
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12678-3
10.1016/j.heliyon.2024.e36647
e36647
Research Article
The presence of spontaneous echo contrast didn't increase the risk for left atrial appendage closure: A propensity score matching analysis based on the CLACBAC study
Zhang Jun ab1
Zhou Lili ab1
Ren Zhongyuan ab
Feng Shiyu b
Wu Jiayu abc
Yang Haotian ab
Zheng Yixing d
Meng Weilun ab
Su Yang a
Xu Jun a
Sun Hui ae
Zhao Yifan a
Xie Yun xieyun@tongji.edu.cn
d⁎⁎⁎
Xu Yawei xuyawei@tongji.edu.cn
a⁎⁎
Zhao Dongdong zhaodd@tongji.edu.cn
a⁎
a Heart Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
b Tongji University School of Medicine, Shanghai, China
c Anhui University of Science and Technology, School of Medicine, Huainan, Anhui Province, China
d Department of Cardiology, Putuo District People's Hospital, School of Medicine, Tongji University, Shanghai, China
e Department of Cardiology, Shanghai Tenth People's Hospital Chongming Branch, Shanghai, China
⁎ Corresponding author. Heart Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. zhaodd@tongji.edu.cn
⁎⁎ Corresponding author. Heart Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. xuyawei@tongji.edu.cn
⁎⁎⁎ Corresponding author. Department of Cardiology, Putuo District People's Hospital, School of Medicine, Tongji University, Shanghai, 200060, China. xieyun@tongji.edu.cn
1 These authors contributed equally to the manuscript.

22 8 2024
15 9 2024
22 8 2024
10 17 e3664731 8 2023
12 8 2024
20 8 2024
© 2024 Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Left atrial appendage closure (LAAC) was effective in preventing thromboembolic events and stroke in patients with atrial fibrillation (AF). However, whether left atrial spontaneous echo contrast (LA-SEC) poses a higher risk for thromboembolism is contradictory. We aimed to investigate whether LA-SEC is a risk factor for thromboembolic events in patients who underwent LAAC.

Methods

258 consecutive patients who underwent successful LAAC were enrolled and divided according to the presence or absence of LA-SEC detected by transesophageal echocardiography (TEE). Propensity score matching (PSM) was used to eliminate covariate imbalances. Baseline characteristics, periprocedural details, and clinical outcomes were compared between LA-SEC and non-LA-SEC groups and PSM-matched groups.

Results

Of the 258 patients enrolled, mean age was 71.8 ± 8.3 years and 59.3 % were male. LA-SEC group had a higher percentage of persistent AF and worse cardiac function. No significant difference in peri-procedure parameters was found. Through follow-up of 38.1 ± 10.7 months, the total incidence of thromboembolic events and stroke was 7.8 % and 6.6 %, respectively. Though the event-free survival rate of thromboembolic events (Log-Rank P = 0.042) and stroke (Log-Rank P = 0.010) was significantly lower in the LA-SEC group, multivariable COX regression analysis showed LA-SEC was not an independent predictor of thromboembolic events (Hazard ratio 2.073, 95 % Confidence interval 0.845–5.082, P = 0.111). Further survival analysis between PSM-matched groups with comparable baseline characteristics presented no significant difference in survival free from thromboembolic events (Log-Rank P = 0.616) and stroke (Log-Rank P = 0.312).

Conclusion

Patients with LA-SEC had worse condition, while LA-SEC per se did not increase the incidence of thromboembolic events and stroke for patients who underwent LAAC.

Keywords

Atrial fibrillation
Spontaneous echo contrast
Left atrial appendage closure
Thromboembolic events
==== Body
pmc1 Introduction

Nearly 15 %–25 % of ischemic strokes are linked to atrial fibrillation (AF) [1]. AF increases the risk of stroke nearly fivefold [2]. As 90 % of atrial thrombus of non-valvular AF occur in the left atrial appendage (LAA) [3], left atrial appendage closure (LAAC) has emerged to prevent thrombus from the LAA. Several clinical trials have demonstrated its non-inferior efficacy and safety compared to anticoagulants in preventing thromboembolic events, stroke, cardiovascular death, and safety events [4,5].

Nevertheless, there remains a risk of thromboembolism after LAAC [[4], [5], [6]]. Spontaneous echo contrast (SEC), commonly detected by transesophageal echocardiography (TEE) in patients with AF [7], is suspected to contribute to thromboembolism due to its association with hypercoagulability, platelet aggregation, and atherosclerosis of the aorta or cerebral artery [8].

However, it has been under debate whether LA-SEC poses a higher risk for thromboembolism. Some studies found no significant interaction between LA-SEC and thromboembolism in AF patients [9,10], while others concluded the opposite [[11], [12], [13]]. Moreover, despite numerous studies on LA-SEC, the effect of LA-SEC on the risk for thromboembolic events and stroke following LAAC remains unclear. Hence, this study aims to investigate whether LA-SEC per se is a risk factor for thromboembolic events or stroke in patients who underwent LAAC.

2 Materials and methods

2.1 Study population

This study included 457 consecutive patients with AF who underwent LAAC from October 2015 to December 2020. Patients meeting at least one of the following criteria were eligible for LAAC: non-valvular AF; CHA2DS2-VASc score ≥2 and/or HAS-BLED score ≥3; contraindication for long-term oral anticoagulant, including the risk of major bleeding (active major bleeding diseases, history of bleeding under oral anticoagulants, inherited hemorrhagic disorder) and severe side effects under oral anticoagulants; reluctance to take oral anticoagulants. Patients with LA thrombosis were excluded from LAAC. Inclusion criteria for this study were: (1) Patients diagnosed with AF; (2) Patients had undergone LAAC. Exclusion criteria were: 1. Patients with history of cardiac disease; 2. Patients with concomitant arrhythmia other than AF, requiring extra-pulmonary vein ablation; 3. Patients who underwent other concomitant procedures in addition to pulmonary vein isolation; 4. Failure of occluder implantation for any reason; 5. Patients for whom echocardiographic data were not available; 6. Patients lost at follow-up; 7. Patients participating in other clinical trials. The data was obtained from the registered study “Combining Left Atrial Appendage Closure with Cryoballoon Ablation in Chinese Population” (hereafter referred to as CLACBAC; registry No. NCT04185142). For each patient, a consent form was signed prior to the procedure after fully understanding the risks and associated complications. This study complied with the Declaration of Helsinki and was approved by the Ethics Committee of Shanghai Tenth People's Hospital.

