Abstract
Background
The safety and efficacy of half-dose ticagrelor (45 mg twice daily) dual antiplatelet therapy (DAPT) for flow diverter (FD) treatment of intracranial aneurysm (IA), particularly in Chinese patients and with PED (Pipeline embolization device) Flex Shield, remains uncertain. This study assessed whether this regimen maintains efficacy while improving safety, including its applicability to PED Flex Shield.
Methods
This single-center retrospective study analyzed consecutive IA patients undergoing FD treatment between 2019–2024, comparing standard-dose clopidogrel (75 mg daily) plus aspirin (100 mg daily) with half-dose ticagrelor (45 mg twice daily) plus aspirin (100 mg daily). Outcomes included adenosine diphosphate-induced maximal platelet aggregation (ADPi-MPA) measured by light transmittance aggregometry, perioperative complications within 30 days post-procedure, and analysis of factors influencing ADPi-MPA levels.
Results
The study included 405 IA patients (half-dose ticagrelor = 224, standard-dose clopidogrel = 181). The half-dose ticagrelor group demonstrated significantly lower ADPi-MPA (26.00 [17.45, 34.25] vs 37.70 [29.50, 43.60], P < 0.001), with comparable ischemic (3.1% vs 5.5%, P = 0.114) and hemorrhagic (2.1% vs 1.2%, P = 0.689) event rates. No significant differences in perioperative complications were found between FD types (PED/PED Flex/TED vs PED Flex Shield) when using the half-dose ticagrelor regimen (all P > 0.05). Similarly, complication rates were comparable between the two DAPT regimens across both FD subgroups (all P > 0.05).
Conclusion
This study demonstrates that half-dose ticagrelor DAPT achieves significantly lower platelet reactivity (ADPi-MPA) compared to standard-dose clopidogrel, with no statistically significant differences in ischemic or hemorrhagic complication rates observed among FD-treated IA patients. Importantly, the half-dose regimen shows consistent performance across different FD devices (including PED Flex Shield) without compromising perioperative safety.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00701-026-06805-7.
Keywords: Flow diverter, Dual antiplatelet therapy, Half-dose ticagrelor, Intracranial aneurysm
Introduction
Perioperative dual antiplatelet therapy (DAPT), combining aspirin with P2Y12 receptor inhibitors (standard-dose clopidogrel 75 mg daily) remains the most widely used regimen for preventing thromboembolic complications during flow diverter (FD) implantation for intracranial aneurysms (IAs) [11]. However, clopidogrel administration has several limitations, including delayed onset, significant inter-patient variability in platelet inhibition, leading to nonresponders and subsequent thrombotic events [1, 33].
Accumulating evidence from previous studies has established comparable efficacy and safety profiles between ticagrelor and clopidogrel in patients with IAs treated with FD [29]. However, the primary clinical consideration regarding ticagrelor administration involves elevated rate intracranial hemorrhage incidence, notably demonstrated in East Asian populations. While standard-dose ticagrelor (90 mg twice daily) provides anti-thrombotic benefits, its clinical application is constrained by elevated bleeding risks [4, 30]. A pooled analysis from four phase III randomized controlled trials demonstrated that the odds of intracranial hemorrhage were 1.69 fold higher with standard-dose ticagrelor (45 of 12,050; 0.37%) versus standard-dose clopidogrel (26 of 11,972; 0.22%) regimens (95% CI; 1.04–2.75; P = 0.04) [12].
To mitigate the risk of major bleeding following percutaneous coronary intervention, reduced-dose ticagrelor-based DAPT regimens have been investigated. In the PEGASUS-TIMI 54 trial and its substudy, the 60 mg twice daily ticagrelor regimen demonstrated non-inferiority compared to the standard-dose regimen in terms of platelet inhibition efficacy [2, 31]. Moreover, the 60 mg dose of ticagrelor was associated with lower rates of bleeding and dyspnea compared to the standard dose. Similarly, Mehta et al. reported that half-dose ticagrelor-based DAPT regimen is feasible for managing ischemic and hemorrhagic events in patients undergoing FD/SAC [25]. These findings show that reduced-dose ticagrelor may offer efficacy and safety similar to standard-dose ticagrelor.
The PED Flex with Shield technology is a third-generation FD used for IAs treatment designed to decrease thrombogenicity through a phosphorylcholine coating with covalent bonding to simulate the cell membrane of surrounding endothelial cells [9]. Currently, despite its antithrombotic properties, the PED Flex Shield still requires DAPT to achieve optimal antiplatelet management [28]. Mario et al. demonstrated that among patients who received PED Flex Shield implantation, 46 out of 50 (92%) were treated with DAPT (aspirin plus standard-dose clopidogrel) for between ≥ 1 month and ≤ 1 year. During the 1-year follow-up, no major strokes or neurological deaths were reported, and complete occlusion was achieved in 81.8% of cases [27]. Additionally, a prospective, single-arm study, focusing on periprocedural and 6-month outcomes after PED Flex Shield placement, confirmed the favorable safety profile of DAPT (standard-dose clopidogrel for ≥ 5 months and aspirin for ≥ 12 months).
However, despite these initial investigations into DAPT regimens with PED Flex Shield, definitive recommendations remain to be established [23], particularly concerning the use of a half-dose ticagrelor-based regimen. Therefore, our study aimed to verify whether the half-dose ticagrelor DAPT regimen could enhance the safety without compromising efficacy in FD treatment, and whether it could be safely and effectively applied in PED Flex Shield.
Methods
Study population
This retrospective study enrolled 405 patients with IAs undergoing FD embolization between June 2019 and December 2024. The inclusion criteria included the following:(1) Aged over 18 years old; (2) IAs treated with PED/PED Flex/TED and PED Flex Shield. Exclusion criteria for the study were:(1) Patients with missing AA and ADP induced maximal platelet aggregation rate; (2) Not taking dual antiplatelet after surgery; (3) Aneurysms with arteriovenous fistulas, arteriovenous malformations, and Moyamoya disease.(4) Recent acute ischemic stroke within 30 days. (5) Other diseases affecting the management of intracranial aneurysms. This study received approval from the institutional review boards of centers, and informed consent was waived owing to the anonymous design of the study.
