This was a prospective, observational and single center study including consecutive eligible participants following percutaneous LAAC between September 2016 and September 2020. Ethics approval of antithrombotic protocols was granted by the Ethics Committee of Zhongshan Hospital, Fudan University. Patients eligible for Watchman (Boston Scientific, Natick, MA, USA) implantation met the following inclusion criteria: (1) age $>$18; (2) diagnosis as NVAF; (3) the potential ischemic stroke score (CHADS${}_2$) $\ge$2 or a congestive heart failure, hypertension, age $\ge$75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65–74 years, sex category (CHA${}_2$DS${}_2$-VAS${}_{\text{c}}$) score $\ge$3; (4) intolerant of long-term anticoagulants or at higher risk for bleeding. Participants who met the following criteria were excluded: (1) receiving long-term DAPT prior to Watchman implantation; (2) participants who were transferred to surgery due to the complications of LAAC procedures; (3) AF ablation planned during the follow-up.

There is currently concern regarding post-LAAC antithrombotic regimens. However, there is limited evidence on DRT and bleeding prevention. Therefore, this observational study sought to provide further data regarding the antithrombotic strategy among Chinese patients following LAAC. The study was not randomized; instead, the antithrombotic protocol was determined by the implanting physicians’ judgment. Subsequently, the patients were divided into three groups based on their prescribed antithrombotic plans, which were at the discretion of the physician. The RRD group comprised participants in the rivaroxaban 10 mg (R${}^{10}$) or 15 mg (R${}^{15}$), who were initially medicated with 45 days of rivaroxaban 10 mg or 15 mg after operation. Subsequently these participants were switched to DAPT (aspirin 100 mg plus clopidogrel 75 mg) after confirming the adequate closure stability and no significant peridevice leak at 45-day trans-esophageal echocardiography (TEE) examination. After 6-month following TEE confirmation, mono-antiplatelet was continued indefinitely. Another group comprised patients with DAPT, who were prescribed aspirin (100 mg) and clopidogrel (75 mg) for 180 days after closure implantation and then long-term aspirin therapy. If the 45-day TEE revealed DRT, the antithrombotic strategy was switched to full dose rivaroxaban (20 mg qd) until the second TEE confirmation a total elimination of DRT.

The LAAC device implantation had been described in detail [17]. The procedure was performed under general anesthesia with fluoroscopy and intracardiac echocardiography guidance. The post-implant anti-thrombotic regimen was individualized, and left to physician discretion. Participants were discharged after observation with no periprocedural complication. A routine TEE examination was performed 45 days after device implantation to determine the presence of significant residual flow ($>$5 mm) or DRT.

Detailed demographic and baseline clinical parameters were recorded from hospital information systems (HIS). CHA${}_2$DS${}_2$-VAS${}_{\text{c}}$ and hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol (HAS-BLED) score were determined in each patient for risk stratification of potential thromboembolism and bleeding risks. Laboratory parameters including liver, renal function and coagulation were also recorded. TEE was conducted to rule out a cardiac effusion post procedure.

Routine outpatient follow-ups performed for each enrolled participant included up to 3 repeated TEE examinations scheduled approximately 45 days, 180 days and yearly post procedure for the presence of DRT. Out-patient visits and trans-telephonic clinical evaluations were conducted every 3 months during the 1-year follow-up. All the follow-up TEE images and recordings were reviewed by one physician and participants who did not complete the follow-up examination were excluded from the final analysis.

The primary clinical endpoint was a composite of effective and safety characteristics of each strategy. The efficacy endpoints were as followings: (1) DRT defined as a well-circumscribed and uniformly echo-dense mass lying on the closure, measured by TEEs, (2) TE events including stroke or transient ischemic attack (TIA) determined on magnetic resonance imaging (MRI) or computed tomography (CT), peripheral thromboembolism, pulmonary embolism and venous thromboembolism. The safety endpoints included clinical major and non-major bleeding complications defined according to the guidance of the International Society on Thrombosis and Haemostasis [18]. The definition of major bleeding in the study involved a decrease in the hemoglobin level of no less than 20 g/L, transfusion of two or more units of blood, or symptomatic bleeding that affected a critical organ. Clinically significant non-major bleeding was defined as bleeding that necessitated medical attention from a healthcare professional, a higher level of intensive care, or an on-site evaluation.

The sample size was calculated based on the lower hospitalization rate of confirmed DRT and TE with long-term RRD compared with a standard antiplatelet therapy. Using PASS statistical software (version 11.0; NCSS, LLC. Kaysville, UT, USA), a class I error rate ($\alpha$) of 0.05 and a statistical power of 90% (class II error rate $\beta$ = 0.1) were selected. To account for a 10% attrition rate, the study sought to enroll a minimum of 240 eligible participants.

