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Clinical effectiveness and safety comparison between direct oral anticoagulants and warfarin for nonvalvular atrial fibrillation patients following percutaneous left atrial appendage closure operation intervention: a prospective observational study

BMC Pharmacology and Toxicology volume 26, Article number: 1 (2025) Cite this article

Abstract

The main objective of this study was to investigate the optimal post-left atrial appendage closure (LAAC) anticoagulation strategy, focusing on minimizing device-related thrombosis (DRT) and thromboembolism (TE) events without increasing bleeding risk. After successful LAAC, consecutive participants were treated with 45-day anticoagulants (rivaroxaban 15 mg daily, dabigatran 110 mg twice a day, and warfarin). The efficacy endpoints included DRT, TE, and hospital readmissions due to cardiac caused, while safety endpoints encompassed bleeding events, monitored over a 12-month follow-up period. The incidence of DRT was relatively lower in the rivaroxaban group compared to both the dabigatran and warfarin groups (rivaroxaban vs. dabigatran: HR = 0.504, 95% CI 0.208–1.223, log-rank P = 0.101; rivaroxaban vs. warfarin: HR = 0.468, 95% CI 0.167–1.316, log-rank P = 0.093). The median [interquartile range] length and width of DRT in the rivaroxaban group were 1.92 [1.68–2.15] mm and 1.49 [1.28–1.76] mm, both significantly lower than those in the dabigatran (length = 2.15 [1.99–2.25] mm, P = 0.036; width = 1.60 [1.54–1.85] mm, P = 0.035) and warfarin groups (length = 2.26 [2.11–2.44] mm, P = 0.006; width = 1.74 [1.54–1.85] mm, P = 0.006). Kaplan-Meier survival analysis indicated that procedural bleeding was more common in the warfarin group. The 12-month incidence of TE was significantly lower in the rivaroxaban group compared to the dabigatran (HR = 0.466, 95% CI 0.221–0.984, log-rank P = 0.029) and warfarin groups (HR = 0.456, 95% CI 0.188–0.966, log-rank P = 0.042). Long-term antithrombotic therapy with reduced dose of rivaroxaban significantly reduced the risk of DRT and composite endpoints without increasing bleeding events, compared to warfarin and dabigatran, for patients following LAAC.

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Introduction

The left atrial appendage (LAA) is a critical site for thrombus formation in patients with atrial fibrillation (AF). Over 90% of thrombi in patients with non-valvular atrial fibrillation (NVAF) originate from the LAA, and left atrial appendage closure (LAAC) has been proven effective and safe in preventing stroke in AF patients. Studies have shown that LAAC surgery can reduce the risk of stroke by 80% in these patients [1]. Long-term follow-up has revealed that LAAC significantly reduces both cardiovascular and all-cause mortality, making it an effective strategy for stroke and embolism prevention in NVAF patients [2]. Clinical studies have further concluded that the efficacy of LAAC in preventing major cardiovascular, neurological, and bleeding events is not inferior to that of direct oral anticoagulants (DOACs) in high-risk AF patients [3]. Percutaneous LAAC is emerging as a new option for NVAF patients who are at higher risk of stroke and have contraindications to anticoagulants [4]. The primary goal of LAAC is to reduce thrombotic risk by preventing thrombus formation in the LAA while minimizing the need for anticoagulants, thereby reducing bleeding risks.

Device-related thrombosis (DRT) following successful LAAC remains a significant clinical challenge. Early clinical studies reported a DRT incidence of 3 to 5%, which was associated with an increased risk of thromboembolic events [5,6,7]. However, with the accumulation of real-world data, the reported incidence of DRT now varies widely, ranging from 1.6 to 16% across different studies [8,9,10,11]. Although DRT was originally recognized as an early complication occurring within 45 days post-LAAC, recent literature suggests the need for extended surveillance imaging to identify delayed DRT [12]. The closure membrane of the device, once exposed to blood, carries a high risk of DRT formation, necessitating post-LAAC antithrombotic medication to prevent DRT, which typically resolves with anticoagulation therapy.