2.2 TEE examination

2D transesophageal echocardiography (TEE) (GE Vivid E9 or Philips EPIQ 7C) was performed following standard practice guidelines [14]. LAA orifice diameter was measured from 3 angles: 45°, 90°, and 135°, and their average was calculated. Spontaneous echo contrast was defined as dynamic “smoke-like” echoes in the atrial cavity, characterized by swirling motions that presisted after adjusting gain settings [15], as illustrated in Fig. 1. For the patient concerned, written consent was obtained to publish the patient's image.Fig. 1 Illustration of LA-SEC. Yellow circle indicates SEC observed in LAA from a participant of our study. LA = left atrium; LAA = left atrial appendage.

Fig. 1

2.3 Percutaneous LAAC

All patients included had undergone standard cryoballoon ablation prior to LAAC, the details of which were described in Supplementary Methods. Both TTE and TEE examinations had been conducted before the procedure. Plug occluders (WATCHMAN; Boston Scientific) and pacifier occluders (LAmbre, Lifetech Scientific, Shenzhen, China) were used for LAAC. To achieve an optimal compression ratio of 10 %–20 %, the size of the plug occluder should be 4–6 mm larger than the landing area. To ensure a complete seal, the pacifier occluder should be 2–3 mm larger than the landing area. LAAC equipment was delivered and deployed under the guidance of TEE and fluoroscopy. Before releasing the occluder, its stability was confirmed through tug testing, and residual flow was evaluated via TEE to verify complete sealing. Subsequently, TEE was employed again to assess device positioning and peri-procedure complications.

After LAAC, oral anticoagulation therapy (Dabigatrian, Rivaroxaban, or Warfarin) was recommended for 3 months. If TEE or computed tomography angiography showed residual flow < 3 mm at the 3-month follow-up, it was advised for an antithrombotic regimen with dual antiplatelet therapy for 3 months, followed by single antiplatelet therapy for 6 months. When a patient experienced a major bleeding event, a milder antithrombotic therapy was taken individually based on his/her history of bleeding, comorbidities, and bleeding severity. Patients undergoing ablation were treated with class I/III antiarrhythmic drugs within 3 months post-procedure.

2.4 Follow-up

Patients were required to attend outpatient follow-ups at the 3rd, 6th, and 12th months post-procedure and annually thereafter. TEE was performed at the 3rd and 12th months to detect device positioning, device-related thrombus, residual flow, pericardial effusion, and other complications. Post-procedure antithrombotic treatment was as follows. Every 3 months, telephone follow-ups were conducted to monitor patients’ cardiovascular status. Composite primary endpoints of follow-up included thromboembolic events and stroke. Secondary endpoints were major hemorrhagic events. Thromboembolic events consisted of cerebral infarction, transient ischemic attack, pulmonary thromboembolism, perivascular thrombus, and device-related thrombus. Stroke was a combination of cerebral infarction, transient ischemic attack, and intracranial hemorrhage. It should be noted that lacunar infarction was not incorporated into cerebral infarction. Major hemorrhagic events were defined as type 3 or type 5 of Bleeding Academic Research Consortium (BARC) [16].

Cerebral infarction and intracranial hemorrhage were confirmed by clear radiographic evidence on computed tomography or magnetic resonance imaging. Transient ischemic attack was diagnosed when neurological symptoms of cerebral ischemia lasted less than 24 h. Additionally, pulmonary thromboembolism was confirmed by computed tomography pulmonary angiogram and device-related thrombus was verified by TEE or computed tomography angiogram.

2.5 Statistics

Patients were divided into two groups based on TEE findings: the LA-SEC and non-LA-SEC groups. Continuous variables were described as mean ± standard deviation if normally distributed, or median with the interquartile range and quartile if not. Categorical variables were described as numbers with percentages. Baseline, peri-procedure and follow-up data were compared using two independent sample T-test for continuous variables with normal distribution, Mann-Whitney U tests for those with skewed distribution, and Chi-square test for categorical variables. The homogeneity of variance test was performed before the independent sample t-test. A gender and age adjusted multivariable logistic regression model was employed to investigate the specific relationship between LA-SEC and AF type or cardiac functional indicators. For survival data, Kaplan-Meier survival analysis and Log-Rank test were used to compare the effect of LA-SEC on prognosis. A univariable Cox proportional risk hazard model and a multivariable model adjusted for age, gender, LAA orifice diameter, and LA-SEC were applied to explore factors causing thromboembolic events and further evaluate the prognostic value of LA-SEC. For the purpose of eliminating the covariate imbalance between the groups, 1:1 propensity score matching (PSM) was carried out, fitting a multivariate logistic regression model, where covariables including AF type, N-terminal pro-B-type natriuretic peptide (NT-proBNP), previous left atrial diameter, sex, age, previous oral anticoagulants treatment was contained. The estimated annual thromboembolic events rate was calculated based on CHA2DS2-VASc score according to the Swedish Atrial Fibrillation cohort study [17], and the observed annual rates were computed according to patients’ follow-up time. A two-sided P-value <0.05 was considered statistically significant. SPSS version 26.0 (SPSS Inc., Chicago, Illinois) was used for data analysis.

3 Results

After screening according to the inclusion and exclusion criteria for this study, a total of 258 patients (mean age 71.8 ± 8.3 years; 59.3 % male) who underwent successful LAAC were enrolled and divided into two groups based on the presence or absence of LA-SEC detected by TEE. There were 68 patients in the LA-SEC group and 190 in the non-LA-SEC group.