Data collection
Demographic data comprised age, gender, comorbidity (hypertension, diabetes, hyperlipidemia, smoking, alcohol use, ischemic stroke, and coronary disease), and preoperative modified Rankin Scale (mRS) score. Angiographic assessments of IAs such as location, morphology, size, neck width, and parent vessel diameter. Two authors evaluated morphological characteristics, including location, morphology, aneurysm size, neck width, and parent vessel diameter (the average diameter of the vessels proximal and distal to the aneurysm). The researchers collected surgical details from the electronic medical record system, including the type of FD and Stent-assisted coiling.
Dual antiplatelet regimen
The included patients were administered aspirin (100 mg daily) plus standard-dose clopidogrel (75 mg daily) or plus half-dose ticagrelor (45 mg twice daily) for at least 3 days [8, 10, 14]. Then, adenosine diphosphate-induced maximal platelet aggregation (ADPi-MPA) and arachidonic acid-induced platelet inhibition rate (AA) were determined by light transmittance aggregometry (LTA), and the responsiveness to these drugs was evaluated before the operation. In the present study, clopidogrel non-responders (defined as LTA ≥ 50% of ADPi-MPA) were switched to half-dose ticagrelor twice daily [3, 17]. Postoperatively, all patients were given aspirin (100 mg daily) plus standard-dose clopidogrel or half-dose ticagrelor. DAPT duration was categorized into two subgroups (< 6 months and 6–12 months), followed by long-term aspirin monotherapy (100 mg daily).
Endovascular treatment procedure
During the procedure, patients were anticoagulated with a 3000 to 5000U bolus of intravenous heparin at the beginning of the procedure. All devices were deployed using a triaxial system that utilized catheters including the Neuron MAX (Penumbra, USA), Navien (Medtronic) or Passageway (Precision Medical, Nanjing, China). Embolization procedures involved the use of the Tubridge embolization device (TED, MicroPort, China) and Pipeline embolization device (PED, Medtronic, USA), PED Flex and PED Flex Shield. The decision on FD selection was at the discretion of the treating neurointerventionalist. In certain scenarios, such as aneurysms with a larger vessel diameter, surgeons preferred selecting a TED owing to its broader vascular adaptability. The following conditions were considered for adjunctive coiling: (1) there was a risk of stent shortening or migration; (2) Wide-necked aneurysms (neck ≥ 4 mm or dome-to-neck ratio < 2) or complex aneurysms.
Study outcomes
The periprocedural complications were identified within the electronic medical records and occurred within the 30 days after FD treatment. Ischemic complications included three rigorously defined categories: (1) Acute cerebral infarction, characterized by permanent neurological deficits in the treatment territory; (2) Transient ischemic attack (TIA), defined as reversible neurological deficits (< 24 h duration) with MRI/CT evidence of perfusion-diffusion mismatch; (3) Stent thrombosis, confirmed via serial DSA demonstrating thrombotic occlusion. Hemorrhagic events, classified into three subtypes, identified through DSA, CTA, or MRA imaging and included intraparenchymal hemorrhage (IPH), subarachnoid hemorrhage (SAH), and not otherwise specified (NOS).
Statistical analysis
Univariate analysis to compare baseline characteristics and outcomes between the 2 groups was performed using the × 2 test, Fisher exact test, Mann–Whitney U test, and standard t tests. Variables with a P value < 0.2 that exhibited clinical significance were integrated into the multivariate logistic regression models—Model 1 and Model 2. Model 1 evaluated perioperative complications associated with half-dose ticagrelor DAPT, while Model 2 focused on other perioperative complications. The monotonic association between ADPi-MPA in the half-dose ticagrelor and standard-dose clopidogrel DAPT regimens were assessed using the Kendall's Tau-b nonparametric correlation coefficient. Subgroup analyses were conducted to evaluate the perioperative complications in half-dose ticagrelor vs standard-dose clopidogrel in PED Flex Shield and PED/PED Flex/TED groups. In addition, univariate analysis was performed on the ADPi-MPA of half-dose ticagrelor and standard-dose clopidogrel to analyze their influencing factors. Significance was defined as P < 0.05. Statistical analyses were performed using SPSS Statistics 27.0 for Windows (IBM).
Results
Patients characteristics
According to the inclusion and exclusion criteria, a total of 405 IAs patients were enrolled in this study. Figure 1 showed the screening process in this study. The patients were divided into two groups according to the DAPT regimens, including 181 cases in the aspirin (100 mg daily) plus standard-dose clopidogrel (75 mg daily) group and 224 cases in the aspirin (100 mg daily) plus half-dose ticagrelor (45 mg/bid) group. Demographic characteristics, previous medical history, aneurysm characteristics and procedure details of the two groups are shown in Supplemental materials 1. 168 (41.5%) patients were treated with PED Flex Shield and 237 (58.5%) patients were treated with PED/PED Flex/TED. Patients who underwent half-dose ticagrelor group were significantly lower ADPi-MPA (26.00 [17.45, 34.25] vs 37.70 [29.50, 43.60], P < 0.001). Most aneurysms (75.1%) were located in the internal carotid artery and 47 (11.3%) aneurysms were non-saccular aneurysms. The median aneurysm neck size was 4.65 mm [3.49, 6.59 mm], and the median parental artery diameter was 4.30 mm [3.72–5.00 mm].
Fig. 1.
Flow chart
The perioperative complications of half-dose ticagrelor and standard-dose clopidogrel groups
The incidence of ischemic events showed no significant difference between the half-dose ticagrelor cohort (7/224, 3.1%; 6 acute cerebral infarction and 1 TIA) and the standard-dose clopidogrel group (10/181, 5.5%; 6 acute cerebral infarction and 4 acute stent thrombosis (P = 0.132). Regarding hemorrhagic events, the incidence was comparable between the two groups (2.1% in the half-dose ticagrelor group versus 1.2% in the standard-dose clopidogrel group, P = 0.689). Specifically, in the half-dose ticagrelor group, five hemorrhagic events occurred, including one IPH, three IPH, and one NOS event, compared to one IPH and one NOS event in the standard-dose clopidogrel group. In concluded, no statistical difference in perioperative complications among the two DAPT regimens (half-dose ticagrelor group: 5.4% vs standard-dose clopidogrel: 6.6%; P = 0.743; Table 1). Additionally, multiple logistic regression analysis failed to demonstrate any statistically significant risk factors for perioperative complications in patients on the half-dose ticagrelor DAPT regimen (Table 2).