Despite the growing clinical evidence supporting LAAC, several concerns remain regarding the optimal antithrombotic strategy for patients undergoing this procedure. Current guidelines recommend an initial 45-day course of anticoagulation (with a DOAC or warfarin), followed by dual antiplatelet therapy (aspirin 100 mg daily and clopidogrel 75 mg daily) for 135 days, and then lifelong aspirin therapy [13, 14]. However, thrombosis, DRT, and bleeding risks continue to be major clinical challenges after LAAC. As most DRTs occur within the first trimester post-operation, oral anticoagulants (OACs) are often recommended during the initial phase of device implantation. Nevertheless, a large fraction of patients post-LAAC are at high risk of bleeding, and comparative studies on the clinical efficacy and safety of different OACs are scarce.

In summary, the optimal antithrombotic strategy post-LAAC must balance the prevention of thrombosis, particularly DRT and thrombotic events (TE), with the risk of bleeding. Notably, rivaroxaban and dabigatran have been used empirically, yet comparative studies between DOACs and vitamin K antagonists (VKAs) remain limited. This has spurred active research into optimizing anticoagulation regimens for successful closure implantation, particularly in light of concerns about the safety profiles for high-risk bleeding patients and the efficacy of DOACs and warfarin in preventing DRT and TE. Specifically, dabigatran, through enhanced thrombin receptor density on platelets, may contribute to thrombus development, whereas rivaroxaban, a selective Xa antagonist, has been shown to reduce thrombin-induced thrombosis [15, 16]. Additionally, a subgroup analysis of the EWOLUTION study indicated that DOAC therapy was associated with a lower thrombus rate without an increase in device thrombus, stroke, or bleeding compared to the standard VKA regimen [17]. Given the increasing clinical concerns regarding post-LAAC antithrombotic strategies, we compared the effectiveness and safety of rivaroxaban, dabigatran, and warfarin when prescribed for 45 days as a post-LAAC anticoagulation approach.

Methods

Study population and design

This was a prospective, observational, single-center study that enrolled consecutive patients who underwent percutaneous LAAC between May 2018 and December 2021. The study was approved by the Institutional Review Board (IRB) of Zhongshan Hospital, Fudan University. Eligible patients for Watchman (Boston Scientific, Natick, MA, USA) implantation met the following inclusion criteria: (1) 18 years of age or older; (2) diagnosis of NVAF; (3) a CHADS2 score ≥2 or a CHA2DS2-VASc score ≥3; (4) meet indications for LAAC. Exclusion criteria included: (1) prior long-term anticoagulation before closure implantation; (2) patients who required surgery due to complications from the LAAC procedure; (3) planned AF ablation during follow-up; LAA ostium sizes <17 mm or >31 mm are unable to be accommodated by the Watchman 2.5 device sizes

The study was non-randomized, with the choice of antithrombotic strategy determined by the implanting physician. Patients were grouped into three cohorts based on the prescribed antithrombotic regimen: warfarin, dabigatran, and rivaroxaban (detailed anticoagulation strategy is listed below).

Device implantation procedure and postoperative anticoagulation strategy

During the study period, the second-generation Watchman device (Watchman FLX) was not yet available in our center. Therefore, all patients were treated using the first-generation Watchman device (Watchman 2.5). Device size selection was based on the maximum diameter of the left atrial appendage (LAA) ostium, with available sizes including 21 mm, 24 mm, 27 mm, 30 mm, and 33 mm [18]. The implantation procedure was performed under transesophageal echocardiography (TEE) guidance to assess the anatomical structure and size of the LAA, as well as to ensure optimal positioning of the occluder. The procedural details have been described previously [19].

Following LAAC, the choice of postoperative antithrombotic therapy was determined by the attending physician based on clinical judgment, patient adherence, economic considerations, overall compliance, and the patient’s specific clinical profile and medication preferences, given the absence of standardized antithrombotic guidelines for post-LAAC management, with no intervention from the researchers. Patients were prescribed one of the following regimens for the first 45 days post-procedure: (1) Warfarin (maintaining an INR between 2.0 and 3.0); (2) Dabigatran 110 mg twice daily; or (3) Rivaroxaban 15 mg twice daily (or 10 mg twice daily for patients aged over 75 years or with a creatinine clearance rate [CRCI] of 30–49 mL/min).

