P2Y₁₂ Reaction Units With Prasugrel in Acute Large Artery Atherosclerosis and Transient Ischemic Attack: An Open-Label Randomized Controlled Study, ACUTE-PRAS

Abstract

Background: The antiplatelet effect of prasugrel for acute ischemic stroke or transient ischemic attack (TIA) remains unclear. This study compared platelet reactivity between prasugrel and clopidogrel, considering cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene polymorphisms (extensive metabolizers [EM], intermediate metabolizers [IM], and poor metabolizers [PM]), in patients with acute large artery atherosclerosis (LAA) or high-risk TIA.

Methods and Results: In this multicenter open-label randomized controlled study, patients with acute LAA or high-risk TIA received prasugrel or clopidogrel with aspirin. The primary endpoint was platelet reaction units (PRU) 5 days after the start of drug administration, stratified according to CYP2C19 polymorphism. In all, 176 patients participated (88 in each group). Compared with the clopidogrel group, PRU on Day 5 in the prasugrel group were significantly lower in the overall population (adjusted mean 136.0 vs. 169.9; estimated difference −33.9; 95% confidence interval [CI] −49.0, −18.8), EM group (118.5 vs. 144.8; estimated difference −26.2; 95% CI −48.0, −4.4), and IM group (140.3 vs. 173.1; estimated difference −32.8; 95% CI −56.6, −9.0), and tended to be lower in the PM group (164.7 vs. 196.2; estimated difference −31.6; 95% CI −68.3, 5.1). The prevalence of new infarct lesions was comparable between the prasugrel and clopidogrel groups, as was the incidence of adverse events (30.7% vs. 26.1%, respectively) and bleeding events up to Day 5 of administration.

Conclusions: In patients with acute LAA or high-risk TIA, prasugrel resulted in stable inhibition of platelet aggregation 5 days after starting drug administration compared with clopidogrel, regardless of CYP2C19 polymorphisms.

Dual antiplatelet therapy, including aspirin and clopidogrel, is an established acute antithrombotic treatment for patients with acute mild non-cardioembolic stroke or high-risk transient ischemic attack (TIA).^1–3 Clopidogrel, a P2Y₁₂ receptor inhibitor, is metabolized via a 2-step process, with the first step heavily reliant on cytochrome P450 family 2 subfamily C member 19 (CYP2C19).⁴ Individuals are classified into 3 main categories according to polymorphisms in the CYP2C19 gene: extensive metabolizers (EM), without any mutations in CYP2C19; intermediate metabolizers (IM), with a heterozygous mutation; and poor metabolizers (PM), with homozygous mutations.⁵ East Asians, including the Japanese population, have a high prevalence of IM or PM (67%).⁶ Individuals categorized as IM or PM have lower serum levels of the active clopidogrel metabolite and reduced inhibition of platelet aggregation compared with EM individuals.⁴ Importantly, clopidogrel with aspirin reduces the rate of new stroke in patients without CYP2C19 loss-of-function alleles (EM) compared with aspirin alone, but not in patients classified as IM or PM.⁷

Prasugrel is a potent antiplatelet agent used for the treatment of ischemic heart disease after percutaneous coronary intervention.⁸ Because the metabolism of prasugrel is less affected by CYP2C19 polymorphisms,⁹ prasugrel could have consistent beneficial effects regardless of metabolizer type. In Japan, based on the results of the PRASTRO-I, -II, and -III studies,^10–12 prasugrel was approved for the prevention of recurrent stroke in patients with large artery atherosclerosis (LAA) or small vessel occlusion. However, these Phase 3 trials did not include patients with acute stroke within 7 days of onset. Therefore, the antiplatelet effects and safety of prasugrel for patients with acute stroke or TIA are unknown.

The objective of this study was to compare platelet reactivity between prasugrel and clopidogrel, in combination with aspirin, in patients with acute LAA or high-risk TIA according to CYP2C19 gene polymorphisms.

