Relationship between vascular calcification assessed by chest CT and CHA₂DS₂-VASc score in patients with atrial fibrillation receiving oral anticoagulant

Introduction

Vascular calcification (VC) is a common pathological feature of atherosclerosis, diabetic vascular disease, hypertension, vascular injury, and chronic kidney disease. It is thought to function as both a consequence and a cause of vascular disease, such as peripheral artery disease and coronary artery disease (1). The development of VC is a complex, active intracellular process in which vascular smooth muscle cells undergo phenotypic transformation into osteoblast-like cells, mediated by the expression of mineralization-promoting factors such as alkaline phosphatase, ultimately resulting in abnormal deposition of hydroxyapatite crystals within the vascular wall. The risk of VC is variable and is influenced by a wide range of both patient and environmental factors (2).

The CHA₂DS₂-VASc [congestive heart failure, hypertension, age ≥75 years (2 points), diabetes, previous stroke/transient ischemic attack/arterial thromboembolism (2 points), vascular disease, age 65–74 years, and female sex] score is a well-validated measure of stroke risk (3), with established capabilities to identify low-risk individuals requiring no antithrombotic therapy, as well as assessing the risk of stroke among patients with nonvalvular atrial fibrillation (AF) (4). Most national and international guidelines recommend using CHA₂DS₂-VASc score to assess individual risk for stroke and recommend the use of oral anticoagulants (OACs) if CHA₂DS₂-VASc scores are greater than or equal to 2 in men and greater than or equal to 3 in women (5,6).

VC is an important marker of cardiovascular morbidity and mortality, particularly in patients with AF (7). VC and AF share common risk factors, such as older age, hypertension, and diabetes, which are also components of the CHA₂DS₂-VASc score (8). Therefore, many patients with AF who require anticoagulation therapy are also at high risk for VC. Despite its potential clinical significance, the relationship between VC and the CHA₂DS₂-VASc risk score, especially during OACs treatment, remains underexplored. Given this critical knowledge gap, we conducted a comprehensive investigation to: (I) systematically evaluate the association between VC burden and CHA₂DS₂-VASc scores in AF patients; (II) examine how different OAC regimens may modify this relationship; and (III) assess the potential prognostic value of VC assessment in stroke risk stratification beyond conventional scoring systems. Our findings aim to evaluate the burden of VC according to the baseline CHA₂DS₂-VASc score and to explore its relationship with OAC use. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-652/rc).

Methods

Study population

Patients with AF who had at least one chest non-contrast computed tomography (CT) scan performed at The Third Xiangya Hospital, Central South University in Hunan, China, between February 2015 and February 2022 were enrolled. All subjects were >18 years of age at the time of the VC scan. Exclusion criteria were as follows: patients who had taken dabigatran etexilate, rivaroxaban, or warfarin for less than 3 months prior to the CT scan (medication use was recorded at the time of the index CT scan), patients who had used multiple OACs prior to the CT scan or whose use was unclear; patients with chronic kidney disease; patients with CT images of insufficient quality for VC assessment; or patients in whom the slice thickness of the reconstructed images was not at 5.0 or 8.0 mm. A total of 1,288 patients were enrolled and classified into three gender-specific CHA₂DS₂-VASc score (as detailed in Table 1) risk categories: low-risk (males: 0 to 1; females: 1 to 2), intermediate-risk (males: 2 to 4; females: 3 to 4), and high-risk (≥5 for both genders). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethics Committee of The Third Xiangya Hospital, Central South University (approval No. 23699). Due to the retrospective and anonymized design of the study, which involved the analysis of pre-existing clinical data, the requirement for obtaining written informed consent was waived by the ethics committee. All patient data were de-identified and coded to ensure confidentiality.

Image acquisition

Non-contrast chest CT scans were acquired on a Philips Brilliance 64-slice scanner (Philips Healthcare, Amsterdam, the Netherlands) at 120 kVp with weight-adapted tube current. Reconstruction slice thickness was either 5.0 or 8.0 mm based on the instituted chest protocol. As a retrospective study encompassing various clinical indications, other technical parameters (e.g., pitch, gantry rotation time) were operator- and protocol-dependent and not uniformly documented.