At 45 days post-implantation, routine TEE was performed to assess for significant residual flow (>5 mm) or DRT. For patients without DRT or significant residual flow, warfarin or DOAC therapy was discontinued, and dual antiplatelet therapy (DAPT) with aspirin (100 mg daily) and clopidogrel (75 mg daily) was initiated for 4.5 months, followed by long-term aspirin therapy. If DRT was detected, the anticoagulation regimen was extended in combination with either aspirin or clopidogrel monotherapy until DRT resolution. Once DRT resolved, the standard post-LAAC antithrombotic protocol was resumed.

In-hospital assessment and TEE follow-up

Detailed demographic and baseline clinical features were recorded from hospital information systems, including CHA2DS2-VASc and HAS-BLED scores for thromboembolism and bleeding risk stratification. Laboratory parameters, including liver and renal function, as well as coagulation profiles, were collected.

For patients without DRT or significant residual flow at 45-day TEE follow up, routine TEE follow-ups were scheduled at 3 months and 6 months post-procedure. In contrast, for patients with DRT or significant residual flow, additional TEE evaluations were performed monthly at the discretion of the physician until DRT resolution was confirmed.

All TEE images were independently reviewed by two experienced echocardiographers to assess for device displacement, residual leakage, or DRT formation. DRT was defined as a highly echogenic mass attached to the atrial side of the device, meeting the following criteria: (1) Cannot be explained by artifacts; (2) Does not correspond to normal healing patterns or typical device-related imaging findings; (3) Visible across multiple TEE views; and (4) Directly connected to the device surface.

Clinical outcomes

Given the differing risk profiles of each antithrombotic regimen, the clinical endpoints were categorized into efficacy endpoints and safety endpoints. The efficacy endpoints were included (1) the incidence of DRT as measured by TEE; (2) TE including ischemic stroke or transient ischemic attack (TIA), diagnosed by neurological examination and confirmed by computed tomography or magnetic resonance imaging, along with systemic embolism (SE); and (3) hospital readmissions related to cardiac causes, encompassing heart failure, acute coronary syndrome, arrhythmias, and LAAC-related complications such as endocarditis, DRT, the need for reintervention, and procedure-related pericardial effusion. Only hospitalizations requiring admission to a hospital ward or intensive care unit were included, while emergency room visits lasting less than 24 h were excluded from this endpoint.

Safety endpoints focused on major and non-major bleeding complications, defined according to the International Society on Thrombosis and Haemostasis guidelines [20].

The follow-up period lasted for 12 months.

Statistical analyses

This study was a single-center, prospective cohort study, primarily aimed at comparing the efficacy and safety of three antithrombotic strategies in reducing composite cardiovascular events and systemic thrombosis. Consecutive participants were enrolled based on their lower hospitalization rates for thrombosis and major adverse cardiovascular events (MACEs). Long-term DOAC therapy was associated with a significant reduction in the composite endpoint of DRT, TE, and major bleeding events compared to standard antiplatelet-based antithrombotic therapy [21]. The sample size was estimated based on the composite of efficacy endpoints including DRT, TE and readmission events. Assuming an overall event rate of 10% in the warfarin group and an expected reduction to 1% in the treatment group [22], with a class I error rate (α) of 0.05 (two-sided) and a statistical power of 80% (β = 0.2) [23], the minimum required sample size was calculated to be 107 in each group. Baseline characteristics were compared between groups using t-tests and χ² tests/Fisher’s exact tests, as appropriate.

To evaluate differences in clinical outcomes, Kaplan-Meier survival curves were constructed to display time-to-first DRT, TE, cardiovascular-related hospital readmissions or bleeding events, and comparisons among groups were performed using the log-rank tests for trend. Additionally, Cox regression analysis was applied to estimate hazard ratios and assess the impact of different antithrombotic strategies on clinical outcomes.

Continuous variables were presented as mean ± standard deviation (SD) and compared using independent-sample t-tests between patient groups. Categorical variables were expressed as frequencies or percentages (n%) and compared using χ² tests. Statistical significance was determined using a two-sided P value, with a threshold of P < 0.05. Statistical analysis was conducted using SPSS software (version 22.0; IBM, Armonk, New York).