Continuous variables were presented as mean $\pm$ standard deviation (SD) and compared by the Mann-Whitney U tests or Student t-tests between the two groups mainly dependent on the normal distribution. Categorical variables were presented as frequencies or percentages n (%) and analyzed using $\chi$${}^2$ or Fisher’s precision probability tests.

The baseline characteristics comparison between groups was conducted using appropriate statistical tests, such as t-tests and $\chi$${}^2$ tests/Fisher’s precision probability test.

The primary efficacy and safety variables were the cumulative occurrence of confirmed DRT, TE, and bleeding complications, for each enrolled patient during the follow-up period. Kaplan-Meier curves were performed to illustrate the time-to-first thrombosis or bleeding, and log-rank tests were used to compare these curves. Statistical analysis was performed using SPSS software (version 22.0; IBM Corp., Armonk, NY, USA), and a p value of 0.05 was considered statistically significant.

This cohort study initially enrolled 779 patients following successful Watchman implantation between December 2017 and December 2021. A total of 12 participants (DAPT group: n = 6 [0.8%]; RRD group: n = 6 [0.8%]) were finally excluded from the study because their follow-up TEEs were completed at a different clinical institution and no images were provided for review. Ultimately, 767 patients (DAPT group: n = 140; RRD group: n = 627; Mean age 68.0 $\pm$ 9.0, male 478 (62.3%), Median CHA${}_2$DS${}_2$-VAS${}_{\text{c}}$ score 4; Median HAS-BLED score 2) were included in the analysis and followed for 12 months. Among participants in the RRD group, the anticoagulant regimen was rivaroxaban 15 mg once a day in 551 (87.9%) patients and 10 mg once a day in 76 (12.1%). The progression of anticoagulation therapy for post-LAAC operation is summarized in Fig. 1.

Fig. 1.

Enrollment flow chart of patients. LAAC, left atrial appendage closure; TEE, trans-esophageal echocardiography; RRD, reduced rivaroxaban doses; DAPT, dual antiplatelet therapy; R${}^{10}$, rivaroxaban 10 mg; R${}^{15}$, rivaroxaban 15 mg; DRT, device-related thrombosis.

Baseline information, cardiovascular risk factors, potential thromboembolic and bleeding risks, and concomitant medication are presented in Table 1. There was a higher percentage of higher HAS-BLED score in participants taking DAPT. After propensity score matching (PSM) with 1:2 ratio (140 patients for DAPT and 280 patients for RRD), the two subgroups were not significantly different in baseline information, cardiovascular risk factors, laboratory indicators and predetermined stroke and bleeding risk.

The RRD group had a 12-month median (interquartile range (IQR): 11–14) follow-up and the DAPT group had a 13-month (IQR: 11–15) median follow-up. In the RRD group, 193 were on R${}^{15}$ and 47 on R${}^{10}$. In the first TEEs (within 2 days after LAAC), peri-device leaks $>$5 mm were recorded in 4 cases (R${}^{15}$(n = 1), R${}^{10}$ (n = 1) and DAPT (n = 2)). A second TEE was performed to confirm the presence of leaks among these patients, who were subsequently scheduled for percutaneous LAA leak closure. The primary efficacy endpoints were defined as a function of both the presence of DRT as well as the occurrence of thrombosis events. Early-phase formation of DRT was investigated, as reflected by the incidence of DRT and thrombus size. These patients were prescribed full-dose rivaroxaban (20 mg qd).

The incidence of DRT was documented in 12 (9.3%) patients in DAPT, 3 (6.3%) in R${}^{10}$ and 7 (3.0%) in R${}^{15}$ (log-rank p = 0.050), which indicated a higher DRT incidence in DAPT than that of R${}^{10}$ and R${}^{15}$. A clear causal relationship between the TE and DRT could be established in 3 cases which were identified as ischemic strokes. As a result of switching to rivaroxaban therapy at full dose (20 mg), the DRTs were successfully managed. In the whole cohort of antithrombotic treated patients, DAPT subgroups were more likely to experience shorter time to DRT (R${}^{10}$vs. DAPT, HR = 0.716, p = 0.603, 95% CI: 0.226–2.275; R${}^{15}$vs. DAPT HR = 0.334, p = 0.015, 95% CI: 0.131–0.850), as demonstrated in Fig. 2A.

Fig. 2.

