Catheter-tissue contact optimizes pulsed electric field ablation with a large area focal catheter.

INTRODUCTION: Pulsed electric field (PEF) ablation relies on the intersection of a critical voltage gradient with tissue to cause cell death. Field-based lesion formation with PEF technologies may still depend on catheter-tissue contact (CTC). The purpose of this study was to assess the impact of CTC on PEF lesion formation with an investigational large area focal (LAF) catheter in a preclinical model. METHODS: PEF ablation via a 10-spline LAF catheter was used to create discrete right ventricle (RV) lesions and atrial lesion sets in 10 swine (eight acute, two chronic). Local impedance (LI) was used to assess CTC. Lesions were assigned to three cohorts using LI above baseline: no tissue contact (NTC: ≤∆10 Ω, close proximity to tissue), low tissue contact (LTC: ∆11-29 Ω), and high tissue contact (HTC: ≥∆30 Ω). Acute animals were infused with triphenyl tetrazolium chloride (TTC) and killed ≥2 h post-treatment. Chronic animals were remapped 30 days post-index procedure and stained with infused TTC. RESULTS: Mean (± SD) RV treatment sizes between LTC (n = 14) and HTC (n = 17) lesions were not significantly different (depth: 5.65 ± 1.96 vs. 5.68 ± 2.05 mm, p = .999; width: 15.68 ± 5.22 vs. 16.98 ± 4.45 mm, p = .737), while mean treatment size for NTC lesions (n = 6) was significantly smaller (1.67 ± 1.16 mm depth, 5.97 ± 4.48 mm width, p < .05). For atrial lesion sets, acute and chronic conduction block were achieved with both LTC (N = 7) and HTC (N = 6), and NTC resulted in gaps. CONCLUSIONS: PEF ablation with a specialized LAF catheter in a swine model is dependent on CTC. LI as an indicator of CTC may aid in the creation of consistent transmural lesions in PEF ablation.

Rationale and design of a randomized study comparing the Watchman FLX device to DOACs in patients with atrial fibrillation.

BACKGROUND: Percutaneous left atrial appendage (LAA) closure (LAAC) was developed as a nonpharmacologic alternative to oral anticoagulants (OACs) in patients with atrial fibrillation (AF) who are at an increased risk for stroke or systemic embolism. The Watchman device permanently seals off the LAA to prevent thrombi from escaping into the circulation. Previous randomized trials have established the safety and efficacy of LAAC compared to warfarin. However, direct OACs (DOACs) have become the preferred pharmacologic strategy for stroke prevention in patients with AF, and there is limited data comparing Watchman FLX to DOACs in a broad AF patient population. CHAMPION-AF is designed to prospectively determine whether LAAC with Watchman FLX is a reasonable first-line alternative to DOACs in patients with AF who are indicated for OAC therapy. STUDY DESIGN: A total of 3,000 patients with a CHA2DS2-VASc score ≥2 (men) or ≥3 (women) were randomized to Watchman FLX or DOAC in a 1:1 allocation at 142 global clinical sites. Patients in the device arm were to be treated with DOAC and aspirin, DOAC alone, or DAPT for at least 3 months postimplant followed by aspirin or P2Y12 inhibitor for 1-year. Control patients were required to take an approved DOAC for the duration of the trial. Clinical follow-up visits are scheduled at 3- and 12-months, and then annually through 5 years; LAA imaging is required at 4 months in the device group. Two primary end points will be evaluated at 3 years: (1) composite of stroke (ischemic/hemorrhagic), cardiovascular death, and systemic embolism compared for noninferiority, and (2) nonprocedural bleeding (International Society on Thrombosis and Haemostasis [ISTH] major and clinically relevant nonmajor bleeding) tested for superiority in the device arm against DOACs. The third primary noninferiority end point is the composite of ischemic stroke and systemic embolism at 5 years. Secondary end points include 3- and 5-year rates of (1) ISTH-defined major bleeding and (2) the composite of cardiovascular death, all stroke, systemic embolism, and nonprocedural ISTH bleeding. CONCLUSIONS: This study will prospectively evaluate whether LAAC with the Watchman FLX device is a reasonable alternative to DOACs in patients with AF. CLINICAL TRIAL REGISTRATION: NCT04394546.

Primary Outcome Evaluation of a Next-Generation Left Atrial Appendage Closure Device: Results From the PINNACLE FLX Trial.