Results

Baseline characteristics

The study initially included 697 patients who underwent successful closure implantation between May 2018 and December 2021. A total of 23 patients (warfarin: n = 5; dabigatran: n = 7; rivaroxaban: n = 11) were excluded from the study due to follow-up TEEs being completed at different institutions and failure to provide images for review. Ultimately, 674 patients were included in the analysis and categorized into three groups based on their antithrombotic strategies. Of these, 126 patients received warfarin, 362 were treated with rivaroxaban, and 186 received dabigatran. The progression of the study is summarized in Fig. 1.

Fig. 1
figure 1

Enrollment flowchart of this study. Patients received one of the following anticoagulants at the discretion of the physician: (1) Rivaroxaban 15 mg once a day; (2) Dabigatran 110 mg twice daily; (3) Warfarin maintaining an international normalized ratio between 2.0 and 3.0. LAAC left atrial appendage closure, TEE trans-esophageal echocardiography, DRT device-related thrombosis

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Baseline characteristics, including cardiovascular risk factors, potential thromboembolic and bleeding risks, and concomitant medications, are presented in Table 1. No significant differences were observed in age, gender, or predetermined stroke and bleeding risk factors among the three groups. The proportion of patients with a high thromboembolic risk (CHA2DS2-VASc score >5) was 16.0% for rivaroxaban, 21.0% for dabigatran, and 21.4% for warfarin, with no statistical difference. Similarly, the bleeding risk (HAS-BLED score ≥3) was 79.0% for rivaroxaban, 79.6% for dabigatran, and 82.5% for warfarin, with no significant differences observed. Baseline characteristics were well-matched across all other variables. The 27 mm Watchman 2.5 device was the most commonly used size across all groups. The average device size was 27.11 ± 3.89 mm in the rivaroxaban group, 27.06 ± 3.93 mm in the dabigatran group, and 27.31 ± 4.21 mm in the warfarin group (P = 0.855), indicating no statistically significant difference in device size among the three groups.

Table 1 Baseline demographic and clinical characteristics among rivaroxaban, dabigatran and warfarin groups
Full size table

Clinical efficacy evaluation

The early-phase formation of DRT was assessed by the incidence of DRT and thrombus size. DRT was detected in 11 of 362 (3.0%) patients in the rivaroxaban group, 11 of 186 (5.9%) in the dabigatran group, and 8 of 126 (6.3%) in the warfarin group, as observed in TEE imaging (Table 2).

Table 2 Primary composite and safety (bleeding complications) endpoints
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The Kaplan-Meier survival curve indicated that patients in the dabigatran and warfarin subgroups were more likely to experience shorter time to DRT compared to those in the rivaroxaban group, although no statistic significant differences were found (rivaroxaban vs. dabigatran: HR = 0.504, 95% CI 0.208–1.223, log-rank P = 0.101; rivaroxaban vs. warfarin: HR = 0.468, 95% CI 0.167–1.316, log-rank P = 0.093). No significant difference was observed between the dabigatran and warfarin groups (HR = 0.927, 95% CI 0.371–2.319, log-rank P = 0.870) (Fig. 2A).

Fig. 2
figure 2

Kaplan-Meier Survival Curves for DRT, TE Events, Bleeding and Re-hospitalization according to different anticoagulants. Kaplan-Meier survival curve of A device-related thrombus (DRT); B thromboembolic events (TE); C hospital readmissions due to cardiac causes; D bleeding events. HR hazard ratio, CI confidence interval

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The median [interquartile range] length and width of DRT in the rivaroxaban group were 1.92 [1.68–2.15] mm and 1.49 [1.28–1.76] mm, respectively, both significantly smaller than those in the dabigatran (length = 2.15 [1.99–2.25] mm, P = 0.036; width = 1.60 [1.54–1.85] mm, P = 0.035) and warfarin groups (length = 2.26 [2.11–2.44] mm, P = 0.006; width = 1.74 [1.54–1.85] mm, P = 0.006) (Fig. 3).

Fig. 3
figure 3

Length and width of device-related thrombus (DRT) evaluated with transesophageal echocardiography. The solid black lines in the scatter show the medians of each subgroup, while the error bars represent the interquartile range

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In all groups, DRT resolved within 3–6 months after detection. For patients with DRT detected during the routine 45-day TEE follow-up, anticoagulation therapy was extended, with the addition of aspirin. In cases where DRT was identified during antiplatelet therapy maintenance, anticoagulation therapy was restarted. Among patients with early DRT, 2 experienced stroke events, and a causal relationship between DRT and TE was confirmed in 5 cases (3 ischemic strokes and 2 systemic embolisms).

