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Dual Antiplatelet Therapy for Platelet Aggregation inhibition Effect in Acute Large Artery Atherothrombotic Stroke or High-Risk TIA Patients: Prasugrel versus Clopidogrel (ACUTE-PRAS)

ACUTE-PRAS (ACUTE-PRAS)

186

A total of 186 patients were enrolled in this study, of which 181 were randomly assigned to groups: 91 patients to the prasugrel group and 90 patients to the standard treatment group. The Full Analysis Set (FAS) was 176 patients (88 patients in the prasugrel group and 88 patients in the standard treatment group) and the Per-protocol Set (PPS) was 167 patients (84 patients and 83 patients, respectively). The safety analysis population was the same as the FAS. There were no significant differences in patient backgrounds between the prasugrel group and the standard treatment group in the FAS. For gender, there were 60 males (68.2%) and 28 females (31.8%) in the prasugrel group, and 64 males (72.7%) and 24 females (27.3%) in the standard treatment group. The average age [Standard Deviation (SD)] was 70.4 (10.8) and 71.1 (11.3), and the mean weight (SD) was 65.58 (13.91) kg and 63.57 (12.80) kg, respectively. For major comorbidities, hypertension was present in 75 patients (85.2%) in the prasugrel group and 74 patients (84.1%) in the standard treatment group. Dyslipidemia was present in 67 patients (76.1%) in each group. Diabetes was present in 39 patients (44.3%) in the prasugrel group and 37 patients (42.0%) in the standard treatment group. Chronic kidney disease was present in 32 patients (36.4%) and 31 patients (35.2%) in each group. Regarding CYP2C19 genetic polymorphisms (phenotypes), Extensive Metabolizers (EM) were 33 patients (37.5%) in the prasugrel group 22 patients (25.0%) in the standard treatment group. Intermediate Metabolizers (IM) were 38 (43.2%) and 43 (48.9%) patients in each group, and Poor Metabolizers (PM) were 14 (15.9%) and 17 (19.3%) patients in each group. unknown phenotypes were identified in 3 patients (3.4%) in the prasugrel group and 6 patients (6.8%) in the standard treatment group . As for diagnoses, atherothrombotic cerebral infarction was observed in 61 patients (69.3%) in the prasugrel group and 64 patients (72.7%) in the standard treatment group, while high-risk TIA was diagnosed in 27 patients (30.7%) in the prasugrel group and 24 (27.3%) in the standard treatment group. The mean P2Y12 reaction unit (PRU) mean (SD) value at baseline was 230.4 (47.9) in the prasugrel group and 241.4 (63.8) in the standard treatment group. The distribution of stenosis in the responsible vessel was as follows: the cervical carotid artery included 14 patients (15.9%) in the prasugrel group and 16 patients (18.2%) in the standard treatment group. The intracranial internal carotid artery included 15 patients (17.0%) and 10 patients (11.4%) in each group. Stenosis in the anterior cerebral artery included 2 patients (2.3%) and 3 patients (3.4%) in the standard treatment group. The middle cerebral artery M1 included 16 patients (18.2%) in the prasugrel group and 30 patients (34.1%) in the standard treatment group, while the M2 or greater stenosis included in 12 patients (13.6%) in the prasugrel group and 9 patients (10.2%) in the standard treatment group, respectively. The posterior cerebral artery included 1 patient (1.1%) in each group. The vertebral artery included in 11 patients (12.5%) in the prasugrel group and 5 patients (5.7%) in the standard treatment group. The basilar artery included 6 patients (6.8%) and 3 patients (3.4%) in each group. In 11 patients (12.5%) from both groups, the location of stenosis was unknown. The degree of stenosis in the responsible vessel was severe in 26 patients (29.5%) in the prasugrel group and 37 patients (42.0%) in the standard treatment group, moderate in 32 patients (36.4%) and 28 patients (31.8%), mild in 6 patients (6.8%) and 7 patients (8.0%), occlusion in 13 patients (14.8%) and 5 patients (5.7%), and unknown in each group with 11 patients (12.5%). The mean time (SD) from the onset to receiving the study treatment was 18.820 (12.008) hours in the prasugrel group and 17.861 (11.305) hours in the standard treatment group.