BACKGROUND: Left atrial appendage (LAA) occlusion provides an alternative to oral anticoagulation for thromboembolic risk reduction in patients with nonvalvular atrial fibrillation. Since regulatory approval in 2015, the WATCHMAN device has been the only LAA closure device available for clinical use in the United States. The PINNACLE FLX study (Protection Against Embolism for Nonvalvular AF Patients: Investigational Device Evaluation of the Watchman FLX LAA Closure Technology) evaluated the safety and effectiveness of the next-generation WATCHMAN FLX LAA closure device in patients with nonvalvular atrial fibrillation in whom oral anticoagulation is indicated, but who have an appropriate rationale to seek a nonpharmaceutical alternative. METHODS: This was a prospective, nonrandomized, multicenter US Food and Drug Administration study. The primary safety end point was the occurrence of one of the following events within 7 days after the procedure or by hospital discharge, whichever was later: death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring cardiac surgery. The primary effectiveness end point was the incidence of effective LAA closure (peri-device flow ≤5 mm), as assessed by the echocardiography core laboratory at 12-month follow-up. RESULTS: A total of 400 patients were enrolled. The mean age was 73.8±8.6 years and the mean CHA2DS2-VASc score was 4.2±1.5. The incidence of the primary safety end point was 0.5% with a 1-sided 95% upper CI of 1.6%, meeting the performance goal of 4.2% (P<0.0001). The incidence of the primary effectiveness end point was 100%, with a 1-sided 95% lower CI of 99.1%, again meeting the performance goal of 97.0% (P<0.0001). Device-related thrombus was reported in 7 patients, no patients experienced pericardial effusion requiring open cardiac surgery, and there were no device embolizations. CONCLUSIONS: LAA closure with this next-generation LAA closure device was associated with a low incidence of adverse events and a high incidence of anatomic closure. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02702271.

In vivo porcine characterization of atrial lesion safety and efficacy utilizing a circular pulsed-field ablation catheter including assessment of collateral damage to adjacent tissue in supratherapeutic ablation applications.

INTRODUCTION: Pulsed-field ablation (PFA), an ablative method that causes cell death by irreversible electroporation, has potential safety advantages over radiofrequency ablation and cryoablation. Pulmonary vein (PV) isolation was performed in a porcine model to characterize safety and performance of a novel, fully-integrated biphasic PFA system comprising a multi-channel generator, variable loop circular catheter, and integrated PFA mapping software module. METHODS: Eight healthy porcine subjects were included. To evaluate safety, multiple ablations were performed, including sites not generally targeted for therapeutic ablation, such as the right inferior PV lumen, right superior PV ostium, and adjacent to the esophagus and phrenic nerve. To evaluate the efficacy, animals were recovered, followed for 30(±3) days, then re-mapped. Gross pathological and histopathological examinations assessed procedural injuries, chronic thrombosis, tissue ablation, penetration depth, healing, and inflammatory response. RESULTS: All eight animals survived follow-up. PV narrowing was not observed acutely nor at follow-up, even when ablation was performed deep to the PV ostium. No injury was seen grossly or histologically in adjacent structures. All PVs were durably isolated, confirmed by bidirectional block at re-map procedure. Histological examination showed complete, transmural necrosis around the circumference of the ablated section of right PVs. CONCLUSION: This preclinical evaluation of a fully-integrated PFA system demonstrated effective and durable ablation of cardiac tissue and PV isolation without collateral damage to adjacent structures, even when ablation was performed in more extreme settings than those used therapeutically. Histological staining confirmed complete transmural cell necrosis around the circumference of the PV ostium at 30 days.

Device-Related Thrombus After Left Atrial Appendage Closure: Incidence, Predictors, and Outcomes.