Across the entire cohort, freedom from TE events was significantly higher in the rivaroxaban group (rivaroxaban vs. dabigatran: 95.9% vs. 91.4%, HR = 0.466, 95% CI 0.221–0.984, log-rank P = 0.029; rivaroxaban vs. warfarin: 95.9% vs. 91.3%, HR = 0.456, 95% CI 0.188–0.966, log-rank P = 0.042) (Fig. 2B). Specifically, there were 3 ischemic strokes and 2 TIAs in the rivaroxaban group, 2 ischemic strokes and 2 TIAs in the dabigatran group, and 2 ischemic strokes and 1 TIA in the warfarin group (Table 2). When compared to the unadjusted, estimated rates of TE events in patients with similar CHA2DS2-VASc scores, a significant decrease of 57.4% in SE event rates was observed in the rivaroxaban group, while slight, non-significant reductions of 13.3% and 9.0% were noted in the dabigatran and warfarin groups, respectively (Fig. 4).

Fig. 4
figure 4

Annualized thromboembolic events (TE) event rates after LAAC vs expected (unadjusted) rates estimated based on the CHA2DS2-VASc score of the 3 study groups

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There were 24 (3.6%) cardiovascular-related hospital readmissions during the follow-up period. The incidence of cardiovascular-related hospital readmission was similar among the three groups: warfarin (4.8%), dabigatran (3.8%), and rivaroxaban (3.3%) (overall P = 0.760) (Fig. 2C).

Safety endpoints evaluation

Details of anticoagulation-related complications are shown in Table 2. Regarding bleeding complications, a higher rate of bleeding was observed in patients receiving warfarin, although no substantial differences were found among the three groups (P > 0.05). Procedural bleeding was more common in the warfarin group compared to the dabigatran and rivaroxaban groups (Table 2). Kaplan-Meier survival curve analysis indicated that patients with rivaroxaban or dabigatran therapy were less likely to experience bleeding events compared to patients with warfarin, though no significant difference was found (Fig. 2D).

Discussion

In this study, we prospectively evaluated the clinical efficacy and safety of three different antithrombotic strategies following successful LAAC. Our key findings are as follows: First, the reduced dose of rivaroxaban led to a significant reduction in DRT and thrombotic events compared to reduced dose of dabigatran and warfarin. Second, bleeding incidence was higher with warfarin. Third, long-term rivaroxaban provided more effective and safer thrombus prevention when compared to unadjusted, estimated rates of TE in patients with similar CHA2DS2-VASc scores.

Current evidence confirms the efficacy of anticoagulation regimens in preventing thrombus formation after successful LAAC implantation, primarily by promoting complete endothelialization of the occluders [24]. While pharmacological studies have shown the superiority of anticoagulation over antiplatelet therapy, the optimal anticoagulation management remains uncertain due to the lack of direct comparisons between different regimens [25]. This prospective study aimed to identify the optimal anticoagulation regimen following LAAC. There is currently no universally accepted standard for postoperative antithrombotic therapy after LAAC, with significant variability across clinical practices. A survey of 36 European centers revealed that 38% of patients received warfarin, 13% low-molecular-weight heparin, and 4% NOACs (Non-Vitamin K Oral Anticoagulants) [26]. Major clinical trials have also shown differing strategies: the PROTECT AF trial used warfarin plus aspirin (81–100 mg/day) for 45 days, followed by aspirin (81–325 mg/day) and clopidogrel (75 mg/day) for 6 months, and then aspirin monotherapy [27, 28]. The PREVAIL trial followed a similar regimen, transitioning to aspirin monotherapy after TEE confirmed no thrombosis and minimal residual flow [29]. In the ASAP trial, patients received clopidogrel/ticlopidine plus aspirin for 6 months, followed by aspirin monotherapy [30]. Real-world data from the EWOLUTION study further illustrated this variability, with 60.2% receiving DAPT, 15.5% warfarin, 10.8% NOACs, 6.9% single antiplatelet therapy, and 6.4% no anticoagulation [31].