The following locations were assessed: the ascending aorta, aortic arch, descending aorta, origins of the left and right common carotid arteries, origins of the left and right subclavian arteries, brachiocephalic artery, and coronary arteries. A region superior to the origin of the right coronary artery but proximal to the origin of the brachiocephalic artery was defined as being in the ascending aorta. The segment between the origin of the brachiocephalic artery and the origin of the left subclavian artery was defined as being in the aortic arch. Calcification caudal to the origin of the left subclavian artery was defined as being in the descending aorta. Calcification superior to the right branch of the brachiocephalic artery was defined as being in the right common carotid artery, while the second branch originating from the aortic arch was defined as being in the left common carotid artery. Calcification superior to the left branch of brachiocephalic artery was defined as being in the right subclavian artery, while the third branch originating from the aortic arch was defined as being in the left subclavian artery (9).

The degree of VC was quantified using the Agatston score (adjusted for slice thickness) with Heartbeat CS software (Philips Healthcare) on a Philips EBW workstation, as illustrated in Figure 1. The Agatston score was calculated by using a categorical weighted value from 1 to 4 depending on the maximum Hounsfield Unit (HU) obtained in each calcification (1 = 130–199 HU, 2 = 200–299 HU, 3 = 300–399 HU, and 4 ≥400 HU), multiplied by the lesion area. VC was categorized as no calcium (Agatston score =0), minimal (total: 1–250, aorta: 1–200, coronary arteries: 1–100, subclavian arteries or common carotid arteries: 1–50), mild (total: 251–1,000, aorta: 201–500, coronary arteries: 101–400, subclavian arteries or common carotid arteries: 51–100), moderate (total: 1,001–4,000, aorta: 501–2,000, coronary arteries: 401–1,000, subclavian arteries or common carotid arteries: 101–200), or severe (total: >4,000, aorta: >2,000, coronary arteries: >1,000, subclavian arteries or common carotid arteries: >200) according to the quartiles of this study (Table 2). The presence of calcification was defined as Agatston score greater than 0. All measurements were made by two radiologists (with 10 and 15 years of experience in CT angiography, respectively), who were blinded to the study hypothesis, purpose, and the clinical parameters. In case of ambiguity, a consensus was reached by discussion.

Figure 1 Images of calcification in different segments. (A) The ascending aorta; (B) aortic arch; (C) the descending aorta; (D) brachiocephalic artery; (E) right subclavian artery; (F) coronary artery.

Given the different protocols for chest CT scans with variable slice thicknesses, the validity of calculating the Agatston score under these circumstances is unknown. To assess internal validity and develop a slice thickness correction factor, we randomly selected 26 patients who had recently undergone a non-contrast chest CT. For each patient, images were reconstructed at both 5.0 and 8.0 mm slice thicknesses. An independent, blinded radiologist with 15 years of CT angiography experience then calculated the Agatston score for each reconstructed scan at different slice thicknesses and derived a correction factor for slice thickness, enabling standardized calcium quantification across different slice thicknesses.

Follow-up

The primary outcome of this study was major adverse cardiovascular events (MACEs), which were assessed through telephone interviews and hospital record reviews. Patients were followed until the occurrence of MACEs, death, or the end of the follow-up period (whichever came first). Clinical pharmacists who conducted follow-up were not aware of the purpose of the study. MACEs included hospitalizations for unstable angina, myocardial infarction, ischemic stroke, and cardiogenic death. Nonfatal myocardial infarction was defined as typical chest pain or characteristic serial electrocardiographic changes accompanied by elevated cardiac troponin levels. Stroke was defined as an acute cerebral infarction confirmed by CT and/or magnetic resonance imaging with persistent neurological dysfunction. Unstable angina was defined as hospitalization for newly developed severe angina or rest angina with normal serum myocardial enzyme levels.

Statistical analysis

Categorical variables were summarized as frequencies and percentages and were compared using the Chi-squared test, Fisher’s exact test, Kruskal-Wallis test, or Cochran-Mantel-Haenszel test, as appropriate. Continuous variables were presented as medians with interquartile ranges. Differences between groups for these continuous variables were assessed using the Kruskal-Wallis test, as the one-way analysis of variance (ANOVA) assumption of homogeneity of variances was violated. All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS, version 22.0; IBM Corp., Armonk, NY, USA). Statistical significance was defined as a two-sided P value of less than 0.05.

Results

Increased CHA₂DS₂-VASc scores related to higher risk of VC

Baseline characteristics of the patient population, according to absence or presence of VC, are presented in Table 3 and Tables S1-S9. Compared to patients without calcification, those with VC were older (P<0.001), and had a higher prevalence of hypertension (54.7% vs. 25.0%, P<0.001), diabetes mellitus (21.2% vs. 11.5%, P=0.001), coronary artery disease (35.9% vs. 13.5%, P<0.001), myocardial infarction (3.1% vs. 0.5%, P=0.03) cerebral infarction (24.7% vs. 8.7%, P<0.001), and heart failure (17.4% vs. 6.7%, P<0.001). Patients with VC also had significantly higher CHA₂DS₂-VASc scores. Furthermore, compared with the non-anticoagulant group, patients taking warfarin or rivaroxaban were more likely to have VC. A multivariable logistic regression analysis confirmed that the use of rivaroxaban, warfarin, and a higher CHA₂DS₂-VASc score were independent risk factors for VC (Table 4).