BACKGROUND: In patients with atrial fibrillation, left atrial appendage closure with the Watchman device prevents thromboembolism from the left atrial appendage; however, thrombus may form on the left atrial face of the device, and then potentially embolize. Herein, we studied the incidence, predictors, and clinical outcome of device-related thrombus (DRT) using a large series of clinical trial cohorts of patients undergoing Watchman implantation. METHODS: We studied the device arms of 4 prospective Food and Drug Administration trials: PROTECT-AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) (n=463); PREVAIL (Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) (n=269); CAP (Continued Access to PROTECT AF registry) (n=566); and CAP2 (Continued Access to PREVAIL registry) (n=578). Surveillance transesophageal echocardiographs were performed at 45 days and 12 months in all patients, and also at 6 months in the randomized control trials. We assessed both the incidence of DRT during these transesophageal echocardiographs (and other unscheduled transesophageal echocardiographs), and clinical outcomes of postprocedure stroke or systemic embolism (SSE) and adjusted for CHA2DS2-VASC and HAS-BLED scores. RESULTS: Of 1739 patients who received an implant (7159 patient-years follow-up; CHA2DS2-VASc=4.0), DRT was seen in 65 patients (3.74%). The rates of SSE with and without DRT were 7.46 and 1.78 per 100 patient-years (adjusted rate ratio, 3.55; 95% confidence interval [CI], 2.18-5.79; P<0.001), and ischemic SSE rates were 6.28 and 1.65 per 100 patient-years (adjusted rate ratio, 3.22; 95% CI, 1.90-5.45, P<0.001). On multivariable modeling analysis, the predictors of DRT were as follows: history of transient ischemic attack or stroke (odds ratio [OR], 2.31; 95% CI, 1.26-4.25; P=0.007), permanent atrial fibrillation (OR, 2.24; 95% CI, 1.19-4.20; P=0.012); vascular disease (OR, 2.06; 95% CI, 1.08-3.91; P=0.028); left atrial appendage diameter (OR, 1.06 per mm increase; 95% CI, 1.01-1.12; P=0.019); left ventricular ejection fraction (OR, 0.96 per 1% increase; 95% CI, 0.94-0.99; P=0.009). DRT and SSE both occurred in 17 of 65 patients (26.2%). Of the 19 SSE events in these patients with DRT, 9 of 19 (47.4%) and 12 of 19 (63.2%) occurred within 1 and 6 months of DRT detection. Conversely, after left atrial appendage closure, most SSEs (123/142, 86.62%) occurred in patients without DRT. CONCLUSIONS: After left atrial appendage closure with Watchman, DRT (≈3.7%) is not frequent but, when present, is associated with a higher rate of stroke and systemic embolism.

Pulmonary Vein Isolation Using the Visually Guided Laser Balloon: Results of the U.S. Feasibility Study.

INTRODUCTION: Visually guided laser balloon (VGLB) ablation is unique in that the operator delivers ablative energy under direct visual guidance. In this multicenter study, we sought to determine the feasibility, efficacy, and safety of performing pulmonary vein isolation (PVI) using this VGLB. METHODS: Patients with symptomatic, drug-refractory paroxysmal atrial fibrillation (AF) underwent PVI using the VGLB with the majority of operators conducting their first-ever clinical VGLB cases. The primary effectiveness endpoint was defined as freedom from treatment failure that included: Occurrence of symptomatic AF episodes ≥1 minutes beyond the 90-day blanking, the inability to isolate 1 superior and 2 total PVs, occurrence of left atrial flutter or atrial tachycardia, or left atrial ablation/surgery during follow-up. RESULTS: A total of 86 patients (mean age 56 ± 10 years, 67% male) were treated with the VGLB at 10 US centers. Mean fluoroscopy, ablation, and procedure times were 39.8 ± 24.3 minutes, 205.2 ± 61.7 minutes, and 253.5 ± 71.3 minutes, respectively. Acute PVI was achieved in 314/323 (97.2%) of targeted PVs. Of 84 patients completing follow-up, the primary effectiveness endpoint was achieved in 50 (60%) patients. Freedom from symptomatic or asymptomatic AF was 61%. The primary adverse event rate was 16.3% (8.1% pericarditis, phrenic nerve injury 5.8%, and cardiac tamponade 3.5%). There were no cerebrovascular events, atrioesophageal fistulas, or significant PV stenosis. CONCLUSIONS: This multicenter study of operators in the early stage of the learning curve demonstrates that PVI can be achieved with the VGLB with a reasonable safety profile and an efficacy similar to radiofrequency ablation.

Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial.