Methods

Study Design

This multicenter open-label randomized controlled trial enrolled patients at 43 institutions in Japan between 4 July 2022 and 26 December 2023. The participating institutions are listed in Supplementary Table 1. The treatment duration was 90 days, and this study includes data up to Day 5 after study drug administration. This wan an open-label study, but the independent evaluation committee responsible for the adjudication of adverse events (AEs) was blinded to the intervention received by each treatment arm.

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and the protocol was approved by the Ethics Committee of the Hattori Clinic Certified Review Board (CRB3180027, April 22, 2022). The study was preregistered with the Japan Registry of Clinical Trials (jRCTs031220079, May 20, 2022), and all patients provided written informed consent.

Patients

To be eligible for this study, patients had to be aged ≥20 years; have either ischemic stroke caused by LAA according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification (i.e., stenosis ≥50% or occlusion of the culprit large vessel)¹³ and a National Institutes of Health Stroke Scale (NIHSS) score of ≤10¹⁴ or high-risk TIA at enrollment (ABCD² risk score ≥4 or paralysis);¹⁵ have ≥1 risk factor (comorbid hypertension, dyslipidemia, diabetes, chronic kidney disease, or a history of stroke prior to the onset of the last ischemic attack); and could receive the study treatment within 48 h of symptom onset. The full exclusion criteria are provided in the Supplementary Methods.^13,16,17

Background factors were recorded, including vascular risk factors and CYP2C19 gene polymorphism (evaluated using the InvaderPlus^® assay; BML, Inc., Tokyo, Japan). Patients were categorized as EM (without mutations; *1/*1), IM (heterozygous mutations; *1/*2 or *1/*3), or PM (homozygous mutations; *2/*2, *2/*3, or *3/*3).

Interventions

Eligible patients were randomly allocated to receive prasugrel or clopidogrel using argatroban treatment as the allocation factor. Patients received an initial dose of prasugrel or clopidogrel orally within 48 h of the onset of stroke symptoms and continued once-daily treatment for 90 days. For the first 21 days, patients received dual antiplatelet therapy with aspirin.¹ The initial clopidogrel dosage was 300 mg as a loading dose (LD) or a maintenance dose of 75 or 50 mg once daily, at the discretion of the attending physician. Prasugrel was administered at a dose of 3.75 or 2.5 mg once daily without the initial LD, per the Japanese package insert.⁸ The concomitant use of antiplatelet agents (other than the study drugs and aspirin), anticoagulants (excluding intravenous argatroban), thrombolytic agents, and omeprazole was prohibited.

Study Endpoints

The primary endpoint was the platelet reaction units (PRU) on Day 5 after the start of study drug administration in the overall population and according to CYP2C19 polymorphism (EM, IM, and PM). PRU were evaluated in 6- to 8-mL whole-blood samples using the VerifyNow^® P2Y₁₂ assay (Accumetrics Inc., San Diego, CA, USA), with collection methods standardized across all facilities.¹⁸ The secondary endpoints were PRU at baseline before study drug administration and 12–48 h after administration; the proportion of patients with high platelet reactivity (HPR), defined as PRU >208 on Day 5 after the start of drug administration;¹⁹ factors associated with HPR (described in the Supplementary Methods); and new infarcts assessed by magnetic resonance imaging diffusion-weighted images (on Day 5 after the start of drug administration; see Supplementary Methods).

The safety endpoints included the incidence of bleeding events, AEs, and adverse drug reactions within 5 days of starting drug administration and were classified using the Japanese language version of the Medical Dictionary for Regulatory Activities version 26.1 by System Organ Class and Preferred Term. AEs were assessed and documented by the attending physicians. An AE was defined as any unwanted or unintended sign (including abnormal laboratory findings), symptom, or disease that occurred during the study period, regardless of its causal relationship to the study drug. Conditions or diseases present prior to study enrollment were classified as comorbidities or medical history and not considered AEs unless they worsened during study, in which case they were categorized as AEs. Bleeding event classifications are described in the Supplementary Methods.²⁰

Statistical Analyses

The target population was 200 patients (100 in each treatment group) or 14 patients categorized as PM in each group (see Supplementary Methods). Enrollment ended when either condition was met. Efficacy analyses were conducted using data from the full analysis set, supplementary efficacy analyses were conducted using data from the per-protocol set, and safety analyses were conducted using the safety analysis set (Supplementary Methods).