Table 1.
Comparison of perioperative complications between half-dose ticagrelor and standard-dose clopidogrel groups
| Standard-dose Clopidogrel group | Half-dose Ticagrelor group | p | |
|---|---|---|---|
| Number | 181 | 224 | |
| Ischemic events | 0.114 | ||
| Non | 171 (94.5) | 217 (96.9) | |
| Acute cerebral infarction | 6 (3.3) | 6 (2.7) | |
| Acute stent thrombosis | 4 (2.2) | 0 (0.0) | |
| TIA | 0 (0.0) | 1 (0.4) | |
| Hemorrhagic events | 0.689 | ||
| Non | 179 (98.8) | 219 (97.9) | |
| IPH | 1 (0.6) | 3 (1.3) | |
| NOS | 1 (0.6) | 1 (0.4) | |
| SAH | 0 (0.0) | 1 (0.4) | |
| Total perioperative complications | 12 (6.6) | 12 (5.4) | 0.743 |
TIA transient ischemic attack, IPH intraparenchymal hemorrhage, NOS not otherwise specified, SAH subarachnoid hemorrhage; *, Statistic difference
Table 2.
Univariable and multivariable analysis for perioperative complications in half-dose ticagrelor DAPT regimen
| Variable | Univariate model | Mutivariate model | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P value | OR | 95% CI | P value | |
| Female | 2.162 | 0.55–14.325 | 0.328 | - | - | - |
| Hypertension | 1.554 | 0.472–5.124 | 0.458 | - | - | - |
| Diabetes | 2.284 | 0.485–8.218 | 0.237 | - | - | - |
| ADPi-MPA | 0.984 | 0.93–1.038 | 0.566 | - | - | - |
| AA | 0.978 | 0.814–1.118 | 0.78 | - | - | - |
| Hyperlipidemia | 0.764 | 0.115–3.031 | 0.734 | - | - | - |
| Coronary | - | - | - | - | - | - |
| Ischemic stroke history | 0.978 | 0.146–3.911 | 0.977 | - | - | - |
| Age | 1.03 | 0.98–1.087 | 0.262 | - | - | - |
| Preoperative mRS: Favorable (mRS score 0–2) | - | - | - | - | - | - |
| Smoking status | - | - | - | - | - | - |
| Alcohol abuse | - | - | - | - | - | - |
| Stent type (PED Flex Shield) | 1.969 | 0.569–9.065 | 0.32 | - | - | - |
| Adjunctive coiling | 2.284 | 0.485–8.218 | 0.237 | - | - | - |
| Aneurysmal morphology (Saccular) | 0.827 | 0.044–4.581 | 0.859 | - | - | - |
| Aneurysmal neck width | 1.075 | 0.938–1.194 | 0.221 | - | - | - |
| Aneurysmal size | 1.089 | 0.997–1.178 | 0.038* | 1.078 | 0.974–1.177 | 0.11 |
| FD diameter | 1.231 | 0.536–2.92 | 0.632 | - | - | - |
| FD length | 1.056 | 0.969–1.39 | 0.177 | 1.023 | 0.936–1.115 | 0.607 |
| Parent vessel diameter | 1.044 | 0.672–1.36 | 0.797 | - | - | - |
Cl confidence interval, OR odds ratio
The ADPi-MPA rate of half-dose ticagrelor and standard-dose clopidogrel groups
ADPi-MPA levels revealed significant differences between the half-dose ticagrelor and standard-dose clopidogrel groups, with median values of 26.00 [IQR: 17.45, 34.25] vs 37.70 [IQR: 29.50, 43.60] (P < 0.001; Supplemental materials 1). Notably, a significant monotonic relationship was observed between ADPi-MPA in the half-dose ticagrelor and standard-dose clopidogrel regimens (P < 0.005; Fig. 2). Multivariable analysis identified female gender as an independent predictor of elevated ADPi-MPA levels across both DAPT regimens, with differential effect magnitudes: OR = 4.77 (95% CI 1.69–7.86, P = 0.003) for half-dose ticagrelor vs OR = 6.01 (95% CI 3.09–8.94, P < 0.001) for standard-dose clopidogrel (Fig. 3).
Fig. 2.
Comparison of ADPi-MPA in different DAPT regimens
Fig. 3.
Factors influencing ADPi-MPA in patients undergoing different DAPT regimens
PED flex shield and PED/PED Flex/TED characteristics in half-dose ticagrelor groups
In the half-dose ticagrelor group, the proportion of females was significantly lower in the PED Flex Shield group (64.2%) compared to the PED/PED Flex/TED group (80.5%, P = 0.014). The PED Flex Shield was preferentially utilized in patients with larger parent vessels, measuring 4.7 mm (IQR: 4.09–5.38) versus 4.1 mm (IQR: 3.8–4.6) in the PED/PED Flex/TED group (P < 0.001; Table 3). Additionally, significant differences were noted in device length (20 mm [IQR: 16–25] vs 20 mm [IQR: 20–25]; P = 0.006) and diameter (4.0 mm [IQR: 3.75–4.50] vs 4.5 mm [IQR: 4.0–4.5]; P = 0.018) when compared to the PED/PED Flex/TED group. In terms of perioperative complications, no significant differences were found in the incidence of hemorrhagic or ischemic events between the two groups (both P > 0.05).
Table 3.
