Occluding to prevent occlusion

The results of Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke have been presented at the American College of Cardiology (ACC) 2021 Congress and simultaneously published in N Engl J Med. doi:10.1056/NEJMoa2101897. The Left Atrial Appendage Occlusion Study (LAAOS III) is a multicenter, randomized trial funded by peer-reviewed funding sources.1 The trial investigated the efficacy and safety of concomitant surgical left atrial appendage occlusion (LAAO) in participants with a history of atrial fibrillation (AF) undergoing cardiac surgery for another indication. Specifically, the trial aimed to determine whether concomitant LAAO would prevent ischaemic stroke or systemic embolism (primary endpoint) in participants who continued to receive usual care, including anticoagulation The trial enrolled 4811 patients (mean age, 71 years; about one-third female) with AF and a CHA2DS2-VASc score ≥2 (mean 4.2), indicating an elevated risk of stroke, scheduled for open-heart surgery at 105 centres in 27 countries. About two-third of the trial participants underwent valve surgery and 20% coronary artery bypass graft. Off-pump surgery, mechanical valves, and reoperations were excluded. Participants were randomly assigned to add-on surgical LAAO or heart surgery alone. After a median follow-up of 3.8 years, LAAO lowered the risk of ischaemic stroke or systemic embolism by 33% [4.8% vs. 7.0%; hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.53–0.85; P = 0.001], mainly driven by a lower risk of ischaemic stroke (4.6% vs. 6.9%; HR 0.66; 95% CI, 0.52–0.84). Analyses of the primary outcome suggested a larger difference between the trial groups after 30 days than early after surgery (with HR of 0.82; 95% CI, 0.57–1.18 during the first 30 days and 0.58; 95% CI, 0.42–0.80 after 30 days), most likely reflecting the immediate effects of cardiac surgery itself versus AF-related cardiac thromboembolism over long term. Over 80% of the participants were discharged on oral anticoagulants, with adequate long-term adherence in both arms. There was no significant difference in perioperative bleeding, heart failure (HF), or death between the trial groups. LAAOS III is the first randomized trial to explore whether surgical LAAO provides an additive benefit to that of oral anticoagulation, in AF patients undergoing cardiac surgery for another indication. The rationale for LAAO is supported by direct evidence proving that a large proportion of strokes in AF are the result of thrombus in the LAA.2 In this setting, LAA pulsatile flow disappears resulting in greatly reduced appendage emptying; this stasis together with increased atrial fibrosis and activation of blood coagulation underlie thrombus formation. Removal or occlusion of the LAA removes a key component of Virchow’s triad, thereby reducing thrombus formation and embolic stroke in AF patients.2 Two randomized studies, PROTECT AF3 and PREVAIL,4 provided evidence for the protective effect of catheter-based LAA closure against thromboembolic events. In these trials, however, after a period presumably characterized by endothelialization of the device, the goal was to stop anticoagulation, thereby using LAAO as an alternative therapy for patients at high risk of AF-related thromboembolism who are unable to tolerate long-term treatment with oral anticoagulation.5 However, percutaneous closure trials were not adequately powered, procedural safety concerns have been raised, and the optimal post-interventional antithrombotic drug regimen as well as treatment duration after percutaneous LAAO remain controversial issues.6 Although surgical LAAO during cardiac surgery in AF patients has been used previously based on the belief that it lowers stroke risk, evidence supporting the practice has been limited.7 LAAOS III may represent a practice-changing trial for several reasons: (i) the enrolled population was well representative of the population undergoing cardiac surgery in contemporary practice; (ii) several LAA occlusion techniques were permitted in the trial, although the preferred approach was amputation of the appendage followed by suture closure of the stump; and (iii) the effect size was such that the number of patients needed to undergo concomitant LAAO during cardiac surgery to prevent one stroke over a period of 5 years was <40 (95% CI, 22–111).1 Hospitalization for HF was the primary safety outcome because left atrial appendage is considered a source of atrial natriuretic peptide and prior studies had shown that removal of the appendage might impair renal clearance of salt and water, thereby increasing the risk of HF. However, LAAOS III did not report an increase in hospitalization for HF, either early after surgery or during long-term follow-up.1 Although warfarin and direct oral anticoagulant are highly effective at preventing stroke in patients with AF, there is still a residual risk, and the present trial showed that this can be reduced with surgical LAAO. It is interesting to note that the absolute 2.3% reduction in stroke incidence in LAAO-treated participants at the end of follow-up is roughly equivalent to the partial loss in the expected benefit of oral anticoagulation associated with a 75% adherence, as reported at the 3-year visit.8,9 Thus, a relatively simple and inexpensive surgical procedure provides continuous and permanent protection against embolic stroke without the inherent limitations of long-term anticoagulation. The next round of clinical practice guidelines is expected to include the new evidence from LAAOS III and its clinical implications, which appear sufficiently robust to warrant a class I recommendation for patients with characteristics similar to those enrolled in the current trial. Conflict of interest: G.L. received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service, and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. She received personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, and Daiichi Sankyo. C.P. received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, Eli Lilly, GlaxoSmithKline, Tremeau, and Zambon and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation.