Long-term Outcomes of Left Atrial Appendage Electrical Isolation in Patients with Non-Paroxysmal Atrial Fibrillation: A Propensity Score-Matched Analysis

Running title: Romero & Di Biase et al.; Long-term clinical outcomes after LAAEI

Jorge Romero, MD, FACC, FHRS1*; Luigi Di Biase, MD, PhD, FACC, FHRS1,2*; Sanghamitra Mohanty, MD, FHRS2; Chintan Trivedi, MD, MPH, FHRS2; Kavisha Patel, MD1; Michael Parides, PhD1; Isabella Alviz, MD1; Juan C. Diaz, MD1; Veronica Natale, BS2; Javier Sanchez, MD2; Domenico G. Della Rocca, MD2; Ruike Yang, MD1,4; Prasant Mohanty, MBBS, MPH2; Carola Gianni, MD2; Rodney Horton, MD2; David Burkhardt, MD2; Amin Al-Ahmad, MD2; Dhanunjaya Lakkireddy, MD3; Andrea Natale, MD, FACC, FESC, FHRS2 Downloaded from http://ahajournals.org by on October 3, 2020

1Montefiore

Medical Center, Albert Einstein College of Medicine, Bronx, NY; 2Texas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, TX; 3Kansas City Heart Rhythm Institute, Overland Park, KS; 4Department of Cardiopulmonary Function, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China *contributed equally

Correspondence Andrea Natale, MD, FACC, FESC, FHRS Executive Medical Director Texas Cardiac Arrhythmia Institute St. David's Medical Center 3000 N. I-35, Suite 720 Austin, TX 78705 Email: [email protected]

Journal Subject Terms: Atrial Fibrillation; Catheter Ablation and Implantable CardioverterDefibrillator; Complications 1

Abstract:

Background - Left atrial appendage electrical isolation (LAAEI) has been proposed for the treatment of non-paroxysmal atrial fibrillation (AF). The long-term clinical outcomes and safety of this approach remain unclear. The objective of our study was to investigate the incremental benefit of LAAEI in patients undergoing catheter ablation (CA) for non-paroxysmal AF. Methods - Propensity score-matched analysis was performed using a prospective registry database from 2010-2014. All patients in the LAAEI group were matched based on baseline characteristics, echocardiographic parameters, and procedural ablation techniques. Results - We identified 1842 patients who underwent CA for non-paroxysmal AF. Propensity score matching yielded 1092 patients, 546 patients with LAAEI and 546 patients without LAAEI. At 5-year follow-up, overall freedom from all-atrial arrhythmia recurrence, off-antiarrhythmic drugs, in patients who underwent LAAEI was 68.9% vs. 50.2% in those who underwent standard ablation alone (p 80% electrogram amplitude reduction and catheter tip impedance monitoring. A medium curve deflectable sheath (Agilis, Abbott Inc., Plymouth, MN, USA) was used to improve stability. Imaging of the catheter tip with ICE was also used to monitor catheter stability and real-time lesion formation. LAAEI was performed by delivering RF energy at the level of the LAA ostium, which is considerably thicker. The ablation catheter stayed at the level of the LAA ostium, and was never advanced beyond the mapping catheter (i.e., Lasso, BiosenseWebster, Diamond Bar, CA, USA or PentaRay, Biosense-Webster, Diamond Bar, CA, USA) in order to avoid inadvertent LAA perforation.4, 15 High-output pacing (20mA/2ms) was performed at the LAA ostium before RFA to avoid LPN injury. RF settings during LAAEI typically included power from 30 W to 40 W while maintaining a catheter tip temperature of 42ºC for a maximum of 30 seconds per ablation site. Yet for the anterior and superior edges of the LAA

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(which are known to be thicker than the inferior and posterior margins),7 longer lesions (i.e., 60 seconds) were required. We targeted an impedance drop of 10-15 ohms per lesion, monitoring ST-segment for elevation during ablation of the anterior wall of the LAA. We performed electrical cardioversion before LAAEI, to allow for clearer visualization of electrical signals. LAAEI was demonstrated with bidirectional block. LAA dormant conduction was assessed using adenosine or isoproterenol to reassess reconnection after a 20-minute waiting period. Anticoagulation following catheter ablation OAC was continued during the blanking period (3 months) in all patients. In the non-LAAEI group, OAC was continued if the CHA2DS2-VASc score was ≥ 2. In the LAAEI group, all patients in sinus rhythm at 6 months post-ablation underwent transesophageal echocardiography (TEE) to assess the LAA function. A cut-off value of 0.4m/s was utilized to determine normal LAA function.16, 17 OAC was discontinued in patients with preserved LAA velocity (>0.4 m/s) Downloaded from http://ahajournals.org by on October 3, 2020

regardless of the CHA2DS2-VASc score. However, lifelong OAC was strongly recommended in all patients with impaired LAA emptying velocity (30 seconds of any atrial arrhythmia was recorded. During follow-up evaluations, patients were interrogated for arrhythmic symptoms (i.e., palpitations) as well as dyspnea, cough, hiccups (suggestive of LPN injury), and angina (suggestive of coronary artery lesion). Statistical analysis PSM was performed to reduce the risk of selection bias. Patients were divided into two cohorts: LAAEI vs. non-LAAEI (Table 1). Due to differences in key baseline characteristics, echocardiographic parameters, and ablation strategies, we used PSM for the two cohorts and assembled a cohort for each comparison; all the measured covariates were well balanced across Downloaded from http://ahajournals.org by on October 3, 2020

comparator groups. The propensity score is defined as the subject’s probability of receiving a specific treatment or exposure (in this case LAAEI) given a set of measured baseline covariates.18, 19 A non-parsimonious logistic regression model was utilized to obtain propensity scores with LAAEI defined as the dependent variable, and age, gender, AF type, clinical characteristics, echocardiographic parameters, and structures ablated (i.e., PVI, SVC, PW, and CS) entered as covariates. Matching was performed using a nearest neighbor matching protocol (matching ratio of 1 to 1 without replacement) and a caliper width of 0.01. The balance of characteristics was assessed by estimating standardized differences (StDiffs) between groups, histograms and jitter plots of the propensity score distribution. StDiff indicates the degree of systematic differences in covariates between groups. Operationally, a StDiff > 10% represents a meaningful imbalance in a given variable between groups.20

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Descriptive statistics are presented as means and standard deviations for continuous variables or number of cases (n) and percentages (%) for categorical variables. Groups were compared for baseline and clinical characteristics by the Student’s t-test and χ2 test. Time to event was calculated from the ablation date to the date of recurrence. Arrhythmia-free survival over time was calculated by the Kaplan-Meier method. The log-rank test was used to compare survival distributions between groups. To identify the predictors of recurrence, multivariate Cox regression analysis was used, and all the variables were entered into the model if a significant association was observed in the univariate analysis or if there was some clinical relevance of the variable with the recurrence. In the multivariate analysis, LAAEI, AF type, age, and gender were included. We had checked the Proportional hazard assumption using Schoenfeld test. Statistical analysis was performed using IBM SPSS Statistics 21.0 (IBM Corp., Armonk, NY) and R version 3.5.0 (The R Foundation for Statistical Computing). PSM was conducted using the Downloaded from http://ahajournals.org by on October 3, 2020

MatchIt package within R. All p-values were two-sided with a significance threshold of