Efficacy and safety of short-term high dosage dual antiplatelet therapy after 0.6 mg/kg rt-PA intravenous thrombolysis for acute ischemic stroke

Abstract

Objective:

To evaluate the efficacy and safety of short-term high-dose of dual antiplatelet therapy after 0.6 mg/kg rt-PA intravenous thrombolysis for acute ischemic stroke (AIS).

Methods:

All 208 patients with AIS were randomized into group 1 (103 cases, after 0.6 mg/kg rt-PA, 300 mg of oral aspirin(ASP) q.d. and 225 mg of oral clopidogrel (CLO) q.d. for for 5 days, then 100 mg of oral ASP q.d. for the next 85 days and 75 mg of oral CLO q.d. for the next 16 days) and group 2 (105 cases, after 0.9 mg/kg rt-PA, 100 mg of oral ASP q.d. for 90 days and 75 mg of oral CLO q.d. for 21 days).The efficacy index was the mRS score, NIHSS score and recurrence risk of stroke, while the safety index was the incidence of bleeding events and mortality. All parameters were evaluated at 30 and 90 days after thrombolysis. Patients whose characteristics may provide the best treatment benefit were further analyzed using the logistic regression model in group 1.

Results:

The proportion of mRS scores between 0 and 1 in group 1 was higher than that in group 2 at both 30 days (44.7% vs 32.4%, P < .05) and 90 days (50.5% vs 35.2%, P < .05). Compared to group 2, the proportion of NIHSS scores less than 4 was significantly higher in group 1 at both 30 days (37.9% vs 25.7%, P < .05) and 90 days (46.6% vs 30.5%, P < .05). At 90 days, Group 1 had a lower stroke recurrence risk than Group 2 (3.9% vs 10.5%, P < .05). The incidence of SICH was significantly different between the 2 groups at both 30 days (2.9% vs 9.5%, P < .05) and 90 days (2.9% vs 10.5%, P < .05). However, other bleeding events and mortality rates were not significantly different between the 2 groups. The lower the baseline NIHSS score and the shorter the OTT, the more favorable the outcomes obtained at 90 days.

Conclusions:

Compared to standard doses, short term high-dose dual antiplatelet therapy after 0.6 mg/kg rt-PA intravenous thrombolysis may be a good choice for AIS patients.

1. Introduction

Thrombolysis and antiplatelet therapy are commonly used to treat acute ischemic stroke.^[1] Since 1996, intravenous injection of recombinant tissue plasminogen activator (rt-PA) with the dosage of 0.9 mg/kg has been approved by the United States.^[2] FDA approved the treatment of eligible patients with acute ischemic stroke within 3 hours, and in 2009, the American Heart Association/American Stroke Association recommended that the treatment time window be extended to 4.5 hours.^[3] Since the National Institute of Neurology and Stroke’s rt-PA Stroke Study (NINDS), 0.9 mg/kg has also been considered the standard dose used for rt-PA.^[4] However, in the Asian population, due to racial differences in blood clotting fibrinolytic factors compared with Caucasians, standard-dose thrombolysis is more likely to cause cerebral hemorrhage problems.^[5,6] Therefore, countries such as China,^[7] Japan,^[6] and Thailand^[8] have conducted clinical trials using a dose of 0.6 mg/kg rt-PA. Although there are differences in the conclusions of the above studies, it is generally believed that the effectiveness of thrombolysis with 0.6 mg/kg rt-PA is not significantly reduced compared to 0.9 mg/kg, while the safety is improved. In addition, patients with acute ischemic stroke in East Asian countries are usually lighter in weight and have a lower income than those in European countries. Each rt-PA package typically contains 2 bottles of 50 milligrams. If a dose of 0.6 mg/kg was used, the upper limit of body weight for each bottle (50 mg) was 83 kg. Therefore, if the dosage of rt-PA is 0.6 mg/kg, most Asian patients only need to prescribe 1 bottle of rt-PA instead of 2 bottles with a standard dose of 0.9 mg/kg.^[9] A low dose of 0.6 mg/kg rt-PA will reduce the cost of thrombolysis by half. Therefore, for Asians, using 0.6 mg/kg rt-PA for thrombolysis may have more potential applications.

