Doshi, Shephal K.

Abstract Since its introduction in 2002, left atrial appendage closure (LAAC) has rapidly expanded as an alternative to anticoagulation in patients with atrial fibrillation at high risk of stroke. Harmonized processes for data collection, analysis, and reporting in LAAC trials are essential to enhance research quality and improve clinical practice. The Left Atrial Appendage Academic Research Consortium (LAARC) initiative is an independent collaboration of academic research organizations, cardiology and neurology experts, clinical trialists, and regulatory authorities from the USA, Europe, and Asia. The consortium engaged clinical experts, regulators—including the US Food and Drug Administration (FDA), European Notified Bodies, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA)—and industry leaders to define standardized study elements and endpoints for LAAC trials. Key considerations included alignment with prior Academic Research Consortium initiatives, procedural and mechanistic insights, and clinical relevance. Consensus definitions were proposed for mortality, stroke, bleeding, and device performance, along with composite endpoints for safety and effectiveness. The proposed LAARC consensus definitions aim to standardize endpoint reporting, improve comparability across studies, and support regulatory and clinical trial applications for this evolving therapy through broad dissemination in the peer-reviewed literature.

Introduction: Left atrial appendage closure (LAAC) device for stroke prevention is a safe and effective alternative to oral anticoagulation (OAC) in patients with atrial fibrillation (AF). The safety of performing LAAC on uninterrupted warfarin (UW) compared to interrupted warfarin (IW) is currently unknown. Hypothesis: Complication rates of performing LAAC on UW vs. IW will be similar. Methods: We reviewed the data from the second half of PROTECT-AF trial, PREVAIL trial, CAP and CAP2 registries. Patients were categorized to the UW group if INR on the day of the procedure was ≥2 and to the IW group if INR was <2. Procedural complications within 7 days of LAAC were reviewed. An association between complications and AC strategy was analyzed. Results: Data from 1580 patients were reviewed and 294 patients (18.6%) received LAAC on UW. The UW group had a mean INR of 2.4±0.4 and IW group had a mean INR of 1.3±0.3. There were several differences in baseline characteristics: lower BMI in the UW group (28.6±5.3 vs 29.5±6.0, p=0.01), fewer patients with hypertension in the UW group (87.1% vs 91.1%, p=0.04), lower HAS-BLED score in the UW group (2.0±1.0 vs 2.1±1.0, p<0.01), and more patients with persistent AF in the UW group (37.1% vs 26.4%, p<0.01). Overall, there were no significant differences in total or individual complication rates between the two groups (UW 5.1% vs IW 6.1%, p=0.59). Although not statistically significant, lower event rates were noted in the UW group for the following: stroke (0% vs 0.3%, p>0.99), pericardial effusion requiring intervention (1.7% vs 1.8%, p>0.99), pseudoaneurysm (0% vs 0.4%, p=0.59), hematoma (0% vs 0.2%, p>0.99), and device embolism (0% vs 0.2%, p=1.0). The UW group had statistically insignificant higher events rates of AV fistula (0.3% vs 0%, p=0.19) and major bleeding requiring transfusion (1% vs 0.5%, p=0.38). In addition, there was no significant difference in periprocedural ischemic stroke (0% vs 0.3%, p>0.99). Conclusion: In this retrospective analysis, no significant difference was observed in procedural complication rates when performing LAAC on UW vs. IW. These results suggest that LAAC can be safely performed without interruption of OAC.

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 CHA 2 DS 2 ‐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; CHA 2 DS 2 ‐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.

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 CHA 2 DS 2 -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.

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 CHA 2 DS 2 -VASC and HAS-BLED scores. Results: Of 1739 patients who received an implant (7159 patient-years follow-up; CHA 2 DS 2 -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.

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.

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 CHADS 2 ≥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.