BACKGROUND: The multicenter PROTECT AF study (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) was conducted to determine whether percutaneous left atrial appendage closure with a filter device (Watchman) was noninferior to warfarin for stroke prevention in atrial fibrillation. METHODS AND RESULTS: Patients (n=707) with nonvalvular atrial fibrillation and at least 1 risk factor (age >75 years, hypertension, heart failure, diabetes, or prior stroke/transient ischemic attack) were randomized to either the Watchman device (n=463) or continued warfarin (n=244) in a 2:1 ratio. After device implantation, warfarin was continued for ≈45 days, followed by clopidogrel for 4.5 months and lifelong aspirin. Study discontinuation rates were 15.3% (71/463) and 22.5% (55/244) for the Watchman and warfarin groups, respectively. The time in therapeutic range for the warfarin group was 66%. The composite primary efficacy end point included stroke, systemic embolism, and cardiovascular death, and the primary analysis was by intention to treat. After 1588 patient-years of follow-up (mean 2.3±1.1 years), the primary efficacy event rates were 3.0% and 4.3% (percent per 100 patient-years) in the Watchman and warfarin groups, respectively (relative risk, 0.71; 95% confidence interval, 0.44%-1.30% per year), which met the criteria for noninferiority (probability of noninferiority >0.999). There were more primary safety events in the Watchman group (5.5% per year; 95% confidence interval, 4.2%-7.1% per year) than in the control group (3.6% per year; 95% confidence interval, 2.2%-5.3% per year; relative risk, 1.53; 95% confidence interval, 0.95-2.70). CONCLUSIONS: The "local" strategy of left atrial appendage closure is noninferior to "systemic" anticoagulation with warfarin. PROTECT AF has, for the first time, implicated the left atrial appendage in the pathogenesis of stroke in atrial fibrillation. CLINICAL TRIAL REGISTRATION: : URL: http://www.clinicaltrials.gov. Unique identifier: NCT00129545.

Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial.

IMPORTANCE: While effective in preventing stroke in patients with atrial fibrillation (AF), warfarin is limited by a narrow therapeutic profile, a need for lifelong coagulation monitoring, and multiple drug and diet interactions. OBJECTIVE: To determine whether a local strategy of mechanical left atrial appendage (LAA) closure was noninferior to warfarin. DESIGN, SETTING, AND PARTICIPANTS: PROTECT AF was a multicenter, randomized (2:1), unblinded, Bayesian-designed study conducted at 59 hospitals of 707 patients with nonvalvular AF and at least 1 additional stroke risk factor (CHADS2 score ≥1). Enrollment occurred between February 2005 and June 2008 and included 4-year follow-up through October 2012. Noninferiority required a posterior probability greater than 97.5% and superiority a probability of 95% or greater; the noninferiority margin was a rate ratio of 2.0 comparing event rates between treatment groups. INTERVENTIONS: Left atrial appendage closure with the device (n = 463) or warfarin (n = 244; target international normalized ratio, 2-3). MAIN OUTCOMES AND MEASURES: A composite efficacy end point including stroke, systemic embolism, and cardiovascular/unexplained death, analyzed by intention-to-treat. RESULTS: At a mean (SD) follow-up of 3.8 (1.7) years (2621 patient-years), there were 39 events among 463 patients (8.4%) in the device group for a primary event rate of 2.3 events per 100 patient-years, compared with 34 events among 244 patients (13.9%) for a primary event rate of 3.8 events per 100 patient-years with warfarin (rate ratio, 0.60; 95% credible interval, 0.41-1.05), meeting prespecified criteria for both noninferiority (posterior probability, >99.9%) and superiority (posterior probability, 96.0%). Patients in the device group demonstrated lower rates of both cardiovascular mortality (1.0 events per 100 patient-years for the device group [17/463 patients, 3.7%] vs 2.4 events per 100 patient-years with warfarin [22/244 patients, 9.0%]; hazard ratio [HR], 0.40; 95% CI, 0.21-0.75; P = .005) and all-cause mortality (3.2 events per 100 patient-years for the device group [57/466 patients, 12.3%] vs 4.8 events per 100 patient-years with warfarin [44/244 patients, 18.0%]; HR, 0.66; 95% CI, 0.45-0.98; P = .04). CONCLUSIONS AND RELEVANCE: After 3.8 years of follow-up among patients with nonvalvular AF at elevated risk for stroke, percutaneous LAA closure met criteria for both noninferiority and superiority, compared with warfarin, for preventing the combined outcome of stroke, systemic embolism, and cardiovascular death, as well as superiority for cardiovascular and all-cause mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00129545.

Two-Year Outcomes With a Next-Generation Left Atrial Appendage Device: Final Results of the PINNACLE FLX Trial.