Comparison of baseline characteristics and LAAC procedure details between the LA-SEC group and non-LA-SEC group before and after PSM were displayed in Table 1. The mean ages and gender composition of the two groups were similar, as were the CHA2DS2-VASc and HAS-BLED scores. Patients in the LA-SEC group have a higher prevalance of persistent AF (89.7 % vs. 65.6 %; P < 0.001) and worse cardiac function indicated by higher value of NT-proBNP (1121.0 [715.6, 2199.5] vs. 779.4 [327.9, 1405.5]; P < 0.001), cardiac troponin T (0.016 [0.011, 0.021] vs. 0.012 [0.009, 0.020]; P = 0.033) and left atrial diameter (46.7 ± 4.8 vs. 44.2 ± 4.5; p < 0.001), a higher proportion of previous heart failure (35.3 % vs. 16.9 %; P = 0.002), as well as a lower left ventricular ejection fraction (LVEF) level (58.0 [52.0, 60.0] vs. 60.0 [57.0, 60.0]; P < 0.001). Logistic regression analysis demonstrated that persistent AF (Odds ratio 4.939, 95 % Confidence interval 2.111–11.555; P < 0.001), history of heart failure (Odds ratio 2.593, 95 % Confidence interval 1.382–4.865; P = 0.003), NT-proBNP (Odds ratio 4.693 95 % Confidence interval 2.136–10.313; P < 0.001) and LAD (Odds ratio 1.126, 95 % Confidence interval 1.056–1.200; P < 0.001) all promoted the occurrence of LA-SEC, while the incidence of LA-SEC reduced as LVEF improved (Odds ratio 0.947, 95 % Confidence interval 0.915–0.980; P = 0.002) (Fig. 2). Both baseline characteristics and peri-procedure parameters were comparable between the PSM-matched groups (Table 1).Table 1 Baseline characteristics and LAAC procedure details of patients with or without LA-SEC before and after PSM.

Table 1	LA-SEC (n = 68)	non-LA-SEC (n = 190)	P value	LA-SECmatched (n = 61)	non-LA-SECmatched (n = 61)	P-value	
Age, yrs	72.0 ± 8.3	71.7 ± 8.3	0.818	71.7 ± 7.8	72.7 ± 7.2	0.463	
Male, n (%)	38 (55.9 %)	115 (60.5 %)	0.504	36 (59.0 %)	36 (59.0 %)	1.000	
Persistent AF, n (%)	61 (89.7 %)	124 (65.6 %)	<0.001*	54 (88.5 %)	54 (88.5 %)	1.000	
CHA2DS2-VASc	4.0 [3.0,5.0]	4.0 [3.0, 5.0]	0.150	4.0 [3.0, 5.0]	4.0 [3.0, 5.0]	0.528	
HAS-BLED	2.5 [2.0, 3.0]	2.0 [2.0, 3.0]	0.484	3.0 [2.0, 3.0]	2.0 [2.0, 3.0]	0.486	
NT-proBNP, pg/ml	1121.0 [715.6, 2199.5]	779.4 [327.9, 1405.5]	<0.001*	962.7 [620.3, 1935.0]	866.5 [495.2, 2061.0]	0.610	
CTnT, μg/L	0.016 [0.011, 0.021]	0.012 [0.009, 0.020]	0.033*	0.015 [0.011, 0.021]	0.015 [0.010, 0.023]	0.706	
eGFR, ml/min	69.6 [60.1, 86.6]	74.9 [62.7, 87.6]	0.277	69.7 [59.9, 87.5]	76.7 [63.3, 93.7]	0.438	
Previous illness	
Stroke, n (%)	24 (35.3 %)	61 (32.1 %)	0.631	23 (37.7 %)	20 (32.8 %)	0.570	
 Cerebral infarction, n (%)	23 (33.8 %)	59 (31.1 %)	0.674	22 (36.1 %)	20 (32.8 %)	0.703	
 Intracranial hemorrhage, n (%)	3 (4.4 %)	5 (2.6 %)	0.750	2 (3.3 %)	0 (0 %)	0.476	
Heart failure, n (%)	24 (35.3 %)	32 (16.9 %)	0.002*	21 (34.4 %)	20 (32.8 %)	0.848	
Hypertension, n (%)	49 (72.1 %)	142 (74.7 %)	0.666	44 (72.1 %)	45 (73.8 %)	0.839	
Diabetes mellitus, n (%)	20 (29.4 %)	51 (26.8 %)	0.684	17 (27.9 %)	16 (26.2 %)	0.839	
Coronary heart disease, n (%)	25 (36.8 %)	54 (28.4 %)	0.200	24 (39.3 %)	20 (32.8 %)	0.451	
Myocardial infarction, n (%)	6 (8.8 %)	6 (3.2 %)	0.117	6 (9.8 %)	2 (3.3 %)	0.273	
Perivascular disease, n (%)	5 (7.4 %)	8 (4.2 %)	0.488	4 (6.6 %)	0 (0 %)	0.127	
Hypertrophic cardiomyopathy, n (%)	3 (4.4 %)	7 (3.7 %)	1.000	2 (3.3 %)	1 (1.6 %)	1.000	
Dilated cardiomyopathy, n (%)	1 (1.5 %)	1 (0.5 %)	0.458	1 (1.6 %)	1 (1.6 %)	1.000	
Previous treatment	
OAC			0.124			0.257	
 NOAC, n (%)	14 (20.6 %)	24 (12.6 %)		12 (19.7 %)	6 (9.8 %)		
 VKA, n (%)	19 (27.9 %)	43 (22.6 %)		17 (27.9 %)	16 (26.2 %)		
Echocardiographic measurement	
LAD, mm	46.7 ± 4.8	44.2 ± 4.5	<0.001*	45.9 ± 4.3	45.8 ± 4.4	0.900	
LVeDD, mm	46.0 [43.0, 51.0]	46.6 [44.0, 50.0]	0.942	46.0 [43.0, 50.5]	46.0 [43.0, 50.0]	0.892	
LveSD, mm	31.0 [27.3, 34.8]	30.0 [27.8, 33.0]	0.260	31.0 [27.5, 35.0]	31.0[28.0, 33.0]	0.865	
LVEF, %	58.0 [52.0, 60.0]	60.0 [57.0, 60.0]	<0.001*	58.0 [51.0, 60.0]	60.0 [55.0, 60.0]	0.233	
LVEF group			0.008*			0.079	
 ≥50 %, n (%)	55 (80.9 %)	176 (92.6 %)		48 (78.7 %)	55 (90.2 %)		
 40%–50 %, n (%)	7 (10.3 %)	4 (2.1 %)		7 (11.5 %)	1 (1.6 %)		
 <40 %, n (%)	6 (8.8 %)	10 (5.3 %)		6 (9.8 %)	5 (8.2 %)		
Mitral regurgitation, n (%)	12 (21.4 %)	28 (17.2 %)	0.478	9 (18.4 %)	16 (29.1 %)	0.201	
LAA measurement	
Mean LAA orifice diameter, mm	23.0 [21.0, 27.0]	23.0 [20.0, 25.2]	0.100	23.0 [21.0, 27.0]	24.0 [21.5, 28.0]	0.332	
LAAC procedure detail	
Plug occluder, n (%)	47 (69.1 %)	144 (75.8 %)	0.282	43 (70.5 %)	41 (67.2 %)	0.696	
Disc size, mm	35.0 [32.0, 36.5]	33.0 [30.0, 36.0]	0.040*	34.0 [32.0, 36.0]	34.0 [32.0, 36.0]	0.424	
Plug size, mm	27.0 [27.0, 30.0]	27.0 [24.0, 30.0]	0.203	27.0 [27.0, 30.0]	27.0 [27.0, 33.0]	0.305	
Compression ratio (plug), %	20.5 [16.9, 26.0]	20.0 [16.7, 24.0]	0.273	20.0 [16.9, 26.0]	18.0 [17.2, 22.1]	0.107	
Deploy time ≥2	12 (17.6 %)	36 (18.9 %)	0.813	10 (16.4 %)	16 (26.2 %)	0.185	
Change size, n (%)	6 (8.8 %)	20 (10.5 %)	0.689	4 (6.6 %)	9 (14.8 %)	0.142	
Post-procedural residual flow, n (%)	1 (1.5 %)	7 (3.7 %)	0.620	1 (1.6 %)	2 (3.3 %)	1.000	
 ≥3 mm, n (%)	0 (0 %)	2 (1.1 %)	1.000	0 (0 %)	1 (1.6 %)	1.000	
 < 3 mm, n (%)	1 (1.5 %)	5 (2.6 %)	0.939	1 (1.6 %)	1 (1.6 %)	1.000	
Cardioversion, n (%)	15 (22.1 %)	62 (32.6 %)	0.102	14 (23.0 %)	22 (36.1 %)	0.112	
Pericardial effusion, n (%)	1 (1.5 %)	3 (1.6 %)	1.000	1 (1.6 %)	1 (1.6 %)	1.000	
Continuous variables are presented as mean ± standard deviation or as median with interquartile range. Categorical variables are presented as frequencies and percentage (%). Asterisk (*) indicates significant P-value. AF = atrial fibrillation; LAA = left atrial appendage; LAAC = left atrial appendage closure; LAD = left atrial diameter; LA-SEC = left atrial spontaneous echo contrast; LVeDD = left ventricular end diastolic diameter; LVeSD = left ventricular end systolic diameter; LVEF = left ventricular ejection fraction; NOAC = novel oral anticoagulant; OAC = oral anticoagulant; PSM = propensity score matching; VKA = Vitamin K antagonist.

