Abstract
Background
Optimal anticoagulation strategies in octogenarians remain controversial owing to age-related risks of thromboembolism and bleeding. This study evaluates real-world outcomes of reduced-dose edoxaban (15–30 mg daily) in very old populations.
Methods
We conducted a retrospective cohort study of 217 patients (aged ≥ 80 years) receiving edoxaban at Peking University First Hospital (2022–2023). Patients were stratified by dosage (30 mg once daily [QD] [n = 95] versus 15 mg QD [n = 122]). Outcomes included pharmacodynamics (anti-Xa levels), clinical endpoints (bleeding, thrombosis, and mortality), and survival analysis.
Results
The 15-mg-QD group was older (90.0 versus 85.8 years, P = 0.001) and had reduced activities of daily living (ADL) scores (65.5% versus 82.6, P = 0.003) and reduced estimated glomerular filtration rate (eGFR) (58.6 versus 62.6 mL/min/1.73 m2, P = 0.005). Anti-Xa peak levels were 0.56 ± 0.25 IU/mL (30 mg) versus 0.35 ± 0.15 IU/mL (15 mg). Over 15.8 ± 9.8 months follow-up, mortality was reduced in the 30-mg group (0.7% versus 3.5%, P = 0.044), with comparable bleeding (3.5% overall) and thrombosis (0.7%) rates.
Conclusions
Reduced-dose edoxaban demonstrates a favorable safety–efficacy profile in advanced-age patients, necessitating comprehensive bleeding–ischemic risk assessment to optimize individualized anticoagulation regimens.
Key Points
| This real-world study characterizes the clinical profile of anticoagulation therapy in Chinese patients, confirming that reduced-dose edoxaban maintains a favorable safety–efficacy profile even among advanced-age octogenarians. |
Introduction
Edoxaban, a direct oral anticoagulant (DOAC), selectively inhibits factor Xa (FXa) in the coagulation cascade. Its rapid onset, fixed dosing regimen without therapeutic window limitations, minimal drug–food interactions, and elimination of routine coagulation monitoring have established it as a preferred option for stroke prevention in nonvalvular atrial fibrillation (NVAF) and management of venous thromboembolism (VTE) [1–3]. However, older patients frequently present with multimorbidity and elevated risks of renal impairment and hemorrhagic complications. Notably, anticoagulant underutilization persists among octogenarians owing to concerns regarding bleeding propensity and fall-related injuries. Even among anticoagulated individuals, empirical dose reduction is commonly practiced without robust clinical evidence validating its anticoagulation efficacy. This single-center retrospective study aims to evaluate the effectiveness and safety profiles of reduced-dose edoxaban (15–30 mg daily) in thromboembolic disease management among octogenarian populations.
Study Participants and Methods
Study Population (Fig. 1)
Fig. 1.
The enrollment process
Inclusion Criteria
Patients meeting all the following criteria were enrolled: hospitalized in the Geriatrics Department of Peking University First Hospital (1 January 2022 to 31 December 2023); indications for anticoagulation with edoxaban; aged ≥ 80 years; complete clinical documentation; and followed via outpatient visits/telephone until discontinuation, death, or study conclusion (1 December 2024).
Exclusion Criteria
The exclusion criteria were (1) active bleeding prior to medication initiation; (2) severe hepatic impairment (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) or bilirubin ≥ 3 times the upper limit of normal (ULN); (3) severe renal dysfunction (estimated glomerular filtration rate [eGFR] ≤ 15 mL/min/1.73 m2); (4) concomitant use of potent P-glycoprotein inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, and erythromycin), CYP3A4 inducers (e.g., phenytoin, carbamazepine, and phenobarbital), or agents interfering with activated partial thromboplastin time (APTT)/anti-Xa assays (e.g., unfractionated heparin and reduced-molecular-weight heparin); and (5) incomplete clinical documentation.
Ethical Considerations
The study was approved by the Bioethics Committee of Peking University First Hospital (2022 Research 055).
Study Methods
Group Allocation
Patients were stratified into two groups on the basis of edoxaban dosage: 30 mg once daily (30 mg QD) and 15 mg once daily (15 mg QD).
