Trispecific antibodies produced from mAb2 pairs by controlled Fab-arm exchange.

Bispecific antibodies and antibody fragments are therapeutics of growing importance. They are clinically applied for effector cell engagement, enhanced targeting selectivity, addressing of multiple cellular pathways and active transfer of certain activities into difficult-to-reach compartments. These functionalities could profit from a third antigen specificity. In this work we have employed symmetrical bispecific parental antibodies of mAb2 format, which feature a novel antigen binding site in the CH3 domains, and engineered them with a minimal number of point mutations to guide the formation of a controlled Fab-arm exchanged trispecific antibody at a high yield after reduction and re-oxidation. Two model antibodies, one reactive with EGFR, Her2 and VEGF, and one with Fab-arms binding to Ang2 and VEGF and an Fc fragment binding to VEGF, were prepared and examined for heterodimeric status, stability, antigen binding properties and biological activity. Resulting molecules were of good biophysical characteristics and retained antigen reactivity and biological activity of the parental mAb2 constructs.

Clinical presentation, diagnosis, and treatment of atrioesophageal fistula resulting from atrial fibrillation ablation.

BACKGROUND: Atrioesophageal fistula (AEF) is a worrisome complication of atrial fibrillation (AF) ablation. Its clinical manifestations and time course are unpredictable and may contribute to diagnostic and treatment delays. We conducted a systematic review of all available cases of AEF, aiming at characterizing clinical presentation, time course, diagnostic pitfalls, and outcomes. METHODS: The digital search retrieved 150 studies containing 257 cases, 238 (92.6%) of which with a confirmed diagnosis of AEF and 19 (7.4%) of pericardioesophageal fistula. RESULTS: The median time from ablation to symptom onset was 21 days (interquartile range [IQR]: 11-28). Neurological abnormalities were documented in 75% of patients. Compared to patients seen by a specialist, those evaluated at a walk-in clinic or community hospital had a significantly greater delay between symptom onset and hospital admission (median: 2.5 day [IQR: 1-8] vs. 1 day [IQR: 1-5); p = .03). Overall, 198 patients underwent a chest scan (computed tomography [CT]: 192 patients and magnetic resonance imaging [MRI]: 6 patients), 48 (24.2%; 46 CT and 2 MRI) of whom had normal/unremarkable findings. Time from hospital admission to diagnostic confirmation was significantly longer in patients with a first normal/unremarkable chest scan (p < .001). Overall mortality rate was 59.3% and 26.0% survivors had residual neurological deficits at the time of discharge. CONCLUSIONS: Since healthcare professionals of any specialty might be involved in treating AEF patients, awareness of the clinical manifestations, diagnostic pitfalls, and time course, as well as an early contact with the treating electrophysiologist for a coordinated interdisciplinary medical effort, are pivotal to prevent diagnostic delays and reduce mortality.

Targeting non-pulmonary vein triggers in persistent atrial fibrillation: results from a prospective, multicentre, observational registry.

AIMS: We evaluated the efficacy of an ablation strategy empirically targeting pulmonary veins (PVs) and posterior wall (PW) and the prevalence and clinical impact of extrapulmonary trigger inducibility and ablation in a large cohort of patients with persistent atrial fibrillation (PerAF). METHODS AND RESULTS: A total of 1803 PerAF patients were prospectively enrolled. All patients underwent pulmonary vein antrum isolation (PVAI) extended to the entire PW. A standardized protocol was performed to confirm persistent PVAI and elicit any triggers originating from non-PV sites. All non-PV triggers initiating sustained atrial tachyarrhythmias were ablated. Ablation of non-PV sites triggering non-sustained runs (<30 s) of atrial tachyarrhythmias or promoting frequent premature atrial complexes (≥10/min) was left to operator's discretion. Overall, 1319 (73.2%) patients had documented triggers from non-PV areas. After 17.4 ± 8.5 months of follow-up, the cumulative freedom from atrial tachyarrhythmias among patients without inducible non-PV triggers (n = 484) was 70.2%. Patients with ablation of induced non-PV triggers had a significantly higher arrhythmia control than those whose triggers were not ablated (67.9% vs. 39.4%, respectively; P < 0.001). After adjusting for clinically relevant variables, patients in whom non-PV triggers were documented but not ablated had an increased risk of arrhythmia relapse (hazard ratio: 2.39; 95% confidence interval: 2.01-2.83; P < 0.001). CONCLUSION: Pulmonary vein antrum isolation extended to the entire PW might provide acceptable long-term arrhythmia-free survival in PerAF patients without inducible non-PV triggers. In our population of PerAF patients, non-PV triggers could be elicited in ∼70% of PerAF patients and their elimination significantly improved outcomes.