However, thrombolysis does not necessarily indicate the end of treatment. After thrombolysis, the surface of the atherosclerotic plaque is exposed, which can easily form a thrombus. During thrombolysis, plaques disintegrate and break, and the embolus blocks the distal branch of the narrowed artery with blood flow, causing circulatory disorders and poor perfusions of the brain tissue at the distal end of arterial stenosis.^[10] Approximately 14% to 34% of patients with vascular recanalization after intravenous thrombolysis experience re-occlusion, leading to worsening of the condition.^[11] Therefore, secondary prevention after thrombolysis, especially how to do well in antiplatelet therapy, has also received attention in recent years. A Chinese study on an Asian population showed that after thrombolysis with 0.9 mg/kg rt-pa, 100 mg aspirin (ASP) and 75 mg Clopidogrel were administered in sequence, which was better than 100 mg aspirin alone after thrombolysis.^[12] This suggests that the combination of thrombolysis and dual antiplatelet therapy may have better effects. We also analyzed the design logic of this treatment approach and believe that the selection of the rt-PA dose may be mainly based on the standard dose of 0.9 mg/kg in NINDS research,^[4] while the selection of the dual antiplatelet dose may be mainly based on CHANCE and POINT research.^[13,14] However, if the focus is on the safety and economic savings of thrombolysis for Asians, reducing the dosage of rt-PA to 0.6 mg/kg, the subsequent selection of antiplatelet drug dosage is currently unknown.

However, the dosage and duration of dual antiplatelet therapy remain uncertain. The lifespan of platelets is 7 to 10 days, and approximately 10% of platelets are regenerated daily. Aspirin regulates Thromboxane A2 by irreversibly inhibiting platelet cyclooxygenase activity and platelet aggregation. Adults taking aspirin 300 to 650 mg once a day can inhibit the formation of thromboxane 2, and achieve significant platelet inhibition within 60 minutes, lasting for 7 to 10 days.^[15] The non-loading dose of clopidogrel (CLO) needs 3 to 5 days to completely inhibit platelet aggregation, while a loading dose of 300 mg of clopidogrel showed significant inhibition within 6 hours.^[16] This indicates that loading doses may have a faster and more effective antiplatelet aggregation effect than low doses. The combined application of loading doses of clopidogrel and aspirin was studied in a non-thrombolytic population with cerebral infarction^[17] and a bridging treatment population after thrombolysis.^[18] The results showed that the loading doses of dual antiplatelet drugs could accelerate the inhibition of platelet aggregation with better therapeutic effects and no decrease in safety. These studies also lead us to propose a scientific hypothesis that, on the basis of using a lower dose of 0.6 mg/kg rt-PA to improve the safety of thrombolysis to a certain extent, administering a loaded dose of dual antiplatelet drugs may be more beneficial for improving the prognosis of Asian patients and reducing the rate of vascular re-occlusion after thrombolysis. Therefore, for the first time, we conducted a study to compare the safety and effectiveness of sequential administration of a loaded dose of dual antiplatelet drug after low dose of 0.6 mg/kg rt-PA thrombolysis with a standard dose of 0.9 mg/kg rt-PA thrombolysis used in previous studies, and to observe whether the combination of low-dose thrombolytic drugs and high-dose dual antiplatelet drugs is more advantageous in the Asian population.

2. Patients and Methods

2.1. Patients

Patients at Tianjin Huanhu Hospital who received thrombolytic therapy between September 2019 and March 2020 were selected for this study. Of all patients, 149 men and 59 women were between 51 and 69 years of age. The thrombolysis inclusion criteria were as follows: Age not more than 80. Diagnosed with acute ischemic stroke (AIS) and the National Institutes of Health Stroke Scale (NIHSS) score between 4 and 25. No intracranial hemorrhage or obvious low-density shadow was found on the head CT scan. The time of onset is not more than 4.5 hours. Thrombolytic informed consent was obtained from family members or patients.^[19] The exclusion criteria were as follows: History of intracranial hemorrhage in the last 3 months, bleeding in the gastrointestinal or urinary system in the last 3 weeks, major surgery in the last 2 weeks and arterial puncture of the oppression-forbidden area in the last week. History of cerebral or myocardial infarction in the last 3 weeks. Severe heart, kidney, liver dysfunction or severe diabetes. Active bleeding or trauma found on examination. Oral anticoagulation and the INR is over 1.5, heparin treatment within 48 hours (activated partial thromboplastin time outside the normal range). Blood platelets less than 100 × 10⁹/L, blood sugar less than 2.7 mmol/L. Blood pressure: systolic blood pressure over 180 mm Hg and diastolic blood pressure over 100 mm Hg. Gestation. Non-cooperation.^[20]