Data Collection
Demographic and clinical data were extracted via structured interviews and electronic medical record review, including baseline characteristics: sex, age, height, weight, comorbidities (coronary artery disease, hypertension, and diabetes), prior bleeding history, and concomitant medications; and laboratory parameters: fasting venous blood samples collected on admission {hemoglobin (HGB), platelet count (PLT), liver function (ALT and AST), renal function (serum creatinine [CREA] and estimated glomerular filtration rate [eGFR])}; coagulation profile: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), anti-Xa activity (AXA)—measured at trough (within 1 h prior to the next dose) and peak (3–4 h post dose) after ≥ 3 consecutive days of edoxaban therapy, on the basis of pharmacokinetic properties [4, 5]. AXA levels were quantified using Hemosil Liquid Anti-Xa (Werfen, Spain) with the coagulation instrument (ACL TOP 700 analyzer; Werfen, Spain).
Patients underwent quarterly outpatient or telephone follow-up until discontinuation, death, or study termination (31 December 2024). Documented endpoints included bleeding events, classified per Bleeding Academic Research Consortium (BARC) criteria as minor bleeding (BARC type 1–2) or major bleeding (BARC type ≥ 3) [6], and thrombotic events: venous thromboembolism (VTE), pulmonary embolism (PE), or stroke.
Study Outcomes
Clinical Characteristics
Baseline parameters, including demographics, laboratory profiles, anticoagulation indications, comorbidities, and concomitant medications, were analyzed to compare clinical features between the 30-mg-QD and 15-mg-QD groups.
Pharmacokinetic Parameters
Anti-Xa activity (AXA), a validated surrogate marker for edoxaban plasma concentration [7, 8], was compared between groups at trough (pre-dose) and peak (3–4 h post dose) levels.
Clinical Endpoints
Major bleeding (International Society on Thrombosis and Haemostasis [ISTH] criteria), or clinically relevant nonmajor bleeding
Thrombotic events (VTE/stroke)
All-cause mortality
Statistical Analysis
Data were analyzed using SPSS version 23.0 (IBM Corp). Continuous variables with normal distribution were expressed as mean ± standard deviation (SD) and compared via independent t-test. Categorical data were reported as n (%) with chi-squared or Fisher’s exact tests. Correlation analyses included: univariate (Pearson [normal variables] or Spearman [non-normal/ordinal]) and multivariate: partial correlation. Survival curves were generated using the Kaplan–Meier method. A two-tailed P < 0.05 defined statistical significance.
Quality Control
Standardized protocols ensured methodological rigor: clinical operations: all investigators possessed certified clinical research qualifications with fixed team composition; data integrity: complete hospitalization/outpatient records verified through source documents; laboratory procedures: strict adherence to standard operating procedures (SOPs) with internal quality controls for all assays.
Results
Clinical Characteristics
The study enrolled 217 octogenarian patients receiving edoxaban therapy (152 males, 70%), with a mean age of 88.2 ± 6.5 years, weight of 66.5 ± 11.2 kg, and activities of daily living (ADL) score of 72.9 ± 31.3. Functional dependence was observed in 61 patients (28.1%). Anticoagulation indications included nonvalvular atrial fibrillation (126 cases, 58.1%) and venous thromboembolism (91 cases, 41.9%), with mean CHA2DS2-VASc and HAS-BLED scores of 4.5 ± 1.1 and 1.8 ± 0.8, respectively (Table 1).
Table 1.
