What's new?

Transesophageal echocardiography (TEE) is a gold standard for the exclusion of left atrial appendage thrombus (LAAT). There are no unequivocal data on whether patients awaiting ablation or electric cardioversion should routinely undergo TEE, which is an invasive procedure performed by trained and experienced personnel. Some patients with atrial fibrillation (AF) develop LAAT despite receiving anticoagulant treatment. The CHADS₂ and CHA₂DS₂-VASc scores are used to assess thromboembolic risk in patients with nonvalvular AF. The CHA₂DS₂-VASc‑RAF score has been developed to improve thromboembolic risk stratification. In this study, we identified sex‑related predictors of LAAT in patients treated with dabigatran or rivaroxaban. All the assessed scores had a similar predictive value in men, while the CHA₂DS₂-VASc‑RAF score had the highest predictive value in women.

Introduction

Atrial fibrillation (AF) is a common life‑threatening arrhythmia affecting 1% to 2% of the general population. Thromboembolic complications constitute the most severe consequences of AF. They may be caused by a thrombus formation due to impaired blood flow in the left ventricle as a result of arrhythmia, most often in the left atrial appendage.¹ So far, numerous clinical and echocardiographic predictors of left atrial appendage thrombus (LAAT) have been identified in patients on anticoagulant treatment. The CHADS₂ and CHA₂DS₂-VASc scores are used for the assessment of thromboembolic risk in patients with nonvalvular AF. The CHA₂DS₂-VASc‑RAF score additionally includes the type of AF and renal dysfunction as LAAT predictors, which appeared to improve the thromboembolic risk stratification.^2-4 Despite optimal treatment with vitamin K antagonists and the currently preferred non–vitamin K oral antagonists (NOACs), LAAT still develops in 2% to 10% of patients on anticoagulant treatment.^5-8 The gold standard for the exclusion of LAAT is transesophageal echocardiography (TEE).^9,10 However, there are no unequivocal data on whether patients awaiting ablation or electric cardioversion should routinely undergo TEE, which is an invasive procedure that should be performed by trained and experienced personnel.^11-14 Risk stratification according to sex is common in clinical practice. Sex‑related differences in myocardial anatomy as well as the epidemiology, pathophysiology, and risk factors of heart diseases, including genetic cardiomyopathies, have been well described. Moreover, differences in the risk of stroke according to sex were reported in clinical trials.^15-17 The aim of this study was to identify differences in the predictors of LAAT between men and women treated with NOACs (dabigatran or rivaroxaban).

Patients and methods

Results

The study included 1256 patients (479 women [38.1%]) with AF hospitalized due to ablation and electrical cardioversion and treated with dabigatran or rivaroxaban. The mean (SD) age of the women was 60 (11.7) years, and of the men 67 (9.7) years. The clinical characteristics of the women and men are compared in Table 2.

LAAT was diagnosed in 51 patients (4.1%), including 22 women (4.6%) and 29 men (3.7%) (P = 0.45). The women with LAAT were older, were more likely to have HF and nonparoxysmal AF, received a reduced dose of anticoagulants, had a higher CHA₂DS₂-VASc‑RAF score and lower left ventricular ejection fraction (LVEF) than the women without LAAT.

The men with LAAT were older, were more likely to have HF, nonparoxysmal AF, and DM, had higher CHADS₂, CHA₂DS₂-VASc, R₂CHADS₂, and CHA₂DS₂-VASc‑RAF scores, as well as lower eGFR and LVEF than the men without LAAT. A detailed comparison between the patients with and without LAAT is shown in Table 3.

The results of the univariable regression analysis in men and women are presented in Table 4. In the multivariable logistic regression analysis, only nonparoxysmal AF was a predictor of LAAT in women (OR, 9.70; 95% CI, 2.24–41.97; P = 0.002). In men, the predictors of LAAT included HF (OR, 4.14; 95% CI, 1.82–9.40; P = 0.001), DM (OR, 2.64; 95% CI, 1.19–5.88; P = 0.002), nonparoxysmal AF (OR, 5.61; 95% CI, 1.29–24.46; P = 0.02), and eGFR <⁠60 ml/min/1.73 m² (OR, 2.77; 95% CI, 1.25–6.13; P = 0.01). The results of the multivariable regression analysis in men and women are presented in Supplementary material, Tables S1 and S2.

Based on the receiver operating characteristic curve analysis, CHA₂DS₂-VASc‑RAF had the highest diagnostic accuracy for predicting LAAT in women (Figure 1, Table 5). In men, all the scores had sufficient diagnostic power for predicting LAAT (Figure 2, Table 6).

