Guiding atrial fibrillation ablation combined with left atrial appendage occlusion procedure by fluoroscopy with or without transesophageal echocardiography achieved comparable outcomes

Abstract Background Atrial fibrillation (AF) is the most common arrhythmia and can be treated with catheter ablation (CA) combined with left atrial appendage occlusion (LAAO). The study is designed to compare the safety and efficacy of guiding the combined procedure by digital subtraction angiography (DSA) with or without transesophageal echocardiography (TEE). Methods From February 2019 to December 2020, 138 patients with nonvalvular AF who underwent CA combined with LAAO procedure were consecutively included, and two cohorts were built according to intraprocedural guidance (DSA or DSA with TEE). Periprocedural and follow‐up outcomes were compared with investigate the feasibility and safety between the two cohorts. Results 71 patients and 67 patients were included in the DSA cohort and TEE cohort, respectively. Age and gender were comparable, despite the TEE cohort having a higher proportion of persistent AF (37 [55.2%] vs. 26 [36.6%]) and hemorrhage history (9 [13.4%] vs. 0). The procedure time of the DSA cohort was significantly reduced (95.7 ± 27.6 vs. 108.9 ± 30.3 min, p = .018), with a nonsignificant longer fluoroscopic time (15.2 ± 5.4 vs. 14.4 ± 7.1 min, p = .074). And the overall incidence of peri‐procedural complications was similar between cohorts. After an average of 24 months of clinical follow‐up, only three patients in the TEE cohort had ≤3 mm residual flow (p = .62). Kaplan–Meier estimates showed nonsignificant differences between the cohorts for freedom from atrial arrhythmia (log‐rank p = .964) and major adverse cardiovascular events (log‐rank p = .502). Conclusions Compared with DSA and TEE guidance, DSA‐guided combined procedure could shorten the procedural time, while achieving similar periprocedural and long‐term feasibility and safety.


| INTRODUCTION
Atrial fibrillation (AF) is the most common chronic degenerative arrhythmia with a 0.65% prevalence over 10 million in China. 1 AF increases the risk of heart failure and stroke, which seriously affects the life quality of patients. [2][3][4] However, due to low compliance of adequate pharmacological anticoagulation and rhythm control in China, AF has become a serious issue in the Chinese population. 5 In terms of limitation of pharmacological stroke prevention, 2019 AHA/ACC guidelines (IIB) recommended left atrial appendage occlusion (LAAO) for AF patients having contraindication for long-term oral anticoagulant (OAC) treatment. 6 Catheter ablation (CA) with minimal lesions has been recommended to treat drug-refractory AF since pulmonary vein isolation (PVI) was reported to effectively control AF. [7][8][9] To control AF and prevent stroke, Swans et al. 10 reported the first 30 symptomatic drug-refractory AF patients who were at a high risk of stroke and had contraindications for OACs with successful CA combined with LAAO in a single procedure.
Many other following studies have proved CA combined with LAAO safe and effective. [11][12][13][14] In the LAAO procedure, it is crucial to ensure the LAAO device to be delivered and deployed in the desired position under safe and feasible evaluation of intraprocedural device surveillance, which can furthest diminish peri-device leakage (PDL) and avoid procedure-related complications. 15 Transesophageal echocardiography (TEE) has been recommended by EHRA/EAPCI expert consensus as the standard method to guide LAAO procedures under general anesthesia. 6 However, TEE application is limited by a dedicated anesthetic and echocardiographic team, increasing the risk of general anesthesia and esophageal injury. 16 By contrast, with the increasing maturity of LAAO technology, there have been many articles describing the safety and feasibility of the LAAO using digital subtraction angiography (DSA) alone. [16][17][18][19] Nevertheless, the current articles about CA combined with LAAO procedure with DSA alone have not been reported. In the present study, we compared the feasibility and safety of intraprocedural guidance of combined procedure with DSA alone to TEE and DSA. Persistent AF (persAF) is defined as AF lasting more than 7 days, including AF that has been terminated after 7 days. The inclusion criteria for the combined procedure patients include at least one of the following three items: (1) CHA2DS2-VASc Score ≥ 2 and/or HAS-BLED Score ≥ 3; (2) contraindications for long-term OACs, including major active bleeding disorders, hereditary bleeding disorders, or serious side effects of OACs; (3) refusal of OACs according to personal willingness despite comprehensive explanation. Exclusion criteria include: (1) the presence of thrombus in the left atrium (LA) or LAA confirmed by TEE examination; (2) LA diameter greater than 65 mm measured by TTE or LAA opening diameter greater than 35 mm measured by TEE; three preprocedural pericardial effusion of medium and above (>4 mm); (4) hemorrhagic or ischemic stroke within 30 days; (5) hemodynamic instability (blood pressure lower than 90/60 mmHg); (6) active hemorrhagic disease(s). Every patient fully understanded the risks of the procedure and related complications and signed an informed consent form before the procedure. Our study complies with the declaration of Helsinki and was approved by the ethics committee of Shanghai Tenth People′s Hospital.