Comparison of baseline characteristics between edoxaban 30-mg-QD and 15-mg-QD groups
| Edoxaban | 30 mg QD | 15 mg QD | P value | ||||
|---|---|---|---|---|---|---|---|
| Sample size, n (%) | 217 | (100.0) | 95 | (43.8) | 122 | (56.2) | – |
| Male, n (%) | 152 | (70) | 72 | (75.8) | 80 | (65.6) | 0.069 |
| Age (years), mean [SD] | 88.2 | 6.5 | 85.8 | 5.3 | 90.0 | 6.7 | 0.001 |
| Weight (kg), mean [SD] | 66.5 | 11.2 | 70.0 | 10.6 | 63.5 | 11.0 | 0.677 |
| ADL score (Barthel index), mean [SD] | 72.9 | 31.3 | 82.6 | 26.7 | 65.5 | 32.6 | 0.003 |
| ˃ 60 score, n (%) | 156 | (71.9) | 80 | (84.2) | 76 | (62.2) | < 0.001 |
| ≤ 60 score, n (%) | 61 | (28.1) | 15 | (15.8) | 46 | (37.7) | |
| Anticoagulation indications | |||||||
| Nonvalvular atrial fibrillation, n (%) | 126 | (58.1) | 59 | (62.1) | 67 | (54.9) | 0.177 |
| Venous thromboembolism, n (%) | 91 | (41.9) | 36 | (37.9) | 55 | (45.1) | |
| CHA2DS2-VASc score, mean [SD] | 4.5 | 1.1 | 4.2 | 1.2 | 4.7 | 1.0 | 0.459 |
| HAS-BLED score, mean [SD] | 1.8 | 0.8 | 1.7 | 0.8 | 2.0 | 0.9 | 0.954 |
| HGB (g/L), mean [SD] | 120.6 | 17.6 | 126.8 | 15.9 | 115.6 | 17.3 | 0.537 |
| PLT (109/L), mean [SD] | 190.6 | 66.2 | 183.3 | 64.3 | 196.4 | 67.5 | 0.441 |
| ALT (IU/L), mean [SD] | 20.2 | 14.7 | 19.1 | 14.0 | 21.0 | 15.3 | 0.229 |
| CREA (µmol/L), mean [SD] | 99.7 | 52.0 | 95.0 | 29.5 | 103.5 | 64.3 | 0.008 |
| eGFR, (mL/min/1.73 m2), mean [SD] | 60.3 | 19.9 | 62.6 | 17.4 | 58.6 | 21.7 | 0.005 |
| ≥ 60 mL/min/1.73 m2, n (%) | 113 | (52.1) | 53 | (55.8) | 60 | (49.2) | 0.240 |
| ˂ 60 mL/min/1.73 m2, n (%) | 104 | (47.9) | 42 | (44.2) | 62 | (50.8) | |
| PT, mean [SD] | 12.1 | 1.2 | 12.3 | 1.3 | 12.0 | 1.1 | 0.504 |
| APTT, mean [SD] | 31.1 | 3.6 | 31.3 | 3.8 | 31.0 | 3.4 | 0.416 |
| INR, mean [SD] | 1.0 | 0.1 | 1.05 | 0.1 | 1.03 | 0.1 | 0.672 |
In the comparative analysis, the 15-mg-QD group exhibited an older age (90.0 versus 85.8 years; P = 0.001), reduced ADL scores (65.5% versus 82.6; P = 0.003), higher dependency rate (75.4% versus 24.6%; P < 0.001), and reduced renal function (eGFR: 58.6 versus 62.6 mL/min/1.73m2; P = 0.005). No statistically significant intergroup differences were observed in comorbidities or concomitant medications. More than one third of patients in both groups had coronary artery disease, hypertension, or diabetes. More than half received angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) agents, β-blockers, statins, or proton pump inhibitors (PPIs) (Table 2).
Table 2.
Comparison of comorbidities and concomitant medications between the edoxaban 30-mg-QD and 15-mg-QD groups
| Edoxaban (n = 217) | 30 mg QD (n = 95) | 15 mg QD (n = 122) | P value | |||||
|---|---|---|---|---|---|---|---|---|
| Comorbidities | ||||||||
| Coronary heart disease, n (%) | 104 | (47.9) | 41 | (43.2) | 63 | (51.6) | 0.135 | |
| Hypertension, n (%) | 183 | (84.3) | 78 | (82.1) | 105 | (86.1) | 0.271 | |
| Heart failure, n (%) | 40 | (18.4) | 15 | (15.8) | 25 | (20.5) | 0.240 | |
| Diabetes mellitus, n (%) | 83 | (38.2) | 40 | (42.1) | 43 | (35.2) | 0.186 | |
| Stroke, n (%) | 23 | (10.6) | 12 | (12.6) | 11 | (9.0) | 0.261 | |
| Chronic kidney disease, n (%) | 37 | (17.1) | 9 | (9.5) | 28 | (23.0) | 0.006 | |
| Concomitant medications | ||||||||
| Aspirin, n (%) | 35 | (16.1) | 17 | (17.9) | 18 | (14.8) | 0.329 | |
| ACEI/ARBs, n (%) | 115 | (53.0) | 54 | (56.8) | 61 | (50.0) | 0.194 | |
| β-Blocker, n (%) | 124 | (57.1) | 60 | (63.2) | 64 | (52.5) | 0.074 | |
| CCBs, n (%) | 57 | (26.3) | 25 | (26.3) | 32 | (26.2) | 0.555 | |
| Diuretics, n (%) | 66 | (30.4) | 26 | (27.4) | 40 | (32.8) | 0.239 | |
| Statin, n (%) | 163 | (75.1) | 70 | (73.7) | 93 | (76.2) | 0.392 | |
| PPIs, n (%) | 116 | (53.5) | 46 | (48.4) | 70 | (57.4) | 0.120 | |
Plasma Concentrations
AXA peak levels were 0.56 ± 0.25 IU/mL (30 mg QD) and 0.35 ± 0.15 IU/mL (15 mg QD). The 15-mg-QD group showed significantly reduced trough (0.08 versus 0.11, P = 0.023) and peak (0.35 versus 0.56, P < 0.001) AXA levels versus the 30-mg-QD group (Table 3).
