-term, >3 months). It was found that the recurrence risk of ischemic stroke was significantly reduced by the continuous use of dual-antiplatelet therapy in short and medium terms. The risk of major cardiovascular events was also significantly reduced. However, in terms of reducing the risk of isch- emic stroke recurrence and major cardiovascular events, long-term use of dual-antiplatelet therapy was not supe- rior to monoclonal antiplatelet therapy. The results of safety assessment showed that the major risk of bleeding increased in the medium- and long-term use of dual-an- tiplatelet therapy, unlike monoclonal antiplatelet thera- py. The major risk of bleeding in the short-term use of dual-antiplatelet therapy is comparable to that of mono- clonal antiplatelet therapy. In addition, the long-term use of dual-antiplatelet therapy may increase all-cause mor- tality. The meta-analysis by Ge et al. [21] drew similar conclusions. Combining current studies and the latest guidelines, as well as considering the relatively high risk of bleeding after intravenous thrombolysis, the duration of dual-antiplatelet therapy was set to 21 days in this study in accordance with the AHA/ASA guidelines for early management of patients with AIS, which was the same as that in the CHANCE study. Finally, our results also re- validated the safety and effectiveness of dual antiplatelet therapy in AMIS of previous studies, and confirmed, for the first time, the safety and effectiveness of short-term (21 days) dual antiplatelet therapy after rt-PA intrave- nous thrombolytic therapy.
There are some limitations to this study. First, this was
a retrospective, double-blind, randomized controlled

study. The patients’ antiplatelet therapy depended more on the physician’s judgment based on the condition at that time. Second, the sample sizes of the 2 groups were not large, especially for the cases with recurrence of stroke and bleeding, which may have impacted the statistical re- sults. Third, this study only studied the patients with mi- nor stroke who received dual antiplatelet therapy after intravenous thrombolysis while excluding patients with bridging therapy, so it could determine the safety and ef- fectiveness of bridging therapy. Finally, this study mainly diagnosed minor stroke, so the results of this study can- not be extended to cases with severe AIS.
To sum up, short-term (21 days) use of ASP/CLO an- tiplatelet therapy after rt-PA intravenous thrombolysis for AMIS can improve the prognosis, reduce the risk of stroke recurrence, without increasing the risk of bleeding and mortality. Thus, it is effective and safe. In the future, prospective, double-blind, randomized controlled stud- ies with larger samples should be conducted to further verify their safety and effectiveness.

Acknowledgement

We do appreciate the efforts by Mei Zheng, Department of Neurology, Linyi People’s Hospital, in assisting in the collection of clinical cases.
Statement of Ethics

This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Eth- ics Committee of Linyi People’s Hospital. Written informed con- sent was obtained from all participants.
Disclosure Statement

The authors have no conflicts of interest to declare.
Funding Sources

There is no funding sources to declare.
Author Contributions

G.Z.: study design, dissertation writing, data collation. F.L. and X.S.: data collation and statistical analysis. Z.W., Y.G., S.Z., Y.C., D.Y., H.L., Z.C., L.W., and D.G.: case collection. Q.Z.: research guidance and study design.

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