2.2. Treatment and grouping

Patients who satisfied the inclusion criteria were divided into 2 groups according to the dosage of rt-PA and antiplatelet medications. Using the block randomization method, the block size was 4. Excel software was used to generate a random number table for individuals who did not directly participate in the experiment, with the number “0” representing group 1 and “1” representing group 2. A random number card was placed in an opaque and numbered envelope. Personnel were arranged to organize eligible subjects to select envelopes with corresponding serial numbers in the order of treatment and take the treatment according to the protocol inside the envelopes. The allocation of groups 1 and 2 was single-blind, and patients were not aware of the grouping situation, but the participating doctors were aware of the grouping situation. Results evaluators, data managers, and statisticians were unaware of treatment allocation. Patients in group 1 received rt-PA thrombolytic therapy with 0.6 mg/kg (total amount less than 60 mg), 10% by intravenous injection in 1 minute and 90% by intravenous drip in 60 minutes. The applied dose of rt-PA in the group 2 is 0.9 mg/kg with the same usage as above. 24 hours after thrombolytic therapy, if intracranial hemorrhage was excluded, Group 1 received a high dosage of dual antiplatelet therapy (300 mg of oral ASP q.d. and 225 mg of oral CLO q.d. for 5 days, then 100 mg of oral ASP q.d. for the next 85 days and 75 mg of oral CLO q.d. for the next 16 days), while Group 2 was treated with a low dosage of dual antiplatelet therapy (100 mg of oral ASP q.d. for 90 days and 75 mg of oral CLO q.d. for 21 days). Simultaneously, hypotensive, hypoglycemic, hyperlipidemia, atherosclerosis, and plaque stability treatments were administered as necessary. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Committee of the Tianjin Huanhu Hospital (Fig. 1).

Figure 1.

The efficacy index was mRS scores, NIHSS scores and recurrence risks of stroke. The safety was the incidence of SICH, other bleeding events and mortality. All these were evaluated both in 30 and 90 days after thrombolysis. mRS = modified Rankin Scale, NIHSS = National Institutes of Health Stroke Scale, rt-PA = recombinant tissue plasminogen activator, SICH = symptomatic intracranial hemorrhage.

2.3. Comparison of effectiveness and safety

The main effective outcomes were evaluated using the modified Rankin Scale (mRS)^[20] and NIHSS.^[21] The mRS and NIHSS scores were evaluated either face-to-face or online (including WeChat or phone calls). Stroke recurrence is defined as acute focal infarction of the brain or retina, with one of the following situations: sudden onset of new focal neurological deficits lasting less than 24 hours, clinical or imaging evidence of infarction or rapid deterioration of existing focal neurological deficits lasting 24 hours or longer, or imaging evidence of new ischemic changes significantly different from the index ischemic events.^[22] Secondary outcomes were evaluated based on stroke recurrence. The main safety outcomes were evaluated on the basis of on symptomatic intracranial hemorrhage (SICH) after thrombolysis and mortality over 90 days. Symptomatic hemorrhage was defined as hemorrhagic lesion on CT scan with clinical worsening of the NIHSS score by more than 4 points.^[23] When the patient’s neurological function deteriorated, CT testing was performed to evaluate SICH. When the patient’s neurological function deteriorates, CT testing was performed to evaluate SICH. Secondary safety outcomes were evaluated based on other bleeding events, including non-symptomatic intracranial hemorrhage (NSICH) and digestive, urinary and gum hemorrhages. All parameters were evaluated at 30 and 90 days after thrombolysis. We set the mRS scores equal to or less than 1 as a favorable outcome and 2 to 5 as a poor outcome. Due to favorable outcomes, patients with which characteristics may receive the best treatment benefit were further analyzed in Group 1.