Arrhythmia profile and ablation-outcome in elderly women with atrial fibrillation undergoing first catheter ablation.

BACKGROUND: This study evaluated the arrhythmia profile and ablation outcome in women with atrial fibrillation (AF) aged ≥75 years. METHODS: A total of 573 consecutive female patients undergoing first AF ablation were classified into group 1: ≥75 years (n = 221) and group 2: < 75 years (n = 352). Isolation of PVs, posterior wall and superior vena cava was performed in all. Non-PV triggers from other areas were ablated based on operator's discretion. RESULTS: Group 1 had higher prevalence of hypertension (154 (69.7%) vs. 188 (53.4%), p < .001) and non-paroxysmal AF (136 (61.5%) vs. 126 (35.8%), p < .001). Non-PV triggers were detected in 194 (87.8%) patients from group 1 and 143 (40.6%) from group 2 (p < .001) and were ablated in 152 (68.8%) and 114 (32.4%) from group 1 and 2 respectively. Remaining patients (group 1: 69/221 and group 2: 238/352) received no additional ablation. At 4 years, 109 (49.3%) and 185 (52.6%) from group 1 and 2, respectively, were arrhythmia-free, p = .69. When stratified by ablation-strategy, success-rate was similar across groups in patients receiving non-PV trigger ablation (96 (63.2%) in group 1 and 76 (66.7%) in group 2, p = .61), whereas it was significantly lower in group 1 patients not receiving additional ablation compared to those from group 2 (13 (18.8%) vs. 109 (45.8%), p < .001). CONCLUSION: Non-paroxysmal AF was more common in women aged ≥75 years. Furthermore, significantly higher number of non-PV triggers were detected in elderly women and ablation of those provided similar ablation success as that in women aged < 75 years.

Clinical and economic impact of multipoint left ventricular pacing: A comparative analysis from the Italian registry on multipoint pacing in cardiac resynchronization therapy (IRON-MPP).

INTRODUCTION: Early evidence suggests that multipoint left ventricular pacing (MPP) may improve response to cardiac resynchronization therapy (CRT). It is unknown whether this benefit is sustained and cost-effective. We used real-world data to evaluate long-term impact of MPP-ON clinical status, heart failure hospitalizations (HFH) and costs. METHODS: The Italian registry on multipoint left ventricular pacing is a prospective, multicenter registry of patients implanted with MPP-enabled CRT devices. For this analysis, clinical and echocardiographic data were collected through 24 months and compared between patients with (MPP-ON) or without (MPP-OFF) early MPP activation at implant. The total cost of each HFH was estimated with national Italian reimbursement rates. RESULTS: The study included 190 MPP-OFF and 128 MPP-ON patients with similar baseline characteristics. At 1 and 2 years, the MPP-ON group had lower rates of HFH vs MPP-OFF (1-year hazard ratio [HR]: 0.14, P = .0014; 2-year HR: 0.38, P = .009). The finding persisted in a subgroup of patients with consistent MPP activation through follow-up (1-year HR: 0.19; P = .0061; 2-year HR: 0.39, P = .022). Total HFH per-patient costs were lower in the MPP-ON vs the MPP-OFF group at 1 year (€101 ± 50 vs €698 ± 195, P < .001) and 2 years (€366 ± 149 vs €801 ± 203, P = .038). More MPP-ON patients had ≥5% improvement in ejection fraction (76.8% vs 65.4%, P = .025) and clinical composite score (66.7% vs 47.5%, P = .01). CONCLUSIONS: In this multicenter clinical study, early MPP activation was associated with a significant reduction in cumulative HFH and related costs after 1 and 2 years of follow-up.