Fig. 2 Forest plot of age and gender adjusted odds ratio for LA-SEC by multivariable logistic regression model. Asterisk (*) indicates significant P-value. AF = atrial fibrillation; LAD = left atrial diameter; LA-SEC = left atrial spontaneous echo contrast; LVEF = left ventricular ejection fraction.

Fig. 2

During a follow-up period of 38.1 ± 10.7 months, event-free survival rate of thromboembolic events (Log-Rank P = 0.042) and stroke (Log-Rank P = 0.010) was significantly lower in the LA-SEC group as displayed in Fig. 3(A and B). Univariate COX regression analysis in Table 2 showed that mean LAA orifice diameter was a predictor of thromboembolic events (Hazard ratio 1.127, 95 % Confidence interval 1.025–1.238; P = 0.013), as was LA-SEC (Hazard ratio 2.424, 95 % Confidence interval 1.004–5.852; P = 0.049). Nevertheless, LA-SEC was not an independent predictor of thromboembolic events (Hazard ratio 2.073, 95 % Confidence interval 0.845–5.082, P = 0.111) after adjusting for age, sex, and mean LAA orifice diameter, only mean LAA orifice diameter was (Hazard ratio 1.117, 95 % Confidence interval 1.016–1.227; P = 0.022) (Table 2). Table 3 showed the follow-up details post-LAAC. There was a higher incidence of thromboembolic events in the LA-SEC group (9 patients, 13.2 %) compared to the non-LA-SEC group (11 patients, 5.8 %) with statistical significance (P = 0.049). Similarly, a higher occurrence of stroke was observed in the LA-SEC group (9 patients, 13.2 %) compared to the non-LA-SEC group (8 patients, 4.2 %) (P = 0.022). Additionally, major hemorrhagic events occurred in 2 patients of the LA-SEC group (all intracranial hemorrhage) and 3 (2 intracranial hemorrhage, 1 traumatic intraventricular hemorrhage) in the non-LA-SEC group. No significant difference was found in post-procedure treatment and rhythm control outcomes (Table 3).Fig. 3 Kaplan-Meier curve for thromboembolic events (A) and stroke (B) among LA-SEC group and non-LA-SEC group. (A) Cumulative survival free from thromboembolic events were significantly lower in the LA-SEC group compared with non-LA-SEC group (Log-Rank P = 0.042); (B) cumulative survival free from stroke were also significantly lower in the LA-SEC group (Log-Rank P = 0.010). LA-SEC = left atrial spontaneous echo contrast.

Fig. 3

Table 2 Predictors of thromboembolic events on univariate and multivariate COX regression analysis.

Table 2	Univariate analysis	Multivariate analysis	
HR (95 % CI)	P value	HR (95 % CI)	P-value	
Age	1.026 (0.973–1.083)	0.339	1.024 (0.967,1.084)	0.413	
Male	0.826 (0.342–1.993)	0.671	0.848 (0.330,2.180)	0.732	
Persistent AF	0.581 (0.238–1.422)	0.235			
Previous stroke	1.338 (0.547–3.273)	0.524			
Hypertension	1.093 (0.397–3.007)	0.864			
Diabetes mellitus	1.147 (0.441–2.986)	0.778			
History of Coronary heart disease	1.241 (0.495–3.110)	0.645			
LAD	1.038 (0.946–1.138)	0.435			
LVEF	0.990 (0.939–1.044)	0.706			
Mean LAA orifice diameter	1.127 (1.025–1.238)	0.013*	1.117 (1.016,1.227)	0.022*	
LA-SEC	2.424 (1.004–5.852)	0.049*	2.073 (0.845,5.082)	0.111	
LA-SEC (PSM)	1.287 (0.479–3.461)	0.616			
Post-procedural OAC**		0.596			
 VKA	–	–			
 NOAC	0.564 (0.072–4.409)	0.585			
 NOAC + SAPT	1.102 (0.133–9.156)	0.928			
 DAPT	0.949 (0.086–10.472)	0.966			
Asterisk (*) indicates significant P-value. Asterisk (**) indicates the hazard ratio and P value are relative to VKA. AF = atrial fibrillation; CI = confidence interval; HR = hazard ratio; LAA = left atrial appendage; LAD = left atrial diameter; LA-SEC = left atrial spontaneous echo contrast; LVEF = left ventricular ejection fraction; NOAC = novel oral anticoagulant; OAC = oral anticoagulant; PSM = propensity score matching; VKA = Vitamin K antagonist.