Comparative analysis of PED Flex Shield and PED/PED Flex/TED in Half-dose Ticagrelor DAPT administration
| PED/PED Flex/TED | PED Flex Shield | P value | |
|---|---|---|---|
| Number | 87 | 137 | |
| AA | 4.00 [1.80, 5.95] | 4.20 [2.30, 6.50] | 0.332 |
| ADPi-MPA | 23.00 [16.90, 31.15] | 27.30 [18.30, 35.00] | 0.019 |
| Age | 54.00 [46.00, 62.50] | 58.00 [48.00, 65.00] | 0.139 |
| Female | 70 (80.5) | 88 (64.2) | 0.014* |
| Preoperative mRS | 0.69 | ||
| Favorable (mRS score 0–2) | 85 (97.7) | 136 (99.3) | |
| Morbidity (mRS score 3–5) | 2 (2.3) | 1 (0.7) | |
| Previous medical history | |||
| Hypertension | 27 (31.0) | 62 (45.3) | 0.048* |
| Diabetes | 9 (10.3) | 21 (15.3) | 0.386 |
| Hyperlipidemia | 31 (35.6) | 15 (10.9) | < 0.001* |
| Coronary disease | 4 (4.6) | 12 (8.8) | 0.361 |
| Ischemic stroke history | 12 (13.8) | 26 (19.0) | 0.409 |
| Smoking status | 2 (2.3) | 0 (0.0) | 0.292 |
| Alcohol abuse | |||
| Aneurysmal segment | 0.322 | ||
| Adjunctive coiling | 14 (16.1) | 16 (11.7) | 0.457 |
| Parent vessel diameter (mm) | 4.10 [3.80, 4.60] | 4.70 [4.09, 5.38] | < 0.001* |
| FD diameter (mm) | 4.50 [4.00, 4.50] | 4.00 [3.75, 4.50] | 0.018* |
| FD length (mm) | 20.00 [20.00, 25.00] | 20.00 [16.00, 25.00] | 0.006* |
| Ischemic events | 0.243 | ||
| Non | 85 (97.7) | 132 (96.4) | |
| Acute cerebral infarction | 1 (1.1) | 5 (3.6) | |
| Acute stent thrombosis | 0 (0.0) | 0 (0.0) | |
| TIA | 1 (1.1) | 0 (0.0) | |
| Hemorrhagic events | 0.248 | ||
| Non | 86 (98.9) | 133 (97.1) | |
| IPH | 0 (0.0) | 3 (2.2) | |
| NOS | 1 (1.1) | 0 (0.0) | |
| SAH | 0 (0.0) | 1 (0.7) | |
| Total perioperative complications | 3 (3.4) | 9 (6.6) | 0.48 |
TIA transient ischemic attack, IPH intraparenchymal hemorrhage, NOS not otherwise specified, SAH subarachnoid hemorrhage
* Statistic difference
Perioperative complications of half-dose ticagrelor and standard-dose clopidogrel DAPT regimens across various FD types
In the PED Flex Shield cohort, the majority of patients were administered half-dose ticagrelor (81.5%) compared to standard-dose clopidogrel (18.5%). Overall, no statistically significant differences were observed in the incidence of perioperative complications between patients receiving half-dose ticagrelor and those receiving standard-dose clopidogrel (6.6% vs 9.7%; P = 0.825). Acute cerebral infarction rates were similar between half-dose ticagrelor (3.6%) and standard-dose clopidogrel (3.2%) in the PED Flex Shield cohort (P > 0.999). Additionally, hemorrhagic events occurred in 2.9% of patients receiving half-dose ticagrelor versus 6.4% with standard-dose clopidogrel, a difference that was not statistically significant (P = 0.606; Table 4).
Table 4.
Perioperative complications: half-dose ticagrelor vs standard-dose clopidogrel in PED flex shield and PED/PED Flex/TED groups
| PED Flex Shield group N = 168 |
PED/PED Flex/TED group N = 237 |
|||||
|---|---|---|---|---|---|---|
| Standard-dose Clopidogrel | Half-dose Ticagrelor | P value | Standard-dose Clopidogrel | Half-dose Ticagrelor | P value | |
| Number | 31 | 137 | 150 | 87 | ||
| Ischemic events | > 0.999 | 0.16 | ||||
| Non | 30 (96.8) | 132 (96.4) | 141 (94.0) | 85 (97.8) | ||
| Acute cerebral infarction | 1 (3.2) | 5 (3.6) | 5 (3.3) | 1 (1.1) | ||
| Acute stent thrombosis | 0 (0.0) | 0 (0.0) | 4 (2.7) | 0 (0.0) | ||
| TIA | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (1.1) | ||
| Hemorrhagic events | 0.188 | 0.782 | ||||
| Non | 29 (93.6) | 133 (97.1) | 150 (100.0) | 86 (98.9) | ||
| IPH | 1 (3.2) | 3 (2.2) | 0 (0.0) | 0 (0.0) | ||
| NOS | 1 (3.2) | 0 (0.0) | 0 (0.0) | 1 (1.1) | ||
| SAH | 0 (0.0) | 1 (0.7) | 0 (0.0) | 0 (0.0) | ||
| Total perioperative complications | 3 (9.7) | 9 (6.6) | 0.825 | 9 (6.0) | 3 (3.4) | 0.578 |
TIA transient ischemic attack, IPH intraparenchymal hemorrhage, NOS not otherwise specified, SAH subarachnoid hemorrhage
* Statistic difference
In the PED/PED Flex/TED cohort, standard-dose clopidogrel (63.3%) was utilized more frequently than half-dose ticagrelor (36.7%). The rate of ischemic complications was numerically higher in the standard-dose clopidogrel group compared to the half-dose ticagrelor group (6.0% vs 2.2%), although this difference did not reach statistical significance (P = 0.16). Specifically, 9 patients in the standard-dose clopidogrel group experienced ischemic complications, including 5 cases of acute cerebral infarction and 4 cases of acute stent thrombosis. In contrast, 2 patients in the half-dose ticagrelor group experienced ischemic complications, comprising one case of acute cerebral infarction and one case of TIA. Regarding hemorrhagic complications, 1 patient (1.1%) in the half-dose ticagrelor group experienced a NOS hemorrhagic event, while no hemorrhagic events occurred in the standard-dose clopidogrel group (P = 0.782; Table 4).
Discussion
In this retrospective cohort study, we evaluated the efficacy and safety of half-dose ticagrelor versus standard-dose clopidogrel DAPT regimen following FD placement for IAs. The results demonstrated that the two DAPT regimens had comparable perioperative complications, but the ADPi-MPA level of the half-dose ticagrelor DAPT regimen was significantly lower than that of the standard-dose clopidogrel DAPT regimen. Notably, this study represents the first to examine the role of half-dose ticagrelor DAPT in PED Flex Shield implantation and has confirmed the feasibility of half-dose ticagrelor.
