Incidence and predictors of left atrial appendage thrombus on transesophageal echocardiography before elective cardioversion

Guidelines recommend transesophageal echocardiography (TEE) before cardioversion in thrombogenic arrhythmias when the requirement of ≥ 3 weeks of anticoagulation is not met. Current data to support this approach, especially with direct oral anticoagulants (DOAC), are scarce. We analyzed consecutive elective pre-cardioversion TEE in a high-volume electrophysiology center for the occurrence of left atrial appendage (LAA) thrombi or reduced LAA flow velocity. Possible predictors were recorded and compared in a multivariate logistic regression analysis. Consecutive pre-cardioversion TEE in 512 patients (148 female, median age 69 years) were included. In all patients, indication for TEE was either intake of anticoagulation < 3 weeks before cardioversion or uncertain adherence to the prescribed anticoagulation regimen. Of the 512 TEE, 19 (3.7%) depicted a LAA thrombus. An additional 41 patients (8.0%) showed either a reduced LAA flow velocity (≤ 20 cm/s), LAA sludge, or both. In a multivariate logistic regression analysis, QRS width on admission 12-lead ECG emerged as a possible predictor of LAA thrombus and reduced LAA flow (p = 0.008). Noteworthy, a high CHA2DS2-VASc score was not associated with an increased risk of reduced LAA emptying velocity and LAA thrombi were even found in patients with a CHA2DS2-VASc score of 0 (n = 1) and 1 (n = 1). The presence of LAA thrombus before an elective cardioversion is a rare event in the age of direct oral anticoagulants. However, LAA thrombi occurred even in supposed low-risk individuals according to the CHA2DS2-VASc score. QRS width may aid in identifying patients at risk of reduced LAA flow velocity.


Methods
Study design. The present report was designed as a cohort study analyzing 512 consecutive TEE studies before a scheduled elective cardioversion between 2017 and 2020 in a high-volume electrophysiology center. All TEE performed before an ECV in this timeframe were included in the analysis. The study was conducted in accordance with the Declaration of Helsinki and all patients gave written informed consent for the planned TEE and cardioversion. As data analysis was retrospectively conducted on anonymized routine clinical data, no ethics committee approval was necessary as specified by the ethics committee of the Westfälische Wilhelms-Universität Münster. Clinical characteristics of included patients were recorded and compared in a multivariate logistic regression analysis (see statistical analysis) to elucidate possible predictors of low-flow situations in the LAA. In total, three patient groups were distinguished: 1. Patients with a solid LAA thrombus on TEE before scheduled ECV (Fig. 1A) 2. Patients with a low-flow state of the LAA, defined as: a. LAA sludge without evidence of a solid thrombus (Fig. 1B) and/or b. LAA emptying velocity ≤ 20 cm/s on PW-Doppler (Fig. 1D) 3. Patients without a LAA thrombus and with normal LAA flow characteristics (Fig. 1C,E).
Transesophageal echocardiography. Transesophageal echocardiography was conducted according to established practice guidelines 7 . After excluding contraindications to TEE, all patients received intravenous sedation with propofol. Once adequate sedation was reached, the ultrasound probe was advanced to a midesophageal position and images of the LAA were obtained. The LAA was imaged in at least two planes (60° and 120°) with and without color doppler and blood flow velocity of the LAA was obtained using pulsed-wave doppler (PW). Additional imaging planes and the use of ultrasound contrast were at the discretion of the performing physician. Once sufficient images were obtained, the ultrasound probe was withdrawn and ECV was attempted if no thrombus was detected.    Figure 1A shows a representative image of a LAA thrombus from one of the included patients. In all of these patients, the scheduled ECV was postponed. In eight patients, the anticoagulation regimen was changed as a result of the TEE study: Five patients were switched to dabigatran (three from apixaban, one from edoxaban, one not previously on oral anticoagulation), one patient was switched from dabigatran to VKA, one patient was switched from low molecular weight heparin to apixaban, and one further patient was switched from ASS to VKA. Of the remaining eleven patients, seven remained on VKA but were instructed on a close INR monitoring. Two patients each remained on apixaban and dabigatran and were instructed on medication adherence. www.nature.com/scientificreports/ LAA emptying velocity and compared these 60 patients with the remaining 452 patients with a normal LAA flow state. Univariate analyses showed a significant association between a reduced LAA flow velocity and age (p = 0.02), LVEF (p = 0.01), heart rate on admission (p = 0.02), and QRS (p = 0.004). In the multivariate logistic regression analysis, only QRS width remained significantly associated with a reduced LAA flow velocity or the presence of a LAA thrombus (p = 0.008, area under curve 0.78, see Table 2). The odds ratio per millisecond of QRS prolongation was 1.02 (95% CI 1.01-1.04). There was no association between reduced LAA flow velocity and a higher CHA 2 DS 2 -VASc score and LAA thrombi were found even in patients with a CHA 2 DS 2 -VASc score of 0 (n = 1) and 1 (n = 1).