| Preprocedural preparation
Before the procedure, we completed the examination of heart rate, blood pressure, breathing, body temperature, 12-lead ECG and 24-h Holter, blood routine, liver and kidney function, electrolytes, coagulation function, myocardial markers, hepatitis B tuberculosis, and other infectious diseases and improved in time abnormal indicators. Furthermore, chest X-ray and echocardiography were inspected to check obvious structural abnormalities and cranial CT was examinated to assess the risk of stroke. TEE (GE Vivid E9 and Siemens ACUSON SC2000) was performed with an empty belly 24 h before the procedure to check for LA and LAA thrombosis. The LAA morphology was observed at 0°/45°/90°/135°and the LAA diameter, depth, the size of the inner and outer orifice, and evaluate whether there was pericardial effusion and abnormal heart structure.
Patients taking new OACs novel oral anticoagulants (NOACs) stopped NOACs 24 h before the procedure; while for patients taking warfarin orally, the preprocedural international normalized ratio needed to be adjusted to 2.0-3.0. For patients who took antiarrhythmic drugs before the procedure, the AADs needed to be stopped before five drug metabolism half-lives.

| Combined procedure
Patients need fasting for at least 6 h before the procedure. The CA combined with LAAO procedure was performed in the cardiac interventional catheterization room under the monitoring of blood pressure, heart rate, and breathing throughout the whole process.
During the combined procedure, the LAAO device was implanted instantly after CA.

| Postprocedural management and follow-up
After the procedure, bilateral femoral vein puncture needed compression bandaging and patients kept bed immobilization for 6-8 h. What's more, NOACs (rivaroxaban or dabigatran) were given and oral antiarrhythmic drugs were given to maintain sinus rhythm or control ventricular rate according to the heart rate. Proton pump inhibitors were given routinely The primary endpoint was the recurrence of atrial arrhythmia (AA) and stroke. AA recurrence was defined as AF, atrial flutter, or atrial tachycardia lasting more than 30 s after 3 months. The first 3 months are defined as a blank period, at which time the onset of AA is not considered as a recurrence. This study did not believe that continued use of antiarrhythmic drugs was a relapse. Stroke (ischemic or hemorrhagic) can be diagnosed by cranial CT or MRI.

| Statistical analysis
Continuous variables were described as mean ± standard deviation (SD) if they conformed to a normal distribution, while those without a normal distribution were presented as median with interquartile ranges. Categorical variables were described as percentages (%). For survival analysis, the Kaplan-Meier estimate with a p value obtained with the log-rank test analyzed the freedom from AA and major adverse cardiovascular events (MACE). Two-sided p < .05 was considered significant for all analyses. The SAS 9.4 software (SAS Institute Inc.) was adopted to conduct all analyses.  tamponade did not reach statistical significance between the DSA cohort and the TEE cohort. There into, two patients were originally planned to undergo TEE evaluation during the procedure, but they could not tolerate it and switched to DSA for evaluation. Table 2 presents the periprocedural details of CA combined with LAAO.  Table 3. Supporting Information: Table 1