With recent advances in neurointerventional techniques, clinicians' understanding of neurointervention has deepened. An increasing number of centers are adopting new-generation FD devices to treat a broader range of cerebrovascular diseases. However, the rapid transition to these new FD devices poses challenges regarding the DAPT regimens used in the past FD era, potentially introducing unknown risks. Given the positive cardiovascular experiences with reduced-dose ticagrelor-based DAPT, it is reasonable to evaluate the safety and efficacy of these regimens for neuroendovascular applications, particularly with the new surface-modified FD devices. A retrospective comparative analysis evaluated DAPT regimens comprising ticagrelor 60 mg/bid plus aspirin 81 mg daily versus standard-dose clopidogrel 75 mg daily combined with aspirin 81 mg daily in intracranial stenting. Results showed no ischemic events in either group, with comparable hemorrhagic event rates (1.7% in both groups) [26]. Moreover, Zhuang et al. reported that among UIA patients undergoing FD/stent-assisted coiling (SAC), the ischemic event incidence was 3.94% with half-dose ticagrelor plus aspirin 100 mg daily versus 6.3% with standard-dose clopidogrel plus aspirin 100 mg daily, while bleeding risks remained similar between regimens [21]. In our study, the half-dose ticagrelor group showed no statistically significant differences in ischemic (3.1% vs 5.5%; P = 0.114) and hemorrhagic (2.1% vs 1.2%; P = 0.689) event rates relative to the standard-dose clopidogrel group. While these between-group differences did not attain statistical significance, they nonetheless hold clinical relevance given the substantial mortality and disability burdens linked to intracranial hemorrhage. Clinicians may consider using the half-dose of ticagrelor DAPT regimen to replace patients who exhibiting clopidogrel resistance, or to reduce the dose of ticagrelor [10]. This adjustment of the DAPT regimen not only alleviates the financial burden of patients undergoing FD treatment, but also aids in balancing the risks associated with bleeding and ischemic events. Moreover, our study included a higher proportion of FD treatments utilizing PED Flex Shield devices compared to prior studies. Variations in FD techniques and device types could influence aneurysm hemodynamics, potentially contributing to subtle outcome discrepancies. Nonetheless, align with existing evidence, our findings support the feasibility of half-dose ticagrelor-based DAPT in FD treatment.
Hemorrhagic complications were the major concern regarding the use of ticagrelor-based DAPT in IAs patients undergoing FD. Besides shortening the duration of DAPT, individualized dose reduction adjustment of Ticagrelor seems feasible. Multiple practices in the field of cardiovascular disease indicate that the reduced-dose (45 mg twice daily or 60 mg twice daily) ticagrelor DAPT, compared with the standard dose (90 mg twice daily), may reduce the risk of major bleeding while maintaining clinical efficacy. In a meta-analyses comparing reduced-dose ticagrelor (included 45 mg twice daily and 60 mg twice daily) with standard-dose clopidogrel DAPT regimens in acute coronary syndrome (ACS) patients demonstrated that low-dose ticagrelor significantly reduced major adverse cardiac event (MACEs) (OR = 0.39, 95% CI 0.26–0.58; P < 0.01) without increasing major bleeding risk (OR = 1.16, 95% CI 0.43–3.08; P = 0.77). Furthermore, low-dose ticagrelor improved left ventricular ejection fraction, reduced left ventricular end-diastolic dimensions, and exhibited significantly lower platelet aggregation compared to standard-dose clopidogrel, indicating favorable efficacy and safety profiles [6]. Another multicenter prospective study confirmed that long-term DAPT with 60 mg/bid ticagrelor DAPT regimen is effective and safe in patients including those with a previous myocardial infarction, and no major bleeding occurred during the 1-year follow-up [5]. In conclusion, reduced-dose ticagrelor may maintain sufficient antiplatelet efficacy while minimizing the risk of adverse events, especially the risk of bleeding, though longer-term follow-up is required for further evaluation.
Owing to the distinct genotype, physiological characteristics, and medical environment between Western and East Asian populations, East Asian patients exhibit differing risk profiles for ischemic and hemorrhagic events relative to Western populations. This suggests that a different “therapeutic window” of on-treatment platelet reactivity might be appropriate in East Asian patients [19]. Furthermore, a phenomenon referred to as the “East Asian paradox” has been described, in which East Asian patients have a lower rate of ischemic events and a higher rate of bleeding events after PCI compared with Western populations, despite a higher on-treatment platelet reactivity [16, 18]. Li et al. demonstrated that in healthy Chinese subjects, reduced-dose ticagrelor (45 mg twice daily) produced an antiplatelet efficacy similar to that of standard-dose ticagrelor (90 mg twice daily), which was faster and more potent than the effect of standard-dose clopidogrel (75 mg daily) [20]. While a meta-analysis evaluating the efficacy and safety of reduced-dose ticagrelor (60 mg twice daily) in East Asian patients undergoing PCI demonstrated its superiority over standard-dose ticagrelor (90 mg twice daily). This superiority was manifested by a lower incidence of MACEs without an augmented risk of bleeding [13]. Therefore, reduced-dose ticagrelor DAPT may be necessary to achieve a better risk–benefit balance in Asian populations, while maintaining comparable therapeutic efficacy.
To mitigate potential confounding effects on perioperative complications, we constructed a multivariable logistic regression model adjusting for biologically plausible covariates, including gender, age, ADPi-MPA, and comorbidity. The adjusted analysis identified previous diabetes (OR 3.338, 95% CI 1.223–8.883; P = 0.015) and aneurysmal size (OR 1.115, 95% CI 1.031–1.202; P = 0.005) as independent predictors of perioperative complications, while female gender, ADPi-MPA, and other comorbidities were not significant (Supplemental Material 2). These findings quantify the predominant impact of diabetic status, suggesting that preoperative glycemic optimization may more effectively attenuate surgical risk in this cohort. To confirm this potential benefit, further prospective studies with longer follow-up durations and larger sample sizes are necessary.