Among the 181 randomized patients (91 in the prasugrel group and 90 in the standard treatment group), four patients (two from each group) did not receive the study drug. As a result, the study drug was administered to a total of 177 patients: 89 in the prasugrel group and 88 in the standard treatment group. Of these, the study treatment was discontinued in 49 patients (25 in the prasugrel group and 24 in the standard treatment group). 128 patients (64 from each group) completed the study treatment. Due to a protocol applied prior to authorization by the site manager, one patient in the prasugrel group was excluded from the FAS and safety analysis population. In the FAS, the initial dose received per treatment group was as follows: all 88 patients in the prasugrel group received 3.75 mg, while in the standard treatment group, 45 patients received clopidogrel at 300 mg and 43 patients received 75 mg. For maintenance doses, 87 patients in the prasugrel group continued on 3.75 mg, while in the standard treatment group, 86 patients continued on clopidogrel 75 mg, with other dosages given to 2 patients. In the prasugrel group, one patient discontinued the study treatment on the first day of the study. In the standard treatment group, one of the two patients discontinued the study treatment after taking clopidogrel at a dose of 300 mg for four days from the start of the study, and the other patient discontinued the study treatment after taking clopidogrel at an initial dose of 75 mg for one day followed by a maintenance dose of 225 mg for one day. The mean total duration of the study treatment (SD) was 70.6 days (34.4) in the prasugrel group and 70.0 days (35.7) in the standard treatment group. The mean duration of concomitant aspirin therapy (SD) was 25.6 days (24.0) for the prasugrel group and 25.5 days (25.4) for the standard treatment group. The mean actual days of study drug administration (SD) were 70.5 days (34.5) for the prasugrel group and 70.0 days (35.7) for the standard treatment group. The adherence rates were 99.76% (2.26) in the prasugrel group and 100.00% (0.00) in the standard treatment group.