Impact of multipoint pacing on projected battery longevity in cardiac resynchronization therapy. An IRON-MPP study sub-analysis.

BACKGROUND: Multipoint pacing (MPP) may improve clinical outcomes in patients with cardiac resynchronization therapy defibrillators (CRT-D), but its impact on battery longevity in a real-world population has not been investigated in large trials. OBJECTIVE: Compare projected battery longevity in CRT-D patients with and without MPP during long-term follow-up. METHODS: The Italian registry on multipoint left ventricular pacing (IRON-MPP) is a prospective, multicenter registry of patients implanted with MPP-capable CRT-D devices. Projected battery longevity during follow-up was compared for patients with MPP (MPP ON) vs single-site (MPP OFF) left ventricular pacing at CRT-D implantation. A sub-analysis excluded crossover patients with MPP activation or deactivation occurring after implantation. A second sub-analysis excluded patients with a right or left ventricular pacing amplitude >2.5 V. RESULTS: Out of 237 CRT-D patients (71 ± 9 years, 81% male) followed for 1.9 ± 0.8 years, 102 (43%) had MPP ON at implantation. Programmed atrial and ventricular outputs and percentage of pacing were similar between groups. MPP was associated with a 0.44 years reduction in projected battery longevity (P = .03) during long-term follow-up. Results were similar for the first and second sub-analyses, with a 0.57 years (P < .001) and 0.71 years (P < .001) reduction in projected longevity, respectively. CONCLUSION: In this long-term real-world registry, early MPP activation is associated with less than a 1-year reduction in projected battery life compared to single-site biventricular pacing.

Impact of weight loss on ablation outcome in obese patients with longstanding persistent atrial fibrillation.

AIMS: This study investigated the impact of weight loss in longstanding persistent (LSPAF) patients undergoing catheter ablation (CA). METHODS: Ninety consecutive obese LSPAF patients were approached; 58 volunteered to try weight loss interventions for up to 1 year (group 1), while 32 patients declined weight loss interventions and were included as a control (group 2). Both groups remained on antiarrhythmic drugs. If they continued to experience AF, CA was performed. Body weight was measured at 6-month intervals and arrhythmia status was assessed by event recorder, electrocardiogram (ECG), and Holter monitoring. Symptom severity and quality of life (QoL) were evaluated by AFSS and SF-36 survey, respectively. A scoring algorithm with two summary measures, physical component score (PCS) and mental component score (MCS), was prepared for QoL analysis. RESULTS: Significant reduction in body weight (median -24.9 (IQR -19.1 to -56.7) kg, P < 0.001) was observed in the group 1 patients, while no such change was seen in group 2. The PCS and MCS scores improved significantly in group 1 only, with a change from baseline of 8.4 ± 3 (P = 0.013) and 12.8 ± 8.2 (P < 0.02). However, AF symptom severity remained unchanged from baseline in both groups (P = 0.84). All 90 patients eventually underwent CA and received PVAI+ posterior wall+ non-PV triggers ablation. At 1-year follow-up after single procedure, 37 (63.8%) in group 1 and 19 (59.3%) patients in group 2 remained arrhythmia-free off AAD (P = 0.68). CONCLUSION: In this prospective analysis, in LSPAF patients weight loss improved QoL but had no impact on symptom severity and long-term ablation outcome.