In the present study, after stratification by DAPT regimens revealed significantly lower median ADPi-MPA levels in the half-dose ticagrelor group compared to the standard-dose clopidogrel group. When stratified by FD types among patients receiving half-dose ticagrelor DAPT, the ADPi-MPA levels in the PED/PED Flex/TED cohort were significantly lower than those in the PED Flex Shield subgroup. Despite differences between the two DAPT regimens, both maintained ADPi-MPA levels within the therapeutic safety window and exhibited comparable perioperative complications. These data indicate that, in Asian populations with a high bleeding risk, half-dose ticagrelor may offer comparable perioperative complication management to standard-dose clopidogrel, while potentially providing improved ADPi-MPA level control.
Moreover, female gender was identified as an independent factor significantly associated with elevated ADPi-MPA levels across both DAPT regimens: half-dose ticagrelor (OR = 4.77, 95% CI: 1.69–7.86, P = 0.003) and standard-dose clopidogrel (OR = 6.01, 95% CI: 3.09–8.94, P < 0.001). In the study by Yanzi et al., female patients were found to be more susceptible to experienced clopidogrel resistance (OR 2.481; 95% CI 1.066–5.771; P = 0.035) [32]. Therefore, clinicians should be cautious of the potential elevation in ADPi-MPA levels in female patients, which may lead to an increased risk of subsequent ischemic events. However, due to the small sample size of the aforementioned study, further research with larger sample sizes is warranted to explore the relationship between ADPi-MPA levels and gender.
The safety and efficacy of the TED have been validated in large-scale multicenter clinical series [15, 22]. As demonstrated in the PARAT trial, TED implantation achieved significantly higher 6-month complete occlusion rates compared to SAC in patients with large or giant internal carotid artery or vertebral artery aneurysms [24]. Furthermore, a meta-analysis evaluating TED outcomes in IAs revealed favorable efficacy with acceptable complication rates, demonstrating consistent performance regardless of aneurysm location and size [7]. Based on its proven clinical performance and mechanistic parallels to the PED/PED Flex devices, TED classification within the PED/PED Flex group is methodologically justified. This stratification supports comparative evaluation of half-dose ticagrelor across FD with analogous thrombogenic profiles.
The PED Flex Shield is an updated version of the PED, featuring a surface phosphorylcholine biocompatible polymer designed to reduce thrombogenicity. Despite this technological advancement, DAPT remains critical for thrombotic risk reducing. To further evaluate the safety and efficacy of half-dose ticagrelor in patients with the PED Flex Shield, we included a limited number of PED Flex Shield cases. In the PED/PED Flex/TED group, no significant differences were observed in perioperative ischemic events (standard-dose clopidogrel: 6% vs half-dose ticagrelor: 2.2%) or hemorrhagic complications (standard-dose clopidogrel: 0% vs half-dose ticagrelor: 1.1%). Similarly, in the PED Flex Shield group, comparable rates of perioperative ischemic events (standard-dose clopidogrel: 3.2% vs half-dose ticagrelor: 3.6%) and hemorrhagic events (standard-dose clopidogrel: 6.4% vs half-dose ticagrelor: 2.9%) were documented. Future multicenter studies should be conducted to validate the potency of half-dose ticagrelor in optimizing the ischemic-hemorrhagic risk equilibrium among Asian populations, while expanding its indications to encompass diverse intracranial/extracranial stent types (whatever surface-modified coating), thereby establishing tailored DAPT regimens.
Limitation
Our study has several limitations. First, it is a retrospective, single-center study, and the selection of FDs depended on the neurointerventionalist’s judgment based on the characteristics of the IAs. Second, the study was conducted in a single institution because LTA testing lacks uniform standards among institutions, thus limiting the generalizability of the results. Third, the uneven distribution of patients receiving half-dose ticagrelor and standard-dose clopidogrel in the PED Flex Shield subgroup restricts the statistical power of our results. Finally, since we utilized only LTA for platelet function testing, the generalizability of our conclusions may be further constrained. Consequently, larger sample studies are needed to validate these findings.
Conclusion
This study demonstrates that half-dose ticagrelor DAPT achieves significantly lower platelet reactivity (ADPi-MPA) compared to standard-dose clopidogrel, with no statistically significant differences in ischemic or hemorrhagic complication rates observed among FD-treated IA patients. Importantly, the half-dose regimen shows consistent performance across different FD devices (including PED Flex Shield) without compromising perioperative safety. These findings support the potential of half-dose ticagrelor as an effective alternative antiplatelet strategy in neurointerventional procedures. However, prospective, randomized comparative studies are warranted further refine the use of half-dose ticagrelor in FD implantation.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary Material 1 (DOCX 23.4 KB)
Supplementary Material 2 (DOCX 19.2 KB)
Supplementary Material 3 (DOCX 25.6 KB)
Supplementary Material 4 (DOCX 21.6 KB)
Supplementary Material 5 (DOCX 14.6 KB)
Author contributions
All authors contributed to the paper. Can Li and Hao Yuan: designed, conceptualized the study and drafted the manuscript; Xin Feng, Jiwan Huang, Chi Huang, Mengshi Huang: analyzed and interpreted the data; Zhuohua Wen, Runze Ge, Hao Yuan, Jiancheng Lin: collected the data; Wenchao Liu, Fa Jin, Ran Li, Shenquan Guo, Chengwei Chen, Shuyin Liang: critically revised the study outcomes; Chuanzhi Duan and Xifeng Li: funding, study supervision, and critical revision of the manuscript.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Natural Science Foundation of China (82201427), the Natural Science Foundation of China (82271297) and the Foundation of National Heath Commission Capacity Building and Continuing Education Center (GWJJ2022100102).
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
This study has been approved by the Ethics Committee of Zhujiang Hospital of Southern Medical University (2023-KY-023–02) and conforms to the ethical standards as per the revised Declaration of Helsinki. Participants gave informed consent to participate in the study before taking part.
Consent for publication
Not applicable.
Clinical trial registration details
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Can Li and Hao Yuan contributed equally to this work, They are joint first authors.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Chuanzhi Duan, Email: doctor_duanzj@163.com.
Xifeng Li, Email: nflxf@126.com.
