By Joshua D. Moss, MD

Associate Professor of Clinical Medicine, Cardiac Electrophysiology, Division of Cardiology, University of California, San Francisco

SYNOPSIS: In a randomized trial of patients with atrial fibrillation, left atrial appendage occlusion during elective cardiac surgery was associated with lower rates of ischemic stroke or systemic embolism after 30 days.

SOURCE: Whitlock RP, Belley-Cote EP, Paparella D, et al. Left atrial appendage occlusion during cardiac surgery to prevent stroke. N Engl J Med 2021;384:2081-2091.

Atrial fibrillation (AF) is a common cause of ischemic stroke, with emboli thought to originate most frequently from the left atrial appendage (LAA). Whitlock et al sought to determine whether LAA occlusion performed at the time of cardiac surgery would reduce the risk of stroke or systemic embolism when added to routine anticoagulation therapy.

A total of 4,811 patients (mean age 71 years, 67.5% male) from 105 centers in 27 countries were randomly assigned to undergo LAA occlusion or no occlusion during their scheduled surgical procedure. Patients were eligible if they were older than age 18 years, presented with a history of AF with a CHA2DS2-VASc score of at least 2, and were scheduled for cardiac surgery for another indication. Patients undergoing off-pump surgery, mechanical valve implantation, surgery for complex congenital heart disease, or isolated implantation of a left ventricular assist device were excluded.

Amputation and closure of the LAA was the preferred technique, used in 56% of patients. A stapler or approved surgical occlusion device also were used commonly (about 26% of patients). Percutaneous closure and purse-string closure were not permitted. Patients and all treating clinicians were blinded to the randomization assignment, while the surgeons and intraoperative teams were not involved in the post-surgical anticoagulation management or data collection. The median CHA2DS2-VASc score was 4. At hospital discharge, just over 80% of patients in both groups were on oral anticoagulation, decreasing slightly to between 75% and 80% at the three-year visit. Mean follow-up was 3.8 years, with follow-up completed by 98% of participants.

The primary outcome measured was first occurrence of ischemic stroke, transient ischemic attack (TIA) with positive neuroimaging, or noncerebral systemic embolism. In the first 30 days after surgery, primary outcome events were similar in the two groups: 2.2% in the LAA occlusion group and 2.7% in the no occlusion group, a statistically non-significant difference. However, a primary outcome event occurred in 2.7% of the occlusion group after 30 days vs. 4.6% in the no occlusion group, for a hazard ratio of 0.58 (95% CI, 0.42-0.80). Primary outcome results were similar using intention-to-treatment, per-protocol, and as-treated analyses. In a secondary analysis, ischemic stroke occurred in 4.6% of the occlusion group and 6.9% of the no occlusion group (HR, 0.66; 95% CI, 0.52-0.84). Mortality rates, hospitalization for heart failure, and incidence of major bleeding or myocardial infarction were not significantly different between groups.

In a further analysis of the primary outcome, point estimates favored LAA occlusion for all predefined subgroups and remained statistically significant in men; patients older than age 72 years; patients with CHA2DS2-VASc score ≤ 4; patients with ejection fraction ≥ 50%; and patients with no prior stroke, TIA, or systemic embolism. The authors concluded LAA occlusion at the time of cardiac surgery in patients with AF, most of whom continued to receive antithrombic therapy, was associated with a lower risk of ischemic stroke or systemic embolism vs. those who did not undergo this extra procedure.

COMMENTARY

Presented as a late-breaking trial at this year’s American College of Cardiology Scientific Session, the Left Atrial Appendage Occlusion (LAAOS III) trial results are noteworthy for both the practice changes they should encourage and those they should not. Randomization was robust, with care taken to keep patients and those managing their anticoagulation blinded to group assignment. The study population was diverse, with well-distributed proportions of paroxysmal, persistent, and permanent AF and a variety of indications for cardiac surgery. Results likely are broadly applicable. The primary endpoint was simple, leaving little room for misinterpreting outcomes. A subgroup analysis suggested consistent effects across the spectrum of patients enrolled. Barring perhaps those patients who would have been excluded from enrolling in the trial (and who generally would have been indicated for permanent anticoagulation regardless), it seems difficult to argue against LAA occlusion during cardiac surgery in just about any patient with a history of AF.

However, clinicians must take care not to mistakenly extrapolate the results as evidence for LAA occlusion to replace therapeutic anticoagulation. Considering blinding to whether LAA occlusion was performed, management of antithrombotic therapy was meant to continue as it would have otherwise. Indeed, by three years post-operation, more than 75% of patients in both groups remained on anticoagulation. Therefore, it remains unknown whether LAA occlusion alone is as protective as anticoagulation (or as protective as LAA occlusion plus anticoagulation). The study also offers no specific insight into LAA occlusion devices implanted percutaneously, such as the WATCHMAN device. The presence of endovascular hardware and potentially incomplete LAA occlusion might reduce the positive effect seen.

From an electrophysiologist’s standpoint, two questions naturally arise. First, did the type and burden of AF affect the rate of stroke or systemic embolism? That would help inform future studies on potentially stopping anticoagulation or using “as-needed” anticoagulation for patients with low arrhythmia burden who undergo surgical LAA occlusion. Second, what was the efficacy of concomitant surgical ablation of AF, which about one-third of the patients underwent? That patient population also could represent a group for whom holding anticoagulation after LAA occlusion might be safe, but this would require additional study. Secondary analyses and additional studies are sure to follow the well-designed and executed LAAOS III trial. Meanwhile, it seems clear patients with AF referred for cardiac surgery are likely to benefit from concomitant LAA occlusion.