Introduction: Endovascular left atrial appendage occlusion (LAAO) is associated with a high incidence of peri-procedure silent cerebral embolism (SCE), while the recommended activated clotting time (ACT) level by the expert consensus is lower than that in atrial fibrillation (AF) ablation. The aim of our study was to investigate whether raising the targeted ACT level during LAAO to the same level as AF ablation could decrease the incidence of SCE. Methods: It was a prospective observational cohort study. Consecutive AF patients receiving LAAO between January 2021 and December 2022 were included and categorized into two groups based on the time of enrollment. Patients enrolled in 2021 (group 250) maintained a target ACT level of ≥250 s during LAAO procedure, while patients enrolled in 2022 (group 300) maintained the peri-procedure ACT ≥300 s. All patients underwent cerebral magnetic resonance imaging before and after the procedure. Results: A total of 81 patients were included (38 in the group 250 and 43 in the group 300). After inverse probability of treatment weighting (IPTW), patients in the group 250 showed a significantly lower incidence of SCE than group 300 (IPTW p = 0.038). Only a stable high ACT pattern could decrease the risk of SCE. No significant differences were found between other ACT change patterns on the SCE incidence. Conclusion: Raising the peri-procedure ACT level to a stable 300 s could decrease the risk of the SCE without increasing the major bleeding events.

Atrial fibrillation (AF) is known to cause microembolisms throughout its long clinical course, which may have correlation with the increased risk of Alzheimer’s disease and decreased quality of life [1‒3]. However, the interventional treatment for AF, which can include either catheter ablation for rhythm control or left atrial appendage occlusion (LAAO) for stroke prevention, has been shown to be associated with a high incidence of acute silent cerebral embolism (SCE) [4, 5]. The incidence of SCE during LAAO has been reported to range from 5% to 54.8% across different magnetic resonance imaging (MRI) sequences [6‒10]. Possible reasons for SCE development include thromboembolic clots, scar formation or tissue clots, and air embolism. Our previous study identified the following risk factors for SCE during the LAAO procedure: high CHA2DS2-VASc score, left atrial (LA) procedure duration, and peri-procedure activated clotting time (ACT) level [10]. Because of the high incidence of SCE and its long-term impact on cognitive function, preventive strategies should be taken to minimize the risk of peri-procedural SCE.

Of all the factors increasing risk of SCE, peri-procedural ACT is perhaps the most modifiable. However, there remains no guideline regarding the most appropriate ACT level for the LAAO procedure. The guideline-recommended ACT level for AF catheter ablation is ≥300 s [11], while the expert consensus recommended regarding the ACT level for LAAO is ≥250 s [12]. The gap in recommended ACT levels between AF ablation and LAAO implantation is worth thoughtful consideration and further investigation. We wondered if increasing the targeted ACT level of LAAO to the same level as AF ablation could decrease the incidence of peri-procedure SCE without increasing the bleeding risk. Thus, we designed this prospective observational study to answer this question and to identify the most appropriate ACT patterns for LAAO procedures.

Study Population

This prospective cohort study was performed at the First Affiliated Hospital of Nanjing Medical University between January 2021 and December 2022. Ethical approval was granted by the Ethical Committee of the First Affiliated Hospital of Nanjing Medical University, number 2022-SR-228.

AF patients receiving WATCHMAN implantation were consecutively enrolled. The inclusion criteria were as follows: (1) ≥18 years of age; (2) previous ischemic stroke or a CHA2DS2-VASc score ≥3; (3) unwilling or unable to take oral anticoagulant; and (4) no contraindications to MRI scan. Patients who were enrolled from January 1, 2021, to December 31, 2021, and from January 1, 2022, to December 31, 2022, were assigned to group 250 (maintaining the target ACT ≥250 s during LAAO implantation) and group 300 (maintaining the target ACT ≥300 s), respectively.

Electrophysiologic Procedures

All procedures were performed under conscious sedation. If AF ablation was combined, pulmonary vein isolation and substrate modification (if needed) were routinely performed as previously described [13]. After AF ablation, LAAO was performed in all patients using the WATCHMAN device [12]. The entire procedure was guided by intracardiac echocardiogram.

