A special issue of JACC published Thursday, Nov. 12, focuses on left atrial appendage closure (LAAC), presenting the most recent results from the ASAP-TOO trial, along with a JACC evidence review for LAAC vs. anticoagulation, and a number of analyses and viewpoints on current LAAC evidence, practice patterns and emerging clinical questions.

"We devoted this issue of JACC to LAAC because of the disagreement over what the trials establish and how their findings should guide decisions," write JACC Executive Associate Editor Behnood Bikdeli, MD, FACC, and Editor-in-Chief Harlan M. Krumholz, MD, SM, MACC, in an accompanying Editor's Page, adding that the issue "can show which decisions the evidence supports, which require extrapolation from the patients who were studied to patients who were not, and what remains to be learned."

Contributing to this conversation are the five-year results from ASAP-TOO, the largest randomized comparison of LAAC vs. single antiplatelet therapy or no antithrombotic therapy in patients with atrial fibrillation (AFib) considered unsuitable for oral anticoagulation. Despite early termination of enrollment, the study showed LAAC implantation had high procedural success and met the prespecified early safety performance goal, with exploratory signals suggesting fewer thromboembolic events, cardiovascular or unexplained deaths and disabling or fatal strokes. Early bleeding was increased during mandated postimplant dual antiplatelet therapy.

Vivek Reddy, MD, and colleagues randomized 481 patients (mean age, 75 years; 39% women) with AFib and CHA₂DS₂-VASc score ≥2 who were not suitable for oral anticoagulation 2:1 to LAAC with a Watchman device, followed by dual antiplatelet therapy for three months and aspirin through 12 months, or to control, consisting of either sing/le or no antiplatelet therapy.

The LAAC success rate was high at 97.8%, and only 31 of the 101 planned primary effectiveness events, defined as time to first ischemic stroke or systemic embolism, occurred. Only three (1.0%) of implant-attempted patients experienced the primary safety endpoint. There was one procedural death, one procedure-related stroke and three pericardial effusions requiring intervention.

At up to five years, the Kaplan-Meier estimates in the LAAC vs. control groups were 7.8% and 11.4% for ischemic stroke or systemic embolism (hazard ratio [HR], 0.73; p=0.39), and 22.1% and 15.7% for major bleeding (HR, 1.64; p=0.067), which was concentrated during the first three months of DAPT. An exploratory analysis showed that disabling/fatal stroke was nominally less frequent with LAAC (2.2% vs. 5.7%; HR, 0.32).

However, early termination, fewer-than-planned events and substantial differential attrition left the trial underpowered to determine whether LAAC was superior to control for preventing ischemic stroke or systemic embolism.

The trial "ultimately remains inconclusive," write the investigators, but "these observations underscore that LAAC is not intrinsically 'bleeding free.' Its net value depends on a number of factors including procedural safety, device generation, and the intensity and duration of postimplantation therapy."

"Despite premature termination, ASAP-TOO provides important randomized and extended follow-up data from a population that has proved exceptionally difficult to study," write Davide Capodanno, MD, PhD; Shubhadarshini Pawar, MBBS, MPH; and Bikdeli in an editorial comment. "ASAP-TOO does not close that gap but is a valuable effort that clarifies why the gap has been so difficult to close. Doing so will likely require phenotype-specific randomization where feasible, and rigorous contemporary comparative evidence where it is not."

The JACC Evidence Review provides a trial-by-trial appraisal of major clinical trials comparing LAAC with anticoagulation for stroke prevention in patients with AFib, tracing the evidence from earlier warfarin-era studies through contemporary trials, including OPTION, CHAMPION-AF and CLOSURE-AF. Authors Bikdeli, Krumholz and colleagues examine differences in patient populations, devices, comparators, antithrombotic regimens, endpoints and follow-up, providing a framework for putting the evidence into context.

The authors write that "ultimately, clinical application requires matching a specific patient phenotype to individual trial evidence through shared decision-making rather than relying on a single summary estimate."

The Review also outlines key evidence gaps and research priorities, with the authors suggesting that "future evidence should be phenotype-specific, use contemporary comparators, and prioritize ischemic stroke and systemic embolism, and total bleeding in separate analyses, alongside patient-centered outcomes."

Additional articles in the issue examine LAAC from clinical, practical and policy perspectives, including sex-based outcomes; racial, geographic and temporal trends; antithrombotic therapy; U.S. utilization and patient selection; and outcomes in patients at high risk for stroke and bleeding.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Atrial Appendage, Atrial Fibrillation, Atrial Function, Left, Anticoagulants, Electrophysiology, Stroke