A linear mixed model was used to calculate the adjusted mean and its 95% confidence interval (CI), the estimated difference in adjusted mean values (the prasugrel group minus the clopidogrel group) and their 95% CIs, and P values. This model used PRU on Day 5 after treatment initiation as the response variable; the treatment group, time point of evaluation, treatment group×time point of evaluation interaction, and randomization allocation factor as fixed effects; each patient as the random effect; and PRU before treatment initiation as the covariate. Other analyses are described in the Supplementary Methods. A 2-sided 5% significance level with a 2-sided 95% CI was used (unless stated otherwise). Statistical analyses were conducted using SAS version 9.4 or later (SAS Institute Inc., Cary, NC, USA).

Results

Patients

In all, 186 patients were enrolled in the study, with enrollment ending because the target number of PM was exceeded, and 181 patients were randomized (Figure 1). The full analysis set included 88 patients per group. The baseline characteristics for the full analysis set and per-protocol set are presented in Table 1 and Supplementary Table 2, respectively. Baseline characteristics were similar between the 2 groups. There were 61 (69.3%) and 27 (30.7%) patients with LAA and high-risk TIA, respectively, in the prasugrel group, compared with 64 (72.7%) and 24 (27.3%) in the clopidogrel group. The respective proportions of EM, IM, and PM were 37.5%, 43.2%, and 15.9% in the prasugrel group, and 25.0%, 48.9%, and 19.3% in the clopidogrel group.

Figure 1.

Patient disposition.

Table 1.

Baseline Characteristics (Full Analysis Set)

	Prasugrel (n=88)	Clopidogrel (n=88)
Age, years	70.4±10.8	71.1±11.3
Age ≥75 years	36 (40.9)	35 (39.8)
Male sex	60 (68.2)	64 (72.7)
Body mass index (kg/m2)	24.54±4.15	23.60±3.24
Diagnosis
Acute large artery atherosclerosis	61 (69.3)	64 (72.7)
High-risk TIA	27 (30.7)	24 (27.3)
NIHSS score	2.2±2.2	1.8±2.2
Initial dose
Prasugrel 3.75 mg	88 (100.0)	0
Clopidogrel 300 mg/75 mg	0	45 (51.1)/43 (48.9)
Complications
Hypertension	75 (85.2)	74 (84.1)
Dyslipidemia	67 (76.1)	67 (76.1)
Diabetes	39 (44.3)	37 (42.0)
Chronic kidney disease	32 (36.4)	31 (35.2)
Medical history
Ischemic stroke	14 (15.9)	5 (5.7)
TIA	6 (6.8)	4 (4.5)
Ischemic heart disease or MI	3 (3.4)	4 (4.5)
Intracerebral hemorrhage	1 (1.1)	0 (0.0)
Gastrointestinal bleeding	1 (1.1)	3 (3.4)
Smoking status
Never	30 (34.1)	34 (38.6)
Former	33 (37.5)	32 (36.4)
Current	25 (28.4)	22 (25.0)
Concomitant medication
Statins	33 (37.5)	31 (35.2)
Antidiabetic medication	29 (33.0)	32 (36.4)
Antihypertensive medication	47 (53.4)	37 (42.0)
CYP2C19 inducer	0 (0.0)	0 (0.0)
CYP2C19 inhibitor	0 (0.0)	0 (0.0)
Concomitant medication
Argatroban	9 (10.2)	12 (13.6)
Pre-onset aspirin	15 (17.0)	9 (10.2)
Time from index stroke onset and trial treatment
≤24 h	69 (78.4)	70 (79.5)
>24 h	19 (21.6)	18 (20.5)
ABCD2 score in high-risk TIA	5.0±1.0	4.9±1.1
CYP2C19 polymorphism
EM	33 (37.5)	22 (25.0)
IM	38 (43.2)	43 (48.9)
PM	14 (15.9)	17 (19.3)
IM+PM	52 (59.1)	60 (68.2)
Unknown	3 (3.4)	6 (6.8)
Stenosis site
Cervical carotid artery	14 (15.9)	16 (18.2)
Intracranial internal carotid artery	15 (17.0)	10 (11.4)
Anterior cerebral artery	2 (2.3)	3 (3.4)
Middle cerebral artery M1	16 (18.2)	30 (34.1)
Middle cerebral artery M2	12 (13.6)	9 (10.2)
Posterior cerebral artery	1 (1.1)	1 (1.1)
Vertebral artery	11 (12.5)	5 (5.7)
Basilar artery	6 (6.8)	3 (3.4)
Unknown	11 (12.5)	11 (12.5)
Severity of stenosis
Complete occlusion	13 (14.8)	5 (5.7)
Severe	26 (29.5)	37 (42.0)
Moderate	32 (36.4)	28 (31.8)
Mild	6 (6.8)	7 (8.0)
Unknown	11 (12.5)	11 (12.5)