The total procedure time was defined as the time between the first puncture of the femoral vein and the end of the procedure. The LA procedure time was calculated from the successful transseptal puncture to the withdrawal of all sheaths and catheters from the LA. The LAAO placement time was defined as the time between inserting the delivery system and successful release of the LAAO device.

Peri-Procedure Antithrombotic Therapy and Assessments of ACT

All patients received uninterrupted anticoagulation therapy with rivaroxaban (15 mg) for at least 3 weeks before the procedure. Rivaroxaban was not interrupted during the whole procedure. LA thrombi were routinely screened by transesophageal echocardiography before the procedure.

In group 250, a weight-adjusted bolus of unfractionated heparin (80 IU/kg) was administered upon TSP. If AF ablation was combined, the additional heparin dosage was adjusted as needed to maintain the ACT ≥300 s [11] (Hemochron® Signature Elite) during the ablation procedure. After ablation, heparin was only supplemented when the ACT level was <250 s during LAAO implantation (target ACT ≥250 s [12]). In group 300, a bolus of heparin (100 IU/kg) was administered upon TSP and supplemented as needed to maintain a target ACT of ≥300 s during the whole procedure. ACT was monitored every 10–15 min. After implantation, all patients were treated with rivaroxaban (15 mg) and aspirin (100 mg) for at least 45 days.

Cerebral MRI Acquisition and Analysis

All patients underwent brain MRI with a 1.5-T unit on the day before LAAO and within 7 days after LAAO. The detailed imaging protocol and definition of SCE have been previously described [10].

MRI images were analyzed by an independent neuroradiologist blinded to the clinical information. All lesions were carefully assessed and recorded for size, depth, and location.

Statistical Analysis

Continuous variables are described as the mean ± SD, and categorical variables are expressed as frequencies and percentages. Pearson’s χ2 test and Student’s t test were used to compare the categorical variables and continuous variables, respectively.

To minimize potential selection bias and enhance the comparability of study subjects between two groups, we applied an inverse probability of treatment weighting (IPTW) matching procedure. Propensity scores were estimated using a multivariable logistic regression model based on baseline characteristics. We used nearest-neighbor 1:1 IPTW matching with a caliper of 0.2 on the IPTW scale.

We categorized ACT values into three levels: ACT <250 s; 250 s≤ ACT <300 s; and ACT ≥300 s (shown in Fig. 1). Using ACTmean and ACTpeak levels during the procedure, we defined five ACT change patterns: stable low pattern (both <250 s), low to medium pattern (ACTmean <250 s and 250 s≤ ACTpeak <300 s), stable medium pattern (250 s≤ both ACT <300 s), medium to high pattern (250 s≤ ACTmean <300 s and ACTpeak ≥300 s), and stable high pattern (both ≥300 s) (shown in Fig. 1). Multivariate logistic regression analysis was used to examine the relationship between different ACT level patterns during the procedure and the incidence of new SCE. Interaction analyses were conducted with respect to ACT level and LAAO procedure time. Statistical analyses were conducted using R version 4.1.3. with 2-sided significance testing and statistical significance set at <0.05.

Fig. 1.

Categorization of ACT change patterns. ACTmean referred to average ACT level during LA procedure time. ACTpeak referred to the peak value of ACT during LA procedure time. ACT, activated clotting time.

Fig. 1.

Categorization of ACT change patterns. ACTmean referred to average ACT level during LA procedure time. ACTpeak referred to the peak value of ACT during LA procedure time. ACT, activated clotting time.

Close modal

Between January 2021 and December 2022, 81 patients were enrolled and underwent pre- and postprocedure MRI examinations, including 38 patients in group 250 and 43 patients in group 300. Thirty-two patients (18 in group 250 and 14 in group 300) received LAAO alone (p = 0.17), and all of them were in AF rhythm during postprocedural MRI scanning periods. Totally, 20 patients in group 250 and 29 patients in group 300 received LAAO-combined AF ablation, who were in sinus rhythm during postprocedural MRI scanning periods.