2.4. Statistical analysis

Statistical analyses were performed using SPSS 25.0. Data were shown as mean ± SD for continuous variables with normal distribution, and median and interquartile range for continuous variables without normal distribution. Continuous variables were compared using the independent Student t test for parametric data and Mann–Whitney U test for nonparametric data. Categorical variables were presented as percentages and compared using the chi-square test or Fisher’s exact test (if any expected value < 5). Multi-factor analysis was performed using a logistics regression analysis model. P < .05 was considered as statistically significant.

3. Results

3.1. General information and baseline characteristics

A total of 306 patients with AIS treated with rt-PA intravenous thrombolysis were retrospectively analyzed, of whom 85 were excluded because of bridging treatment. Other 13 were excluded due to incomplete data or loss of contact. In total, 208 AIS patients who met the inclusion criteria were enrolled in this study. There were no statistical differences in the baseline characteristics between the 2 groups, including demographic factors, vascular risk factors, medication before admission, laboratory examination and etiological classification of stroke (Table 1).

Table 1.

Comparison of demographic and baseline clinical data between groups.

Characteristics	Group 1 (n = 103)	Group 2(n = 105)	All cases, n = 208	P
Demographic factors
Age, years, median (IQR)	62 (53–68)	61 (51–69)	62 (51–69)	.45
Gender, male, n (%)	75 (72.8)	74 (70.5)	149 (71.6)	.52
Weight, kg, median (IQR)	65 (44–90)	66 (45–89)	66 (44–90)	.32
OTT, min, median (IQR)	158 (120–185)	164 (108–190)	162 (108–190)	.29
DNT, min, median (IQR)	37 (27–43)	38 (26–45)	37 (26–45)	.51
Before this stroke mRS 0-1 scores, n (%)	103 (100)	105 (100)	208 (100)	.99
Before thrombolysis mRS scores, median (IQR)	2.9 (1–4)	2.8 (1–4)	2.8 (1–4)	.72
Before this stroke NIHSS 0–4 scores, n (%)	100 (97.1)	101 (96.2)	201 (96.6)	.88
Before thrombolysis NIHSS scores, median (IQR)	12.2 (4–25)	12.8 (4–25)	12.5 (4–25)	.69
Vascular risk factors, n (%)
Hypertension	90 (87.3)	94 (89.5)	184 (88.5)	.85
Hypercholesterolemia	81 (78.6)	78 (74.3)	159 (76.4)	.75
Hyperlipidemia	75 (72.8)	70 (66.7)	145 (69.7)	.65
Diabetes	69 (67)	71 (67.6)	140 (67.3)	.82
Ischemic heart disease	35 (34)	39 (37)	74 (35.6)	.76
Atrial fibrillation	8 (7.8)	10 (9.5)	18 (8.7)	.68
Previous cerebral infarction	21 (20.4)	20 (19)	41 (19.7)	.83
Smoking	85 (82.5)	87 (82.9)	172 (82.7)	.84
Drinking	96 (93.2)	99 (94.3)	195 (93.8)	.88
Medication before admission, n (%)
Anticoagulant medication	9 (8.7)	10 (9.5)	19 (9.1)	.79
Antiplatelet medication	42 (40.8)	48 (45.7)	90 (43.3)	.81
Statin medication	35 (34)	39 (37.1)	74 (35.6)	.87
Laboratory examination, median (IQR)
TT, s, median (IQR)	13.5 (11.7–15.2)	13.8 (11.2–15.9)	13.7 (11.2–15.9)	.91
APTT, s, median (IQR)	30.2 (25.2–37.2)	31.8 (24.3–36.9)	30.8 (24.3–37.2)	.92
PT, s, median (IQR)	12.1 (11.2–14.1)	11.8 (11.1–13.9)	11.9 (11.1–14.1)	.88
Fibrinogen, g/L, median (IQR)	3.3 (2.1–3.9)	3.5 (2–3.9)	3.4 (2–3.9)	.93
Platelet, median (IQR)	136 (95–250)	144 (89–268)	139 (89–268)	.78
Etiological classification of stroke, n (%)
LAA	49 (47.6)	55 (52.4)	104 (50)	.69
SAO	36 (35)	34 (32.4)	70 (33.7)	.92
CE	10 (9.7)	11 (10.5)	21 (10.1)	.94
SOC	6 (5.8)	4 (3.8)	10 (4.8)	.96
SUC	2 (1.9)	1 (0.9)	3 (1.4)	.72
Anterior circulation infarction	82 (79.6)	77 (73.3)	159 (76.4)	.78
Posterior circulation infarction	21 (20.4)	28 (26.7)	49 (23.6)	.69
Intracranial	77 (74.8)	86 (81.9)	163 (78.4)	.71
Extracranial	26 (25.2)	19 (18.1)	45 (21.6)	.68