Differential Association of Exercise Intensity With Risk of Atrial Fibrillation in Men and Women: Evidence from a Meta-Analysis.

BACKGROUND: Despite widespread interest and extensive research, the association between different levels of physical activity (PA) and risk of atrial fibrillation (AF) is still not clearly defined. Therefore, we systematically evaluated and summarized the evidences regarding association of different intensity of PA with the risk of AF in this meta-analysis. METHODS AND RESULTS: An extensive literature search was performed on databases for studies showing association of exercise with AF risk. Twenty-two studies were identified that included 656,750 subjects. Meta-analytic estimates were derived using random-effects models and pooled odds ratio estimates were obtained. Potential sources of heterogeneity were examined in sensitivity analyses, and publication biases were estimated. Pooled analysis of 7 studies with 93,995 participants reported high risk of incident AF with sedentary lifestyle (pooled OR 2.47 [95% CI 1.25-3.7], P = 0.005). In 3 trials, 149,048 women involved in moderate PA were 8.6% less likely to develop AF compared to women with sedentary life (OR 0.91 [95% CI 0.78-0.97], P = 0.002). Women performing intense exercise were found to have 28% lower risk of AF (OR 0.72 [95% CI 0.57-0.88], P < 0.001). The overall pooled estimate indicated a protective impact of moderate PA in men (pooled OR 0.8133 [95% CI 0.26-1.004], P = 0.06) whereas vigorous PA was associated with a significantly increased AF risk (pooled OR 3.30 [1.97-4.63], P = 0.0002). CONCLUSION: Sedentary lifestyle significantly increases and moderate amount of physical activity reduces the risk of AF in both men and women. However, intense exercise has a gender-specific association with AF risk.

Sharks give a handle to potent anti-tumor multiparatopic antibodies inducing membrane depletion of PD-L1.

Despite the immense clinical success of the antibody therapeutics that neutralize programmed death receptor ligand 1 (PD-L1) and thus resurrect T cell antitumor activity, the patient response rates remain low. In this issue of Cell Chemical Biology, Ludwig et al.1 reveal novel topologies of multiparatopic antibodies that mediate potent PD-L1 downregulation.

Incidence of Device-Related Thrombosis in Watchman Patients Undergoing a Genotype-Guided Antithrombotic Strategy.

OBJECTIVES: This study sought to report the incidence of device-related thrombosis (DRT) and thromboembolic (TE) events when an alternative to clopidogrel is prescribed in loss-of-function (LOF) allele carriers of the cytochrome P450 2C19 (CYP2C19) gene. BACKGROUND: LOF polymorphisms of the CYP2C19 gene are associated with reduced hepatic bioactivation of clopidogrel. METHODS: A total of 1,002 Watchman patients were included. Six hundred forty-five patients underwent CYP2C19 genetic testing; among patients with clopidogrel resistance, clopidogrel was replaced by either prasugrel (pilot cohort) or half dose direct oral anticoagulant ([DOAC]/Group 1), both in combination with aspirin. We compared the incidence of DRT/TE events among genotyped patients and a control group which received standard dual antiplatelet therapy (DAPT) (Group 2; n = 357). All reported events occurred during a timeframe between 45- and 180-day follow-up transesophageal echocardiograms, when the 2 different antithrombotic strategies (genotype-guided vs standard DAPT) were adopted. RESULTS: In the pilot cohort (n = 244), bleeding events occurred in 10.2% of patients who received aspirin plus prasugrel, leading to early discontinuation of the prasugrel-based protocol. DOAC Group 1 patients (n = 401), 25.7% were reduced metabolizers, and clopidogrel was replaced by half dose direct oral anticoagulant. DRT was documented in 1 (0.2%) patient of Group 1 and 7 (1.96%) patients of Group 2 (log-rank P = 0.021). The composite endpoint of DRT/TE events was significantly lower among patients receiving a genotype-guided antithrombotic strategy (0.75% vs 3.10%; log-rank P = 0.017). CONCLUSIONS: In Watchman patients, a genotype-based antithrombotic strategy with aspirin plus half dose DOAC in reduced clopidogrel metabolizers was superior to standard DAPT with respect to DRT/TE events.