No serious complications (including closure-device disengagement, stroke, major bleeding, and severe pericardial tamponade) occurred during the peri-procedural period. Three patients in group 250 and 5 patients in group 300 suffered from bruising or mild hematoma formation at the venepuncture site (p = 0.850), which resolved gradually with conservative treatment.

Patient Characteristics

The baseline and clinical characteristics are summarized in Table 1. There were no significant differences between these two groups in age, sex, hypertension, coronary artery disease, diabetes, AF type, CHA2DS2-VASc score, HASBLED score, left atrium diameter, left ventricular ejection fraction, procedure duration, or baseline ACT level. A history of prior ischemic stroke was more common in group 300 than in group 250 (95.3% vs. 73.7%, p = 0.015). However, the incidence of procedure-related SCE tended to decrease in patients in group 300 compared with patients in group 250 (32.6% vs. 55.3%, p = 0.067), although these trends were not statistically significant. The peri-procedural average ACT (292.54 ± 29.29 vs. 272.13 ± 51.22 s, p = 0.028) and peak ACT (311.70 ± 35.21 vs. 288.37 ± 51.76 s, p = 0.019) were significantly longer in the patients in group 300.

Table 1.

Baseline characteristics of study patients

All patientsIPTW
Group 250 (n = 38)Group 300 (n = 43)p valueGroup 250 (n = 25.66)Group 300 (n = 24.92)p value
Age, years 69.13±7.48 67.6±7.73 0.393 67.71±6.69 67.43±8.20 0.877 
Male 19 (50.0%) 28 (65.1%) 0.25 13.5 (52.6%) 13.1 (52.5%) 0.993 
Hypertension 26 (68.4%) 27 (62.8%) 0.766 16.6 (64.7%) 16.6 (66.6%) 0.871 
CAD 12 (31.6%) 13 (30.2%) 8.1 (31.7%) 8.2 (32.8%) 0.925 
Diabetes 11 (28.9%) 6 (14.0%) 0.167 5.4 (20.9%) 5.1 (20.4%) 0.963 
NPAF 25 (65.8%) 28 (65.1%) 16.0 (62.3%) 14.4 (57.6%) 0.704 
Prior ischemic stroke 28 (73.7%) 41 (95.3%) 0.015 23.6 (92.1%) 22.9 (92.0%) 0.980 
CHA2DS2-VASc score 4.26±1.72 4.47±1.24 0.543 4.42±1.61 4.63±1.29 0.552 
HASBLED score 2.45±0.86 2.33±0.78 0.506 2.53±0.81 2.32±0.78 0.275 
LAD, mm 43.16±4.53 44.65±4.63 0.147 43.57±4.30 43.39±4.43 0.858 
LVEF, % 62.89±3.03 62.88±4.38 0.992 62.67±3.38 62.65±4.78 0.985 
LAAO placement time, min 45.18±25.70 40.93±19.02 0.396 43.99±25.28 42.23±19.07 0.749 
LA procedure time, min 110.87±60.19 110.44±49.55 0.972 114.38±60.16 112.10±48.11 0.865 
Entire procedure time, min 137.68±66.36 147.79±55.99 0.459 142.98±64.75 150.30±54.89 0.620 
New SCE 21 (55.3%) 14 (32.6%) 0.067 16.2 (63.2%) 9.2 (37.0%) 0.038 
Baseline ACT, s 140.87±32.46 136.56±32.37 0.552 138.51±32.20 137.96±33.58 0.946 
Average ACT, s 272.13±51.22 292.54±29.29 0.028 265.82±46.43 294.31±28.22 0.002 
Peak ACT, s 288.37±51.76 311.70±35.21 0.019 283.68±49.13 312.23±34.52 0.006 
All patientsIPTW
Group 250 (n = 38)Group 300 (n = 43)p valueGroup 250 (n = 25.66)Group 300 (n = 24.92)p value
Age, years 69.13±7.48 67.6±7.73 0.393 67.71±6.69 67.43±8.20 0.877 
Male 19 (50.0%) 28 (65.1%) 0.25 13.5 (52.6%) 13.1 (52.5%) 0.993 
Hypertension 26 (68.4%) 27 (62.8%) 0.766 16.6 (64.7%) 16.6 (66.6%) 0.871 
CAD 12 (31.6%) 13 (30.2%) 8.1 (31.7%) 8.2 (32.8%) 0.925 
Diabetes 11 (28.9%) 6 (14.0%) 0.167 5.4 (20.9%) 5.1 (20.4%) 0.963 
NPAF 25 (65.8%) 28 (65.1%) 16.0 (62.3%) 14.4 (57.6%) 0.704 
Prior ischemic stroke 28 (73.7%) 41 (95.3%) 0.015 23.6 (92.1%) 22.9 (92.0%) 0.980 
CHA2DS2-VASc score 4.26±1.72 4.47±1.24 0.543 4.42±1.61 4.63±1.29 0.552 
HASBLED score 2.45±0.86 2.33±0.78 0.506 2.53±0.81 2.32±0.78 0.275 
LAD, mm 43.16±4.53 44.65±4.63 0.147 43.57±4.30 43.39±4.43 0.858 
LVEF, % 62.89±3.03 62.88±4.38 0.992 62.67±3.38 62.65±4.78 0.985 
LAAO placement time, min 45.18±25.70 40.93±19.02 0.396 43.99±25.28 42.23±19.07 0.749 
LA procedure time, min 110.87±60.19 110.44±49.55 0.972 114.38±60.16 112.10±48.11 0.865 
Entire procedure time, min 137.68±66.36 147.79±55.99 0.459 142.98±64.75 150.30±54.89 0.620 
New SCE 21 (55.3%) 14 (32.6%) 0.067 16.2 (63.2%) 9.2 (37.0%) 0.038 
Baseline ACT, s 140.87±32.46 136.56±32.37 0.552 138.51±32.20 137.96±33.58 0.946 
Average ACT, s 272.13±51.22 292.54±29.29 0.028 265.82±46.43 294.31±28.22 0.002 
Peak ACT, s 288.37±51.76 311.70±35.21 0.019 283.68±49.13 312.23±34.52 0.006 

