These findings contribute valuable insights to the ongoing discourse on the optimal management strategy for non-valvular AF patients, shedding light on both the safety and efficacy aspects of the combined LAAC + PVI approach.
Feasibility and safety of combined procedure
The LAAC procedure has emerged as a viable alternative to Oral Anticoagulants (OACs) for preventing ischemic stroke in Atrial Fibrillation (AF) patients, offering the advantage of reduced bleeding risk compared to long-term OAC use. Simultaneously, rhythm control, encompassing both pharmacological and ablative approaches, plays a crucial role in improving patient symptoms. Results from the randomized CABANA trial have underscored the superiority of catheter ablation (CA) over antiarrhythmic drugs in AF patients [
9,
14]. Therefore, the prospect of combining LAAC and CA in a single procedure, sharing a common access point, appears to be an appealing strategy for symptomatic AF patients, addressing both stroke prevention and rhythm control.
Previous studies have demonstrated the feasibility and safety of undergoing a combined procedure of LAAC and Pulmonary Vein Isolation (PVI) in a single session for AF patients. The initial study, reporting on the feasibility and safety of the combined procedure, revealed a complete occlusion rate of 77.0%, which increased to 93.0% at the Transoesophageal Echocardiography (TOE) examination conducted 6 months later [
11]. A recent multi-centre study from China reported an average occlusion rate of 94.3% in patients undergoing the combined procedure [
15]. Notably, even when using two different types of devices (WATCHMAN and ACP), the complete occlusion rates remained comparable (92.8% in the WATCHMAN group and 97.4% in the ACP group).
Data from the CLACBAC study, conducted at our centre, demonstrated an overall success rate of 97.3% for the combined procedure, with 76 patients receiving three different types of LAAC devices (WATCHMAN, Lafort, and Lacbes, respectively) [
10]. This evidence collectively establishes the feasibility of the combined procedure of LAAC and PVI, attesting to its safety and success rates.
While combined procedures inherently increase the complication rate compared to individual procedures (catheter ablation or LAAC), the amalgamation of two procedures in a single session appears more patient-friendly than performing them separately. A Propensity Score Matching (PSM) study by Mo et al. comparing single and combined procedures reported a complication rate of 3.9% in the combined procedure group, slightly higher than the rates of 2.6% in both the catheter ablation (CA) alone and LAAC alone groups [
16]. Notably, Wintgens et al. demonstrated a comparable complication rate of 4% in their study discussing a staged procedure of CA after LAAC [
17]. In our study, we reported a slightly higher complication rate of 5.9% in both the combined procedure and LAAC alone groups, with no significant difference between the two. This discrepancy may be attributed to the relatively small cohort size. Moreover, compared to performing procedures separately, combining two procedures may help avoid complications in common procedural aspects such as groin hematoma and bleeding caused by femoral vein puncture.
Major complications primarily stem from femoral vascular access-site issues, transeptal puncture-related access-site problems like pericardial effusion (PE), device-related thrombosis (DRT), and peripheral device leakage (PDL)/residual leakage. Among these, femoral access-site problems and PE are linked to operators’ experience. Previous studies comparing combined procedures with LAAC alone have shown a low incidence of femoral access site problems and PE, with no significant difference between the two groups [
16]. In our study, the incidence of femoral access site problems and PE in the combined group and LAAC alone group were comparable and lower than those reported in previous studies [
16,
18]. This suggests that operators’ experience, rather than the procedure itself, influences the incidence of complications.
For patients with previously identified patent foramen oval (PFO) or atrial septal defect (ASD), performing left atrial appendage closure (LAAC) via PFO/ASD can be considered as an alternative to reach the left atrium and concurrently avoid access site problems associated with transeptal puncture. A single-centre cohort study demonstrated that, when compared to LAAC with transeptal puncture access, LAAC via trans-PFO/ASD access achieved comparable results in terms of procedure success rate, procedural-related complications rate, and the incidence rate of cardiovascular adverse events during follow-up [
19]. It is noteworthy, however, that the co-axiality of the catheter sheath and the left atrial appendage may be affected by the relatively cranial position of the PFO, potentially resulting in unsuccessful occlusion of the left atrial appendage.
Furthermore, peripheral device leakage (PDL), or residual leak, remains a concern, particularly in combined procedures. Studies have suggested that residual leak after left atrial appendage closure (LAAC) may be associated with thromboembolism, increasing the risk of stroke [
20]. While minimal residual leakage (< 1 mm) is generally considered less worrisome [
21], the reliability of findings regarding the size of peripheral device leakage (PDL) and its impact on clinical outcomes remains debatable.