Table 3 Follow-up detail of patients with or without LA-SEC.

Table 3	LA-SEC (n = 68)	non-LA-SEC (n = 190)	P-value	
follow-up outcome after LAAC	
Thromboembolic events, n (%)	9 (13.2 %)	11 (5.8 %)	0.049*	
 Cerebral infarction/transient ischemic attack, n (%)	7 (10.3 %)	7 (3.7 %)	0.080	
 Pulmonary thromboembolism, n (%)	1 (1.5 %)	2 (1.1 %)	1.000	
 Perivascular thrombus, n (%)	1 (1.5 %)	2 (1.1 %)	1.000	
 Device-related thrombus, n (%)	2 (2.9 %)	1 (0.5 %)	0.171	
Stroke, n (%)	9 (13.2 %)	8 (4.2 %)	0.022*	
 Cerebral infarction/transient ischemic attack, n (%)	7 (10.3 %)	7 (3.7 %)	0.080	
 Intracranial hemorrhage, n (%)	2 (2.9 %)	2 (1.1 %)	0.610	
Major hemorrhagic events, n (%)	2 (2.9 %)	3 (1.6 %)	0.852	
Treatment	
OAC			0.939	
 VKA, n (%)	2 (3.0 %)	8 (4.2 %)		
 NOAC, n (%)	46 (68.7 %)	127 (66.8 %)		
 NOAC + SAPT, n (%)	13 (19.4 %)	40 (21.1 %)		
 DAPT, n (%)	6 (9.0 %)	14 (7.4 %)		
PVI, n (%)	2 (2.9 %)	4 (2.1 %)	1.000	
Rhythm control outcome	
AF recurrence, n (%)	18 (26.5 %)	48 (25.4 %)	0.862	
AF recurrence after AADs, n (%)	6/19 (31.6 %)	24/107 (22.4 %)	0.568	
AF recurrence after ablation, n (%)	2/2 (100 %)	3/4 (75.0 %)	1.000	
Categorical variables are presented as frequencies and percentage (%). Asterisk (*) indicates significant P-value. AADs = antiarrhythmic drugs; AF = atrial fibrillation; DAPT = dual antiplatelet therapy; LAAC = left atrial appendage closure; LA-SEC = left atrial spontaneous echo contrast; NOAC = novel oral anticoagulant; OAC = oral anticoagulant; PSM = propensity score matching; PVI = pulmonary vein isolation; SAPT = single antiplatelet therapy; VKA = Vitamin K antagonist.

Further survival analysis between PSM-matched groups with comparable baseline characteristics presented no significant difference in survival free from thromboembolic events (Log-Rank P = 0.616) and stroke (Log-Rank P = 0.312) [Fig. 4(A and B)]. Meanwhile, the incidence of follow-up outcomes for both thromboembolic events (14.8 % vs. 11.5 %; P = 0.592) and stroke (14.8 % vs. 8.3 %; P = 0.256) did not differ between the two groups (Table 4). In addition, the estimated annual rate of thromboembolic events was 7.7 and 7.4 per 100 patient-years in the PSM matched LA-SEC group and non-LA-SEC group, and LAAC reduced the thromboembolic events rate by 32.9 % and 41.2 %, respectively (Fig. 5).Fig. 4 The Kaplan-Meier curve for thromboembolic events (A) and stroke (B) among the matched LA-SEC and non-LA-SEC groups after PSM. (A) There was no significant difference in survival free from thromboembolic events between the matched LA-SEC and non-LA-SEC groups (Log-Rank P = 0.616); (B) cumulative survival free from stroke were also comparable between the two groups (Log-Rank P = 0.312). LA-SEC = left atrial spontaneous echo contrast.

Fig. 4

Table 4 Follow-up detail of patients with or without LA-SEC after PSM.

Table 4	LA-SEC (n = 61)	non-LA-SEC (n = 61)	P-value	
follow-up outcome after LAAC	
Thromboembolic events, n (%)	9 (14.8 %)	7 (11.5 %)	0.592	
 Cerebral infarction/transient ischemic attack, n (%)	7 (11.5 %)	4 (6.6 %)	0.343	
 Pulmonary thromboembolism, n (%)	1 (1.6 %)	1 (1.6 %)	1.000	
 Perivascular thrombus, n (%)	1 (1.6 %)	1 (1.6 %)	1.000	
 Device-related thrombus, n (%)	2 (3.3 %)	1 (1.6 %)	1.000	
Stroke, n (%)	9 (14.8 %)	5 (8.2 %)	0.256	
 Cerebral infarction/transient ischemic attack, n (%)	7 (11.5 %)	4 (6.6 %)	0.343	
 Intracranial hemorrhage, n (%)	2 (3.3 %)	2 (3.3 %)	1.000	
Major hemorrhagic events, n (%)	2 (3.3 %)	3 (4.9 %)	1.000	
Treatment	
OAC			0.120	
 VKA, n (%)	1 (1.7 %)	4 (6.6 %)		
 NOAC, n (%)	42 (70.0 %)	44 (72.1 %)		
 NOAC + SAPT, n (%)	13 (21.7 %)	13 (21.3 %)		
 DAPT, n (%)	4 (6.7 %)	0 (0 %)		
PVI, n (%)	2 (3.3 %)	2 (3.3 %)	1.000	
Rhythm control outcome	
AF recurrence, n (%)	16 (26.2 %)	19 (31.7 %)	0.510	
AF recurrence after AADs, n (%)	5/18 (27.8 %)	9/37 (24.3 %)	1.000	
AF recurrence after ablation, n (%)	2/2 (100 %)	2/2 (100 %)	1.000	
Categorical variables are presented as frequencies and percentage (%). Asterisk (*) indicates significant P-value. AADs = antiarrhythmic drugs; AF = atrial fibrillation; DAPT = dual antiplatelet therapy; LAAC = left atrial appendage closure; LA-SEC = left atrial spontaneous echo contrast; NOAC = novel oral anticoagulant; OAC = oral anticoagulant; PSM = propensity score matching; PVI = pulmonary vein isolation; SAPT = single antiplatelet therapy; VKA = Vitamin K antagonist.

Fig. 5 Efficacy of LAAC in reducing thromboembolic events in the matched LA-SEC group and non-LA-SEC group. The predicted thromboembolic event rates based on CHA2DS2-VASc score were 7.7 and 7.4 per 100 patient-years in the LA-SEC group and non-LA-SEC group, and LAAC reduced thromboembolic event rates by 32.9 % and 41.2 %, respectively. LA-SEC = left atrial spontaneous echo contrast.

Fig. 5

4 Discussion

This is a cohort study exploring the impact of LA-SEC on the prognosis of LAAC. The main findings were as follows: (1) Patients with LA-SEC had a higher percentage of persistent AF and worse cardiac function. (2) Event-free survival rate of thromboembolic events and stroke was significantly lower in the LA-SEC group. Multivariable COX regression analysis showed that LA-SEC was not an independent predictor of thromboembolic events. (3) No significant difference was found in survival free from thromboembolic events and stroke between PSM-matched groups with comparable baseline characteristics.

Spontaneous echo contrast was defined as dynamic “smoke-like” echoes with characteristic swirling motions that cannot be eliminated despite adjusting gain settings [15], indicating the hypercoagulable state of the blood [18], as well as the result of the low flow velocity of blood and interactions between red blood cell and plasma proteins, especially fibrinogen [19,20]. Despite the deep association between LA-SEC and thrombus formation, whether LA-SEC clinically promotes stroke or thromboembolic events is still controversial. The ARISTOTLE trial, which included 1251 patients (217 with LA-SEC) with AF anticoagulated with Apixaban or Warfarin, found no significant increase in the risk of stroke or systemic embolism (Hazard ratio 0.96; 95 % confidence interval 0.25–3.60; P = 0.95) and ischemic stroke (Hazard ratio 1.09; 95 % confidence interval 0.21–5.60; P = 0.92) in patients with LA-SEC [9]. S.V. Patel and G. Flaker's review of nine studies also concluded that LA-SEC didn't improve stroke risk after cardioversion in AF patients without thrombus [10]. Conversely, other studies reported a significant increase in the risk of stroke or thromboembolic events associated with LA-SEC in patients with AF [[11], [12], [13]] and those undergoing AF ablation [21]. These contradictory conclusions were attributed to limitations in the design of current studies, such as neglecting confounding factors, different definitions of LA-SEC, and varying study subjects and follow-up duration. The EHRA/EAPCI expert consensus suggests that patients with LAA/LA thrombus should be excluded from LAAC [22]. However, the suitability of LA-SEC for LAAC procedure and its effect on the prognosis of LAAC remain uncertain. Our study concluded that LA-SEC did not add the risk of thromboembolic events or stroke for LAAC.

We believe that LAAC plays a critical role in reducing the risk of thromboembolism in patients with LA-SEC. Our study observed that LAAC decreased the incidence of thromboembolic events by 32.9 % and 41.2 % in the LA-SEC and non-LA-SEC groups, respectively, demonstrating LAAC's efficacy regardless of LA-SEC presence. Previous studies have also proven LAAC's efficacy in preventing stroke or embolism [4,23]. Although the LA-SEC group had a relatively higher occurrence of thromboembolic events, the difference in the rate of thromboembolic events between the two groups was not significant. Given that the thromboembolic events rate we predicted was based on the CHA2DS2-VASc score according to the Swedish Atrial Fibrillation cohort study [17], without considering the LA-SEC as a potential promoter of thromboembolism, the estimated thromboembolic rate and reduction of thromboembolic risk by LAAC in the LA-SEC group might be higher than expected. Thus we hypothesize that patients with LA-SEC would derive no less benefit from LAAC than patients without LA-SEC. However, more evidence is required to support it. To further investigate LAAC's efficacy in LA-SEC, future studies should include all AF patients with LA-SEC, grouping them based on whether they underwent LAAC, and compare the incidence of thromboembolic events.

In our study, LA-SEC was correlated with more prevalent persistent AF and worse cardiac function (elevated NT-proBNP, cardiac troponin T and left atrial diameter, a higher proportion of previous heart failure, as well as lower LVEF value). Our results were consistent with previous studies that identified congestive heart failure and left atrial enlargement were independent predictors of LA-SEC [24,25]. Non-paroxysmal AF was also reported to significantly increase the incidence of LA-SEC compared with paroxysmal AF [24,[26], [27], [28]]. The underlying mechanism is that non-paroxysmal AF carries a higher AF burden and greater degree of atrial fibrosis, thereby contributing to LA-SEC [24]. Considering that left atrial enlargement as the manifestation of atrial remodeling implies AF progression and increased fibrosis, the association between larger LAD and LA-SEC is intelligible. Enhanced pulmonary artery wedge pressure and reduced LA appendage velocities in patients with heart failure may also cause LA-SEC [29]. It has been demonstrated that both cardiac function and AF type have been proven to correlate with thromboembolism. Congestive heart failure/left ventricular dysfunction is a critical component of CHA2DS2-VASc score, and left atrial enlargement and non-paroxysmal AF have been reported to significantly add the risk of thromboembolism [30,31]. Consequently, we propose that higher risk of stroke or thromboembolic events in patients with LA-SEC possibly due to poorer heart function and worse AF type associated with LA-SEC. Moreover, our study showed that event-free survival rate of thromboembolic events and stroke was significantly lower in the LA-SEC group compared to the non-LA-SEC group, while the survival was comparable in the two groups after PSM, which verified our conjecture.

In order to avoid thromboembolism during cardiac transcatheter procedures, cerebral protection devices have emerged and gained attention. As was reported in a recent review on cerebral protection, investigators attempted to combine cerebral protection devices with LAAC in AF patients with LAA thrombosis, demonstrating the feasibility and safety of the combined procedure [32]. Since cerebral devices have yielded optimistic results in LAAC with LAA thrombus, we were intrigued by their performance in LA-SEC, which is viewed as a pre-thrombotic state of left atrium. Therefore, we intend to use cerebral protection devices during LAAC in patients with LA-SEC in the future and try to investigate the efficacy and safety.