Efficacy Endpoints The cumulative incidence rate of cerebrovascular and cardiovascular events up to 90 days after the start of the study treatment was as follows. 1. Composite endpoint (cerebral infarction, myocardial infarction, and death due to ischemic vascular disease and TIA) was observed in 7 patients in the prasugrel and 7 patients in the standard treatment groups, with cumulative incidence rates [95% CI] of 8.4 [4.1, 16.9] % and 9.4 [4.5, 18.7] %, respectively. 2. Composite endpoint (cerebral infarction, myocardial infarction, and death due to ischemic vascular disease) was observed in 6 patients in the prasugrel group and 5 patients in the standard treatment group, with cumulative incidence rates [95% CI] of 6.9 [3.2, 14.8] % and 6.5 [2.7, 15.0] %, respectively. 3. Stroke was observedin 7 patients in the prasugrel group and 4 patients in the standard treatment group, with cumulative incidence rates [95% CI] of 8.2 [4.0, 16.4] % and 5.3 [2.0, 13.5] %, respectively. Of these, cerebral infarction was observed in 6 patients in the prasugrel group and 4 patients in the standard treatment group, with cumulative incidence rates [95% CI] of 6.9 [3.2, 14.8] % and 5.3 [2.0, 13.5] %, respectively. Cerebral hemorrhage was observed in 1 patient in the prasugrel group, with a cumulative incidence rate [95% CI] of 1.3 [0.2, 8.8] %. TIA was observed in 1 patient in the prasugrel group and 2 patients in the standard treatment group, with cumulative incidence rates [95% CI] of 1.5 [0.2, 10.3] % and 3.0 [0.8, 11.5] %, respectively. 4. Myocardial infarction was observed in 1 patient in the standard treatment group, with a cumulative incidence rate [95% CI] of 1.3 [0.2, 9.0] %. 5. Death was observed in 2 patients in the prasugrel group and 1 patient in the standard treatment group, with cumulative incidence rates [95% CI] of 2.7 [0.7, 10.6] % and 1.3 [0.2, 8.9] %, respectively. The breakdown was 2 other deaths in the prasugrel group and 1 vascular death in the standard treatment group. 6. Other arterial thrombotic and embolic events was observed in 2 patients in the prasugrel group, with a cumulative incidence rate [95% CI] of 2.7 [0.7, 10.4] %. Safety Endpoints The cumulative incidence of bleeding events [95% CI] up to 90 days after the start of the study treatment was as follows. 1. Major bleeding by ISTH criteria was observed in 2.7 [0.7, 10.4] % in the standard treatment group. Life-threatening bleeding by MATCH criteria was observed in 2.7 [0.7, 10.4] % in the standard treatment group. Clinically significant bleeding was observed in 2.5 [0.6, 9.6] % of the prasugrel group and 2.5 [0.6, 9.8] % of the standard treatment group. Other bleeding was observed in 11.6 [5.8, 22.5] % of the prasugrel group and 3.6 [1.2, 10.6] % of the standard treatment group. Severe or life-threatening bleeding by GUSTO criteria was observed in 1.3 [0.2, 8.9] % in the standard treatment group, and moderate bleeding was observed in 1.4 [0.2, 9.7] % in the standard treatment group. Minor bleeding was observed in 13.9 [7.5, 24.8] % of the prasugrel group and 4.9 [1.9, 12.6] %of the standard treatment group. 2. Major bleeding according to the POINT trial criteria was 2.7 [0.7, 10.4] % in the standard treatment group. 3. Minor bleeding was observed in 1.3 [0.2, 8.5] % in the standard treatment group. 4. Intracranial hemorrhage (including both symptomatic and asymptomatic) was observed in 3.6 [1.2, 10.8] % of the prasugrel group and 1.4 [0.2, 9.5] % of the standard treatment group. Symptomatic intracranial hemorrhage was observed in 1.3 [0.2, 8.8] % of the prasugrel group. Asymptomatic intracranial hemorrhage was was observed in 2.4 [0.6, 9.1] % in the prasugrel group and 1.4 [0.2, 9.5] % in the standard treatment group. - AEs: No significant differences between the two treatment groups were observed in AEs and adverse drug reactions. Details in the safety analysis population were as follows: - In the prasugrel group, 44 out of 88 patients (50.0 [95% CI: 39.1, 60.9] %) experienced 97 AEs. - In the standard treatment group, 36 out of 88 patients (40.9 [30.5, 51.9] %) experienced 66 AEs. -SAEs: - In the prasugrel group, 14 patients (15.9 [9.0, 25.2] %) experienced 15 SAEs. - In the standard treatment group, 13 patients (14.8 [8.1, 23.9] %) experienced 14 SAEs. -AEs Leading to Discontinuation of Study Treatment: - In the prasugrel group, 10 patients (11.4 [5.6, 19.9] %) experienced 11 AEs leading to discontinuation of study treatment. - In the standard treatment group, 5 patients (5.7 [1.9, 12.8] %) experienced 5 AEs leading to discontinuation. -AEs Leading to Death: - In the prasugrel group, 2 patients (2.3 [0.3, 8.0] %) experienced 2 AEs leading to death. - In the standard treatment group, 1 patient (1.1 [0.0, 6.2] %) experienced an AE leading to death. -Adverse Drug Reactions: - In the prasugrel group, 8 patients (9.1 [4.0, 17.1] %) experienced 9 side effects. The main side effects (reported in 2 or more patients) included subcutaneous hemorrhage and hematuria, each in 2 patients (2.3%). - In the standard treatment group, 6 patients (6.8 [2.5, 14.3] %) experienced 8 side effects. The main adverse drug reaction (reported in 2 or more patients) was constipation in 3 patients (3.4%). - Serious Adverse Drug Reactions: - In the prasugrel group, 1 patient (1.1 [0.0, 6.2] %) experienced a serious adverse drug reaction, and it was cerebral hemorrhage. - In the standard treatment group, 1 patient (1.1 [0.0, 6.2] %) experienced a serious adverse drug reaction, and it was hemorrhagic infarction. - Adverse Drug Reactions Leading to Discontinuation of Study Treatment: - In the prasugrel group, 1 patient (1.1 [0.0, 6.2] %) experienced an adverse drug reaction leading to discontinuation of study treatment, and it was cerebral hemorrhage. - In the standard treatment group, 1 patient (1.1 [0.0, 6.2] %) experienced an adverse drug reaction leading to discontinuation of study treatment, and it was hemorrhagic infarction. - Adverse Drug Reactions Leading to Death: - No adverse drug reactions leading to death were reported in either group.