Time to clinical events in antithrombotic treated patients, stratified into three subgroups (DAPT, R${}^{\mathrm{10}}$ and R${}^{\mathrm{15}}$) according to the different antithrombotic strategy. (A) referred as the comparison between DAPT and R${}^{10}$. (B) referred as the comparison between (C) DAPT and R${}^{15}$. (A) Kaplan-Meier survival curve of device-related thrombus (DRT), (B) Kaplan-Meier survival curve of thromboembolic (TE) events, (C) Kaplan-Meier survival curve of bleeding events. DAPT, dual antiplatelet therapy; R${}^{10}$, rivaroxaban 10 mg; R${}^{15}$, rivaroxaban 15 mg; HR, hazard ratio.

In the DAPT group, a total of 14 patients (10.0%) experienced TEs in terms of ischemic stroke or systemic embolism during the follow-up period compared with 6 patients (12.7%) in the R${}^{10}$ and 8 (3.4%) in the R${}^{15}$ matched group. Based on Kaplan-Meier survival analysis, TE reduction was significantly more favorable in the R${}^{15}$ group (R${}^{15}$vs. DAPT HR = 0.362, p = 0.018, 95% CI: 0.149–0.878, Fig. 2B).

The median length of DRT in the R${}^{15}$ group was significantly lower than that of the DAPT group (1.721 [1.610–1.818] mm vs. 1.820 [1.725–1.925] mm, p = 0.029), while no significant difference was detected between R${}^{10}$ and DAPT (1.806 [1.740–1.924] mm vs. 1.820 [1.725–1.925] mm, p = 0.775), as shown in Fig. 3A. No significant difference in DRT width was observed among the three groups (R${}^{10}$ 1.486 (1.402–1.620) vs. DAPT 1.520 [1.400–1.610], p = 0.809; R${}^{15}$ 1.457 (1.372–1.578) vs. DAPT 1.520 [1.400–1.610], p = 0.360, Fig. 3B).

Fig. 3.

(A) Length and (B) width of device-related thrombus (DRT) evaluated with transesophageal echocardiography. The solid black lines medians of each subgroup, while the error bars represent the interquartile range. DAPT, dual antiplatelet therapy; R${}^{10}$, rivaroxaban 10 mg; R${}^{15}$, rivaroxaban 15 mg.

Compared with the unadjusted estimated rates of ischemic events for patients with similar CHA${}_2$DS${}_2$-VAS${}_{\text{c}}$ scores, a significant decrease of 68.6% in ischemic stroke rates was noted in the R${}^{15}$ group, while slight insignificant reductions of 28.6% and 15.4% was observed in the DAPT and R${}^{10}$ groups (Fig. 4A). In the whole cohort study, R${}^{15}$ contributed a 54.9% reduction of overall TE events, as shown in Fig. 4B.

Fig. 4.

(A) Annualized ischemic stroke and (B) TE event rates after implantation vs expected (unadjusted) rates estimated based on the CHA${}_{\mathrm{2}}$DS${}_{\mathrm{2}}$-VAS${}_{\text{𝐜}}$ (congestive heart failure, hypertension, age $\mathrm{>}$75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65–74 years, sex category) score of the 3 study groups. DAPT, dual antiplatelet therapy; R${}^{10}$, rivaroxaban 10 mg; R${}^{15}$, rivaroxaban 15 mg; TE, thromboembolic.

Details of the bleeding events in the entire patient cohort are reported in Table 2. No major bleeding was documented throughout the 12-month follow-up period. The rate of overall minor bleeding was not significantly different amongst the groups (8.5% among R${}^{10}$ patients, 9.9% among R${}^{15}$ patients and 10.7 among DAPT patients, (p = 0.944).

Table 2 shows the accumulated anticoagulation-related complications and coagulation function tests among the groups. There was no significant reduction in levels of platelet (PLT), hemoglobin (Hb), or prothrombin time (PT) among R${}^{10}$, R${}^{15}$ and DAPT groups (p $>$ 0.05). Based on Kaplan-Meier survival curve analysis, procedural bleeding was more common in the DAPT group, as compared with the R${}^{10}$ and R${}^{15}$ groups (Fig. 2), however, there was no significant difference among three groups.

The present study has many limitations. Firstly, our study is non-randomized and conducted at a single center, which might restrict the generalizability of the results to other cardiovascular centers and healthcare systems. Secondly, the sample size was relatively small and the follow-up duration of only 12 months may not be sufficient to determine the long-term efficacy and safety of different anticoagulation regimens, which potentially led to a low incidence of DRT. The exclusion of 12 participants due to incomplete follow-up TEEs and failure to provide images for review may have introduced selection bias. Thirdly, our study was followed up only by the cardiology department. Finally, the study only enrolled participants receiving RRD and DAPT, which may limit the generalizability of the findings to other anticoagulants. In conclusion, these limitations highlight the need for further studies with larger sample sizes, more frequent monitoring, and more diverse patient populations to confirm the conclusions and establish the clinical efficacy and safety of different antithrombotic strategies.