Values are mean ± SD or n (%).

ACT, activated clotting time; CAD, coronary artery disease; LA, left atrial; LAAO, left atrial appendage occlusion; LAD, left atrium diameter; LVEF, left ventricular ejection fraction; NPAF, nonparoxysmal atrial fibrillation; IPTW, inverse probability of treatment weighting; SCE, silent cerebral embolism.

All of the baseline characteristics and procedure duration were well balanced after IPTW (Table 1). The incidence of procedure-related SCE was significantly lower in group 300 than in group 250 (p = 0.038).

Results of MRI Images

MRI found a total of 106 lesions, including 28 lesions among 14 patients in group 300 and 78 lesions among 21 patients in group 250. Eleven patients in group 250 and 5 patients in group 300 suffered from multiple lesions. A total of 77.4% (82/106) of the lesions were located in the cortex (89.3% in group 300 and 73.1% in group 250) (shown in Fig. 2). A total of 47.2% (50/106) of the lesions were located in the frontal lobe, and 30.1% (32/106) were located in the parietal lobe. No significant differences were observed between these two groups in lesion size (4.02 mm vs. 4.35 mm, p = 0.49) and depth (shown in Fig. 2). Lesions located in the cortex were significantly smaller than those in the subcortex (3.97 mm vs. 5.25 mm, p = 0.009). The incidence of SCE (49.0% vs. 34.4%, p = 0.20) tended to increase in patients receiving combined AF ablation compared with patients receiving LAAO only, but the differences were not statistically significant.

Fig. 2.

MRI results of the two groups. a The locations of SCE lesions between these two groups exhibited significant difference (p = 0.001). b There was no evidence for a difference in the depth of the lesion between group 250 and group 300 (p = 0.135).

Fig. 2.

MRI results of the two groups. a The locations of SCE lesions between these two groups exhibited significant difference (p = 0.001). b There was no evidence for a difference in the depth of the lesion between group 250 and group 300 (p = 0.135).