1) Primary Endpoint The adjusted mean platelet reactivity (PRU) [95% CI] for FAS at 5 days after the start of study treatment was 136.0 [122.7, 149.3] in the prasugrel group and 169.9 [157.0, 182.8] in the standard treatment group. The estimated adjusted mean difference [95% CI] between the prasugrel group and the standard treatment group was -33.9 [-49.0, -18.8], significantly lower in the prasugrel group (p<0.001). For EM, the prasugrel group had 118.5 [100.6, 136.5] and the standard treatment group had 144.8 [125.4, 164.1], with an estimated adjusted mean difference [95% CI] of -26.2 [-48.0, -4.4], significantly lower in the prasugrel group (p=0.020). For IM, the prasugrel group had 140.3 [119.0, 161.5] and the standard treatment group had 173.1 [151.7, 194.4], with an estimated adjusted mean difference [95% CI] of -32.8 [-56.6, -9.0], significantly lower in the prasugrel group (p=0.008). For PM, the prasugrel group had 164.7 [132.6, 196.8] and the standard treatment group had 196.2 [171.2, 221.3], with an estimated adjusted mean difference [95% CI] of -31.6 [-68.3, 5.1] (p=0.088). For IM+PM, the prasugrel group had 145.3 [127.8, 162.7] and the standard treatment group had 180.1 [163.8, 196.4], with an estimated adjusted mean difference [95% CI] of -34.8 [-54.5, -15.2], significantly lower in the prasugrel group (p<0.001). Multivariate analysis identified treatment group, presence of dyslipidemia, smoking history (previously smoked), CYP2C19 genotype, and pre-treatment HPR as factors highly associated with PRU at 5 days after the start of study treatment. The mean PRU (SD) by initial dose at 5 days after the start of study treatment was 136.5 (56.2) for prasugrel 3.75 mg, 159.4 (60.8) for clopidogrel 300 mg, and 194.8 (52.2) for clopidogrel 75 mg in the standard treatment group. Lower PRU values were observed in patients with higher initial doses of clopidogrel, and even lower values in the prasugrel group (initial dose 3.75 mg). 2) Secondary Endpoints There were no major differences in Aspirin Reaction Unit (ARU) at each evaluation point between the two treatment groups. The mean ARU (SD) by CYP2C19 genotype at 5 days after the start of study treatment was 425.8 (67.4) in the prasugrel group and 425.3 (55.5) in the standard treatment group for FAS; 435.7 (81.7) and 440.8 (65.9) for EM; 410.7 (49.1) and 416.0 (46.6) for IM; 445.9 (69.7) and 430.3 (61.5) for PM; and 419.3 (56.2) and 419.9 (51.0) for IM+PM. The proportion of HPR [95% CI] at 5 days after the start of study treatment was 11.0 [5.1, 19.8] % in the prasugrel group and 29.1 [19.4, 40.4] % in the standard treatment group, with a difference [95% CI] of -18.1 [-30.2, -6.1] %, significantly lower in the prasugrel group. The proportion of High Platelet Reactivity (HPR) [95% CI] by CYP2C19 genotype at 5 days after the start of study treatment was as follows: for EM, it was 3.1 [0.1, 16.2] % in the prasugrel group and 20.0 [5.7, 43.7] % in the standard treatment group, with a difference [95% CI] of -16.9 [-35.4, 1.7] %. For IM, the proportion was 10.5 [2.9, 24.8] % in the prasugrel group and 27.9 [15.3, 43.7] % in the standard treatment group, with a difference [95% CI] of -17.4 [-34.0, -0.8] %, which was significantly lower in the prasugrel group. For PM, it was 33.3 [9.9, 65.1] % in the prasugrel group and 43.8 [19.8, 70.1] % in the standard treatment group, with a difference [95% CI] of -10.4 [-46.5, 25.7] %. For IM+PM, the proportion was 16.0 [7.2, 29.1] % in the prasugrel group and 32.2 [20.6, 45.6] % in the standard treatment group, with a difference [95% CI] of -16.2 [-31.9, -0.5] %, which was significantly lower in the prasugrel group. MRI diffusion-weighted imaging at 5 days after the start of study treatment reported new infarct lesions in 21 patients, no lesions in 60 patients, and unknown in 3 patients in the prasugrel group (84 patients); and in 25 patients, no lesions in 55 patients, and unknown in 1 patient in the standard treatment group (81 patients). There were no major differences between the two treatment groups, as well as CYP2C19 genotype. The NIHSS score decreased in both groups after the start of administration. The mean change (SD) at either 21 days after the start of study treatment or discharge, whichever was earlier, was -1.4 (1.7) in the prasugrel group and -0.8 (1.3) in the standard treatment group. The modified Rankin Scale also decreased in both groups at 90 days after the start of study treatment, with the mean change (SD) from baseline being -0.3 (1.6) in the prasugrel group and -0.3 (1.5) in the standard treatment group.