| DISCUSSION
In the present study, we first investigated the feasibility and safety of intraprocedural guidance of CA combined with LAAO procedure with DSA alone to TEE and DSA. By comparing their periprocedural and follow-up clinical results, we concluded that intraprocedural DSA alone is not inferior to TEE with DSA evaluation for the feasibility and safety of the combined procedure. TEE has been recommended by EHRA/EAPCI expert consensus as the standard method to guide LAAO procedures under general anesthesia. 6 Although serious complications including esophageal perforation, esophageal injury, hematoma, laryngeal palsy, dysphagia, dental injury, or death, occur in less than 3% of TEE, the application of TEE is still limited in oral, esophageal, or gastric diseases. 21 Moreover, general anesthesia not only increases the complexity and cost of the procedure but also has the potential transient of persistent cognitive dysfunction in the elderly. 22 According to the various limitation of intraprocedural TEE guidance with general anesthesia, many centers have reported the feasibility and safety of applying DSA alone under local anesthesia without sedation to guide the LAAO procedure. [16][17][18][19] They mostly  16,19,23 In the present study, compared with the TEE cohort, the procedure time of the DSA cohort was significantly reduced and there was no significant difference in the complication rate and fluoroscopy time. In the TEE cohort, two patients who could not tolerate TEE during the procedure were temporarily T A B L E 1 Baseline characteristics. Abbreviations: AF, atrial fibrillation; BMI, body mass index; CHD, coronary heart disease; eGFR, estimated glomerular filtration rate (calculated via CKD-EPI formula); LVEF, left ventricular ejection fraction; NOAC, new oral anticoagulant; OAC, oral anticoagulant; persAF, persistent atrial fibrillation; proBNP, pro brain natriuretic peptide.

MENG ET AL.
| 553 changed to the DSA cohort. This again illustrates the limitation of TEE in the patient's tolerance.
In our study, there were two patients with intraprocedural residual flow < 3 mm, and both patients were from the TEE cohort.
Although the results are not statistically different, it is difficult to detect minor PDL under the guidance of the DSA and the detection rate may be lower than the actual incidence. Whether such the size of the PDL is meaningful has not been determined. Although the results of the clinical trial of LAAO indicate that a leak size of no more than 5 mm is considered safe, some reports of strokes related to smaller leaks have been described. 24,25 Regarding the classification of PDL, the mainstream view is that PDL size is categorized as minor (<3 mm), small (≥3-5 mm), moderate (≥5-9 mm), or large (≥10 mm).
PDL caused by incomplete LAAO may promote blood flow stagnation, thrombosis, and embolism. The latest systematic review showed that LAAC patients with minor PDL could discontinue OAC and there had been no indications or data to support PDL closure, which required more research to verify. 26 Compared with TEE, the main disadvantage of DSA is that it may underestimate device-related thrombosis and minor PDL. Therefore, it is critical for them to take a standardized anticoagulation regimen after the procedure. In fact, on the basis of anticoagulation, devicerelated thrombosis was a rare event. 27 In this study, there have been no patients with device-related thrombus under the detection of TEE/CTA in the DSA cohort. For minor PDL, there has been no conclusion on its harm. 26 In addition to the guidance of the combined procedure, TEE can also be applied to evaluate acute left atrial ridge lesions after PVI. However, whether it is necessary to apply to evaluate such a situation remains to be discussed. 28 The latest metaanalysis in 2020 showed that intracardiac echocardiography (ICE) is as effective and safe as TEE in LAAO, and it also eliminates the need for general anesthesia and can be performed with local anesthesia.
However, ICE requires separate intravenous access, which may increase the risk of vascular complications, and the high cost and additional equipment make many centers more inclined to other methods of intraprocedural guidance. 29 T A B L E 2 Periprocedural safety and efficacy evaluation between groups.

| CONCLUSION
Compared with DSA and TEE guidance, DSA-guided combined procedure could shorten the procedural time while achieving similar periprocedural and long-term feasibility and safety.

CONFLICTS OF INTEREST STATEMENT
The author declare no conflict of interest.

DATA AVAILABILITY STATEMENT
All data included in this study are available upon request by contact with the corresponding author.