Methods

Study population

Based on the registered retrospective study Combining Left Atrial Appendage Closure with Cryoballoon Ablation in Chinese Population (CLACBAC, registry No. NCT04185142), from June 2017 to Aril 2019, 117 consecutive patients underwent combined procedure were included. Patients diagnosed with drug-refractory, non-valvular AF and met at least one of the following inclusion criteria:
a. CHA2DS2-VASc score≥2 or/and HAS-BLED score≥3,b. contraindications to long-term oral anticoagulants (OACs) (active major hemorrhagic diseases, inherited hemorrhagic disorders, severe side effects under OACs),c. refusal of OACs according to personal willingness despite comprehensive explanation.
While exclusion criteria were:
a. thrombus in LA or LAA presented and confirmed by TEE,b. oversized left atrium (LA, diameter>65mm) by transthoracic echocardiography (TTE) or LAA (ostium>35mm) by TEE,c. pericardial effusion (≥ 4mm by TTE or TEE),d. hemodynamic unstable patients,e. patients with active hemorrhagic diseases,f. ischemic or hemorrhagic stroke within 30 days.
The diagnosis of paroxysmal, persistent and long-persistent AF was in accordance with 2016 ESC guideline (10). The diagnosis of bleeding events referred to 2011 BARC consensus (11). For every patient, inform of consent was signed before the procedure with procedural risks and related complications fully informed. Our study complies with the declaration of Helsinki and approved by the ethics committee of Shanghai Tenth People’s Hospital.

Combined procedure

All the procedure was performed under local anesthesia with lidocaine. Procedure details were as previously described (12). Briefly, following a transseptal puncture, a 28 mm 2nd generation cryoballoon (CB, Arctic Front, Medtronic, MN, USA) was cannulated to the ostium of PV. Once complete occlusion was confirmed by angiography, cryo-energy was delivered with a time-to-isolation (TTI) guided freezing strategy (13). Phrenic pacing was applied to prevent phrenic nerve lesion. Activate clotting time (ACT) was monitored and maintained above 300 seconds during the whole procedure.
LAAC was performed instantly after CB ablation. Either Watchman (Watchman, Boston Scientific, MA, USA) or LAmbre device (Lifetech Scientific Co, Ltd, Shenzhen, China) was used. Under TEE (GE Vivid E9 and Siemens ACUSON SC2000) guidance, LAAC device was delivered and deployed. Before release, stable anchoring was confirmed by tug test and complete sealing was confirmed by TEE assessment of residual flow. Once released, TEE was applied again to reconfirm device positioning and evaluate procedure-related complications.

Post-procedure management

The anti-thrombotic therapy was recommended as follows: 1. 3-month OACs (Warfarin, dabigatran or rivaroxaban), 2. according to TEE examination in the 3rd month, double anti-platelet therapy for another 3 months 3. lifelong single anti-platelet therapy. All patients were required to have outpatient follow-up in the 1st, 3rd, 6th, 12th month, and every year after the procedure. TEE was scheduled to perform in the 3rd month and the 12th month if necessary.
Primary endpoints comprise LAAC related complications (residual flow, device related thrombosis (DRT)). Secondary endpoints encompass all-cause death, early (before the 3rd month) and late atrial arrhythmia (AA) recurrence (recorded atrial tachycardia (AT) lasting longer than 30s), stroke (confirmed by either computed tomography (CT) or magnetic resonance imaging (MRI)), major hemorrhagic events, redo-ablation, cardiovascular intervention, pericardial effusion rehospitalization due to cardiovascular events.

LAR measurement

For every patient, TEE was performed according to the ASE guideline and standards (14). Preprocedural, postprocedural and follow-up TEE were thoroughly collected. LAR profile and LAA ostium were measured on TEE at 45°/90° planes. LAR was recognized as a high-echo band between LAA and left superior PV (LSPV). The width of LAR was measured as the maximal length between LAA side and PV side, while the thickness of LAR was measured from the most proximal site of LAR to the base where a prominent reduction of echo signal was observed compared with LAR (Figure 1 ). The outer ostium was measured from the tip of LAR to the circumflex artery, as the landing zone of plug device (Watchman). While the inner ostium was measured from the circumflex artery to a point 1 to 2 cm superiorly within LAR, as the landing zone of pacifier device (LAmbre) (15). All the images were independently measured on TEE machine by 3 proficient echocardiologists, and the final LAR width, thickness, LAA inner and outer ostium diameters were acquired from the average of 3 measurements.

Statistical analysis

Continuous variables were described as mean ± standard deviation (SD) if they conformed to normal distribution, while those without a normal distribution were presented as the median and interquartile ranges (IQR). The P-value was generated from 2 sample t-tests or a Mann-Whitney test according to the equality of variance, or singed-rank test if a normal distribution was not presented.
Categorical variables were described as percentages (%), and P value was generated from χ2 test.
The changes of LAR profile were analyzed using repeated measures analysis of variance, and the correlation between width and thickness change was assessed through Spearman correlation analysis. LAR lesion was divided into mild or severe group by whether the width after procedure was larger than 2-fold of its original width or not. The association of LAR lesion size and clinical information and were evaluated by logistic regression analysis. Further multivariate model was applied that adjusted for age, gender, body mass index (BMI), LA diameter, AF type. The influence of LAR lesion on prognosis was analyzed through survival analysis with Kaplan-Meier estimate, and P value was generated from Log-Rank test.
2-side P-value < 0.05 was considered significant for all analysis. SAS 9.4 software (SAS Institute Inc., Cary, NC, USA) and GraphPad Prism 8.0.2 (GraphPad software Inc., CA, USA) adopted to conduct all the analysis.