This study compared platelet reactivity between prasugrel and clopidogrel, considering CYP2C19 gene polymorphisms, in patients with acute large artery atherosclerosis (LAA) or high-risk TIA. The primary endpoint, PRU 5 days after the start of administration, was more stable inhibition in the prasugrel group than in the standard treatment group, regardless of CYP2C19 polymorphisms as EM, IM and PM. No significant differences between the two treatment groups were observed in AEs and adverse drug reactions.

Aug. 01, 2025

July. 15, 2025

https://www.jstage.jst.go.jp/article/circrep/advpub/0/advpub_CR-25-0077/_article/-char/en

Yes

The datasets generated and/or analyzed during the current study will be available from the corresponding author and the study sponsor on reasonable request.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031220079

Fujimoto Shigeru

Jichi Medical University Hospital

3311-1, Yakushiji, Shimotsuke-shi, Tochigi-ken, Japan

shigeruf830@jichi.ac.jp

Fujimoto Shigeru

Jichi Medical University Hospital

3311-1,Yakushiji, Shimotsuke-shi, Tochigi-ken, Japan

+81-285-58-7352

shigeruf830@jichi.ac.jp

Complete

May. 20, 2022

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1. Patients age are over 20 years at informed consent
2. Patients with acute atherothrombotic cerebral infarction (with a stenosis rate of >= 50% in diameter or complete occlusion of the culprit vessel due to atherosclerosis) with a NIH Stroke Scale score of <= 10 or patients with high-risk TIA (ABCD2 risk score >= 4 or paralyzed)
3. Patients who can receive the study drug within 48 hours after onset of symptoms. The origin of symptom onset is defined as the time point when the normal condition was finally confirmed
4. Patients with at least one of the following risk factors
i) Hypertension: patients with a systolic blood pressure of 140 mmHg and a diastolic blood pressure of 90 mmHg or higher, or patients who received therapeutic drugs
ii) Diabetes mellitus: HbA1c >= 6.5% or patients who received therapeutic drugs
iii) Chronic kidney disease: patients with eGFR < 60 mL/min/1.73 m2 or urinary protein >= 1+
iv) Dyslipidemia: LDL cholesterol >= 120 mg/dL, HDL cholesterol < 40 mg/dL, triglyceride >= 150 mg/dL, or therapeutic drugs
v) Medical history of cerebral infarction before the onset of index cerebral infarction or TIA
5. Patients from whom written informed consent is obtained after receiving an explanation on the details of this clinical study (consent obtained from patients as long as possible after consent from their legally acceptable representative in urgent situations)