Data are given as n (%) or mean±SD. CYP2C19, cytochrome P450 family 2 subfamily C member 19; EM, extensive metabolizers; IM, intermediate metabolizers; MI, myocardial infarction; NIHSS, National Institutes of Health Stroke Scale; PM, poor metabolizers; TIA, transient ischemic attack.

PRU Results

PRU at baseline and 12–48 h after the start of drug administration were similar between the prasugrel and clopidogrel groups (Figure 2A; Supplementary Figures 1,2A,B). Compared with the clopidogrel group, PRU on Day 5 (the primary endpoint) in the prasugrel group was significantly lower in the overall population (adjusted mean 136.0 vs. 169.9; estimated difference −33.9; 95% CI −49.0, −18.8; P<0.001) and in the EM (adjusted mean 118.5 vs. 144.8; estimated difference −26.2; 95% CI −48.0, −4.4; P=0.020) and IM (adjusted mean 140.3 vs. 173.1; estimated difference −32.8; 95% CI −56.6, −9.0; P=0.008) groups, and tended to be lower in the PM group (adjusted mean 164.7 vs. 196.2; estimated difference −31.6; 95% CI −68.3, 5.1; P=0.088; Figure 2B). Among patients receiving clopidogrel, 51.1% received the LD (300 mg). The PRU at 12–48 h and 5 days after the start of administration of prasugrel and clopidogrel with or without the LD are shown in Supplementary Figure 3. The PRU (arithmetic mean) 5 days after the start of drug administration were 136.5 with prasugrel, 159.4 in the clopidogrel group with an LD, and 194.8 in the clopidogrel (75 mg) group without an LD (Supplementary Figure 3B). Similar results were observed in the per-protocol set (Supplementary Figure 4).

Figure 2.

Platelet reaction units (A) before treatment and (B) on Day 5 after the start of treatment (primary endpoint) with prasugrel or clopidogrel overall and according to cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene polymorphisms (metabolizer type) in the full analysis set. Horizontal lines indicate median values; upper and lower box edges indicate the interquartile range (IQR); and the upper and lower whiskers represent the first quartile − 1.5 × IQR and the third quartile + 1.5 × IQR, respectively. Diamonds represent the arithmetic mean and outliers are denoted by asterisks. Adjusted means were calculated using a linear mixed model with treatment group, time of evaluation, and treatment group×time of evaluation as fixed effects, and PRU before treatment initiation as the covariate. CI, confidence interval; EM, extensive metabolizers; IM, intermediate metabolizers; PM, poor metabolizers.

High Platelet Reactivity

The proportion of patients with HPR was lower overall in the prasugrel than clopidogrel group (difference −18.1%; 95% CI −30.2, −6.1; Figure 3). Similar results were observed in the per-protocol set (Supplementary Figure 5). The factors associated with HPR were the presence of HPR before treatment (odds ratio 30.2; 95% CI 2.8, 322.7) and PM status (odds ratio 6.5; 95% CI 1.5, 28.9; Table 2).

