Three-year clinical outcomes of transcatheter left atrial appendage occlusion

To the Editor: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia,[1] particularly among elderly individuals, bringing huge socio-medical burdens due to its link to ischemic stroke.[2] Although systemic oral anticoagulant (OAC) medication is highly efficacious, many patients struggle with adverse effects, issues with adherence, and concerns about quality of life.[3] Percutaneous left atrial appendage occlusion (LAAO) is an alternative to anticoagulation for patients with AF and contraindications for long-term anticoagulant treatment, which has been endorsed in guidelines from the American College of Cardiology (ACC) and the European Society of Cardiology (ESC).[2] Notably, the pivotal randomized controlled trials (RCTs) and registries that have investigated LAAO and provided the evidence base for these guidelines were predominantly carried out in the United States or Europe, with 92–94% of the participants being Caucasian while other ethnic groups significantly underrepresented. Compared with other ethnic groups, East Asian individuals with AF exhibit distinct risk-benefit profiles in the management of stroke prevention, with reduced anti-ischemic benefits alongside elevated bleeding risk with anti-thrombotic therapies, especially intracranial bleeding, known as the “East Asian paradox”. Consequently, East Asian patients may experience greater benefits from non-pharmacological strategies for stroke prevention, such as LAAO. The Registry to Evaluate Chinese Real-World Clinical Outcomes in Patients With AF Using the WATCHMAN Left Atrial Appendage Closure Technology (RECORD) study (NCT03917563) was a multicenter, prospective study that enrolled 3096 patients from 39 centers in China between April 1, 2019 and October 31, 2020,[4] and was designed to assess the safety and effectiveness of the WATCHMAN (Boston Scientific, Natick, Massachusetts, USA) LAAO device. The study was approved by the First Affiliated Hospital of Fourth Military Medical University (No. KY20182078-C-1). All participants provided informed consent prior to the procedure. Previous reports from the RECORD study showed rates of all-cause death, stroke, and systemic embolism within 30 days and 1 year of 0.52%[4] and 4.51%,[5] respectively. The present study aimed to provide the three-year clinical outcomes of the RECORD study. The primary endpoint was a composite endpoint of death, stroke, and systemic embolism at three years. Other endpoints included the individual components of the primary endpoint, Bleeding Academic Research Consortium (BARC)-defined types 2, 3, or 5 bleeding, device-related thrombosis, peri-device leak, and re-admission. Death, stroke, systemic embolism, and bleeding events were adjudicated by an independent clinical event committee (CEC) comprising five physicians with expertise in Electrophysiology and/or Interventional Cardiology. The adjudication of events was based on the definitions included in the Munich consensus document for percutaneous LAAO. Bleeding was evaluated using the BARC criteria. Data were collected during the hospitalization for implantation, at the time of discharge, and during scheduled follow-up visits occurring at 45 days (±14 days), 180 days (±30 days), 360 days (±30 days), and annually thereafter (±30 days). Continuous variables are presented as mean ± standard deviation (SD) or median (Q1–Q3), and categorical variables as counts and percentages. We did not fill in missing values. The Fisher’s exact test and t-test analysis, or Mann–Whitney U test, were used to compare categorical and continuous variables when appropriate. The cumulative rates of events were calculated using the Kaplan–Meier (KM) method. The cumulative incidence function (Aalen–Johansen estimator) was used to account for the competing risk of death for stroke and systemic embolism. Univariable and multivariable Cox regression analysis was conducted to assess the predictors of death, stroke, and systemic embolism at three years. The covariates with clinical relevance or a univariate relationship with outcome (P <0.05) were included into multivariable Cox models. Analyses were performed using R-project version 4.2.3 (R Foundation, Vienna, Austria). A two-sided P-value less than 0.05 was considered statistically significant. A total of 3082 patients successfully received an LAAO