Close modal

Relations of Peri-Procedure ACT Level Patterns with the Incidence of SCE

Of the 81 enrolled patients, 35 suffered from procedure-related SCE (21 in group 250, 14 in group 300). Table 2 shows the association between 5 ACT level patterns and the incidence of SCE, using the stable low group as the reference. As expected, stable high ACT levels had decreased risks of SCE incidence (p = 0.008), and the other 3 groups had no significant difference from the stable low group. Furthermore, the stable high group was significantly different from the other groups (p = 0.036, 0.002, 0.024, and 0.008, respectively) (shown in Fig. 3). Although we previously described that a high CHA2DS2-VASc score, low peak ACT level, and prolonged LAAO placement time were all risk factors for SCE [10], no significant interaction was found between ACT level patterns and LAAO placement time (p interaction = 0.472) or CHA2DS2-VASc score (p interaction = 0.592).

Table 2.

Multivariate logistic regression analysis of ACT patterns and SCE incidence

GroupNo. SCE/No. populationModel 1 OR (95% CI)Model 2 OR (95% CI)p value
Stable low 7/10 Reference Reference 1.000 
Low to medium 4/6 0.86 (0.1, 7.51) 0.04 (0, 9.06) 0.240 
Stable medium 17/25 0.91 (0.19, 4.48) 0.08 (0, 7.82) 0.283 
Medium to high 6/15 0.29 (0.05, 1.57) 0 (0, 1.06) 0.053 
Stable high 1/25 0.02 (0, 0.2) 0 (0, 0.08) 0.008 
GroupNo. SCE/No. populationModel 1 OR (95% CI)Model 2 OR (95% CI)p value
Stable low 7/10 Reference Reference 1.000 
Low to medium 4/6 0.86 (0.1, 7.51) 0.04 (0, 9.06) 0.240 
Stable medium 17/25 0.91 (0.19, 4.48) 0.08 (0, 7.82) 0.283 
Medium to high 6/15 0.29 (0.05, 1.57) 0 (0, 1.06) 0.053 
Stable high 1/25 0.02 (0, 0.2) 0 (0, 0.08) 0.008 

Reference group: stable low group.

Model 1 is unadjusted. Model 2 is adjusted for CHA2DS2-VASc score, LAAO placement time, age, stroke, and CAD by backward stepwise regression.

CAD, coronary artery disease.

Fig. 3.

Logistic regression models investigating the relationship of ACT patterns and SCE incidence. Reference group: stable high group. SCE, silent cerebral embolism.

Fig. 3.

Logistic regression models investigating the relationship of ACT patterns and SCE incidence. Reference group: stable high group. SCE, silent cerebral embolism.

Close modal

This prospective observational study is the first to investigate the relationship between the incidence of LAAO procedure-related SCE and different ACT levels and patterns in Asian individuals. Five ACT patterns in terms of ACTmean and ACTpeak levels during the LAAO procedure were innovatively defined to explore the most appropriate ACT level. The important finding is that increasing the peri-procedure ACT level by increasing the first dose bolus of heparin upon TSP can significantly decrease the incidence of SCE without additional risk of bleeding compared with traditional practice. Only participants in the stable high group (ACTpeak ≥300 s and ACTmean ≥300 s) had the lowest risk of SCE incidence. These findings underscore the importance of maintaining a stable high level of ACT during the LAAO procedure, especially in patients with a high risk of stroke and in patients with a prolonged procedure duration.