Table 3.
Comparison of laboratory parameters between the edoxaban 30-mg-QD and 15-mg-QD groups
| Edoxaban (n = 217) | 30 mg QD (n = 95) | 15 mg QD (n = 122) | P value | ||||
|---|---|---|---|---|---|---|---|
| AXA (trough), IU/mL, mean [SD] | 0.1 | 0.07 | 0.11 | 0.08 | 0.08 | 0.06 | 0.023 |
| AXA (peak), IU/mL, mean [SD] | 0.44 | 0.23 | 0.56 | 0.25 | 0.35 | 0.15 | < 0.001 |
Clinical Outcomes
Follow-Up
The mean follow-up duration in the edoxaban group was 15.8 ± 9.8 months, with a maximum follow-up of 42 months. Death occurred in 12 patients (annual incidence rate 4.2%) after edoxaban treatment: two cases (0.7%) in the 30-mg-QD group and ten cases (3.5%) in the 15-mg-QD group, all due to noncardiac causes. Bleeding events were reported in ten patients (3.5%): two cases (0.7%) in the 30-mg-QD group and eight cases (2.8%) in the 15-mg-QD group, with two major bleeding events (0.7%) observed in the 15-mg-QD group and the remainder classified as minor bleeding. Thrombotic events occurred in two patients (0.7%), both being deep vein thrombosis in the 30-mg-QD group (Table 4).
Table 4.
Comparison of follow-up between the edoxaban 30-mg-QD and 15-mg-QD groups
| Edoxaban (n = 217) | 30 mg QD (n = 95) | 15 mg QD (n = 122) | P value | ||||
|---|---|---|---|---|---|---|---|
| Follow-up duration (months), mean [SD] | 15.8 | 9.8 | 16.8 | 10.0 | 15.0 | 9.7 | 0.023 |
| Death, n (%) | 12 | 5.5 | 2 | 2.1 | 10 | 8.2 | – |
| Noncardiac causes, n (%) | 12 | 5.5 | 2 | 2.1 | 10 | 8.2 | |
| Cardiac causes, n (%) | 0 | 0 | 0 | 0 | 0 | 0 | |
| Bleeding events, n (%) | 10 | 4.6 | 2 | 2.1 | 8 | 6.6 | – |
| Major bleeding, n (%) | 2 | 0.9 | 0 | 0 | 2 | 1.6 | |
| Minor bleeding, n (%) | 8 | 3.7 | 2 | 2.1 | 6 | 4.9 | |
| Thrombotic events, n (%) | 2 | 0.9 | 2 | 2.1 | 0 | 0 | – |
| Deep vein thrombosis, n (%) | 2 | 0.9 | 2 | 2.1 | 0 | 0 | |
| Pulmonary embolism, n (%) | 0 | 0 | 0 | 0 | 0 | 0 | |
| Stroke, n (%) | 0 | 0 | 0 | 0 | 0 | 0 | |
Survival Analysis of Bleeding, Thrombosis, and Mortality
Survival analysis for mortality demonstrated a statistically significant difference between the edoxaban 30-mg-QD and 15-mg-QD groups (log-rank χ2 = 4.075, P = 0.044). No significant differences were observed in survival distributions for bleeding (P = 0.092) or thrombotic events (P = 0.131) (Fig. 1).