Our study has limitations. Firstly, this was a single-center retrospective study with a limited sample size and flaws in the design. However, we have made some efforts to make our conclusions more supportive. On one hand, we conducted the multivariable COX regression analysis and 1:1 PSM to minimize the effects of confounders. On the other hand, in addition to cerebral infarction and transient ischemic attack, we incorporated pulmonary thromboembolism, perivascular thrombus, and device-related thrombus into thromboembolic events, so that the bias in the results caused by the limited number of endpoint events was minimized to a significant extent. Besides, left ventricular conditions are also important confounding factors for thromboembolic events, as anatomical and functional abnormalities of the left ventricle may contribute to left ventricular thrombosis, yet we did not fully assess these conditions such as apical akinesia. Hence, well-designed, randomized studies are required in order to verify the reliability of our conclusions. Secondly, patients with AF and LAAC were enrolled and grouped according to the presence or absence of LA-SEC based on TEE results, but the severity of LA-SEC was not graded. However, previous studies have indicated that more severe LA-SEC is significantly associated with more serious stroke and poorer functional outcomes [33], as well as a higher risk of thromboembolic events [[11], [12], [13]]. Further investigation is required to analyse the classification of LA-SEC in relation to thromboembolic events.

5 Conclusions

Patients with LA-SEC presented worse condition and a worse prognosis for the LAAC procedure, whereas LA-SEC per se did not increase the risk of thromboembolic events and stroke in patients who underwent LAAC. Furture studies should be conducted to further investigate the efficacy of LAAC in patients with LA-SEC.

Ethics statement

This study complied with the Declaration of Helsinki and was approved by the Ethics Committee of Shanghai Tenth People's Hospital (approval number SHSY-IEC-4.1/21/231/01; approval date 2021.10.9). Written informed consent was obtained from all patients to participate in the study and to publish the data.

Data availability statement

Data used to support the findings is available upon request.

CRediT authorship contribution statement

Jun Zhang: Writing – original draft, Visualization, Investigation, Formal analysis. Lili Zhou: Writing – original draft, Visualization, Investigation, Formal analysis. Zhongyuan Ren: Writing – review & editing, Visualization, Investigation. Shiyu Feng: Validation. Jiayu Wu: Data curation. Haotian Yang: Data curation. Yixing Zheng: Software. Weilun Meng: Validation. Yang Su: Funding acquisition, Data curation. Jun Xu: Resources. Hui Sun: Funding acquisition, Data curation. Yifan Zhao: Writing – review & editing. Yun Xie: Methodology, Funding acquisition, Conceptualization. Yawei Xu: Methodology, Conceptualization. Dongdong Zhao: Project administration, Methodology, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following is the Supplementary data to this article:Multimedia component 1

Multimedia component 1

Acknowledgments

This study was supported by Shanghai Tenth People's Hospital (recipient Yang Su, Grant No. YNCR2C006 ); Shanghai Tenth People's Hospital Chongming Branch (recipient Hui Sun, Grant No. CKY2022-25 ); 10.13039/100018696 Health Youth Talent Project of 10.13039/100017950 Shanghai Municipal Health Commission (recipient Yifan Zhao, Grant No. 2022YQ023 ); 10.13039/100017950 Shanghai Municipal Health Commission Clinical Research Project (Youth) (recipient Yifan Zhao, Grant No. 20214Y0152 ); Shanghai Putuo District Health System Science and Technology Innovation Project (recipient Yun Xie, Grant No. ptkwws202218 ).

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e36647.
==== Refs
References