Background The PINNACLE FLX (Protection Against Embolism for Non-valvular AF [Atrial Fibrillation] Patients: Investigational Device Evaluation of the Watchman FLX LAA [Left Atrial Appendage] Closure Technology) trial evaluated the safety and efficacy of a next-generation left atrial appendage closure device (WATCHMAN FLX; Boston Scientific, Marlborough, MA). At 1 year, the study met the primary end points of safety and anatomical efficacy/appendage closure. This final report of the PINNACLE FLX trial includes the prespecified secondary end point of ischemic stroke or systemic embolism at 2 years, also making it the first report of 2-year outcomes with this next-generation left atrial appendage closure device. Methods and Results Patients with nonvalvular atrial fibrillation with CHA2DS2-VASc score ≥2 (men) or ≥3 (women), with an appropriate rationale for left atrial appendage closure, were enrolled to receive the left atrial appendage closure device at 29 US centers. Adverse events were assessed by an independent clinical events committee, and imaging was assessed by independent core laboratories. Among 395 implanted patients (36% women; mean age, 74 years; CHA2DS2-VASc, 4.2±1.5), the secondary efficacy end point of 2-year ischemic stroke or systemic embolism was met, with an absolute rate of 3.4% (annualized rate, 1.7%) and an upper 1-sided 95% confidence bound of 5.3%, which was superior to the 8.7% performance goal. Two-year rates of adverse events were as follows: 9.3% all-cause mortality, 5.5% cardiovascular death, 3.4% all stroke, and 10.1% major bleeding (Bleeding Academic Research Consortium 3 or 5). There were no additional systemic embolisms, device embolizations, pericardial effusions, or symptomatic device-related thrombi after 1 year. Conclusions The secondary end point of 2-year stroke or systemic embolism was met at 3.4%. In these final results of the PINNACLE FLX trial, the next-generation WATCHMAN FLX device demonstrated favorable safety and efficacy outcomes.

Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry.

BACKGROUND: The Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF (PROTECT AF) randomized trial compared left atrial appendage closure against warfarin in atrial fibrillation (AF) patients with CHADS2 ≥1. Although the study met the primary efficacy end point of being noninferior to warfarin therapy for the prevention of stroke/systemic embolism/cardiovascular death, there was a significantly higher risk of complications, predominantly pericardial effusion and procedural stroke related to air embolism. Here, we report the influence of experience on the safety of percutaneous left atrial appendage closure. METHODS AND RESULTS: The study cohort for this analysis included patients in the PROTECT AF trial who underwent attempted device left atrial appendage closure (n=542 patients) and those from a subsequent nonrandomized registry of patients undergoing Watchman implantation (Continued Access Protocol [CAP] Registry; n=460 patients). The safety end point included bleeding- and procedure-related events (pericardial effusion, stroke, device embolization). There was a significant decline in the rate of procedure- or device-related safety events within 7 days of the procedure across the 2 studies, with 7.7% and 3.7% of patients, respectively, experiencing events (P=0.007), and between the first and second halves of PROTECT AF and CAP, with 10.0%, 5.5%, and 3.7% of patients, respectively, experiencing events (P=0.006). The rate of serious pericardial effusion within 7 days of implantation, which had made up >50% of the safety events in PROTECT AF, was lower in the CAP Registry (5.0% versus 2.2%, respectively; P=0.019). There was a similar experience-related improvement in procedure-related stroke (0.9% versus 0%, respectively; P=0.039). Finally, the functional impact of these safety events, as defined by significant disability or death, was statistically superior in the Watchman group compared with the warfarin group in PROTECT AF. This remained true whether significance was defined as a change in the modified Rankin score of ≥1, ≥2, or ≥3 (1.8 versus 4.3 events per 100 patient-years; relative risk, 0.43; 95% confidence interval, 0.24 to 0.82; 1.5 versus 3.7 events per 100 patient-years; relative risk, 0.41; 95% confidence interval, 0.22 to 0.82; and 1.4 versus 3.3 events per 100 patient-years; relative risk, 0.43; 95% confidence interval, 0.22 to 0.88, respectively). CONCLUSION: As with all interventional procedures, there is a significant improvement in the safety of Watchman left atrial appendage closure with increased operator experience. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00129545.

Efficacy of tuned waveforms based on different membrane time constants on defibrillation thresholds: primary results from the POWER trial.

