Left Atrial Appendage Closure versus Oral Anticoagulation: Still a Matter of Debate

Atrial fibrillation (AF) is the most common cardiac arrhythmia and the prevalence is expected to double during next decades, considering the progressive increase in the population’s age, comorbidity, and new technologies that can make easier AF detection [1]. AF is linked to a 5-fold increased risk of embolic stroke, accounting for 15–20% of total cerebrovascular events. Significant progress has been made in recent years in the therapeutic management of thrombotic risk associated with AF, also aimed at reducing potential hemorrhagic complications. Historically, anticoagulant therapy has always been the first-line therapeutic choice, providing a clear benefit in reducing cerebral embolic events in those patients with high stroke risk, detected using a CHADsVASc score (recently modified in CHADsVA according to the last ESC AF Guidelines). This benefit has to be balanced with the increased bleeding risk, above all in special populations such as end-stage renal disease or hematological disorders. Actually, direct oral anticoagulants (DOACs) represent the first-line therapy, given the non-inferiority in terms of efficacy and the reduced risk of intracranial hemorrhage with respect to the vitamin K antagonist (VKA). Patients who cannot receive OAC for relative or absolute contraindication due to high bleeding risk remain unprotected with a significant risk of stroke or systemic thromboembolism. During the last years, percutaneous left atrial appendage closure (LAAC) has been raised as a valid alternative to long-term anticoagulation in patients with AF and high hemorrhagic risk, considering that left atrial appendage is the place of thrombus genesis in 90% of cases [2]. Actually, there are still few randomized controlled trials (RCTs), whereas there are several registries and retrospective studies. This study aims to further define the role of LAAC in real-world settings [3].The first two RCTs, the percutaneous LAAC versus warfarin for atrial fibrillation (PROTECT-AF) and the percutaneous closure of the left atrial appendage versus warfarin therapy for the prevention of stroke in patients with atrial fibrillation (PREVAIL) demonstrated the non-inferiority in terms of efficacy and safety of LAAC using Watchman device compared to VKA [4]. Also, a derived meta-analysis from these two trials confirmed the role of Watchman device as a non-inferior therapeutic strategy compared to VKAs for stroke prevention and was associated with a significantly lower risk of hemorrhagic stroke and non-procedure-related major bleeding. Moreover, long-term follow-up data from the PROTECT Trial showed a statistical benefit to cardiovascular mortality (HR 0.40; 95% CI, 0.21–0.75; p = 0.005) and all-cause mortality (HR, 0.66; 95% CI, 0.45–0.98; p = 0.04) of LAAC over VKA [4]. Also, the Amulet occluder is an alternative device for LAAC, because it was non-inferior in an RCT to the Watchman and an Italian registry demonstrated high procedural success and an adequate safety and efficacy profile [5].However, these trials introduced LAAC as an alternative therapeutic strategy to VKAs in patients with low hemorrhagic risk, given that the selected population had to be eligible for 6 weeks of OAC, followed by 6 months of DAPT (if peri-device leaks greater than 5 mm are excluded) and finally lifelong aspirin therapy, in order to facilitate device endothelialization and exclude device thrombosis. First comparative data between LAAC and DOACs were provided by the PRAGUE-17 trial, an RCT with a high stroke and hemorrhagic risk population (mean CHADsVASc score 4.7 with a previous history of bleeding requiring intervention or hospitalization). LAAC was performed either with Watchman or Amulet device and was non-inferior to DOACs (95.5% of patients in apixaban) in preventing major AF-related cardiovascular, neurological and bleeding events. Despite all, at discharge, most patients treated with LAAC (85.5%) received DAPT treatment (ASA and clopidogrel) [6]. In contrast to PROTECT trial, no beneficial effect on cardiovascular mortality was observed.Given these conflicting findings, the role of LAAC in patients with AF is still a matter of debate. The most common justification for LAAC in clinical practice is for patients with high bleeding risk and absolute contraindications for OAC, but actually RCTs are lacking in this subset of the population. For this reason, the recent European AF guidelines [1] confirmed the role of LAAC in patients with contraindications to OAC therapy, without modifying the class of recommendation with respect to previous version (class IIb, level of evidence C), because no data from RCTs are actually available for extending and strengthening LAAC indication.Furthermore, the adequate post-procedural antithrombotic regimen after a successful LAA closure device is not well-defined and clouded by device-related thrombus (DRT), leaks and bleeding events. Recent AF guidelines do not clarify which post-implant therapy should be considered in patients at high hemorrhagic risk and real-world practice is often various. The current protocol derives from the first two RCTs (PROTECT and PREVAIL), which require VKA treatment for 45 days after device implantation, followed by 6 months of DAPT (if peri-device