1 Hendriks J.M.L. de Wit R. Vrijhoef H.J.M. An integrated chronic care program for patients with atrial fibrillation: study protocol and methodology for an ongoing prospective randomised controlled trial Int. J. Nurs. Stud. 47 10 2010 1310 1316 10.1016/j.ijnurstu.2009.12.017 20089253
2 Wolf P.A. Abbott R.D. Kannel W.B. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study Stroke 22 8 1991 983 988 10.1161/01.str.22.8.983 1866765
3 Mahajan R. Brooks A.G. Sullivan T. Importance of the underlying substrate in determining thrombus location in atrial fibrillation: implications for left atrial appendage closure Heart 98 15 2012 1120 1126 10.1136/heartjnl-2012-301799 22572045
4 Reddy V.Y. Doshi S.K. Kar S. 5-Year outcomes after left atrial appendage closure: from the PREVAIL and PROTECT AF trials J. Am. Coll. Cardiol. 70 24 2017 2964 2975 10.1016/j.jacc.2017.10.021 29103847
5 Osmancik P. Herman D. Neuzil P. Left atrial appendage closure versus direct oral anticoagulants in high-risk patients with atrial fibrillation J. Am. Coll. Cardiol. 75 25 2020 3122 3135 10.1016/j.jacc.2020.04.067 32586585
6 Freeman J.V. Varosy P. Price M.J. The NCDR left atrial appendage occlusion registry J. Am. Coll. Cardiol. 75 13 2020 1503 1518 10.1016/j.jacc.2019.12.040 32238316
7 Tsai L.M. Chen J.H. Lin L.J. Teng J.K. Natural history of left atrial spontaneous echo contrast in nonrheumatic atrial fibrillation Am. J. Cardiol. 80 7 1997 897 900 10.1016/s0002-9149(97)00543-2 9382005
8 Leung D.Y. Black I.W. Cranney G.B. Prognostic implications of left atrial spontaneous echo contrast in nonvalvular atrial fibrillation J. Am. Coll. Cardiol. 24 3 1994 755 762 10.1016/0735-1097(94)90025-6 8077549
9 Vinereanu D. Lopes R.D. Mulder H. Echocardiographic risk factors for stroke and outcomes in patients with atrial fibrillation anticoagulated with apixaban or warfarin Stroke 48 12 2017 3266 3273 10.1161/STROKEAHA.117.017574 29089455
10 Patel S.V. Flaker G. Is early cardioversion for atrial fibrillation safe in patients with spontaneous echocardiographic contrast? Clin. Cardiol. 31 4 2008 148 152 10.1002/clc.20172 17763365
11 Bernhardt P. Schmidt H. Hammerstingl C. Patients with atrial fibrillation and dense spontaneous echo contrast at high risk a prospective and serial follow-up over 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging J. Am. Coll. Cardiol. 45 11 2005 1807 1812 10.1016/j.jacc.2004.11.071 15936610
12 Soulat-Dufour L. Lang S. Etienney A. Correlation between left atrial spontaneous echocardiographic contrast and 5-year stroke/death in patients with non-valvular atrial fibrillation Arch. Cardiovasc. Dis. 113 8–9 2020 525 533 10.1016/j.acvd.2020.02.003 32873521
13 Wang B. Wang Z. Fu G. Left atrial spontaneous echo contrast and ischemic stroke in patients undergoing percutaneous left atrial appendage closure Front. Cardiovasc. Med. 8 2021 723280 10.3389/fcvm.2021.723280
14 Hahn R.T. Abraham T. Adams M.S. Guidelines for performing a comprehensive transesophageal echocardiographic examination: recommendations from the American Society of Echocardiography and the Society of Cardiovascular Anesthesiologists J. Am. Soc. Echocardiogr. 26 9 2013 921 964 10.1016/j.echo.2013.07.009 23998692
15 Black I.W. Hopkins A.P. Lee L.C. Walsh W.F. Left atrial spontaneous echo contrast: a clinical and echocardiographic analysis J. Am. Coll. Cardiol. 18 2 1991 398 404 10.1016/0735-1097(91)90592-w 1856407
16 Mehran R. Rao S.V. Bhatt D.L. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium Circulation 123 23 2011 2736 2747 10.1161/CIRCULATIONAHA.110.009449 21670242
17 Friberg L. Rosenqvist M. Lip G.Y.H. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study Eur. Heart J. 33 12 2012 1500 1510 10.1093/eurheartj/ehr488 22246443
18 Black I.W. Chesterman C.N. Hopkins A.P. Hematologic correlates of left atrial spontaneous echo contrast and thromboembolism in nonvalvular atrial fibrillation J. Am. Coll. Cardiol. 21 2 1993 451 457 10.1016/0735-1097(93)90688-w 8426010
19 Merino A. Hauptman P. Badimon L. Echocardiographic "smoke" is produced by an interaction of erythrocytes and plasma proteins modulated by shear forces J. Am. Coll. Cardiol. 20 7 1992 1661 1668 10.1016/0735-1097(92)90463-w 1452941
20 Rastegar R. Harnick D.J. Weidemann P. Spontaneous echo contrast videodensity is flow-related and is dependent on the relative concentrations of fibrinogen and red blood cells J. Am. Coll. Cardiol. 41 4 2003 603 610 10.1016/s0735-1097(02)02898-x 12598072
21 Gedikli Ö. Mohanty S. Trivedi C. Impact of dense "smoke" detected on transesophageal echocardiography on stroke risk in patients with atrial fibrillation undergoing catheter ablation Heart Rhythm 16 3 2019 351 357 10.1016/j.hrthm.2018.10.004 30312757
22 Glikson M. Wolff R. Hindricks G. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion - an update EuroIntervention 15 13 2020 1133 1180 10.4244/EIJY19M08_01 31474583
23 Holmes D.R. Reddy V.Y. Gordon N.T. Long-term safety and efficacy in continued access left atrial appendage closure registries J. Am. Coll. Cardiol. 74 23 2019 2878 2889 10.1016/j.jacc.2019.09.064 31806131
24 Liu K. Li Y. Wu K. Retrospective study of 1255 non-anticoagulated patients with nonvalvular atrial fibrillation to determine the risk of ischemic stroke associated with left atrial spontaneous echo contrast on transesophageal echocardiography Med. Sci. Mon. Int. Med. J. Exp. Clin. Res. 27 2021 e934795 10.12659/MSM.934795
25 Han D. Chu Y. Wu Y. Wang X. Determinants of left atrial thrombus or spontaneous echo contrast in nonvalvular atrial fibrillation Thromb. Res. 195 2020 233 237 10.1016/j.thromres.2020.07.055 32799130
26 Lin W.-D. Xue Y.-M. Liu F.-Z. Left atrial enlargement and non-paroxysmal atrial fibrillation as risk factors for left atrial thrombus/spontaneous Echo contrast in patients with atrial fibrillation and low CHADS-VASc score J. Geriatr. Cardiol. 17 3 2020 155 159 10.11909/j.issn.1671-5411.2020.03.001 32280332
27 Akamatsu K. Ito T. Ozeki M. Left atrial spontaneous echo contrast occurring in patients with low CHADS or CHADS-VASc scores Cardiovasc. Ultrasound 18 1 2020 31 10.1186/s12947-020-00213-2 32738924
28 Kishima H. Mine T. Fukuhara E. Predictors of left atrial thrombi and spontaneous echocardiographic contrast in the acute phase after cardioembolic stroke in patients with atrial fibrillation J. Stroke Cerebrovasc. Dis. 28 6 2019 1571 1577 10.1016/j.jstrokecerebrovasdis.2019.03.003 30930240
29 Ito T. Suwa M. Left atrial spontaneous echo contrast: relationship with clinical and echocardiographic parameters Echo. Res. Pract. 6 2 2019 R65 R73 10.1530/ERP-18-0083 30959476
30 Cho M.S. Choi K.-J. Kim M. Relation of left atrial enlargement to subsequent thromboembolic events in nonvalvular atrial fibrillation patients with low to borderline embolic risk Am. J. Cardiol. 143 2021 67 73 10.1016/j.amjcard.2020.12.034 33359192
31 Nicolau A.M. Corbalan R. Nicolau J.C. Efficacy and safety of edoxaban compared with warfarin according to the burden of diseases in patients with atrial fibrillation: insights from the ENGAGE AF-TIMI 48 trial Eur. Heart. J. Cardiovasc. Pharmacother. 6 3 2020 167 175 10.1093/ehjcvp/pvz061 31687762
32 Preda A. Montalto C. Galasso M. Fighting cardiac thromboembolism during transcatheter procedures: an update on the use of cerebral protection devices in cath labs and EP labs Life 13 9 2023 10.3390/life13091819
33 Yoo J. Song D. Baek J.-H. Poor outcome of stroke patients with atrial fibrillation in the presence of coexisting spontaneous echo contrast Stroke 47 7 2016 1920 1922 10.1161/STROKEAHA.116.013351 27188406