The prevalence and severity of VC increased with higher CHA₂DS₂-VASc scores at the following sites: the overall vascular level (for both prevalence and severity: P<0.001), thoracic aorta (P<0.001), ascending aorta (P<0.001), aortic arch (P < 0.001), descending aorta (P<0.001), left common carotid artery (P<0.001), right common carotid artery (prevalence: P=0.002, severity: P=0.003), left subclavian artery (P<0.001), right subclavian artery (P<0.001), brachiocephalic artery (P<0.001) and coronary arteries (P<0.001) (Table S10, Table 5 and Figure 2).

Figure 2 Agatston score categories in patients with different CHA₂DS₂-VASc score according to different segments. (A) Total level; (B) thoracic aorta; (C) the ascending aorta; (D) aortic arch; (E) the descending aorta; (F) left CCA; (G) right CCA; (H) left SA; (I) right SA; (J) BCA; (K) coronary artery. BCA, brachiocephalic artery; CCA, common carotid artery; CHA₂DS₂-VASc, congestive heart failure, hypertension, age ≥75 years (2 points), diabetes, previous stroke/transient ischemic attack/arterial thromboembolism (2 points), vascular disease, age 65–74 years, and female sex; SA, subclavian artery.

Prevalence of VC across CHA₂DS₂-VASc groups by OAC use

Increasing CHA₂DS₂-VASc scores were associated with a higher incidence of VC across all four anticoagulant groups: in the dabigatran group, VC rates ranged from 75.0% (in the low CHA₂DS₂-VASc score group) to 100.0% (in the high CHA₂DS₂-VASc score group). In the rivaroxaban group, the rates ranged from 88.0% to 96.4% (P=0.46). Similarly, rates in the warfarin group ranged from 80.0% to 97.4% (P=0.007) and in the non-anticoagulant group, from 64.1% to 99.2% (P<0.001). Additionally, a significant difference in VC prevalence was observed among the different anticoagulant groups specifically in patients with low CHA₂DS₂-VASc scores (P=0.007). However, chi-square analysis did not reveal a statistical difference between any other groups.

Given the potential for differential drug effects across vascular beds (Table S11), we analyzed the prevalence of VC in multiple specific arteries: the ascending aorta, aortic arch, descending aorta, left and right common carotid arteries, left and right subclavian arteries, brachiocephalic artery, and coronary arteries. Table 6 details the prevalence of VC in each of these vascular distributions according to OAC use. Notably, the incidence of VC in the left common carotid artery was higher in the rivaroxaban group than in the non-anticoagulant group. Similarly, in the left subclavian artery, the warfarin group had a higher incidence of VC compared to the non-anticoagulant group.

VC severity across CHA₂DS₂-VASc groups by OAC use

The severity of VC increased with higher CHA₂DS₂-VASc scores, irrespective of the type of OAC or the specific vascular bed involved. Furthermore, we found that patients with low CHA₂DS₂-VASc scores in the rivaroxaban group (P=0.020) and the warfarin group (P=0.021) had more severe VC overall compared to patients in the non-anticoagulant group. Similarly, patients on rivaroxaban with low CHA₂DS₂-VASc scores had more severe calcification in the thoracic aorta (P=0.044) and aortic arch (P=0.043) than those in the non-anticoagulant group. In addition, patients on warfarin with low CHA₂DS₂-VASc scores had more severe VC in the left subclavian artery (P=0.027) and coronary arteries (P=0.001) than those in the non-anticoagulant group (Figure 3).

Figure 3 Agatston score categories in patients with different OAC use according to different segments and different groups related to CHA₂DS₂-VASc scores. (A) Total level; (B) thoracic aorta; (C) the ascending aorta; (D) aortic arch; (E) the descending aorta; (F) left common carotid artery; (G) right CCA; (H) left subclavian artery; (I) right SA; (J) BCA; (K) coronary artery. BCA, brachiocephalic artery; CCA, common carotid artery; CHA₂DS₂-VASc, congestive heart failure, hypertension, age ≥75 years (2 points), diabetes, previous stroke/transient ischemic attack/arterial thromboembolism (2 points), vascular disease, age 65–74 years, and female sex; OAC, oral anticoagulant; SA, subclavian artery; VKA, vitamin K antagonist.