Discussion
The present study provides an update on the available evidence for LAA thrombus detection on transesophageal echocardiography before an elective cardioversion in a large cohort. We were able to show that the incidence of LAA thrombi before ECV was below 4% in this contemporary patient population with an additional 8% of patients displaying a significantly reduced LAA flow velocity. In a multivariate logistic regression model, QRS width was significantly associated with the presence of a LAA thrombus or reduced LAA flow velocity, which were combined for statistical analysis to increase power and to aid clinicians in detecting patients who should receive a thorough TEE examination before cardioversion. In their seminal study evaluating the use of TEE published in 2001, Klein et al. reported an incidence of LAA thrombi of 13.8% in a patient population of 549 patients scheduled for elective cardioversion for AF 8 . In comparison, we were able to document a dramatically reduced incidence of 3.7%. Multiple factors may explain this difference. Firstly, atrial fibrillation management has undergone various changes in the time since Klein et al. published their results. Since the establishment of CHA 2 DS 2 -VASc score, more patients receive continuous effective oral anticoagulation than in previous decades. This is reflected by the fact that about 85% of our included patients were on effective anticoagulation, albeit either for < 3 weeks or with uncertain adherence. Additionally, DOAC are likely more effective anticoagulating agents than VKA and patients remaining on vitamin K antagonists may benefit from a closer monitoring, for example by utilizing home INR measurements. Furthermore, advances in ultrasound devices may enable echocardiographers to better visualize the LAA and by decreasing uncertainty allow more patients to be cardioverted. Our reported incidence also more closely resembles the very low incidence of LAA thrombi in patients before a pulmonary vein isolation procedure as reported recently in a study by Göldi et al. 9 . It should be noted, however, that these patients were younger (61 vs. 69 years) and comparatively healthier (e.g., CHA 2 DS 2 -VASc score of 1.8 vs. 2.7) than our included patient population.
Interestingly, our statistical analysis was unable to show an association between established risk factors for systemic embolism in atrial fibrillation such as the CHA 2 DS 2 -VASc score and reduced LAA velocities or LAA thrombus. In contrast, only QRS width remained significantly associated with a reduced LAA emptying velocity or thrombus in a multivariate logistic regression analysis. This may be an indicator that comorbidities more Table 2. Comparison between pre-cardioversion patients with normal LAA flow, patients with significantly reduced flow and patients with a LAA thrombus. Statistical significance was calculated between the group with normal flow and a combination of the other two groups (n = 60) in a multivariate logistic regression analysis. Significant values of the multivariate analysis are in bold.  www.nature.com/scientificreports/ specific to the heart may play a larger role in the creation of LAA thrombi than in peripheral embolism. A slightly wider QRS during atrial fibrillation may indicate an impaired electrical conduction system or a subclinically diseased ventricular myocardium. Although they did not reach significance in the multivariate analysis, a low heart rate during atrial fibrillation and reduced LVEF were associated with a low LAA flow velocity or thrombus in a univariate analysis and would be aligned with this explanation. Importantly, a lack of power due to the comparatively low number of patients does not allow for the interpretation that reduced LVEF does not play a role in LAA thrombus formation. Further reports by other working groups are needed to confirm or refute these findings. While the occurrence of a LAA thrombus before an elective cardioversion is a rare event, our data show that it presents in a very heterogeneous group of patients. Importantly, no single risk factor or established scoring system can identify a patient population without a relevant risk for a significantly reduced LAA flow velocity or thrombus. Since the risks associated with transesophageal echocardiography are minute 10 , our data support the use of TEE when the patient is not on anticoagulation or adherence is unclear.
Limitations. As a single-center cohort study, the present report should only be viewed as hypothesis-generating and possible predictors of reduced LAA emptying velocities or LAA thrombi should be interpreted cautiously due to low patient numbers. Data on individual medication adherence before ECV was limited and thus no correlation could be drawn between the number of missed doses (in case of DOAC) or time outside of therapeutic INR (in case of VKA) and the occurrence of LAA thrombi. However, LAA emptying velocity is not influenced by anticoagulation regimen and thus the analysis for possible predictors of low LAA flow were unlikely to be affected.

Conclusion
In a contemporary cohort of 512 patients, LAA thrombi were found in 3.7% of transesophageal echocardiography studies before a scheduled elective cardioversion. An additional 8% of patients had a significantly reduced LAA emptying velocity, representing a high-risk group for the formation of a LAA thrombus. In a multivariate logistic regression analysis, only QRS width was significantly associated with reduced LAA flow velocities. Interestingly, a high CHA 2 DS 2 -VASc score was not associated with reduced LAA flow. Our data support the routine use of TEE before ECV even in the changed landscape of modern atrial fibrillation treatment, as no patient groups were able to be identified in which the risks of TEE conceivably outweigh the benefits. www.nature.com/scientificreports/ Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.