The National Cardiovascular Data Registry Left Atrial Appendage Occlusion (NCDR LAAO) registry indicated that patients with small PDL (< 5 mm) may be associated with a higher incidence of adverse clinical events after LAAC compared to those with large PDL (> 5 mm) or no PDL [
22]. However, the asymmetry of cohort sizes and variations in antithrombotic treatments between groups raise questions about the reliability of these results. In our opinion, the enlargement of residual flow size is a more pertinent concern than the size itself.
Although the incidence of residual leak tends to increase in atrial fibrillation (AF) patients undergoing LAAC alone, the impact of catheter ablation (CA) on residual leak in the LAAC procedure remains uncertain. Most studies on combined LAAC with CA follow an ablation-first strategy. However, CA-induced left atrial appendage (LAA) oedema can lead to an underestimation of the LAA orifice, resulting in the implantation of a smaller device and incomplete occlusion with a residual flow exceeding 5 mm. Recent research suggests that combined procedures are associated with a higher incidence of residual leak, primarily attributed to CA. Hence, a device size recommendation of 20% or more larger than the LAA diameter, as opposed to the 10–20% often recommended, has been proposed for patients undergoing combined procedures [
23]. Additionally, findings from the Western Atrial Fibrillation Ablation Strategy and Practice (WASP) registry underscore the need for larger occlusion devices in the Asian population due to their larger average LAA diameter [
24]. In our study, the incidence of residual leak after the procedure did not significantly differ between the two groups, aligning with previously reported low rates. While our results do not fully support conclusions drawn by certain studies, we nonetheless recommend employing LAAC devices with larger sizes to minimize the risk of residual leak in patients undergoing combined procedures.
Antithrombotic therapy is commonly recommended to mitigate the risk of device-related thrombosis (DRT) and stroke in patients undergoing left atrial appendage closure (LAAC). However, balancing the need for anticoagulation with the risk of bleeding events remains a critical concern. Historically, the PROTECT AF study proposed an antithrombotic strategy involving 45 days of warfarin post-procedure, followed by 6 months of dual antiplatelet therapy (aspirin and clopidogrel) and subsequent lifelong aspirin use [
25]. Nonetheless, the PREVAIL trial, employing a similar antithrombotic strategy, demonstrated a disparity in the rates of major bleeding events (0.4% in PREVAIL vs. 3.5% in PROTECT AF) [
26].
Recent research suggests that shortening the duration of post-procedure anticoagulation may help reduce the incidence of bleeding events while maintaining efficacy in preventing DRT and stroke [
27]. However, challenges such as variations in cohort populations and differences in medication adherence have limited the establishment of a universally accepted international consensus on post-LAAC antithrombotic strategies. Moreover, tailored anticoagulation strategies may be necessary for patients with unique clinical situations or those with different implanted devices. Achieving an optimal balance between preventing thromboembolic events and minimizing bleeding risks remains an ongoing area of investigation in the field of LAAC.
Can combined procedure bring more long-term clinical benefits compared with LAAC alone?
The comparative evaluation of long-term clinical benefits between combined procedures (LAAC + PVI) and LAAC alone remains an active area of research. While LAAC has shown superiority to oral anticoagulants (OACs) in reducing the risk of stroke, evidence regarding the combined procedure is still limited.
In previous single-centre retrospective studies, Mo et al. found that the combined procedure had comparable efficacy to LAAC alone in preventing stroke [
16], while Zhang et al. reported a significantly lower incidence of thrombotic events during follow-up in patients undergoing the combined procedure compared to LAAC alone [
18].
In our study, the observed incidence of thrombotic events was 7.8% in the LAAC alone group and 4.0% in the combined procedure group. This rate appears relatively high when compared to findings from other studies. However, when assessed using person-years rate calculation, the thrombotic event rate was 2.6 per person-year in the LAAC alone group and 1.31 per person-year in the combined procedure group. Although this represents a significant decrease, it remains higher than the rates reported in the PROTECT AF trial [
25] and a European study [
28]. We attribute this difference to potential variations in race and geographical region among the study populations, as well as challenges related to poor follow-up compliance with anti-thrombotic medication. Notably, the reported incidence of ischemic infarction in Asia is higher than in Europe and the United States [
29], and suboptimal adherence to follow-up protocols is a pervasive issue not only in our study but also nationally [
30]. Additionally, we cannot entirely exclude the possibility that some patients had preexisting cerebrovascular conditions, contributing to the occurrence of strokes after LAAC.