Discussion
In recent years, China has progressively entered an aging society, with a growing population of advanced older individuals. Since advanced age is a dual risk factor for both thromboembolism and bleeding, anticoagulation therapy in this population poses a clinical dilemma. Current practice among the very old frequently involves the use of nonstandard recommended doses of direct oral anticoagulants (DOACs), where clinicians adjust dosages on the basis of individual patient characteristics. However, the efficacy and safety of such individualized dosing strategies remain controversial [7–12].
The current recommended dosage of edoxaban for patients with nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE) is 60 mg/day. However, the dose should be reduced to 30 mg/day in patients with moderate-to-severe renal impairment (creatinine clearance [CrCl] 15–50 mL/min), reduced body weight (≤ 60 kg), or concomitant use of P-glycoprotein inhibitors [1, 2]. However, the mean/median age of participants in previous pivotal clinical trials was 70–73 years [13–16], which is 5–10 years younger than the actual atrial fibrillation (AF) population, limiting the generalizability of their conclusions to very old patients aged ≥ 80 years [17, 18].
Older patients frequently exhibit multiple comorbidities, high renal insufficiency prevalence, and elevated bleeding risk. For DOAC-treated older patients, clinical practice commonly implements dose adjustments on the basis of clinical characteristics. A Japanese study reported 38.7% reduced-dose rivaroxaban use versus 79.2% for edoxaban in this population [10]. The ETNA-AF-Europe subgroup analysis demonstrated greater reduced-dose edoxaban utilization among frail older individuals [11]. A US community atrial fibrillation survey found 12.5% of older individuals used non-recommended DOAC doses [19]. Chan et al. reported 27% reduced-dose DOAC use [12] versus 51.9% in South Korea [20]. Reduced-dose anticoagulation serves two primary objectives: standard-intensity anticoagulation (stroke prevention in dose-adjusted patients with NVAF) and reduced-intensity anticoagulation (extended VTE treatment). Despite widespread reduced-dose DOAC use, no consensus exists regarding older-specific benefits or personalized dosing protocols (Fig. 2).
Fig. 2.
Hazard functions for mortality in survival analysis between the edoxaban 30-mg-QD and 15-mg-QD groups
Previous studies demonstrate no significant differences in bleeding or thrombotic outcomes between reduced-dose DOACs and standard-dose DOACs/warfarin [21]. A retrospective study observed no significant bleeding or thrombotic risk differences between reduced-dose and standard-dose DOAC groups in octogenarians with atrial fibrillation [22]. Perreault et al. reported reduced bleeding and thrombotic risks with reduced-dose dabigatran versus warfarin (hazard ratio [HR] 0.59) with comparable safety [23]. Fukaya et al. found no significant thrombosis difference between reduced-dose rivaroxaban/edoxaban and standard-dose users with atrial fibrillation [10]. Wei-Chieh et al. identified no significant bleeding/thrombotic risk differences versus warfarin in patients with atrial fibrillation with chronic kidney disease [24]. Suwa et al. studied 348 patients with atrial fibrillation receiving FXa inhibitors; the substandard-dosing subgroup (n = 119) had zero bleeding/thrombotic events during follow-up [25]. A South Korean study showed reduced thrombotic events (HR 0.53) and all-cause mortality (HR 0.57) with reduced-dose rivaroxaban versus warfarin in patients with atrial fibrillation, with comparable bleeding risk (HR 1.10) [20]. Montrasio et al. analyzed 3236 Swiss patients with NVAF and found no significant association between reduced-dose DOACs and major adverse events [26]. Ashraf et al. studied 8125 patients with DOAC-treated atrial fibrillation (n = 1724 off-label dosing), observing no significant differences in bleeding, thrombosis, or mortality between standard-dose and reduced-dose groups [27].