References
- 1.Alexopoulos D, Xanthopoulou I, Goudevenos J (2014) Effects of P2Y12 receptor inhibition in patients with ST-segment elevation myocardial infarction. Am J Cardiol 113:2064–2069. 10.1016/j.amjcard.2014.03.053 [DOI] [PubMed] [Google Scholar]
- 2.Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K et al (2015) Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 372:1791–1800. 10.1056/NEJMoa1500857 [DOI] [PubMed] [Google Scholar]
- 3.Bobescu E, Covaciu A, Rus H, Rogozea LM, Badea M, Marceanu LG (2020) Low response to clopidogrel in coronary artery disease. Am J Ther 27:e133–e141. 10.1097/MJT.0000000000001099 [DOI] [PubMed] [Google Scholar]
- 4.Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, Storey RF (2007) Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non–ST-segment elevation acute coronary syndrome. J Am Coll Cardiol 50:1844–1851. 10.1016/j.jacc.2007.07.053 [DOI] [PubMed] [Google Scholar]
- 5.Cesaro A, Taglialatela V, Gragnano F, Moscarella E, Fimiani F, Conte M, Barletta V, Monda E, Limongelli G, Severino S et al (2020) Low-dose ticagrelor in patients with high ischemic risk and previous myocardial infarction: a multicenter prospective real-world observational study. J Cardiovasc Pharmacol 76:173–180. 10.1097/FJC.0000000000000856 [DOI] [PubMed] [Google Scholar]
- 6.Chen Q, Zhang Y, Wang Z, Wang S, Zhang H, Wang Y, Lu C, Xuan H, Wang C, Li D et al (2020) Efficacy and safety of low dose ticagrelor in patients with acute coronary syndrome: a systematic review and meta-analysis. Postgrad Med J 96:693–702. 10.1136/postgradmedj-2019-137180 [DOI] [PubMed] [Google Scholar]
- 7.Fan Y, Lei J, Fei F, Liu J, Liu Y (2023) A novel flow diverter device (Tubridge) for the treatment of intracranial aneurysms: a systematic review and meta-analysis. Neurosurg Rev 46:198. 10.1007/s10143-023-02100-6 [DOI] [PubMed] [Google Scholar]
- 8.Feng X, Huang C, Tong X, Wen Z, Zhu Y, Huang M, Lin J, Huang J, Yuan H, Xu A et al (2025) Effect of LDL-cholesterol levels and oral atorvastatin on outcomes after Pipeline therapy for intracranial aneurysms. Stroke 56:3002–3013. 10.1161/STROKEAHA.124.049833 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Girdhar G, Li J, Kostousov L, Wainwright J, Chandler WL (2015) In-vitro thrombogenicity assessment of flow diversion and aneurysm bridging devices. J Thromb Thrombolysis 40:437–443. 10.1007/s11239-015-1228-0 [DOI] [PubMed] [Google Scholar]
- 10.Ge R, Lin J, Feng X, Huang C, Huang J, Li C, Wen Z, Xu A, Huang M, Yuan H et al (2025) Analysis of the effect of platelet function and different doses of ticagrelor after flow diverter treatment of intracranial aneurysms. Neurosurg Rev 48:90. 10.1007/s10143-025-03225-6 [DOI] [PubMed]
- 11.Gupta R, Moore JM, Griessenauer CJ, Adeeb N, Patel AS, Youn R, Poliskey K, Thomas AJ, Ogilvy CS (2016) Assessment of dual-antiplatelet regimen for pipeline embolization device placement: a survey of major academic neurovascular centers in the United States. World Neurosurg 96:285–292. 10.1016/j.wneu.2016.09.013 [DOI] [PubMed] [Google Scholar]
- 12.Ha ACT, Bhatt DL, Rutka JT, Johnston SC, Mazer CD, Verma S (2021) Intracranial hemorrhage during dual antiplatelet therapy. J Am Coll Cardiol 78:1372–1384. 10.1016/j.jacc.2021.07.048 [DOI] [PubMed] [Google Scholar]
- 13.Hu X, Zhao W, Zhang Q, Hu H, Luo S (2021) Efficacy and safety of aspirin combined with low-dose P2Y12 receptor antagonists in East Asian patients undergoing PCI. Int Heart J 62:742–751. 10.1536/ihj.20-772 [DOI] [PubMed] [Google Scholar]
- 14.Huang C, Ma G, Tong X, Feng X, Wen Z, Huang M, Xu A, Yuan H, Shi H, Lin J et al (2024) Comparison of Pipeline embolization device versus Tubridge embolization device in unruptured intracranial aneurysms: a multicenter, propensity score matched study. J Neurointerv Surg 17:467–474. 10.1136/jnis-2024-021623 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Huang C, Ma G, Tong X, Feng X, Wen Z, Huang M, Xu A, Yuan H, Shi H, Lin J et al (2025) Comparison of Pipeline embolization device versus Tubridge embolization device in unruptured intracranial aneurysms: a multicenter, propensity score matched study. J Neurointerv Surg. 10.1136/jnis-2024-021623 [DOI] [PMC free article] [PubMed]
- 16.Jeong YH (2014) East asian paradox": challenge for the current antiplatelet strategy of “one-guideline-fits-all races” in acute coronary syndrome. Curr Cardiol Rep 16:485. 10.1007/s11886-014-0485-4 [DOI] [PubMed] [Google Scholar]
- 17.Jia W, Jia Q, Zhang Y, Zhao X, Wang Y (2021) Association between insulin resistance and aspirin or clopidogrel resistance in Chinese patients with recent ischemic stroke/TIA. Neurol Res (New York) 43:406–411. 10.1080/01616412.2020.1866371 [DOI] [PubMed] [Google Scholar]
- 18.Lee YJ, Kim H, Choi J, Lee BH, Lee S (2018) Evaluation of pharmacokinetic, pharmacodynamic, efficacy, and safety data of low-dose ticagrelor versus standard dose in East Asians: a systematic review. Ther Clin Risk Manag 14:83–93. 10.2147/TCRM.S152276 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Levine GN, Jeong YH, Goto S, Anderson JL, Huo Y, Mega JL, Taubert K, Smith SJ (2014) World heart federation expert consensus statement on antiplatelet therapy in east asian patients with ACS or undergoing PCI. Glob Heart 9:457–467. 10.1016/j.gheart.2014.08.001 [DOI] [PubMed] [Google Scholar]
