INTRODUCTION
As the effectiveness of best medical treatment in preventing ischemic stroke has improved, reducing perioperative complications associated with carotid artery stenting (CAS) has become increasingly important [16]. The complications associated with CAS can be broadly categorized into ischemic, hemorrhagic, and systemic events. In particular, various strategies have been explored to minimize ischemic complications, including the use of protection devices and perioperative antithrombotic therapy. Dual antiplatelet therapy (DAPT) has been shown to reduce the risk of ischemic events without significantly increasing bleeding complications within 30 days compared to single antiplatelet therapy (SAPT), suggesting it may improve neurological outcomes following CAS [13]. In Japan, DAPT is employed in approximately 81.7% of CAS cases as part of perioperative management [19]. However, no standardized regimen has been established [2].
Traditionally, DAPT has consisted of aspirin (ASA) and clopidogrel (CLP). However, in Japan and other Asian populations, the prevalence of CYP2C19 polymorphisms is higher than in Western populations, and resistance to CLP is more common. This resistance has been implicated in increased perioperative neurological events following CAS [16]. Prasugrel (PRAS), on the other hand, exerts a more consistent antiplatelet effect regardless of CYP2C19 polymorphism due to its unique metabolic pathway. Therefore, DAPT regimens including PRAS may reduce perioperative neurological events, although its superiority in CAS has not yet been clearly demonstrated [12,22].
The aim of this study was to evaluate the utility of individualized DAPT regimens based on platelet reactivity testing as a form of precision medicine in CAS, and to determine whether this approach could reduce perioperative ischemic changes.
MATERIALS AND METHODS
Study design
This was a single-center, retrospective study of 187 consecutive patients who underwent elective CAS at our institution between January 2018 and September 2024. The study was approved by the Institutional Review Board of Yokohama Municipal Citizen’s Hospital (IRB No. Z250306).
All patients received antiplatelet therapy for at least 14 days prior to CAS [11]. Beginning in January 2021, the perioperative DAPT protocol was changed to an individualized approach using the VerifyNow (Werfen) assay. Based on this, patients were divided into two groups : those who underwent CAS between January 2018 and January 2021 were assigned to the conventional DAPT group (c-DAPT), while those treated between February 2021 and September 2024 were assigned to the precision DAPT group (i-DAPT). In the c-DAPT group, ASA 100 mg/day plus CLP 75 mg/day was administered. In the i-DAPT group, patients received either ASA 100 mg/day + CLP 75 mg/day or ASA 100 mg/day + PRAS 3.75 mg/day.
Treatment indications for internal carotid artery (ICA) stenosis were as follows : for symptomatic lesions, ≥50% stenosis by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method on cerebral angiography with transient or permanent symptoms such as hemiparesis, aphasia, or amaurosis fugax; for asymptomatic lesions, ≥70% stenosis. Patients with ICA occlusion, ICA dissection, or re-treatment cases were excluded. Data were retrospectively collected from medical records, including patient backgrounds (hypertension, diabetes mellitus, dyslipidemia, cardiac disease, prior cerebral infarction, smoking, atrial fibrillation), lesion characteristics (degree of stenosis, ulceration, calcification, unstable plaque), antiplatelet therapy, procedural details, and perioperative complications (ischemic changes, ischemic and hemorrhagic events). There were no missing values for the analyzed variables, as only items consistently available from medical records and imaging were included.
Plaque assessment was performed preoperatively using magnetic resonance (MR) imaging. Using axial T1- and T2-weighted MR images, regions of interest were placed within the sternocleidomastoid muscle and the plaque at the point of maximum ICA stenosis, and the plaque-to-muscle ratio (P/M ratio) was calculated. An unstable plaque was defined as having a higher signal intensity than the sternocleidomastoid muscle (P/M ratio >1) on either T1- or T2-weighted images, or on both [8]. Image evaluation was independently performed by two neurosurgeons. Interobserver agreement for the diagnosis of unstable plaque was assessed using Cohen’s kappa coefficient.
All patients underwent diffusion-weighted imaging (DWI) on the day after CAS, and new hyperintense lesions were defined as ischemic changes [5,17]. The imaging findings were evaluated by multiple neurosurgeons, and in cases of disagreement, a consensus decision was reached. Among these, ischemic complications were defined as those that resulted in clinical symptoms. We compared ischemic changes and ischemic/hemorrhagic complications between the c-DAPT and i-DAPT groups.
Adjustment of antiplatelet therapy using VerifyNow
In the i-DAPT group, platelet reactivity was measured 4 days prior to treatment using VerifyNow. Antiplatelet regimens were adjusted to achieve an optimal P2Y12 reaction units (PRU) range of 95-208 [15]. For patients with PRU <95 (hyper-responders), CLP was reduced to 50 mg or PRAS to 2.5 mg as appropriate. For patients with PRU >208 (hypo-responders), CLP was switched to PRAS 3.75 mg. If PRU remained above 208 despite this adjustment, intravenous ozagrel was administered intraoperatively as a rescue therapy.