Figure 3.

Number of patients with high platelet reactivity (HPR) on Day 5 after treatment initiation (full analysis set). CI, confidence interval.

Table 2.

Multivariate Analysis for Factors Associated With High Platelet Reactivity (Full Analysis Set)

	No. patients	OR (95% CI)
Drug
Clopidogrel	77	Ref.
Prasugrel	75	0.351 (0.116, 1.061)
Diagnosis
Atherothrombotic stroke	106	Ref.
High-risk TIA	46	2.148 (0.687, 6.717)
Age
≤75 years	97	Ref.
>75 years	55	1.126 (0.370, 3.425)
Sex
Male	109	Ref.
Female	43	1.924 (0.633, 5.854)
Body mass index
≤30 kg/m2	144	Ref.
>30 kg/m2	8	1.068 (0.081, 14.067)
Dyslipidemia
No	36	Ref.
Yes	116	0.211 (0.068, 0.651)
Diabetes
No	87	Ref.
Yes	65	1.086 (0.357, 3.302)
Chronic kidney disease
No (eGFR ≥60 mL/min/1.73 m2)	96	Ref.
Yes (eGFR <60 mL/min/1.73 m2)	56	0.956 (0.338, 2.703)
Smoking status
Never	55	Ref.
Former	55	0.532 (0.149, 1.892)
Current	42	0.798 (0.221, 2.876)
Past history of ischemic stroke or TIA
No/unknown	126	Ref.
Yes	26	0.919 (0.200, 4.232)
CYP2C19 polymorphism
EM	48	Ref.
IM	77	1.339 (0.363, 4.946)
PM	27	6.505 (1.464, 28.901)
HPR before administration
No	43	Ref.
Yes	109	30.205 (2.827, 322.718)

CI, confidence interval; eGFR, estimated glomerular filtration rate; HPR, high platelet reactivity; OR, odds ratio. Other abbreviations as in Table 1.

Imaging Results

The prevalence of new infarcts (symptomatic and asymptomatic) up to Day 5 after the start of drug administration, as assessed by diffusion-weighted imaging on Day 5, was comparable between the prasugrel and clopidogrel groups, regardless of CYP2C19 polymorphisms (Table 3). The mean (±SD) PRU were 169.3±64.8 and 151.4±59.1 for patients with (n=46) and without (n=112) new infarcts (P=0.095).

Table 3.

Proportion of New Infarcts, Assessed by Diffusion-Weighted Magnetic Resonance Imaging, on Day 5 After Treatment Initiation (Full Analysis Set)

	Prasugrel (n=88)		Clopidogrel (n=88)		P value
	N	n (%)	N	n (%)
All	81	21 (25.9)	80	25 (31.3)	0.489
EM	32	8 (25.0)	22	6 (27.3)	1.000
IM	37	11 (29.7)	43	15 (34.9)	0.642
PM	12	2 (16.7)	15	4 (26.7)	0.662
IM+PM	49	13 (26.5)	58	19 (32.8)	0.530

P values were calculated using Fisher’s exact test. Abbreviations as in Table 1.

Safety Results

The incidence of AEs within 5 days after the start of drug administration was similar between the prasugrel and clopidogrel groups (30.7% and 26.1%, respectively; Table 4). Two (2.3%) patients with prasugrel developed other bleeding per the Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH) criteria and 3 (3.4%) patients with clopidogrel developed other bleeding. No major bleeding per the International Society on Thrombosis and Haemostasis (ISTH) criteria occurred in either group within 5 days after the start of study drug administration.

Table 4.

Adverse Events and Bleeding Events Within 5 Days of Starting Drug Administration (Safety Analysis Set)

	Prasugrel (n=88)		Clopidogrel (n=88)
	No. events	No. patients (%)	No. events	No. patients (%)
Any adverse event	41	27 (30.7)	31	23 (26.1)
Bleeding events		2 (2.3)		4 (4.5)
ISTH criteria
Major bleeding		0		0
MATCH criteria
Life-threatening bleeding		0		0
Major bleeding		0		0
Clinically significant bleeding		0		1 (1.1)
Other bleeding		2 (2.3)		3 (3.4)

Adverse events and bleeding events were tabulated separately. ISTH, International Society on Thrombosis and Haemostasis; MATCH, Management of Atherothrombosis with Clopidogrel in High-risk patients.