MACEs across CHA₂DS₂-VASc groups by OAC use

Of the 1,288 patients enrolled, 153 patients were lost to follow-up, leaving a total of 1,135 patients (43 in the dabigatran group, 121 in the rivaroxaban group, 193 in the warfarin group, and 778 in the non-anticoagulant group) for inclusion in the final analysis. Multivariate Cox regression analysis showed that before adjustment, the type of anticoagulant (P=0.005), CHA₂DS₂-VASc score [hazard ratio (HR) =2.948, 95% CI: 2.445–3.554, P<0.001], and the severity of VC (HR =1.406, 95% CI: 1.271–1.555, P<0.001) were all associated with MACEs. However, after adjustment, only the CHA₂DS₂-VASc score showed statistical significance (adjusted HR =2.728, 95% CI: 2.211–3.367, P<0.001), while the rivaroxaban group did not show a significantly elevated MACE risk compared to non-anticoagulated patients (adjusted HR =1.389, 95% CI: 0.957–2.018, P=0.084) (Table 6). Kaplan-Meier curves illustrating the univariate association between CHA₂DS₂-VASc score categories and MACE-free survival are provided in Figure S1.

Discussion

Our study demonstrates a graded, positive association of the CHA₂DS₂-VASc score with the prevalence and severity of VC and the incidence of MACEs. Furthermore, we found that among patients with low CHA₂DS₂-VASc scores, those treated with rivaroxaban or warfarin exhibited a significantly higher burden of VC compared to non-anticoagulated counterparts. These findings compel a re-evaluation of current stroke prophylaxis strategies in AF, suggesting that anticoagulation decision-making should incorporate an assessment of vascular health status. Additionally, this study indicates that different classes of anticoagulants may exert varying effects on the vasculature, implying that the choice of anticoagulant agent may have implications extending beyond stroke prevention to influence long-term vascular health outcomes.

The traditional OAC warfarin, a coumarin derivative, inhibits vitamin K epoxide reductase complex subunit 1. This action disrupts the vitamin K cycle, impairing the synthesis of clotting factors II, VII, IX, and X. Crucially, this mechanism also suppresses the activation of vitamin K-dependent proteins, including matrix Gla protein (MGP), a potent endogenous inhibitor of calcification. Consequently, the anti-calcific capacity of the vasculature is compromised. This pathophysiological pathway provides a plausible explanation for the well-documented association between warfarin therapy and accelerated VC in both experimental and clinical settings (10-12). Our study not only corroborates the pro-calcific effect of warfarin in patients with low CHA₂DS₂-VASc scores but also reveals a comparable trend in rivaroxaban users. This suggests that certain direct oral anticoagulants (DOACs) may pose a vascular safety concern analogous to that of warfarin.

While DOACs have largely superseded warfarin in clinical practice (5,6,13-16), their long-term influence on VC progression remains unclear. Prior evidence (17) has indicated that rivaroxaban may share a pro-calcific propensity similar to warfarin, whereas dabigatran has not demonstrated such an effect. Our analysis is consistent with this finding: among patients with low CHA₂DS₂-VASc scores, those receiving rivaroxaban (median treatment duration 317 days) or warfarin therapy (median treatment duration 673 days) presented greater severity of VC compared to those in the non-anticoagulant group. Notably, this pro-calcific effect was not evident in patients with intermediate-to-high CHA₂DS₂-VASc scores, suggesting that the CHA₂DS₂-VASc score holds important value for risk stratification in identifying patients susceptible to drug-related vascular effects. We propose that in lower-risk patients, who possess relatively fewer traditional atherogenic risk factors, the iatrogenic impact of these anticoagulants on VC is more readily apparent. Conversely, among higher-risk individuals, powerful drivers of calcification such as advanced age, diabetes, and hypertension likely dominate the vascular pathology, thereby attenuating or masking the additional drug-related effect.

Further analysis revealed that the impact of various anticoagulants on VC demonstrated distinct site-specificity. Rivaroxaban was primarily associated with calcification in large elastic arteries (such as the thoracic aorta and aortic arch), whereas warfarin was more strongly associated with calcification in medium-sized muscular arteries (such as the left subclavian artery) and coronary arteries. The underlying mechanisms responsible for these divergent vascular effects of warfarin and rivaroxaban remain unclear. This discrepancy might stem from differential expression profiles of vitamin K-dependent proteins across vascular beds or drug-specific perturbations of distinct calcification pathways.