Discussion

Our study yields several major findings. First, women and men are at a similar risk of LAAT. Second, the frequency of LAAT in women and men is independent of the NOAC dose. Third, men and women differed in terms of the LAAT predictors and the predictive value of the thromboembolic risk scores.

The prevalence of LAAT was similar in women and men treated with dabigatran and rivaroxaban. Risk stratification according to sex is a common approach in clinical practice. There have been numerous studies assessing the risk of stroke depending on sex. Girijala et al¹⁵ analyzed sex‑related differences in terms of the epidemiology of risk factors, symptoms, as well as methods and results of stroke treatment. Epidemiological data indicated a higher rate of stroke in older women, which raised the question of the neuroprotective role of sex hormones.¹⁶ In a retrospective study on the frequency of ischemic stroke in women and men with AF, Yoshida et al¹⁷ assessed sex‑related differences in the risk factors for stroke as well as the anatomy and function of the left atrium. They concluded that for the same level of increase in the risk of stroke, worsening of left atrial function is greater in women than in men, which could explain a more frequent occurrence of ischemic stroke in women. In our study, women had a smaller left atrial size, smaller left ventricular diastolic diameter, and higher LVEF than men. Similarly, Shah et al¹⁸ observed that left atrial dilation, absence of severe mitral regurgitation, and lower LVEF are associated with an increased risk of LAAT.

HF is a component of all thromboembolic risk scores.¹⁹ In our study, the patients with LAAT significantly more often had HF. In the univariable logistic regression analysis, it was a strong predictor of LAAT both in men and women.

Di Mino et al²⁰ conducted a meta‑analysis including 72 studies and a total of 20 516 patients, in which they investigated the frequency of LAAT in individuals undergoing electric cardioversion or ablation. A higher frequency of LAAT was observed in women than in men (OR, 1.35; 95% CI, 1.04–1.75). The frequency of LAAT in women and men was independent of NOAC dose. Rivaroxaban was used by 52% of the patients, of which 55.1% were women. Dabigatran was used by 48% of the patients, of which 44.9% were women. However, the differences were not significant. A reduced dose of dabigatran and rivaroxaban was used by 13.2% of women and 6% of men (P <⁠0.001). The reduced dose was not a predictor of LAAT in either of the sexes. Similarly, Bertaglia et al⁷ studied a group of 414 patients treated with NOACs for more than 3 months, who underwent TEE before cardioversion or ablation. The reduced dose was not a predictor of LAAT either in men or in women.

Renal impairment is a documented risk factor for cardiovascular disease and it is associated with hypertension and DM, which are included in the CHADS₂ and CHA₂DS₂-VASc scores. Arnson et al²¹ conducted a retrospective analysis of 85 116 patients with AF and concluded that advanced kidney disease was associated with a higher risk of stroke, death, and bleeding. Some studies^2,3 identified renal dysfunction to be an important predictor of LAAT, enhancing the prognostic value of the CHA₂DS‑VASc score. In our study, eGFR below 60 ml/min/1.73 m² was reported in 54.9% of the women and only 18.4% of the men. Impaired renal function was a predictor of LAAT only in men.

We found that the type of AF (ie, nonparoxysmal AF) was the strongest independent predictor of LAAT both in men and women. In men, additional independent predictors of LAAT were HF, DM, and impaired kidney function. In a retrospective study, Wei‑dong et al²² assessed 705 of the 1346 patients with a low CHA₂DS₂-VASc score in whom TEE was performed before ablation or cardioversion. Nonparoxysmal AF was the strongest independent risk factor of LAAT / spontaneous echo contrast (OR, 3.766; 95% CI, 1.282–11.061; P = 0.02).

The guidelines of the European Society of Cardiology indicated that the type of AF does not affect the thromboembolic risk. However, some studies on this issue have been recently published. Dimitrova et al²³ conducted a systematic overview of epidemiological studies on thromboembolic risk depending on the duration of AF, which were published in the MEDLINE and PubMed in the years 2005–2019. The authors emphasized a relatively low number of relevant studies, which may be due to methodological reasons (difficulty in a reliable assessment of the incidence of paroxysmal AF, which may be asymptomatic and thus underestimated or, on the other hand, it may recur frequently, resulting in a relatively long duration of arrhythmia). Importantly, in a meta‑analysis of 12 studies including a total of 99 996 patients, Ganesen et al²⁴ confirmed that the thromboembolic risk is higher in patients with nonparoxysmal than paroxysmal AF. Interesting conclusions were also reported in a retrospective study by Go et al.²⁵ They assessed the thromboembolic risk in patients with paroxysmal AF depending on the total arrhythmia time. The patients with a longer total time of AF episodes had a higher risk of nonischemic stroke.