implant. Among them, 2989 (97.0%) patients have completed three-year follow-up [Supplementary Figure 1, https://links.lww.com/CM9/C696]. The mean age of the 3082 participants was 69.1 ± 9.4 years, and 1771 (57.5%) were men [Supplementary Table 1, https://links.lww.com/CM9/C696]. Participants had a high risk of stroke (congestive heart failure, hypertension, age ≥75 years [2 points], diabetes mellitus, prior stroke or transient ischaemic attack or thromboembolism [2 points], vascular disease, age of 65–74 years, sex category [CHA2DS2-VASc] score of 4.0 ± 1.8 [mean ± standard deviation]) and a moderate-to-high risk of bleeding (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio [INR], elderly [≥65 years], drugs/alcohol concomitantly [HAS-BLED] score of 2.4 ± 1.2 [mean ± standard deviation]). Procedures were performed under general anesthesia in 58.4% of cases (n = 1799); intra-procedure image guidance was performed using transesophageal echocardiography (TEE) or intracardiac echocardiography (ICE) in 84.0% of cases (n = 2590); percutaneous LAAO was combined with ablation in 42.0% (n = 1295) of cases. The distribution of the missing data is described in Supplementary Table 2, https://links.lww.com/CM9/C696. At three years, the composite endpoint of death, stroke, and systemic embolism occurred in 321 (10.5%) patients, consisting of 220 (7.2%) deaths, 122 (4.1%) strokes, and 8 (0.3%) systemic embolisms [Supplementary Table 3, Supplementary Figure 2, https://links.lww.com/CM9/C696]. BARC-defined types 2, 3, or 5 bleeding occurred in 159 (5.2%) patients, consisting of 66 (2.2%) BARC-defined types 3 or 5 bleeding and 94 (3.1%) BARC-defined type 2 bleeding [Supplementary Table 3, Supplementary Figure 3, https://links.lww.com/CM9/C696]. Fatal stroke occurred in 17 (0.6%) patients, disabling stroke occurred in 25 (0.9%) patients, and minor stroke occurred in 80 (2.7%) patients [Supplementary Table 3, Supplementary Figure 4, https://links.lww.com/CM9/C696]. Stroke recurrence was found in 12 (0.3%) patients, and 2171 (70.4%) participants had computed tomography angiography (CTA) or TEE examinations. Device-related thrombus, ≥5 mm peri-device leak, and re-admission occurred in 65 (3.0%), 10 (0.5%), and 1380 (45.7%) patients, respectively. The cumulative incidence data for the competing risk of death for stroke and systemic embolism are provided in Supplementary Table 4, https://links.lww.com/CM9/C696. At three-year follow-up, 253 (8.6%) patients underwent either cardiac or non-cardiac procedures or surgeries [Supplementary Table 5, https://links.lww.com/CM9/C696]. At discharge, 66.8% (n = 2058) of patients were using novel oral anticoagulants (NOACs), 13.1% (n = 403) NOAC+antiplatelet (NOAC+APT), 12.1% (n = 373) vitamin K antagonists (VKA), 5.0% (n = 154) dual antiplatelet therapy (DAPT), 1.6% (n = 50) single antiplatelet (SAPT), 1.3% (n = 40) VKA+APT, and 0.1% (n = 4) were not taking any antithrombotic medication [Supplementary Figure 5 and Supplementary Table 6, https://links.lww.com/CM9/C696]. Anticoagulation was continued in 210/3082 (6.8%), 360/3082 (11.7%), and 345/3082 (11.2%) of patients at 1, 2, and 3 years post-LAAO, respectively [Supplementary Table 6, https://links.lww.com/CM9/C696]. Predictors of the composite endpoint of death, stroke, and systemic embolism are detailed in Supplementary Table 7, https://links.lww.com/CM9/C696. In the multivariable model, age (per 5-year increase; hazard ratio [HR] 1.35; 95% confidence interval [95% CI] 1.27–1.45; P <0.001), diabetes (HR: 1.34; 95% CI: 1.05–1.71; P = 0.017), hypertension (HR: 1.38; 95% CI: 1.05–1.81; P = 0.022), chronic heart failure (HR: 1.90; 95% CI: 1.46–2.46; P <0.001), abnormal renal function (HR: 1.90; 95% CI: 1.19–3.03; P = 0.007), abnormal liver function (HR: 2.79; 95% CI: 1.59–4.90; P <0.001), INR (HR: 1.62; 95% CI: 1.07–2.46; P = 0.023), and combined one-stage ablation (HR: 0.66; 95% CI: 0.51–0.84; P = 0.001) were independent predictors of three-year death, stroke, and systemic embolism. Independent predictors of death are detailed in Supplementary Table 8, https://links.lww.com/CM9/C696. The main findings of our study can be summarized as follows: (1) The three-year incidence of death, stroke, and systemic embolism in patients with AF who underwent LAAO was 10.5%, whereas the incidence of BARC-defined types 3 or 5 bleeding was 2.2%. (2) Anticoagulation was administered