BACKGROUND: The efficacy of tuned defibrillation waveforms versus the nominal fixed-tilt waveform has been previously studied. However, the optimal membrane time constant for tuning was not known. The POWER (Pulsewidth Optimized Waveform Evaluation tRial) trial was designed to determine the optimal membrane time constant for programming "tuned" biphasic waveforms. METHODS: This acute, multicenter study included 121 implantable cardioverter-defibrillator/cardiac resynchronization therapy defibrillator patients who were randomized at implant to any two of the three membrane time constant waveforms (2.5, 3.5, and 4.5 ms). Fixed pulse widths were programmed using the measured high voltage shock impedance. The defibrillation threshold (DFT) estimates were obtained using a hybrid protocol starting with an upper limit of vulnerability estimate followed by a step-up/step-down ventricular fibrillation induction process. RESULTS: DFT voltage was significantly lower using 3.5- and 4.5-ms waveforms as compared to the 2.5-ms waveform (P = 0.004 and 0.035, respectively). DFT voltage with both 3.5- and 4.5-ms waveforms was ≤ that obtained with the 2.5-ms waveform in 78.5% of the cases. The mean difference in DFT voltage using the 3.5-ms waveform and the 4.5-ms waveform was not significant (P = 0.4). However, the 3.5-ms waveform gave a lower DFT than the 4.5-ms waveform in 19 patients although the reverse was true in only nine (P = 0.02 not significant for multiple comparisons). CONCLUSIONS: The use of a 3.5- or 4.5-ms time constant-based waveforms had lower DFTs when compared to the 2.5-ms waveform. This study suggests that the first defibrillation attempt at implantation should be with 3.5- or 4.5-ms time constant-based waveforms. The 3.5-ms-based waveform trended toward the best choice.

Impact of Peridevice Leak on 5-Year Outcomes After Left Atrial Appendage Closure.

BACKGROUND: In the U.S. Food and Drug Administration (FDA) clinical trials of left atrial appendage (LAA) closure, a postimplantation peridevice leak (PDL) of ≤5 mm (PDL≤5) was accepted as sufficient LAA "closure." However, the clinical consequences of these PDLs on subsequent thromboembolism are poorly characterized. OBJECTIVES: We sought to assess the impact of PDL≤5 on clinical outcomes after implantation of the Watchman device. METHODS: Using combined data from the FDA studies PROTECT-AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation), PREVAIL (Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation vs Long Term Warfarin Therapy), and CAP2 (Continued Access to PREVAIL), we assessed patients with successful device implantation for PDL by means of protocol-mandated transesophageal echocardiograms (TEEs) at 45 days and 1 year. Five-year outcomes were assessed as a function of the absence or presence of PDL≤5. RESULTS: The cohort included 1,054 patients: mean age 74 ± 8.3 years, 65% male, and CHA2DS2-VASc 4.1 ± 1.4. TEE imaging at 45 days revealed 634 patients (60.2%) without and 404 (38.3%) with PDL≤5, and 1-year TEE revealed 704 patients (71.6%) without and 272 (27.7%) with PDL≤5. The presence of PDL≤5 at 1 year, but not at 45 days, was associated with an increased 5-year risk of ischemic stroke or systemic embolism (adjusted HR: 1.94; 95% CI: 1.15-3.29; P = 0.014), largely driven by an increase in nondisabling stroke (HR: 1.97; 95% CI: 1.03-3.78; P = 0.04), while disabling or fatal stroke rates were similar (HR: 0.69; 95% CI: 0.19-2.46; P = 0.56). PDL≤5 was not associated with an increased risk of cardiovascular or unexplained death (HR: 1.20; P = 0.45) or all-cause death (HR: 0.87; P = 0.42). CONCLUSIONS: PDL≤5 at 1 year after percutaneous LAA closure with the Watchman device are associated with increased thromboembolism, driven by increased nondisabling stroke, but similar mortality. (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation [PROTECT-AF; NCT00129545]; Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation vs Long Term Warfarin Therapy [PREVAIL; NCT01182441]; Continued Access to PREVAIL [CAP2; NCT01760291]).

Antithrombotic Therapy After Left Atrial Appendage Occlusion in Patients With Atrial Fibrillation.