Half-Dose Direct Oral Anticoagulation Versus Standard Antithrombotic Therapy After Left Atrial Appendage Occlusion.

OBJECTIVES: This study evaluated the long-term efficacy of a standard antithrombotic strategy versus half-dose direct oral anticoagulation (DOAC) after Watchman implantation. BACKGROUND: No consensus currently exists on the selection of the most effective antithrombotic strategy to prevent device-related thrombosis (DRT) in patients undergoing endocardial left atrial appendage closure. METHODS: After successful left atrial appendage closure, consecutive patients were prescribed a standard antithrombotic strategy (SAT) or long-term half-dose DOAC (hdDOAC). The primary composite endpoint was DRT and thromboembolic (TE) and bleeding events. RESULTS: Overall, 555 patients (mean age 75 ± 8 years, 63% male; median CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category] score 4 [interquartile range (IQR): 3-6]; median HAS-BLED [hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol] score 3 [IQR: 2-4]) were included. Patients were categorized into 2 groups (SAT: n = 357 vs hdDOAC: n = 198). Baseline clinical characteristics were similar between groups. The median follow-up duration was 13 months (IQR: 12-15 months). DRT occurred in 12 (2.1%) patients, all in the SAT group (3.4% vs 0.0%; log-rank P = 0.009). The risk of nonprocedural major bleeding was significantly more favorable in the hdDOAC group (0.5% vs. 3.9%; log-rank P = 0.018). The rate of the primary composite endpoint of DRT and TE and major bleeding events was 9.5% in SAT patients and 1.0% in hdDOAC patients (HR: 9.8; 95% CI: 2.3-40.7; P = 0.002). CONCLUSIONS: After successful Watchman implantation, long-term half-dose DOAC significantly reduced the risk of the composite endpoint of DRT and TE and major bleeding events compared with a standard, antiplatelet-based, antithrombotic therapy.

Radiofrequency Energy Applications Targeting Significant Residual Leaks After Watchman Implantation: A Prospective, Multicenter Experience.

OBJECTIVES: The aim of this study was to evaluate the efficacy of radiofrequency (RF) energy applications targeting the atrial side of a significant residual leak in patients with acute and chronic evidence of incomplete percutaneous left atrial appendage (LAA) occlusion. BACKGROUND: RF applications have been proved to prevent recanalization of intracranial aneurysms after coil embolization, thereby favoring complete sealing. From a mechanistic standpoint, in vitro and in vivo experiments have demonstrated that RF promotes collagen deposition and tissue retraction. METHODS: Forty-three patients (mean age 75 ± 7 years mean CHA2DS2-VASc score 4.6 ± 1.4, mean HAS-BLED score 4.0 ± 1.1) with residual leaks ≥4 mm after Watchman implantation were enrolled. Procedural success was defined as complete LAA occlusion or presence of a mild or minimal (1- to 2-mm) peridevice leak on follow-up transesophageal echocardiography (TEE), which was performed approximately 45 days after the procedure. RESULTS: RF-based leak closure was performed acutely after Watchman implantation in 19 patients (44.2%) or scheduled after evidence of significant leaks on follow-up TEE in 24 others (55.8%). The median leak size was 5 mm (range: 4-7 mm). On average, 18 ± 7 RF applications per patient (mean maximum contact force 16 ± 3 g, mean power 44 ± 2 W, mean RF time 5.1 ± 2.5 minutes) were performed targeting the atrial edge of the leak. Post-RF median leak size was 0 mm (range: 0-1 mm). A very low rate (2.3% [n = 1]) of major periprocedural complications was observed. Follow-up TEE revealed complete LAA sealing in 23 patients (53.5%) and negligible residual leaks in 15 (34.9%). CONCLUSIONS: RF applications targeting the atrial edge of a significant peri-Watchman leak may promote LAA sealing via tissue remodeling, without increasing complications. (RF Applications for Residual LAA Leaks [REACT]; NCT04726943).