in 6.8%, 11.7%, and 11.2% of patients at 1, 2, and 3 years post-LAAO, respectively. (3) Patients with concomitant advanced age, diabetes, hypertension, chronic heart failure, abnormal liver function, abnormal renal function, and labile INR were independently associated with a higher three-year risk of the composite primary endpoint of death, stroke, and systemic embolism, whilst combining ablation with LAAO lowered the risk. Historically, most LAAO studies predominantly enrolled Caucasians based in the United States and Europe, leaving other ethnic groups, such as East Asians, underrepresented. The RECORD trial was a large-scale real-world registry that provided evidence of the safety and efficacy profiles of the LAAO device among the East Asian population. In real-world practice, antithrombotic regimens and durations vary widely. The lack of randomized data led to the 2024 ESC guidelines replacing specific recommendations regarding anti-thrombotic therapy post-LAAO, with the suggestion for an individualized decision. In the present study, the prescription of OAC varied year-on-year with rates of 6.8%, 11.7%, and 11.2% at 1, 2, and 3 years post-LAAO, respectively. Dedicated RCTs are needed to provide an evidence-based antithrombotic strategy post-LAAO. A previous study showed that among all baseline and procedural variables, use of image guidance with echocardiography was the strongest independent predictor of the absence of LAAO procedure-related complications within 7 days of the implant.[6] In the RELEXAO study (NCT03279406), thrombus on the device and vascular disease were the two independent predictors of ischemic stroke and transient ischemic attack during a 13-month follow-up.[7] However, these studies primarily focused on the independent predictors of peri-procedural or one-year outcomes. In the current study, we demonstrated that seven demographic variables and one procedural variable (combined procedure of LAAO and ablation) were independent predictors for death, stroke, and systemic embolism risk within three years after the procedure. These results suggest, as expected, that baseline clinical risk factors, as opposed to procedural factors, are more likely to influence long-term outcomes. This study has several limitations. First, the RECORD registry exclusively included Chinese patients. Second, the device used in this study was the WATCHMAN 2.5, rather than the most recent version WATCHMAN FLX, which was not commercially available during the study period. Third, whether patients were eligible to receive the WATCHMAN device or not was due to their physician’s discretion, following appropriate local and international guidelines; we did not focus on the reasons for LAAO. Fourth, the antithrombotic medications administered post-LAAO were recorded at the time point of follow-ups and were prescribed according to the physician’s discretion; it is not possible to establish a causal relationship between the use of antithrombotic medications and the occurrence of ischemic or bleeding events. Fifth, the course of follow-up coincided with the coronavirus disease 2019 (COVID-19) pandemic, which may have caused patients to be hesitant or unable to undergo routine CTA/echo imaging follow-up. Consequently, only ~70% of participants had imaging follow-up, and thus, the event rates of device-related thrombus or peri-device leak might be over- or under-estimated. In conclusion, this study characterizes the long-term real-world clinical outcomes of patients undergoing transcatheter LAAO in China. We found that patients with an LAAO device had a low rate of the composite endpoint of death, stroke, and systemic embolism. However, given the observational nature of the current study, the results should be considered as hypothesis-generating only. Conflicts of interest Dr. Serruys reports personal consultancy fees from Sino Medical Sciences Technology, Philips/Volcano, Xeltis, outside the submitted work. Dr. Garg reports personal consultancy fees from Biosensors. Dr. Gao reports personal consultancy fees from CoretechMed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The RECORD was supported by the Boston Scientific Corporation (Marlborough, MA, USA). Boston Scientific had no role in the study design, data collection, data anal­yses, and interpretation of the study data, nor were they involved in the decision to publish the final manuscript.