- 20.Li P, Gu Y, Yang Y, Chen L, Liu J, Gao L, Qin Y, Cai Q, Zhao X, Wang Z et al (2016) Low-dose ticagrelor yields an antiplatelet efficacy similar to that of standard-dose ticagrelor in healthy subjects: an open-label randomized controlled trial. Sci Rep 6:31838. 10.1038/srep31838 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Li Y, Yi M, Wang R, Xu M, Liu T, Na S, Shao T, Ding L, Ge W, Peng Y et al (2024) Half-dose ticagrelor versus standard-dose clopidogrel in a dual antiplatelet regimen for stent-assisted coiling or flow diversion of unruptured intracranial aneurysms: a cohort study. J Neurointerv Surg 21792. 10.1136/jnis-2024-021792 [DOI] [PubMed]
- 22.Li Q, Lv N, Li L, Gu Y, Xu L, Lv M, Huang C, Mao G, Lu H, Zhong S et al (2024) Intracranial aneurysms managed by parent artery reconstruction using Tubridge flow diverter study: 1-year outcomes. J Neurosurg 141:1697. 10.3171/2024.3.JNS232116 [DOI] [PubMed] [Google Scholar]
- 23.Lim J, Monteiro A, Cortez GM, Benalia VH, Baig AA, Jacoby WT, Donnelly BM, Levy BR, Jaikumar V, Davies JM et al (2023) Early termination versus standard regimen duration of dual antiplatelet therapy in intracranial aneurysm patients treated with Pipeline Embolization Device Flex with Shield Technology: preliminary experience of 3 U.S. centers. World Neurosurg 178:e465–e471. 10.1016/j.wneu.2023.07.101 [DOI] [PubMed] [Google Scholar]
- 24.Liu JM, Zhou Y, Li Y, Li T, Leng B, Zhang P, Liang G, Huang Q, Yang PF, Shi H et al (2018) Parent artery reconstruction for large or giant cerebral aneurysms using the Tubridge flow diverter: a multicenter, randomized, controlled clinical trial (PARAT). AJNR Am J Neuroradiol 39:807–816. 10.3174/ajnr.A5619 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Mehta T, Topiwala K, Masood K, Grande A, Tummala R, Jagadeesan B (2023) Half-dose (45 mg twice daily) ticagrelor versus clopidogrel in neuroendovascular dual antiplatelet therapy: a single-center cohort study. Stroke Vasc Interv Neurol 3. 10.1161/SVIN.122.000479 [DOI] [PMC free article] [PubMed]
- 26.Mehta A, Reddi P, Bose SJ, Finesilver J, Goldman D, Sembhi P, De Leacy RA, Fifi JT, Mocco J, Yim B et al (2025) Lower ticagrelor dosing in the dual antiplatelet regimen for neurointerventional procedures. J Neurointerv Surg. 10.1136/jnis-2024-022536 [DOI] [PubMed] [Google Scholar]
- 27.Martínez-Galdámez M, Lamin SM, Lagios KG, Liebig T, Ciceri EF, Chapot R, Stockx L, Chavda S, Kabbasch C, Faragò G et al (2019) Treatment of intracranial aneurysms using the pipeline flex embolization device with shield technology: angiographic and safety outcomes at 1-year follow-up. J Neurointerv Surg 11:396–399. 10.1136/neurintsurg-2018-014204 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Ramirez-Velandia F, Enriquez-Marulanda A, Filo J, Young M, Fodor TB, Sconzo D, Muram S, Granstein JH, Shutran M, Taussky P et al (2024) Comparison of thromboembolic events between Pipeline embolization device (PED) Shield and PED/PED Flex: a propensity score-matched analysis. Neurosurgery 95:330. 10.1227/neu.0000000000002883 [DOI] [PubMed] [Google Scholar]
- 29.Soize S, Foussier C, Manceau P, Litré C, Backchine S, Gawlitza M, Pierot L (2019) Comparison of two preventive dual antiplatelet regimens for unruptured intracranial aneurysm embolization with flow diverter/disrupter: a matched-cohort study comparing clopidogrel with ticagrelor. J Neuroradiol 46:378–383. 10.1016/j.neurad.2019.01.094 [DOI] [PubMed] [Google Scholar]
- 30.Storey RF, Becker RC, Harrington RA, Husted S, James SK, Cools F, Steg PG, Khurmi NS, Emanuelsson H, Cooper A et al (2011) Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 32:2945–2953. 10.1093/eurheartj/ehr231 [DOI] [PubMed] [Google Scholar]
- 31.Storey RFMD, Angiolillo DJM, Bonaca MPMM, Thomas MRM, Judge HMP, Rollini FM, Franchi FM, Ahsan AJM, Bhatt DLMM, Kuder JFM et al (2016) Platelet inhibition with ticagrelor 60 mg versus 90 mg twice daily in the PEGASUS-TIMI 54 trial. J Am Coll Cardiol 67:1145–1154. 10.1016/j.jacc.2015.12.062 [DOI] [PubMed] [Google Scholar]
- 32.Wu Y, Shen H, Cai B, Chen C, Yin Q, Zhao Y, Zhou G (2024) Factors associated with clopidogrel resistance and clinical outcomes in ischemic cerebrovascular disease: a retrospective study. J Stroke Cerebrovasc Dis 33:107684. 10.1016/j.jstrokecerebrovasdis.2024.107684 [DOI] [PubMed] [Google Scholar]
- 33.Yao Y, Tang X, Zhang J, He C, Ma Y, Xu J, Song Y, Liu R, Meng X, Song L et al (2016) Association of PEAR1 genetic variants with platelet reactivity in response to dual antiplatelet therapy with aspirin and clopidogrel in the Chinese patient population after percutaneous coronary intervention. Thromb Res 141:28–34. 10.1016/j.thromres.2016.02.031 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material 1 (DOCX 23.4 KB)
Supplementary Material 2 (DOCX 19.2 KB)
Supplementary Material 3 (DOCX 25.6 KB)
Supplementary Material 4 (DOCX 21.6 KB)
Supplementary Material 5 (DOCX 14.6 KB)
Data Availability Statement
No datasets were generated or analysed during the current study.