Surgical procedure
The CAS procedure was tailored to the patient’s vascular anatomy and plaque characteristics. The transfemoral approach was generally used; if access was difficult, the brachial approach was selected. Under local anesthesia, systemic heparinization was performed to maintain activated clotting time >275 seconds.
Distal balloon protection or distal filter protection was used to prevent distal embolism, and flow reversal was added as needed. Pre- and post-dilatation were performed in all cases using balloon sizes based on the reference diameter distal to the stenosis. Balloon inflation pressure and duration were adjusted based on the patient’s condition. The stent type - Precise (Kaneka medics, Tokyo, Japan), CASPER (TERUMO, Tokyo, Japan), Wallstent (Boston Scientific, Marlbourough, New zealand), or Protégé (Medtronic, Dublin, Ireland) - was selected based on plaque morphology and vessel tortuosity (see Supplementary Table 1).
Statistical analysis
Categorical and continuous variables regarding patient background were compared using Fisher’s exact test and the t-test, respectively. To identify independent risk factors for ischemic changes after CAS, we performed multivariate logistic regression using a stepwise method with the following variables : diabetes mellitus, hypertension, VerifyNow use, atrial fibrillation, symptomatic lesion, and unstable plaque. Furthermore, to evaluate the effect of VerifyNow-guided therapy in high-risk subgroups, we calculated odds ratios for ischemic changes between the c-DAPT and i-DAPT groups stratified by risk factors. To determine the extent to which VerifyNow-guided precision antiplatelet therapy reduces the risk of postoperative ischemic changes, we examined the relative risk in each group. A p-value <0.05 was considered statistically significant. Analyses were performed using JMP Pro version 18 (JMP Statistical Discovery LLC, Cary, NC, USA).
RESULTS
A total of 187 patients were included : 89 in the c-DAPT group and 98 in the i-DAPT group. There were no significant differences in age or sex between the two groups. Dyslipidemia and ischemic heart disease were more common in the c-DAPT group, while other comorbidities such as diabetes mellitus, hypertension, prior cerebral infarction, atrial fibrillation, and smoking were similarly distributed.
Lesion characteristics, including the frequency of symptomatic lesions, ulcerated plaques, and unstable plaques, were comparable between groups. The average NASCET stenosis rate also showed no significant difference (Table 1). The interobserver agreement for the diagnosis of unstable plaque was substantial (κ=0.79).
In the i-DAPT group, 34 patients (34.6%) received ASA + CLP 75 mg/day, and 64 patients (65.4%) received ASA + PRAS 3.75 mg/day. VerifyNow testing performed 4 days before treatment showed that therapeutic PRU values (95-208) were achieved in 64.7% of patients on CLP and 67.2% of those on PRAS. Hyper-responders (PRU <95) and hypo-responders (PRU >208) were observed in both subgroups, and dose adjustments were made accordingly (Fig. 1).
Ischemic changes detected on postoperative DWI occurred in 62.9% of the c-DAPT group and 51.0% of the i-DAPT group, showing a trend toward reduction in the i-DAPT group. Symptomatic ischemic events were rare and comparable between groups. Hemorrhagic complications were also infrequent and did not differ significantly (Table 2).
Multivariate logistic regression identified hypertension, unstable plaque, and diabetes mellitus as independent risk factors for ischemic changes following CAS (Table 3). Subgroup analysis demonstrated a statistically significant reduction in ischemic changes in patients with unstable plaque who received VerifyNow-guided antiplatelet adjustment, while no significant effect was observed in other subgroups (Table 4).
DISCUSSION
In this single-center, historical control study, we evaluated the efficacy of individualized DAPT using VerifyNow in patients undergoing CAS. All patients in this study received DAPT during the periprocedural period, and tailored CAS procedures were performed using protection devices and stents selected based on plaque characteristics and vascular anatomy. The overall complication rate was 5.3% (5.6% in the c-DAPT group vs. 5.1% in the i-DAPT group), demonstrating a favorable safety profile comparable to the JR-NET3 study cohort [3]. Individualized DAPT was found to be safe and did not increase the rate of hemorrhagic complications. Notably, the use of VerifyNow-guided DAPT resulted in a 24% reduction in the risk of ischemic changes in patients with unstable plaques.
CAS has become an established treatment for ICA stenosis alongside carotid endarterectomy (CEA). However, large-scale clinical trials comparing CAS and CEA have reported a higher incidence of periprocedural ischemic events in the CAS group, highlighting the need to minimize such complications in order to further improve CAS safety [18,20].