Beyond Pulmonary Vein Isolation in Nonparoxysmal Atrial Fibrillation: Posterior Wall, Vein of Marshall, Coronary Sinus, Superior Vena Cava, and Left Atrial Appendage.

The optimal ablation strategy for non-paroxysmal atrial fibrillation remains controversial. Non-PV triggers have been shown to have a major arrhythmogenic role in these patients. Common sources of non-PV triggers are: posterior wall, left atrial appendage, superior vena cava, coronary sinus, vein of Marshall, interatrial septum, crista terminalis/Eustachian ridge, and mitral and tricuspid valve annuli. These sites are targeted empirically in selected cases or if significant ectopy is noted (with or without a drug challenge), to improve outcomes in patients with non-paroxysmal atrial fibrillation. This article focuses on summarizing the current evidence and the approach to mapping and ablation of these frequent non-PV trigger sites.

Fluoroless Atrial Fibrillation Catheter Ablation: Technique and Clinical Outcomes.

Fluoroscopy continues to be considered an indispensable part of atrial fibrillation (AF) ablation worldwide. Deleterious effects of radiation exposure to patients, physicians, and catheter laboratory personnel are gaining increased consideration. Safety and efficacy of a fluoroless approach for AF ablation is comparable with outcomes achieved with fluoroscopy use. This article focuses on AF ablation with zero fluoroscopy use as well as current evidence on efficacy and safety of this technique. In contrast, minimal fluoroscopy is an alternative. Relying on intracardiac echocardiography for transseptal access and electroanatomic mapping for catheter manipulation can help implement this approach on a wider scale.

Long-Term Outcomes of Left Atrial Appendage Electrical Isolation in Patients With Nonparoxysmal Atrial Fibrillation: A Propensity Score-Matched Analysis.

BACKGROUND: Left atrial appendage electrical isolation (LAAEI) has been proposed for the treatment of nonparoxysmal atrial fibrillation (AF). The long-term clinical outcomes of this approach remain unclear. The objective of our study was to investigate the incremental benefit and safety of LAAEI in patients undergoing catheter ablation for nonparoxysmal AF. METHODS: Propensity score-matched analysis was performed using a prospective registry database from 2010 to 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 catheter ablation for nonparoxysmal 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% versus 50.2% in those who underwent standard ablation alone (P<0.001). Acute complication rates were similar between groups (LAAEI 1.3% versus non-LAAEI 0.73%, P=0.36). At 5-year follow-up, 382 (70%) patients in the LAAEI group remained on oral anticoagulation versus 217 (39.7%) in the non-LAAEI group. At 5-year follow-up, thromboembolic events occurred in 15/546 (2.75%) in the LAAEI group and 4/546 (0.73%) in the non-LAAEI group (P=0.01). No thromboembolic events occurred in either group on-oral anticoagulation. In patients who were off-oral anticoagulation, at 5-year follow-up, thromboembolic events occurred in 15/164 (9.1%) in the LAAEI group and 4/329 (1.2%) in the non-LAAEI group (P<0.001). CONCLUSIONS: At 5-year follow-up, LAAEI was associated with significantly higher freedom from all-atrial arrhythmia recurrence in patients with persistent and long-standing persistent AF without increasing acute procedural complication rate. In patients off-oral anticoagulation, there appears to be a higher risk of thromboembolic events in the LAAEI group.

First Experience of Transcatheter Leak Occlusion With Detachable Coils Following Left Atrial Appendage Closure.