The 2023 SCAI/HRS consensus statement emphasizes an individualized antithrombotic approach based on patient characteristics. For patients without contraindications to anticoagulation, the guideline recommends NOACs or warfarin ± aspirin (100 mg/day) during the initial 45 days. For those with contraindications to anticoagulation, DAPT is suggested as the primary strategy for 3–6 months, followed by long-term aspirin monotherapy [32].

In our study, reduced doses of dabigatran and rivaroxaban were used. While the standard dose of dabigatran for patients with NVAF is typically 150 mg twice daily, previous clinical studies on post-LAAC antithrombotic therapy have consistently employed a 110 mg twice daily regimen [33, 34]. In Asian populations, lower body mass index and increased sensitivity to bleeding often lead to a preference for reduced doses of DOAC for safety considerations. The J-ROCKET AF trial demonstrated that in Asian NVAF patients, low-dose rivaroxaban (10 or 15 mg) provided comparable efficacy to standard doses while significantly reducing the risk of major bleeding compared to warfarin [35]. Currently, evidence supporting reduced-dose anticoagulation strategies following LAAC remains limited. Therefore, our study sought to compare the efficacy and safety of reduced-dose dabigatran and rivaroxaban with warfarin in this specific clinical setting.

Regarding efficacy, the rivaroxaban group demonstrated significantly lower DRT and TE rates compared to the dabigatran and warfarin groups, consistent with previous studies [36,37,38]. Although limited evidence directly correlates antithrombotic strategies with thrombus formation on closures, one multicenter study indicated that DOACs are a feasible and safe alternative to warfarin for preventing DRT and thromboembolic events after LAAC without increasing the risk of bleeding [21]. Another study showed that anti-Xa inhibitors like rivaroxaban are superior to dabigatran in preventing periprocedural DRT, likely due to their ability to attenuate platelet activity and aggregation by inhibiting coagulation factor Xa, which increases platelet activity via Protease Activated Receptor-1 (PAR-1) [39]. The EHRA/EAPCI expert consensus on LAAC recommends that patients with DRT following LAAC may benefit from subcutaneous heparin or OAC therapy with warfarin or a DOAC for several weeks to months, potentially leading to thrombus resolution. In our study, patients were advised to undergo warfarin therapy with INR monitoring or subcutaneous heparin, coupled with regular TEE follow-ups. For those on warfarin, the dosage should be adjusted accordingly, and in some cases, subcutaneous heparin or a DOAC may also be considered.

From a pathophysiological perspective, platelet activation and aggregation during thrombus formation are directly mediated by FXa signaling pathways, which can be attenuated with rivaroxaban [40]. In contrast, dabigatran therapy has been associated with elevated platelet reactivity, mainly due to enhanced thrombin receptor density on platelets. These observations have been supported by prospective clinical studies, which provide further insight into coagulation changes after successful LAAC with different antithrombotic regimens [15, 41]. A previous study illustrated that rivaroxaban might better prevent periprocedural DRT and thrombus events in 105 patients compared to dabigatran. The prothrombotic status was measured using platelet aggregation biomarkers such as thrombin-antithrombin complex (TAT), P-selectin, von Willebrand factor (vWF), and CD40L, which were significantly reduced in rivaroxaban patients [39].

Another important consideration is the safety of long-term anticoagulation with different antithrombotic regimens in LAAC patients. Notably, DOAC strategies have been associated with lower bleeding rates in NVAF patients compared to vitamin K antagonists (VKAs) in East Asian populations. A large cohort study in East Asia indicated that post-extraction bleeding was lower with DOACs compared to warfarin (HR: 0.84; 95% CI: 0.54–1.31) [42]. In our study, significant reductions in coagulation biomarkers were observed in the warfarin group, indicating potential procedural hemostasis. Given the bleeding prophylaxis provided following LAAC, the adoption of DOACs exhibited a better safety profile than warfarin.

The relationship between DRT and TE, though plausible, has been inconsistent. In PROTECT AF and PREVAIL, DRT was associated with a significant increase in ischemic stroke or systemic embolization (adjusted HR: 3.9; 95% CI: 2.3–6.8; P < 0.001) [5]. However, the EWOLUTION registry and the Amulet IDE study found no significant differences in stroke rates between patients with and without DRT [43, 44]. While a temporal relationship between DRT and stroke has been observed, many patients with DRT do not experience ischemic events, suggesting that factors such as DRT characteristics (size, location, mobility) and treatment regimens may influence outcomes [5, 44].