DAPT has been shown to reduce ischemic complications without increasing 30-day hemorrhagic events when compared with SAPT [3], and has thus become widely used in clinical practice. However, standardized DAPT regimens remain undefined. CLP is frequently used but is known to have hypo-responders. CLP hypo-responsiveness can be attributed to both intrinsic factors (e.g., CYP2C19 polymorphisms, common in Asian populations; gastrointestinal absorption; hepatic metabolism) and extrinsic factors (e.g., drug interactions), with varied reported prevalence [4,10,21,22]. In cardiology, VerifyNow-guided adjustment of antiplatelet therapy has been associated with reduced thrombotic and hemorrhagic events, and PRAS-based DAPT has shown efficacy in reducing major cardiovascular events following coronary stenting [1].
In the neurointerventional field, CLP hypo-responsiveness has been linked to increased periprocedural neurologic events after CAS [3], though specific management strategies have not been established [4]. Therefore, in the present study, we investigated whether individualized adjustment of antiplatelet therapy based on VerifyNow prior to CAS could reduce ischemic events.
Previous studies have shown that a higher number of DWI-positive lesions is associated with increased risk of symptomatic stroke, making DWI positivity an important surrogate marker of periprocedural outcomes [5]. Our study identified hypertension, diabetes mellitus, and unstable plaque as independent predictors of DWI-positive ischemic changes following CAS. Prior systematic reviews have identified other risk factors such as advanced age, vascular anatomical complexity, and plaque vulnerability [5]. The findings of this study support those observations, as hypertension and arteriosclerosis have been associated with tortuosity at the origin of the ICA [6], which increases the risk of plaque disruption during stenting [9]. Diabetes is both a risk factor for carotid atherosclerosis and for increased periprocedural risk during CAS [7]. Furthermore, unstable plaque was confirmed as an independent predictor of ischemic changes in our cohort.
Importantly, the ischemic risk reduction effect of individualized DAPT was observed only in patients with unstable plaques. This suggests that individualized DAPT mitigates the risk of platelet aggregation triggered by plaque rupture during stent deployment in unstable plaque lesions [14]. This finding may explain why the efficacy of individualized DAPT is not generalizable to all CAS patients, as ischemic events may also result from uncontrollable factors such as anatomical complexity and aging. Thus, comprehensive periprocedural management including appropriate protection device selection and stent choice remains essential. Nonetheless, in high-risk patients with unstable plaques, individualized DAPT may contribute significantly to the reduction of thromboembolic complications.
This study has several limitations. It was a single-center, nonrandomized historical control study, and potential selection and treatment biases may have influenced the results. The sample size was limited, and the low incidence of DWI positivity and adverse events constrained the statistical analysis. Moreover, although DWI positivity was used as a surrogate marker for ischemic change, long-term clinical outcomes were not assessed. Additionally, although subgroup analysis suggested that VerifyNow-guided DAPT significantly reduced ischemic events in patients with unstable plaque, a formal interaction test did not confirm a statistically significant difference in treatment effect between subgroups (interaction p=0.495). Therefore, this finding should be interpreted with caution and regarded as exploratory.
In addition, subgroup analyses inherently carry several limitations, including reduced statistical power, increased risk of type I error, and the absence of formal interaction testing. This study was retrospective, and the protocol, including the treatment device, was not standardized; the device used changed during the study period. Importantly, substantial differences in procedural characteristics and stent selection were observed between the c-DAPT and i-DAPT groups. In the i-DAPT group, flow reversal method was more frequently applied, which may have reduced the risk of distal embolization, particularly in patients with sufficient ICA occlusion tolerance. Furthermore, the CASPER dual-layer micromesh stent, which requires more stringent antiplatelet management due to its thrombogenic profile, was used in over half of the i-DAPT cases. These procedural factors may have contributed to the observed reduction in ischemic complications, suggesting that the effect may not be solely attributable to VerifyNow-guided therapy but rather to a combination of improved periprocedural management strategies.
Despite these limitations, the study provides important insights into a specific subgroup of CAS patients—those with unstable plaques—who may benefit from individualized DAPT. To strengthen and validate these findings, large-scale prospective multicenter studies with standardized procedural protocols and long-term follow-up are warranted.
CONCLUSION
Individualization of antiplatelet regimens using the VerifyNow assay may help reduce perioperative ischemic complications in patients with unstable plaque undergoing CAS, a high-risk subgroup. This individualized approach to antiplatelet therapy may enhance the safety of CAS procedures in selected patients. Further multicenter and randomized studies are needed to optimize antiplatelet strategies, identify the useful subgroup and confirm the clinical benefit of individualized therapy.
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