APTT = activated partial thromboplastin time, CE = cardiogenic cerebral embolism, DNT = door-to-needle time, IQR = interquartile range, LAA = large atherosclerotic stroke, mRS = modified Rankin Scale, NIHSS = National Institutes of Health Stroke Scale, OTT = onset-to-treatment time, PT = prothrombin time, SAO = small artery occlusion, SOC = small artery occlusion, SUC = stroke of undetermined cause, TT = thrombin time.

3.2. Effectiveness evaluation

The proportion of mRS scores between 0 and 1 in Group 1 was higher than that in Group 2 at both 30 days (44.7% vs 32.4%, P < .05) and 90 days (50.5% vs 35.2%, P < .05). At 30 days, the mRS score distribution of group 1 was also better than that of group 2 (χ² = 14.495, P < .05). However, there was no significant difference in the distribution of the mRS scores at 90 days (χ² = 10.124, P > .05). Compared to Group 2, the proportion of NIHSS scores less than 4 was significantly higher in Group 1 at both 30 days (37.9% vs 25.7%, P < .05) and 90 days (46.6% vs 30.5%, P < .05). At 90 days, Group 1 had a lower stroke recurrence risks than group 2 (3.9% vs 10.5%, P < .05; Fig. 2; Table 2).

Figure 2.

Functional outcomes on D30 and D90 mRS range from 0 to 5, with 0 indicating no symptoms, 1 symptoms without clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability. mRS = modified Rankin Scale.

Table 2.

Effectiveness evaluation.

	30 d									90 d
	mRS (0–1)	mRS score distribution						NIHSS (0–4)	Death (Miss)	mRS (0–1)	mRS score distribution						NIHSS(0–4)	Stroke Recurrence	Death (Miss)
		0	1	2	3	4	5				0	1	2	3	4	5
Group 1	46	20	26	32	17	6	1	39	1	52	22	30	28	15	5	2	48	4	1
Group 2	34	14	20	22	27	17	5	27	0	37	15	23	24	22	16	4	32	11	1
Value	3.312	14.495						3.543	1.024	4.938	10.124						5.713	3.667	0
P	.047	.029						.041	.5	.019	.072						.012	.049	.75

mRS = modified Rankin Scale, NIHSS = National Institutes of Health Stroke Scale.

3.3. Safety evaluation

The incidence of SICH was significant different between the 2 groups at both 30 days (2.9% vs 9.5%, P < .05) and 90 days (2.9% vs 10.5%, P < .05). Other bleeding events and mortality rates were not significant different between the 2 groups. However, subgroup analysis revealed that Group 2 mainly suffered from intracranial hemorrhage and gum bleeding, whereas Group 1 mainly suffered from gastrointestinal bleeding (Table 3).

Table 3.

Safty evaluation.

	30 d							90 d
	SICH	Other bleeding events					Mortality	SICH	Other bleeding events					Mortality
		NSICH	Gastrointestina	Urinary	Gum	Other			NSICH	Gastrointestina	Urinary	Gum	Other
Group 1	3	2	1	0	0	0	1	3	2	2	0	0	0	1
Group 2	10	6	0	0	3	0	0	11	7	0	0	3	0	1
Value	3.809	1.962	1.034	0	2.957	0	1.024	4.66	2.48	2.06	0	2.986	0	0
P	.046	.149	.493	>.05	.129	>.05	.5	.028	.107	.244	>.05	.127	>.05	>.05

NSICH = non-symptomatic intracranial hemorrhage, SICH = symptomatic intracranial hemorrhage.

3.4. Analysis of effectiveness related factors

Through logistics regression analysis of group 1, it was found that the lower the baseline NIHSS score and the shorter the onset to treatment time, the more favorable the outcome obtained at 90 days (Table 4).