LAAC may lead to hemodynamic regulation, potentially resulting in heart failure and subsequent hospitalization [45, 46]. Although anticoagulants may not have a profound impact on this pathological process, our study confirmed that patients who received early DOAC had a lower rate of rehospitalization due to cardiovascular events (though this result did not reach statistical significance). This finding could be associated with potentially lower compliance in patients on warfarin [47]. Despite providing patients with medication education upon discharge, and emphasizing the importance of post-procedure anticoagulation by clinical pharmacists and physicians, we were unable to assess warfarin’s time in therapeutic range (TTR).

This study primarily focused on evaluating post-LAAC anticoagulation strategies and did not specifically analyze the influence of device size, implantation characteristics, or detailed DRT morphology. Previous studies have suggested that the next-generation Watchman FLX device may be associated with a lower risk of embolization compared to earlier iterations [48]. However, the increased risk of DRT associated with larger device sizes has been primarily observed in studies using the Watchman FLX occlude [49]. The latest device version, Watchman FLX Pro, with its polymer-coated fabric, shows promise in reducing DRT risk, although larger devices (e.g., 40 mm) may still pose a higher risk [50]. For the first-generation Watchman 2.5 device used in our study, prior research indicated that device oversizing was associated with a reduced risk of significant leakage or device embolization without increasing the likelihood of other adverse events [18]. In our study, TEE was the primary imaging modality for DRT detection. Although cardiac computed tomography offers enhanced capabilities for evaluating device surface membrane thickness and can quantify hypoattenuated thickening (HAT) to assess the extent of endothelialization, such evaluations were not included in our protocol. High-grade HAT (grades 2 and 3) indicate DRT [51]. However, it is important to note that HAT assessment is primarily validated for the Watchman FLX and Amulet devices [52, 53].

Study limitations

Some limitations of this study are acknowledged. First, the non-randomized nature of this observational study poses challenges in drawing definitive conclusions. External validation data are needed to confirm our findings. Second, the relatively low frequency of TEE monitoring may have led to underreporting of DRT cases. Larger sample sizes are required to establish the clinical efficacy and safety of different antithrombotic strategies. Third, due to the low incidence of DRT and the short duration of follow-up, we did not observe a causal association between DRT and thromboembolic events. Additionally, due to limitations in the study design, certain potential risk factors were not fully recorded, such as the proportion of patients with non-paroxysmal atrial fibrillation and the time in TTR for patients on warfarin. Finally, this study only enrolled participants receiving DOACs with rivaroxaban and dabigatran, so our findings may not be generalizable to other DOACs.

Conclusions

Long-term antithrombotic therapy with reduced dose of rivaroxaban significantly reduces the risk of DRT and TE without increasing bleeding events compared to warfarin and dabigatran in patients following LAAC. Future multicenter randomized controlled trials are needed to further evaluate the safety and efficacy of different antithrombotic strategies.

Data availability

The data are available from the corresponding authors upon reasonable request.

Code availability

Not applicable.

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Authors and Affiliations

  1. Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Yao Yao & Qianzhou Lv

  2. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Qinchun Jin & Xiaochun Zhang

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Contributions

Study concept and design: QL and XZ; acquisition of data: YY and QJ; analysis and interpretation of data: YY and QJ; drafting of the manuscript: YY; critical revision of the manuscript: QL. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Xiaochun Zhang or Qianzhou Lv.

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This research was performed in accordance with the Declaration of Helsinki. The study received ethics approval from the Institutional Review Board (IRB) of Zhongshan Hospital, Fudan University, with the approval number B2020-288R. Signed informed consent was obtained from all patients.

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Yao, Y., Jin, Q., Zhang, X. et al. Clinical effectiveness and safety comparison between direct oral anticoagulants and warfarin for nonvalvular atrial fibrillation patients following percutaneous left atrial appendage closure operation intervention: a prospective observational study. BMC Pharmacol Toxicol 26, 1 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40360-024-00834-7

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BMC Pharmacology and Toxicology

ISSN: 2050-6511

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