BACKGROUND: Pivotal trials of percutaneous left atrial appendage occlusion (LAAO) used specific postprocedure treatment protocols. OBJECTIVES: This study sought to evaluate patterns of postprocedure care after LAAO with the Watchman device in clinical practice and compare the risk of adverse events for different discharge antithrombotic strategies. METHODS: We evaluated patients in the LAAO Registry of the National Cardiovascular Data Registry who underwent LAAO with the Watchman device between 2016 and 2018. We assessed adherence to the full postprocedure trial protocol including standardized follow-up, imaging, and antithrombotic agents and then evaluated the most commonly used antithrombotic strategies and compared the rates and risk of adverse events at 45 days and 6 months by means of multivariable COX frailty regression. RESULTS: Among 31,994 patients undergoing successful LAAO, only 12.2% received the full postprocedure treatment protocol studied in pivotal trials; the most common protocol deviations were with discharge antithrombotic medications. The most common discharge medication strategies were warfarin and aspirin (36.9%), direct oral anticoagulant (DOAC) and aspirin (20.8%), warfarin only (13.5%), DOAC only (12.3%), and dual antiplatelet therapy (5.0%). In multivariable Cox frailty regression, the adjusted risk of any adverse event through the 45-day follow-up visit were significantly lower for discharge on warfarin alone (HR: 0.692; 95% CI: 0.569-0.841) and DOAC alone (HR: 0.731; 95% CI: 0.574-0.930) compared with warfarin and aspirin. Warfarin alone retained lower risk at the 6-month follow-up. CONCLUSIONS: In contemporary U.S. practice, practitioners rarely used the full U.S. Food and Drug Administration-approved postprocedure treatment protocols studied in pivotal trials of the Watchman device. Discharge after implantation on warfarin or DOAC without concomitant aspirin was associated with lower risk of adverse outcomes.

Evaluation of Multimodality LAA Leak Closure Methods Following Incomplete Occlusion: The LAA Leak Study.

BACKGROUND: Incomplete left atrial appendage (LAA) closure is an evolving topic of clinical significance and thromboembolic potential, with recent long-term studies suggesting lower cutoffs for relevant leak size. OBJECTIVES: The aim of this prospective observational study was to assess 3 different closure techniques for persistent peridevice leaks after incomplete LAA closure and compare their efficacy and safety outcomes. METHODS: We studied 160 patients (mean age 72 ± 9 years; 71% men) who underwent 1 of the 3 available modalities (detachable embolization coils, vascular plugs or septal occluders, and radiofrequency ablation) for residual central or eccentric leak closure. Both acute postprocedural success (closure or <1-mm leak at the end of the procedure) and closure at 1-year follow-up transesophageal echocardiography imaging were evaluated. RESULTS: Of 160 patients, 0.6%, 41.3%, and 58.1% had mild (1-2 mm), moderate (3-5 mm), and severe (≥5 mm) leaks, respectively. Baseline LAA closure type was 72.5% Watchman FLX, 16.3% Lariat, 5.6% surgical ligation, 1.9% AtriClip, and 1.9% Amulet. Successful closure (0- or <1-mm leak) was seen in 100% of patients in all cohorts following intervention, with overall complete closure (0-1 mm) or mild or minimal leaks (1-2 mm) on 1-year follow-up transesophageal echocardiography seen in 100% of the atrial septal occluder or vascular plug cohort, 85.9% of the coil cohort, and 83.3% of the radiofrequency ablation cohort (P < 0.001). Two patients (1.3%) experienced cardiac tamponade, and there were no deaths or other complications. CONCLUSIONS: Peridevice leaks can safely and effectively be closed using 3 different modalities depending on size and location.

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).

Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial.

BACKGROUND: In patients with non-valvular atrial fibrillation, embolic stroke is thought to be associated with left atrial appendage (LAA) thrombi. We assessed the efficacy and safety of percutaneous closure of the LAA for prevention of stroke compared with warfarin treatment in patients with atrial fibrillation. METHODS: Adult patients with non-valvular atrial fibrillation were eligible for inclusion in this multicentre, randomised non-inferiority trial if they had at least one of the following: previous stroke or transient ischaemic attack, congestive heart failure, diabetes, hypertension, or were 75 years or older. 707 eligible patients were randomly assigned in a 2:1 ratio by computer-generated randomisation sequence to percutaneous closure of the LAA and subsequent discontinuation of warfarin (intervention; n=463) or to warfarin treatment with a target international normalised ratio between 2.0 and 3.0 (control; n=244). Efficacy was assessed by a primary composite endpoint of stroke, cardiovascular death, and systemic embolism. We selected a one-sided probability criterion of non-inferiority for the intervention of at least 97.5%, by use of a two-fold non-inferiority margin. Serious adverse events that constituted the primary endpoint for safety included major bleeding, pericardial effusion, and device embolisation. Analysis was by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00129545. FINDINGS: At 1065 patient-years of follow-up, the primary efficacy event rate was 3.0 per 100 patient-years (95% credible interval [CrI] 1.9-4.5) in the intervention group and 4.9 per 100 patient-years (2.8-7.1) in the control group (rate ratio [RR] 0.62, 95% CrI 0.35-1.25). The probability of non-inferiority of the intervention was more than 99.9%. Primary safety events were more frequent in the intervention group than in the control group (7.4 per 100 patient-years, 95% CrI 5.5-9.7, vs 4.4 per 100 patient-years, 95% CrI 2.5-6.7; RR 1.69, 1.01-3.19). INTERPRETATION: The efficacy of percutaneous closure of the LAA with this device was non-inferior to that of warfarin therapy. Although there was a higher rate of adverse safety events in the intervention group than in the control group, events in the intervention group were mainly a result of periprocedural complications. Closure of the LAA might provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with non-valvular atrial fibrillation. FUNDING: Atritech.