In this study, the edoxaban 15-mg-QD group exhibited significantly older mean age (90.0 versus 85.8, P = 0.001), reduced activities of daily living (ADL) scores (65.5% versus 82.6, P = 0.003), a higher proportion of dependent individuals (75.4% versus 24.6%, P < 0.001), worse renal function, and reduced estimated glomerular filtration rate (eGFR) (58.6 versus 62.6, P = 0.005). These findings suggest clinicians tend to prescribe reduced-dose edoxaban (15 mg QD) for patients with the following characteristics: extreme age (≥ 85 years), functional dependence (ADL ≤ 60), and renal impairment (CrCl ≤ 60 mL/min). This aligns with prior evidence [28], though current guidelines lack standardized dose-reduction criteria, warranting further investigation.
While anti-Xa (AXA) activity reliably reflects the anticoagulant intensity of factor Xa inhibitors, no consensus exists on therapeutic AXA targets for these agents. Clinicians often extrapolate from reduced-molecular-weight heparin (LMWH) standards: prophylaxis in moderate thrombotic risk: 0.10–0.25 IU/mL; prophylaxis in high thrombotic risk: 0.20–0.50 IU/mL: and therapeutic anticoagulation for deep vein thrombosis: 0.5–1.2 IU/mL [29, 30]. Our laboratory uses Hemosil Liquid Anti-Xa detection compliant with internationally certified LMWH standards to ensure global comparability of anticoagulation therapy monitoring results. In our cohort, peak AXA levels reached 0.56 ± 0.25 IU/mL in the 30-mg-QD group and 0.35 ± 0.15 IU/mL in the 15-mg-QD group, both exceeding minimum effective anticoagulation thresholds. This demonstrates that even ultra-reduced-dose edoxaban maintains adequate plasma concentrations in very old patients [18, 31, 32].
The ELDERCARE-AF trial in Japanese octogenarians with AF showed edoxaban 15 mg QD significantly reduced annualized stroke/systemic embolism rates versus placebo (2.3%; HR 0.34, 95% confidence interval [CI] 0.19–0.61, P < 0.001), with comparable major bleeding (3.3%) and all-cause mortality (9.9%) [18]. This study demonstrated significantly reduced all-cause mortality with edoxaban 30 mg QD versus 15 mg QD (HR 0.20, P = 0.044), while exhibiting comparable bleeding and thrombotic event rates. The annualized bleeding rate (2.8%) and major bleeding rate (0.7%) were both lower than those reported in the ELDERCARE-AF trial. Even at reduced doses, edoxaban maintained a favorable safety–efficacy profile in Chinese octogenarians. This may be attributed to strict indication adherence, comprehensive pretreatment assessment (renal function/bleeding/ischemic risks), and individualized anticoagulation regimen development. The mortality advantage in the 30-mg-QD cohort likely reflects baseline disparities; the 15-mg-QD group exhibited more advanced age, higher frailty burden, and worse renal function.
As a retrospective cohort study of high-risk patients ≥ 80 years with multiple comorbidities and medications, our findings reflect real-world anticoagulation practices in China. While limited by sample size and inherent selection bias, these data provide clinically relevant insights for optimizing geriatric anticoagulation strategies.
Conclusions
Reduced-dose edoxaban demonstrates a favorable safety–efficacy profile in advanced-age patients, necessitating comprehensive bleeding–ischemic risk assessment to optimize individualized anticoagulation regimens.
Declarations
Funding
This study was supported by the High-Quality Clinical Research Special Fund of Peking University First Hospital (2023HQ04).
Conflict of interest
Ruiqi Zhang, Jiali Du, and Meilin Liu declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.
Authors’ contributions
Ruiqi Zhang participated in the conception or design of the work, data collection, and drafting and editing of the paper. Ruiqi Zhang, Jiali Du, and Meilin Liu participated in data analysis and revision of the paper. All authors reviewed and approved the final version, and no other person made a substantial contribution to the paper.
Data availability statement
Raw data for this study are not publicly available to preserve individuals’ privacy under the European General Data Protection Regulation. The relevant data for the research can be obtained by contacting the corresponding author.
Ethics approval
The study was approved by the Bioethics Committee of Peking University First Hospital (no. 2022 Research 055).
Code availability
Not applicable.
Consent to participate
Not applicable (retrospective study).
Consent for publication
Not applicable.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Raw data for this study are not publicly available to preserve individuals’ privacy under the European General Data Protection Regulation. The relevant data for the research can be obtained by contacting the corresponding author.