Discussion

This study evaluated PRU in patients with acute LAA or high-risk TIA treated with prasugrel or clopidogrel in combination with aspirin. PRU after 5 days of drug administration were significantly lower in the prasugrel than clopidogrel group. This pattern of lower PRU with prasugrel was consistent across all patients regardless of CYP2C19 polymorphisms, even in patients categorized as EM (in whom there is less effect on clopidogrel metabolism). Moreover, a significantly lower proportion of patients in the prasugrel than clopidogrel group had HPR. The prevalence of newly detected infarcts identified by diffusion-weighted imaging up to Day 5 was comparable between the 2 groups, indicating similar efficacy in preventing ischemic events. There were no notable differences between the 2 groups in the incidence of AEs or bleeding events within 5 days of the start of drug administration, and no new safety concerns were identified.

Because clopidogrel is metabolized into its active form by CYP2C19,⁴ its effects are delayed in patients categorized as IM or PM. Previous studies reported that peak concentrations of the active form of clopidogrel were highest in individuals categorized as EM and were approximately 25–75% lower in patients categorized as IM or PM.^21,22 Moreover, clopidogrel-treated patients with CYP2C19 IM or PM polymorphisms have an increased risk of death and complications than patients without these polymorphisms.²³ To overcome the effect of CYP2C19 polymorphisms on the inhibition of platelet aggregation, interest in other P2Y₁₂ receptor inhibitors that are less affected by CYP2C19 polymorphisms has increased. Ticagrelor is less affected by CYP2C19 polymorphisms and reduces the risk of stroke at 90 days compared with clopidogrel in patients with minor ischemic stroke or TIA who were carriers of CYP2C19 loss-of-function alleles.²⁴

In the present study, prasugrel (which, like ticagrelor, is less affected by CYP2C19 polymorphisms) showed stable platelet aggregation inhibition by Day 5 of treatment in patients with acute LAA or high-risk TIA, even in EM individuals, in whom clopidogrel metabolism is less affected. The PRU values for prasugrel and clopidogrel with a LD, as well as PRU values at 12–48 h after the start of drug administration, were almost similar. However, compared with clopidogrel, prasugrel appeared to reduce PRU relatively earlier (at least 5 days after the start of administration) and PRU values remained stable. Another study found that residual platelet reactivity at 72 h after administration of a clopidogrel LD was substantially higher in patients with acute ischemic stroke than in patients treated with elective neurointerventional treatment, independent of the presence of CYP2C19 polymorphisms.²⁵ Compared with clopidogrel, prasugrel was associated with a reduced incidence of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in patients with acute coronary syndrome,^23,26 and a lower incidence of major adverse cardiovascular events in patients with coronary artery disease undergoing elective percutaneous coronary intervention.⁹ Although a prasugrel dose of 3.75 mg/day failed to show non-inferiority to clopidogrel in patients with non-cardioembolic stroke 1–26 weeks after onset (PRASTRO-I),¹⁰ a subsequent subanalysis of the same trial, categorized by stroke subtype, found that prasugrel was effective in patients with thrombotic stroke.²⁶ In Japan, prasugrel was approved for the prevention of recurrent stroke in patients with LAA or small vessel occlusion based on the results of the PRASTRO-III trial.¹²