1. Patients with a baseline modified Rankin Scale of >= 3
2. Patients who cannot undergo a brain MRI
3. Patients with moderate or high-risk cardiogenic embolic sources in the TOAST classification
4. Patients with or have a medical history of symptomatic nontraumatic intracranial hemorrhage, excludes asymptomatic microbleeding found only on MRI
5. Patients with subarachnoid hemorrhage or with high risk of subarachnoid hemorrhage such as an untreated unruptured cerebral aneurysm of 5 mm or more
6. Patients with cerebral hemorrhage at enrollment which are hemorrhagic infarction, vitreous bleeding, retinal bleeding, blood stasis, hematemesis, bloody urine, bloody stool, melena, hemorrhage, etc., and patients with a high risk of cerebral hemorrhage which are congenital or acquired bleeding diseases, blood coagulation disorders, platelet abnormalities, peptic ulcer etc.
7. Patients who were planned to undergo endovascular thrombectomy or cerebral revascularization, which are carotid endarterectomy, carotid artery stenting etc., for the last cerebral ischemic attack at enrollment
8. Patients who have undergone or were planned to undergo Intravenous rt-PA therapy etc., for the index cerebral infarction at enrollment
9. Patients who scheduled for surgery requiring discontinuation of the study drug during clinical trial
10. Patients who have severe hepatic disorder (fulminant hepatitis, cirrhosis, malignant liver tumors etc.,)
11. Patients who have severe renal disorder requiring dialysis
12. Patients with malignant tumors with requirement for treatment
13. Autoimmune disease
14. Patients who received antiplatelet drugs except for aspirin (such as clopidogrel, prasugrel, cilostazol, ticlopidine or ozagrel sodium) and Anticoagulant (excluding argatroban) within 14 days prior to the initiation of the study treatment
15. Patients who have a medical history of significant side effects or contraindications to prasugrel, clopidogrel or aspirin and patients with a medical history of serious drug allergy (including hypersensitivity to ingredients of this drug)
16. Patients who were pregnant, breastfeeding, or possibly pregnant or planned to be pregnant
17. Patients who are planning to participate in or are participating in other clinical trials during this clinical trial
18. Patients who were judged by the investigator to be ineligible for the study

Both

Acute-phase Atherothrombotic Cerebral Infarction and high risk TIA

Prasugrel group
Plasugrel and aspirin are administered once daily by Oral.
The basic duration of dual antiplatelet therapy is 21 days according to the stroke treatment guidelines 2021.

Standard group
Clopidogrel and aspirin are administered once daily by Oral.
The dose of clopidogrel is set at the discretion of the investigator for each patients according to the Japanese and overseas guidelines.
The basic duration of dual antiplatelet therapy is 21 days according to the stroke treatment guidelines 2021.

EFFICACY ASSESSMENTS
-Platelet aggregation (PRU) at 5 days after administration of the study drug in patients with each genetic polymorphism of CYP2C19
-Platelet aggregation (PRU) at 5 days after administration of the study drug in all patients

EFFICACY ASSESSMENTS
-Proportion of PRU/Asprin Reaction Unit and high platelete reactivity (PRU > 208) by CYP2C19 genetic polymorphism in all patients, Extensive Metabolizer, Intermediate Metabolizer, and Poor Metabolizer (predose, at 12 hours to 48 hours postdose, and at 5 days postdose)
-Presence or absence of a new infarction evaluated by MRI diffusion-weighted imaging (before administration, at 5 days after administration)
-Cumulative Incidence of the following Cerebro and Cardiovascular Events
1. Stroke (cerebral infarction, cerebral hemorrhage, and Subarachnoid hemorrhage) and TIA
2. myocardial infarction
3. death (all-cause death, vascular death, ischemic vascular death, other reasons)
4. composite endpoint 1 (cerebral infarction, myocardial infarction, ischemic vascular death)
5. composite endpoint 2 (composite endpoint 1, and TIAs)
6. Other event of arterial thrombosis and embolism
-NIHSS score (before administration, at 5 days after administration, at 21 days after administration, or at discharge, whichever comes first)
-Modified Rankin Scale (at 21 days after administration or at discharge, whichever comes first, and 90 days after administration)

Safety endpoints
-Cumulative Incidence of the following Bleeding Events
1. Major bleeding (POINT study criteria)
2. Minor bleeding (POINT study criteria)
3. Intracranial hemorrhage (Symptomatic intracranial hemorrhage, asymptomatic intracranial hemorrhage)
4. Other bleeding events (ISTH bleeding criteria: major bleeding, GUSTO bleeding criteria: Severe or life-threatening bleeding, moderate bleeding, minor bleeding, MATCH bleeding criteria: life-threatening bleeding, major bleeding, clinically significant bleeding, and other bleeding)
-Other Adverse Event Items

+81-3-3470-3360

April. 22, 2022

none