SCE has long been recognized as a common phenomenon during interventional procedures in the systemic circulation [4, 5, 14] which is associated with memory impairment and cognitive impairment and doubles the risk of clinical stroke and dementia [2, 15‒18]. Previous studies have demonstrated that transcatheter LAAO has a surprisingly high incidence of peri-procedural SCE [9, 10] detected by thin-layer MRI scans, even higher than catheter ablation. Fundamentally, transcatheter LAAO was introduced with the aim of preventing thromboembolism [19] and improving cognitive status [20] and quality of life. Therefore, avoidance of peri-procedural SCE is of great importance. The larger sheaths and delivery system, the introduction of foreign bodies and frequent anchoring, and retrieval of the occluders are all at high risk of minor thromboembolism. Theoretically, these risks could be decreased by adequate heparinization during the LAAO procedure, yet related studies are very rare. Although the agreement had been reached by the expert consensus [12] indicating that the target ACT level should remain at ≥250 s during LAAO implantation, our previous observation demonstrated that the incidence of procedure-related SCE was very high [10]. We wondered whether the ACT level be recommended the same as that of AF ablation (≥300–350 s) [11] could reduce the incidence of SCE while not increasing the bleeding risk. In our study, we did observe significant differences among different ACT change patterns. Raising the targeted ACT level of LAAO to the same level as AF ablation significantly decreases the incidence of SCE without increasing the bleeding risk. Therefore, it might be reasonable and necessary to apply a more intensive anticoagulation therapy to increase the target ACT to ≥300 s.

Additionally, for patients with multiple exchanges of devices and prolonged catheter manipulation, which was reported to be associated with a higher thromboembolic risk [21], enhanced heparinization to a target ACT to ≥300 s can still decrease the risk of procedure-related SCE. Patients with more cardiovascular comorbidities reflecting more impaired LA endothelial function [22] might also need a higher target ACT level. These findings seem to be of great importance for the management of anticoagulation during LAAO in future practice.

Although possible mechanisms of SCE during transcatheter procedures might also include air embolism and char or tissue embolism, the incidence of SCE tended to decrease when the ACTpeak level reached 300 s. In the ACT stable high group, the SCE incidence was as low as 4%. These results suggest that LAAO with the WATCHMAN device can be a safe procedure under enhanced heparinization.

However, it is crucial to consider that even with optimal anticoagulation, the risk of perioperative micro-embolic events cannot be entirely eliminated. This concern is particularly acute in certain high-risk populations, such as patients with thrombus formation in the LA appendage, for whom the LAAO procedure itself poses a significant threat, as well as those with elevated bleeding risks who may not tolerate more intensive anticoagulation regimens. In light of these considerations, cerebral protection devices have garnered increasing attention in recent years as a potential safeguard [23]. However, strong evidence of the routine use of cerebral protection devices during LAAO remains lacking. Further investigations are needed to ascertain the precise indications for the deployment of cerebral protection devices during LAAO and identify the selected, higher risk AF populations that would benefit most from their use.

Our study also has several limitations needed to be acknowledged. First, the overall sample size was relatively small. The small sample size might increase the stochasticity of the incidence of adverse events. However, the primary findings were still statistically significant even with the small sample size. Second, this study was non-randomly designed. We enrolled consecutive eligible patients, and propensity score matching was used to avoid the bias. However, our study will trigger the mind for a more intensive anticoagulation therapy during LAAO procedure to the same level of AF ablation. This certainly needs large-scale and multicenter clinical trials to achieve strong evidence. Lastly, the long-term improvement on cognitive function of this measure should be further evaluated during follow-up based on the present results.

Raising the targeted ACT level of LAAO to 300 s reduces the risk of SCE without increasing the major bleeding events compared to the conventional 250 s strategy. Only a stable high ACT level can result in a significantly lower SCE incidence. Future trials to achieve solid evidences of a suitable ACT level during LAAO procedure and the studies to assess the long-term effect of this proposal on cognitive function are necessary.

We thank all patients for participating in this study and all clinicians for their invaluable assistance in the evaluation of imaging data and neurologic clinical assessments.

This study protocol was reviewed and approved by the First Affiliated Hospital of Nanjing Medical University, approval number 2022-SR-228. All participants provided written informed consent.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

The study conception and design and first draft of the manuscript were performed by Kexin Wang and Weizhu Ju; formal analysis and investigation were performed by Mingjia Xu; data analysis was performed by Zhe Wang; patient enrollment was performed by Zidun Wang, Mingfang Li, Hailei Liu, and Hongwu Chen; review and editing were performed by Minglong Chen. All authors commented on previous versions of manuscript and read and approved the final manuscript.

Additional Information

Kexin Wang and Mingjia Xu contributed equally to this work.

The raw data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.

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