Table 4.

Analysis of effectiveness related factors.

	β	SE	Wald χ2	P	OR	95% CI
NIHSS	−0.44	0.168	5.78	.03	0.71	0.5–0.96
OTT	0.017	0.009	6.002	.045	1.022	1.008–1.035

NIHSS = National Institutes of Health Stroke Scale, OTT = onset to treatment time.

4. Discussion

The administration of thrombolytic agents such as rt-PA is the mainstay of AIS management.^[24] Thrombolytic therapy aims to dredge the vascular occlusion and restore blood flow in the infarct zone.^[25] However, on account of the risk of bleeding events, the use of rt-PA is strictly limited.^[5] Evidence from the randomized control trials and meta-analysis supports the efficacy of rt-PA in the 4.5 hours window after AIS, but little information is obtained from investigations in Asian populations.^[26,27] Blood coagulation fibrinolysis factors, including fibrinogen and factor XIII differ between Japanese and Caucasians.^[28] East Asian patients are at a higher risk of bleeding after thrombolysis. Currently, the recommended dosage of rt-PA (0.9 mg/kg) is based on the results of studies involving a large number of Caucasians. According to existing research, a lower dosage, particularly 0.6 mg/kg, might be more suitable for East Asian patients.^[5,7,29,30]

AIS patients with initial recanalization after intravenous thrombolysis still have the risk of re-occlusion which can be effectively resolved by antiplatelet therapy. CHANCE and POINT studies have revealed that antiplatelet therapy is beneficial for secondary prevention of ischemic stroke.^[31] However, existing guidelines do not provide a definite strategy for what dosage should antiplatelet be used after thrombolysis, not to mention after 0.6 mg/kg rt-PA infusion.^[13,14] Since antiplatelet therapy at regular doses requires a long time to reach an effective concentration in the body, we conducted a study for the first time to apply large doses of dual-antiplatelet in a short period of time after administration of the rt-PA at 0.6 mg/kg to try to improve the effectiveness and safety of the treatment.

The results of this study indicate that the short-term use of a large dosage of dual-antiplatelet after 0.6 mg/kg rt-pa intravenous thrombolysis for AIS is both effective and safe. The favorable outcome (mRS scores between 0 and 1) in group 1 was both significantly higher at 30 days (44.7% vs 32.4%, P < .05) and 90 days (50.5% vs 35.2%, P < .05), suggesting that experimental therapy can improve the prognosis of patients. There was significant difference in stroke recurrence between the 2 groups at 90 days (5% vs 11%, P = .049), which means that high doses of dual antiplatelet therapy can play an important role in secondary prevention. The results of our control group are roughly similar to those of recent studies, but there are also some differences. A study that used short-term dual antiplatelet therapy (100 mg ASP plus 75 mg CLO) after 0.9 mg/kg rt-PA intravenous thrombolysis conducted by Zhang et al showed that 82.4% of subjects had an MRS score of 0 to 1 at 90 days.^[9] The main reason for this difference is that Zhang et al only enrolled patients with minor stroke (NIHSS score less than 5), while our study included patients with more severe stroke (NIHSS score between 4 and 25). The data of our experimental group were better than other studies. In an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials, for AIS patients received 0.9 mg/kg rt-PA, 41.6% patients gained favorable functional outcomes.^[32] A study in Japan involving 7492 patients, using 0.6 mg/kg rt-PA with time to initiation less than 3h, found that 33.1% of the mRS scores were 0 to 1 at 3 months.^[33] In addition to the benefits of short-term high dosage of dual antiplatelet therapy and low dosage of rt-PA, there may be 2 other reasons for the favorable outcome in our study. First, most patients in our study had moderate to moderate-severe stroke (NIHSS score between 4 and 20), and only 24 patients (11.5%) had severe stroke (NIHSS score higher than 21 points). The median of NIHSS score at admission was only 12 points, which is much lower than that in other studies.^[34–36] Second, since we are a specialized neurological hospital, our stroke green channel is relatively standardized and door to needle time is only about 40 minutes. Through logistic analysis, we found that the baseline NIHSS scores and onset to treatment time were independent factors that were similar to previous research results.^[37–39] Approximately, 40% of the patients in the study had taken antiplatelet drugs for a long time before this admission, which may have had an impact on the experimental results. However, the study by Malhotra et al^[40] confirmed that antiplatelet drug pretreatment had little effects on the outcome after thrombolysis, so the impact of medical history would not be significant. However, it is worth noting that there is no significant difference in the distribution of the mRS scores at the 90th day. This may be because of 2 reasons. One is that there is a “ceiling effect” in the improvement of the scores of patients with mild stroke^[41] and the other is that both methods are ineffective for patients with severe stroke patients.^[42,43] Therefore, these patients may be more suitable for endovascular treatment.^[44]