OBJECTIVES: The aim of this study was to assess the feasibility and efficacy of transcatheter leak closure with detachable coils in patients with incomplete left atrial appendage (LAA) closure. BACKGROUND: Incomplete LAA closure is common after interventional therapies targeting the LAA, potentially hindering effective thromboembolic prevention. Detachable coils have found a wide range of applications for transcatheter vascular occlusion and embolization procedures. METHODS: Thirty consecutive patients at high thromboembolic risk with clinically relevant residual leaks (mean age 72 ± 9 years, 73.3% men, mean CHA2DS2-VASc score 4.4 ± 1.4, mean HAS-BLED score 3.6 ± 0.8) underwent percutaneous closure of the LAA patency using embolization coils. Transesophageal echocardiography was performed at 60 ± 15 days post-procedure. RESULTS: LAA closure had been previously attempted with the Watchman device in 25 patients, the Amulet device in 2 patients, and the LARIAT device in 3 patients. Baseline transesophageal echocardiography documented moderate and severe leaks in 20 (66.7%) and 10 (33.3%) patients, respectively. After a single procedure, 25 patients (83.3%) showed complete LAA sealing or minimal leaks. Five patients (16.7%) had moderate residual leaks; 3 patients of them were offered repeat procedures. Mean procedure and fluoroscopy times were 76 ± 41 min and 21 ± 14 min, respectively; the mean volume of iodinated contrast medium used was 80 ± 47 ml. Coil deployment was successful in all cases. The overall complication rate was 6.1%. After a median follow-up period of 54 days (range 43 to 265 days) and an average of 1.1 procedures/patient, transesophageal echocardiography revealed complete LAA sealing or negligible residual leaks in 28 patients (93.3%; 25 with no residual leak, 3 patients with minimal to mild residual leaks) and moderate residual leaks in 2 patients (6.7%). CONCLUSIONS: Transcatheter LAA leak occlusion using endovascular coils appears to be a safe, effective, and promising approach in patients at high echo time risk with incomplete LAA closure. (Transcatheter Leak Closure With Detachable Coils Following Incomplete Left Atrial Appendage Closure Procedures [TREASURE]; NCT03503253).

Use of a Novel Septal Occluder Device for Left Atrial Appendage Closure in Patients With Postsurgical and Postlariat Leaks or Anatomies Unsuitable for Conventional Percutaneous Occlusion.

BACKGROUND: Interventional therapies aiming at excluding the left atrial appendage (LAA) from systemic circulation have been established as a valid alternative to oral anticoagulation in patients at high thromboembolic risk. However, their efficacy on stroke prophylaxis may be compromised owing to incomplete LAA closure. Additionally, the need for an alternative thromboembolic prevention may remain unmet in patients with contraindications to oral anticoagulation whose appendage anatomy is unsuitable for some conventional devices commercially available. We aimed at evaluating the feasibility of LAA closure with the novel Gore Cardioform Septal Occluder in patients with incomplete appendage ligation or anatomic features which do not meet the manufacturer's requirements for Watchman deployment. METHODS: Twenty-one consecutive patients (mean age: 72±6 years; 85.7% males; CHA2DS2-VASc: 4.5±1.4; HAS-BLED: 3.6±1.0) were included. Transesophageal echocardiography was performed within 2 months to assess for residual LAA patency. RESULTS: Fourteen patients had incomplete LAA closure following surgical (n=6) or Lariat ligation (n=8). In 7 patients with an appendage anatomy unsuitable for Watchman deployment, the mean maximal landing zone size and LAA depth were 14.4±1.3 and 18.6±2.8 mm. Successful Cardioform Septal Occluder deployment was achieved in all patients. No peri-procedural complications were documented. Procedure and fluoroscopy times were 46±13 and 14±5 minutes. Follow-up transesophageal echocardiography after 58±9 days revealed complete LAA closure in all patients. CONCLUSIONS: Transcatheter LAA closure via a Cardioform Septal Occluder device might be a valid alternative in patients with residual leaks following failed appendage ligation or whose LAA anatomy does not meet the minimal anatomic criteria to accommodate a Watchman device. Graphic Abstract: A graphic abstract is available for this article.