In the present study, the prevalence of newly detected infarcts (both symptomatic and asymptomatic) by diffusion-weighted imaging up to Day 5 after the start of drug treatment was comparable between the prasugrel and clopidogrel groups. The PRU were numerically higher in patients with than without new infarcts. One study of patients with stroke reported that CYP2C19 polymorphisms affect clopidogrel efficacy and clinical outcomes, with PM status being correlated with poor outcomes and reduced inhibition of platelet aggregation;²⁷ however, that study did not investigate recurrent stroke. A previous study found that high PRU (≥254) after 24 h were significantly associated with recurrent ischemic stroke, especially in the acute phase (within 7 days), and high PRU (≥254) had the same or conditionally better predictive ability for recurrence within 7 days compared with the PM CYP2C19 genotype.²⁸ Lowering PRU further and resolving HPR in the acute phase is likely to improve the clinical outcomes of patients with acute ischemic stroke. Although the imaging results of the present study were insufficient to enable firm conclusions, the platelet reactivity results indicate the potential effect of prasugrel on patients with acute non-cardioembolic stroke or TIA, regardless of CYP2C19 polymorphism.

Approximately half (51%) the patients treated with clopidogrel received a LD. Treatment with a clopidogrel LD is recognized as an effective way to prevent recurrence of acute non-cardioembolic stroke and TIA; however, in Japan, there are concerns regarding its coverage by insurance, which often results in its infrequent use in daily medical practice, particularly in community hospitals. Different perceptions of clopidogrel LD between academic and community hospitals may have influenced whether patients received a clopidogrel LD in the present study.

Patients with an NIHSS score <10 were eligible for inclusion in this study, including those with moderate stroke. Previous studies have shown that patients with minor ischemic stroke (NIHSS score ≤3) treated with clopidogrel plus aspirin had a reduction in the number of new recurrent strokes within 24 h^29,30 and 72 h.³¹ In contrast, another study found that patients with mild to moderate stroke (NIHSS score 4–10) who received clopidogrel plus aspirin within 48 h of stroke onset did not have a significantly reduced incidence of new strokes.³² Therefore, it is possible that this combination has a limited effect in patients with moderate stroke. Although the prevalence of new infarcts at Day 5 after the start of drug administration was similar between the prasugrel and clopidogrel groups, long-term recurrence could not be assessed within this period. Nevertheless, our findings support the antiplatelet effects of prasugrel in patients with a wide range of NIHSS scores, including those with moderate stroke.

Bleeding is a known risk of antiplatelet therapy, particularly among patients with chronic kidney disease.³³ A recent study found that Japanese patients who had undergone percutaneous coronary intervention and who were treated with prasugrel or clopidogrel monotherapy had a similar 1-year cumulative incidence of bleeding events.³⁴ Consistent with this, the prasugrel and clopidogrel groups had a similar occurrence of bleeding events in the present study.

This study has several limitations. First, only Japanese patients were included; therefore, the findings may not be applicable to other populations. Second, although the target PM number was reached, the study had a small overall sample size. The non-significant difference in PRU at Day 5 in the PM group may be attributable to the small population in this subgroup. Third, not all patients in the clopidogrel group received the clopidogrel LD. Because clopidogrel was administered at the discretion of the attending physician, we suspect that the proportion of patients who received the clopidogrel LD reflects current clinical practice. Fourth, we could not show clinical outcomes, such as NIHSS, modified Rankin Scale score, or results of brain imaging. These data will be included in future analyses of this study. Fifth, genetic factors such as CYP2C19*17, ATP binding cassette subfamily B member 1 (ABCB1), and PON genes, which may affect antiplatelet drug response, were not assessed in this study. The lack of these assessments is a study limitation, and future studies should consider incorporating a more comprehensive genetic analysis to better understand the impact of genetic variability on drug efficacy and safety.

Conclusions

In patients with acute LAA or high-risk TIA, prasugrel resulted in stable inhibition of platelet aggregation 5 days after the start of drug administration compared with clopidogrel in the overall population, as well as in those with CYP2C19 polymorphisms. Within 5 days of starting drug administration, bleeding events and new infarct lesions were similar between the prasugrel and clopidogrel treatment groups. Further studies are needed to determine the inhibition of these events by prasugrel.