leaks greater than 5 mm are excluded) and finally lifelong aspirin therapy. Otherwise, several observational studies and metanalysis suggest using various therapies without the necessity of OAC [7], while others propose DOAC or a reduced dose. In a large metanalysis, DAPT after LAAC device implantation is associated with a lower incidence of thromboembolic events compared with SAPT and may be a preferred option in patients unable to tolerate anticoagulation.The ASAP trial (ASA Plavix Feasibility Study with Watchman Left Atrial Appendage Closure Technology) was the first non-randomized study conducted in patients with VKAs ineligibility (93% of patients had a history of hemorrhagic and bleeding episodes). The study demonstrated that Watchman device implantation can be safely performed without a VKA transition, and that DAPT can be a reasonable alternative therapy to consider for patients at high risk for stroke but with contraindications to systemic oral anticoagulation [8].The Ewolution registry is a prospective, observational, real-world, multicenter study conducted at 47 European centers, collecting data on approximately 1,020 patients who underwent LAAC with Watchman device, with a follow-up of 2 years [9]. Many insights are derived from this large registry. The majority of enrolled patients had an absolute contraindication to anticoagulant therapy (72%) and about half were considered at high thromboembolic risk (history of ischemic and hemorrhagic stroke). The post-implant antithrombotic strategy was highly variable, consisting of DAPT in 60%, VKA in 16%, NOAC in 11%, single antiplatelet agent in 7%, and no therapy in 6%, with a shift to single antiplatelet therapy or no therapy at 3 or 6 months. Screening trans-esophageal echocardiography or cardiac CT at 3 or 6 months evaluated potential LAAC device-related complications. The stroke rate was only 1.3% per year, with results similar to the annualized rates derived from the PROTECT AF and PREVAIL RCTs. The rate of DRT was 4.1%, consistent with the results of a meta-analysis derived from the four major RCTs with the Watchman device (3.7%) and the ASAP registry (4%). In particular, the complication occurred mainly (90%) within the first 3 months, with a higher incidence in cases of DAPT (4.9%) and NOAC (4.8%) compared to VKA (0.8%). No data suggests an increased mortality in patients with DRT compared with those without. The nonprocedural major bleeding rate in the study was 2.7%. Moreover, the bleeding rate was reduced if the switch from DAPT to single antiplatelet therapy was performed within 3 months (1.1% vs. 3.5%), without significantly impacting on thromboembolic risk and DRT. These data suggest that this is the optimal timing for shifting to single antiplatelet therapy. Although it is not an RCT, the Ewolution registry provides extensive information on therapeutic management of patients undergoing LAAC, encouraging its use in patients with contraindications to anticoagulant therapy.During next years, several ongoing RCTs will be able to change actual LAAC indications. The COMPARE LAAO trial is the first randomized study aimed at evaluating the statistical superiority in preventing thromboembolic events of percutaneous LAAC in patients at high stroke risk and with absolute contraindications to OAC therapy. Patients are randomized into a treatment arm with LAAC and subsequent dual antiplatelet therapy (DAPT) and a control arm where patients will continue their current treatment consisting of no antithrombotic therapy [10]. Also, the ASAP-TOO will randomize patients to LAAC versus single antiplatelet/no therapy in patients with contraindications to OAC therapy [11]. The OCCLUSION-AF trial is designed to assess whether LAAC is non-inferior to DOAC therapy for the reduction of a combined endpoint (stroke, systemic embolism, and major bleeding) and all-cause mortality in patients with AF and a recent ischemic stroke or transient ischemic attack, as secondary prevention [12]. Finally, the STROKE-CLOSE is another RCT in AF patients with increased risk of stroke and a prior history of intracerebral hemorrhage randomly assigned to receive either the Amplatzer Amulet device or medical therapy.LAAC represents a valid therapeutic option in preventing both ischemic stroke and major bleeding events. As widely demonstrated by RCTs and real-world registries, the procedure has a high success rate and is associated with a low risk of complications, making it an interesting therapeutic alternative to anticoagulant therapy, particularly for patients at high bleeding risk and with contraindications to anticoagulant therapy. Currently, LAAC is recommended exclusively in this patient setting, albeit with a low class of recommendation (IIb), due to the lack of availability of randomized clinical trials. Nevertheless, many registries and meta-analyses of retrospective studies have described the beneficial role of LAAC in routine clinical practice. Post-implant device therapy remains unclear, especially in patients at high bleeding risk.The authors have no conflicts of interest to declare.This study was not supported by any sponsor or funder.Dott. Raffaele Falco: writing – original draft; Dott. Patrizio Mazzone: writing – review and editing; Prof. Gavino Casu: writing – review and editing, project administration.