Follow-up imaging after left atrial appendage closure.

BACKGROUND: Because device-related thrombus (DRT) portends a poor prognosis after left atrial appendage closure with the Watchman device, surveillance transesophageal echocardiography (TEE) is recommended at 45 days and 1 year. However, oral anticoagulants are just discontinued at 45 days, rendering this early TEE unlikely to detect DRT. Indeed, DRT is most likely to occur after instituting aspirin monotherapy. OBJECTIVE: The purpose of this study was to evaluate the alternative strategy of first TEE imaging (or computed tomography) at 4 months post-Watchman implantation. METHODS: After Food and Drug Administration approval, consecutive patients undergoing Watchman implantation at 2 centers received TEE or CT at 4 months and 1 year, along with a truncated drug regimen: 6 weeks of an oral anticoagulant (or clopidogrel in a subset) plus aspirin, then 6 weeks of dual antiplatelet therapy, and finally aspirin monotherapy. RESULTS: Of the 530-patient cohort (mean age 78.7±7.9 years; 65.5% (n = 347) male; CHA2DS2-VASc score 4.5±1.4), 465 patients (87.7%) received 4-month imaging: 83.0% (440 of 530) TEE and 4.7% (25 of 530) computed tomography. Over a median follow-up of 12 months, 16 ischemic strokes (ISs), 8 transient ischemic attacks, and 1 systemic embolization occurred. Importantly, no IS occurred between 45 days and 4 months; the sole transient ischemic attack in this period (at ∼2 months) occurred 1 week after transcatheter aortic valve replacement. DRT was detected in 2.4% (11 of 465) at 4 months and 0.9% (2 of 214) at 1 year. No IS, but 1 leg embolization, was observed after DRT detection. CONCLUSION: Delaying the first imaging post-Watchman implantation to 4 months was associated with no IS between 45 days and 4 months, the "vulnerable" period of this follow-up strategy.

Long-Term Safety and Efficacy in Continued Access Left Atrial Appendage Closure Registries.

BACKGROUND: Long-term data on the safety and efficacy of left atrial appendage closure (LAAC) for stroke prevention in patients with nonvalvular atrial fibrillation remain limited. OBJECTIVES: The purpose of this study was to evaluate 4.5- to 5-year data in 2 U.S. Food and Drug Association LAAC mandated registries (CAP [Continued Access to PROTECT-AF] and CAP2 [Continued Access to PREVAIL]) for safety and efficacy. METHODS: Two registries of patients implanted with LAAC devices provide the largest source of follow-up data. Both accompanied their respective randomized clinical trials, PROTECT-AF (Watchman Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device In Patients with Atrial Fibrillation versus Long Term Warfarin Therapy), which used the same endpoints (primary efficacy of composite of stroke, systemic embolism, cardiovascular/unexplained death, and safety). RESULTS: CAP included 566 patients with an average follow-up of 50.1 months (2,293 patient-years), and CAP2 included 578 patients with an average follow-up of 50.3 months (2,227 patient-years). CAP2 patients were significantly older and had higher CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) scores (4.51 vs. 3.88; p < 0.001). Procedural success was similar in both (94%). The primary composite endpoint occurred at a rate of 3.05 per 100 patient-years in CAP and 4.80 per 100 patient-years in CAP2; events contributing to this endpoint were most commonly cardiovascular/unexplained death (1.69 per 100 patient-years for CAP and 2.92 per 100 patient-years for CAP2). Hemorrhagic stroke was significantly less than ischemic stroke (0.17 per 100 patient-years in CAP and 0.09 per 100 patient-years in CAP2), and total stroke rates were significantly less than predicted by CHA2DS2-VASc score (78% reduction with CAP, 69% reduction with CAP2). CONCLUSIONS: These registries, which contain the longest and largest follow-up data of patients with the Watchman device, support LAAC as a safe and effective therapy for long-term anticoagulation in patients with nonvalvular atrial fibrillation, and document the lowest rate of hemorrhagic stroke identified in this population.