Acknowledgments

The authors thank all the study investigators, including those involved in the evaluation of images (Teruyuki Hirano, MD, PhD, Department of Stroke and Cerebrovascular Medicine, Kyorin University; Makoto Nakajima, MD, PhD, Department of Neurology, Graduate School of Medical Sciences, Kumamoto University) and judgment of AEs (Hidehiro Takekawa, MD, PhD, Department of Neurology, Dokkyo Medical University; Akira Tsujino, MD, PhD, Department of Clinical Neuroscience, Unit of Clinical Medicine, Nagasaki University Graduate School of Biomedical Sciences; Yuji Ueno, MD, PhD, Department of Neurology, Juntendo University Faculty of Medicine). The authors thank Hannah Read, PhD, of Edanz, for medical writing services, and CMIC Co., Ltd., for data management and statistical analysis, which were funded by Daiichi Sankyo Co., Ltd.

Sources of Funding

This study was supported by Daiichi Sankyo Co., Ltd., which was involved in the study design, planning of data analysis, data interpretation, and development of the manuscript, but was not involved in data management or statistical analysis. Y.Y. received research funding from the Japan Society for the Promotion of Science (KAKENHI Grant no. 21K10510), Smoking Research Foundation, and Fujii Setsuro Memorial Osaka Basic Medical Research Foundation. R.T. received research funding from the Japan Society for the Promotion of Science (KAKENHI Grant no. 21K07442).

Disclosures

S.F. has received research funding from Daiichi Sankyo Co., Ltd., and honoraria from Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., and Bristol-Myers Squibb K.K. Y.I. has received research funding from Medical Concierge Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Nagatanien Co., Ltd., and honoraria from Chugai Pharmaceutical Co., Ltd. and Daiichi Sankyo Co., Ltd. H.Y. has received research funding from Bristol-Myers Squibb K.K. and Daiichi Sankyo Co., Ltd.; honoraria from Daiichi Sankyo Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Stryker Japan K.K., Medtronic Japan K.K., Boston Scientific Japan K.K., Abbott Japan L.L.C., and Bristol-Myers Squibb K.K.; and is affiliated with endowed departments by Japan Agricultural Cooperatives of Ibaraki Prefecture. M.K. has received research funding from Daiichi Sankyo Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd., and honoraria from Daiichi Sankyo Co., Ltd. R.I. has received honoraria from Daiichi Sankyo Co., Ltd. Y.Y. has received research funding from Daiichi Sankyo Co., Ltd. and honoraria from Daiichi Sankyo Co., Ltd. and Eisai Co., Ltd. N.K. has received research funding from Daiichi Sankyo Co., Ltd. and honoraria from Stryker Japan K.K. T.S. has received research funding from Daiichi Sankyo Co., Ltd. Y.M. has received research funding from Daiichi Sankyo Co., Ltd. O.M. has received honoraria from Daiichi Sankyo Co., Ltd. S. Arakawa has received research funding and honoraria from Daiichi Sankyo Co., Ltd. R.T. has received research funding from Daiichi Sankyo Co., Ltd. and honoraria from Daiichi Sankyo Co., Ltd. and Bayer Yakuhin Ltd. W.H., S. Abe, G.K., and T.F. are employees of Daiichi Sankyo Co., Ltd. K. Kimura has received research funding from Daiichi Sankyo Co., Ltd. and Medtronic plc.; consulting fees from Daiichi Sankyo Co., Ltd.; and honoraria from Daiichi Sankyo Co., Ltd. and Bayer Yakuhin, Ltd. K. Kowata, Y.T., K.O., H.M., and T.U. have no conflicts of interest to disclose.

IRB Information

The study protocol was approved by the Ethics Committee of the Hattori Clinic Certified Review Board (CRB3180027, April 22, 2022).

Data Availability

The deidentified participant data and related study documents will be shared on request for up to 36 months after the publication of this article. Requests should be made to the corresponding author and the requestor should include a methodologically sound proposal on how the data will be used; the proposal may be reviewed by the responsible personnel at Daiichi Sankyo Co., Ltd., and the data requestor will need to sign a data access agreement. Once approved, the data will be shared in an appropriate way depending on the type of data requested.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0949

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