In our safety evaluation, the incidence of SICH was significantly different between the 2 groups at 30 days (2.9% vs 9.6%, P = .046) and 90 days (2.9% vs 10.6%, P = .028). SICH which may lead to neurological deterioration and death is the main concern for thrombolysis and antiplatelet therapy in patients with AIS. Dual antiplatelet therapy after intravenous thrombolysis may increase the risks of SICH but without sufficient evidence.^[45] Our results are similar to those of previous studies. Using 0.6 mg/kg rt-PA will lead the incidence of SICH to be 0% to 9.4%.^[46,47]When the dosage was adjusted to 0.9 mg/kg, the incidence was 2.1% to 19.8%.^[35,48] According to the POINT study, the incidence of SICH caused by dual antiplatelet drugs is only 0.9%, which is lower than rt-PA.^[19] Our research also revealed that thrombolytic medication is the major cause of SICH. Even high-dosage dual antiplatelet drugs did not cause a significant increase in the incidence of SICH. Other bleeding events and mortality rates were not significantly different between the 2 groups. Although there were no severe bleeding events in the 2 groups, Group 2 mainly suffered from intracranial hemorrhage and gum bleeding, and Group 1 mainly suffered from gastrointestinal bleeding. As we conventionally review CT to evaluate intracranial hemorrhage, only few patients have more sensitive tests such as susceptibility weighted imaging and Gradient echo. Therefore, the number of NSICH cases may not be accurate. However, previous studies have shown that NSICH may be closely related to thrombolytic drugs, because such medicine may promote the occurrence and deterioration of cerebral amyloid angiopathy which would lead to remote brain hemorrhage.^[49] Gastrointestinal bleeding may be related to the pharmacological mechanism of aspirin and stress ulcers. However, under the protection of conventional acid inhibitors, no serious adverse events occurred.^[50]

This study has several limitations. Firstly, the choice of thrombolysis and antiplatelet therapy mainly depended on the actual situation of each patient, so that undetected deviations might exist. Secondly, we did not perform DSA examination or ASPECTS scores in all patients. Therefore, we failed to determine the vascular occlusion accurately, so that we could not compare the advantages and disadvantages between our strategy and endovascular treatment such as mechanical thrombus removal. Thirdly, the sample size used in this study might have limited the power to detect significant differences between the 2 groups. Therefore, additional prospective studies involving larger cohorts of patients are needed.

In summary, short term high-dose dual antiplatelet therapy was effective and safe for AIS patients after 0.6 mg/kg rt-PA intravenous thrombolysis. In the future, prospective, double-blind, randomized controlled studies with larger sample sizes should be conducted to verify their safety and effectiveness.

Author contributions

Conceptualization: Peilan Zhang.

Data curation: Jing Chen.

Formal analysis: Jing Chen, Peilan Zhang, Yuxin Wang.

Funding acquisition: Yanchen Lin, Jingjing Li, Peilan Zhang.

Investigation: Jing Chen, Peilan Zhang, Yuxin Wang.

Methodology: Jing Chen, Yanchen Lin, Chenhao Zhang.

Project administration: Jing Chen, Yan Chen, Chenhua Li.

Resources: Jing Chen, Yan Chen.

Software: Jing Chen, Jingjing Li, Yan Chen, Chenhao Zhang, Chenhua Li.

Supervision: Yuxin Wang, Chenhao Zhang, Chenhua Li.

Validation: Yuxin Wang, Yan Chen.

Visualization: Yan Chen.

Writing – review & editing: Yanchen Lin, Jingjing Li.