No significant differences were observed in major adverse cerebrocardiovascular events (MACCE), rehospitalization due to cardiovascular disease (CVD), and rehospitalization due to atrial tachycardia (AT) between the combined procedure group and the LAAC alone group. This aligns with findings from the study by Mo et al. [
16], where the incidence of stroke was comparable between the combined procedure and LAAC alone groups. However, it’s noteworthy that Zhang et al., in their study with a larger sample size, reported a significantly lower incidence of thrombotic events in the combined group compared to the LAAC alone group [
18]. Differences in study populations, sample sizes, and follow-up durations could contribute to variations in outcomes across studies.
The relatively smaller sample size in our study compared to Zhang et al.’s study might be one reason for not finding significant differences in clinical follow-up events between the combined procedure and LAAC alone groups. Additionally, the possibility of patients undergoing repeat ablations during the follow-up period could impact the incidence of stroke and other cardiovascular adverse events, potentially narrowing the differences between the two groups.
In summary, the interpretation of clinical outcomes in combined procedures versus LAAC alone may be influenced by factors such as sample size, patient characteristics, and the follow-up duration. Future studies with larger cohorts and rigorous study designs will contribute to a more comprehensive understanding of the comparative effectiveness of these procedures.
Regarding the AF recurrence rate, we conducted a survival analysis comparing patients who underwent the combined procedure with those who underwent PVI alone, as illustrated in Fig.
1f. The results revealed that patients who underwent PVI alone had an AF recurrence rate of 15.8% over a mean follow-up of 26.7 ± 7.9 months. This rate was lower than that observed in patients who underwent the combined procedure (28%), but the difference between the two groups was not statistically significant (Log-Rank
p = 0.075). This finding aligns with a randomized study reported by Romanov et al. [
13]. However, further research necessitates randomized, prospective studies for more conclusive insights.
In a recently published study investigating the impact of the combined procedure on left atrial function, Yang et al. demonstrated that the combined procedure can improve left atrial ejection function during long-term follow-up. Notably, the beneficial effect primarily arises from ablation rather than LAAC [
31]. Similarly, Wang et al. showed a significant improvement in left ventricular ejection fraction (LVEF) in AF patients undergoing either the combined procedure or catheter ablation (CA) alone. In contrast, patients undergoing drug therapy alone or LAAC alone experienced a decrease in LVEF after a 1-year follow-up [
32]. Our study aligns with these findings, indicating that the average LVEF of patients in the combined group without AF recurrence exhibited significant improvement during post-procedure follow-up. In contrast, there was no significant change in average LVEF in the LAAC alone group and the combined group with AF recurrence. This suggests that heart function can benefit from the control of heart rhythm in patients undergoing the combined procedure. We postulate that the improvement in heart function may be attributed to patients undergoing the combined procedure achieving sinus rhythm through CA, thereby achieving a better hemodynamic status in the left atrium (LA). We believe that the enhancement of LA function by restoring sinus rhythm, allowing blood to fully fill and eject from the left atrium, contributes to the increase in LVEF in patients undergoing the combined procedure during follow-up. Therefore, we contend that the increase in LVEF not only reflects the improvement of left ventricular (LV) function but also indirectly signifies the improvement of LA function. In contrast, the role of LAAC in improving cardiac function remains controversial. Some small-scale studies have reported the occurrence of acute heart failure (AHF) after LAAC, mostly attributed to preexisting heart failure [
33‐
35]. However, as a part of the left atrium, the left atrial appendage (LAA) is partially responsible for accommodating blood volume and pressure in the left atrium. It regulates hemodynamic through the secretion of natriuretic peptides [
36].
Bartus et al. demonstrated, for the first time, that epicardial left atrial appendage occlusion (LAAC) using the LARIAT device has a long-term effect on lipid and glucose metabolism [
37]. Additionally, they observed a reduction in systolic and diastolic blood pressure at 1 year and 2 years after epicardial LAAC, indicating a systemic effect resulting from left atrial appendage occlusion and its impact on endocrine function [
38]. Upon completion of left atrial appendage (LAA) occlusion, there is an acute reduction in the volume of the total left atrial (LA) chamber, accompanied by an increase in LA pressure, leading to the inhibition of LAA endocrine function [
39,
40]. These factors can contribute to the development of post-left atrial appendage occlusion acute heart failure (AHF).
However, with the progress of ablation technology and the emergence of new ablation strategies, such as LAA ligation, which can achieve both complete electrical isolation of the LAA and LAA occlusion, we believe that patients can benefit more from a combined procedure.