Is transesophageal echocardiography necessary in patients undergoing ablation of atrial fibrillation on an uninterrupted direct oral anticoagulant regimen? Results from a prospective multicenter registry.

BACKGROUND: Thromboembolic stroke is a rare but devastating consequence of atrial fibrillation (AF) ablation. Transesophageal echocardiography (TEE) is recommended to rule out left atrial appendage thrombus; however, its use is variable. OBJECTIVE: The purpose of this study was to assess whether TEE is mandatory in patients undergoing AF ablation on uninterrupted direct oral anticoagulants (DOACs). METHODS: Data from our prospective multicenter registry of patients with AF undergoing radiofrequency catheter ablation on uninterrupted DOACs were analyzed. All the included patients were on anticoagulation for at least 4 weeks before ablation. All AF ablation procedures were performed under intracardiac echocardiography guidance. Before transseptal puncture, heparin bolus was administered, followed by continuous infusion, with a target activated clotting time of >300 seconds. RESULTS: A total of 6186 patients (3180 on apixaban [51.4%], 2528 on rivaroxaban [40.9%], 404 on dabigatran [6.5%], and 74 on edoxaban [1.2%]) were analyzed. The mean age of the study population was 69.4 ± 10.3 years; 4194 patients (67.8%) were male, and 5120 patients (82.8%) had persistent and long-standing persistent AF. The mean CHA2DS2-VASc score was 2.86 ± 1.58; the mean CHADS2 score was 1.65 ± 1.14. Intracardiac echocardiography ruled out left atrial appendage and left atrial thrombi in all patients and revealed "smoke" in 1672 patients (27.03%). Transient ischemic attack was noted in 1 patient with long-standing persistent AF in the setting of a missed dose of rivaroxaban before ablation. CONCLUSION: Our study showed that performing AF ablation in patients on uninterrupted DOACs without TEE is safe and feasible in high stroke risk patients. Elimination of routine preablation TEE would have significant economic and clinical implications.

Stroke Risk in Patients With Atrial Fibrillation Undergoing Electrical Isolation of the Left Atrial Appendage.

BACKGROUND: Loss of contractility leading to stasis of blood flow following left atrial appendage electrical isolation (LAAEI) could lead to thrombus formation. OBJECTIVES: This study evaluated the incidence of thromboembolic events (TE) in post-LAAEI cases "on" and "off" oral anticoagulation (OAC). METHODS: A total of 1,854 consecutive post-LAAEI patients with follow-up transesophageal echocardiography (TEE) performed in sinus rhythm at 6 months to assess left atrial appendage (LAA) function were included in this analysis. RESULTS: The TEE at 6 months revealed preserved LAA velocity, contractility, and consistent A waves in 336 (18%) and abnormal parameters in the remaining 1,518 patients. In the post-ablation period, all 336 patients with preserved LAA function were off OAC. At long-term follow-up, patients with normal LAA function did not experience any stroke events. Of the 1,518 patients with abnormal LAA contractility, 1,086 remained on OAC, and the incidence of stroke/transient ischemic attack (TIA) in this population was 18 of 1,086 (1.7%), whereas the number of TE events in the off-OAC patients (n = 432) was 72 (16.7%); p < 0.001. Of the 90 patients with stroke, 84 received left atrial appendage occlusion (LAAO) devices. At median 12.4 months (interquartile range: 9.8 to 15.3 months) of device implantation, 2 (2.4%) patients were on OAC because of high stroke risk or personal preference, whereas 81 patients discontinued OAC after LAAO device implantation without any TE events. CONCLUSIONS: LAAEI is associated with a significant risk of stroke that can be effectively reduced by optimal uninterrupted OAC or LAAO devices.