A positive correlation was also observed between the CHA₂DS₂-VASc scores and MACEs incidence. However, this association was not directly attributable to anticoagulant therapy, as the components of the CHA₂DS₂-VASc score are themselves well-established risk factors for MACEs (18-20). Given the significant baseline differences in CHA₂DS₂-VASc scores across anticoagulant groups in our cohort (P<0.001), we performed a multivariate Cox regression analysis adjusted for both the CHA₂DS₂-VASc score and VC severity. This analysis revealed no significant difference in MACEs risk among the anticoagulant groups (P=0.34), indicating that the incidence of adverse cardiovascular events is likely mediated by the collective burden of traditional risk factors (as captured by the CHA₂DS₂-VASc score) and VC, rather than by a direct, independent effect of anticoagulant drugs.

In addition, several potential confounding factors should be considered in the interpretation of our findings. The pro-calcific phenomenon observed predominantly in patients with low CHA₂DS₂-VASc scores may be partially attributable to clinical indications or comorbidities not fully captured by this scoring system, such as chronic kidney disease (excluded from our cohort) or subclinical vitamin K deficiency. The latter is particularly relevant, as it can impair the activation of key endogenous calcification inhibitors, including matrix Gla protein and osteocalcin (10-12), thereby potentially amplifying the vascular impact of anticoagulant therapy. Additionally, inherent limitations of the CHA₂DS₂-VASc score itself should be acknowledged, particularly concerning gender-based risk stratification. Growing evidence (21-23) indicates that female sex functions primarily as a risk modifier for age-related risk rather than an independent risk factor. The inclusion of this parameter not only introduces clinical ambiguities for healthcare providers and patients alike (24) but also fails to account for gender-diverse populations. Notably, current ESC and AHA guidelines avoid direct application of CHA₂DS₂-VASc score, instead recommending sex-specific thresholds for initiating OAC in AF patients. In line with this, emerging clinical evidence supports the use of the modified CHA₂DS₂-VA scoring system, which omits sex criteria, as a more inclusive and clinically applicable tool for OAC decision-making, particularly in settings lacking validated local risk assessment (25,26). The proposal to refine this risk score is further supported by well-established sex differences in VC burden. For example, the Multi-Ethnic Study of Atherosclerosis (MESA; n=6,610) reported a greater coronary artery calcium burden in men (27), a pattern often attributed to the cardiovascular protective effects of estrogen in premenopausal women. Consistent with this, among individuals over 70 years old, VC is observed in > 90% of men compared to only 67% of women. These findings underscore the necessity for refined risk assessment tools, such as the gender-neutral CHA₂DS₂-VA score (25,26), to improve stratification accuracy and clinical utility.

There are several limitations in this study. First, the relatively small overall sample size (n=1,288) and particularly limited numbers within each anticoagulant subgroup may restrict the generalizability of our findings at a population level. Second, the single-center design from a Chinese academic institution raises valid concerns about the applicability of our results to the non-Asian population, and the study only included patients who had undergone a single CT scan, which makes baseline calcification levels prior to anticoagulation initiation unknown and introduces a potential selection bias. Third, the loss-to-follow-up rate in this study was 12%. Upon reanalyzing the baseline data, excluding these patients who were lost to follow-up, the results remained unchanged, thereby supporting the robustness of the primary findings. Future larger-scale prospective cohort studies with standardized vascular imaging are warranted to provide more evidence regarding the relationship between the risk of VC and CHA₂DS₂-VASc scores in patients with AF receiving OAC therapy.

Conclusions

In summary, this study demonstrates that among AF patients receiving OACs, a higher CHA₂DS₂-VASc score is positively associated with an increased burden of VC and a higher risk of MACEs. Most importantly, we identified that rivaroxaban and warfarin may accelerate the progression of VC in patients with low stroke risk. These findings support the integration of vascular health assessment (such as coronary artery calcium scoring) into the individualized anticoagulation decision-making process for AF patients, aiming to balance stroke prevention against long-term vascular safety. For AF patients with low CHA₂DS₂-VASc scores and longer life expectancy, clinicians should exercise greater caution when initiating anticoagulation, undertaking a comprehensive evaluation of potential vascular risks to develop more precise and holistic therapeutic strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-652/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-652/dss

Funding: This study was supported by research grants from the National Natural Science Foundation of China (Grant No. 82504928) and the Natural Science Foundation of Hunan Province (Grant Nos. 2025JJ50595 and 2025JJ50666).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-652/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The retrospective analysis of personal health data of the study subjects was approved by the Ethics Committee of the Third Xiangya Hospital, Central South University (No. 23699), and written informed consent was waived because of the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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